MeritCare Medical Center

Aunt Cathy’s

Some Ideas for Trying to Cathy Breedon PhD, RD, CSP, FADA Eat More of Those Terrific Clinical Nutrition Specialist MeritCare Health Systems, Fargo, ND Antioxidant Phytochemicals and UND School of Medicine . . . and Liking It.

Recipe 1: Cranberry-Raspberry-Orange-Jello Thing-y.

This one is originally out of the Better Homes and gardens cookbook . . . probably an older one (1950s - the red and white plaid one) or one that was a re-issue. It is called something like "Cranberry Raspberry Ring" or something close. It is in the salad section.

Here's my version:

1. Cut up an orange and remove the seeds and stem area. Put it into a food processor (rind and all) with a little orange juice (a splash or so) to blenderize it into mass of orange pulp.

2. Take a fresh or frozen bag of cranberries and pick out any bad ones (there are usually a few - they often float up if you put them into some water to wash them off.) Pour the rest of the bag into the food processor and blend it up with the orange. You can process it to bigger chunks of cranberry or down to tiny, as you prefer. As a rule, frozen ones mush up faster than fresh but the fresh ones are the best tasting if they are available.

3. Boil some water and pour 1-1/2 cups boiling water into a large bowl that can take changes in heat and cold. Stir in a packet of Jello (or whatever brand) lemon gelatin and a packet of raspberry gelatin. Stir while sprinkling it in so it dissolves well without globbing up into gelatinous strangely chewy masses. You can use regular or sugar free. I use sugar free because I don't need the calories and one of my Thanksgiving guests has diabetes. Using sugar free means she gets to have a lot more of it.

4. Stir in the cranberry/orange mixture. Pour in a bag of frozen raspberries (the kind that are frozen without any added sugar.) The cold berries will gel it up pretty quickly. At this point, I just stick the bowl into the fridge with some saran wrap on top and it is ready to eat in literally just a few minutes. Just scoop some out and put it in a bowl or on a plate. Replace saran wrap on the remainder.

The original recipe has two additional steps:

1. After it is partially gelled, gently stir in 6 oz of a diet or regular lemon-lime soda. (Chug the rest . . . you have to stay hydrated while slaving over a hot stove.) The soda idea is to trap the carbonation, which gives it a little fizzy kick. I usually don't bother with that part. I forgot once and barely noticed, and since it was so much more work . . .

2. They have you put it into a ring mold or bundt pan so you can serve it in an attractive way, flipped over and very home-ec looking. I have done this but it is pretty messy and really only looks nice for about 3.5 minutes, or until people start taking some. If it gets a bit warm in the room it can experience some melting. What a mess! So, I just keep it in the mixing bowl itself in the fridge for normal use, or pour it all into a nice serving bowl and put it into the fridge so it can go to the table later.

Bottom line: It tastes great. Calories are low: cranberries are very low kcal, the sugar free version adds no additional calories. So really, it is just the berries, and they are not high. However, both cranberries and raspberries are full of those terrific red/blue anthocyanin antioxidant pigments. It also keeps a person regular if consumed in large volumes daily. My mother likes it a little sweeter so she sprinkles some splenda or nutrasweet on hers and mixes it in. I like it with a bit more bite. It is a nice healthy and yummy snack. My mother also puts it on ice cream. Mothers are very wise.

Variation: My husband likes it even better if I use a bag of the frozen triple berry mixture (frozen raspberries, blueberries and blackberries or boysenberries) instead of raspberries alone. He loves blueberries and since all those berries are great antioxidant phytochemicals, we try different combos.

Recipe 2: Spinach and Raspberry Salad.

Get a bag of ready-to-use spinach (preferably minus the e-coli) and put some on a plate. Get a bag of frozen raspberries (the same kind as above, frozen separately initially and without syrup) and pour some onto the spinach. You can pour a little or a lot. I pour a lot.

Put it into the fridge ahead of time and the berries will melt a bit and some juices will be on the spinach leaves. You can also have the berries already thawed, or whatever. The juices of the raspberries (from a bit of smashing) is all I use as a dressing. My husband likes to put on a bit of raspberry vinaigrette dressing. For special deluxe salads (that is . . . company) we sprinkle it with slivered almonds and fresh sliced pears. The pears should be added just before serving so they don't get brown, or use some fruit fresh. The raspberries usually go on top of the pears, and then the nuts on top of it all. Really yummy and industrial strength phytochemicals and magnesium!

I once fed this to my niece’s third grade class along with several other brightly colored fruits and vegetables that were likely to be regarded as new and exotic (and therefore perceived to be icky.) If the kids tasted everything they were rewarded (bribed) with cool glitter pens. Afterward they voted and in general they liked a lot of the foods, but the spinach raspberry salad was the food they elected as the clear favorite. (SPINACH??!!) My niece asked me if I would make this for her for her birthday. I said yes.

Recipe 3: Pretty Darn Good Broccoli

I learned about this in a Russian restaurant in St. Paul. They served what looked like just a ton of plain steamed broccoli as a side dish and I was preparing to be brave and eat it because a bunch of nutrition people were there with me that I did not know. I remember thinking "Ratz! I'm going to have to eat that!" :-)

I love broccoli if there is enough hollandaise sauce, but plain can taste kind of bitter to me, especially raw broccoli. But when I tasted it I discovered that it was really good! (Not just “I can eat this” good . . . it was “I WANT to eat this” good.)

I asked them what the secret was. Just before the chef served it, he just sprinkled it with a little warm water into which a small amount of honey had been dissolved. Plain sugar would likely work well, too. The point of that one is that for many people who can taste some bitter substances in vegetables like broccoli or kale (like a lot of little kids and immature people like me,) a touch of sweet can cut the bitterness quite a lot.

But since foods like broccoli and kale are real nutrition giants (tons of nutrients and friendly phytochemicals, fiber and extremely low calories . . . as in, practically none,) if the little bit of sugar used makes them palatable enough for the "I-hate-broccoli" set to eat them and enjoy them, it is a very good trade-off.

Recipe 4: Stealth Vegetables

Take any kind of left-over fruits or vegetables from a meal and put them into a freezer bag and pop them into the freezer (using appropriately safe food handling techniques, etc., of course.) Do this for several days, weeks or months. When the volume of these little freezer treats reaches critical mass, put all of them into a food processor and blend the heck out of them.

Put the pureed vegie/fruit/whatever combo into an ice cube tray and freeze it. When frozen, pop out the cubes and put them into a freezer bag. Keep them handy there in the freezer section where they are visible, easy to grab and easy to remember that you have them. If they are out of sight or you have to dig for them . . . well, you know.

Anyway, whenever you make something with a lot of flavor (chili, spaghetti sauce, soups, curry, meatloaf, etc.) toss a cube or two or six into the mix. Depending what you put in there, you can add a dollop of a nice variety of beneficial phytochemicals, vitamins and minerals and hardly any calories.

Now, here’s an important thing to remember: You must be sure to blenderize the stuff sufficiently so there are no recognizable chunks of vegetable carcass remaining. That’s the stealth part.

Enjoy! Cathy B. MeritCare Medical Center and 5/2010 Roger Maris Cancer Center

Aunt Cathy’s Guide to Nutrition: Aunt Cathy Cathy Breedon PhD, RD, CSP, FADA Nutrition and Clinical and Metabolic Nutrition Specialist MeritCare Medical Center, Fargo, ND, Breast Cancer UND School of Medicine Dept. of Pediatrics and Breast Cancer Survivor (This is the shorter little-or no-references version; (Roger Maris Cancer Center Class of ’98) a version with more references cited is also available)

This is a quick summary of some things in the nutrition news related to breast cancer. Although very few references are provided in this brief version, all the suggestions are based on reports in the legitimate scientific literature and the references are available on my more thorough papers that are also on MeritCare Medical Center’s website. My recommendations are not based on goofy things found on the Internet.

When “researching” a topic on the internet, it is important to consider the reliability of the source. After all, there is no law against fiction in America! People can pretty much print anything. For example, websites that end in .edu (colleges and universities) tend to be more reliable than sites designed primarily to sell you something.

We are learning a lot of new things every day, so the information here is subject to change at any moment! ☺ (That’s why there is always a date on my papers.) And of course, none of the following suggestions are intended to take the place of the advice of your health care provider.

Outline: page

1. A Plant-Based Diet 2

2. Soybeans … a Special Kind of Plant 6

3. Bundles of Joy: “Baby Plants” (Nuts, Seeds, Beans and the Germ of Grains) 8

4. Amounts and Types of Fats 9

5. Vitamin and Mineral Antioxidants 12

6. Intake of Other Vitamins and Minerals 14

7. Other Plant Chemicals 19

8. “Conditionally Essential” Nutrients 20

9. Miscellaneous 21

10. Quick Summary of My Best Guess for Reducing Risk of Breast Cancer 22

1 1. A PLANT-BASED DIET

Increasing the proportion of fruits, vegetables and whole grains in the diet reduces risk of many cancers. They provide an amazing assortment of cancer-fighters, including vitamins and certain “phytochemicals” (plant chemicals), some of which are potent protective substances called “antioxidants.”

Although the word phytochemicals just means chemicals found in plants, and the term does not indicate whether certain ones are good, bad or neutral, there is another clear benefit of a primarily plant-based diet: it also decreases meat intake, a source of saturated fat. Additionally, it has been found that curing or grilling meats or cooking meat to a “well done” state can produce some substances that can increase risk of cancer, including cancer of the breast. [Note: Under-cooking meat is not safe either because of the risk of bacterial food-borne illness, so that won’t help.]

Research reports can be very confusing with different conclusions reached based on different study designs. Additionally, the studies brought to our attention via media sound- bytes tend to be those perceived to be newsworthy because they are in disagreement with a lot of other studies. [As a rule of thumb, one study reporting a contradictory finding does not negate the findings of hundreds of other studies showing the opposite … it just makes for better headlines.]

One thing that makes things so confusing is that in nature nothing occurrs in a vacuum. But research studies often try to study an issue by looking to see what happens when everything is kept constant except for one particular variable, like, say, “hot dog consumption.” But since these food qualities can interact with other circumstances, the results may be only applicable under certain specific conditions. For example, a generous antioxidant intake like eating brightly colored fruits and vegetables with the hot dog (or even putting ketchup on it) decreases some of the negative effects of some components of cured meats.

An example of one of these potentially cancer-causing substances is called “sodium nitrite” which is used in curing meats to protect against certain bacteria and to preserve the red/pink quality of the meat. In the stomach nitrites can be converted to nitrosamines … which are the substances that appear to increase risk of cancer. However, eating foods at the same time that provide generous antioxidants can prevent the formation of nitrosamines. Some cured meats actually have some vitamin C (an antioxidant vitamin) added to prevent nitrosamine production.

In any case, we Americans tend to eat quite a lot of meat … some estimates are that we on average eat 3 times the suggested amount. And processed meats are usually very high in sodium. So simply filling up on more veggies and fruits can help cut back on the sheer volume of meats consumed. The fruits and veggies are the source of some of the most potent beneficial antioxidant phytochemicals.

2

Many of the beneficial plant chemical substances happen to be the brightly colored pigments that give fruits and vegetables their color. These pigments are very promising as agents of reducing risk of cancers and many other threats to health (such as the complications of diabetes or blindness due to macular degeneration.) As an example of how powerful these pigments are, consider that lycopene, the red color in tomatoes, ketchup and tomato sauce, has 200 times the protective antioxidant capacity of the same amount of vitamin E, a well-known antioxidant vitamin.

The research questions now are about figuring out HOW, WHEN and WHY various plant substances appear to be protective,

not IF there is a role for any of them.

3

So, a good rule-of-thumb is to eat all the brightly colored fruits and vegetables you can get your hands on!

They are low in fat and calories, and they have lots of other important substances like vitamins, minerals and fiber. Foods like these that have lots of goodies relative to calories are called “nutrient dense” foods, which is the opposite of much less desirable “empty calorie” foods, which have lots of calories but few nutrients or other health benefits.

Here are a few of the specific substances in the news that have been studied the most and which (in addition to their vitamin and mineral content) clearly have something special to offer in decreasing risk of cancer:

“Cruciferous” vegetables like cauliflower, Brussels sprouts, cabbage, and broccoli contain many anti-cancer substances, including one called sulforaphane.

Dark green plants have lutein that is a potent antioxidant that also has a special role in eye health.

Green plants like broccoli, spinach and asparagus also often have hidden orange pigment like the beta carotene that can be seen in orange-colored plant foods like carrots, peaches, cantaloupe and yams.

Green and black tea have polyphenols.

Limes have limonene

Blue/red colored fruits and vegetables like red grapes, blueberries, strawberries, beets, egg plant, cherries, raspberries, pomegranates, and cranberries have anthocyanins.

4 Yellow corn and squash have zeaxanthin, which also appears to be especially important in eye health.

Tomatoes and watermelon have lycopene, one of the phytochemical pig,ents that has been studied the most so far.

Tea, apples, onion, grapes, and green vegetables have a beneficial “flavonoid” called Quercetin.

Garlic has Allicin and SAC; they do not give it color but they certainly give it a smell. (I have also heard that it repels vampires. ☺)

Wine has several polyphenols and a very interesting substance called resveratrol.

The best thing about these phytochemicals is that they are being found to be beneficial in a broad range of health conditions, so eating these fruits and vegetables decreases our risk of much more than cancer. Many of these plant substances are not destroyed by heat, so fresh, frozen and canned fruits and vegetables all have something to offer. There are MANY others … literally thousands more in plant foods. Most have not even been studied yet.

So although claims are sometimes made for taking certain ones of these substances as supplements to reduce risk of cancer, (especially by people selling them) it is clear that it would be naïve to think that the few we have researched so far are “The Ones,” or that supplementing large amounts of one or a few of them would likely substantially decrease risk of cancer for an individual.

Supplements of lutein and lycopene are common, and they have not been shown to be injurious. They may or may not be helpful, but they are fairly expensive and each provides only that one useful substance, so they are not as likely to be as beneficial as eating a wide variety of actual fruits and vegetables that provides so many more. This is in part because many of these substances are known to act most effectively together.

Fruits, vegetables and whole grains are also much less expensive than exotic supplements. They provide lots of other important nutrients, they more filling and they taste good, too! What’s not to like?

If you don’t like certain ones there are bound to be plenty of others that you WILL like. Preparing them in many different ways can help too. You can even make what I call “stealth vegetables” to sneak some into your family’s meals.

[See my handout on line called “Some Ideas for Trying to Eat More of Those Terrific Antioxidant Phytochemicals . . . and Liking It.”]

5 The complex composition of fruits and vegetables make it hard to tease out the substances of special importance. In addition, it is not just what one eats, but the relative balance of many diet elements. For example, one could follow a completely “vegetarian” diet but still eat way too much nutrient-poor (empty calorie) food. After all, french fries, soda, candy and beer are “vegetarian.” In America, in fact, the french fry is THE most commonly eaten vegetable!

The ratio of vegetables-to-meat consumption and the ratio of the amount of calories-from-vegetables to calories-from-animal-products have been used successfully to evaluate dietary patterns related to cancer risk. Research into these beneficial “phytochemicals” is absolutely spilling over with new exciting findings.

2. Soybeans … a Special Kind of Plant

Soybeans are in a class of plantfoods called “legumes” that includes dried beans (like kidney beans, black beans, navy beans, etc.,) peanuts, lentils and peas. Foods made from soybeans, like soy milks, soy nuts, tofu and soy sauce, provide a number of phytochemicals called isoflavones including one called genestein that may lower risk of many cancers. They have other health benefits as well. These substances are often described as “plant estrogens” and they are chemically and functionally similar to human hormones. One definition of a hormone is that it is a substance that causes your body to DO something, so hormones in general (plant or animal-based) are more likely to cause problems if they are not in balance than other food substances are.

Think about all the things your very own estrogen can give you: acne, cramps, babies, etc. ☺ Pretty important stuff. And it is well known that hormones have a lot of importance in breast cancer in particular, although the details are far from clear. However, is it reasonable to assume that a plant-based estrogen supplement in a generous dose is desirable or even safe? Recent studies have not found consistent relationships in the use of these products relative to breast cancer. Much of the data comes from animal research that tends to look at just the effect of varying one diet component at a time, which is not as easy to generalize to real people eating a varied diet. Large human studies are underway, and some have also reported conflicting results.

For example, it appears that there are certain personal genetic factors that affect whether soy intake has a role in various cancers. It was first found to be of potential benefit several years ago when it was noted that the incidence of breast and prostate cancer is about six times lower in some parts of the world where soy is a regular part of the diet. However, there are a great many other differences in the diets and lifestyles and genetic patterns of those population groups besides just the average soy intake.

That kind of large epidemiologic (population-wide) study is useful to stimulate questions and to guide further research, but it can never show that when two things are often found together, one of the things is the cause of another. For example, it is true that, overall, taller children have more math skills than short ones. Is that because being tall

6 makes you smart? No … it’s actually because older children in higher grades at school have been taught more math … and they happen to also be taller than younger children. (But that doesn’t keep me from trying to get taller to help me do better at math! ☺)

“Soy nuts” provide the most soy isoflavones found naturally in a small serving of food in the US. However, many other substances besides isoflavones in soybeans appear to be important as well, including fiber, protein, vitamins, and minerals. One of the most recently identified players on this team is the mineral magnesium. Large national studies indicate that the majority of Americans take in at less than 2/3 of the recommended amount of magnesium. Recently published studies of over 35,000 women in Iowa suggest that there is an inverse association of dietary magnesium intake with incidence of colorectal cancer. That is, the highest intakes of magnesium were associated with the lowest incidence of colon cancer.

Colon cancer risk factors have often been found to be risk factors for breast cancer and prostate cancer as well. So, paying attention to research in those areas also helps us learn how we might decrease risk of breast cancer. And, hey – we all have a colon, so reducing both kinds of cancer risk at once sounds like a smart idea!

It is recognized that soy foods are fine, certainly nutritious, and possibly helpful in decreasing risk of cancer. But it is not clear that taking concentrated isoflavone supplements (instead of just eating soy foods) is safe. In fact, some research suggests that taking one type of concentrated soy isoflavone (daidzein) may enhance the cancer- preventive properties of the drug tamoxifen, but another (genestein) may actually interfere with the protective effects of tamoxifen. Oh, fine!

It is interesting that people seem to perceive concentrated soy isoflavone products as being “natural” and therefore automatically safe and more effective. However, high concentrations of isolated plant chemicals (natural or not) put into pills and then taken out of a little bottle is a long way from nature. And of course, just because something is a plant, it is natural, and God made it does not mean it is safe or that it works to solve a particular problem. There are a million examples of this … poison ivy, cocaine and foxglove come right to mind. God may have made them all, but He does not want you to eat them.

At this time the best advice is to include soy FOODS as desired, but to avoid supplements that feature concentrated isoflavones until these issues are sorted out.

7 2. Bundles of Joy: “Baby Plants” Nuts, Seeds, Legumes/Beans and the Germ of Grains

Because improving magnesium intake has the potential to improve cardiovascular health, diabetes incidence and management, and neurologic health, and it has many more benefits, there is clearly no reason NOT to be sure that you get the recommended amount. The very best sources include the parts of the plants that will turn into the baby plant. That is … seeds, nuts, beans and the “germ” of grains. Those are by far the best sources of magnesium and quite a lot of other critical nutrients.

“Refined” grains like “enriched white flour” are missing the highly nutritious germ part of the grain, and most of the lost nutrients are not added back when the flour is “enriched.”

That process only adds back three B vitamins (thiamin, riboflavin and niacin) and iron. That is why there is so much interest now in helping people choose “whole grain” products instead of refined grains. Any whole grains will do … it does not have to be wheat.

To have a good amount of whole grains, the first or second ingredient on the list should have the word “whole” in it.

Just calling a product “wheat bread” does not mean that it is WHOLE wheat bread. Similarly, “12-Grain” bread has 12 different grains in it, but the name doesn’t tell you if any of them are WHOLE grains.

If the word “whole” comes much later on the list than the first or second ingredient, it essentially means: “a whole grain walked by when we were making this.”

To give you an example of the amount of some “baby plant” foods one might eat to obtain some benefit, consider that in large studies, for several health conditions measured, differences were shown between a pattern of eating about an ounce of nuts or peanuts four

8 times a week or more, or never or rarely eating these foods. The measurably better health outcomes were associated with eating those foods four or more times a week, and the worst health outcomes were associated with the pattern of rarely eating them.

If you are allergic to a lot of these “baby plant” foods or simply do not like to eat them, you should check into supplementing magnesium. These really are the richest sources of magnesium (and several other minerals,) and most multivitamins with minerals provide only about 10-25% of the recommended amount of magnesium. That may be enough if your diet is just a bit low, but some folks will definitely benefit from an additional supplement. But before you cross ALL these baby plant foods off your list, remember that cocoa powder comes from cocoa beans --- another baby plant!--- (see picture below) … and that means that chocolate covered peanuts might be considered a “health food” in certain circumstances. ☺

[Please see my Magnesium handout for all the details and specific recommendations about suggested forms and amounts.]

3. AMOUNTS AND TYPES OF FATS

Reducing total dietary fat is less important than previously believed, but lowering the proportion of omega-6 fats and increasing the proportion of omega-3 fats and monounsaturated fats appears to decrease risk of breast cancer.

Omega-6 fats are predominant in cornoil, safflower oil and many other cooking oils.

Omega-3 fats are most generous in flaxseed, canola oil, walnuts, fish and fish oils.

Monounsaturated fats are in nuts and legumes and in peanut oil and olive oil.

That’s another benefit of eating nuts and peanuts: the fat tends to be “happy fat.” That is, it has the same calories of other fat, but it does not increase your risk of heart disease or cancer. I like to think of them as “dangerous to your butt but not to your heart!”

The fish-oil omega-3 fats (EPA and DHA) have important anti-cancer properties that are not available from the vegetable sources, especially among people who have been found to be less able to convert the plant-forms to these longer forms. The finding that some folks are more dependent on a ready-to-go source of EPA and DHA is

9 a fairly new discovery and it is often unrecognized at present. Inability to produce your own EPA and DHA from plant oils is a serious (and not uncommon) problem.

This is why flax oil and fish oil are not equally helpful to all people. Although both are omega-3 fats, some folks cannot convert the oil (linolenic acid) in flax and other plants to EPA and DHA, the omega-3 fats so important in humans and other animals.

However, the flax seeds themselves have some substances besides the omega-3- rich oil that may be useful in decreasing risk of cancer. First, because they are seeds (baby plants) they are very nutrient dense and good sources of magnesium. Second, they contain substances called “lignins” that may specifically reduce risk of breast cancer. This combination makes the flax seeds, but not flax oil capsules, a particularly good food to incorporate into the diet. Be creative … add ground flax to your meatloaf!

[Also, flax is a North Dakota product, so be sure to buy a lot! ☺]

Both EPA and DHA appear to be beneficial, and they also have benefits in a wide variety of health concerns from heart disease to MS, diabetes, arthritis, depression and dementia, so this seems like a prudent direction to go. [EPA stands for the molecular description of this fat (EicosaPentaenoic Acid), but I always think of it as standing for “Environmental Protection Agency” because it helps protect our internal environment!] Fish oil is the source of both EPA and DHA, and the American Heart Association and others encourage most people to take 1000 mg fish oil capsule daily, in part because we can’t readily tell who the individuals are who cannot make their own.

Omega-3 fatty acids also may increase the effectiveness of certain cancer treatments. Certain types of chemotherapy seem to work better when additional omega-3 fatty acids are provided in the diet.

Increasing the ratio of omega-3 fatty acids relative to omega-6 fatty acids in the diet has additional benefit in dealing with cardiovascular disease, diabetes and in autoimmune disorders like MS and arthritis. Most Americans eat a diet that provides 10 or more grams of omega-6 fat for every gram of omega-3 fat --- that is, a 10-to-1 ratio. For most people it is recommended that we try to change the ratio to be closer to 4-to-1, which is the ratio typically found in the “Mediterranean Diet” … a pattern associated with decreased risk of cancer and heart disease.

10 If a person has an inflammatory disease like multiple sclerosis, diabetes or arthritis, a ratio of 2-to-1 might be even better. [Please see my handout on line for more detail about oils and fats and omega-6:omega-3 ratios, and also my papers on nutrition for people with diabetes or MS for more information on this topic, including many references.]

“Monounsaturated” fats are a type of fat that also seems to be protective against cancer. They are mostly found in olive oil, peanut oil, nuts and avocados. Some of the protection is related to beneficial phytochemicals found in those foods. For example, olive oil is recognized as a source Of additional cancer-fighting phytochemicals. That is not a surprise, since these oils are also made from foods that are “baby plants!”

Using monounsaturated fats also can displace some of the less desirable omega-6 fats (like corn oil), saturated fats or trans fat in our diet.

Trans Fats

It appears to be beneficial to decrease intake of certain types of saturated fat (animal fat, coconut oil) and especially trans-fats (found in many types of shortening, margarine and commercial baked goods.) Trans fats are accidentally formed by the traditional process used to make vegetable oils into soft spreadable solids. The process is called “partial hydrogenation.”

It turns out that trans fats are particularly not healthy to eat. Trans fats in foods are beginning to be banned in some places, such as in all New York City restaurants. Manufacturers are developing ways to get it out of our food supply, but for now we still need to check labels.

11 Since 2006, trans-fats in foods have to be listed on the food labels, but looking for the words “partially hydrogenated” in the ingredient list is the best indication of whether a food actually contains any trans fat.

This is useful because by law amounts under 1 gram “per serving” (like a teaspoon of margarine) can be reported as “zero trans fat” on the label. Their idea of what constitutes a “serving” and those of consumers are often quite different.

Many foods now being advertised that they are “trans free” and they actually are because they have not used the partial-hydrogenation process to solidify them into a spreadable texture.

Although most nutrition advice suggests limiting intake of amimal fat in general, it may be that dairy fat may be less cancer-promoting than some other animal fats. This is possibly because it contains a special form of fat called conjugated linoleic acid. High-fat dairy food and conjugated linoleic acid intakes were found to be associated with a lower incidence of colorectal cancer in Swedish men and women. As noted earlier, often the cancer risk factors associated with colon cancer and prostate cancer in particular are very similar to those in breast cancer.

Conjugated linoleic acid is currently receiving a lot of attention as a possible anti-cancer substance but no conclusions are available yet. As always, the factors associated with the “dairy fat” piece, like the calcium intake piece and the vitamin D piece, are very hard to separate in studies with humans. But it appears that all three of these substances may contribute to decreased risk. (More on vitamin D later.)

5. Vitamin and Mineral Antioxidants

In general, generous amounts of antioxidants automatically accompany a diet rich in fruits and vegetables. That diet pattern also has been shown to have benefits in decreasing breast cancer risk. As discussed earlier, the antioxidant strength of the phytochemical pigments far exceeds that of the antioxidant vitamins and minerals. However, most vitamins and minerals have many other important roles to play in metabolism.

As discussed earlier, it appears that many dietary antioxidants work in conjunction with each other, so studies that examine the effects of a substance in isolation are less likely to

12 demonstrate any effect that might potentially be present. Effects observed of vitamins C and E and selenium are likely related in part to their antioxidant properties. A very low-fat diet may actually provide inadequate vitamin E because the major natural food source is polyunsaturated oil. (Saturated fats like fat in meat or milk are not very good sources of vitamin E.) Other minerals like zinc and copper are involved in antioxidant activity as one of many important functions.

The mineral selenium has several roles in the body as an antioxidant and in the function of energy metabolism and in the immune system. Inadequacy causes serious health problems. Selenium inadequacy is more common in America than vitamin C or E deficiency, so it will get a closer look here. There is a large amount of promising research into the role of assuring selenium adequacy in several types of cancer. There is also data that suggests that assuring selenium adequacy may help in the effectiveness of certain chemotherapy medications.

Some recommendations for decreasing cancer risk suggest aiming for at least 200 iu vitamin E, about 500 mg vitamin C and 60 mcg selenium daily as safe and appropriate intake levels, along with a diet rich in fruits, vegetables and whole grains. For comparison, the RDA-type recommendations for most healthy people sets the level of vitamin E at 30 iu, vitamin C at 90 mg and selenium at 60 mcg. Notice that the suggested levels here for vitamins E and C are more generous than the usual recommended amount, but the selenium level is at the usually recommended amount. This is because assuring normal adequacy of selenium is likely important in protecting against the development of several cancers, but taking more provides no additional benefit, and high doses can be unsafe.

The toxic level of selenium has been shown to be about 800 mcg/day over a long period of time, and experts have suggested an upper limit of safety to be 600 mcg/day. The selenium content of foods varies with where the food was grown, so it is hard to assess the amount in a particular person’s diet. However, a supplemental amount of 50-70 mcg is safe. Even if a person lives in a “high selenium” region, that amount is unlikely to contribute significantly to toxicity problems. The amount in supplements varies from none to about 200 mcg, so check the label. Your State Extension Service Agent can tell you about the selenium level in the soil where you live.

Recently some confusion about the role of selenium in cancer risk was raised by a large study called the Selenium and Vitamin E Cancer Prevention Trial [SELECT] that involved 35,533 “healthy” men. They gave some of the men 200 mcg/day of selenium and/or 400 iu of vitamin E and after five-seven years they found no difference in the incidence of prostate cancer in the group given extra selenium compared with the men who received no extra selenium (the “placebo” treatment.)

The fact that this regimen did not have an effect on the incidence of developing cancer, however, was very likely due to the fact that none of the men in the study were ever selenium deficient. Other research studies showing benefit from providing additional selenium have involved correcting deficiency and assuring adequacy. In other words, if one’s selenium intake is fine, throwing more into the mix does not provide further protection. But this study tells us nothing at all about whether correcting selenium inadequacy might have decreased the incidence of developing cancer.

13

Inadequacy of any nutrient can cause all kinds of problems, so it is always wise to assure an adequate intake of all of them.

6. INTAKE OF OTHER VITAMINS AND MINERALS

The body's defenses against cancer depend on adequacy of all the tools needed by the immune system. That is just what many vitamins and minerals are … the tools you need to run your body. Many nutrients have been shown to be important for fighting cancer in particular. For example, as described earlier, assuring adequacy of the mineral magnesium has been found to reduce risk of colon cancer. Several B-vitamins are looking like they are important as well.

For example, in one report, older women with the lowest vitamin B-12 levels were at greatest risk of breast cancer. Many people become less able to absorb vitamin B12 from food as they age. When vitamin B12 status has been most carefully assessed, it has been shown that about 1/3 of the elderly are actually vitamin B12 deficient. Taking acid-blocking medications for gastro-esophageal reflux (heartburn) can also cause this problem regardless of age. In both situations, the form of vitamin B-12 found in vitamin pills can bypass the problem and prevent deficiency.

Vitamin B-12 is also important for nerve health, and prevention of anemia and hearing loss. There are some genetic conditions that result in vitamin B12 deficiency for other reasons that require other methods to correct. [Please see my “Vitamin B12” paper on MeritCare’s website for more information about this issue.]

Adequacy of vitamin B6 and folic acid has long been found to be important in lowering the risk of breast and/or colon cancer, especially among women who drink alcohol regularly. Interestingly, regular alcohol use or chronic antibiotic use specifically impairs absorption of folic acid in the intestine. A collection of genetic patterns and health conditions also affect absorption or utilization of folates at the tissue level. That makes for a lot of unaccounted-for variability in trying to see large over-riding patterns about intake and breast cancer risk.

For a look at the complexity involved with trying to figure out the role of any nutritional factor in health, cancer prevention and treatments, lets look a bit closer just at the folic acid research:

• Some studies show that inadequacy of folic acid increases risk of breast cancer.

• Some suggest that high intakes might increase the rate of breast cancer.

14 • At the same time, others are showing that generous folic acid may increase protection agains breast cancer.

• Then there are others noting that the effects of folate in foods or folic acid as a supplement or additive may affect people’s risk of breast cancer differently depending on several well-recognized genetic differences in folate metabolism, and things like hormone status, age and status relative to menopause. An example of this is the well-recognized MTHFR gene most commonly seen in some people of Irish heritage … and there are quite a lot of us Irish (or part-Irish) people out there. Other ethnic groups have also been found to have similar genetic problems with folic acid.

[This gene pattern affects one’s ability to utilize certain food forms of folates, and the problem is invisible without special testing. Luckily, the answer is not to get yourself tested for possible Irish gene patterns … simply taking a standard multivitamin will solve the problem whether you have that genetic pattern or not. The form in the multivitamin is able to bypass the whole difficulty with the food forms of folate.]

• In nature, folic acid often works together with vitamin B12. That means that the consistent finding of poor vitamin B12 status in many people can affect the outcome of studies exploring folate intake in cancer prevention or treatment. However, in most studies, the vitamin B12 status of the people being studied is not evaluated.

• Food folates are also associated closely with consumption of certain vegetables and fruits. [That’s where the word “folate” comes from … the Latin name for “foliage.”] So, how can we tell whether it is the folate or the other things in the food like other nutrients, phytochemicals or even pesticides that are related to cancer risk?

• Then, we know that some food forms of folate are just naturally much less available to be absorbed than others by everyone, so it matters a lot which ones were actually used by the people in the studies. But of course, that is generally not actually evaluated in any of these studies.

• There is also a raft of information looking at applications of folates (from foods or supplements) in various forms as adjuncts (helpers) to make chemotherapy more effective or to decrease certain bad side effects of the treatments. In some cases, it has been shown to make it possible for a patient to tolerate a higher dose of chemotherapy and to increase effectiveness of treatment. This was something my oncologist and I utilized in my own cancer treatments over ten years ago with great success. But these effects are very specific to the particular chemotherapy regimen, so there is no universal one-size-fits-all recommendation in this area. I wish there were.

Bottom line on Folic Acid / Folate and Breast Cancer: This research is much too complicated to come up with a definitive statement that addresses all these issues.

15 However, with the usual caveat that the information provided here is not intended to take the place of the advice of your heath care professional nor is it intended to provide personal specific nutrition guidance for any particular individual, here’s my current best guess about folic acid and breast cancer (subject to change at any moment. ☺):

• Eat lots of fruits and vegetables, some of which will contain absorbable folates (along with a lot of good other stuff.) Interestingly, in some studies that questioned a slightly increased risk of breast cancer in postmenopausal women only, the increased risk was only related to food folate intake, but not to supplemental folates or to total folates, and no “dose-response” was observed. That means that there was no pattern apparent among the people in each group related to how much folate they took in. Hmmm … that makes it kind of hard to assume that it’s the folate causing whatever effect they found. [Am J Clin Nutr. 2009 Feb;89(2):624-33. Folate and one-carbon metabolism nutrients from supplements and diet in relation to breast cancer risk.]

• Eat plenty of whole grains that are less “processed/refined” for many reasons. Of the processed grains you eat, folic acid has been added in a well- absorbed form since 1998, but that is not the reason for using more whole grains and less refined grains. … it’s the other good stuff in the germ of the grains. Many studies show no effect on increased rates of various cancers since fortification began, but since 1998 the folic acid fortification of grain products in the US has hugely decreased birth defects and certain types of stroke. [An example of the kind of reports out there: J Clin Pharmacol. 2010 May 10. Pediatric Cancer Rates After Universal Folic Acid Flour Fortification in Ontario. “…These data may also provide some reassurance that universal flour fortification does not heighten the risk of pediatric cancer.”]

• Taking a multivitamin supplement that includes folic acid (e.g. 400 mcg, the RDA) is not scary, and it can also improve intake of absorbable vitamin B12, vitamin D and some magnesium … plus other good things. It also helps you out if you are secretly part Irish. [Am J Clin Nutr. 2010 Apr 21. Folate and other one- carbon metabolism-related nutrients and risk of postmenopausal breast cancer in the Cancer Prevention Study II Nutrition Cohort. “CONCLUSIONS: Our study of predominantly supplement users suggests that high intakes of folate averaged over 10 y do not increase breast cancer risk, but may be protective, particularly against ER- breast cancers.”]

• If you are being treated for cancer, ask your health care provider before using any supplements. In terms of eating lots of good nutritious FOOD, I am willing to bet that he/she will think that is a fine idea.

16 Vitamin D

Vitamin D adequacy is known to reduce the risk of breast cancer, colon cancer, prostate cancer, pancreatic cancer and more recently lung cancer, cervical cancer, stomach cancer, and ovarian cancer. New research is published very regularly now associating vitamin D adequacy with lower risk of cancer in yet another body part. It is now quite reasonable (and very important) to urge people to assure adequacy and not to simply assume it. This strategy is not scary … what is scary about “assuring adequacy?” What is scary is inadequacy!

The World Health Organization estimates that 40-50% of the world’s population is vitamin D deficient (based on results of many studies in which vitamin D status is actually assessed.) Traditionally, it rarely has been evaluated. Leading medical journals have described the situation as an unrecognized epidemic of deficiency in the north especially but truly an epidemic / pandemic all over the world because of variable sun exposure due to clothing, skin color, sun screen use, fear of melanoma and the lure of air conditioning. Factors like aging skin also result in significantly reduced production of vitamin D even with generous sun exposure.

Some people are covered up always because of modesty or religious beliefs, some because they live in the desert and only long robes will protect from the heat. I am just covered up as a public service. ☺ The point is … lots of people are now known to be deficient regardless of where they live because now we are beginning to actually check. Vitamin D is the number one assay requested in America at present, but most people are still not having their deficiency recognized and corrected. The consequences are severe in terms of a multitude of health problems, including cancer, heart disease, osteoporosis, diabetes, MS and a variety of autoimmune diseases, falls, frailty and depression. Nobody needs vitamin D deficiency but lots of folks have it.

Vitamin D has also been shown to be helpful as an adjunct to chemotherapy. In its role as an “antiproliferative” agent, vitamin D helps to control inappropriate cell growth and it makes some treatments work better. Additionally, it has been shown to be a factor in managing the side effects of discomfort, pain and weakness associated with various chemotherapy treatments.

For example, a recent study was reported of women taking an aromatase inhibitor as part of their breast cancer treatment. They were asked to rate the discomfort/pain they were experiencing. Afterward, vitamin D levels were checked and those who had described the most pain were found to be the ones who also had the lowest vitamin D levels. Low vitamin D levels were then corrected in the deficient women and when they rated their pain again they described it as much less severe. At the time of the study, neither the women nor the researchers were aware of any particular woman’s vitamin D level, her reported pain level, nor whether a vitamin D correction was made.

In most cases, assuring adequacy has been found to require an intake significantly higher than the RDA level, which was long ago set at 400 iu daily. Most recent research is showing that the maintenance (not therapeutic) intake level for many people is 1000-4000 iu/day. This is a level that is impossible to get just from food. Supplementation is required to provide that much.

17 Luckily, vitamin D supplements in that range (1000-4000 iu/day) are safe, inexpensive, easily available, tiny and easy to swallow. The treatment dose to correct deficiency varies but it is often 50,000 iu vitamin D per week for eight weeks. [Note that that amount is PER WEEK – NOT PER DAY.]

Many oncologists will check a person’s vitamin D level at the beginning of treatment to determine whether a corrective dose of vitamin D is needed or if just a maintenance level of 2,000 iu or so will keep them in the optimal range of around 40-50 ng/dL. The earlier level of 25 ng/dL that was thought to be “normal” is now recognized as not being an adequate blood level to promote optimal health. Around the country, some laboratory print-outs still have the old “25” level shown as normal, so it is a good idea to ask what the actual number is and not just rely on a report of “normal.”

Vitamin K

As always, assuring adequacy of all essential nutrients supports our ability to prevent or fight cancer. We learn more about this every day. For example, recent research found that vitamin K inadequacy increased risk of colon cancer and liver cancer, along with many other serious health problems like heart disease, osteoporosis and kidney problems. It was also found that, as has been the case with vitamin D, we very rarely check it and just assume that it is fine. However, it has now been shown that inadequacy of vitamin K is fairly common. It is also easy, cheap and safe to fix.

The best food sources are dark green leafy vegetables. Interestingly, no upper level of safety has ever been established for vitamin K because overdose has never been seen. I know this is a big relief to all you fans of the dark-leafy-green veggies out there. Nobody has ever overdosed on spinach!

[Only people taking a particular medication called Coumadin need to be sure to eat a consistent amount of vitamin K daily to regulate the effectiveness of the drug. Nobody benefits from vitamin K deficiency … including people on this medication. Vitamin K inadequacy actually makes the drug more dangerous to use. If you use this medication please see my separate handout on line about vitamin K before making any changes to your vitamin K intake. Your health care provider will want to see the new research on this before making any changes.]

At this time, many multivitamins do not even contain vitamin K --- until recently no one knew it was a problem! This omission is in the slow process of being fixed, but one can take vitamin K separately if there is a reason why those terrific leafy green vegetables are not an option.

The details about vitamin D and vitamin K (lots of ‘em!) are in my “Top Five Recommendations” handout and in the separate “Vitamin K” handout, which (like all the others) you can get for free by Googling “Cathy Breedon Handouts” or typing my name in the search box at www.meritcare.com. Please feel free to share any of my papers you find there with others. Health care providers can also contact me for a special paper addressing the specific issues of vitamin K nutrition for patients using the drug Coumadin.

18 7. WHAT ABOUT OTHER PHYTOCHEMICALS?

Besides all the phytochemical research with the pigment antioxidants and soy products described earlier, there is a great deal of interest in literally thousands of other plant substances in the prevention and treatment of cancer of all types. Some of these substances have anti-cancer properties, and some appear to be able to minimize side effects of chemotherapy or help it work better. On the other hand, some are not safe to take in amounts beyond what one would get from eating the plants that contain them for dinner. And some are not safe at all … remember poison ivy and cocaine? Actually, most of our current pharmaceutical products are derived from phytochemicals.

Most of this kind of phytochemical research is just in the discovery and initial confirmation phase, where many current well-established medications once started out. Most of these substances have not yet been studied in the large carefully controlled clinical trials needed to show that they are both effective and safe, even though they may be described as having been used somewhere in the world for some purpose for many years. Some have only been shown to be potentially useful in test tubes and labs and they have not yet been tested in animals or people. Some have turned out to help with cancer but cause some other type of serious problem. An example of the opposite problem is the use of chaparral tea, a beverage traditionally used as a relaxing agent. It is now banned because it was discovered to also be a potent cause of liver cancer. [Herbal interactions with anticancer drugs: mechanistic and clinical considerations. Curr Med Chem. 2010;17(16):1635-78]

So it is much too premature to recommend that people should seek to take in abnormally high amounts of these plant substances in an effort to prevent or treat cancer. When we isolate and concentrate a plant chemical because it has some particular chemical activity, we move out of the world of nutrition and into the world of pharmacy. In other words, a much better description of the use of concentrated herbal substances would be “herbal pharmacy” and not “herbal nutrition.”

The reason that the terms “herbal nutrition” or “food supplement” are used is not because the substance is actually a nutrient or a food. It is because there is a loop-hole in the FDA’s laws governing the sale of drugs. The law does not require safety testing or even testing to show effectiveness of a product if the manufacturer simply labels it as a food or nutritional supplement. If the same substance were marketed as a pharmaceutical product or drug, such (expensive and time-consuming) testing would be required. In other words, we are essentially not at all protected from scams nor from harm when we use these products.

Although this labeling seems confusing, usually one can quickly tell the difference between what is an actual nutrition function and what is truly a pharmacy function. Just ask yourself whether the substance under discussion is being taken in a concentrated amount to cause some chemical effect on body functions, or if it is just your dinner. An example is shown on the next page.

19 Sorting it out: Is it a food/nutrient or is it a pharmaceutical product?

Some examples:

Food Pharmacy Slice of cinnamon toast 1000 mg powdered cinnamon in a capsule

Piece of licorice candy 1000 mg of the isolated plant flavonoid “isoliquiritigenin” found in licorice.

Bowl of vegetable curry 1000 mg isolated curcumin, a phytochemical flavored with the common found in the common curry curry spice tumeric spice turmeric.

There are WAY too many reports of this type to cite here, and the whole herbal pharmacy issue is outside of my area of expertise … I only know about nutrition. But interested health care professionals … or anyone at all … can find them easily on line at www.pubmed.gov (Free Public Medline from the National Library of Medicine, National Institute of Health.) Just type the words cancer and herb in the search box … or you can limit your search by specifying a particular substance … like the spice curcumin … or a particular form of cancer … like breast cancer. This is also how I keep up with the nutrition and cancer research. (Ain’t technology wonderful?!)

However, it is encouraging to note that there are so many potentially helpful substances waiting to be discovered and developed in a wide variety of plant foods. And while we wait for the definitive research on concentrated plant chemicals in the battle against cancer, it is certainly reasonable to eat lots of fruits, vegetables and whole grains, and to cook with a variety of commonly used interesting spices that appear to have health benefits.

8. “Conditionally Essential” Nutrients

Conditionally essential means that usually one makes enough of a necessary substance, but sometimes we can’t make enough of it. When that happens, that nutrient becomes “essential” to take in from outside the body, just like well-recognized essential vitamins and minerals. Three of these substances of interest in breast cancer are CoQ10, alpha-lipoic acid and carnitine.

Coenzyme Q (CoQ10 – also called ubiquinone) and alpha lipoic acid (also called thioctic acid) are both potent antioxidant substances that one can normally make enough of, but in certain medical conditions patients benefit from being provided with a supplemental amount. They are “conditionally essential.” Both are very safe, but as supplements they can be pricey. Some applications of alpha lipoic acid (e.g. in diabetic neuropathy) showed benefit when the dosage was at least 600 mg/day.

20 In the cancer applications, both substances look to be helpful in helping people physically cope with side effects of chemotherapy and other treatments for cancer that can result in neuropathy and heart damage. They both have several other roles in normal metabolism, especially in energy production.

Carnitine is a tiny molecule normally made in the liver and kidney. It is important for making energy for muscles to work, and that includes the heart muscle. Carnitine also has a role as an antioxidant. Some people are normally less able to make carnitine as well as others can. Some medications and treatments also result in inadequate production of carnitine. This results in considerable fatigue and even heart damage. Some “cancer fatigue” studies have shown benefit from 4000 mg carnitine daily.

There is evidence that some people fighting cancer may benefit significantly from receiving supplemental carnitine, CoQ10 and alpha-lipoic acid with their cancer treatments. All three are very safe and they are available over the counter and also by prescription. Prescriptions are more likely to be covered by insurance. The only apparent down side is the cost. As always, be sure to discuss the use of any of these substances with your health care provider. I have a paper just on carnitine on Meritcare’s website because it has many other important health applications. Additionally, all three of these supplements are discussed in more detail in my paper on nutrition for people with diabetes which is also on the website.

9. Miscellaneous

There is plenty of evidence that exercising, not smoking, maintaining a healthy weight and breast-feeding one’s infants are also players on the team to decrease the risk of breast cancer. I’m going to go out on a limb here and advocate that we all try to do these things too. ☺

Also, remember to laugh a lot.

I think finding something to laugh about went a long way toward helping me cope with cancer and its treatment. In fact, as the memories of the tough times recede, it’s the funny stuff that hangs around … like shaving my head with duct tape after chemotherapy, or Here’s the picture that won by a having a contest at work to help me find the landslide: it’s my husband Dan and I right look when picking out a wig. wearing the 1970s “Sonny and Cher” look. What do you think?

Don’t let worries about nutrition suck the joy out of life.

At our house we have battled cancer, and we eat lots of wonderfully healthy foods and dutifully take our appropriate nutrition supplements. But my husband and I also like

21 having a regular ten-o’clock date in the kitchen with the local news on TV and a some brownies or some other treat. And anyway … most of the time my brownies: • Have lots of walnuts (baby plants!) • Are made with olive oil (monounsaturated fat!) • And they usually even have some of those “stealth vegetables” in there (like powdered spinach … sounds icky but it isn’t.)

That means that these brownies may actually be “health foods” … kind of like chocolate-covered peanuts. Consider the terrific nutrient density … the ratio of good-for- you stuff to calories. They just happen to taste good and to impart a certain party atmosphere to the end of the day! But even if a food has very minimal nutrition value, whatever you choose to enjoy and share with family and friends can be a “health food” … especially for mental health. Bon appetite!

10. Quick Summary: My Best Guesses for Breast Cancer Risk Reduction:

• Eat lots and lots of fruits, vegetables and “baby plants” and aim for most of your overall diet to be “plant-based”, with less meat than Americans usually eat.

• If you do eat cured meats or grilled meats, be sure to eat lots of fruits or vegetables with them, and avoid charring the outside … or the inside, for that matter.

• Take a standard multivitamin with minerals for many reasons. I use a store brand – it does NOT have to be expensive. Take it whenever it is convenient for you; I have a bad memory so I won’t remember to take things through the day. So, I just take everything in the morning and let it fight it out in there! It doesn’t have to be perfect.

• Have your vitamin D level checked. Lot’s of folks are deficient and completely unaware of the problem. Take a 2000 iu vitamin D capsule to maintain a good level. If your level is deficient, your doctor can help you correct it with a temporary higher dosage.

• Check to see if your multivitamin contains vitamin K if you do not regularly eat a good amount of dark leafy greens. If you usually don’t eat those dark leafy greens, either switch to a multivitamin with about 100 mcg of vitamin K, or add a separate vitamin K supplement.

• It is a good idea for your multivitamin or some combination of supplements to provide 50-60 mcg of selenium (the advisable intake.) Vitamins C and E can be taken at the advisable intake of 90 mg C and 30 iu of E, but in general they can be safely taken at 5-10 times that amount.

• Increase your ratio of omega-3 to omega-6 fats by replacing omega-6 fats (e.g. corn oil) with monounsaturated oils (olive and peanut). Eat some flax seed or use flax oil if you like it. Take at least one 1000 mg fish oil capsule daily (one that says EPA and DHA) if you do not eat fatty fish like salmon or mackerel at least twice a week. (And, no, deep-fried breaded fish does not count … wrong kind of “fatty.” Darn!).

• If you do not eat much in the way of baby plants, consider both a magnesium and chromium supplement, and be sure you are getting a good amount of dietary fiber in some form.

• Enjoy every day, every friendship, and every meal!

22 Sanford Medical Center

Aunt Cathy’s Guide to Nutrition:

Calcium Odds and Ends: 12-2010 Absorption and Where it Ends Up … Cathy Breedon PhD, RD, CSP, FADA Role of Vitamins D and K Clinical & Metabolic Nutrition Specialist Sanford Medical Center, Fargo, ND and UND School of Medicine

------

1

------Food Sources of Calcium (Serving Size and mg of Calcium)

------Dairy Nuts, Dry Beans and Seeds Carrots 1/2 cup 25 American cheese, processed 1 oz 175 Almonds 1/2 cup 150 Celery 1/2 cup 25 Blue cheese 1 oz 150 Beans (cooked) 1/2 cup 45-100 Collard greens, ** 1/2 cup 180 Cheddar cheese 1 oz 200 Brazil nuts 1 oz 50 Dates 1/2 cup 50 Cottage cheese 1/2 cup 80 Hazelnuts 1/2 cup 120 Kale (cooked) 1/2 cup 100 Cream cheese 1 oz 25 Sesame seeds 1 Tblsp 90 Lettuce, iceberg 1/4 head 25 Ice cream 1 cup 175 Soybeans, roasted “nuts” 1/2 cup 120-230 Mustard greens ** 1/2 cup 95 Milk (any regular kind) 1 cup 300 Onions (cooked) 1/2 cup 25 Calcium fortified milk 1 cup 500 Fruits / Vegetables Parsnips (cooked) 1/2 cup 35 Parmesan cheese 1 oz 390 (calcium absorption is mixed; oxalates Raisins 1/2 cup 25 Swiss cheese 1 oz 275 decrease absorption of double-starred ** Rhubarb (cooked) 1/2 cup 100 Yogurt 1 cup 275-350 items.) Spinach (cooked) ** 1/2 cup 85 Apricots, dried 1/2 cup 45 Squash, summer or winter 1/2 cup 55 Seafood Asparagus 1/2 cup 15 Turnip greens (cooked) ** 1/2 cup 125 Clams, raw 3 oz 60 Beans, green ** 1/2 cup 30 Calcium-fortified orange juice1/2 cup 150 Oysters, raw 1/2 cup 110 Beet greens (cooked) 1/2 cup 75 Salmon, canned with bones 3 oz 165 Broccoli 1/2 cup 70 Food Data Source: Agriculture Handbook Sardines, canned w bones 3 oz 370 Cabbage (cooked) 1/2 cup 35 No. 8-4 US Dept. of Agriculture Shrimp 3 oz 100 Cabbage, bok choy 1/2 cup 125 Science & Education Admin.

2 Sanford Medical Center 2011

Aunt Cathy’s Guide to Nutrition:

Aunt Cathy By Request: Cathy Breedon PhD, RD, CSP, FADA Prenatal/Pediatric Nutrition Specialist A SHORT CARNITINE Clinical and Metabolic Nutrition Specialist DISCUSSION THAT Sanford Medical Center, Dept. of Pediatrics and Clinical Associate Professor of Pediatrics MIGHT BE HELPFUL UND School of Medicine, Fargo, ND

The role of supplemental carnitine in conditions characterized by excessive obesity, hunger, lethargy, hypotonia, and poor exercise endurance

Carnitine is a substance normally made in the liver and kidney, and it is also available in meats. It consists of a molecule of methionine and a molecule of lysine — two essential amino acids. It plays a critical role in the ability to burn fat for fuel because it is part of the enzyme system "carnitine palmitoyl transferase" which transfers fat molecules into the mitochondria to produce ATP. Because muscle (including and especially heart muscle) is very dependent on fat fuels for aerobic energy production, anything that compromises carnitine's operation can result in a variety of problems. For example, for people with inborn errors of mitochondria metabolism, providing additional carnitine can help to prevent extremely serious consequences. An example is the not uncommon beta-oxidation disorder MCADD (Medium-Chain AcylCoA Dehydrogenase Deficiency.)

Some drugs impair the production of carnitine so that one is more dependent on an exogenous source than normal. Valproic acid is an example of this, and relative carnitine insufficiency can often be a big contributor to the lethargy and certain other side effects reported with the use of this medication. Additionally, inadequate carnitine also compromises the efficacy of the valproic acid itself, resulting in break-through seizures and increased risk of liver toxicity. With this medication, carnitine supplementation appears to decrease liver toxicity significantly. Valproic acid is the seizure medication most studied in relation to carnitine, but other seizure medications appear to affect carnitine requirements as well. Certainly if the child is symptomatic a trial on carnitine is very reasonable.

People on ketogenic diets for seizure control also need extra carnitine because they are burning fat as almost their only fuel - - they need much more carnitine than they could be relied upon to make on their own. Additionally, many people on these special diets do continue to need seizure medications, which may further increase the need for an outside source of carnitine.

People with various liver and kidney conditions are sometimes supplemented with carnitine because production can be compromised. We also use it with premature infants on TPN in the NICU because their ability to produce carnitine is compromised by the immaturity of the liver and kidney.

Carnitine-related problems contribute to difficulty burning fat for fuel resulting in symptoms that may include: ______

1. excessive fat storage

2. low muscle tone

3. excessive appetite due to failure to make the needed amount of ATP (usable energy) from food consumed

4. very poor tolerance of aerobic activity and endurance-type of exercise

5. abnormally high sense of fatigue or excessive sleeping

6. muscle pain with exertion

7. cardiomyopathy

8. episodes of dangerously low blood sugars that can result in brain damage, or even death … sometimes labeled a SIDS event.

9. unusual difficulty with control of blood sugar in people with insulin- dependent diabetes … we should be especially suspicious of carnitine inadequacy among those with blood sugar volatility who are carefully following their nutrition plans and medications.

These are among the symptoms that have been corrected by carnitine supplementation in at least 25 people (not counting premies) that I have worked with personally who turned out to have had unrecognized metabolic abnormalities. [This also does not count the patients for whom we automatically initiated carnitine therapy in anticipation of need, thereby preventing the problems described.] If someone way out here in Fargo, ND has found that many patients with what turned out to be (previously unrecognized) carnitine-related health problems, the likelihood is good that there are lots of folks out there whose carnitine problems are simply not being looked for and therefore not recognized.

There are clearly many people who have some of the symptoms described above for whom carnitine adequacy/inadequacy is completely unrelated. To determine if carnitine is a problem, a trial on carnitine will often result in noticeable changes within few weeks … 2 sometimes days. If it is not a factor, supplemental carnitine could be discontinued after a trial of about a couple months. We would normally continue the trial at least that long before writing it off because some conditions result in a degree of carnitine depletion so pervasive that it takes a while to get enough cells operating well enough to see a benefit. [Please see the note on the last page regarding special carnitine issues to consider for people who are candidates for bariatric surgery.]

Carnitine used as described is very safe. The only problem with the stuff is that it is pricey. Insurance will usually cover it (ordered as "Carnitor, or the generic equivalent,") but the amount of coverage varies. For this reason, we do not do this kind of trial casually. However, as I mentioned earlier, the metabolic abnormalities in symptomatic patients that I have seen who benefitted markedly from carnitine supplementation were undetected at the time the trial was initiated. As you know, what we often think is extremely rare can sometimes be fairly common but just rarely recognized. The only way to know for sure is a trial on carnitine. I much prefer a prescription form of carnitine for the trial, as some OTC carnitine products may not provide the amount of carnitine on the label. [I do not want to miss a potential effect because the product used in the trial provided the wrong amount. People can use OTC carnitine after the trial if they wish, but insurance will usually not pay for that form.]

Blood levels can reflect inadequacy when they are low or if the total:free carnitine ratio is disturbed. However, the blood level apparently does not necessarily reflect the muscle tissue level, including the level available to the heart muscle. So if a person is symptomatic but labs are normal, one would still do the trial and watch for changes in symptoms. In other words, there is probably little reason to get labs except for curiosity or research. Certainly, when labs do indicate deficiency, we would supplement. But when labs do not reflect a deficiency state, we would still do a trial of supplemental carnitine in a symptomatic patient. So, the labs are really not of great use in this situation. As the health effects of carnitine inadequacy (for whatever reason) are not benign, my prejudice is to do a rule-out trial with symptomatic patients.

So, that is the story in a nutshell. If you decide to do a trial, the usual trial in adults is about 1 gram three times a day (i.e. 3000 mg/day.) The pills are in a 330 mg size, so 3000 mg can be adequately approximated by three pills 3 times a day. The pills are spread out (any way that is comfy for the patient) to avoid an osmotic diarrhea that can result from giving the whole lot of tiny particles all at once. The pediatric dose (PDR info) is 50-100 mg/kg/day divided into 3 doses, with a 3000 mg/day the usual upper level. The therapeutic/maintenance amount may be much less than this, but the higher end of the usual range is often best in a test situation, since the person may be starting out with a significant deficiency. If we under-shoot with a low dose, there may not be enough carnitine to see changes during the trial period. I don't want to miss something if it is there.

I have had some very large patients whose symptoms (hypotonia, excessive hunger, lethargy, excessive weight gain and poor endurance, etc.) have responded very well, but an amount above the theoretical 3000 mg “top” was sometimes needed to bring the positive changes about. One very heavy and fatigued adolescent responded beautifully but he required 6000 mg/day to bring about the changes we were looking for. [Happy aside: He is now normal weight and going to college.] As is usually the case, when one is very far outside the “normal” rage for body weight, a standard per/kg intake level may no longer directly apply. 3 A number of patients with “familial hypotonia of unknown etiology” have responded amazingly well to this therapeutic intervention even though as yet no one has identified their actual metabolic problem. All we know is that something about their genetic pattern causes problems, some of which may be ameliorated by providing supplemental carnitine.

This picture (hypotonia, excessive hunger, lethargy, excessive weight gain and poor endurance) is intriguingly like some of the typical symptoms observed in Prader-Willi Syndrome. The #15 chromosome is missing all or part of a leg, but exactly what disturbance in metabolism results from the deletion is not well understood, nor is it the same in all people with PWS. However, as these individuals suffer greatly from their condition, it is reasonable to do a trial as described above. It will either help or it won’t in any individual, but I do have four patients with PWS for whom supplementation appears to significantly help control the symptoms, making their lives and those of their families much better.

The children also have more energy to learn and to engage in play. They also learn better because they are not as obsessed with accessing food. Prader-Willi Syndrome is currently treated with growth hormone in some children, so one cannot ascribe all of any observed benefit to carnitine in children treated with both. However, it is reasonable to do both, as the efficacy of growth hormone treatment could certainly be compromised if energy metabolism was limited by a relative problem with carnitine adequacy. Certainly a trial would be in order if the symptoms described above continue to be observed after growth hormone therapy has been initiated.

When a patient demonstrates that supplemental carnitine is helpful, the level that seems to be effective needs to progress with growth (i.e. mg/kg body weight). I have seen some situations in which a child out-grew his prescription because this aspect of his care was not being monitored and the treatment became less effective the more he grew. With math-competent parents (and the doctor’s permission, of course) I teach the parents how to increase the dosage as the child attains certain weights. Other families call me each month with the baby’s weight and I calculate the level for them,

When initiating treatment, the carnitine dose is generous in an attempt to correct a possible inadequacy … that is, the bucket may be empty so we need to fill it up as part of our test. However, once the bucket is appropriately full, the therapeutic level is no longer needed and a maintenance level should be identified. This will be quite individual. As a marker for having reached the point of having a “full bucket” I tell parents that an indication of this will be that the child may “start to smell a bit like a little fish” (reflecting getting rid of unneeded carnitine.) One mother called me and left this message: “At last! We have achieved fishiness!” At that point we back off and set about to find the maintenance level for that particular child.

Other conditions can be characterized by the same symptoms (lethargy, weight gain, hypotonia, etc.) Some of my patients with Down Syndrome or Phenylketonuria have struggled with the same set of energy-related problems, and in several cases, the carnitine supplementation has helped tremendously. It has been life-altering. For others, the carnitine was not shown to alter the situation at all. The only way to know which person with these symptoms will respond to carnitine supplementation is to do a trial.

4 There are many other applications of supplemental carnitine being studied in addition to the scenario discussed above. These include (among others): hypertriglyceridemia, mitochondrial diseases, retinal health and macular degeneration, cardiovascular disease, metabolic syndrome, diabetes, renal disease, parkinsonism, chemotherapy adjunct to minimize neurologic damage and fatigue, various chronic conditions characterized by fatigue, prevention of liver toxicity due to use of certain medications, age-related cognitive impairment and osteoporosis. (See my Diabetes hand-out, Eye Health hand-out and Prental Nutrition hand-out for more information about those specific carnitine issues.)

SOME THOUGHTS ABOUT BARIATRIC SURGERY IN INDIVIDUALS WHO HAVE A CARNITINE-RELATED WEIGHT PROBLEM ______

I think it would be very reasonable to do a trial on generous carnitine in severely obese individuals prior to moving to bariatric surgery.

One reason is that people who do respond to carnitine can likely avoid the costs, pain and complication risks of bariatric surgery. Carnitine use does not interfere with an individual’s ability to absorb micronutrients the way the surgery does, which avoids the documented problems of clinically significant vitamin and mineral deficiencies like copper, vitamin B12, thiamin (vitamin B1) and many others months or years after surgery. These three nutrients are mentioned specifically because neurologic injury (sometimes irreversible injury) from deficiency is documented in spite of generous oral intake in some bariatric surgery patients.

Long term follow-up of these micronutrient issues is absent in many bariatric surgery programs, and often the only outcome of professional interest has been whether or not weight loss occurred, and whether there were improvements in dyslipidemias or diabetes management. Failure to establish long-term nutrient adequacy is particularly problematic because many women of childbearing age do become pregnant after bariatric surgery. That increases risk of birth defects and other types of poor pregnancy outcome. And now some places have begun to do bariatric surgery on pediatric patients. They do lose weight post-surgically … but they are likely to lose much more than weight unless overall nutrition is carefully monitored.

One other reason for doing a trial on carnitine before moving on to surgery is that if patients do have a carnitine-related weight problem they will continue to have it. The surgery does not correct the problem. That means they will continue to be unable to burn fat efficiently, and they will continue to experience significant hunger that may drive them to overeat in spite of surgery. This may be a factor especially in the number of individuals who regain their weight after surgery or who undergo a second bariatric surgery. Therefore, a trial on carnitine would help to identify the people who might fail to do well in terms of maintaining weight loss after surgery unless carnitine supplementation was a continued part of their regimen. For those bariatric surgery patients who do need supplemental carnitine, continuing to provide it can play a role in successfully keeping the weight off. 5 Typical intake from food: Carnitine: Content of Foods and Quick Fact Sheet Generally, 20 to 200 mg are ingested per day by those on an omnivorous diet, while a strict vegetarian diet Foods providing about 100 mg of carnitine may provide only 1 mg/day. The word carnitine comes from the Latin word for meat but the amount Beef steak 100 g 95 mg varies with type of meat. Also note the high variability in carnitine in Ground beef 100 g 94 mg commercial “complete nutrition” products.

Foods providing 10-30 mg of carnitine Production:

Pork 100 g 28 mg In animals, carnitine is biosynthesized primarily in Bacon 100 g 23 mg the liver and kidneys from the amino acids lysine or methionine. Vitamin C (ascorbic acid) is essential to Tempeh 100 g 20 mg the synthesis of carnitine. Promote 100 ml 12 mg Requirements: Foods providing 1 to 6 mg of carnitine

During growth, pregnancy or wound healing Cod fish 100 g 5.6 mg requirements for carnitine can exceed its natural Chicken breast 100 g 3.9 mg production. That is, it is conditionally essential during periods of anabolism, and also in a variety of American cheese 100 g 3.7 mg other metabolic conditions. Ice cream 100 ml 3.7 mg Whole milk 100 ml 3.3 mg People with liver or kidney problems may have difficulty producing it. Renal patients may also be Avocado one medium 2.0 mg eating a low meat diet, which can result in a diet PediaSure 100 ml 1.7 mg low in pre-formed carnitine. It is also lost in dialysate, so needs of dialyzed patients are greater Cottage cheese 100 g 1.1 mg than they would otherwise be.

Foods providing less than 1 mg of carnitine The seizure medication valproic acid impairs production of carnitine, but needs it to work. Whole-wheat bread 100 g 0.36 mg Inadequate carnitine reduces effectiveness and Asparagus 100 g 0.20 mg increases potential for liver toxicity of the drug, White bread 100 g 0.15 mg and it accounts for some of the reported side effects such as lethargy and weight gain. Macaroni 100 g 0.13 mg Beneficial Applications: Foods providing less than 1/10th of a mg of carnitine Supplemental carnitine has a role in low muscle tone, managing diabetes, exercise tolerance, Peanut butter 100 g 0.08 mg macular degeneration, obesity, heart failure, cancer- Rice (cooked) 100 g 0.04 mg related and HIV-related fatigue, male infertility, Eggs 100 g 0.01 mg ischemia / reperfusion brain injury, peripheral Orange juice 100 ml 0.002 mg neuropathies, dementia, depression and cognitive impairment associated with various conditions. Ensure 100 ml 0 mg 6 MeritCare Medical Center 6/2009 Aunt Cathy’s Guide to:

Thinking About

OTHER

Nutrition Issues Cathy Breedon PhD, RD, CSP, FADA in Celiac Disease Clinical Nutrition Specialist MeritCare Medical Center, Fargo, ND and UND School of Medicine

1. General Nutrition Adequacy Issues

It is important for individuals avoiding gluten to take a close look at the nutritional adequacy of the foods remaining in the diet. This may mean getting some help from a Registered Dietitian, as not all the threats to complete nutrition are obvious. Any diet that eliminates a number of common foods has the potential to leave some gaps in nutrient intake.

In addition to general nutritional adequacy, there are diet/nutrition factors besides gluten control that can provide additional benefit to people with celiac disease. Many chronic health conditions have an inflammatory component. CD, MS, diabetes, rheumatoid arthritis, inflammatory bowel disease and lupus, for example, all have the potential to result in increased inflammation. It is now recognized that inflammation is an important contributor to heart disease as well, so the recommendations included here to decrease inflammation and to protect tissues from the negative effects of inflammation are of great potential benefit.

2. Omega-3 and Omega-6 Fats in the Diet and the Problem of Inflammation.

One of the most important issues in controlling inflammation is the ratio of two different families of certain polyunsaturated oils in our diets. The two families are called omega-3 and omega-6 fats, and in America we tend to eat far more omega-6 fats than omega-3 fats - - in fact we eat them in a ratio of 10-to-1! There is a clear benefit for all of us in moving toward a ratio of 4-to-1 (as in the heart healthy “Mediterranean Diet.”)

Some researchers believe that for people with inflammatory conditions, a ratio of 2-to-1 may be even more beneficial. This is because certain inflammatory substances (prostaglandins) are made out of these fats, and the ones made out of omega-6 fats are much more inflammatory than the ones made out of omega-3 fats. That means that by altering the ratio of these fats in our diet, we can decrease the degree of inflammation experienced. In brief here is how to change the ratio:

1 A. Replace corn oil (high in omega-6 and very low in omega-3) in cooking and baking with olive oil (neutral, so it displaces the high omega-6 oils) or canola oil (an oil with a better ratio of omega-3 and omega-6 fat.)

B. Incorporate ground flax seed and fatty fish like salmon in the diet. These are terrific sources of omega-3 fat. Flax oil is a good source of omega-3 fat, but the rest of the flax seed is very nutrient dense as well, including nutrients that are often low in the diets of Americans, like magnesium and chromium. Additionally, it has some substances (lignans) that appear to decrease risk of breast cancer. For that reason, the ground flax has a better benefit-to-cost ratio that buying flax oil or flax oil capsules.

C. If eating fish is not attractive (or if you are worried about mercury), you should consider taking fish oil capsules. These are labeled “EPA and DHA” and a Consumer Reports survey showed that all the brands in the US were safe and equal in quality, with price being the only difference. The price ranged from 6 cents each to 60 cents each, so check out a local warehouse-type or discount store for the best buy. The capsules tend to be a bit large for some folks to easily swallow. Because the benefits of taking fish oil (for nearly everyone,) are being recognized, more and more products will be available in the near future. Many new forms are already available, including liquids and pastes that are citrus flavored and not fishy-tasting. You can find many products on line just by googling fish oil or omega 3.

Although flax is rich in a certain omega-3 fat (linolenic acid --- a vegetable oil,) there is a special benefit to taking in at least some of the omega-3 fat in the forms found in fish (EPA and DHA.) Think of EPA as standing for “Environmental Protection Agency” – protecting your internal environment! Even the American Heart Association (a very conservative organization) recommends that most people take 1000 mg of fish oil daily. Fish oil is also being used to decrease risk of cancer and as an adjunct to chemotherapy. The form of fat that is DHA in fish is also particularly important in brain / neurologic health. Some people have been found to be unable to make enough EPA and DHA out of the vegetable oil linolenic acid (the one in flax and canola) so taking some in a ready-to-go form is a wise idea.

3. Fiber Issues.

Unless carefully planned, the gluten-free diet can also be low in dietary fiber, including the kind that “moves things along” (like cellulose in wheat bran), and the kind that helps to lower cholesterol. That type is called “water soluble fiber”, and it includes Guar gum, Legumes, Oat bran and Pectin – which can be remembered by the acronym “GLOP.” Some of the cholesterol eaten and some that enters the intestinal tract in the form of bile from the liver can be thought of as “getting stuck in the GLOP” and excreted instead of being absorbed into the body.

People with celiac disease obviously cannot have wheat bran, and the oat bran can be iffy because of cross contamination, so they need to work a little harder to obtain the many benefits of foods that contain both kinds of dietary fiber. Legumes are one option … dried beans and peas (like chili beans, navy beans, pinto beans, split peas, etc.) are great sources of fiber and additionally they are very nutritious. This is because any plant part that is actually what turns into a baby plant is full of all the nutrients needed by the new plant. In grains it is the “germ.” The rest of any grain is

2 primarily starch and the fibrous coating. Other foods that are high in both fiber and nutrients like this are nuts and seeds (like the flaxseed discussed earlier.)

4. Increased “Free Radical” Production and Protection by Antioxidants:

Just running your body produces a certain type of waste product called “free radicals.” They can cause injury to cells, but normally they are kept from causing injury by substances that we eat or make collectively called “antioxidants.” They include certain vitamins (like vitamins C and E), and a substance made with the mineral selenium (glutathione peroxidase.) There is some new evidence that assuring adequacy of selenium may be a therapeutic tools to prevent both tissue damage and complication of CD such as autoimmune thyroid diseases (AITD.)

A number of substances in plants (certain phytochemicals) are now known to be terrific antioxidants, and there is a lot of interest in these plant substances for promoting good health in general. The plant pigments (coloring agents) especially, such as “lutein” in leafy greens, “lycopene” in tomatoes and “anthocyanins” in blueberries are examples of some very promising protective substances. Eating plenty of brightly colored vegetables and fruits is a very good idea for many reasons for everyone.

Inflammatory conditions result in a much greater production of free radicals than is usual. For this reason, people with inflammatory conditions like CD and diabetes should aim for a much more generous intake of antioxidants than usual to minimize the increased risk of cell damage. In this situation, a reasonable and safe daily amount of vitamin E is 400 iu, vitamin C 500-1000 mg, and selenium 100-200 mcg, plus lots of brightly colored fruits and vegetables. The vitamin C, E and selenium amounts shown above are higher than the usual Recommended Dietary Allowance (RDA) amount, because the RDA is designed to meet the needs of folks without a chronic inflammatory disease. Do not take more than this (especially of selenium) without consulting your health care provider.

Even more potent antioxidants are the phytochemicals that are pigments (coloring agents) naturally occurring in plants. For example, lycopene, the red color in tomatoes, is 200 times more potent as an antioxidant than vitamin E, and it has been shown to help minimize the oxidation damage from excess free radicals related to CD. [Neurologic impairment due to vitamin E and copper deficiencies in celiac disease. Neurology 2009 Sept 9; 71(11):860-1. Selenium deficiency in celiac disease: risk of autoimmune thyroid diseases. Minerva Med. 2008 Dec;99(6):643-53. Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-gamma. Eur J Pharmacol. 2007;566(1-3):192-9.]

5. Vitamin K Inadequacy: A Newly Recognized National Problem Needing Special Attention in Celiac Disease

Eating leafy green vegetables has an additional benefit because it is now recognized that vitamin K is often inadequate in Americans. Dark leafy greens are broccoli are the very best natural sources. At the moment, vitamin K is not included in most multivitamins because the serious inadequacy

3 problem is only newly recognized. It has now been discovered that inadequate vitamin K contributes to osteoporosis, arterial calcinosis (an independent risk factor for cardiovascular disease,) kidney calcinosis and liver cancer as well as pregnancy problems and bleeding problems, so eating these foods is very important for everyone. Additionally poorly controlled CD greatly increases the risk of vitamin K deficiency. For more on this, including issues for people using the blood-thinning medication Coumadin, please see my handout just on vitamin K.

[Celiac disease with diffuse cutaneous vitamin K-deficiency bleeding. Adv Ther. 2007 Nov-Dec;24(6):1286-9. Coagulopathy due to celiac disease presenting as intramuscular hemorrhage. J Gen Intern Med. 2007 Nov;22(11):1608-12.]

6. Re-emergence of Iodine Insufficiency in the USA

Another new problem on the horizon for everyone is a re-emergence of iodine deficiency disease in the United States and the world. In short, the problems are these: Certain regions are known to have inadequate iodine in the soil and this results in IDD (Iodine Deficiency Disease) if iodine is not provided in some other way. Iodizing salt has been the traditional approach, but that intervention was initiated before we advised people to cut way back on salt consumption to help control high blood pressure. [see iodine map on the last page.]

Additionally, there is a popular fad of using exotic “gourmet” salts from around the world, most of which are not iodized. “Sea salt” is usually not iodized, but some brands are. Even the common salt at the grocery store looks pretty similar … iodized vs non-iodized … and folks are no longer being reminded to pick the iodized version. Most vitamins, (including many prenatal vitamins) contain no iodine because of the assumption that the iodization of salt program “took care of” the widespread public health problem of iodine deficiency.

Recently the World Health Organization increased the iodine recommendation for pregnant women, in part because they found that even in regions where salt was regularly iodized, the amount was insufficient for the best pregnancy outcome. (Iodine deficiency is actually the number one cause of preventable mental retardation in the world.) Thyroid function is very reliant on adequacy of both iodine and selenium. So, in addition to issues in brain development of infants, iodine deficiency can rob people of energy because of hypothyroidism.

What is the connection to celiac disease? Well, people with celiac disease are not protected from this deficiency, nor is the issue likely to be in the radar of most health care professionals yet, so I am bringing it up here. It is not unreasonable to suppose that any person with nutrient absorption problems would have an increased risk of poor iodine status beyond that of the general public. Additionally, as described above, there is the suggestion of a possible connection to autoimmune thyroid disease for selenium deficiency. Selenium and iodine work together for the thyroid to function. I have not seen any specific celiac/iodine connection in the scientific literature, but the whole issue is very new. In general, in the US most men tend to get an adequate amount of iodine, but many women do not … this is probably just a reflection of how much total food one typically eats.

[Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009 Feb;89(2):668S-72S. Iodine Content of prenatal multivitamins in the United States. NEJM. 2009;360:939-940. Iodine status of the U.S. population, National Health and Nutrition Examination Survey 2003-2004. Thyroid. 2008 Nov;18(11):1207-14.]

4 7. “Eat Right” AND take a Multivitamin with Minerals AND take extra vitamin D!

It is now well recognized throughout the scientific community that most people would benefit from taking a standard multivitamin with minerals. The old advice to “just eat right” has been found to be extremely unlikely to assure optimal health in most people. The new advice is “Eat right … and take a multivitamin with minerals … and take additional vitamin D” References for these audacious claims are in the handouts in great number.

There are many reasons for the recommendation that everyone should take a multivitamin with minerals even if one does “eat right,” including significant individual variability in absorbing certain vitamins in the forms found in foods. For example, folic acid and vitamin B-12 are actually more reliably absorbed in the pill form than in the forms found in foods. There are 1) genetic reasons, 2) aging-related reasons, 3) drug interaction reasons, and 4) intestinal injury (e.g. CD) reasons that make it hard for some people to absorb adequate amounts of these vitamins from the usual food sources. It is wise to simply assure an intake at (at least) the RDA level of these two vitamins in the form found in vitamin pills because this form bypasses the problem in all of the above situations except for intestinal injury from poorly controlled CD.

Both of these vitamins have been shown to be critical to cardiovascular health because they prevent the build-up of a substance called “homocysteine” and other problems that the high homocysteine level reflects. It is prudent to simply prevent the problem. Inadequate folic acid is a known risk factor for cancer of the breast, colon and prostate, and for depression and birth defects. Vitamin B-12 is critical for neurologic health. Assuring adequacy of these vitamins in an easy-to- absorb form has broad benefits. If your CD is not in good control, a much more generous intake is certainly needed. These nutrients are commonly inadequate in newly diagnosed individuals with CD … poor control would mimic that situation.

[Effect of B vitamin supplementation on plasma homocysteine levels in celiac disease. World J Gastroenterol. 2009 Feb 28;15(8):955-60. Celiac disease and ischemic stroke. Rev Neurol(Paris);2009 Jan 12. Vit A Celiac Disease Presenting as Xeropthalmic Fundus. Retina;2008 Mar 28(3):525-5. Undiagnosed coeliac disease and nutritional deficiencies in adults screened in primary health care. Scand J Gastroenterol. 2007 Jan;42(1):60-5; Celiac sprue, hyperhomocysteinemia, and MTHFR gene variants. J Clin Gastroenterol. 2006 Aug;40(7):596-601; Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: role of B12, folate, and genetics. Clin Gastroenterol Hepatol. 2005 Jun;3(6):574-80.]

Additionally, inadequate vitamin D intake is now recognized as a serious under- diagnosed and widespread problem with a great many serious health consequences. These include congestive heart failure, heart attack, MS, diabetes, osteoporosis, muscle/nerve pain, muscle weakness, rheumatoid arthritis and cancer of the breast, prostate, colon and pancreas, to name a few. Note the many “autoimmune” conditions listed. It appears that vitamin D deficiency can be a trigger for the development of many of these conditions in genetically susceptible people, just as certain viruses can trigger them.

Over 200 tissues in your body have receptors looking for vitamin D in order to operate correctly. The current RDA is 200-400 iu of vitamin D, and it is now known that in the northern third of the US especially, this amount is inadequate to maintain appropriate blood levels of the vitamin. [see map]

5 This is also true in people who are elderly, or have dark skin, or who are covered up or out of the sun. In these situations, 1000-2000 iu has been shown to be needed in several recent studies. It is now known that the upper level of safety for vitamin D is actually over 10,000 iu daily chronically, so this amount is nowhere near a dangerous amount. What is a real and present danger now is inadequacy.

There are few foods that are naturally good sources of vitamin D-- salmon is the only one that one might actually eat, so the 400 iu provided by a vitamin pill is a good place to start. Milk is fortified with vitamin D (it doesn’t have it naturally) and only a few other foods are fortified, such as some orange juice and some yogurt. So, while milk is one of the very best dietary sources in the US, one cup has only 100 iu of vitamin D added to it. It is clear that relying on milk to provide the target amount of vitamin D described is unrealistic without additional vitamin supplements on the team. If you are in an at-risk group (e.g. dark skin, living up north, etc.) it is necessary to take an additional vitamin D supplement even if you drink a lot of milk and take a multivitamin. Note that milk “straight from the cow” does not contain any vitamin D, so some of our farm families get none and are quite unaware if it.

Here are some examples of 4 ways to obtain adequate vitamin D (~ 1000-2000 iu):

Plan 1 -- The “I love milk plan”: 1 multivitamin 400 iu 4 cups milk 400 iu 1,000 iu vitamin D supplement 1000 iu Total = 1800

Plan 2 -- The “I hate milk plan”: 1 multivitamin 400 iu 0 cups milk 0 iu 1,000 vitamin D supplement 1000 iu Total = 1400

Plan 3 – The “I insist on getting my vitamin D only in the form of fortified foods and not from pills” plan: 0 vitamin supplements 0 iu 4 oz daily salmon (110 iu/oz) 440 iu 10 cups of milk (WHATTTT???) 1000 iu Total = 1440

Plan 4 – The “I insist on getting my vitamin D only in the form naturally occurring in the foods I eat and not from fortification or pills” plan: 0 vitamin supplements 0 iu 0 cups milk 0 iu 14 oz daily salmon (110 iu/oz) 1540 iu Total = 1540 iu

As you can see, one really cannot realistically get there from here without supplementation.

6 For people who are eliminating wheat, rye, barley and often oats from their diet, and often dairy foods as well for other reasons, there is great potential for failing to obtain the best health-promoting level of a number of nutrients. Not all of these will be corrected with the multivitamin with minerals, but it is certainly a good start. You do not need to buy an expensive product – the best-known discount and warehouse stores have very good ones that are well absorbed (contrary to the information provided by people selling more expensive products.)

Another important CD note regarding vitamin D is that the recommended amounts described are not taking any malabsorption into account. If your CD is in good control, those levels (1000-2000 iu) could be fine. If your CD is NOT in good control, you could easily have a seriously inadequate intake. However, having intestinal symptoms of celiac disease is not necessary for it to result in severe vitamin D deficiency. In some cases the only symptom of celiac a person had was the pain and bone damage from vitamin D deficiency. Additionally, there was no difference in some studies of nutrient status between people with partial villous atrophy compared with those who had severe villous atrophy. So although avoiding gluten is clearly the most important factor in CD, it appears that generous supplementation of vitamins is a very reasonable adjunct factor in making CD hurt people less even if they have the gluten–free diet well in place.

Interference with absorption of bone-related nutrients (vitamins A,D, K and the minerals calcium, phosphorus and magnesium in particular) are all seen commonly in celiac disease. For example, poor bone density was found in 75% of newly diagnosed children, but it was still very common (40%) among those who were not newly diagnosed and who were said to be following the gluten restricted diet.

Assessment 0f bone mineral density in children with celiac disease. Pol Merku Kekarski. 2008 Mar 24(141);219-26. Severe primary hypothyroidism masked by asymptomatic celiac disease. Endocr. Pract. 2008 Apr 14(3);347-50. Adult celiac disease with severe or partial villous atrophy: a comparison study. Gastroenterol Clin Biol. 2008 Mar;32(3):236-42. A correlation of symptoms with vitamin D deficiency and system response to cholecalciferol treatment: a randomized controlled trial. Endocr Pract. 2009 May-Jun;15(3):203-12. Resistance to vitamin D treatment as an indication of celiac disease in a patient with primary hypoparathyroidism. Clinics(Sao Paulo)2009 Jan;64(3):259-61. Disabling osteomalacia and myopathy as the only presenting feature of celiac disease: a case report. Cases J 2009 Jan 7;2(1)20. Osteoporosis in celiac disease and in endocrine and reproductive disorders. World J Gastroenterol. 2008 Jan 28;14(4):498-505;Bone in celiac disease. Osteoporos Int. 2008 Apr 17. Osteomalacic myopathy associated with coexisting celiac disease and primary biliary cirrhosis. Med Princ Pract 2008; 17(5):428-8.

Because a low vitamin D level is so dangerous, it is a VERY good idea to ask your health care provider to check your blood vitamin D level at least annually in the winter. Ask him/her to order a “25-hydroxy cholecalciferol level” --- the form of vitamin D that tells if you have enough on board.

Please share this handout with him/her as well so that it is clear how important this is. Interestingly, it is looking like EVERYONE should probably have vitamin D levels checked annually – not just folks with CD -- because they are finding what has been described as “an unrecognized epidemic of vitamin D deficiency” in the US and around the world. Because the symptoms are nearly always invisible, and the problem is very common and very dangerous, the only way to be sure that any individual is “OK” is to check the blood level. Until fairly recently this has rarely been done.

7 8. New investigations into milk intolerance in CD: Casein and/or Lactose

Many people with CD experience some difficulty drinking milk at all, let alone drinking 10 cups a day. For them, it is useful to remember that there is no reason why one must take their vitamin D supplement in a form that involves drinking milk. The form in milk is just a supplement of vitamin D – it is not naturally there. All that is required is that one make sure to get the nutrients one would expect to get from milk -- i.e. calcium, phosphorus, potassium, vitamins D and B12 and B2 (riboflavin) – from some other sources. A Registered Dietitian can help figure out lots of ways to reach a nutrition goal.

The milk-intolerance itself has often been attributed to lactose intolerance – trouble digesting milk sugar because of intestinal injury. This causes cramps, gas and diarrhea. Certainly some individuals may be lactose intolerant for reasons unrelated to CD, but that would likely be a minority of them. So, it has been hard to explain the continued gastro-intestinal distress when the individual has been controlling the CD diet very well and there is no expectation of intestinal injury that would lead to lactose intolerance. Now there is a new clue:

It appears that for many people with CD, there is an actual intolerance of the cow’s milk protein that is similar in many respects to the intolerance of gliadin protein in gluten. In that situation, it would be especially inappropriate to try to meet one’s vitamin D requirement in the form of dairy foods. It appears that it is the casein part of the protein that is the problem … that is, the curds rather than the whey. (The whey part is primarily a protein called lactoglobulin.) That means that foods made from milk that happen to be very low in lactose could still be a problem for some people with CD. For example, cheese is very low in lactose, but the protein is almost all casein. I have included some highlights of a study that looked at this recently:

Mucosal reactivity to cow's milk protein in coeliac disease. Clin Exp Immunol. 2007 Mar;147(3):449-55. Patients with coeliac disease (CD) on a gluten-free diet may still have gastrointestinal symptoms. On clinical grounds cow's milk (CM) protein sensitivity may be suspected. Here, using rectal protein challenge, we investigated the local inflammatory reaction to gluten and CM protein in adult patients with CD in remission. … Casein, in contrast to alpha-lactalbumin, induced an inflammatory response similar to that produced by Cow’s milk. A mucosal inflammatory response similar to that elicited by gluten was produced by CM protein in about 50% of the patients with coeliac disease. Casein, in particular, seems to be involved in this reaction.

One practical suggestion that comes from this research is that people who continue to have celiac symptoms in spite of careful avoidance of gluten should do a trial of strictly avoiding casein for a few weeks to see if symptoms improve. If it doesn’t help, then that is not the problem so dairy foods can be re-introduced. But if it does result in improvement, consider removal of milk protein from the diet and replacing of the nutrients usually contributed by milk in the American diet as described earlier. And as emphasized earlier, it is NOT SAFE to simply remove this kind of food and then not replace the nutrients.

8 9. A Mineral of Special Note: Magnesium

Magnesium is critical for over 300 processes in the body. And yet, according to a large national survey by the CDC (the NHANES Report), this important mineral is low in the diets of the majority of Americans. Inadequacy contributes to diabetes, obesity, migraine, muscle spasms, poor pregnancy outcome, and many other problems, but it is often unrecognized. Because one of the most important dietary sources is the “germ” part of whole grains, there is a greater likelihood of poor intake among people avoiding gluten. Other good sources include nuts and legumes, but many people do not eat much of these foods for a variety of reasons. Most multivitamins with minerals contain very little magnesium -- often only 10-25% of the recommended amount for healthy people. For these reasons, some folks will need an additional magnesium supplement of 200-300 mg/day in the form of magnesium oxide or magnesium chloride. Others can do well with just some diet tinkering. Check out the Magnesium handout on the website for the particulars and specific recommendations.

10. Iron, Copper and Zinc

These three minerals have all been found to be problematic in celiac disease, especially when The diet is poorly managed and intestinal damage is present. It is well known that the first recognized symptom of celiac disease is often anemia. Iron deficiency because of intestinal injury can be a cause of this. However, newly recognized as a factor in this picture is copper deficiency, which can result in inability to transport iron well and therefore looks like iron-deficiency anemia. This is one reason why treatment with supplemental iron alone can often be ineffective. Another is that chronic inflammation alone can result in an anemic state in spite of iron status.

Additionally, there are many factors that affect both iron and zinc absorption … enhancing it or impairing it. Both are affected by the same factors, but often only iron status is measured in the form of hemoglobin or hematocrit measures. A good rule of thumb is to assume unrecognized zinc inadequacy when one is known to be iron deficient. As zinc is a factor in over 200 enzyme systems in the body, including the immune system, making DNA, growth, and wound healing (including intestinal injury repair), inadequacy can be globally damaging. If one supplements zinc, however, it is important to also supplement copper, because supplementation of zinc alone can interfere with copper absorption.

New reports also suggest that there may be an increased urinary loss of copper in the urine of women with celiac disease … a factor separate from the question of impaired absorption. And in addition to the anemia issue, unrecognized copper deficiency can also result in irreversible muscle/nerve damage.

I have additional information available on line with lots of information about factors that affect absorption of these nutrients that can be used to help improve the situation: “Nutrition Support of Iron Deficiency” is on line with other handouts of potential interest as described at the end of this paper.

[Copper deficiency in celiac disease. J Clin Gastroenterol. 2009 Feb;43(2):162-4. Serum zinc in small children with celiac disease. Acta Paedoiatr 2009 Feb 98(2); 343-5. Neurologic disorders in adults with celiac disease. Can J Gastroenterol 2008 Nov 22(11);909-11, .Serum copper, ceruloplasmin and 24-h urine copper evaluations in celiac patients. Dig Dis Sci. 2008 Jun;53(6):1564-72. Copper

9 Deficiency in Celiac Disease: A Report of 5 Cases and a Review of the Literature. J Clin Gastroenterol. 2008 May 15. Anemia of chronic disease. Haematologia 2008:dec 93(12);1785-91. Neurologic impairment due to vitamin E and copper deficiencies in celiac disease. Neurology 2008 Sept 9; 71(11):860-1. The soluble transferrin receptor (sTfR)-ferritin index is a potential predictor of celiac disease in children with refractory iron deficiency anemia. Clin Chem Lab Med. 2005;43(1):38-42.Hematologic manifestation of childhood celiac disease. Acta Haematol. 2004;111(4):211-4.Refractory iron deficiency anemia as the primary clinical manifestation of celiac disease. J Pediatr Hematol Oncol. 2003 Feb;25(2):169-72. Efficacy of gluten-free diet alone on recovery from iron deficiency anemia in adult celiac patients. Am J Gastroenterol. 2001 Jan;96(1):132-7.]

11. A Newer Topic: Carnitine and Celiac Disease

Carnitine (also called L-carnitine) is a substance one produces in the liver and kidneys, but which is also found in meats. It is important for getting fuel into your muscles, so having an inadequate amount contributes substantially to fatigue and even to heart muscle problems (cardiomyopathy.) Normally we hear little about it because most folks take in or produce all they need. However, in a number of health conditions, adequacy may require an additional supplemental intake. For several years there has been interest in evaluating the possibility of a relative carnitine deficiency in people with CD.

[Encephalopathy due to carnitine deficiency in an adult patient with gluten enteropathy. Clin Neurol Neurosurg. 2006 Dec;108(8):794-7. Plasma carnitine ester profile in adult celiac disease patients maintained on long-term gluten free diet. World J Gastroenterol. 2005 Nov 14;11(42):6671-5. Carnitine deficiency in patients with coeliac disease and idiopathic dilated cardiomyopathy. Nutr Metab Cardiovasc Dis. 2005 Aug;15(4):279-83. Intestinal permeability in long-term follow-up of patients with celiac disease on a gluten-free diet. Dig Dis Sci. 2005 Apr;50(4):785-90. Serum carnitine and selenium levels in children with celiac disease. Indian J Gastroenterol. 2004 May-Jun;23(3):87-8. Plasma L-carnitine levels in children with celiac disease. Minerva Pediatr. 1992 Sep;44(9):401-5 Serum carnitine and selenium levels in children with celiac disease. Indian J Gastroenterol. 2004 May-Jun;23(3):87-8.]

A recent prospective investigation looking specifically at carnitine supplementation in CD patients with fatigue found that they benefitted from supplementation. I have included the complete abstract of the research study below so that you can share this information with your health care provider. This benefit in fatigue-reduction is consistent with applications in many other conditions in which fatigue is a common problem. I listed a few examples of those after the abstract below.

L-Carnitine in the treatment of fatigue in adult celiac disease patients: a pilot study. Dig Liver Dis. 2007 Oct;39(10):922-8. BACKGROUND: Fatigue is common in celiac disease. L- Carnitine blood levels are low in untreated celiac disease. L-Carnitine therapy was shown to improve muscular fatigue in several diseases. AIM: To evaluate the effect of L-carnitine treatment in fatigue in adult celiac patients. METHODS: Randomised double-blind versus placebo parallel study. Thirty celiac disease patients received 2 g daily, 180 days (L-carnitine group) and 30 were assigned to the placebo group (P group). The patients underwent clinical investigation and questionnaires (Scott-Huskisson Visual Analogue Scale for Asthenia, Verbal Scale for Asthenia, Zung Depression Scale, SF-36 Health Status Survey, EuroQoL). OCTN2 levels, the specific carnitine transporter, were detected in intestinal tissue. RESULTS: Fatigue measured by Scott-Huskisson Visual Analogue Scale for Asthenia was significantly reduced in the L-carnitine group compared with the placebo group (p=0.0021). OCTN2 was decreased in celiac patients when compared to normal subjects (-134.67% in jejunum), and increased

10 after diet in both celiac disease treatments. The other scales used did not show any significant difference between the two celiac disease treatment groups. CONCLUSION: L-Carnitine therapy is safe and effective in ameliorating fatigue in celiac disease. Since L-carnitine is involved in muscle energy production its decreased absorption due to OCTN2 reduction might explain muscular symptoms in celiac disease patients. The diet-induced OCTN2 increase, improving carnitine absorption, might explain the L-carnitine treatment efficacy.

A few examples of related elated applications of carnitine in the treatment of fatigue: Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition. 2006. Levocarnitine administration in elderly subjects with rapid muscle fatigue: effect on body composition, lipid profile and fatigue. Drugs Aging. 2003. Safety, tolerability and symptom outcomes associated with L-carnitine supplementation in patients with cancer, fatigue, and carnitine deficiency: a phase I/II study. J Pain Symptom Manage. 2006. Double-blind, multicenter trial comparing acetyl l-carnitine with placebo in the treatment of fibromyalgia patients. Clin Exp Rheumatol. 2007. L-carnitine decreases severity and type of fatigue induced by interferon-alpha in the treatment of patients with hepatitis C. Neuropsychobiology. 2003.

12. Effects of Gluten Exposure on Absorption of Nutrients in the Intestine

As a recap, poor control of gluten intake results in poor absorption of essentially all nutrients, whether in food or taken as supplements. Several examples of this were described earlier, but the poor absorption would affect all nutrients, so your body would not have a “level playingfield” to do all the things it needs to do. This includes brain function as well. So, as always, gluten avoidance remains the cornerstone of nutrition for Celiac Disease. All the other issues described above are just the icing on the (gluten-free) cake.

[Metabolic and nutritional features in adult celiac patients. Dig Dis. 2008;26(2):128-33.Affective and psychiatric disorders in celiac disease. Dig Dis. 2008;26(2):140-8.]

11 MAPS of INTEREST: VITAMIN D and IODINE

VITAMIN D: https://www.health.harvard.edu/newsweek/images/latitude-vitaminD.jpg Except during the summer months, the skin makes little if any vitamin D from the sun at latitudes above 37 degrees north (in the United States, the shaded region in the map) or below 37 degrees south of the equator. People who live in these areas are at relatively greater risk for vitamin D deficiency.

(Actually, that’s where I live … but you can see why it’s a really big deal Up North!”)

IODINE: Map showing spatial correlation between the former "Goiter Belt" in the northern U.S. and areas where the iodine content of drinking water is naturally low. www.uwsp.edu/gEo/faculty/ozsvath/images/goiter_belt.htm

12

For additional information on these and other topics you can go to MeritCare’s website (www.meritcare.com) and find other articles in the “Aunt Cathy’s Guide to Nutrition” series.

Just type Cathy Breedon in the “search box” and a page comes up where you can click “Cathy Breedon: Handouts.”

Topics include information and references especially for people interested in:

1. Specific health problems (diabetes, celiac disease, cancer, MS, hemochromatosis, epidermolysis bullosa, etc.

2. Pregnancy and infant nutrition

3. Summaries providing much more detail about nutrients discussed here, such as magnesium, vitamin D, vitamin K, vitamin B12, iron, and different kinds of fat and oil.

13 Sanford Medical Center 2/2011

Aunt Cathy’s Guide to:

Choosing Aunt Cathy Cathy Breedon PhD, RD, CSP, FADA Appropriate Prenatal/Pediatric Nutrition Specialist Clinical Nutrition Specialist Infant Milks and Sanford Medical Center, Dept. of Pediatrics and Clinical Associate Pr ofessor of Pediatrics Formulas UND School of Medicine, Fargo, ND

Part 1: Nutrition Issues in Breastfeeding.

The ideal food for most babies is human milk. Even for this nearly Universal Truth however, there are exceptions (e.g. infants with the rare inborn metabolic error "galactosemia" may not have human milk.) Formulas are attempts to provide similar nutrition for healthy babies who are not breast-fed, or to meet the nutritional requirements of infants with special health problems. The American Academy of Pediatrics recommends human milk for at least the first year of life.

Although it is less common in America than in other nations, nursing through the second year (or even longer) is also beneficial and the practice is increasing. [However, it is important to note that, for reasons described later, it is not recommended to breastfeed the baby exclusively without the addition of selected other foods after six months, and without vitamin D supplementation throughout breastfeeding.]

This part of the paper will focus primarily on some evolving issues regarding the assurance of macronutrient and micronutrient adequacy in human milk. Commercial formulas and cow’s/goat’s milk issues in infant feeding will follow.

[For a more complete discussion of the many benefits of human milk and a review of the data now available that demonstrates its clear superiority to any formula for most babies, please see my separate paper entitled “Some Issues in Breastfeeding.”]

Macronutrients: Protein, Carbohydrate and Lipids

The best infant diets are those which provide adequate but not excessive amounts of calories, protein, vitamins, minerals and fluid, with a distribution of calories from carbohydrate, protein and fat in the "desirable range". This is the range within which babies have been seen to grow well without excessive metabolic stress (Fomon, 1974.) It appears that most babies are fairly flexible little people and tend to do well within a fairly broad range of feeding practices.

1 Percent of calories from: CHO PRO FAT ______Desirable range: 35 - 65 7 - 16 30 - 55 ______Human milk: 38 7 55 ______

Protein Why is human milk at the lower end of the range in protein?

Human milk has a protein content on the lower end of the range and a fat content on the upper end. This is acceptable because the forms of protein and fat are so perfectly suited to baby's immature digestive and metabolic systems that absorption and utilization of these nutrients is optimal. The protein content of human milk will continue to stay in the appropriate range even when mothers are protein deficient. This is because protein goes into the milk at mother’s expense if there is an inadequacy.

No other food has protein that is so well absorbed or well utilized, so it is best to avoid the extremes of the “desirable range” if something other than human milk is fed. In other words, a diet that provides only 7% of calories as protein from formula or any other source could be inadequate for optima growth.

As discussed in a later section, commercial formulas do provide a more generous percentage of calories as protein for that reason (milk-based formulas provide ~9-11 % of calories as protein, and soy products provide 11-13%. But both human milk and formula protein adequacy can be compromised by practices such as adding lots of additional carbohydrate or fat calories for babies with higher calorie needs, or giving a substantial amount of cereals, fruits or juices to the diet.

Neither the protein nor calcium content of human milk is greatly affected by current maternal diet, but that does mean that maternal dietary inadequacies will be compensated for by a loss from the mother’s stores or tissues. For that reason, a poor intake is certainly not optimal for mother’s health. Mother and baby should not be in competition for nutrients. There are also specific examples of the many benefits associated with assuring the adequacy and absorbability of maternal calcium intake during both pregnancy and breastfeeding.

For example, the adequacy of current calcium intake and absorption has been shown to decrease the developing baby’s exposure to harmful substances that may be stored in the mother’s bones. This includes heavy metals like lead. If the mother has to mobilize her bone calcium to replace blood calcium lost to the fetus or the milk, any lead present in her bones would be freed and enter the bloodstream along with the calcium. It would therefore reach both mother and baby.

2 Carbohydrate

The carbohydrate of human milk is lactose …a combination of glucose and another simple sugar (a monosaccharide) called galactose. The lactose is broken apart by lactase enzyme and the two monosaccharides are then small enough to be absorbed. Failure to break it apart means the lactose will not be absorbed. If the problem is severe enough this can result in wasted calories, diarrhea and intestinal gassiness … the classical picture of “lactose intolerance.”

So how common is lactose intolerance in infants? Actually, babies all around the world are rarely truly “lactose intolerant” even in populations who become less able to digest lactose as they get older. Babies can be temporarily lactose intolerant due to intestinal damage due to malnutrition, infection, or certain diseases like unrecognized celiac disease (after gluten has been introduced.) But even then, the benefits of continuing to provide human milk far outweigh any potential problem with lactose in most instances.

The popular conception that lactose intolerance is a big problem with infants is very overblown, and it is primarily a marketing opportunity. As discussed later, many formulas that are advertised as lactose free also have other changes in their construction that can contribute to baby’s tolerance.

Lipids: Fats and Sterols

Cholesterol One of the components of human milk that is not in any formula is ready- made cholesterol. Cholesterol is actually a very important structural sterol, being a key component of all cell membranes and the myelin around nerves. Babies need to grow rapidly so they need to make lots of new cell membranes, and they need to myelinate their nervous system in utero and in the first two years after delivery. Several hormones and bile are also made out of cholesterol.

We have always assumed that babies could simply make their own cholesterol from the other substances in formula. However, if a baby had difficulty making the optimal amount of cholesterol, no commercial formulas would help him/her out. But human milk would provide that extra boost.

[There is a rare genetic condition of severe inability to produce cholesterol called Smith- Lemli-Opitz Syndrome. Impairment of cholesterol production is so severe that even the human milk pre-formed cholesterol content is insufficient to solve the problems for several reasons. However, babies having difficulty producing optimal cholesterol temporarily for reasons of serious illness or prematurity might truly benefit from having some delivered “ready-made.”]

Essential fatty acids The fatty acid distribution depends on the mother’s diet, and in most instances in America, people take in generous total fat (or other calorie sources,) and sufficient amounts of linoleic and alpha-linolenic acids from plant oils (the “essential” fatty acids.) It is not difficult to assure caloric adequacy and adequate amounts of these two essential fatty acids for the fetus and for human milk.

3 However, it now appears that some other fatty acids may also be “essential” because the ability of some people to make enough of them on their own is insufficient. Pregnancy and lactation in particular appear to be periods where some people fail to make an optimal amount from the two 18-carbon essential vegetable oils.

One example of a potentially essential form of fat is the 22-carbon omega-3 fat called DHA (DocosaHexaenoic Acid). DHA is critical to brain and retinal development. Our assumptions have been that this fat can be readily made from alpha-linolenic acid by way of an intermediate 20-carbon fat called EPA (Eicosapentaenoic Acid.). Now it appears that the omega-3 fats EPA and DHA, and the 20 carbon omega-6 fat ARA (Arachidonic Acid) are “conditionally essential.” In other words, some people can make enough on their own and some people cannot, and they are especially unable to do it during pregnancy and lactation when providing DHA is so important for brain development.

Milk DHA levels can be quite variable depending on the mother’s current intake and stores, and worldwide the DHA content of human milk has been found to be decreasing. This is now seen to be a serious issue during pregnancy as well. Bottom line: It is now recognized that the ability of most humans to produce DHA from the essential plant fatty acid linolenic acid via EicosaPentaenoic Acid (EPA) is much less than was presumed.

Long-Chain Omega 3 Fats in Mother’s Milk:

Fetal and Infant Development Issues:

The discussion of omega-3 fats in particular is included here because it is unrelated to the macronutrient (calorie) function of fat discussed later. Oils rich in omega-3 fatty acids perform many specific important metabolic functions. They have important implications in pregnancy and infant nutrition in particular. As described, DHA is a major fat of the brain, and research is growing that providing some pre-formed DHA is advantageous. Other health benefits continue to be identified, including the (so far) a possibility of decreased risk of preterm delivery and decreased risk of allergies.

[There are many additional health benefits identified for other age groups as well, including maintaining cognition as we age, and issues related to attention and mood. These are described in some detail in my paper “All Those Lipids: Recommendations for Using Different Types of Fats and Oils (Omega-3, Omega-6 and Monounsaturated Oils)” That paper also explains the relationship of the different fatty acids more clearly … and it has pictures!]

Food sources of EPA and DHA: Fish and fish oil provide ready-made EPA and DHA. Taken during pregnancy they improve the DHA content of the fetal brain, and during lactation it increases the amount of pre-formed DHA provided to the infant.

The “pre-formed” part is important: it is now recognized that there is considerable variation in the ability of different individuals to efficiently operate the pathways that make alpha-linolenic acid into EPA and then into DHA. Alpha-linolenic acid is the form of omega-3

4 fat found in plants. Flax, canola and walnut oil are the most generous sources. Many --- perhaps even most ---people can use it to make the DHA as needed. But for many people there is a clear benefit from getting at least some EPA and DHA “ready-made” in fish and fish oil supplements. This appears to be particularly true during pregnancy and lactation.

That means that many people must rely on an outside source of EPA and DHA to assure adequacy for their own needs and for the baby. In essence, this means that for some people, these fats are also “essential” because that term means that a person cannot make enough on their own.

This discovery of impaired ability to make adequate EPA and DHA from linolenic acid is well demonstrated now. For example, it is one of the reasons behind the recommendation of the American Heart Association that people eat fatty fish twice a week or take supplemental fish oil because that is the ready-made source of both EPA and DHA. So, clearly, we need to look closer at the adequacy of the mother’s diet and nutritional status in general.

Many health professionals erroneously assume that mother’s milk will have all the nutrients needed by the baby regardless of mother’s nutrient intake. As noted earlier, it is the same concept as the old “perfect parasite” theory of a generation or two ago that presumed that babies simply took whatever they needed from the mother’s body during pregnancy. That view has been disproved and discarded long ago, but the same old idea continues to be erroneously applied to the concept of nutritional adequacy in both pregnancy and lactation.

DHA made from an algae source is also available as a supplement, and it is the kind used in some supplements designed for pregnant women and in some children’s gummi DHA supplements. This is the same form used to provide pre-formed DHA in infant formulas. It can be a reasonable source of DHA depending on the dosage or amount of DHA per-gummi. And comparison shopping shows that gummi-type DHA supplements for often children provide very little DHA per gummi and they can be quite costly. Additionally, the algae-based products do NOT contain any EPA … the omega-3 fat between linolenic acid and DHA.

EPA has many metabolic roles in the body involving inflammation, blood clotting, the immune system and other functions, and a person with an inability to produce DHA will likely have a difficulty making EPA as well. For that reason, fish oil as a supplement for pregnant and nursing women has advantages over the products that only provide DHA. Fish oil supplements are easily available now that are free of mercury and other substances that would be of concern when eating fish to get these special oils.

Do breast-fed babies need anything else?

A Look at Micronutrients: Vitamins and Minerals

5 Maternal diet/stores CAN be a factor in the amount of several vitamins and minerals in mother’s milk as well. These include iodine, zinc, selenium, all the B-vitamins and vitamin C, so attention must be paid to the adequacy of her intake. The fat soluble vitamins (A, D, E and K) are now being re-evaluated in this regard as well.

This is a surprise to many health professionals because earlier models of prenatal and infant nutrition were based on assumptions that the fetus was a “perfect parasite” taking everything it needed, even at mother’s expense. The same assumption carried over to assumptions about the nutritional content of human milk.

This was all in the absence of being able to confirm things scientifically. However, now that these issues have been able to be evaluated, it is clear that the presumption of nutritional adequacy provided to the fetus or breastfed infant needs to be replaced with careful attention to a number of nutrients in the mother’s diet.

Micronutrient Issues: Vitamins

Vitamin D

An epidemic of vitamin D inadequacy in people of all ages has been the focus of literally hundreds of recent reports in the scientific literature. For years, vitamin D inadequacy has been assumed to be a non-issue because most of the time, deficiency lacks the only symptom that has traditionally led physicians to even look for it: that is, overt bone deformity in children.

It has long been (erroneously) assumed that everybody easily produces generous amounts of vitamin D from the action of sunlight on skin. Additionally, as vitamin D is found naturally in very few foods, it has been added to milk and a few other foods more recently in the US. However, the amount currently added is insufficient to maintain appropriate blood vitamin D levels in most cases. Vitamin D deficiency is now recognized as very common, very dangerous, very often unevaluated and rarely corrected. The health consequences are very serious, but the entire situation is very easy to fix once the issue is recognized.

Maternal/child vitamin D deficiency issues deserve a close look here.

[The following is an excerpt on specific vitamin D deficiency issues in lactation from my paper “Aunt Cathy’s Guide: My Current Top Five Ways to Improve Your Family’s Nutrition.”

There is much more on multiple vitamin D issues in that publication, including recommendations for action. A version is also available with many references from reports in the scientific literature.]

------

6 Vitamin D Inadequacy in Breastfeeding Alert

Interestingly, mother’s milk is an amazingly nutritious food and breastfeeding is certainly encouraged. However, the milk does not contain vitamin D. This is probably because when people were invented nobody lived in Fargo. As an adaptation to live well up here, we need to have a furnace, a coat, really good mittens and vitamin D. It is that simple. It is also a possibility that the milk would provide adequate amounts if the mother herself were not vitamin D deficient. This question is being studied, but in the meantime, for the health of both mother and baby, it is best to assume that it provides too little unless it is actually checked.

Because of the finding of serious vitamin D deficiency in many breast-fed babies, in 2003 the American Academy of Pediatrics recommended that breastfed babies be given “at least 200 iu of vitamin D by two months of age.” In 2008 that recommendation was changed to 400 iu/day for ALL infants and they recommended starting it right away because many babies were actually born with inadequate stores of vitamin D because their mothers were deficient during pregnancy (in spite of taking prenatal vitamins.)

This recommended change also included formula-fed babies and not just breast-fed babies because the standard formulas provided 400 iu only when about a quart (32 oz) a day is consumed. Newborns usually take only about 20 oz, so formula-fed infants would also fail to obtain 400 iu without supplementation.

This change brings US recommendations in line with those of their Canadian colleagues who have recommended 400 iu for babies, and at least 800 iu for everyone else up there for several years now. Here are some details of the kind of research that led to this change in recommendation:

A recent study in Boston of 380 healthy infants and toddlers who were seen for a routine health visit evaluated the prevalence of vitamin D inadequacy or overt deficiency. Forty four of 365 children,12%, had levels lower than 20 ng/mL (clearly deficient) and 146 children (40%) had inadequate vitamin D status based on levels below an accepted optimal threshold (<30 ng/mL.*) [Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers. Arch Pediatr Adolesc Med. 2008;162(6):505-512. Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency. J Perinatol. 2007 Sep;27(9):568-71.]

The same Boston authors studied the therapeutic amounts of vitamin D supplementation needed to correct the low vitamin D status of the children. They concluded that these two approaches were effective for bringing low vitamin D levels into the range of >30 ng/mL* within a 6 week treatment period: Daily 2000 IU vitamin D2 or D3, or Weekly 50,000 IU vitamin D2. [Treatment of Hypovitaminosis D in Infants and Toddlers. J Clin Endocrinol Metab. 2008 Apr 15.]

7 *However, note that a report described earlier suggested that the healthiest ranges of serum vitamin D may in fact be above this “optimal threshold” of >30 ng/mL, and that it might be in the range of 36-48 ng/mL. [Optimal serum 25- hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.]

Many other approaches to therapeutic supplementation are being investigated as well.

There are concerns about inadequacy of vitamin D in breastmilk (or in any infant feeding regimen) in MANY areas beyond its relationship to the pattern of overt bone deformity we call rickets. Most are not visible.

Inadequacy of vitamin D is now known to be an independent risk factor for an ever-widening range of negative health conditions:

“All-Cause Mortality”

Asthma Diabetes (both Type 1 & Type 2)

Cancer of the Breast, Colon, Prostate, Pancreas and other types, with roles in both prevention and treatment.

Cardiovascular Disease both heart attack and especially congestive heart failure

Depression and Dementia

Developmental Problems

End-Stage Renal Disease

Immune System Compromise

Lupus, Fibromyalgia and Scleroderma

Multiple Sclerosis

Osteoarthritis, Osteomalacia and Osteoporosis

Pain in Muscle, Nerve and Bone

Pre-eclampsia in Pregnancy

Rheumatoid Arthritis

Sarcopenia (muscle weakness) and Falls

8 Clearly, assuring the mother’s vitamin D adequacy is very important to her health as well as the health of her infant, but this is a topic outside the scope of the present article.

“The recommended adequate intakes for vitamin D are inadequate, and, in the absence of exposure to sunlight, a minimum of 1000 IU vitamin D is required to maintain a healthy concentration of 25(OH)D in the blood.”

Optimal serum 25- hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.

Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512. Treatment of Hypovitaminosis D in Infants and Toddlers. J Clin Endocrinol Metab. 2008 Apr 15.] Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512. Vitamin D Status: Measurement, Interpretation, and Clinical Application. Ann Epidemiol. 2008 Mar 8. Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S. Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency. J Perinatol. 2007 Sep;27(9):568-71.Am J Clin Nutr. 2004 Mar;79(3):362-71) ] [See my “Top Five” handout for much more on vitamin D.]

This topic is absolutely mushrooming in the scientific literature and the issue is too big to describe thoroughly. Note that the references cited above were from 2007 and 2008. Below are just a few of the 2008-9 references out there I had in one of my other papers, and the 2010 literature has even more Every day another study pops out! I just don’t have time to organize it all in time for this Feb. 2011 paper to get where it has to go.

However, anyone interested in looking further into this issue can easily go to www.pubmed.org and enter the search term vitamin D. The response is overwhelming. You can also limit your search, say, by entering the words vitamin D infant or lactation, or whatever. “Pubmed” stands for “Public Medline.” It is a free service provided by the National Library of Medicine at the National Institute of Health in Washington DC)

A Sample of Some of the Many 2007-2009 Vitamin D References in the Scientific Literature

2009 Modern concepts in the diagnosis and treatment ovitamin D deficiency and its clinical consequences. J Environ Pathol Toxicol Oncol. 2009;28(1):1-4. Vitamin D and aging. J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):78- 84. Vitamin D and type 2 diabetes Is there a link? Prim Care Diabetes. 2009 Apr 21. Behavioural and physical characteristics associated with vitamin D status in women. Bone. 2009 Jun;44(6):1085-91 Hypovitaminosis D is Associated with Greater Body Mass Index and Disease Activity in Pediatric Systemic Lupus Erythematosus. J Pediatr. 2009 May 14. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):722-9. Sex-specific association of serum vitamin D levels with physical function in older adults.Osteoporos Int. 2009 May;20(5):751-60. Vitamin D status and muscle function in post-menarchal adolescent girls. J Clin Endocrinol Metab. 2009 Feb;94(2):559-63. 25.

9 Vitamin D Supplementation and Reduced Risk of Preeclampsiain Nulliparous Women. Epidemiology. 2009 May 15. Association of 25-Hydroxyvitamin D With Blood Pressure in Predominantly 25-Hydroxyvitamin D Deficient Hispanic and African Americans. Am J Hypertens. 2009 May 14. Effect of vitamin D supplementation in the institutionalized elderly. J Bone Miner Metab. 2009 May 15. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009 Feb 23;169(4):384- 90. Nutrition and health: guidelines for dental practitioners.Oral Dis. 2009 May 15. Circulating calcitriol concentrations and total mortality. Clin Chem. 2009 Jun;55(6):1163-70. Vitamin D and cardiovascular disease.Pharmacotherapy. 2009 Jun;29(6):691-708.Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis. 2009 Jun 6. Prospective Study of Serum 25-Hydroxyvitamin D Level, Cardiovascular Disease Mortality, and All-Cause Mortality in Older U.S. Adults. J Am Geriatr Soc. 2009 Jun 22 Increased Levels of 25 Hydroxyvitamin D and 1,25-Dihydroxyvitamin D After Rosuvastatin Treatment: A Novel Pleiotropic Effect of Statins? [Crestor] Cardiovasc Drugs Ther. 2009 Jun 20.

2008 Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162 (6):505-512. Treatment of Hypovitaminosis D in Infants and Toddlers. J Clin Endocrinol Metab. 2008 Apr 15. Optimal serum 25- hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71. Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S.] [Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother. 2008 Jan;9(1):107-118. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med. 2008:162(6):505-512 Hypovitaminosis D among healthy children in the United States. .Arch Pediatr Adolesc Med. 2008:162(6):513-519. ndependent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008:168(12):1340-1349. Vitamin D and cardiovascular disease risk. Curr Opin Clin Nutr Metab Care. 2008 Jan;11(1):7-12. Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism. 2008 Feb;57(2):183-91. 25- Hydroxyvitamin D and Risk of Myocardial Infarction in Men A Prospective Study Arch Intern Med. 2008;168(11): 1174-1180. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother. 2008 Jan;9(1):107-118. Vitamin D in Health and Disease. Clin J Am Soc Nephrol. 2008 Jun 4. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-9,

2007 Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency. J Perinatol. 2007 Sep;27(9):568-71. Dose response to vitamin D supplementation among postmenopausal African American women. Am J Clin Nutr. 2007 Dec;86(6):1657-62. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007 Mar;85(3):649-50. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103(3-5):708-11 Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512. Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency. J Perinatol. 2007 Sep;27(9):568-71. Macro- and micronutrients in patients with congestive heart failure, particularly African-Americans. Vasc Health Risk Manag. 2007;3(5):743-7. Vitamin D supplementation & total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007 10;167:1730-7

Vitamin K

A new focus on a previously unrecognized inadequacy of vitamin K in many Americans is showing that many people get far too little and that it contributes to serious health problems such as osteoporosis, kidney damage, calcification of the arteries, pre-eclampsia, diabetes and cancer of the liver and colon. This is in addition to the long recognized role of vitamin K as a tool needed when one needs to clot blood.

10 Until fairly recently (starting in about 2005) the blood-clotting function was the only known role of vitamin K. Another factor recently identified as contributing to inadequacy is our assumption that generous amounts of vitamin K are provided by intestinal bacteria. Because of this, little nutrition advice focused on this nutrient, it was not included in many multivitamin products, and even the MyPyramid.gov website neglected to include it (or vitamin D) in the sample two-week diet for nutritional adequacy evaluation.

However, it appears that we are all actually much more dependent on an outside source (dietary or supplement) than was assumed. Vitamin K status was (and still is) rarely evaluated, so it is still assumed that all is well. Recent research makes it clear that many people are in fact getting far too little of this nutrient, and it is hurting them.

Concerns about “toxicity” of vitamin K based on the observation that it dissolves in oil have also been shown to be incorrect. In fact, vitamin K is so non-toxic that there is not an upper end of safety identified for its intake. No-one has ever demonstrated an overdose. One reason it is not toxic is that it operatesna s a simple co-factor … a tool that must be present for certain things to move forward. It does not MAKE you clot your blood … it LET’S you clot your blood if your body is telling you to do it.

[Aside: People on the anti-coagulation drug Coumadin need to have a very consistent amount because the drug works by interfering with vitamin K. Inadequacy is dangerous for them too, however because it increases the volatility of coagulation. It also puts them at risk for osteoporosis, cardiovascular disease and cancers like everyone else. No one benefits from a vitamin deficiency situation. The Coumadin issue is a specific drug/nutrient interaction … not a general nutrition issue. For people NOT on this drug, vitamin K is not scary … although inadequacy of vitamin K IS scary.

Please see my paper “New Roles for Vitamin K” for all the details and references, and another paper I have available for health professionals specifically on the Coumadin issue and the new research that should significantly change how we manage it.]

Some of the new issues being identified have significant implications for pregnancy and lactation. Women who have insufficient vitamin K are at risk of hemorrhage at delivery and have an increased risk of pre-eclampsia. Their infants are at risk of intrauterine hemmorhagic events.

Consider that in America it is common to give infants a vitamin K shot at birth, to reduce the risk of hemorrhage in newborns who received inadequate vitamin K in utero. That means that overt consequential deficiency in the newborn was a common enough occurrence to make vitamin K administration at birth become a standard practice.

I think that means that we should look more closely at maternal vitamin K status (and everyone’s for that matter.) For one thing, the vitamin K shot at birth does not protect against hemorrhagic events in either mom or fetus. Studies of newborns have demonstrated that some

11 children are born with evidence of earlier hemorrhagic events that can contribute to developmental delays.

Additionally, not all babies actually receive the vitamin K shot because of home delivery options, parents’ right of refusal, etc. Teleologically, it would seem to be an inefficient plan to design people in such a way that infants all around the world would be born vitamin deficient and at great risk unless someone is on hand with a syringe full of vitamin K. This is an issue requiring attention from both the obstetric and pediatric medical experts working together.

In the meantime, mother’s milk can easily be low in vitamin K if mother is low. And many mothers have been shown to be low. If the baby received the vitamin K shot, the low vitamin K status of her milk will not be an issue any more for the baby (Although it will still be a problem for mother.)

But any breastfed baby to whom that shot was not administered really needs to have vitamin K reliably provided. And again … at the moment it is not standardly in many vitamin supplement products. Additionally, it would be a good idea to provide that extra vitamin K to a formula-fed infant as well if the shot was not given … the amount provided in the formula does not provide a generous enough amount to compensate for a combination of low stores at birth and no vitamin K shot.

Vitamins B12 and B6

The B vitamins play many critical roles in metabolism and inadequacy can compromise the growth and development of the baby. In America, serious deficiency of B vitamins is presumed to be extremely rare, but it is now recognized that some of them need a much closer look. Most health professionals are aware that alcohol abuse frequently results in dangerous deficiency of thiamin and folic acid, and of course, perinatal alcohol abuse is even more problematic. But there are other specific concerns about vitamins B12 and B6 that deserve some special attention during both pregnancy and breastfeeding.

As described earlier, for some nutrients (e.g. calcium and protein,) a relatively deficient mother will still provide a good amount to the fetus/baby even at her own body’s expense. However, all of the water soluble vitamins (B vitamins and vitamin C) will fail to be provided optimally to the baby if mother is deficient … maternal needs for these nutrients must be met before she “shares.”

Vitamin B12

Recently, for example, it was found that babies of mothers who had an inadequate intake of vitamin B12 have deficiency levels even if the mother’s labs show her own vitamin B12 level to still be in the normal range. Deficiency is extremely injurious to the nervous system of both mother and baby. The following are three circumstances that put people at special risk.

12 1. Because vitamin B12 is found naturally only in animal products, vegans are well known to be at great risk unless they take a vitamin supplement containing vitamin B12. There are MANY reports in the scientific literature about this problem and the damage to the infants when it occurs during pregnancy or lactation. But simply assuring that the vegan mother has been taking a supplement regularly for quite some time is all one needs to do.

But if she has not been taking one, or has only begun to take vitamin B12 during pregnancy, for example, her vitamin B12 status could easily still be too low for the fetus/baby to receive the needed amount for optimal development. As vitamin B12 is extremely non-toxic, ideally in this situation a physician or other provider should consider giving her a therapeutic level to correct a suspected deficiency right away.

2. One of the less-well-recognized emerging risk factors for vitamin B12 deficiency is among people who have GERD (gastro-esophageal reflux disease) and use PPI (proton pump inhibitor) medications that prevent gastric acid production. Natural sources of vitamin B12 require the presence of gastric acid before it can be absorbed. [This is different from the role of Intrinsic Factor in vitamin B12 absorption.]

People who use these medications cannot absorb vitamin B12 from natural sources, but they can easily get around this problem by taking a supplement that contains vitamin B12 … just like vegans but for a different reason. In this case it is because the crystalline B12 in supplements does not require the presence of acid in order to become absorbable. But also just like vegans, if she has been taking the medication for a long time and has only recently begun to take supplemental vitamin B12, there may be a degree of deficiency sufficient to warrant giving a therapeutic amount.

3. It is becoming increasingly common for women of childbearing age to have undergone bariatric surgery (gastric bypass for weight loss) prior to becoming pregnant. Long- term vitamin and mineral status in the women is rarely evaluated, but when it IS, there are several nutrients commonly found to be seriously inadequate even with the use of prescribed supplements.

Some of these, like copper deficiency (generally extremely rare in the general public and therefore not monitored) are showing up as causes of serious neurologic damage. The potential damage to a fetus or breast-fed infant is huge. Additionally, months/years after the actual surgery many woman stop taking their prescribed supplements for a variety of reasons. This is even more common among people with less ability to afford them. Long term follow-up is rarely undertaken for anything besides weight status and effect on cholesterol or diabetes. By the time micronutrient inadequacies are recognized it is because they are severe enough to be visible … and that is often past the point where prevention of injury is an option.

An additional important observation is that a study evaluating the nutritional status of people considering bariatric surgery found that the majority had significant inadequacy of a number of nutrients even before having the surgery. This may be because of a likely history of trying various restrictive or unbalanced diets to lose weight. But it is also

13 a reflection of the fact that many people whose appearance suggests that they are very “well-fed” are actually not “well-nourished” at all in terms of vitamins and minerals. In fact, intake of several vitamins and minerals is recognized in large national studies to be unsatisfactory in a large number of Americans.

[Please see my “Carnitine Explanations” paper for more information about another important problem issue that may be present in some people undergoing bariatric surgery.]

Deficiency of vitamin B12 is just one of several problems that are of great concern in the special pregnancy/lactation context. This mother may have several severe nutritional problems that are very likely to have gone unrecognized. Unfortunately, the simple multivitamin that solved vitamin B12 problems for vegans and PPI users is unlikely to be an adequate intervention here. What should be done about it is outside the scope of this paper, but vitamin B12 shots would likely be a needed. Heightening the awareness of healthcare professionals about the existence of the problem is a good place to start.

[Please see my “Vitamin B12” handout for more information about problem issues with this nutrient.]

Vitamin B6

Adequacy of vitamin B6 in exclusively breast-fed infants has been found to rely often on gestationally accumulated stores. For some infants, human milk alone without supplemental foods may be insufficient to meet vitamin B6 needs after 6 months of age (Pediatr Gastroenterol Nutr 1996 23(1):38-44.) Earlier introduction of meats or the use of a multivitamin drop will correct this situation. Most infant vitamin drops contain vitamin B6 and they often contain iron, but they do not contain zinc. Meats are the richest sources of vitamin B6 and well-absorbed iron and zinc … the three nutrients that have been observed to “drop out” of breastmilk after 6 months.

This argues for reversing our most recent traditional pattern of introduction of solids by introducing meats by about age 6 months instead of introducing it after 10 months or later. This problem can also be addressed by using a crushable-type multivitamin with minerals instead of an infant vitamin drop; it contains all three of the micronutrients (zinc, iron and vitamin B6) that decrease so precipitously in mother’s milk after 6 months. It can be crushed and added to baby food.

Micronutrient Issues: Minerals

Iron

The iron in human milk is very well absorbed – the best of them all, with estimates between 25% and 50% absorption. Compare this with the next best source of iron (meats, at about 20%) and with the much less absorbable form in plants and pills (which are only about

14 0.25-2% absorbed.) But although iron in human milk is well absorbed, but there is not a great deal of it.

Most term babies are presumed to have enough iron stored up so they do not "run out" until about 4 months of age. Since this is the age at which many babies begin to have the developmental skills to eat from a spoon, providing foods that are good iron sources plus the iron in mother’s milk may be adequate.

On the other hand, one might argue for providing an additional source of iron (e.g. an iron drop) to avoid emptying baby's iron reserves before he/she actually “runs out.” Premature babies often have poorer iron stores because the iron (like zinc, calcium and other minerals) is stored in the baby's body primarily in the third trimester of pregnancy. They simply get out of line too soon.

The iron "cost" of growth is high, and inadequacy of iron stores can have serious consequences. Anemia is associated with decreased ability to learn and to pay attention that can remain a problem for months after the anemia itself is corrected by treatment. Additionally, the “presumed iron stores” of the average term baby are just that … “presumed” … not “assessed.” Historically this approach has not always served us well.

Iron-deficiency anemia has also been found to be associated with increased likelihood of being identified as having mild or moderate developmental delay in school. This is likely because iron has many important rolls in all of the cells of the body, including such tasks as oxygen transport, energy production, protection against environmental toxins, and function of brain neurotransmitters. For example, some iron-related brain-development functions in utero are on such a strict time-table that inadequacy of iron during that period can cause irreparable impairment.

As was the case with calcium, good iron status also decreases the absorption of lead from the environment, a known agent of severe injury to brain, bone and kidneys, and a contributor to hypertension. Iron deficiency results in an attempt to increase absorption of iron in the intestine, and the process accidentally increases the absorption of lead as well.

Reliance on hemoglobin to screen for poor iron status is risky without also having information about the adequacy of the person’s iron intake. This is because hemoglobin levels can actually remain normal until iron stores are depleted. A low hemoglobin is a sign of trouble, but a normal one tells very little about the status of iron stores. Measures of iron stores (like a “ferritin” level) are rarely used at present in evaluating babies who appear to be healthy. But asking specific questions about regular iron supplement use and/or meat consumption tells us a lot about the likelihood of there being an unrecognized compromised iron status in a particular woman or infant.

There is some concern that providing additional iron to a breast-fed baby may decrease the effectiveness of one of the substances in human milk that helps to control bacterial growth. Lactoferrin in human milk binds iron that E. coli bacteria in the gastro-intestinal tract need in order to reproduce. Giving additional iron would make more free iron available to the bacteria as well as to the baby.

15 It is not clear that this is a big problem, however, since there are many other bacteria- fighting substances in human milk that are not affected by the presence of iron. Also, the fact that most formula-fed infants thrive while regularly receiving generous dietary iron that is not bound to lactoferrin suggests that is not a major problem. After all, these babies receive none of the many other protective substances in breast milk either.

Complicating the picture is the finding that the iron in infant cereal that has traditionally been used to provide iron in baby's diet may not be as well absorbed as had been believed. Its ability to provide useable iron to the infant has been questioned, but so far no one has questioned whether iron provided in the form of fortified cereal increases the risk of E coli infection in breast-fed (or any) infants.

Two feeding practices can sometimes have an effect on the absorption of iron in infants:

1) Iron supplements given with a (non-human) milk or formula feeding are likely to be less well absorbed compared with supplements fed with an acidic food or meat. Meat contains “Meat Protein Factor” which enhances absorption of inorganic iron from other foods fed with the meat.

2) Although in some cultures it is common to feed tea to infants, the tannins in it greatly reduce inorganic iron absorption in both infants and adults. This does not appear to be a problem for organic iron forms such as are found in breastmilk and meats, so feeding tea to breastfed infants does not induce iron deficiency anemia the way it can in those not breastfed.

Interestingly, in some world situations the traditional feeding of tea to infants has actually been of great benefit in terms of child survival for the simple reason that the water fed to baby has been boiled and germs have been destroyed. Together, protective elements in mother’s milk and boiling any water fed to baby are a terrific combination where bacteria and parasites make the water unsafe.

However, there is a risk of iron (and zinc) deficiency in a non-breastfed infant who is regularly given tea, and people in many cultures do commonly give it. One way to solve this potential problem (besides encouraging breastfeeding) would be to advise them to introduce meats earlier, because the generous iron and zinc content is in a form that is unaffected by the presence of tannins, plus the effects of Meat Protein Factor can help avoid the problem.

Zinc

Iron often described as the micronutrient most likely to be deficient in Americans. However, it is useful to remember that iron status is also the only non-electrolyte nutrient we evaluate in many settings. Status of many other nutrients may be suboptimal, but one that is particularly likely to be “iffy” in an individual with iron deficiency is zinc.

16 This is because in nature iron and zinc tend to be distributed similarly in foods and they are also similarly affected by substances that impair or increase intestinal absorption. A person who is iron deficient may also be zinc deficient, although we rarely evaluate it and therefore do not recognize it. And if that person is iron deficient in spite of taking iron supplements and eating iron-fortified foods (which are usually NOT also fortified with zinc,) the odds are even greater that zinc adequacy may be compromised. The exception would be a person has relative iron deficiency because of excessive blood loss.

This is not to make a case for checking zinc levels in people’s blood … the point is that we can regard iron inadequacy as a marker/screening-tool for suspicion of unrecognized inadequacy of zinc in particular, and many other nutrients as well. In general, people do not consume a diet that gives them a terrific amount of all the nutrients needed except for just the only one we check. Think of that low iron measure as the “canary in the coal mine” that tips you off to an otherwise invisible threat in time to do something about it.

Why is zinc such an issue here?

Zinc is a co-factor in over two hundred metabolic pathways in the body, including making DNA (the genetic center of every cell and hugely important for growth), making T-cells, and metabolizing alcohol and other potentially dangerous substances. Inadequacy is known to impair growth and the function of the immune system. However, zinc has been found to need some attention in breast-fed infants. The same mineral storage patterns are seen for both iron and zinc, with the third trimester being the major period of mineral accretion in the fetus. For this reason, preterm infants are also especially likely to have poor zinc stores.

For term infants, the combination of a well-nourished mother who provided normal fetal zinc stores and then provides human milk should meet growth needs until about age six months. After that time, zinc and iron may be inadequate as described earlier. Of course, a history of poor zinc nutrition of the mother complicates the picture further. Some studies have found that zinc supplementation of exclusively breastfed infants in these circumstances improves growth or other parameters of zinc adequacy [e.g. Lancet 2000 Jun 10;355(9220.)]

Supplementing a mother to maintain adequate zinc status does not correct this problem because the zinc content of the milk begins to drop regardless of her zinc status. As described earlier, a change in recommended “starter food” patterns has been suggested that includes an earlier introduction of meats (the most abundant source of bioavailable forms of both iron and zinc, and also a generous source of vitamin B6) in breast-fed infants [Acta Paediatr 1998;87(6); J Mammary Gland Biol Neoplasia 1999;4(3)].

Again, note that infant vitamin drops do not provide zinc (or any minerals except iron and sometimes fluoride) and they contain no folic acid. So if earlier introduction of meats is undesirable, the best way to assure adequacy of zinc, iron and vitamin B6 would be to give a crushed chewable children’s multivitamin with minerals.

Nutrient levels will not exceed safe ranges with this dosage, and this approach also provides baby with the 400 iu of vitamin D recommended for all infants by the American

17 Academy of Pediatrics and the Canadian health groups as well. If texture is an issue, the pill can be crushed to a fine powder using a small mortar and pestle. These are sold in kitchen stores and discount stores (often for $10 or less) because they are used to crush fresh spices. The powder can be mixed into any baby food.

More information about the zinc content and foods, zinc absorption and some special zinc-related issues in fetal alcohol syndrome, are included in my handouts: “Nutrition Support of Iron Deficiency” and “Thinking about Prenatal Nutrition and Fetal Alcohol Syndrome (FAS.)”

Iodine

Another nutrient problem that has recently been found to need more attention is IODINE DEFICIENCY. In many parts of the world (including parts of the US) iodine deficiency is common, and the traditional international approach to solving it has been to add iodine to salt. However, it appears that the amount obtained from iodized salt is actually not sufficient during pregnancy, and that even in areas that have been thought to have corrected iodine deficiency many women obtain too little.

Iodine Deficiency Disease (IDD) is the number one cause of preventable mental retardation in the world. The resurgence of the problem of iodine deficiency in the US has great importance in pregnancy and lactation in particular because of the devastating effects on the intellectual development of the child. Iodine deficiency can also result in deafness, and a serious lack of energy in anyone affected because it impairs the function of the thyroid gland. The World Health Organization is now increasing the recommendation for iodine intake by 25%, especially in pregnancy.

Here is an excerpt from a presentation by UNICEF Deputy Executive Director Kul Gautam:

“… IDD is the single greatest cause of preventable mental retardation. Severe deficiencies cause cretinism, stillbirth and miscarriage. But even mild deficiency can significantly affect the learning ability of populations. Scientific evidence shows alarming effects of IDD. Even a moderate deficiency, especially in pregnant women and infants, lowers their intelligence by 10 to 15 IQ points, with incalculable damage to social and economic development of nations and communities. Today over 1 billion people in the world suffer from iodine deficiency, and 38 million babies born every year are not protected from brain damage due to IDD…”

UNICEF Deputy Executive Director Kul Gautam This quotation comes from the website http://www.saltinstitute.org/Issues-in-focus/Food-salt-health/Iodized-salt- other-additives. It has much more information about the problems of (and solutions for) IDD.

[For more detail on the most recent research on this topic in the scientific literature, please see my handout “New Attention to an Old Problem: Iodine Deficiency in Pregnancy and Lactation”

18

The area of the United States that used to be designated the “goiter belt” because of low iodine in the soil is shown on the map on the next page. The actual iodine content of foods depends on where they were grown, and some protection has likely been provided to the low- iodine regions by the fact that at least some produce may have been grown in an iodine-sufficient region.

This is a new issue to keep in mind as we promote growing one’s own food and buying from local producers instead of transporting produce from far away. Local food production is terrific for many reasons, but if one lives in an iodine-poor region, it is important to assure iodine sufficiency via a demonstrably adequate intake from some form of iodine supplement.

Map showing spatial correlation between the former "Goiter Belt*" in the northern U.S. and areas where the iodine content of drinking water is naturally low.

www.uwsp.edu/gEo/faculty/ozsvath/images/goiter_belt.htm

[*Goiter is an abnormal enlargement of the thyroid gland, often due to iodine deficiency.]

Back home in America, many people under age 50 who live in iodine-poor regions of the country are quite unaware that they should select “iodized salt.” The public health hoopla that accompanied the iodizing of salt in the early 1950s (yes, I remember it … I was THERE!) somehow faded away and the issue went off the radar. Many people of child-bearing age today have no knowledge that this was once a widespread deficiency disease in the US of critical

19 importance to everyone’s health and especially dangerous to the development of infants and children … and they don’t know it has come back

Even when one intends to buy the iodized salt, the packaging is often very similar and they are side-by-side on the shelf at the store. Most specialty salts that are popular now, like sea salt or exotic salts, are also not iodized. So generally, one should choose iodized salt if one uses salt at home, and people who use little salt should be sure to find an iodine supplement, especially if they live in the northern half of the country.

Additionally, we frequently are advised to cut back on salt for other health reasons, which can further limit iodine intake. Recently some national health recommendations pushed for an even lower daily sodium intake than before … instead of 3000 mg/day they recommended 1500 mg. I am not arguing against this recommendation … just pointing out the need to make sure that people who follow this health advice are not accidentally injured by iodine deficiency.

Remember that the choice of salt as the way to supplement dietary iodine was made well before ideas of sodium restriction were common for health reasons. Other factors have made an inadequate intake much more likely today. For example, in the 1950s people made most meals from scratch, so iodized salt would be added whenever salt was used in cooking. Now most of our sodium intake comes in the form of processed foods, which are high in salt but the salt is not iodized. Here is an excerpt from a website on this topic:

“…In the United States, from the outset, salt producers cooperated with public health authorities and made both iodized and plain salt available to consumers at the same price. Even so, the Salt Institute estimates that only about 70% of the table salt sold in the United States is iodized.

Salt used in processed foods is not iodized. Given that people are cooking less at home and buying either restaurant or processed foods, iodine intakes in the U.S. have declined from about 250 μg/day to 157 micrograms/day. Public health authorities recommend 150 μg or more and the need is particularly acute for expectant mothers. Daily Iodine intakes of 1,000 - 1,100 μg are safe for adults and children over 4 years of age…”

http://www.saltinstitute.org/Uses-benefits/Salt-in-Food/Essential-nutrient/Iodized-salt

Also, because it has long been assumed that the iodine deficiency problem was “solved” in the US by the iodizing program, at present many vitamin pills contain no iodine at all, including many prenatal vitamins. So, this is one more nutrient that a person should check for when they select a multivitamin.

20 The WIC Program recently added use of a prenatal vitamin without iodine as a nutrition risk factor for women enrolling in the program. That means that some low income women of childbearing age may soon begin to have this addressed.

At least an awareness of the problem is developing. However, MOST women are NOT on the WIC Program so this problem is unlikely to be readily recognized. There is great potential for harm.

There has been a resurgence of goiter development (a marker of iodine deficiency) in America as well as around the world, and thought to be a problem. Additionally, data it is often missed because it is no longer shows that average iodine intakes have decreased markedly in the US. It is also reported that on average iodine intake is sufficient here [Iodine status of the U.S. population, National Health and Nutrition Examination Survey 2003-2004. Thyroid. 2008 Nov;18(11):1207-14.]

However, when one stratifies the data it becomes clear that a great many women here (and around the world) do NOT have a sufficient iodine intake even when men generally do. The risk to fetal and maternal health is substantial, and easy to fix once the problem is recognized.

Major Point: The problem of iodine deficiency needs to be put back on our radar; this is a very newly recognized and extremely important health problem that needs attention.

Please see my paper “Aunt Cathy’s Guide to Nutrition: New Attention to an Old Problem: Iodine Deficiency in Pregnancy and Lactation 2011” for detail on this topic, including an annotated bibliography.

Some newer references are included here since this topic may be quite new to many readers and I don’t want them to think I am making this stuff up! ☺ Iodine deficiency in infancy - a risk for cognitive development. Dtsch Med Wochenschr. 2010 Aug;135 (31- 32):1551-6.Parameters of thyroid function throughout and after pregnancy in an iodine-deficient population. Thyroid. 2010 Sep;20(9):995-1001. Some subgroups of reproductive age women in the United States may be at risk for iodine deficiency. J Nutr. 2010 Aug;140(8):1489-94. Iodine intake and maternal thyroid function during pregnancy. Epidemiology. 2010 Jan;21(1):62-9.Georgian Med News. 2010 Jan; (178):65-8.Iodine deficiency in the prenatal period may form learning ability deficiency in the postnatal period. Epidemiology of iodine deficiency: Salt iodisation and iodine status. Best Pract Res Clin Endocrinol Metab. 2010 Feb;24(1):1- 11. Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. 2010 Feb;24(1):29-38.Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009 Feb;89(2):668S-72S.

21 Fluoride

Fluoride is low in human milk and whether the mother's fluoride intake affects the amount in milk is still subject to some debate. The recommendations for using fluoridated water, fluoride drops, fluoride toothpaste and topical fluoride treatments have changed many, many times over the years that I have been involved in pediatric nutrition. They are being changed again this year regarding the recommended amount of fluoride to add to low-fluoride-containing water supplies.

The American Dental Association has a current list of very specific recommendations on all aspects of the topic of fluoride as it relates to dental issues. It is available at this website:

http://www.ada.org/public/topics/fluoride/infantsformula.asp

22 Sanford Medical Center I received this excellent question in the mail, and I think it’s a discussion worth sharing:

“At our WIC program, we are able to provide Aunt Cathy several different formulas if an infant does not Cathy Breedon PhD, RD, CSP, FADA tolerate our contract formulas. Typically, at Prenatal/Pediatric Nutrition Specialist the age of 5-6 months we will ask parents to reintroduce a contract product. We do this on the basis that as an infant gets older, he or she Regarding “A Trial Back on . . .” may tolerate the formula better than before A WIC Nutritionist Question (mainly due to the fact that the infant is tolerating solid foods at this point). This has been in practice long before my time here and I’m now looking for evidence/research to back this up.”

Reply: The practice of re-trying a baby who did not tolerate a formula back on the original product was originally based on three things:

1) For many years, doctors and nutrition people perceived that soy-based products were inherently significantly lower quality than milk-based products. My formula handout discusses where we are with that. Basically, unlike some years ago, there is no big nutritional advantage to switching back to milk-based formulas for non-premature babies or those who are otherwise healthy.

If the baby's initial intolerance problem was in fact allergy-related (i.e. involving immunoglobulin E and not just a lactose intolerance type of issue,) such a trial would not be a great idea because allergy to cow's milk CAN "go away" but not usually in the first year. If it were a true allergy I would be very hesitant to just switch them back at 6 months (or whenever) without specific orders for safety reasons. If the baby were to have a severe anaphylactic reaction, for example, there could be very serious consequences.

An additional feature to consider here is the issue of trust between the nutritionist and the client. Many parents perceive the insistence on a re-trial of the formerly-problematic formula as being dangerous and foolhardy. We say, "well, if he still has the problem we can always switch back." However, the "if he still has the problem" part suggests that we pretty casually put their baby in what may be jeopardy.

Now, if it were very important to switch back, that is one thing. But if not? Why would we put them through this kind of anxiety-inducing experience? This is especially a problem when the parents feel very strongly about staying on the present product. We have the power to make them switch ("take it or leave it,") but to do it when there is no pressing reason (like a relative non-issue such as the perceived nutritional value of milk-based vs soy-based) it does have the potential to harm to our relationships with them.

1 2. A lot of the "switch back to the old formula" has roots in the use of more pricey hypoallergenic formulas in place of standard or soy products. In this situation, if the problem is not of a true allergy nature (rendering the hydrolyzation of the protein unnecessary) then the family or the WIC program can save some money by moving toward an intact-protein formula.

However, if it is a true allergy, the same caveats apply as above. Example: hypoallergenic formula might be used for a colicky baby for whom it seemed to be helpful in the first months of life; however, most babies are not colicky after 6 months and they would likely do fine on standard or soy formula, saving big bucks. But colic is not an “allergy” and a recurrence is not potentially life-threatening the way an allergic response can be.

3. WIC costs have also been players in this drama, as the more costly hypoallergenic formulas have sometimes not been on a state's rebate formula list. In that case, the WIC people may be very eager to get back onto any of the “contract” formulas for budgetary reasons. However, again, in that case the primary urge is financial and not baby health, so we really have to be cautious about the circumstances in which we “make” the baby switch back.

So, the bottom line is that it is sort of a relic of the past to insist on switching back from soy-based back to milk-based. In regard to trials of intact protein in place of a hypoallergenic formula, it would depend on whether or not the reason for the switch initially was because of a true allergy. If it is an allergy I wouldn't see any big (non-financial) reason to switch back. Risks to baby health trump thriftiness every time in this situation.

Hope this helps! Cathy B.

2 Aunt Cathy’s “PMS” System for Decision-Making: Aunt Cathy Cathy Breedon PhD, RD, CSP, FADA Whole, 2% or Skim Milk for Ages 1-2. Prenatal/Pediatric Nutrition Specialist

Sorting out the formulas or questions about when to use whole milk or skim milk can be complicated by issues unrelated to the science of nutrition. For example, a formula may not be usable in a situation for which it might be helpful because of costs, contracts with other formula companies, or confusion because of the way a product is promoted.

Health professionals serving large infant-feeding programs like WIC (“Special Supplemental Food Program for Women, Infants and Children” of the Dept. of Agriculture) often find this sort of confusion to be very costly in terms of time, money and frustration. In response to hearing these concerns raised by many state WIC programs, I devised a way of thinking about a formula and milk choice issue that attempts to sort out the important aspects from those that are irrelevant or changeable. The following example examines the question of the need to use whole milk after the first birthday until a child is two (which remains the current AAP recommendation):

The “Whole Milk Dilemma”

Many health professionals expressed concern that insisting on the use of whole milk for all of this age group of children may be inappropriate for those with lower than average ability to expend calories (e.g. children with spina bifida) and those who are already in the overweight / obese categories. However, they felt obligated to follow the official AAP recommendation.

In some states WIC programs did not allow clients to use whole milk without getting a physician’s prescription. Much time and money was invested in obtaining documentation that the child needed a lower-calorie product. Policies and flow-charts had to be established to assure that these issues were handled correctly. Here’s a great example:

“Proposed Policy Regarding the Use of 2% or Skim Milk by Children under Age Two Participating in the _____ State WIC Program.

1. For children observed to have three rolls of fat on the thigh, the Nutritionist may call the child’s physician to request a prescription for skim or 2% milk to be used in place of whole milk.

2. Children under age two who have two or fewer rolls of fat on the thigh are to receive whole milk. Their fat stores will be monitored at clinic visits. Should they develop a third roll of fat, a prescription will be requested as described above.”

It sounds pretty silly and unhelpful, but it was real.

This is especially irritating to the client and the MD when have both agreed that the child is doing very well on 2% or skim milk. So, lets look at the “PMS” of this issue:

1 P = Policy M = Marketing S = Science

Policy: “Only whole milk will only be allowed from the end of the first year of life until age two.”

Marketing is not really an issue/problem with this issue (but it sometimes certainly IS.)

Science:

1. The only difference between whole, 2% and skim milk is in the amount of fat and calories per ounce. Other nutrients are provided in the same amounts.

2. The form of fat in the milk is a very poor source of essential fatty acids, it can be somewhat constipating, and there is no special property of cow’s milk fat (or goat’s milk fat) that promotes brain development … babies just need calories for that. None of the formulas contain milk fat so a formula-fed infant got none in the important first year. Neither did the breastfed baby because Mother’s milk does not contain cow’s milk fat either. So why would it be so important that children between ages 1 and 2 be fed a large percentage of their calories in the form of cow’s milk fat, and why would we insist on it? Answer: I can’t think of one.

3. Babies need adequate calories to grow and to myelinate their brains. Before the WIC Program was established many poor babies did not get enough calories because skim milk was a few cents cheaper than whole milk. The reason for the AAofP recommending whole milk was to try to at least provide enough calories for the baby’s growth and development, and whole milk has twice the calories of skim. Once the WIC Program was established, no infant should be at risk of obtaining inadequate calories for growth and development because of poverty. The original reason for the recommendation is gone.

4. Insisting on using high fat milk in this situation may result in excess caloric intake, and if so it could contribute to obesity, the more common problem these days. However, usually it does NOT result in over consumption of calories, because the baby self –regulates caloric intake. But in that case it would certainly decrease the content of vitamins, minerals and protein in the children’s diets because satiety induced by all those fat calories would cause them to eat less of other foods.

5. However, in the extreme, such as when a child has very low caloric requirements because of being able to move very little, this can cause lots of trouble. Similarly, it can cause real problems if (for example) the child is tube-fed and therefore unable to regulate his/her caloric intake. Additionally, policies that require waiting until a child is demonstrably overweight or obese before allowing a lower fat milk to be used are clearly not in children’s best interests. (See my handout on nutrition for children with special needs for more information.)

Conclusions: In this scenario, it appears that the Science evaluation did not argue against using skim or 2% milk in children ages 1-2. What remains then is to determine if there is a good reason for continuing a Policy of requiring WIC nutritionists to provide only whole milk for children of this age group. If so, this also totally undermines the idea that professional WIC nutritionists are able to evaluate the appropriateness of a child’s nutrition and to act on it. If no good reasons can be proposed for requiring whole milk at this age, then CHANGE THE POLICY to use the form of milk or milk substitute judged to be best by the WIC health care professional who is considering the needs of the individual child in his/her care.

2

2/2011 Sanford Medical Center

Aunt Cathy’s Guide to: Choosing Aunt Cathy Cathy Breedon PhD, RD, CSP, FADA Appropriate Prenatal/Pediatric Nutrition Specialist Clinical Nutrition Specialist Infant Milks and Sanford Medical Center, Dept. of Pediatrics and Clinical Associate Professor of Pediatrics Formulas UND School of Medicine, Fargo, ND

Part 3: Cow’s/Goat’s Milk and Evaporated Milk Formulas as the Primary Feeding Product for Infants.

Cow’s milk and goat’s milk are inappropriate for use as the primary feeding product in place of human milk or commercial formula. They fall outside of the "desirable range" of carbohydrate, protein and fat, and can present problems for some infants.

This is especially true for very young babies or for those who have special health problems. In addition, 2% (low fat) and skim milk provide inadequate calories (about 15 and 11 calories per ounce, respectively), so babies tend to drink even more of these products than they would whole milk, formula or human milk, which all provide about 20 calories per ounce.

Percent of calories from: CHO PRO FAT ______Desirable range: 35 - 65 7 - 16 30 - 55 ______Cow's milk: Whole: 30 20 50

2% : 38 26 36

Skim : 57 40 3

Goat's milk: 27 19 54

Are there any other problems?

At a time when many American infants were being fed skim milk, Fomon et al, (1974) showed that young infants fed skim milk as their major food drank about 1.5 times the amount normally taken, in an effort to get adequate calories. As you can see on the chart above, the amount of protein would be very high, and since so much of the baby's energy would be derived from protein,

1 there would be a large amount of nitrogenous waste produced that must be excreted via the kidney (i.e., a high "Renal Solute Load.")

This has the potential to result in dehydration because of the obligatory loss of water to excrete the waste products. Sometimes the loss of fluid can be more than the baby can afford. In very young infants or in those with special health problems, including those with growth failure, diarrhea, or fluid limits, a high "Renal Solute Load" can be dangerous.

These milks are also less than ideal because they contain up to 8 times as much sodium as is in human milk and formula. If skim milk is used as described above, that can mean a sodium intake of 12 times the amount in human milk, since the baby will drink so much more of it.

In addition, these milks do not provide complete nutrition, because they are poor sources or iron, vitamins C and B-6, copper, zinc and essential fatty acids. Vitamins A and D are also low unless they are added in processing.

Most commercial milk has vitamin D added, but milk obtained directly from a dairy farm or the family barnyard often has none. As a result, severe vitamin D deficiency is not uncommon among many “farm” children, especially in the north [Rickets in the Dairy State. Wisconsin Medical Journal. 2004;103:84-87. 7.]

In addition to these problems, goat's milk (but not cow’s milk) is also naturally too low in folic acid (a B-vitamin especially important during periods of rapid growth because of its role in DNA production), and offers no special advantage over cow's milk. Many commercially canned goat's milks do have folic acid added. Babies who are allergic to cow's milk protein are often allergic to goat's milk, too.

I was involved in the care of an infant whose exclusive (“natural”) diet of raw goat’s milk landed him in the hospital at age 4 months, very near death, with overt scurvy, anemia and neurologic problems from deficiency of folic acid, vitamins C, B6, D, iron, zinc and several other nutrients. Fortunately, emergency treatment saved this baby’s life, but there is no way to determine if there will be any long-term consequences of such severe malnutrition of multiple nutrients during infancy. These are serious issues.

Unpasteurized milks are not recommended due to the risk of bacterial contamination. This includes conditions like listeria, brucellosis and salmonella, to mention just a few. Heat treatment also improves the digestibility of the milk, but the milk fat remains much harder for babies to digest than the fat in human milk or commercial formulas, and it is a poor source of linoleic and alpha-linolenic acid, the essential fatty acids.

Some babies appear to have a sensitivity to unheated cow's milk (but usually not to formula) that causes bleeding from the intestine. The amount of blood loss is often so small as to be unnoticeable in the stool, but it can result in a serious loss of iron. This blood loss, along with the poor iron content of cow's milk and its impairment or iron absorption from other sources, can contribute to the development of anemia.

2 I have seen young children with this kind of “cow’s milk anemia” related to these factors plus a diet pattern that provided too much of the child’s calories in the form of milk/yogurt/cheese, etc., and very little other foods. Interestingly, several children had been identified as anemic, but the solution recommended was just to give a supplement of inorganic iron (e.g. ferrous sulfate.) This is particularly unlikely to be very helpful because:

1) milk impairs absorption of inorganic iron and

2) the basic problem of dietary imbalance is not addressed so multiple other critical (but less likely to be tested for) nutritional inadequacies remain uncorrected. For example, this dietary pattern would also lead to relative inadequacy of zinc and copper, both of which can be very serious inadequacies.

Essential Fatty Acid Deficiency

Of the linoleic acid found in butterfat (the fat in cow’s milk,) it appears that only 50-80% of the total amount is in the form of linoleic acid that is biologically active (Fomon 93), so the values shown on the chart on the next page overestimate the actual amount of linoleic acid available for metabolic uses. This is another clear indication why cow’s milk or goat’s milk should only be used as a part of a child’s diet and certainly not as the main source of calories.

Other forms of fat need to be included in an infant’s diet, as cow’s milk fat alone can actually result in essential fatty acid deficiency. I once observed this situation in a child admitted to the intensive care unit in our hospital with a variety of unusual symptoms. A careful diet assessment revealed that nearly all of his fat intake was in the form of dairy fat. A laboratory measurement of the triene:tetraene ratio then confirmed the suspected EFA deficiency.

Note that the table on the next page addressing the relative inadequacy of linoleic acid (the omega-6 essential fatty acid.) It does not address the additional inadequacy of linolenic acid (the omega-3 essential fatty acid) discussed earlier as being so important for making subsances such as EPA and DHA. Further, most vegetable oils are not well-balanced in the ratio of omega-6 to omega-3 fatty acids. The essential fatty acids in corn oil, for example, are almost all omega-6.

[For additional information on this issue please see “All Those Lipids: Recommendations for Using Different Types of Vegetable Oils (Omega-3, Omega-6 and Monounsaturated Oils.)”]

3 Essential Fatty Acids

______Suggested Intake: (FAO/WHO) and regulation level for formulas is 1.2 % of energy as Linoleic Acid. Goal is to provide 500 mg/day (Foman 93) ______

Linoleic Acid per 100 kcals & Linoleic Acid as a Total PUFAs Total PUFAs as a intake per 18 or 24 oz milk/day Percent of Total Fat mg/oz Percent of Total Fat (Fomon 93) (Worthington Roberts 96) (Pennington: Bowes & Church 94) ______Cow's milk: Whole: 1.12 mg/100 kcals 1% 37 4 18 oz = 4.1 mg 24 oz = 5.4 mg ______2% : 0.92 mg/100 kcals 1% 25 4 18 oz = 2.5 mg 24 oz =3.3 mg ______Skim : 0.02mg/100 kcals 1% 18 oz = 0.04 mg 24 oz =0.05 mg ______

Human milk: 5% 200 14.3

So why do people want to use cow's milk for infants?

Some people have the mistaken notion that unpasteurized cow's milk or goat's milk is somehow more nutritious or "natural" . . . which it is for baby cows and goats. For human infants it is significantly less appropriate than human milk or formula, and as already described, it is potentially dangerous. The major reasons for switching from commercial formula to cow's milk (pasteurized or not) during the first year are cost and convenience factors.

For young infants or those with health problems, this practice should not be encouraged. However, if the infant is at least six months old, is a healthy baby, and is eating the equivalent volume of 2-1/2 to 3 jars of baby food daily, some of the problems with whole cow's milk can be tempered.

For example, by adding three 4-oz servings of cereal, fruit, or vegetables daily, the carbohydrate portion of the diet moves into the acceptable range, and the protein percentage decreases down to the acceptable range. By filling up on other foods, the baby will probably also drink less milk, which will also decrease the protein and sodium intake. If one selects the other foods carefully (including meats and a wide variety of other nutrient-dense foods), some of the other nutritional shortcomings can be remedied as well, such as decreasing the high sodium content and improving the vitamin /mineral content of the diet.

4 Because of the observations about inadequacy noted above, a few years back (about 30, actually) when I was first working for the (brand new) WIC Program, the American Academy of Pediatrics decided that switching from human milk or formula to whole milk would be acceptable after age six months “for babies who were eating a variety of foods.”

However, studies were done that showed that although it is possible to achieve a balanced diet this way, most babies who had been put onto whole milk, in fact did not receive a balanced and appropriate diet. So the recommendation of human milk or formula for the first year of life was re- instituted. The more recent questions about the safety of pasteurized cow's milk products during infancy (e.g. yogurt, cottage cheese and ice cream) as adjunct foods do not represent a major policy change. [Interestingly, during the AAP’s “6-months-is-ok” period, WIC held its ground and continued to provide only iron-fortified formula to non-breastfeeding infants for the entire first year of life. Way to go, WIC!]

One further caution before switching to cow’s milk or goat’s milk is to be sure that the baby regularly eats table foods that contain some (especially omega-3 rich) vegetable oils in order to obtain appropriate levels of essential fatty acids. Most baby foods are extremely low in fat, as are many of the “starter” table foods like fruit, crackers and cereals. Other dairy foods like cheese, butter or yogurt provide only the same limited amount as milk does, even when the total fat content is high.

So, especially when the baby is eating commercial baby foods as a major part of the diet and has switched to milk, extra care must be taken to provide sufficient essential fatty acids. Fortunately, this can be done quite easily when one is aware that it is an issue. Hydrogenated oils like margarine and shortening should not be considered as sources of essential fatty acids because the hydrogenation process significantly decreases the essential fatty acid content of the product. This is in addition to the well-known concerns about partially hydrogenated oils forming trans fat.

What about evaporated milk formula?

Many people have been raised on home-made evaporated milk formula, although it is rarely used today. Its major advantage is its lower cost than commercially made formulas, while being better suited to infants than regular cow's milk. Because it is canned, it has been sterilized and the heat treatment makes the protein more digestible.

Corn syrup or sugar has traditionally been added to adjust the proportion of carbohydrate, protein and fat, as shown below. Water is added to adjust the calories to 20 calories per oz, (the same calories as in human milk, formulas and whole milk). (See the chart on below)

______Percent of calories from: CHO PRO FAT

______Desirable range: 35 - 65 7 - 16 30 - 5

Evaporated Milk Formula made with Corn Syrup: 45 15 40 ______

5 Digestion and absorption are still not as good as is seen with human milk and formula, because the form of fat is more difficult for babies to digest in addition to being a poor source of essential fatty acids. Milk fat can be quite constipating for some children, but the corn syrup usually has an osmotic laxative effect to counter it. (Somehow that arrangement does not sound optimal!)

In the 1980s a concern was raised about the safety of corn syrup for small infants (J. Food Protect. 1989:45,1028.) Some samples were found to contain heat-resistant spores of Clostridia botulinum, a type of bacteria that has been associated with a form of SIDS (Sudden Infant Death Syndrome). It was estimated that about 5% of SIDS cases at that time may have been due to "infant botulism" linked to the use of corn syrup or honey in young infants.

For this reason it was suggested that when this type of formula is used, the corn syrup or honey should be replaced by table sugar. Since then, manufacturing techniques have improved and corn syrup no longer is regarded as a risk factor for developing infant botulism (J Food Protect. 1991), although honey should continue to be avoided in the first year of life. [Note: Honey baked into foods like graham crackers is safe because the high temperature of preparation kills the spores. This question still comes up often.]

Human milk or commercial infant formulas are still preferred over evaporated milk formula because of their more complete nutrition and better digestibility. As with any cow's milk product, evaporated milk formula is naturally low in iron, copper, selenium, zinc, essential fatty acids, and vitamins C and B-6. Vitamins A and D are usually added, but might not be. This product should be of historical interest only. It belongs to what I call the “This is white … just feed it to ‘em School of Nutrition”

Because of the great potential for nutrient inadequacy, a registered dietitian or physician who is knowledgeable about these issues should look carefully at a baby's whole feeding plan to assess its adequacy. A supplement should be recommended if other foods are not providing these missing nutrients. However, my experience has been that nobody looks at this issue at all, so careful nutrient supplementation in this situation is theoretically possible but practically non-existent. And, as the babies do not “look funny” their deficiency state usually remains unrecognized.

And finally, I found on the internet a blog from a woman who has discovered the joys of making one’s own evaporated milk infant formula. The main benefit she cited was that it was much cheaper than regular formula. [But not as cheap as breastfeeding! ☺] The best part: she is quite comfortable about using it for her baby because she has “talked to some people over fifty and they seem to be OK.”

As it happens, I was fed evaporated milk formula with corn syrup in 1950 and I lived to tell about it. But in those days we were not fed that product exclusively … we were also fed iron- fortified cereal practically before we left the hospital, and right away we were regularly fed egg yolks and liver as well. The yolks were also given “for iron,” since then (as now) that was about the only nutrient ever evaluated so anemia was actually sometimes recognized as a problem. But it turns out that the iron was not wonderfully absorbable from either the cereal or the yolks.

6 In retrospect, the yolks turned out to have lots of other good things we didn’t even know existed, like choline. Choline is looking like a very important nutrient for brain function (as in the neurotransmitter “acetylcholine”) and providing some ready-made choline to babies looks like a very good idea. Pre- and Postnatal Health: Evidence of Increased Choline Needs. JADA August 2010)

And thank heaven for that liver, which provided actually absorbable iron and zinc, plus lots of choline and vitamins A and D and many other nutrients!

Using the classical (translation: “old”) evaporated milk formula with today’s typical feeding patterns (e.g. waiting to introduce other foods until 4-6 months) has the potential to do significant harm to that baby.

And even if some of us over-fifty people are actually “OK,” it is really quite foolish to trust that precious baby’s health and development to our scientific knowledge base of 60 years ago. We old folks didn’t have seat belts either and we’re still here. Well … at least, SOME of us are!

7

2/2011 Sanford Medical Center

Aunt Cathy’s Guide to: Choosing Aunt Cathy Cathy Breedon PhD, RD, CSP, FADA Appropriate Prenatal/Pediatric Nutrition Specialist Clinical Nutrition Specialist Infant Milks and Sanford Medical Center, Dept. of Pediatrics and Clinical Associate Professor of Pediatrics Formulas UND School of Medicine, Fargo, ND

Part 4: Thinking about When to Recommend Whole Milk, Low Fat (2%) Milk or Skim Milk before Age Two

A. What percent of calories is provided by fat in each type of milk?

At a time when many American infants were often being fed skim milk, Fomon et al, (1974) showed that young infants fed skim milk as their major food drank about 1.5 times the amount normally taken, in an effort to get adequate calories. This was a concern for several reasons:

1. The amount of protein would be very high because skim milk provides 40% of calories as protein. This is much more than in whole milk (20%) or human milk (7%.) Because so much of the baby's energy would be derived from protein, there would be a large amount of nitrogenous waste produced that must be excreted via the kidney (i.e., it would contribute to a high "Renal Solute Load").

In the first months of life, this can result in dehydration because of the obligatory loss of water to excrete the waste products; sometimes the loss of fluid can be more than the baby can afford. In very young infants or in those with special health problems, including those with growth failure, diarrhea, or fluid limits, a high "Renal Solute Load" can be dangerous. It becomes much less of an issue in an older baby or child who is growing normally.

2. The volume of milk required to achieve a particular caloric intake is about twice as much for skim milk compared with whole milk or human milk. Some children, as noted above, simply could not take in enough volume to maintain appropriate fat stores and to grow. I call that problem “Tiny Tummy Syndrome.” However, they will try hard to take in the calories they need and so they do increase the volume of milk, resulting in an even higher net protein intake provided in inadequate calories.

1 3. The essential fatty acid content of cow’s milk was discussed earlier in the infany feeding section and there is a chart there of EFA levels indifferent types of cow’s milk. The same applies here. The major point is that NONE of these milks (skim, 2% or whole) have much in the way of essential fatty acids, so it is not a reason to insist on whole milk for a child.

What About after One Year? Whole? 2%? Skim?

After one year, whole cow's milk has been recommended for most children until age two. This recommendation is being seriously reconsidered at this time. Lower fat milks can also be appropriate based on a particular child’s caloric requirements and the presence of other sources of fat in the diet. A complete review of this topic is beyond the scope of this paper, but it is useful to note that the global “whole-milk-to-age-two” concept is a public health guideline, and it is not intended to tie the hands of qualified health care professionals who determine that an individual child would be better served by using 2% or even skim milk. As shown later, there are no magic qualities of cow’s milk fat that make it an essential component of a child’s diet.

Consider that the breast-fed baby receives no cow’s milk fat at all, nor does the formula-fed baby because the fat is replaced by vegetable oils. So why, at age one, would a child suddenly “need” milk fat? And unlike human milk, infant formulas provide no cholesterol (the precursor to myelin) at all. Interestingly, the milk fat is not the baby’s primary source of cholesterol, so skim milk is not very different in regard to pre-formed cholesterol content than whole milk. (See chart on the next page.)

As noted earlier, cow’s milk fat is a poor source of essential fatty acids, including those leading to production of DHA, a major fat involved in brain development. It is no more beneficial to the myelinization of a child’s brain than any other source of acetate (the 2-carbon unit that is the substance from which cholesterol and then myelin are produced.) Acetate can be made from any calorie source … carbohydrate, protein or fat. Interestingly, the reason I am given most often by health professionals for insisting on whole milk for a toddler is because “he needs it for brain development.” Unfortunately, all that milk fat only provides a lot of calories and not the truly and directly brain-building components DHA or cholesterol.

It is useful to consider that children have a growth schedule to keep, and if for some reason calories are inadequate, the child will burn fat stores to continue to grow in length and continue brain-building operations. If calories remain inadequate, linear growth will next be compromised and available energy will be preferentially used for brain-building. What this means is a child with inadequate calories will not have to make a judgment like “Gosh! I just can’t decide! Should I make a brain or a fat bottom?”

Anyway, it means that one could conclude that a child of appropriate/normal weight and apparent fat stores would have adequate calories for brain-building. When I see a little “Three-Roller” toddler (related to the number of rolls of fat on thighs) in my office, I do not worry that he would be at risk of getting inadequate calories “for his brain” if I switch him to skim milk from whole.

2 Consideration of these issues can allow for safe and intelligent departures from the “whole milk until two” recommendations, even as we wait for official changes to come from professional associations.

This is especially true when insisting on feeding a high fat milk is contrary to the child’s best interests, as is often the case with children with handicaps that decrease mobility, or overweight children whose caloric intake is clearly already generous.

The negative effect of whole milk on the overall nutritional quality of the diet

Many American toddlers are already consuming a generous amount of calories as fat from other food sources. The use of whole milk also actually decreases the amount of other foods that a child with a normal appetite would consume. If our model is that healthy infants will control their intake of calories to match their caloric requirements (and it is,) then feeding a diet that is higher in calorie-to-nutrient ratio would certainly decrease the over-all nutrient content.

Here is a simple example:

The calories in 4 oz whole milk is equal to the calories in 4 oz skim milk + 4 oz strained carrots.

They provide the same calories. Which provides more nutrients?

Insisting on using a high fat milk with a chubby toddler is generally not in his/her best interest. One consideration might be whether this would encourage excessive caloric intake, but the more likely response of an otherwise healthy child is that he/she will simply eat less food in general to obtain the appropriate (lower) number of calories, so the nutrient:calorie ratio of the diet will decline.

This is especially non-helpful if the parent tells you that the child’s usual diet features foods already high in fat like macaroni and cheese, french fries, potato chips, butter, gravy, peanut butter and hot dogs [I know … there is a choking issue with these last two especially that is very real. But the fact is, in real life many babies and toddlers are commonly fed these foods: “I give it to him because he really likes it.”]

3 If the rest of the child’s diet is described as above, it is already a very generous source of fat. It would be hard to come up with a logical reason why one would want to increase it further by insisting that the baby use whole milk simply because he/she is “not yet two.”

Is there a risk of essential fatty acid deficiency if we give skim milk before age two instead of whole milk? No, for these reasons:

1. There is the same risk of EFA deficiency whether one uses whole, 2% or skim milk because, as shown earlier, none of these milks is a good source of essential fatty acids.

2. For “normal, healthy children” who were either breastfed or fed commercial formulas for the first year, both feeding products provided generous EFAs and the child’s fat stores would therefore contain generous amounts. This assumes that the child has reasonably appropriate “normal healthy” fat stores upon visual inspection; an emaciated child would of course be at greater risk of EFA deficiency … but that child is not a member of the “normal, health children” group and a lot of rules will be different.

3. Ironically, an example of the primary exception to the assumption of good EFA stores in a child with reasonable fat stores would be one who was switched to milk (whole, 2% or skim) at age 6 months or so of age. That child will have had 6 months of EFA-free milk, so his/her fat stores are less trustworthy in this regard. In terms of stored EFA fat at least, we ARE what we eat!

There is also an historical perspective to consider:

When the “whole milk until age two” recommendation was established, there was no WIC Program, and many poor children actually got too few calories to grow and develop well.

Skim milk costs a few cents less per gallon, so the poorest families chose it. The AAP “whole milk” recommendation was an attempt at that time to remedy that situation to at least improve the adequacy of calories during this important period of brain development. That is ALL it addressed.

The WIC Program was established in the late 1970s to encourage breast-feeding by giving food to low-income nursing mothers, and by funding replacement of cow’s milk (of any kind) for non-nursing infants with far more nutritious commercial formula. This particular poverty-related health problem has long ago disappeared … no poor babies in America have to be fed skim milk

4 because of financial need. But the whole milk recommendation remains with us in spite of considerable evidence that it is really not ideal, and sometimes frankly suboptimal. It takes a long time for official positions to be changed.

The protein and micronutrient content of skim, 2% and whole milk is quite comparable. Vitamins A and D are equally fortified in all three. The only real difference is the calorie content:

Per 8 fluid oz Protein Calories Cholesterol Calcium Phosphorus Vit. D Vit. A Vit. B2 Potassium (g) (Kcals) (mg) (mg) (mg) (iu) (iu) (mg) (mg)

Skim milk 8.4 86 4 300 300 100 500 0.3 406

2% Low Fat milk 8.1 121 18 297 232 100 500 0.2 399

Whole milk 8.2 159 33 291 228 100 500 0.4 370

(data from Pennington, J. Bowes & Church’s Food Values of Portions Commonly Used 16th Ed. )

Interpretation of the chart above:

The difference in the cholesterol content is not a very significant, especially as we know that infants fed formula instead of mother’s milk receive no pre-formed cholesterol at all for the first year. This means that infants apparently can make their own cholesterol to myelinate their brains and for normal formation of cell membranes. The exceptions are those with a rare metabolic defect called Smith-Lemli-Opitz Syndrome which interferes with the ability to make cholesterol.

The protein and micronutrient differences are also not significant.

The difference in calories is significant:

A teaspoon pat of butter has about 36 kcals. The difference between skim and 2% milk is 35 kcals. The difference between 2% and whole milk is 38 kcals.

So, one could picture their relative caloric and fat value as follows: Skim milk = 8 oz Skim Milk 2% milk = 8 oz skim milk with a pat of butter floating in it. Whole milk = 8 oz skim milk with 2 pats of butter floating in it.

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Comparison of Skim Milk, 2% Low Fat Milk and Whole Milk

Today in the USA, the situation is quite different from the situation in the early 1970s described above. Because of programs like WIC, more babies are being breastfed, and no non- breastfed baby has to use skim milk instead of formula to save a few pennies and in the process receive only half the calories per oz.

It is also interesting to note that there is a priority system among the body’s tissues, and a child’s calories will be preferentially used for brain development at the potential cost to other tissues. Therefore, if a child has normal-to-generous fat stores on board one can assume that calories, at least, are sufficient for brain development. [Think of it this way: A toddler who takes in too few calories to meet all of his/her needs will NOT choose to have “thunder thighs”(also called “two-rollers”) instead of a well-made brain.] The misunderstanding of this situation often leads to inappropriate use of high fat milk out of concern “for his brain.”

See “Aunt Cathy’s PMS System of Baby Formula Decision-Making” on the next page for a quick example of problem solving that uses the “Whole-2%-or-Skim” issue as an example.

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Aunt Cathy’s Guide for Problem Solving:

How Much Should Cathy Breedon, PhD, RD, CSP, FADA This Baby Eat? Perinatal/Pediatric Nutrition Specialist MeritCare Medical Center and Clinical Associate Professor of Pediatrics Troubleshooting in the Front Lines UND School of Medicine, Fargo, ND

It is well known that healthy, typically developing infants will tend to take the amount of breast milk, formula and/or food needed to meet their energy (calorie) needs. When lower energy foods are provided, these babies increase their intake; when higher energy foods are provided, they will eat less. Of course, this depends on a few major factors:

1. The food must not be SO LOW in energy that the baby cannot possibly eat the volume of food required to get enough, or SO HIGH in energy that the amount needed to quench thirst carries with it exorbitant calories.

2. The feeder must make the food easily accessible to the baby.

3. The feeder must not coax, prod or force baby to take more than the amount needed to meet hunger needs, or fail to feed enough in an effort to prevent having a “fat baby.”

4. The baby must be able to eat, to keep the food down, and to digest and absorb it adequately.

This article will provide some tools for judging the adequacy and appropriateness of an infant’s or child’s intake, including checklists to aid in the detective work needed to identify the reason for a particular growth pattern or reported intake. While these tools can be useful in working with healthy infants and children, they can be especially helpful in evaluating the nutritional status of those children with special health care needs and for identifying appropriate nutrition interventions.

A registered dietitian (RD) can evaluate in detail a child’s intake by working together with the primary care provider (PCP), nurse or other health care professionals. Some RDs are also board certified as pediatric nutrition specialists. They will have the credential CSP after their names in addition to the letters RD.

GUIDLEINES FOR EVALUATING AN INFANT’S INTAKE

Caregivers are often concerned about finding the magic number of ounces or spoons of food that a baby “should” take. Once a mother’s milk supply is established, a breast-fed baby has much more control over the amount of food taken than a formula fed infant. The breast-fed infant’s mother

cannot see how much is taken and how much is left. Bottle feeding tends to encourage “empty bottle syndrome”: making baby take every last drop or bite whether it’s needed or not. (“Come on, Baby….finish this stuff! It’s too expensive to waste!”) This can teach a child to ignore internal hunger cues and it also teaches that the best way to make Mom and Dad happy is to eat everything in sight!

This sort of learning may contribute to later obesity, as suggested by studies assessing the effects of internal and external clues for eating among normal weight and overweight adults. In some studies it was found that overweight individuals tended to eat more in response to external cues to eat (the sight of food, the time of day when one usually eats) rather than in response to an actual sensation of hunger. Breast-feeding as well as bottle-feeding could contribute to this same pattern if one uses feeding as a pacifier and cure for all upsets and discomforts.

Many of us have learned to use food as a therapy for stress, depression, boredom or nervousness. These eating patterns can contribute to weight problems because we are not eating in response to a physical hunger stimulus, but to meet a psychological need.

If a baby is growing appropriately we do not need to be so over-concerned about the amounts an individual infant consumes. Since each baby has his/her own pattern and rate of growth, periods of growth spurts and variable activity levels, it is reasonable to try to let healthy babies set their own energy intake on a daily basis.

For example: a record of normal intakes at 6 months of age indicated that the average intake was 37 oz/day of formula or milk, with an additional 9% of calories coming from other foods.1 However, the range of normal intakes (between the 10th and 90th percentiles) at this age was 30 to 50 oz per day. There is no reason to suppose that an individual 6 month old infant should take the “average” amount of formula, especially when the amount of other food eaten by the baby could be far less or far greater than 9% of calories.

There is also no pressing scientific reason behind the “rule” that a baby should never be given more than a quart (32 ounces) of formula a day. This non-helpful guideline probably evolved from four factors:

1. By the time most babies drink a quart of formula daily they have reached a developmental age when it is appropriate to begin to take solids. That is, the baby is usually 4-6 months old, so the rule is a good reminder to begin introducing other foods.

2. A quart (32 oz) of formula provides the RDA for vitamins, minerals and protein, so healthy babies do not need to take more than that volume to meet those guidelines. At this point, if developmentally ready, infants can very safely work on learning to eat other foods. The nutrient balance of baby’s sometimes unpredictable beginning food choices will not be a problem.

3. Because a quart of formula does provide for adequate levels of vitamins, minerals and protein, and since formula can be quite expensive, it is financially reasonable to use no more than 32 ounces of formula each day and provide the additional energy baby needs as other foods.

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4. Some confusion on this point has also arisen from the fact that the WIC Program (Special Supplemental Food Program for Women, Infants and Children) provides formula for infants in an amount each month that makes about 26 ounces per day (one can of formula concentrate per day, or a similar amount mixed from formula powder.) People sometimes fail to realize that WIC is a supplemental food program, not a program that purports to meet all of the nutritional needs of its clients.

When infants reach a size when 26 ounces of formula no longer meets their needs, their caregivers are expected to either purchase some additional formula or, if age-appropriate, other foods can be offered to the baby. This WIC program limit of formula provided is based on funding limitations. It is not intended to be used as the upper limit of formula an infant may safely or appropriately take.

So, although the commonly heard “32 ounce limit” of formula daily may be a useful guide, it is certainly not a Rule. Consuming over 32 ounces is not harmful or dangerous. Many infants regularly take over 32 oz/day without any problems. As long as the child is growing appropriately and being given opportunities to acquire developmentally appropriate eating skills, a formula intake above 32 oz/day is of no concern.

However, the quantity of human milk or formula consumed can be a limiting factor in the nutrient quality of an infant’s diet even if the baby’s energy needs are being appropriately met. Babies who are healthy, growing normally and taking the great majority of their nutrition as a nutritionally complete or near-complete product (e.g. human milk or commercial formula) will likely be obtaining the right amount of food and individual nutrients. [Vitamin D needs closer attention, of course.] With the introduction of other foods however, the complete nutrition product will begin to be displaced. This is reflected in the average milk or formula intake at age eleven months dropping to 18-24 oz/day from the peak intake at around 6-7 months of age. Additionally, the content of iron, zinc and vitamin B6 decreases markedly in human milk after 6 months.

The nutrient quality of the diet then becomes more dependent on the particular foods offered and consumed. Many infants are fed an appropriate amount of a variety of foods, but it is at this point that a more careful look at diet proportions is warranted. For example, it is sometimes erroneously assumed that the baby’s diet will be balanced as long as formula or human milk is provided, even when the volume consumed is extremely low.

A quick-and-easy estimate of the “typicalness” of a formula intake volume for screening healthy infants:

Multiply the ounces taken in by 20 kcal/oz (this assumes the formula is prepared following the usual directions ) and divide by the infant’s weight.

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In the first year of life, an intake of about 90-120 kcal/kg (kilocalories per kilogram of body weight) which is the same as 41-50 kcal/lb (kilocalories per pound of body weight) is typical, with the numbers in the higher end of the range mort often seen in the first half of the year. In the past, 100-120 kcal/kg (45-50 kcal/lb) have been used as guidelines, but more recently it was found that many infants will grow normally and thrive on the smaller caloric intake levels as well.2

The key of energy (caloric) adequacy will always be :

Look at the baby’s growth, especially weight for length (weight/length) ratio and apparent body fat stores.

If other food sources are included in the infant’s diet, you can easily calculate the energy contribution of baby foods using the tables of average values from manufacturers’ product information or food nutrient tables. New labeling laws also make this much easier than in the past. Additionally, a simplified system like the old diabetic exchange system can be used for table foods.

Calculating the energy intake and then comparing it with the “typical” range is a useful screening tool to help identify problems not immediately apparent. Values above or below this range, even in apparently healthy infants, certainly warrant a closer look since they may be indicators of certain problems. However, the typical range is not be to used as a feeding rule that a particular child must conform to on a regular basis.

This method to interpret the appropriateness of a baby’s energy intake for its weight assumes that the baby is of fairly normal weight for age and length. Remember that very thin or very chubby babies will not play by the same rules because their unusual weight for length and age significantly changes the denominator in the ratio:

• Very thin babies will appear to have a more generous caloric intake than they actually do.

• Conversely, a high caloric intake in a chubby baby may appear to be within the usual range because there are so many pounds or kilograms to spread the calories over.

To correct for this effect, it can be helpful to recalculate kcal/kg or kcal/lb using the average weight for a child of the baby’s length.

(See Case Studies 1 and 2 for examples.)

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TROUBLESHOOTING ON THE FRONT LINES

Looking for Explanations when Unusual Intake Patterns are Reported

Note: All of the case studies and scenarios presented here have come from actual experiences with babies for whom these questions and considerations detected the real cause of inappropriate growth.

Things to Consider in Assessing All Intake Records:

1. How accurate is the intake record?

Is the person describing the intake:

ƒ Providing first-hand information (e.g. is baby fed by others part of the day?)

ƒ Guessing?

ƒ Clear about arithmetic and the actual size of the bottle or cup used? ƒ Remembering to count night feedings, all beverages and all snacks?

ƒ Able to accurately describe formula preparation?

2. How typical is the intake record?

ƒ Is the record from the weekend at home but baby is fed at a sitter’s house five days a week?

ƒ Is the child ill or just now recovered from an illness and weight loss?

3. Check that the total day’s intake volume reported is consistent with estimates obtained through other approaches.

For example, compare a reported estimate of total ounces of formula consumed per day with both the number of ounces prepared daily and the sum obtained when asking the caregiver to go through a typical day describing each feeding.

In addition you may ask the number of cans of concentrate used in a day or how many days one can of powdered formula feeds the baby. This type of cross-checking will pick up errors like missed night feedings, and it can clarify complex situations like Case Study 3 (a very thin infant who was reported to take a lot of formula but who never seemed to be satisfied.)

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Things to Consider in Assessing Specific Patterns of Unusual Intake:

Figure 1 below describes four scenarios that often are seen when evaluating the intake of infants. Explanations of each of four scenarios follows the figure.

Authors Note: I often use the term “fluffy” instead of obese when discussing a child with caregivers because it is less judgmental. Our society equates generous adiposity with many negative personal qualities. In order to optimize the therapeutic relationship it is important for the family to know that I care about and like their child. Although this term is not scientific or technical, I find that it works well for me and my clients, and it fits my Aunt Cathy patient-care style.

Figure 1:

Four scenarios to consider when the reported intake seems to be at odds with the baby’s appearance

Infant Reported Intake Appearance High Low 1 3 Thin 2 4 Fluffy

SCENARIO 1:

A very high reported intake, especially for a slim or normally proportioned baby

BABY Problems to Consider

• Is baby experiencing any malabsorption? Ask about stool patterns.

• Is baby vomiting excessively or does the baby have reflux?

Ask about the frequency, forcefulness and volume. Note that volume of vomitus is often overestimated even by health professionals. To better estimate amounts lost, one can pour a small amount of water on a table surface or cloth and ask the caregiver to compare it with the reported volume. (“Is it about this much?”) It is surprising how a small amount can appear to be quite a lot.

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If vomiting is reported to be significant, has pyloric stenosis or gastroesophageal reflux (GER) been ruled out by the physician? In infants reflux can be related to immaturity of the lower esophageal sphincter.

• Does baby vomit consistently or only under certain circumstances, such as:

ƒ Only when left alone after a feeding, as has been reported in cases of rumination associated with nonorganic failure to thrive.

ƒ Only when made to intake more than a certain volume.

ƒ Only when fed certain foods or when certain water is used to prepare formula.

ƒ Only when fed in an “infant seat.”

ƒ Only when a certain person is the feeder.

• Is the baby much more physically active, irritable and/or jittery than usual?

• Is baby “hypermetabolic”?

Higher metabolic rates are sometimes seen when babies are working hard to breath, born small for gestational age, fighting infections, trying to achieve catch-up growth, recovering from an acute illness and sometimes when they have been exposed to significant mounts of alcohol or other drugs in utero.

• Is the baby adequately oxygenated?

Progressing to a state of health in which extra oxygen is no longer needed is seen as highly desirable by caregivers both as a significant marker of progress for the baby and because it makes infant care and transportation much easier. For this reason, there can be a tendency for families and health care professionals to want to get the baby off oxygen as soon as possible.

However, sometimes adequate food intake and growth are only able to be achieved because of assisted oxygenation. Prematurely removing oxygen support can result in a baby having to use so much energy to breathe that growth is impaired. Also, exhaustion from the excessive breathing effort can make a baby stop eating before nutritional needs are met.

Providing oxygen when it is needed assures that the child does not have to choose between eating and breathing. Helping all concerned understand these concepts is very important.

CAREGIVER Problems to Consider

• Is the formula mixed incorrectly?

If too much water is added, baby must drink a very large volume to try to get enough calories. He/she mail fail to get enough to maintain appropriate weight for length.

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SCENARIO 2:

A very high reported intake, especially “fluffy” baby

BABY Problems to Consider

• Is baby truly fluffy (having a very high weight/length ratio) or just large for age (weight/length ratio normal)?

If the weight/length ratio is within normal limits then the baby likely is managing his/her own intake appropriately. Do not attempt to make baby take less to match some average intake for age.

• If baby is truly fluffy and also consuming a very high caloric intake, is he able to sense satiety normally?

Some children with brain injury (such as congenital hydrocephalus) can experience problems with this even as infants. Other children (such as those with Prader-Willi Syndrome) are more likely to experience this problem later in childhood.

CAREGIVER Problems to Consider

• Is food being used as a pacifier?

• Does the caregiver understand that babies often cry for reasons other than hunger?

• Does the caregiver believe that baby needs to take in a particular amount regardless of appetite?

• Is there pressure from family members or other to:

ƒ Keep that kid quiet!

ƒ Put some meat on his bones!

ƒ Giver her a lot of food or formula to make her sleep through the night!

• Is formula being prepared correctly?

Failure to add enough water to the formula can contribute to dehydration. Babies may be forced by thirst to take more formula than they are hungry for (calorically,) creating a vicious cycle.

• Is baby being kept too warm and sweating a lot, leading to taking extra formula in an effort to meet fluid needs?

If so, and if the heat situation cannot be adjusted, give guidelines for a reasonable formula intake and provide additional water in some form as appropriate.

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SCENARIO 3:

A low reported intake, especially for a slim or normally-proportioned baby

BABY Problems to Consider

• Is the baby much more physically active, irritable and/or jittery than usual?

Does this behavior use up energy quickly and also interfere with baby’s ability to eat because of distractibility or exhaustion?

• Is the baby hypermetabolic?

Higher metabolic rates are sometimes seen when babies are working hard to breathe. Some babies in this situation are those with heart or lung conditions. Some were born small for gestational age and they may be trying to achieve catch-up growth.

Babies fighting infections, or recovering from an acute illness may fall into this category. Sometimes babies who have been exposed to significant amounts of alcohol or other drugs in utero will have this problem.

• Is baby adequately oxygenated?

(See Scenario 1)

• Is there anything physically interfering with the baby’s ability to suck and swallow adequately?

Poor lip closure, structural tongue or lip problems, and poor coordination of sucking, swallowing and breathing can all interfere with getting enough in. They can make feeding very time consuming and also quite unpleasant for the baby. Evaluation and recommendations by a pediatric speech therapist or occupational therapist can be very helpful in this situation.

• Is tummy capacity adequate?

If a higher caloric density feeding were used, would the baby continue to take the same volume or would he/she decrease intake to maintain the same caloric level?

How long does baby take to finish a feeding?

How often does baby eat?

Does baby seem to experience early satiety?

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• Does the baby perceive hunger?

Can baby communicate hunger adequately?

Does baby ever cry to be fed or does the caregiver have to initiate the feedings?

Is baby taking any medications that can suppress appetite or cause gastrointestinal distress or drowsiness?

CAREGIVER Problems to Consider

• Can the caregiver recognize baby’s signals that he/she wants to eat?

• Does the caretaker have realistic expectations about baby’s feeding abilities and needs?

• Does the feeder stop feeding too soon, when baby is only catching his/her breath?

• Does the feeder engage the baby during feeding? Is there eye contact and cuddling?

• Are the feeding utensils appropriate?

For example, is the type of nipple appropriate and the nipple hole the right size so baby does not become exhausted or frustrated, or choke when eating?

• Does the feeder have an eating disorder?

Does the caretaker eat regularly? Does he/she have extreme views about fitness or about not wanting to have a fat baby?

• Is the caregiver very young and/or inexperienced in basic baby care?

• Are there other children to care for, or other obligations? Who actually feeds this baby?

• Is the caregiver afraid that frequent feeding or cuddling with “spoil” the baby?

• Does the caregiver think that snacking between meals is bad and so feeds baby only three times a day?

• Is the feeder engaged in a “Food War,” -- a battle of wills -- with an infant that has resulted in disordered eating (e.g. near total food refusal) on the part of the infant?

• Is being fed unpleasant for the baby?

A history of having been intubated or forcibly fed can cause a baby to associate oral eating with unpleasant experiences. Children who have experienced only minimal oral feeding because of

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health problems can also find the introduction of an oral feeding regimen to be quite unpleasant and frightening. Those with some degree of dysphagia (“unsafe swallowers”) may experience oral food intake as a terrifying exercise in trying not to choke and aspirate food into the lungs.

Some babies and children are extremely sensitive to certain textures and oral sensations. Some have a “hypersensitive gag reflex.” Again, the RD can assist the family as they talk with the PCP to consider a feeding evaluation by a Pediatric Occupational Therapist and/or Speech Therapist. Many of them have special programs and experience in overcoming this type of feeding aversion.

SCENARIO 4:

Low reported intake, especially for a very fluffy baby

BABY Problems To Consider

• Is baby hypotonic or less active than usual?

A baby with low energy requirements will often take less formula than average because of decreased hunger, especially when fat stores are quite generous. But even so, baby may still get more calories than are required because of the drive to meet fluid needs. Sometimes only high calorie fluids are available.

Baby may also be coaxed or forced to take more than he/she would choose because caregivers are concerned about an unusually low intake volume. Chubby children with Down Syndrome or certain types of nerve and/or muscle diseases can sometimes present this way

Tube-fed children with minimal energy expenditure are especially vulnerable to overfeeding when caregivers or health professions set goals based on the usual caloric intake levels observed for the “average” baby’s age, activity/movement or size. Weight gain goals can sometimes be set at levels that are that are inappropriate when baby’s body composition is atypical.

CAREGIVER Problems to Consider

• Is the formula mixed incorrectly?

As noted above, if too little water is added, baby may appear to be taking a relatively low volume of formula but he/she actually may be getting quite a lot of calories.

• Is baby receiving substantial amounts of corn syrup (60 kcal/oz) for constipation problems?

• Is a lot of cereal or other thickener added to the formula in an attempt to prevent spitting up or gastroesophageal reflux, or because of dysphagia concerns?

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The caloric contribution of thickeners and corn syrup can be substantial: infant cereals are 9 kcals per level teaspoon, and corn syrup contributes 10 kcals per teaspoon. These additives can also seriously alter the ratios of carbohydrate and/or fat to protein, sometimes leading to a relative inadequacy of protein. The micronutrient content of the diet is also quite likely to be disturbed unless carefully assessed and adjusted.

CASE STUDY 1:

A “fluffy” baby with a reported intake in the typical kcal/kg range

DATA: At age 3 months, LS is a very fluffy-looking baby. He weighs 6.6 kg (14 lb 8 oz) and is 57 cm long (22.5 in). His weight/length is above the 95th percentile.

He takes about 760 kcal daily, all from formula, which is 115 kcal/kg, and well within the normal range for his age.

Question: Why is he gaining weight at an excessive rate on this apparently normal intake?

ANSWER: Since his weight/length ratio is not in the normal range; the Rule-of-Thumb kcal/kg range will not apply directly. It assumes a normal distribution of lean body mass and fat stores.

Children with a disproportionately high amount of fat relative to lean body mass will need fewer Kcal/kg than average to support themselves. This is because lean body mass is the most metabolically active tissue, and the caloric requirements to maintain fat stores are much lower.

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One can use this alternate calculation to get a sense of the energy needed to support his (tentatively presumed to be normal “non-fat” tissues) plus a more typical amount of fat stores for age.

1. On the weight/length NCHS growth chart above find L.S.’s length along the bottom of the page. Follow a straight line upward at that point until it intersects the 50th percentile. Then go to the side to find the average weight for children of that length.

The average weight for this length is ______(a).

2. Recalculate the kcal/kg (kcal/lb) using this weight as the denominator. Is the intake still in the typical range? Depending on the situation, it may or may not be. This calculation can provide a clue to help you assess the situation correctly.

760 kcals= kcal/kg average wt for length (a)

For example, if the intake is now above the usual range, it may be that the child has normal caloric requirements and he is “fluffy” due to higher than usual caloric intake. In this case continue your assessment using Scenario 2.

However, if his recalculated intake is still in the typical range, it may be a clue that the child has lower than normal caloric requirements. This may occur with children who are hypotonic (who have low musle tone,)those who move less than usual for any reason and in certain forms of muscle disease. In this case, continue your assessment using Scenario 4.

Which scenario is suggested by L.S.’s history? (answers on page 16)

If a lower weight/length is desirable (e.g. for a child whose condition results in decreased physical activity or decreased lean body mass, such as spine bifida or certain neuro-muscular conditions), pick a percentile that would decrease the risk of overfeeding and of inducing what could be very debilitating “over-fatness.” These children can be quite overfat but not look especially overweight on the charts. Depending on the child’s degree of mobility or muscular impairment, a weight-to-length ratio between the 10th to 25th percentile may actually be optimal for continued independence. Use that weight to calculate the caloric intake goal.

[Please see my handout “Why Are Children With Chronic Illnesses or Handicapping Conditions at High Risk of Receiving Suboptimal Nutrition?” for more specific information.]

As always, it is critical to:

• follow each child’s individual growth pattern since all of these Rules-of-Thumb are just starting guesses. Assessment of body fat stores is an important adjunct for children with unusual body composition, in order to assure that fat stores are not depleted or excessive. This may be an “official” assessment – using a caliper and following skinfold thickness – or sometimes just an

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educated eye and a “finger pinch” can be just as helpful. Many neurologically-affected children can have a slim appearance but actually have adequate-to-generous fat stores. In such cases, it is not in their best interests to push for a somewhat arbitrary weight gain that would only make it harder for them to move themselves or to be cared for my others.

• assess the adequacy of protein, vitamins, minerals and fluid especially when low caloric requirements result in decreased total food intake or when certain food groups must be eliminated due to allergies or texture problems.

• consider the potential for altered nutrient requirements. These may accompany a particular medical condition or therapeutic regimen such as drug nutrient interactions, nutrient malabsorption or excessive losses.

CASE STUDY 2:

A very thin baby with an intake in the typical kcal/kg range.

DATA: at 7 kg and 72 cm (15 lb 6 oz; 28.3 in), AG is quite thin. Her weight-to-length is below the 5th percentile and yet she appears to take 100 kcal/kg (45.5 kcal/lb), which is a typical intake.

Why does she fail to gain well on what appears to be a normal intake?

ANSWER: As with L.S., this baby has an unusual body composition that makes the Rule-of-Thumb not apply. She is virtually all lean body mass (with minimal fat,) so her metabolic rate for her length is higher than would be expected.

1. Use the alternate calculation: Find the average weight for her length. The average weight for this length is ______(a). (See Figure 3 on the next page.)

2. Recalculate kcal/kg (or kcal/lb) using this weight as the denominator.

700 kcals = ______kcals/kg (a)

Is the intake still in the typical range? If it is, this would be a clue that something else is getting in her way, so continue your assessment using Scenario 1.

If the intake now looks low, it appears that something is preventing her from taking enough volume to meet her needs, so continue your assessment using Scenario 3.

Which Scenario is suggested by A.G.’s history? (answers on page 16) ------

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This alternate calculation can also assist in setting intake goals for children with special medical or physical problems when it is clinically appropriate to do so.

Example: In Case Study 2, if this child’s nutrition care plan established a caloric and protein intake based on her actual weight, she would continue to be underfed. Instead, choose a weight denominator (using the weight/length ratio on the NCHS growth chart) that is more desirable.

If an average weight/length is desirable (e.g. for a child with nutritional needs in the typical range, but whose intake is controlled by others because all feedings are via a tube), base the energy and protein recommendations on an average weight for a child of that length. Then follow up by monitoring growth carefully and adjusting the feeding as needed. For catch-up growth, even higher intakes may be needed on a temporary basis. It is not uncommon for children to “outgrow” their feeding unless someone checks this periodically. What was once adequate per kg of body weight drops to a level that fails to support appropriate growth, so follow-up is crucial. Sometimes caregivers can be taught to do this calculation and progress the feeding volume themselves as the child grows.

CASE STUDY 3:

A thin infant with a very large reported formula intake volume.

DATA: B.W., a very thin-appearing 6.2 kg baby boy, was reported by his mother to have had a regular intake for many weeks of five 8 oz bottles of formula daily and no solids (40 oz x 20 kcal/oz = 800 kcal/day; 800 kcal/6.2 kg = 129 kcal/kg) which is a higher intake than usual, especially for such a thin baby.

15

B.W.’s mother reported that he “seems to want to eat all the time” and is “never satisfied” with a feeding. This pattern could reflect a serious medical problem and if found to be a true representation of the situation, it should result in a referral for medical evaluation.

ANSWER: On further questioning however, the mother was asked to describe formula preparation and feeding in greater detail and from several different angles. She then described preparing only one can of formula concentrate daily. Formula concentrate contains 40 kcal/oz and comes in 13 oz cans, providing a maximum of only 84 kcal/kg for a 6.2 kg baby). It was discovered that mother was not comfortable with arithmetic or measurement, and that the bottles she was using held only 4 to 5 oz each rather than 8 oz.

B.W.’s mother had been afraid to give the baby more in spite of his evident hunger. She was told by a person staffing a professional pediatric health phone consultation line at a local clinic that giving him 40 oz (as she had been) was “probably over feeding since 32 ounces was the limit.” The health care professional indicated that the child’s reported desire for more to eat when his intake was already so high was “probably just attention-getting behavior.”

If the health care professional had asked about the child’s appearance (very thin), and obtained a more thorough description of formula preparation, the problem would have been immediately apparent and easily resolved.

A similar picture might have occurred with the overdilution of the formula, and there is an additional threat of water intoxication. This mother avoided that measuring problem by using the empty formula concentrate can as the measuring device for adding water 1:1. Over- and under-dilution of formula are actually fairly common mistakes. One study found that as up to 5% of people preparing formula misunderstand the directions and dilute the formula twice; another 5% fail to dilute the formula concentrate at all. However, only very careful questioning will detect the real problem.

SUMMARY

A good understanding of the underlying assumptions about growth and body composition which provide the basis for the usual nutritional recommendations for infants and children is very important. It makes it possible for the health care professional to make “intelligent departures” from the usual feeding recommendations in order to meet the needs of children with special health problems.

Careful questioning can be of great value in helping to differentiate between the serious health problems that require medical care, and the problems which are correctable by simple dietary adjustments. Knowing the right questions to ask can make it easier to be a successful nutrition detective and an advocate for these young children.

Answers to Case Studies 1 and 2

Case 1 L.S. Intake = 160 kcal/kg (72 kcal/lb) Scenario 2

Case 2 A.G Intake = 78 kcal/kg (36 kcal/lb) Scenario 3

16 MeritCare Medical Center 2009 Aunt Cathy’s Guide to:

Nutrition Support Cathy Breedon PhD, RD, CSP,FADA Clinical Nutrition Specialist of Iron Deficiency MeritCare Health Systems and UND School of Medicine Fargo, ND Iron deficiency can result in poor ability to deliver oxygen to the body, loss of energy, poor ability to concentrate, impaired growth and mental development in children, impaired carnitine producion, and many other problems. Iron deficiency can be quite common and it can be caused by a variety of factors. It may be related to:

1. Diets that provide poor amounts of iron or iron in forms that are poorly absorbed.

2. Abnormal iron losses, such as hemorrhage, heavy menstrual periods, or losses related to childbirth or surgery.

3. Conditions that impair iron absorption, such as Cystic Fibrosis, or intestinal diseases like Crohn’s disease or Inflammatory Bowel Disease. “Bariatric” surgery for weight loss is also associated with significant iron deficiency. In many parts of the world, people commonly have severe iron deficiency because of intestinal parasites.

4. Conditions that increase requirements, (such as rapid growth of tissues during pregnancy, infancy or childhood,) can result in inadequacy when the usually adequate intake of iron is not enough to meet all the increased iron needs.

A Cautionary Note: Iron deficiency is NOT ALWAYS the cause of anemia. There are conditions in which iron may only appear to be inadequate when a person has a low hemoglobin level in his/her blood that is detected by a laboratory test that measures hemoglobin. A low hemoglobin level can be related to problems that are quite unrelated to inadequate iron intake. It is important to determine the likely cause of what may only look like iron deficiency, because giving more iron will not be helpful and it may actually be harmful. For example, conditions like Sickle Cell Anemia and Thalassemia cause red blood cells to break too easily. Their iron stores may even be generous, but the individual simply can’t make new red blood cells fast enough to make up for the broken ones. Chronic diseases like arthritis, celiac disease, and infections can also result in low hemoglobin measurements that look like iron deficiency anemia in the laboratory but for which inadequate iron is not the problem. This is called “the anemia of chronic disease.” Inadequacies of other nutrients like copper can also cause hemoglobin to be low. Iron deficiency is a common cause of anemia, but if providing generous absorbable iron does not correct it, it will not be helpful to just continue to give more and more iron. [Anemia of chronic disease and defective erythropoietin production in patients with celiac disease. Haematologica. 2008 Dec;93(12):1785-91.]

Detective work is in order in this case.

Now back to the major focus of this paper: Solving the problem when iron deficiency IS the problem:

FOODS THAT ARE GENEROUS SOURCES OF WELL-ABSORBED IRON:

MEATS: 1. “Heme iron” vs “Inorganic iron” issues

Meats of all kinds contain iron in an especially absorbable form called “heme” iron. This is also called “organic iron.” Absorption of organic iron is not affected by the presence or absence of certain other substances in foods the way plant iron is. Iron in this form is about 20% absorbed.

Twenty percent absorption does not sound very high, but “inorganic iron” is much less well absorbed. Inorganic iron is the kind in plants and in supplements with the word “ferrous” or “ferric” in them. Ferrous sulfate and ferrous gluconate are examples you will see on most iron supplement labels. An “organic iron” supplement that contains the well-absorbed “heme” form of iron is available though less commonly used. It is called “heme iron polypeptide.” However, if iron deficiency is not corrected by the usual inorganic iron supplements or diet changes, this can be a very helpful nutritional supplement. It is well absorbed, it does not compete with other substances for absorption, and it is better tolerated by many people than the inorganic iron supplements. The nature of these inorganic iron “tolerance” issues will be discussed below.

2 Like other nutrients, supplemental or dietary iron does no good at all if it is not absorbed into the bloodstream from the intestines. It just passes right out in the stools. Ferrous sulfate, a very commonly used iron supplement product, is less than 2% absorbed. Some plant forms of iron in foods like spinach that naturally contain “oxalates” are only 0.025% absorbed! Spinach is a terrific food to include in your diet for many reasons, but it is NOT a terrific iron source.

Often at the higher doses used to treat anemia, inorganic iron supplements like ferrous sulfate can cause stools to turn a black color and they may also contribute to constipation. Neither is an unmanageable problem – the color is not a problem, and the constipation can be addressed a variety of ways with certain helpful foods or by using a laxative.

However, the reality is that people often discontinue taking this form of supplement because of these problems. In fact, when you hear about children being poisoned by iron supplements, it is often because they got into the medicine cabinet and took a handful of the small but high-dose ferrous sulfate pills that some adult quit taking for just these reasons! And of course, no iron supplements will solve an iron deficiency problem if a person doesn’t take them.

2. Meat Protein Factor”

In addition to being a generous source of absorbable iron, meat also has a special property of causing increased absorption of iron from the inorganic iron sources in the meal! In other words, the iron in chili beans will be much more easily absorbed if there is meat in the chili. This is called the “Meat Protein Factor” effect. It is not well understood how it works, but it clearly does increase absorption of inorganic iron in other foods and supplements, so it helps to further improve recovery from low iron stores.

3. Meat: Variable AMOUNT of Iron

The total AMOUNT of iron in different kinds of meat varies. Red meat is the highest in absorbable iron. Poultry and fish have much less iron than red meat, but what they have is still a much greater amount than what is found in plant foods, and it also much better absorbed than inorganic iron. Additionally, white meat chicken/turkey has less iron than dark meat. Think of the iron content of meat as “color-coded” … darkest is highest and lightest is lowest. But all have the “Meat Protein Factor” effect described above, and the form of iron is well absorbed.

Of the different types of meat, liver is an extremely generous source of absorbable iron. This also includes foods made from liver like paté or liverwurst. Not surprisingly, the iron content of blood is high and it is in an absorbable “heme” form, so things like Scandinavian/ German “blood sausage,” and “blood pudding” are rich in iron. This is not a universally popular choice, however.

3 FOODS THAT INCREASE ABSORPTION OF (INORGANIC) IRON:

Acid

Any acid substance, including vinegar, citric acid and vitamin C (ascorbic acid) can enhance iron absorption from sources of inorganic iron (the form of iron found in pills or plants, like ferrous sulfate.) Because of this, people with iron deficiency are often advised to take their iron supplement or iron fortified cereal with orange juice, or some other acidic beverage. However, the size of the increase in absorption is not as great as many people think, so that intervention alone is not likely to be that helpful.

For example, as noted earlier inorganic iron is generally only about 2% (or less) absorbed, with some forms being much less absorbable than that because of substances in some foods that interfere with absorption. For that reason, the “take with orange juice” effect is a much less important factor affecting iron absorption than the highly absorbable and generous heme iron found in meat (especially red meat.)

As described above, the presence of acid and/or meat will contribute to improved absorption of inorganic iron. Other food substances can significantly impair absorption of inorganic iron but they have minimal effect on absorption of organic iron. For example, the organic iron forms like “heme” iron are about 20% absorbed, which is at least ten times as well absorbed as any inorganic iron. In addition, the per cent of absorption of inorganic iron is much more likely to be negatively affected by other substances in a meal.

FOODS THAT DECREASE ABSORPTION OF (INORGANIC) IRON:

Dairy foods

Dairy foods are notoriously poor sources of iron that also decrease absorption of the iron in plants and pills. That means that taking iron supplements with milk, or putting milk on iron-fortified cereal, or cheese on a sandwich can result in less of the iron present in the pill, cereal or bread being absorbed. This is one of the issues behind the phenomenon of iron deficiency anemia in infants and toddlers who have cow or goat milk in place of mother’s milk or iron fortified formulas. Those who drink quite a lot of milk will be displacing other foods that are good sources of iron, in addition to actually impairing iron absorption. Not surprisingly, this effect is most likely seen in children who do not eat much meat and do not take a multivitamin with minerals. The presence of milk does not impair absorption of the generous organic iron in meat.

4 Tea Tea contains “tannins,” a plant substance that binds iron very well in the intestines and significantly reduces its absorbability. This effect is so marked that tea is the one food shown to be interfere with iron absorption enough to be helpful for people who have hemochromatosis, a serious genetic problem of absorbing way too much iron. And, as seen before, it has the most marked effect in decreasing absorption of inorganic iron. Tea has many other excellent healthful properties, but for the anemic individual it is important to remember that improving iron status is not one of them.

Clinical trial on the effect of regular tea drinking on iron accumulation in genetic hemochromatosis. “A significant reduction in iron absorption was observed when the test meal was accompanied by drinks of tea instead of water. In the tea drinking group, the increase in storage iron was reduced by about one third compared with that of the control group.” Gut. 1998;43(5):699-704.

Hemochromatosis is dangerous and it is now known to be much more common than previously thought. For information on nutrition factors that can be helpful in this dangerous condition of excessive iron absorption, please see “Nutrition Support of Hemochromatosis Therapy” at www.meritcare.com. Other nutrition topics can also be found there. Put my name (Cathy Breedon) in the search box, press enter, and click the line that says “Cathy Breedon’s Handouts.”

Leafy greens Many foods like spinach contain “oxalates” that bind up iron in the intestinal tract and make it too big a molecule to be absorbed well. This is true even though the iron and vitamin C content are generous. Some green plants like broccoli do not have oxalates and so their iron is better absorbed. As noted before, these are extremely nutritious foods … it is just that the oxalate-containing ones should not to be relied on to solve the problem if a person is iron deficient.

Bran

The bran is the fibrous coating on grains. Bran contains “phytates” which impair iron absorption as tannins and oxalates do. For that reason, taking a bowl of iron-fortified bran cereal in milk along with a cup of tea is not the best way to get iron where you want it to go. Some grains naturally contain less phytate than others, but it is still an issue.

Eggs

Interestingly, although in the 1950s egg yolk used to be fed to infants as an iron source, the form of iron in eggs has been found to be poorly absorbed. Eggs are an excellent source of protein (the protein in one egg is like the amount in 1 ounce of meat) and other nutrients as well. The egg white has most of the protein (6 of the 7 grams) and essentially none of the iron at all. Nearly all of the iron is in the yolk.

5 Iron-fortified foods and enriched grains

Iron “fortification” involves adding inorganic iron to foods that would not usually have iron, such as milk-based infant formulas or similar “nutrition beverages” for adults or children. “Fortified” also can mean that the iron (or another nutrient) was added to achieve a level higher than would naturally be in the food. Total-type cereals are an example: it is fortified to provide 18 mg of iron per cup compared with 4.5 mg iron in a cup of a similar but unfortified whole wheat cereal like regular wheat flakes.

“Enrichment” means that a nutrient was removed by processing but then it was added back to the level it contained before processing. In America, iron is added back to refined grains. The available iron naturally in the grains is in the “germ” part of the grain that is lost when grains are refined. Unfortunately, we do not add back any other minerals; only iron and three B vitamins are added back (B1, B2 and B3.) That is all … no magnesium, no chromium, no vitamin E, etc. This is one of the reasons why “whole grain” products (containing the germ and bran) are nutritionally superior to enriched grains. In 1998, processed grains products, whole or enriched, began to have the B vitamin “folic acid” added to improve the folic acid status of Americans. This was food “fortification”… a nutrient was added that was not there very much naturally.

The iron content of commercial cereals can be quite variable, depending on the enrichment or fortification of the product. For example, “Quick” iron-fortified cream-of-wheat has over 15 mg of (inorganic) iron per cup, but unfortified cream-of- wheat or oatmeal only has about 2 mg. Foods that have had iron added will indicate that they are fortified or enriched with iron if you check the label. The words “ferrous” or “ferric” in the ingredient list is an indication of iron being added. The amount of iron contained naturally in some other foods Legumes like lima beans and peas have 5-6 mg of iron per cup, but vegetables like corn and carrots have only about 1 mg. Prune juice contains quite a lot of iron (over 9 mg per cup compared with about 1 mg per cup of other fruit juices) and it naturally contains some other substances that help one avoid the constipation issues. Absorbability of the iron has not been well studied, however.

Iron and Zinc Content Chart of Food in General The chart on the next page shows the iron and zinc content of a number of foods and some factors described earlier that affect absorption of both minerals. As you can see, the foods that are highest in absorbable iron tend to also be high in absorbable zinc, and vice versa. This is important in anemia because inadequate zinc can also impair the production of red blood cells. Zinc is involved in over 200 processes in the body but it is harder to evaluate with labs than iron is. Iron deficiency is the most often recognized nutrient deficiency in the USA, but that is in part because it is the one we actually look for by checking hemoglobin levels. So unless the person is anemic because of blood loss, a person who is found to be iron deficient in an “iron fortified/enriched” world could easily have unrecognized poor zinc status as well.

6 MeritCare Health Systems Aunt Cathy’s Cathy Breedon PhD, RD, CSP, FADA Guide to Nutrition: Clinical Nutrition Specialist MeritCare Medical Center Iron and Zinc in Food UND School of Medicine Fargo, ND

(Data Source: Agriculture Handbook No. 8-4 US Dept. of Agriculture Science & Education Admin.)

7 MeritCare Health System

Aunt Cathy’s

General Thoughts about Cathy Breedon PhD, RD, CSP, FADA Clinical & Perinatal/Pediatric Nutrition Specialist Safely Discontinuing the MeritCare Health Systems, Fargo, ND and UND Ketogenic Diet School of Medicine for Seizure Control

Children on the ketogenic diet for seizure control can sometimes go off the diet and continue to experience good seizure control. Often they will continue to need some seizure-control medications, but they may need less.

Anytime the family or the child’s physician wants to do a trial off the ketogenic diet we can easily set up a trial. However, there are some important things about the process to know about, so this information should be shared with all concerned. That way everyone will be on the same page regarding how to safely discontinue the ketogenic diet, and what may need to be done afterward.

What needs to happen before the trial off diet is initiated:

The physician will need to decide if he/she wants to give the child some additional seizure-control medication ahead of time.

Here is the rationale for this:

1. If the child IS still depending heavily on being in ketosis to control seizures, without the extra medication protection at the start of the trial, when he/she goes out of ketosis there would be a risk of an increase in seizure activity.

2. If the child does well after going out of ketosis while on this more generous medication level, the family and the physician can then set about to wean the medications back down to see how well seizure control is maintained off diet.

The nature of the ketogenic diet is that it is not the kind of thing from which a person can be "slowly weaned off." Once carbohydrate is introduced, the person almost immediately stops producing ketones. In other words you can “walk down” with her medications, but the diet is either "all or none" so there is no safety net. There is no gradual change in ketone production ... when carbohydrate comes in, ketones go away.

The trial off diet is easy from a food/nutrition standpoint:

1. For children who eat foods orally, just give the child something to eat with a generous amount of carbohydrate in it, like a glass of milk or a jelly sandwich … whatever is age appropriate and that the child might like. In other words, just switch to a typical diet for age and the carbohydrate normally present there will naturally put a stop to ketone production. (The nutritionist / dietitian can help figure out what carbohydrate-containing foods would work if there are any questions.)

2. For the tube-fed child using RCF formula (Ross Carbohydrate Free,) the simplest solution is to just add carbohydrate to the RCF. According to the manufacturer, 3-1/2 level tablespoons of table sugar and 12 oz of water per 13 oz can of RCF will make a product with the average amount of carbohydrate found in standard infant formula (20 calories per oz.) For this situation, however, it is perfectly fine to just round it off to 4 Tablespoons, which is ¼ level cup of sugar per can of RCF concentrate. The resultant product will provide closer to 24 calories per oz, another caloric density commonly used in infants.

So, if it is decided to do a trial off diet, the safe way is as described above. If one then weans the medications back down and finds that there is good seizure control in spite of the diet change, here's what should be done next:

1. Get together with the pediatric nutritionist after the child has been off the diet for a while to take a look at the nutrient intake on the new unrestricted diet. The reason is related to the fact that the child often has had such an unusual diet for so long, it may take a while to learn to like a nice variety of food. Maybe he/she will dive right in ...that would be great! ... but if it doesn't go that way the nutritionist can always figure out some things that will make sure to provide good nutrition while the child is getting used to the new foods.

2. When children do well with seizure control after they go off the diet, they still may need some amount of seizure medications. Needing none would be terrific, but it might turn out that the child still needs to have some. The physician and family will decide this. Since there are some nutrition issues associated with any kind of seizure medication use, the nutritionist should look the whole picture over and figure out what, if anything, needs to be done to adjust for drug/nutrient interactions.

Additionally, some children have other issues that put them at risk of vitamin and mineral inadequacies that will still need to be addressed. An example of this is a child who moves very little and therefore has very low calorie requirements. A feeding program that will meet his/her calorie needs will clearly not meet the requirements for other critical nutrient requirements without appropriate supplementation. Similarly, for some children restricted food texture tolerance limits the variety of foods, and nutrient inadequacy is common unless the overall feeding plan is looked at closely.

For more information on a variety of related subjects, please see my “Guide to Nutrition for Children with Special Health Care Needs.”

It can be downloaded for free from our website (www.meritcare.com.) Just type my name in the search box in the upper right corner, and click “Cathy Breedon: Handouts.” A list of many topics will appear, and this one is about 2/3 of the way down the list. Sanford Medical Center

Aunt Cathy's Guide To: Aunt Cathy

Cathy Breedon PhD, RD, CSP, FADA The Unsaturated Fat Clinical/Metabolic Nutrition Specialist Sanford Medical Center and Families: Mono & Poly UND School of Medicine, Fargo, ND

Omega 3 family Omega 6 family Omega 9 family “The Fisher Family” “The Cornelius Family” “The Olivetti Family” Plant Polyunsaturated (more Polyunsaturated (more Monounsaturated (only one forms than one double bond) than one double bond) double bond) 18 carbons Alpha linolenic (18:3) Linoleic (18:2) Oleic, etc. (18:1) Gamma Linolenic (18:3)

Essential Essential

Critter Polyunsaturated (more Polyunsaturated (more forms than one double bond) than one double bond) 20 carbons EPA (EicosaPentaenoic ARA (20:4) Acid) (20:5) (Arachidonic Acid)

(May be essential too) (May be essential too) Important New Discovery: 22 carbons DHA (DocosaHexaenoic Many people are now Acid) (22:6) known to be much less able to do the conversions

( ) than we thought, so EPA, DHA and ARA are also “essential fats” for (May be essential too) them in addition to linoleic and linolenic acid. What does “omega” mean when talking about fatty acid carbon chains?

It sounds very scientific, but it just means that you start counting the carbons in the chain from the very end of the fatty acid chain.

“A to Z” = alpha to omega in the Greek alphabet = “beginning and end”

alpha end omega end

18-carbons-in-a-chain fats: 9 8 7 6 5 4 3 2 1

18 carbons, 1 double bond (monounsaturated) fatty acid starting after 9 carbons from the “omega” (z) end of the chain, so it is in the “omega 9” family) 18:1 = (18 carbons, one double bond)

Linoleic 6 5 4 3 2 1

18 carbons, 2 double bond (monounsaturated) fatty acid starting after 6 carbons from the “omega” (z) end of the chain, so it is in the “omega 6” family) 18:2 = (18 carbons, two double bonds) Linolenic 3 2 1

18 carbons, 3 double bond (monounsaturated) fatty acid starting after 6 carbons from the “omega” (z) end of the chain, so it is in the “omega 6” family) 18:3 (18 carbons, three double bonds)

“Essential Fatty Acids” Linoleic and alpha-Linolenic How to keep them sorted out:

Linoleic Alpha-Linolenic

The only difference is the second n … write it in script and turn it on its side and it is a 3!

= 3 (It’s the omega 3 one. The other one isn’t.)

We can add two more carbons and stick in another double bond to make 20 carbon fatty acids, and then do it again to make 22 carbon fatty acids. These are “critter-level” fatty acids, not plant fatty acids like linolenic and linoleic acid. [This process is called “enlongation and desaturation”]

20-carbons-in-a-chain fats:

Omega-3 = EPA Eicosapentaenoic Acid (Eicosa = 20 carbons Penta = 5 enoic = double bonds) 3 2 1

Omega-6 = Arachidonic Acid (the name is from an old system and so it is not very helpful. If it were named today it would be ETA Eicosatetraenoic Acid (Eicosa = 20 carbons Tetra= 4 enoic = double bonds) 6 5 4 3 2 1

------22-carbons-in-a-chain fats:

Omega-3 = DHA Docosahexaenoic Acid (Docosa = 22 carbons Hexaenoic = 6 double bonds) 3 2 1

Why is this important:

Although these fats can be burned as fuel like any fat, the big deal with these is that we make several important things out of them

Prostaglandins Thromboxanes The 20-carbon fats are the material from which The 20-carbon fats are the material from which one makes prostaglandins … inflammatory one makes thromboxanes … messengers that messengers. If one makes a prostaglandin out tell your blood to clot. If one makes a of ARA (the omega 6 one) the response is thromboxane out of ARA (the omega 6 one) REALLY INFLAMMATORY! But if one the coagulation response is REALLY makes a prostaglandin out of EPA (the omega CLOTTY! But if one makes a thromboxane 3 one) instead, the inflammatory response is out of EPA (the omega 3 one) instead, much MUCH LESS! LESS BLOOD CLOTTING results.

Excessive tendencies to clot blood and inflame the arterial walls increase risk of cardiovascular disease. Both are increased a lot by making these substances from ARA instead of EPA. Both are also increased by making them from EPA (because that’s what prostaglandins/thromboxanes do) but the ones made out of EPA cause a much milder response than the ones made from ARA do.

DHA is a critical fat of the brain and retina, and it has roles in development, maintenance of cognition as we age, mood and attention, and decreasing risk of macular degeneration. As we now know that many people are not as able to make these very long chain fats, it is a very good idea to obtain some “ready made.”

Most Americans get adequate ARA (the omega 6 fat) from meat, but the source of ready made EPA and DHA (the omega 3 fats) is fatty fish like salmon or mackerel, and many Americans eat very little of these foods. That is why the American Heart Association recommends that people eat fatty fish twice weekly or take 1000 mg fish oil capsule daily. For certain health situations, such as having “high triglycerides,” they suggest that 2-4 capsules daily can be helpful with a physician’s supervision.

This is why I always say you should think of EPA as “Environmental Protection Agency” since it protects your internal environment from excessive inflammation and blood clotting … both of which are very important in cardiovascular disease and other serious health concerns. And it comes pre-packaged with DHA in ready made form.

The typical “American Diet” (whatever THAT is) is described as having 10-20 omega 6 fattyacids for every one omega 3 fatty acid. That is, a 10:1 ratio up to a 20:1 ratio.

The “Mediterranean Diet” is a heart-healthy eating pattern also associated with decreased riskof cancer, and one feature of this diet is a ratio of only 4 omega 6 fatty acids for every omega 3 fatty acid. That is, a 4:1 ratio.

How to remember this stuff: “6 is always bigger than 3”

Omega 6 fats make more clotty (“aggregatory”) thromboxanes than Omega 3 fats do.

Omega 6 fats make more inflammatory prostaglandins than Omega 3 fats do.

In all the ratios described above, the larger number of the two is ALWAYS the omega 6

MeritCare Health System 2009 Aunt Cathy's Guide To: All Those Lipids Recommendations for Using Aunt Cathy Different Types of Vegetable Cathy Breedon PhD, RD, CSP, FADA Clinical Nutrition Specialist Oils (Omega-3, Omega-6 and MeritCare Health Systems and Monounsaturated Oils) UND School Of Medicine Fargo, ND

Practical Applications: The Bottom Line (Subject to change at any moment! ☺):

1. When buying margarine and shortening, look for some brands that are now available labeled "free of trans fatty acids." Trans fatty acids are formed as a by-product of the process that produces “partially hydrogenated” vegetable oils – which converts the liquid oils to a more solid, spreadable texture. The trans fats seem to be as bad (or worse) for the heart as “saturated” fats like lard and coconut oil in terms of causing a person’s body to produce more cholesterol. It also is a factor in whether or not the cholesterol in the blood “sticks” to the inside of arteries and clogs things up. Other health problems are being identified as well. High consumption of trans fat is associated with increased inflammation and high “oxidative stress” in humans. This could increase the risk of the development or acceleration of several diseases, such as cancer, atherosclerosis, and type 2 diabetes, and a possible increased risk of infertility. (Am J Clin Nutr. 2007 Jan;85(1):231-7. Am J Clin Nutr. 2006 Nov;84(5):981-8. J Nutr. 2005 Mar;135(3):562-6. )

Some new techniques for making margarine and shortening from vegetable oils do not cause trans fatty acids to be formed at all, so look for the phrase “no trans fat” on the label. Starting January 2006, a law went into effect requiring the trans fat content to appear on the label. This requirement is stimulating research by food producers to explore more ways to prepare foods without trans fat. Foods produced prior to this date will still be able to have undisclosed trans fat.

Foods may be labeled “No Trans Fat” if they contain less than a gram per serving, so the better way to be sure to minimize intake of trans fat is to also look on the ingredient list for the words “partially hydrogenated.” In addition to trans fats that we might add to our foods, the ingredient list of many commercially made baked goods and other commercial foods also need to be looked at. Removing trans fat from our food supply is the goal and it is a work in progress. Until it is gone we should read ingredient lists carefully.

1 2. Nuts and peanuts are generally friendly in terms of the type of fat they contain, and they also are great sources of important minerals like magnesium and other goodies. Like other foods that contain a generous amount of fat, nuts and peanuts are high calorie foods, but the forms of fat they contain appears to be primarily dangerous to your width and not to your heart! In other words, the calories they contribute may be a problem for people who are aiming to take in fewer calories, but the form of fat is not as contributory to health problems as certain other forms of fat are. It now appears that besides not contributing to the risk of heart disease and cancer, adding nuts and legumes to the diet can actually be a tool to decrease the risk.

Nuts and legumes tend to have good proportion of the fat as monounsaturated fat, and of the polyunsaturated fats a reasonable ratio of omega-6 to omega-3 fat. (More on that topic will follow.) A large Harvard study of women followed for 16 years, eating nuts or peanuts four or more times a week was associated with a 25% decreased risk of developing diabetes compared with women who rarely ate them. A recent review of research studies found that nut consumption can actuallylower bad cholesterol (LDL) more than following a diets that are “low fat” and nuts can be an excellent food in the fight against what is called “metabolic syndrome.”

[Edible nuts and metabolic health. Curr Opin Lipidol. 2007 Feb;18(1):25-30. Tree nuts and the lipid profile: a review of clinical studies. Br J Nutr. 2006 Nov;96 Suppl 2:S68-78. Nut and peanut butter consumption and risk of type 2 diabetes in women. JAMA. 2002;288(20):2554-60. Effect of diets enriched in almonds on insulin action and serum lipids in adults with normal glucose tolerance or type 2 diabetes. Am J Clin Nutr. 2002;76(5):1000-6. Evidence-based dietary recommendations for patients with type 2 diabetes mellitus. Nutr Clin Care. 2003;6(2):51-61.] Peanuts were counted separately in the study of likelihood of developing diabetes because they are really not a nut but a member of the bean (legume) family. However, both had the same apparent beneficial effect. Note that both nuts and legumes are excellent sources of fiber and important nutrients like magnesium and chromium, which also are especially important in diabetes. The fat, protein, fiber, and vitamin/mineral content are all part of that complex puzzle, but the bottom line is that it is good to include nuts and legumes in one’s diet.

[Role of cellular magnesium in health and human disease. Front Biosci. 2004 Jan 1;9:262-76. Magnesium intake and risk of type 2 diabetes in men and women.Diabetes Care. 2004 Jan;27(1):134-40. Dietary magnesium intake in relation to plasma insulin levels and risk of type 2 diabetes in women. Diabetes Care. 2004 Jan;27(1):59-65. The association between magnesium intake and fasting insulin concentration in healthy middle-aged women. J Am Coll Nutr. 2003 Dec;22(6):533-8.Low plasma magnesium in type 2 diabetes. Swiss Med Wkly. 2003 May 17;133(19-20):289-92. Magnesium deficiency in African-Americans: does it contribute to increased cardiovascular risk factors? J Natl Med Assoc. 2003 Apr;95(4):257-62. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care. 2003 Apr;26(4):1147-52. Role of magnesium in insulin action, diabetes and cardio- metabolic syndrome X.Mol Aspects Med. 2003 Feb-Jun;24(1-3):39-52.]

(Please see “Aunt Cathy’s Guide to Nutrition: Magnesium and Chromium” and “Aunt Cathy’s Guide to OTHER Nutrition Issues in Diabetes” if you want details about their role in diabetes.)

3. For cooking and baking, canola oil, olive oil, non-hydrogenated soy oil and walnut oil are best and they appear to be better for you than corn oil. They all contain the same amount of calories – about 9 calories per gram, or about 100 per tablespoon. But both have better proportions of the “friendlier” oils (monounsaturated and omega-3 polyunsaturated fats); corn oil is almost all the “omega-6” kind of fat. The reason for this is explained more fully below.

4. Adding ground flax to foods is also good for you. It needs to be ground up, though (or purchased that way -- you can get it at most grocery stores now) because otherwise the intact flax seeds just pass right on through like a high fiber supplement, and the good stuff inside is not absorbed into the body. Use a coffee grinder if you want to grind whole flaxseeds at home – the tiny seeds just jump over the blades in a regular food processor. The generous amount of

2 "friendly" fat in flax is an omega-3 fat called "alpha-linolenic acid." Ground flaxseeds can be added to hot or cold cereal or granola, or used in muffins, pancakes, meatloaf, etc. Some ready- to-eat cereals are now available that have ground flaxseed in them; some have the whole intact seeds in them so they may be less helpful. Most ground flax products are best stored in the refrigerator or they can turn rancid.

It appears that the ground flaxseed is more beneficial than taking the flax oil in capsules, probably because of the micronutrients and the fiber. A fiber-like material in the seeds called “lignins” appears to have health benefits as well. Soybeans and walnuts will also provide many additional nutrients besides “friendly” fat.

[Supplementation with flaxseed alters estrogen metabolism in postmenopausal women to a greater extent than does supplementation with an equal amount of soy. Am J Clin Nutr. 2004; 79(2):318-25. Flaxseed and cardiovascular risk. Nutr Rev. 2004;62(1):18-27. Flax facts. A grain for good health. Diabetes Self Manag. 2003;20(6):18, 20-2. The effect of flax seed cultivars with differing content of alpha-linolenic acid and lignans on responses to mental stress. J Am Coll Nutr. 2003;22(2):157-64. Dietary flaxseed meal is more protective than soy protein concentrate against hypertriglyceridemia and steatosis of the liver in an animal model of obesity. J Am Coll Nutr. 2003 ;22(6):494-501.] 5. Eat fish when able (avoiding the swordfish and other big fish known to contain high levels of mercury), and consider taking a couple of fish oil capsules daily, especially if you do not eat fish. This has to do with trying to eat more oils from the "omega-3" family and less from the "omega-6" family. Taking in the forms of omega-3 oils in fish (EPA and DHA) has certain advantages over only eating the plant/vegetable form (linolenic acid.) There is more on this topic later. The fish oil supplements are less likely to contribute mercury in part because the mercury tends to be distributed mostly in the flesh of the fish and not as much in the fat. Also, various treatments are used to make the capsules safer. There is a table on Page 8 that shows the amount of omega-3 fat in oils, flax and fish.

[Measurement of organochlorines in commercial over-the-counter fish oil preparations: implications for dietary and therapeutic recommendations for omega-3 fatty acids and a review of the literature. Arch Pathol Lab Med. 2005 Jan;129(1):74-7. Measurement of mercury levels in concentrated over-the-counter fish oil preparations: is fish oil healthier than fish? Arch Pathol Lab Med. 2003 Dec;127(12):1603-5. Mercury, fish, fish oil and the risk of cardiovascular disease]Tidsskr Nor Laegeforen. 2004;124(2):198-200. Bio-accumulation profiles of chemical contaminants in fish from the lower Willamette River, Portland Harbor, Oregon. Arch Environ Contam Toxicol. 2004;46(1):114-23. Childhood urine mercury excretion: dental amalgam and fish consumption as exposure factors. Environ Res. 2004;94(3):283-90. Is fish consumption safe? J La State Med Soc. 2004;156(1):42, 44-9. Mercury and selenium in whole blood and serum in relation to fish consumption and amalgam fillings in adolescents. J Trace Elem Med Biol. 2003;17 (3):165-70. Ameri-can Society for Circumpolar Health. Comparison of mercury in selected subsistence foods from western Alas-ka. Int J Circumpolar Health. 2003;62(4):448. Survey of total mercury and methylmercury levels in edible fish from the Adriatic Sea. Food Addit Contam. 2003;20(12):1114-9. Hazards of heavy metal contamination.Br Med Bull. 2003;68:167-82.]

Why do we care about the amounts and the ratios of “Omega-3” to “Omega-6” fat? The reason for the recommendations in suggestions #3-5 above is that increasing the ratio of the omega-3 family of oils relative to the omega-6 family is looking very helpful in decreasing risk of developing a number of serious health conditions. It may also slow the progression and/or decrease complications of many medical conditions. It also appears to be a factor in having a healthy pregnancy and in the development of the infant both before and after birth.

There will likely be a lot more fine-tuning of the recommendations coming out for specific types of fat and not just broad classes of fat. For example, new knowledge about certain special types of omega-6 fats is looking interesting as well. An example is one called gamma-linolenic (different from alpha linolenic acid) that appears be quite promising in decreasing nerve damage

3 (neuropathy) related to diabetes, and in decreasing inflammation. It is also being studied in critically ill patients with very encouraging results, along with other specific types of oil. The best food sources of gamma linolenic acid include nuts, and some leafy greens (like evening primrose oil.) Mother’s milk is usually rich in gamma linolenic acid. Although there is still much to learn, there is a rapidly growing body of research being reported in the scientific literature exploring these issues. References of a sampling of the most recent research is shown below:

At Low Doses, a {gamma}-Linolenic Acid-Lipoic Acid Conjugate Is More Effective Than Docosahexaenoic Acid-Enriched Phospholipids in Preventing Neuropathy in Diabetic Rats. J Nutr. 2007 Feb;137(2):368-372. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Pharm Biotechnol. 2006 Dec;7(6):531-4. Tumoricidal and anti-angiogenic actions of gamma-linolenic acid and its derivatives. Curr Pharm Biotechnol. 2006 Dec;7(6):457-66. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006 Sep;34(9):2325-33.

Additionally, there is a huge amount of research showing that the special forms of omega-3 fats found in fish and fish-oil supplements (EPA and DHA) have certain very important advantages for many people. EPA decreases inflammation in a wide range of inflammatory diseases like MS, cardiovascular disease and arthritis. I think of EPA (whose real name is eicosapentaenoic acid) should be thought of as “Environmental Protection Agency” instead, because it seems to be very protective against a number of health problems.

DHA in particular appears to be very important for the development of the brain and the retina of the eye, so it is critical during pregnancy and infancy. It has also been shown to be helpful in the continued good operation of the brain (e.g. in possibly helping to ward off age-related problems like alzheimers and other forms of dementia,) and for decreased risk of, or progression of, depression, blindness due to macular degeneration, attention deficit disorder and Parkinson’s disease.

More research is ALWAYS needed, of course, but the cumulative results of a great many studies have been in the same direction. Assuring an adequate intake of these fats looks like a VERY good idea. Additionally, it is now recognized that for some people it is difficult to efficiently convert the plant omega-3 oils (like those in canola, flax and walnuts) into the important EPA and DHA oils that are found ready-made in the fish oil. This may be a factor in a broad range of inflammatory conditions and critical in pregnancy.

The American Heart Association recommends 1000 mg of fish oil for most people with risk of heart disease. People at risk include those who smoke, who have disturbed blood lipids (too much LDL cholesterol or triglycerides, or too little HDL cholesterol,) who are overweight or sedentary, or who have high blood pressure, diabetes, or a family history of heart disease. Other factors contribute to heart disease risk as well.

[Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives. Atherosclerosis. 2007 Dec 24 n-3 Fatty Acids: Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA, May 21, 2005. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S.] Specific Health/Medical Conditions:

AIDS/ HIV Nutritional treatment for acquired immunodeficiency virus infection using an enterotropic peptide-based formula enriched with n-3 fatty acids: a randomized prospective trial Eur J Clin Nutr. 2001 Dec;55(12):1048-52. Effects of protein- energy malnutrition and human immunodeficiency virus-1 infection on essential fatty acid metabolism in children. Nutrition. 2000 Jun;16(6):447-53. Effects of fish oil on cytokines and immune functions of mice with murine AIDS. J Lipid Res. 1998 Aug;39(8):1677-87.

4 Alzheimer’s Disease A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005 Mar 23;25(12):3032-40. Polyunsaturated fatty acids in the central nervous system: evolution of concepts and nutritional implications throughout life. Reprod Nutr Dev. 2004 Nov-Dec;44(6):509-38. Chronic administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid beta-infused rats. J Nutr. 2005 Mar;135(3):549-55. Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model.Neuron. 2004 Sep 2;43(5):633-45. Importance of "health foods", EPA and DHA, for preventive medicine. Rinsho Byori. 2004 Mar;52(3):249-53.Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study.Br J Nutr. 2003 Apr;89(4):483-9. J Neurosci. 2005 Mar 23;25(12):3032-40. Neuroinflammatory perspectives on the two faces of Alzheimer's disease. J Neural Transm. 2004;111 (3):281-94. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60(7):940-6. Essential fatty acids and the brain. Can J Psychiatry. 2003;48(3):195-203. Omega-6/omega-3 ratio and brain-related functions. World Rev Nutr Diet.2003;92:37-56. J Neural Transm. 2003;11 (1):95-110. Dietary lipids in the aetiology of Alzheimer's disease: implications for therapy. Drugs Aging. 2003;20(6):399-418. Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study. Br J Nutr. 2003;89(4):483-9. The role of diet in cognitive decline. J Neural Transm. 2003;110(1):95-110.

Arthritis Biological basis for the benefit of nutraceutical supplementation in arthritis. Drug Discov Today. 2004 15;9 (4):165-72. Omega-6/omega-3 fatty acids and arthritis. World Rev Nutr Diet.2003;92:152-68. Dietary fatty acids and immune reactions in synovial tissue. Eur J Med Res. 2003;8(8):381-7. A biomarker of n-3 compliance in patients taking fish oil for rheumatoid arthritis. Lipids. 2003;38(4):419-24. N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. Lipids. 2003;38(4):343-52. Dietary n-3 fats as adjunctive therapy in a prototypic inflamma-tory disease: issues and obstacles for use in rheumatoid arthritis. Prostaglandins Leukot Essent Fatty Acids.2003;68(6):399-405. The role of fish oils in the treatment of rheumatoid arthritis. Drugs.2003;63(9):845-53. Nutritional management of rheumatoid arthritis: a review of the evidence. J Hum Nutr Diet.2003;16(2):97-109. Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system? Prostaglandins Leukot Essent Fatty Acids.2003;68(3):219-24. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int. 2003;23(1):27-36.

Asthma Eur Respir J. 2000;16(5):861-5. Cochrane Database Syst Rev. 2000;(4):CD001283.

Bone Health Repletion with (n-3) fatty acids reverses bone structural deficits in (n-3)-deficient rats. J Nutr. 2004 Feb;134(2):388-94.

Cancer Prevention (General) Tumoricidal and anti-angiogenic actions of gamma-linolenic acid and its derivatives. Curr Pharm Biotechnol. 2006 Dec;7(6):457-66.Carcinogenesis. 2003;24(5):919-25. Chin Med J (Engl).203;116(3):453-8; Eur J Cancer. 2002;11 Suppl 2:S1.

Lung Cancer Nutr Cancer.203;45-2:106-7; Nutr Cancer.2002;42(1):18-24; J Nutr.2002;132(7):2069-75.

Breast Cancer Nutr Cancer.2003;45(2)211-217. Dietary flaxseed inhibits human breast cancer growth and metastasis and downregulates expression of insulin-like growth factor and epidermal growth factor receptor. Nutr Cancer. 2002;43(2):187-92. Int J Cancer. 2003;107(2):276-82; J Nutr.203;133(5):1409-14; J Nutr Biochem. 2002;13(12):711-16; Nutr Cancer.2002;43(2):187-92. . Flaxseed inhibits metastasis and decreases extracellular vascular endothelial growth factor in human breast cancer xenografts. Cancer Lett. 2002 8;185(1):31-7

Colon Cancer Effect of an omega-3 fatty acid containing lipid emulsion alone and in combination with 5 fluorouracil (5 FU) on growth of the colon cancer cell line Caco-2.Eur J Nutr. 2003;42(6):324-31. Colon Detect Prev.200327(1):55-6; Cancer Res.203;63(5):972-9; Int Epidemiol.203; 32(2):200 9; Carcinogenesis 2003;4 [Epub ahead of print]. J Nutr 2002;132(11 Suppl):3508S:3512S.

Prostate Cancer Harv Mens Health Watch.2003;7(10):5; Cancer Epidemiol Biomarkers Prev.2003l;12(1):64-7; Prostaglandins Leukot Essent Fatty Acids.2002;66(5-6):467-77. Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice.Urology. 2002 N;60(5):919-24.

Adjunct to Chemotherapy in Cancer Treatment Formation and anti-proliferative effect of prostaglandin E3 from eicosapentaenoic acid in human lung cancer cells. J Lipid Res. 2004 Mar 1 [Epub ahead of print]Nutr Cancer. 2002;44(2):176-81; J Control Release.2001;74(1-3):233-6; Clin Cancer Res 2001.7(7):2041-9; Anticancer Res.2001;21 (1A):29-38; Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin. Cancer Chemother Pharmacol. 2001;47(1):34-40. Anticancer Res.1999;19(6C):5583-6.

5 Cardiovascular Disease (Esp. Heart Disease, Hypertriglyceridemia and Stroke) Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives. Atherosclerosis. 2007 Dec 24 n-3 Fatty Acids: Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA, May 21, 2005. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S. Blood omega-3 and trans Fatty acids in middle-aged acute coronary syndrome patients. Am J Cardiol. 2007 Jan 15;99(2):154-8. Greater fish, fruit, and vegetable intakes are related to lower incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology. Circulation. 2007 Jan 16;115(2):188-95. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic factors in type 2 diabetes. Diabetologia. 2007 Feb;50(2):250-8. Depression and cardiovascular mortality: a role for n-3 fatty acids? Am J Clin Nutr. 2006 Dec;84(6):1513-7. Tumoricidal and anti-angiogenic actions of gamma-linolenic acid and its derivatives. Curr Pharm Biotechnol. 2006 Dec;7(6):457-66. NEJM.2004;350(1) :29-37. Nutr Rev. 2004;62(1):18-27. J Nutr. 2005 Mar;135(3):562-6. Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction. n-3 fatty acids and the risk of sudden cardiac death. Emphasis on heart rate variability. Dan Med Bull. 2003;50(4):347-67. Dietary fish oil up-regulates cholesterol 7alpha-hydroxylase mRNA in mouse liverleading to an in-crease in bile acid and cholesterol excretion. FEBS Lett. 2004 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia. Metabolism. 2004;53(2):153-8. Fish oil increases antioxidant enzyme activities in macrophages and reduces atherosclerotic lesions in apoE-knockout mice. Cardiovasc Res. 2004;61(1):169-76. Fish oil interaction with warfarin. Ann Pharmacother. Microalgal docosahexaenoic acid decreases plasma triacylglycerol in normolipidaemic vegetarians: a randomised trial. Br J Nutr. 2006 Apr;95(4):779-86.2004;38(1):50- 2. Vitamins, supplements, herbal medicines, and arrhythmias. Cardiol Rev. 2004;12(2):73-84. Cardiovasc Res. 2004;61(1):169- 76. Flaxseed and cardiovascular risk. Nutr Rev. 2004;62(1):18-27. Flax facts. A grain for good health. Diabetes Self Manag. 2003;20(6):18, 20-2. Dietary flaxseed meal is more protective than soy protein concentrate against Hypertriglyceridemia and steatosis of the liver in an animal model of obesity. J Am Coll Nutr. 2003 ;22(6):494-501.Int J Vitam Nutr Res.2003;73(3):163-70; J Throm Haemost.2003;1(4):690-7; J Women’s Health-Larchmt. 2003;12(2):109-14; Int J Clin Pract.2003;57(4):305-14; Circulation.2003;108(7):820-5. Am J Cardiol.2003;91 (7A):1 8E-23E. Circulation.2002;106:289-91.;559(1-3):125-8.]

Chronic Fatigue Syndrome In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation. Neuro Endocrinol Lett. 2005 Dec;26(6):745-51. Determination of fatty acid levels in erythrocyte membranes of patients with chronic fatigue syndrome. Nutr Neurosci. 2003 Dec;6(6):389-92. Treatment of chronic fatigue syndrome by dietary supplementation with omega-3 fatty acids--a good idea? Med Hypotheses. 2002 Mar;58(3):249-50.

Cystic Fibrosis Bioavailability and safety of a high dose of docosahexaenoic acid triacylglycerol of algal origin in cystic fibrosis patients: a randomized, controlled study. Nutrition. 2006 Jan;22(1):36-46. Biological effects of a dietary omega-3 polyunsaturated fatty acids supplementation in cystic fibrosis patients: a randomized, crossover placebo-controlled trial. Clin Nutr. 2006 Jun;25(3):418-27. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med. 2004;350 (6):560-9. JPEN J Parenter Enteral Nutr. 2003;27(1):52-7. Cochrane Database Syst Rev. 2002;(3):CD002201. J Appl Physiol. 2002;92(5):2169-76. Curr Opin Pulm Med. 2000;6(6):530-2.

Diabetes At Low Doses, a {gamma}-Linolenic Acid-Lipoic Acid Conjugate Is More Effective Than Docosahexaenoic Acid- Enriched Phospholipids in Preventing Neuropathy in Diabetic Rats. J Nutr. 2007 Feb;137(2):368-372. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Pharm Biotechnol. 2006 Dec;7(6):531-4Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr. 2003;78(6):1128-34. Flax facts. A grain for good health. Diabetes Self Manag. 2003;20(6):18, 20-2. Circulation.2003;107(14: 1852-7; Atherosclerosis. 2003; 166(1):85-93; Circulation.2003.107(14): 1852-7; Exp Clin Endocrinol Diabetes.2003;111(2):60-5; Exp Clin Endo-crinol Diabetes.2003; 111 (5):239-45. Int J Cardiol.2003(88:2-3):183-90; J Nutr.2003;133(7):2239-43; Diab. Metab. 2002;28(1):20-Lipids.2000;35(8):927-31. Nutrition. 2003;19(3):213-28. Dietary flax oil reduces renal injury, oxidiz-ed LDL content, & tissue n-6/n-3 FA ratio in experimental polycystic kidney disease. Lipids.2002;37(11):1059-65.

Epilepsy Epilepsia.2002;43(1):103-4; Nutr Health.2002;16(1):51-3; Synapse.2000;37(2):90-4.

Eye Health – Macular Degeneration and others Dietary fatty acids and the 5-year incidence of age-related maculopathy. Arch Ophthalmol. 2006 Jul;124(7):981-6. Cigarette smoking, fish consumption, omega-3 fatty acid intake, and associations with age-related macular degeneration: the US Twin Study of Age-Related Macular Degeneration. Arch Ophthalmol. 2006 Jul;124(7):995-1001. Improvement of visual functions and fundus alterations in early age-related macular degeneration treated with a combination of acetyl-L-carnitine, n-3 fatty acids, & coenzyme Q10. Ophthalmologica.2005;219(3);154-66. Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. Brain Pathol. 2005;15(2):159-66. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res. 2005;24(1):87-138. Hypothesis on the role of nutritional factors in ocular hypertension and glaucoma. J Fr Ophtalmol.2005;28(3):312-6.Effect of docosahexaenoic acid supplementation on retinal function in a patient with autosomal

6 dominant Stargardt-like retinal dystrophy. Br J Ophthalmol. 2004 Feb;88(2):305-6. Biological safety assessment of docosahexaenoic acid supplementation in a randomized clinical trial for X-linked retinitis pigmentosa. Arch Ophthalmol. 2003 Sep;121(9):1269-78. J Nutr Sci Vitaminol (Tokyo). 2003 Jun;49(3: 210-3. Invest Ophthalmol Vis Sci. 2003;44(5):2252-9; Invest Ophthalmol Vis Sci. 2003 44(8): 3685-91; Exp Eye Res. 2003;77(2):167-73.

Inflammatory Diseases (general) n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1505S-1519S Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Pharm Biotechnol. 2006 Dec;7(6):531-4. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1505S-1519S. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Opin Clin Nutr Metab Care.2003;6(4):413-9l; Prostaglandins Leukot Essent Fatty Acids.2003;68(3):219-24; Prostaglandins Leukot Essent Fatty Acids. 2003;69(1):51-9; J Am Col Nutr. 2002;21(6):495-505; Isr Med Assoc J.2002;4(1):34-8.

Inflammatory Bowel Disease – IBD-- Crohn’s Disease & Chronic Ulcerative Colitis. Nutr Hosp;2003;18(2):57-64; Lipids.2002;37(10):935-40; Proc Nutr Soc.2002;61(3): 391-5; J Nutr.2002;132(1):11-9.

Kidney Disease. J Am Diet Assoc. 2003;103(9):1174-7. Lipids. 2002;37(11):1059-65. J Am Soc Nephrol. 2003;14(2):389-96. Pol Arch Med Wewn. 2002;108(2):753-60. JPEN J Parenter Enteral Nutr. 2002;26(6):351-6. Prostaglandins Leukot Essent Fatty Acids. 2001;65(5-6):265-70. Mol Cell Biochem. 2001;225(1-):109-19.

Lupus J Clin Immunol.23(1):23-33; J Clin Immunol.2003;22(4):206-19; Lupus.2002.10(3):246-8.

Mental Health:

General: Dietary omega-3 fatty acids for women. Biomed Pharmacother. 2007 Jan 2; Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 2 : macronutrients. Omega-3 fatty acids and mood disorders. Am J Psychiatry. 2006 Jun;163(6):969-78. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry. 2006 Dec;67(12):1954-67 Current clinical applications of omega-6 and omega-3 fatty acids. Nutr Clin Pract. 2006 Aug;21(4):323-41. J Nutr Health Aging. 2006 Sep-Oct;10(5):386-99. S-adenosyl Methionine: a Connection between Nutritional and Genetic Risk Factors for Neurodegeneration in Alzheimer's Disease. J Nutr Health Aging. 2006 Nov-Dec;10(6):541-4. Omega-3 fatty acids upregulate adult neurogenesis. Neurosci Lett. 2007 Jan 7; Selective Deficits in the Omega-3 Fatty Acid Docosahexaenoic Acid in the Postmortem Orbitofrontal Cortex of Patients with Major Depressive Disorder Biol Psychiatry. 2006 Dec 2. Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: Gender differences and partial normalization with antipsychotic medications. Schizophr Res. 2007 Jan 18 Lower omega-3 polyunsaturated fatt y acids and lower docosahexaenoic acid in men with pedophilia. Neuro Endocrinol Lett. 2006 Dec;27(6):719-23. Omega-3 Fatty Acids Supplementation in Children with Autism: A Double-blind Randomized, Placebo- controlled Pilot Study. Biol Psychiatry. 2006 Aug 22; Polyunsaturated fatty acids: do they have a role in the pathophysiology of autism? Neuro Endocrinol Lett. 2006 Aug;27(4):465-71. Are neurodegenerative disorder and psychotic manifestations avoidable brain dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(3):203-15. Subtle changes in the aging human brain. Nutr Health. 2006;18(3):217-24. Nutrigenomic approaches to study the effects of n-3 PUFA diet in the central nervous system. Nutr Health. 2006;18(3):227-32. Docosahexaenoic acid in neural signaling systems. Nutr Health. 2006;18(3):263-76. The impact of diet and exercise on brain plasticity and disease. Nutr Health. 2006;18(3):277-84. Are neurodegenerative disorder and psychotic manifestations avoidable brain dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(3):203-15. Emerging treatments for depression. Expert Opin Pharmacother. 2006 Dec;7(17):2323-39. Polyunsaturated fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. Omega-3 fatty acids on the forced-swimming test. J Psychiatr Res. 2006 Oct 30; Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 1: micronutrients. J Nutr Health Aging. 2006 Sep-Oct;10(5):377-85. Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 2 : macronutrients. J Nutr Health Aging. 2006 Sep-Oct;10(5):386-99.The n-3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Dec 19; The protective effects of omega-3 fatty acids against MK-801-induced neurotoxicity in prefrontal cortex of rat. Neurochem Int. 2007 Jan;50(1):196-202. Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):259-69. The effect of childhood malnutrition on externalizing behavior. Curr Opin Pediatr. 2006 Oct;18(5):565-70. Relationship between omega-3 fatty acids and plasma neuroactive steroids in alcoholism, depression and controls. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):309- 14. Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):329-49 Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: An overview. Prog Neuropsycho-pharmacol Biol Psychiatry. 2007 Jan 30;31(1):12-26. Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: implications for the pathophysiology and treatment of recurrent neuro-psychiatric illness. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):237-57. The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):323-7. Are neurodegenerative disorder and psychotic manifestations avoidable brain

7 dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(2):89-101. Omega-3 fatty acids, energy substrates, and brain function during aging. Prostaglandins Leukot Essent Fatty Acids. 2006 Sep;75(3):213-20. Omega-3 fatty acids in ADHD and related neurodevelopmental disorders. Int Rev Psychiatry. 2006 Apr;18(2):155-72. Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia. Int Rev Psychiatry. 2006 Apr;18(2):119-31. Omega-3 fatty acid deficiencies in neurodevelopment, aggression and autonomic dysregulation: opportunities for intervention. Int Rev Psychiatry. 2006 Apr;18(2):107-18. Essential fatty acids and their role in conditions characterised by impulsivity. Int Rev Psychiatry. 2006 Apr;18(2):99-105. Essential fatty acids and mental illness. Int Rev Psychiatry. 2006 Apr;18(2):81-4.

Autism: Omega-3 Fatty Acids Supplementation in Children with Autism: A Double-blind Randomized, Placebo-controlled Pilot Study. Biol Psychiatry. 2006 Aug 22; Polyunsaturated fatty acids: do they have a role in the pathophysiology of autism? Neuro Endocrinol Lett. 2006 Aug;27(4):465-71. (More under Mental Health: General)

Depression: . Emerging treatments for depression. Expert Opin Pharmacother. 2006 Dec;7(17):2323-39. Polyunsaturated fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. Omega-3 fatty acids on the forced- swimming test. J Psychiatr Res. 2006 Oct 30; . Relationship between omega-3 fatty acids and plasma neuroactive steroids in alcoholism, depression and controls. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):309-14. Ethyl- eicosapentaenoate and dexamethasone resistance in therapy-refractory depression. Int J Neuro-psychopharmacol. 2004;1-9.Eur Neuropsychopharmacol.2003;13(4):267-71; Tidjschr Diergeneeskd. 2003; 128(6): 191-2; Am J Clin Nutr.2003;78(1):40-6; J Affect Disorder.1998;48(2-3):145-55. (More under Mental Health: General)

Schizophrenia: . The metabolic syndrome, omega-3 fatty acids and inflammatory processes in relation to schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):323-7. Are neurodegenerative disorder and psychotic manifestations avoidable brain dysfunctions with adequate dietary omega-3? Nutr Health. 2006;18(2):89-101. Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: Gender differences and partial normalization with antipsychotic medications. Schizophr Res. 2007 Jan 18. The n-3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Dec 19; Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia. Int Rev Psychiatry. 2006 Apr;18(2):119-31. J Neural Transm Suppl.2003;(64):105-17; Cochrane Database Syst Rev.2003;(2):CD)1257; Psychiatr Clin North Am.2003;26(1)85-102; Biol Psychiatry.2003;53(1):56-64. (More under Mental Health: General)

Multiple Sclerosis – MS Polyunsaturated fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73 (5): 397-404. Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases. Evid Rep Technol Assess (Summ). 2005 Feb;(114):1-3.Omega-3 fatty acids in health and disease: part 2--health effects of omega-3 fatty acids in autoimmune diseases, mental health, and gene expression. J Med Food. 2005 Summer;8(2):133-48. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495-505Pancreatitis J Parenter Enteral Nutr. 2002 Nov- Dec;26(6):351-6. Polyunsaturated fatty acid supplementation in MS. Int MS J. 2005 Nov;12(3):88-93. Prostaglandins Leukot Essent Fatty Acids.2003;68(3):219-24. J Am Coll Nutr. 2002; 21(6):495. 505; Acta Neurol Scand;2000(102-3). Clin Exp Immunol. 2000;122(3): 445-52; Acta Neurol Scand. 2000;102(3):143-9.

Parenteral Nutrition (Feeding via an I.V.) Omega-3 fatty acids improve the diagnosis-related clinical outcome. Crit Care Med. 2006 Apr;34(4):972-9. Omega-3 fatty acids- supplemented parenteral nutrition in the critically ill: another step forward on the "great journey"? Use of fish oil in parenteral nutrition: Rationale and reality. Proc Nutr Soc. 2006 Aug;65(3):264-77. Fish oil in the critically ill: from experimental to clinical data. Curr Opin Clin Nutr Metab Care. 2006 Mar;9(2):140-8. Metabolic effects of parenteral nutrition enriched with n-3 polyunsaturated fatty acids in critically ill patients. Clin Nutr. 2006 Aug;25(4):588-95. Effects of enteral feeding with eicosapentaenoic acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis and septic shock. Crit Care Med. 2006 Sep;34(9):2325-33. Parenteral fish oil supplementation in patients with abdominal sepsis. Clin Nutr. 2003 Aug;22(S1):S23.Nutr.2003;19(3):275-9.

Polycystic Ovary Disease and Ovarian Function Trans fatty acid intakes and the risk of ovulatory infertility. Am J Clin Nutr. 2007 Jan;85(1):231-7. J Nutr.2003;133(1):108-6; Lipids. 2002;37(11):1059-65; Srp Arh CelokLek. 2002;130(7- 8):251-7.

8 Pregnancy and Infant Development Issues: Oils rich in omega-3 fatty acids appear to have important implications in pregnancy and infant nutrition in particular. DHA (a long-chain omega-3 fatty acid) is a major fat of the brain, and the research is growing that suggests that providing some pre-formed DHA is advantageous. [Eur J Clin Nutr. 2004;58(3):429-37. Pediatrics 2003;111(1):e39-44; Arch Dis Child Fetal Neonatal Ed.2003;88(5):F383-F390.] DHA is known to be essential for retinal development in infants [Invest 44(8):3685-91; Ophthalmol Vis Sci.2003;Invest Ophthalmol Vis Sci.2003;44(8):3685-9.] It has also been reported that maternal alcohol intake can alter fatty acid transport by the human placenta, decreasing fetal availability of polyunsaturated fats in general and of DHA especially. (Br J Nutr. 2002; 87(3):247-52.) It may be that this decreased DHA transport is one of the (many) mechanisms of FAS (Fetal Alcohol Syndrome.) Omega-3 fats are also associated with decreased risk of premature delivery. As premature delivery is the most common cause of low infant birth weight, and infant morbidity and mortality, this is a very important observation. [J Nutr.2003;133(5 Suppl 2): 1606S-1625S. Exp Biol Med (Maywood). 2001;(226(6):498-506; BMJ.2002;324(7335):447; Obstet Gynecol Serv.2001;56(5 Suppl 1):S1-S13; Pediatrics. 2001 Aug;108(2):359-71; Obstet Gynecol Surv. 2001;56(5 Suppl 1):S1-13; Pediatr Clin North Am.2001;48(1):173-88; BJOG.2000;107(3):382-95.]

There is growing interest in the potential role of maternal supplementation of anti- inflammatory n-3 polyunsaturated fattyacids (n-3 PUFAs) in the prevention of allergic disease. [J Allergy Clin Immunol. 2003 Dec;112(6):1178-84.] For more information on this topic please see “Aunt Cathy’s Guide to Nutrition: A Top Ten Nutrtion Plan for Optimizing Pregnancy.”

Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev. 2006 May;64(5 Pt 2):S24-33; discussion S72-91. Nutrition and theory of mind--The role of polyunsaturated fatty acids (PUFA) in the development of theory of mind. Prostaglandins Leukot Essent Fatty Acids. 2006 Jul;75(1):33-41. Omega 6 to omega 3 fatty acid imbalance early in life leads to persistent reductions in DHA levels in glycerophospholipids in rat hypothalamus even after long-term omega 3 fatty acid repletion. Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain. J Nutr. 2006 Jun;136(6):1570-5. Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain. Neuroscience. 2006;139(4):1397-403. Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain. Neuroscience. 2006;139(4):1397- 403. Reduced brain DHA content after a single reproductive cycle in female rats fed a diet deficient in N-3 polyunsaturated fatty acids. Biol Psychiatry. 2006 Nov 1;60(9):987-90. Role of docosahexaenoic acid in neuronal plasma membranes. Sci STKE. 2006 Feb 7;2006(321):pe6. Docosahexaenoic acid facilitates cell maturation and beta-adrenergic transmission in astrocytes. J Lipid Res. 2006 Mar;47(3):571-81. Overexpression of dopamine receptor genes and their products in the postnatal rat brain following maternal n-3 fatty acid dietary deficiency. J Neurochem. 2005 Dec;95(6):1550-62. A randomized trial of docosahexaenoic acid supplementation during the third trimester of pregnancy. Obstet Gynecol. 2003 Mar;101(3):469-79 What is a Good Ratio of Omega-3 to Omega-6 Fatty Acids to Aim For? Most Americans eat about ten grams of omega-6 fat for every one gram of omega-3. That is, the ratio is ten to one. Some estimates are even higher. We should try to change that ratio to four-to-one, and if we have an inflammatory disease, two-to-one might even be better. Corn oil is almost all omega-6, so it is not the best choice. Compared with omega-3 fats, the omega-6 fats tend to increase inflammatory responses. If you buy a fish oil supplement, look for the words "EPA and DHA" on the label -- these are the "good guy" omega-3 fats that you are trying to get. (I remember this by thinking of EPA as "Environmental Protection Agency" since it protects your personal internal environment.) A report on EPA-DHA (NOT on cod-liver oil, which is different in a number of ways) supplements available in the U.S. appeared in Consumer Reports (2003Jul;68(7):30-2.) They evaluated the safety of products on the market (e.g. related to mercury concerns, etc.), the actual content of each product, and the price. The good news is that they found all to be safe, and all products contained what the label said was in there. However the price per 300 mg of supplemental fish oil ranged from 6 to 60 cents each! Expensive items provided no additional benefit. The cheapest are

9 found at bulk-sales stores like Sam's Club or Costco, etc. (in BIG bottles.) Most pharmacies carry them in smaller bottles.

Alpha linolenic acid is the form of omega-3 fat found in plants. Flax, canola and walnut oil are the most generous sources. Usually we can use it to make the EPA and DHA we need, but many people clearly benefit from getting at least some EPA and DHA “ready-made,” (i.e. in fish and fish oil supplements.) For example, some people may have difficulty making adequate EPA out of the omega 3 fats in plants. Another group of people at particular risk of cardiovascular disease was identified who have a different genetic trait for which providing EPA may be especially helpful. They have a variant 5-lipoxygenase genotype affecting leukotriene production and inflammation. (NEJM.2004;350(1):29-37; Nutr Rev. 2004 Jan;62(1):18-27.) Some guidelines are now available: A qualified health claim for fish oil supplements with EPA and DHA in capsule form has been approved by the FDA. The supplements should be used with a physician’s knowledge and approval, as certain aspects of the use of high doses of fish oil can increase bleeding problems among people taking certain medications to decrease risk of clots. These include anticoagulant and antiplatelet medications like Coumadin. Supplements that provide about a gram (1000 mg) of omega-3 fat daily can benefit persons with cardiovascular disease. Higher dose (2–4 grams, or 2000-4000 mg) intakes appear to greatly improve high triglyceride levels in particular. The higher doses (over 3 grams daily) should be taken only with physician approval. (n-3 Fatty Acids: Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA, May 21, 2005. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S. AHA Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-2757.)

The chart on the next page shows the families of oils and the names of the fats in each family. To help me remember them, I gave each “family” a last name that reminds me of some of the major food sources of each. The omega-3 family is the “Fishers,” the omega-6 family’s last name is “Cornelius,” and the monounsaturated fats are the “Olivetti” family. The dotted line is the marker of the forms of these fats found in plants, and the forms that are found only in “critters” like fish and animals, including people. The critters themselves can usually make the EPA, DHA and ARA out of the plant forms that they eat, and they also take them in by eating other critters. Why we care about this: Prostaglandins, thromboxanes, prostacyclins, and leukotrienes are made from 20 carbon polyunsaturated fatty acids (EPA and ARA). Thromboxanes made from ARA are much more aggregatory (promoting of blood clots) than those made of EPA. Prostaglandins made of ARA are much more inflammatory than those made of EPA. Decreasing the ratio of omega 6 to omega 3 fatty acids in the diet decreases the likelihood of forming blood clots, and decreases inflammation. This is particularly important in cardiovascular health, in diabetes, and in autoimmune diseases such as MS, inflammatory bowel disease, lupus and arthritis. A typical omega 6:omega 3 ratio in the US is often as high as 10:1. A suggested ratio goal for healthy people: 4:1. A ratio of 2:1 has been suggested for people with inappropriately inflammatory or aggregatory conditions.

10 The Unsaturated Fat Families: ______Number of Carbons: Omega 3 Omega 6 Omega 9 Number of Double Bonds “The Fisher family” “The Cornelius family “The Olivetti family” (“Monounsaturated”) ______Linoleic* 18:2 (plants) 18 carbons Alpha Linolenic* 18:3 Gamma Linolenic 18:3 Oleic 18:1 ------ ------ ------20 carbons EPA** 20:5 Arachidonic (ARA) 20:4 (critters) 22 carbons DHA*** 22:6 ______* Essential fatty acids *linoleic = 18:2 *alpha linolenic = 18:3 ** Eicosapentaenoic acid Eicosa: 20 (carbons) Penta :with 5 Enoic: double bonds

*** Docosahexaenoic acid (an important component of the brain) Docosa: 22 (carbons) Hexa: with 6 Enoic: double bonds

(New research issue: Is docosahexaenoic acid (DHA) essential? Lessons from DHA status regulation, our ancient diet, epidemiology and randomized controlled trials. J Nutr. 2004 Jan;134(1):183-6)

The chart on the next page shows the plant and animal food and oil sources for omega-3 fats in descending order. The animal sources (including fish) are on the right, and plant sources are on the left. It is interesting to note that olive oil and peanut oil are not very generous sources of omega-3 fat. Their contribution to heart health (for example, as a part of the “Mediterranean Diet”) appears to be due to their displacement of other, less-healthful fats in the diet, such as the omega-6 fats and saturated fats. Displacing some of the dietary omega-6 fats is another way to decrease the ratio omega-6 toomega-3 fat.

11 Omega 3 Fatty Acids in Foods

Plant Forms: Animal Forms: ______Linolenic Acid (18:3) EPA and DHA (20:5 and 22:6) ______(Eicosapentaenoic Acid and omega-3 fatty acids mg per tablespoon Docosahexaenoic Acid) of food (unless otherwise noted) ______Seafood portion in ounces to provide Linseed oil (flax) 7300 300 mg of omega-3 fatty acids (uncooked weight) Rapeseed (Canola) Oil 1500 Walnuts, English, chopped 1440 Fish oil 300 mg capsule 1 capsule Walnut Oil 1400 Mackerel, Atlantic 0.4 Wheat germ 900 Soybean oil 900 Trout, Lake 0.5 Soybean Sprouts, cooked 1 oz 600 Hydrogenated Soybean Oil 300 Herring, Atlantic 0.7 Sardines 0.7 Olive Oil 100 Safflower Oil 100 Anchovies, European 0.8 Sunflower Oil 100 Salmon, Pink 1.0 Corn Oil 100 Tuna, white 1.3 Peanut Oil 0 Bass, striped 1.3 Palm Oil 0 Palm Kernel Oil 0 Trout, Brook 1.8 Cottonseed Oil 0 Coconut Oil 0 Tuna, Light 2.1 ______Source: Cod 3.5 Omega 3 values from “Provisional Table on Crab, king 3.5 Content of Omega-3 Fatty Acids and Other Fat Components in Selected Foods” USDA Human Nutrition Information Service 1986, and Shrimp 5.3 Agriculture Handbook No. 8-4 Flounder 5.3 US Dept. of Agriculture Science and Haddock 5.3 Education Administration Lobster 5.3 Scallops 5.3 New Source: DHA produced by the use Snapper, Red 5.3 of microorganisms. Biotechnological production Swordfish 5.3 and applications of the omega-3 polyunsaturated fatty acid docosahexaenoic acid. Appl Microbiol Biotechnol. 2004 Jan 22 Sole 10.5

12 MeritCare Health System’s

Aunt Cathy’s Aunt Cathy 2009 Guide to Nutrition: Cathy Breedon PhD, RD, CSP, FADA Perinatal/Pediatric Nutrition Specialist MeritCare Health Systems and MAGNESIUM UND School of Medicine Dept. of Pediatrics Fargo, ND

Short Version with Minimal References Included

This shorter version includes only a few of the many references from the scientific literature. If you are interested in seeing the rest of the references, you can access a version on line that includes this information. Go to www.meritcare.com and type Cathy Breedon in the search box. A page will come up that has a box labeled “Cathy Breedon’s Handouts” and you can check the one they have labeled “Guide to Nutrition: Magnesium (PDF)” Other topics are also available at this site.

RDA: Adult women 320; men 420mg Pregnancy 350-400 mg Lactation 320-360 mg

1) This mineral plays a role in over 300 functions in the body, including energy production, nervous system activity, and bone flexibility.

2) Most American adults take in less that 2/3 of the RDA.

3) Some estimates indicate that as many as a third of hospitalized patients have a low magnesium level in their blood that can complicate their care. Poor magnesium status upon entering a hospital is a predictor of a less favorable outcome. Blood magnesium level does not necessarily reflect magnesium adequacy, however. Usually it just indicates that a person’s kidneys are on the job, since the blood Mg level is regulated by the kidney. So if one’s blood level is low, it may reflect inadequate intake or excessive losses (and so this is a very important laboratory finding.) However, a normal blood level tells us very little about the adequacy of magnesium inside the body’s cells, where most of the magnesium-dependent work is trying to be done. In other words, the best way to know if people’s intake of magnesium is appropriate is to obtain a careful history of their usual intake from foods and supplements. This is rarely done.

4) Low magnesium status is associated with a number of adverse health conditions. However, as is the case for most minerals, excessive intake from high-dose supplements is not safe.

1 A Brief Overview of Associations of Magnesium Status with Adverse Health Conditions:

Diabetes:

High blood sugar contributes to magnesium loss in the urine and at the same time poor magnesium status can increase insulin resistance because magnesium is required by the insulin receptors on the cells. Low magnesium intake may also contribute to the development of diabetes, heart disease and stroke, and to certain complications of diabetes such as retinopathy and neuropathy. Many studies have shown that people with diabetes often have poor magnesium status. Improved blood sugar control is associated with eating a “high fiber diet, ” which also provides a better intake of magnesium and chromium, both of which play very important roles in blood sugar and lipid metabolism.

For example, recently researchers at Harvard University published the results of a prospective study at of almost 84,000 women who were followed for 16 years. It was found that those who ate nuts or peanut butter four times a week or more had 25% less likelihood of developing Type II diabetes (the adult type) than was found for women who ate these foods rarely or never. Nuts and peanut butter are especially rich in magnesium, chromium, vitamin E, monounsaturated fat and omega-3 polyunsaturated fats. All of these nutrients have the potential to have played a protective role in this study. Later the data was analyzed differently, it was found that the same pattern existed when the highest and lowest magnesium intake groups were compared. Magnesium inadequacy also is being implicated as a contributor to the development of Type II diabetes in young people that is evolving from the epidemic of childhood obesity .

Cardiovascular Disease and Hypertension:

Abnormal magnesium status is common in patients with cardiovascular diseases for a number of reasons, including poor dietary intake or excessive losses due to use of diuretics or diabetes. Dietary magnesium inadequacy is an independent risk factor in predicting the development of hypertension and cardiovascular disease. Some of the benefits of high fiber diets, legumes (especially peanuts) and nut consumption in decreasing cardiovascular risk are likely due in part to the magnesium content.

Osteoporosis and Bone Health:

Healthy bone production relies on the implantation of calcium into a flexible core called the bone “matrix.” Magnesium is crucial for the development of the bone matrix, and so inadequacy can increase the fragility of bone (because it is less flexible) and it can impair recovery from bone injury.

It is also important to note that calcium and magnesium also interact in other areas of the body, such as nervous system function, blood pressure control and blood clotting, so maintaining an appropriate ratio is extremely important. For example, there is concern that excessively generous calcium supplementation without attention to the calcium:

2 magnesium ratio may increase risk of thrombosis and stroke. With so much calcium fortification and supplementation taking place, we cannot afford to ignore the fact that many Americans have a poor magnesium intake and/or high magnesium losses.

Pregnancy:

Some researchers feel that prenatal magnesium adequacy has a higher priority than even iron supplementation because of the over 300 enzyme systems in the body that depend on magnesium to function properly. Several measures of pregnancy outcome, such as higher frequency of spontaneous abortions (miscarriage), fetal growth retardation, birth defects, maternal hospitalizations, preterm delivery, SIDS and referrals to NICUs have been found to be associated with poor magnesium status in pregnancy. [These issues are related to general nutrition and are separate from issues related to the acute therapeutic i.v. magnesium sometimes used in the treatment of pre- eclampsia or premature labor.]

Other studies have shown a benefit of assuring magnesium adequacy (i.e. providing the RDA level of magnesium) in the reduction of leg cramps in pregnancy. Pregnant women with diabetes need special attention to adequacy of magnesium intake because of the potential for increased losses and the common finding of poor magnesium status among people with diabetes in particular. In addition, inadequacy of magnesium is a risk factor for the development of gestational diabetes as well as Type II diabetes.

Migraine Headaches:

For some migraine sufferers, assuring adequacy of magnesium intake resolves migraine problems. For others, it decreases the frequency or intensity of the headaches. So, while Mg status is certainly not the only factor involved in the development of mi- graines, this intervention can be helpful, and it is safe and inexpensive, so many experts in headache treatment regard assuring magnesium adequacy as a primary intervention.

Premenstrual Syndrome (PMS):

Providing magnesium at the RDA level has been shown to improve “affect” (mood or emotional well-being), and certain tissues of women suffering from PMS have been shown to be low in magnesium. Brain levels of the neurotransmitter serotonin appear to be significantly involved in PMS, and medications that adjust serotonin levels are now being used. Assuring adequacy of magnesium may be a factor (both with and without other medication) because it also is required for the production and metabolism of serotonin (and all neurotransmitter metabolism.)

Cancer: In 2005 a population-based prospective study of 61,433 women suggested that a high magnesium intake may reduce the occurrence of colorectal cancer. Animal studies have also suggested that a higher dietary intake of magnesium is associated with decreased risk of colon cancer, possibly related to an effect of the magnesium-containing substance

3 called chlorophyll protecting against cancer-promoting properties of a structurally similar substance in red meat called heme (or “haem” in the UK.) In addition, in 2004 it was reported that a lower magnesium level in drinking water was associated with risk of death from ovarian cancer.

Kidneys, stone forming, and other renal issues: Low magnesium intake has a role in the development of kidney stones, and the kidney has an important role in regulating magnesium in the blood.

Miscellaneous:

Magnesium adequacy has been found to be a factor in the development and/or management of many chronic conditions, such as asthma, certain thyroid conditions, alcoholism, pancreatitis, hearing loss, and possibly Tourette’s Syndrome, Raynaud's phenomenon, pain management, corneal disease, skin problems, attempts to quit smoking, and certain hyperexcitable states.

Magnesium Losses and Safety Issues:

Conditions like chronic diarrhea, high blood sugar, or the regular use of certain drugs (such as thiazide diuretics) cause magnesium loss. As a rule, drugs for which patients are advised to eat a high potassium diet or to take potassium supplements are also likely to cause loss of magnesium. This problem is often unrecognized, however, and because of an interaction between magnesium and potassium, the failure to correct magnesium losses along with potassium losses further compromises the body’s ability to achieve normal potassium status in the cells. As is the case with potassium, most vitamin/mineral supplements contain little magnesium or none at all. And also like potassium, there may be a need to take in less when one has certain kidney problems.

Excessive intake from supplements or magnesium-containing medications can also cause problems, so never give nutritional supplements of magnesium above the level described above unless prescribed by a doctor. It is also useful to know that magnesium oxide, chloride and diglycinate are the kinds of magnesium that are usually used as a supplement . . . magnesium sulfate (Epsom salts) and hydroxide ("milk of magnesia") are less well absorbed and more likely to cause diarrhea instead (which is why they are used to treat constipation . . . in fact, magnesium citrate is often used as a pre-surgical bowel-cleaning product!) There are a number of magnesium-containing medications, like some over-the-counter antacid products. Check with a pharmacist about magnesium in specific products.

4 Food Sources of Magnesium:

Food sources are the best way to safely assure adequacy, with the added benefit of the other nutrients they provide and the pleasure derived from eating them. Unlike supplement sources, dietary sources of magnesium do not contribute to diarrhea, and there is not a concern about potential overdose. Only individuals with renal failure or another serious medical condition may be advised by a physician to limit intake of dietary magnesium.

As can be seen below, the best sources or magnesium are also foods recommended as healthy choices by the American Dietetic Association, and by many professional health associations concerned with cardiovascular health, diabetes and cancer. And although the nuts and peanut butter do contribute fat and calories, they can easily be included as a part of a healthy diet when used in place of other high calorie or high fat foods. As an added bonus, the form of fat in these foods is rich in monounsaturated fat and omega-3 fatty acids. They are low in saturated fat and trans fatty acids, have no cholesterol, and compared with other forms of fat, they are generally found to be protective against heart disease, diabetes and cancer.

Some of the Best Dietary Sources of Magnesium:

Magnesium (mg per 1/2 cup)

500 mg or more Peanuts and Peanut butter

100-300mg Wheat germ*, Bran cereals*, Wild rice Lentils, Split peas, Tofu, Cashews, Almonds

*Note that refining grains removes most of the magnesium and it is not added back as iron is when grain is “enriched.” The phytate content of the grain is also a factor in the availability of dietary magnesium.

25-90 mg Fortified breakfast cereals, Oatmeal, Miso, Spinach, Milk, Yogurt, Fish, Brewer's yeast (80 mg/Tblsp), Cocoa powder (25 mg/Tblsp)

5 Aunt Cathy’s Guide to Nutrition: 2009 Nutrition Issues in MeritCare Health System Multiple Sclerosis (“With References” Version) Cathy Breedon PhD, RD, CSP, FADA (For people with MS, their Clinical and Metabolic Nutrition Specialist MeritCare Health Systems and families and interested UND School of Medicine, Fargo, ND health care professionals) Multiple Sclerosis (MS) is an inflammatory disease of the myelin of the central nervous system, the origin of which is still unknown. Genetic, infectious, immunological and environmental factors have all been blamed, but none of these factors on their own can explain the whole spectrum of this disease.

There Are Two Major Areas of Concern Regarding Nutrition and MS:

Nutrition factors in the development and progression of MS

Nutrition problems resulting from MS and its treatment

Nutrients of interest in the development and progression of MS * *(Each of these will be discussed in the following pages.)

• Vitamin D • Fats (amounts and forms, such as saturated fat, monounsaturated fat, and omega-3 and omega-6 polyunsaturated fats) • Antioxidants (e.g. vitamin E, selenium, alpha-lipoic acid, certain phytochemicals) • B vitamins (B6, B12, folic acid. biotin) • Minerals (magnesium, iron and phosphorus) • Carnitine

Nutrition issues will also interact with other factors:

• Individual factors including genetic vulnerabilities, ethnicity, skin pigment and gender. • Exposure to certain viral agents or other infectious agents during sensitive periods. • Age at which a nutritional contributing factor to MS is experienced. • Geographic variables such as latitude, altitude, soil mineral patterns and proximity to sea coasts.

1 For ease of reading, only a few references will be included in the text. A large number of references will be grouped at the end of each section, and some annotated references / abstracts will be included at the end of the paper.

Vitamin D

The results of large recent studies supported a protective effect of vitamin D intake on risk of developing MS. Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able to improve symptoms of multiple sclerosis. (Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest. 2005. Vitamin D intake and incidence of multiple sclerosis Neurology.,2004)

Vitamin D inadequacy is related to the ability of the sun’s rays to activate skin receptors. There is a clear latitude gradient, so that the likelihood of making inadequate vitamin D in the skin is greater in the north. Living in the north is also a known risk factor for MS, which is why the northern tier is called the “MS Belt” as well as the “Rickets Belt.”

The map below is from Tufts Health & Nutrition Newsletter 1996. It shows that sunlight is too weak for vitamin D synthesis from November through February at the 42nd parallel. Between the 40th and 42nd, the sunlight is too weak to make vitamin D in January and February. At that rate, it suggests that for every degree of latitude, there is an additional month of inadequate vitamin D production. The northern border is the 49th parallel across much of the USA. Alaskans and Canadians are even farther up there.

Why have we assumed that people, especially those in the northern tier, are obtaining adequate vitamin D? I think we have missed this because we do not ordinarily obtain vitamin D levels as part of our regular health care assessment, and most

2 importantly, because people with vitamin D deficiency do not look funny unless they are infants (who may develop the bowed legs of rickets, or other apparent bone deformity.) After childhood, the effects of vitamin D deficiency are often far less visible and unrecognized. Our nutrition health model has tended to be “If you don’t look funny, you must be fine.” Now that vitamin D levels are beginning to be done as part of health check-ups, it has been noted that there is actually “an unrecognized epidemic of vitamin D deficiency in the northern tier.” [The vitamin D epidemic and its health consequences. J Nutr. 2005 Nov;135(11):2739S-48S.]

Fracture history and bone loss in patients with MS: MS patients have significantly reduced bone mass and a high prevalence of abnormal vitamin D status. In one study, in the absence of major trauma, fractures occurred in only 2% of controls but in 22% of MS patients. After over two years of prospective follow-up both men and women with MS lost substantially more bone annually in the spine and in the femoral neck (the part of the leg bone where it meets the hip) than did the people without MS. Having had steroid treatment for more than 5 months, and a person’s ambulatory status (ability to walk) were both predictors of bone loss as well. (Vitamin D deficiency and reduced bone mineral density in multiple sclerosis: effect of ambulatory status and functional capacity. J Bone Miner Metab. 2005 Long-term effects of intravenous high dose methylprednisolone pulses on bone mineral density in patients with multiple sclerosis. Eur J Neurol. 2005 (Fracture history and bone loss in patients with MS. Neurology. 1998) Reduced bone mass and fat-free mass in women with multiple sclerosis: effects of ambulatory status and glucocorticoid use. Calcif Tissue Int. 1997)

Nutrition Connection: Bone loss in the spine occurred significantly faster in MS patients who had low 25-hydroxyvitamin D levels (<20 ng/mL). In those with normal levels, bone loss was insignificant. At the femoral neck, bone loss was substantial in all MS patients compared with controls, but was somewhat faster in the group with low vitamin D. These authors concluded that MS patients have more frequent fractures and lose bone mass more rapidly than do healthy age- and gender-matched peers, in part related to insufficient vitamin D. Vitamin D repletion might reduce the rate of bone loss and decrease osteoporosis-related fractures.

“Vitamin D deficiency and reduced bone mineral density in multiple sclerosis: effect of ambulatory status and functional capacity. J Bone Miner Metab. 2005;23(4):309-13 …In conclusion, BMD is significantly lower in MS patients than in healthy controls, vitamin D deficiency is prevalent in MS, and ambulatory status is a determinative factor for osteoporosis in MS. Patients should be encouraged to have adequate sunlight exposure and to increase their mobility. Specific strengthening exercises for hip and back muscles in MS patients would have a substantial impact on bone density, osteoporosis, fracture risk, and mobility.” [CB comment: Since this was published it has become apparent that trying to solve the problem with sunlight exposure alone will be unsuccessful much of the year if you live up north. In other situations, the sunlight approach may be hampered by intolerance of warm weather. These and other reasons often make it necessary to approach the problem with supplemental vitamin D, either in milk or in vitamin pills. More on this later.]

Genetic Defect in Vitamin D Metabolism? 1,25-Dihydroxyvitamin D3 is the hormone (biologically active) form of vitamin D. It exerts an immuno-suppressive effect and can completely prevent experimental autoimmune encephalomyelitis (EAE – the mouse model of MS.) Nataf et al (1996) and Cantorna et al (1996) reported that the non- activated vitamin D from diet or sunlight has no effect on mice with this condition. However, providing the 1,25 form of vitamin D resulted in decreased progression of EAE, and in some mice actual improvement of myelin injury. It is possible that failure to activate vitamin D may account for some forms of MS. Degrees of impaired activation may account for the variation seen in the severity of symptoms. And clearly, some people may have no genetic defect like this at all . . . they just have poor vitamin D intake and poor production in the skin (e.g. they live up north.)

3 The active (1,25-dihydroxy vitamin D exerts most of its actions only after it has bound to its specific receptors in the nucleus of a cell. Fukazawa et al. (1999) found an association of MS with Vit D Receptor Gene (VDRG) polymorphism. Polymorphism just means that the receptors on body cells that are looking for vitamin D apparently come in different forms in different groups of people. In other words, there appears to be variation in the form of the vitamin D receptor in some people. This may be another genetic trait involved in the development of MS. [Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population. J Neurogenet. 2005 Jan-Mar;19(1):25-38. …Our results support a role for the VDR gene increasing the risk of developing multiple sclerosis, particularly the progressive clinical subtypes of MS. CTLA-4 gene polymorphism may modulate disease in Japanese multiple sclerosis patients. J Neurol Sci. 1999 Dec 1;171(1):49-55.]

Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Except in those with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <140 nmol/L, which require a total vitamin D supply of 250 mcg (10000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of > or = 1000 mcg (40000 IU)/d. Because vitamin D is potentially toxic, intake of >25 mcg (1000 IU)/d has been avoided even though the weight of evidence shows that the currently accepted “no observed adverse effect limit” of 50 mcg (2000 IU)/d is too low by at least 5-fold. (Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr. 2006 Apr;136(4):1117-22.)

Point: Since it now looks like 1000-2000 iu is needed up north just to assure adequate blood levels of vitamin D (which is important for many reasons,) and since this level is clearly safe, and since some people with MS are avoiding milk (the major dietary source of vitamin D,) vitamin D supplementation is a very good idea. It is not invasive or expensive. Assuring vitamin D adequacy may help to prevent the “excess” cases of MS seen in northern latitudes. Variations in diet or sun exposure that alter adequacy may explain some differences in severity and relapsing of symptoms. Some people may have a defect in activation of vitamin D to the active form, and may need to receive “calcitriol” (a prescription form of vitamin D that is already activated). A one-time blood test of 1,25 dihydroxy vitamin D level may be useful in identifying this problem if it exists. For more on vitamin D, please refer to one of my other handouts: “Aunt Cathy’s Guide to Calcium and Vitamin D Supplements”

As can be seen below, the scientific research in this area is growing incredibly rapidly in just a short time. I have put some shortened versions of the abstracts of some recent studies at the end of this paper for those of you who are interested in the actual studies, including the health care professionals who may be looking at this handout. (I want to be sure they believe me that I am not making this stuff up! ☺ )

However, the summary of it all is “Yes . . . Vitamin D adequacy is a really big deal in MS.” The vitamin D recommendations will be reviewed in the summary at the end of this paper. In the meantime, here is just a list of some vitamin D / MS References from 2000-2007.

4 2000- spring 2009 vitamin D and MS references

2009

Diet and nutrition: vitamin D regulates MS gene. Environ Health Perspect. 2009 May;117(5):A196. Clinical implications of a possible role of vitamin D in multiple sclerosis. J Neurol. 2009 Apr 28. The relevance of vitamin D receptor gene polymorphisms for vitamin D research in multiple sclerosis. Autoimmun Rev. 2009 Jun;8(7):621-6. Metabolism of 1alpha,25-dihydroxyvitamin D2 by human CYP24A1. Biochem Biophys Res Commun. 2009 Jun 26;384(2):144-8. Multiple sclerosis and the major histocompatibility complex. Curr Opin Neurol. 2009 Jun;22(3):219-25. Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 Vitamin D receptor variant in this interaction. Mult Scler. 2009 May;15(5):563-570. Vitamin D status and effect of low-dose cholecalciferol and high-dose ergocalciferol supplementation in multiple sclerosis. Mult Scler. 2009 Jun;15(6):735-40. Fok-I vitamin D receptor gene polymorphism (rs10735810) and vitamin D metabolism in multiple sclerosis. J Neuroimmunol. 2009 Feb 15;207(1-2):117-21. Serum vitamin B12, folate, and homocysteine levels and their association with clinical and electrophysiological parameters in multiple sclerosis. J Clin Neurosci. 2009 Mar;16(3):399-403. A salmon based diet protects mice from behavioural changes in the cuprizone model for demyelination. Clin Nutr. 2009;28(1):83-7. 2008

Therapeutic potential of vitamin D for multiple sclerosis. Curr Med Chem. 2008;15(5):499-505. Vitamin D as an immune modulator in multiple sclerosis, a review. J Neuroimmunol. 2008 Feb;194(1-2):7-17. Vitamin D and multiple sclerosis: an update. Nutr Rev. 2008 Oct;66(10 Suppl 2):S135-8. A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10. Med Hypotheses. 2008;71(1):85-90. Therapeutic potential of vitamin D for multiple sclerosis. Curr Med Chem. 2008;15(5):499-505. Coagulation status and biochemical and inflammatory markers in multiple sclerosis. J Clin Neurosci. 2008 Apr;15(4):393-7. Future research directions in multiple sclerosis therapies. Semin Neurol. 2008 Feb;28(1):121-7. Epidemiology of multiple sclerosis: from risk factors to prevention. Semin Neurol. 2008 Feb;28(1):17-28. Ectopic thymic parathyroid adenoma and vitamin D deficiency rickets: a 5-year-follow-up case report and review of literature. Bone. 2008 Apr;42(4):819-24. Hormonal influences in multiple sclerosis. Curr Top Microbiol Immunol. 2008;318:267-311. A longitudinal study of serum 25-hydroxyvitamin D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):152-7. Vitamin D status modulates the immune response to Epstein Barr virus: Synergistic effect of risk factors in multiple sclerosis. Med Hypotheses. 2008;70(1):66-9. Vitamin D-dependent rickets as a possible risk factor for multiple sclerosis. Arch Neurol. 2008 Jun;65(6):809-11. Update on the etiology and pathogenesis of multiple sclerosis and neuromyelitis optica. Nippon Rinsho. 2008 Jun;66(6):1087-91. The immunology of multiple sclerosis: disease mechanisms and therapeutic targets. Minerva Med. 2008 Apr;99(2):119-40. Pathways and products for the metabolism of vitamin D3 by cytochrome P450scc. FEBS J. 2008 May;275(10):2585-96. A unifying multiple sclerosis etiology linking virus infection, sunlight, and vitamin D, through viral interleukin-10. Med Hypotheses. 2008;71(1):85-90. Vitamin D: a candidate for the environmental effect in multiple sclerosis - observations from Norway. Neuroepidemiology. 2008;30(3):140-6. Vitamin D(3) in fat tissue. Endocrine. 2008 Feb;33(1):90-4. Vitamin D and multiple sclerosis: an update. Nutr Rev. 2008 Oct;66(10 Suppl 2):S135-8. Assessment of vitamin D status and definition of a normal circulating range of 25-hydroxyvitamin D. Curr Opin Endocrinol Diabetes Obes. 2008 Dec;15(6):489-94. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-9. 2007 The immunological basis for treatment of multiple sclerosis. Scand J Immunol. 2007 Oct;66(4):374-82. Novel biomarkers in autoimmune diseases: prolactin, ferritin, vitamin D, and TPA levels in autoimmune diseases. Ann N Y Acad Sci. 2007 Aug;1109:385-400. 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. Neurosci Res. 2007 Aug 15;85(11):2480-90.2007 Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18.

2006 Dysfunction of the vitamin D endocrine system as common cause for multiple malignant and other chronic diseases. Anticancer Res. 2006 Jul-Aug;26(4A):2581-8. New insights into the mechanisms involved in the pleiotropic actions of 1,25dihydroxyvitamin D3. Ann N Y Acad Sci. 2006;1068:194203.

5 Epidemiology and natural history of multiple sclerosis: new insights. Curr Opin Neurol. 2006 Jun;19(3):248-54 The role of vitamin D in multiple sclerosis. Ann Pharmacother. 2006 Jun;40(6):1158-61 Vitamin D & autoimmune disease--implications for practice from the MS literature. J Am Diet Assoc. 2006 Mar;106(3):418-24. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8. Vitamin D and its role in immunology: MS, and inflammatory bowel disease. Prog Biophys Mol Biol. 2006 Sep;92(1):60-4 Vitamin D physiology. Prog Biophys Mol Biol. 2006 Sep;92(1):4-8. 1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res. 2006 May 15;83(7):1299-309. Epidemiology of disease risks in relation to vitamin D insufficiency. Prog Biophys Mol Biol. 2006 Sep;92(1):65-79. The photobiology of vitamin D--a topic of renewed focus. Tidsskr Nor Laegeforen. 2006 Apr 6;126(8):1048-52. IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol. 2006 Nov 1;177(9):6030-7. Vitamin D physiology. Prog Biophys Mol Biol. 2006 Sep;92(1):4-8. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards. J Nutr. 2006 Apr;136(4):1117-22. Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry. 2006 Dec;14(12):1032-40.] 2005 25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult Scler. 2005 Jun;11(3):266-71. Why we should offer routine vitamin D supplementation in pregnancy & childhood to prevent MS. Med Hypotheses. 2005;64(3):608-18. Effects of alfacalcidol therapy on serum cytokine levels in patients w multiple sclerosis. Srp Arh Celok Lek.2005;133 Suppl 2:124-8. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1294-6. Vitamin D deficiency & reduced bone mineral density in MS: effect of ambulatory status & functional capacity. J Bone Miner Metab. 2005 Long-term effects of intravenous high dose methylprednisolone pulses on bone mineral density in patients with MS. Eur J Neurol. 2005. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest. 2005. The vitamin D epidemic and its health consequences. J Nutr. 2005 Nov;135(11): 2739S-48S. Variation in the vitamin D receptor gene is associated with multiple sclerosis in an Australian population. J Neurogenet. 2005;19(1):25-38. 2000-2004

Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):575-9. Mounting evidence for vit. D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med 2004;229(11):1136-42. Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr. 2004 Aug;58(8):1095-109. Vitamin D intake and incidence of multiple sclerosis Neurology. 2004 Jan 13;62(1):60-5. Dodging MS & RA with vitamin D. Health News. 2004;10 (3):4. The pleiotropic actions of vitamin D. Bioessays. 2004;26(1):21-8. D-vitamin: old paradoxes & new perspectives Ugeskr Laeger. 2004; 166(1-2):36-40. The vitamin D deficit. Science. 2003 12;302(5652):1886-8. Vitamin D target proteins: function & regulation. J Cell Biochem. 2003; 88(2):238-44. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr. 2003. Ultraviolet radiation & autoimmune disease: insights from epidemiological research. Toxicology. 2002;181-182:71-8. Vitamins for chronic disease prevention in adults: clinical applications. JAMA. 2002; 287(23):3127-9. Vitamin D: its role & uses in immunology. FASEB J. 2001;15(14): 2579-85 Vitamin D & autoimmunity: is vitamin D status an environmental factor affecting autoimmune disease prevalence?. Proc Soc Experi Biol Med. 2000. 1,25-dihydroxyvitamin D3 treatment decreases macrophage accumulation in the CNS of mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2000. Vitamin D: a natural inhibitor of multiple sclerosis. Proc Nutr Soc. 2000.

Total Fat Intake: The Swank Studies (Swank & Dugan 1990.)

In this famous study, 144 MS patients followed a very low-fat diet for 34 years. Patients who adhered to the diet (which contained less than 20 g fat/day – a VERY small amount) showed significantly less deterioration and much lower death rates than did those who ate more fat. The greatest benefit was seen in those with minimum disability at the start of the trial. In this group, when those who died from non-MS diseases were excluded from the analysis, 95% survived and remained physically active. Only 20% who did not follow the diet survived for the whole the study period. Interpretation Caution: It has

6 been argued that maybe those for whom the diet appeared to be helpful (that is, people doing well in terms of their MS) stayed on the diet, and those for whom it appeared to be unhelpful (those with worsening MS for whatever reason) gave up the diet and quit. So, maybe it was not the diet that accounted for the difference in outcome. Or maybe it was.

Other observations: Swank (1991) also found that women did better than men, and that patients treated early did better than when treatment was delayed. “High sensitivity to fats suggests that saturated animal fats are directly involved in the genesis of multiple sclerosis.” In addition to the issue of Total Amount of Fat in the diet, the Forms of Fat may be an important factor. The distinctions between the various forms of dietary fats being investigated now in this area had not been identified at the time the Swank studies were undertaken.

Biological effects of fish oils in relation to chronic diseases. Omega-3 marine lipids (polyunsaturated fish oils) affect the types of substances called eicosanoids produced in the body. These include important substances like prostaglandins, leukotrienes, prostacyclins, and thromboxanes. The involvement of prostaglandins and leukotrienes in immune responses has led to studies on the effects of fish oil on various chronic diseases associated with abnormalities of the immune system, such as MS. One example of an early observation was that Greenland Eskimos have a high intake of seal, whale and fish, (rich sources of Omega-3 marine lipids), and MS is uncommon in Eskimos.

Supplementation of Polyunsaturated Fatty Acids (PUFAs). In 1990, Bates reviewed published controlled trials of omega-6 PUFAs involving 172 patients with acute remitting MS and one study with omega-3 PUFAs in a double blind controlled study of 312 patients. A trend was found suggesting that the addition of omega-6 and omega-3 PUFAs to the diet of patients with MS results in a reduction of the severity and frequency of relapses and in a mild overall benefit in a two year period.

Omega-3 polyunsaturated fatty acids and cytokine production in health and disease. In 1997, Calder studied eicosanoids made from omega-6 oils because they modulate the production of pro-inflammatory and immunoregulatory substances called cytokines. Overproduction of these cytokines is associated with both septic shock and chronic inflammatory diseases. The omega-3 polyunsaturated fatty acids (PUFAs) called EPA and DHA are found in fish oils. They suppress the production of the eicosanoids made from Omega-6 PUFAs. EPA is used for making an alternative family of eicosanoids that are less inflammatory. So, dietary fats which are rich in omega-3 PUFAs have the potential to alter cytokine production (Gallai et al. 1995 Endres & von Schacky 1996.) Deficiencies of PUFAs and replacement by nonessential forms of fat has been reported in the plasma lipids in multiple sclerosis (Holman et al. 1989.) They found that phospholipids in people with MS have normal levels of (omega 6) linoleic acid and the next fatty acid in the pathway to make eicosanoids was elevated. But all the omega 6 fatty acids greater than 18 carbons long were subnormal in MS. This pattern is an indication of impaired ability to add carbons to lengthen the carbon chain to make the eicosanoids. All the omega-3 acids were found to be subnormal in people with MS.

7 Depression in MS Hibbeln and Salem (1995) reported that decreased omega-3 fatty acid intake (especially DHA) correlates with increasing rates of depression, and this may be a factor in depression in MS. Depressed individuals with MS have a worse outcome than non-depressed individuals. There is now evidence of impaired phospholipid metabolism and impaired fatty acid-related cell communication processes. Impaired phospholipid and fatty acid metabolism (e.g. involving DHA – an omega-3 fat that is critical for brain function) may be a primary cause of depression in many patients and may explain the interactions with MS and other diseases (Horrobin & Bennett, 1999.) Additionally, there are depression issues related to (what else?) Vitamin D and folic acid (a B vitamin discussed later.) Specific MS-related research with omega-3 fats and other polyunsaturated fats is limited, although the research on benefits of these fats in many aspects of human health is quite impressive. More information about wider applications is available in my handouts on line on various types of fats and oils. [Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry. 2006 Dec;14(12):1032-40.]

Here are some of the most recent reports investigating the role of various forms of fat specifically in MS: Polyunsaturated fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. This review summarizes the knowledge of the role of dietary PUFAs, especially omega-3, on normal brain function. It reports the evidence pointing to potential mechanisms of omega-3 fatty acids in development of neurological disorders and efficacy of their supplementation in terms of symptom management. Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. These authors concluded that “Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.”

Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):397-404. This study suggests that “a low fat diet supplemented with omega-3 PUFA can have moderate benefits in RRMS patients on concurrent disease modifying therapies.”

Polyunsaturated fatty acid supplementation in MS. Int MS J. 2005 Nov;12(3):88-93. This article focuses on polyunsaturated fatty acid (PUFA) supplementation. Small-scale studies have demonstrated trends towards some beneficial effects. PUFA supplementation is generally well tolerated, although some specific supplements are best avoided and some clinical situations warrant caution. A review of the efficacy and safety data suggests that PUFA supplementation may be a promising approach. Large-scale trials are required to confirm the benefits.

Effects of omega-3 fatty acids on cognitive function with aging, dementia, and neurological diseases. Evid Rep Technol Assess (Summ). 2005 Feb;(114):1-3.

Omega-3 fatty acids in health and disease: part 2--health effects of omega-3 fatty acids in autoimmune diseases, mental health, and gene expression. J Med Food. 2005 Summer;8(2):133-48.

Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr. 2002 Dec;21(6):495-505. “… There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.”

Antioxidants. Reactive Oxygen Species (ROS) are byproducts of metabolism that are thought to be involved in causing or contributing to MS and also to experimental allergic encephalomyelitis (EAE – the mouse model of MS.) Another common name for ROS is “free radical.” These substances can cause injury to a person’s cells if they are not handled properly (that is “quenched” or “extinguished” by substances called antioxidants.)

8 Van der Goes et al. (1998) found that phagocytosis of myelin by macrophages triggers the production of ROS. Free radical action has been suggested as a causal factor in multiple sclerosis (J Neurol 1999.) For example: malondialdehyde in the blood (a marker for low vitamin E or other antioxidant protection) was increased by 38% during MS exacerbations (periods of worsening symptoms.) These changes suggest that there is increased free radical (ROS) production and consumption of the scavenger molecules during the active phase of the disease.

Demyelination: the role of reactive oxygen and nitrogen species. Smith et al.(1999) found that reactive oxygen (ROS) and nitrogen species (RNS) play a role in demyelination, such as in the inflammatory demyelinating disorders like multiple sclerosis. The concentrations of reactive oxygen and nitrogen species (e.g. superoxide, nitric oxide & peroxynitrite) can increase dramatically under conditions such as inflammation. This can overwhelm the person’s antioxidant defenses within tissues.

Such oxidative and/or nitrative stress can damage the lipids, proteins and nucleic acids of cells and mitochondria, potentially causing cell death. The reactive species (ROS and RNS) may also damage the myelin sheath, promoting its attack by macrophages. Damage can occur directly by lipid peroxidation, and indirectly by the activation of proteases and phospholipase A2. The neurological deficit resulting from experimental autoimmune demyelinating disease has generally been reduced by trial therapies [that is, antioxidants] that diminish the concentration of reactive oxygen species. However, therapies aimed at diminishing reactive nitrogen species have had a more variable outcome, sometimes exacerbating disease.

Selenium Issues: Selenium (Se) is a mineral in the news in many areas of medical research, such as diabetes, prostate cancer, thyroid disease, immune system function and multiple sclerosis (Foster HD,1993.) Glutathione peroxidase is a very important antioxidant in the body and selenium is a key component of it. Mazzella et al., (1983) found that the Se-dependent glutathione peroxidase activity in the red blood cells was lower in the MS patients.

In addition, the Se concentration in the diet of MS patients was studied and found to be less than the minimum values suggested by the US Food and Nutrition Board. The authors’ interpretation: “Modified glutathione peroxidase activity found in erythrocytes [red blood cells] of MS patients is independent from the Se concentration in blood.” The reported dietary inadequacy was not addressed further.

My observations: It is likely that suboptimal Se intake affects various tissues differently, and that possibly the blood levels had a “higher priority” for the Se available. In view of new knowledge about the significant health risks associated with Se inadequacy, it is a good idea to assure an intake within recommended ranges (60-150 mcg). Studies in the late ‘90s have revealed that dietary Se intakes are sub-optimal in diets of many people. This is especially true in certain geographic regions (such as Phoenix, AZ) where the soil is quite low in selenium.

9 It is very hard to estimate a person’s actual selenium intake because it is so variable in foods. Selenium is an unusual mineral because the amount in a food depends on where it was produced, and especially in this country, that can be difficult to determine. Excessive selenium intake can be toxic however, so the upper limit of safety is set at 600 mcg/day, and the level regarded as toxic is a regular intake of 800 mcg/day. My handouts on “Nutrition and Eye Health” and “Nutrition in Prostate Cancer” both contain additional information, as selenium and the selenium-containing antioxidant glutathione peroxidase are looking very important in general. It is also being found to be very important in the operation of the immune system and the thyroid gland.

Other potent antioxidants are also being explored in relation to MS, such as “alpha- lipoic acid.” This substance is also looking to be potentially very beneficial in diabetes, most specifically with some of the neurologic problems (neuropathy) experienced by people with diabetes over time. In general, it appears that any inflammatory or autoimmune condition results in greater production of free radicals, and so as a generality, a more generous intake of antioxidants is reasonable.

Alpha-lipoic acid is similar to B vitamins in several ways. It is extremely unlikely to be toxic ven at high doses. Most studies have shown that about 600 mg/day over time is the level associated with measurable benefits in diabetes research.

It is also reasonable (and a very good idea) to seek out generous potent dietary antioxidants (like the brightly colored pigments fruits and vegetables . . . lycopene, anthocyanins, lutein, etc.) The antioxidant vitamins (C and E) are not nearly as potent as antioxidants as the plant pigments are. For example, lycopene (the red color in tomatoes) is 200 times as potent an antioxidant as vitamin E. These substances are not vitamins or minerals, but they fall into a class called “phytochemicals” which just means “plant chemicals.”

Not all plant chemicals in the world are safe, of course . . . consider poison ivy and opium, for example. However, the family of these plant pigments (called carotenoids) are very safe. The only side effect is that eating lots of beta-carotene in carrots, squash and sweet potatoes may give your skin a harmless orange-ish glow. [That can pass for a tan up her in North Dakota! ☺] The huge health benefits now being recognized is the reason behind the recent change from the familiar “Five-a-Day” recommendation for fruits and vegetables in everyone’s diet to something approximating:

“Eat a whole bunch of brightly colored vegetables and fruits every day for a whole bunch of reasons!!!!”

Antioxidants and MS: Here is a list of some research specifically about antioxidants and MS. There is much more since 2006 but I didn’t get a chance to add it all here.

10 An annotated set of references / abstracts follows at the end of this paper for people who want more detail.

2006 Dietary chelators as antioxidant enzyme mimetics: implications for dietary intervention in neurodegenerative diseases. Behav Pharmacol. 2006 Sep;17(5-6):425-30. Antioxidants in multiple sclerosis: do they have a role in therapy? CNS Drugs. 2006;20(6):433-41. Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation. Curr Pharm Des. 2006;12(27):3521-33. 2005 Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005 Feb;11(1):24-32. The role of methallothioneins in experimental autoimmune encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci. 2005 Jun;1051:88-96 Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis. Neuroscience. 2005;132(4):1135-49. 2004 Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol. 2004 Nov 1;173(9):5794-800. Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis. J Neurosci Res. 2004 Nov 1;78(3):362- 70. Protective effects of caffeic acid phenethyl ester against experimental allergic encephalo-myelitis-induced oxidative stress in rats. Free Radic Biol Med. 2004 Aug 1;37(3):386-94 The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004 Mar;251(3):261-8. Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004 Mar;148(1-2):146-53. 2003 Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis. J Neuroimmunol. 2003 Jun;139(1-2):27-35. 2002 Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J Neuroimmunol 2002 Oct;131(1-2):104-14.

My comments on all these fat and antioxidant issues: Different types of fat and the adequacy of antioxidant protection interact with each other. Clearly there is deranged metabolism of fatty acids in MS. Is it a cause of MS, or the result of having MS? Can it be manipulated? Future directions of research should include evaluating these substances together and not just as individual agents. For example, it would be useful to study:

• Comparisons of ratios of omega 3 to omega 6 PUFAs (PolyUnsaturated Fatty Acids), with attention also paid to the ratios of antioxidants to PUFAs.

• Evaluation of fat issues while accounting for oxidation status.

• Fish x Fat x Antioxidants Antioxidants inhibit the enzyme lipoxygenase and so inhibits leukotriene synthesis. The fish oil leads to production of less inflammatory leukotrienes. Antioxidants also protect the fish oils from oxidation We need to learn which of these factors can be useful in trying to prevent the development of MS, or slow its progress.

• Differentiate in the study between omega-3 and omega-6 PUFAs in terms of the size of the molecule (shorter vs longer chain length,) because this is now looking like an important feature to consider in research related to many other health conditions.

Issues involving dietary fat and antioxidants are intimately related. For more detail on these issues, including food sources and supplement considerations, please see my other

11 handouts “Aunt Cathy’s Guide to Eye Health” (for more information about antioxidants) and “Aunt Cathy’s Guide to Omega 3 Fatty Acids.”

Other areas of investigation-- B Vitamins: Biotin, Vitamin B6, Vitamin B12, and Folic Acid

What the Heck is Biotin? It is a B vitamin involved in many body functions that process carbohydrates, fats and proteins. The recommended intake is 30-100 mcg (based on reported dietary intakes in healthy people in the US.) Biotin is not toxic, even at levels as high as 10,000 mcg/day (1000 times the upper end of the assumed adequacy level.) Bacteria in the intestine produce biotin and they contribute a significant amount, so getting an adequate amount is unlikely for any person who chronically uses antibiotics, unless biotin is supplemented. Symptoms of inadequacy include “tingling in extremities.”

Biotin is a B vitamin that usually receives little attention, since most people obtain an adequate amount from the intestinal bacteria. However, it is looking interesting in other autoimmune diseases such as diabetes. (The effect of chromium picolinate and biotin supplementation on glycemic control in poorly controlled patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized trial. Diabetes Technol Ther. 2006 Dec;8(6):636-43. Use of chromium picolinate and biotin in the management of type 2 diabetes: an economic analysis. Dis Manag. 2005 Aug;8(4):265-75.)

There is little activity in the MS research at present. However, Anagnostouli et al.(1999), looked at concentrations in human cerebral-spinal fluid (CSF) & blood serum. Patients with common neurologic disorders (including MS) were compared with people who had no evidence of nutritional or neurologic disorders. They found significantly lower values for biotin in people with MS (both CSF & serum). They concluded that this low level could be the result of poor biotin absorption in the intestine caused by the underlying disease, or related to a biotin-binding immunoglobulin which may be involved in MS development and progression.

Vitamin B6 (Pyridoxine) It is well known that this vitamin plays a vital role in many physiological processes, such as nerve communication, processing protein and fats, and supporting the immune system. Levels higher than the RDA appear to have be of some benefit in decreasing damage to nerves in other autoimmune conditions such as diabetes. In many of these activities, vitamin B6 is paired with the mineral magnesium (more on magnesium later) and it appears that both substances need to be present at the same time for efficient operation. This is just one more situation in which studying a single nutrient is unlikely to be as useful as studying them in combination.

Of all the B vitamins, B6 is the most likely to be a problem in very high doses fora pretty long time . . . such as 200-500 mg/day chronically in the most sensitive individuals. (The RDA level is only 1-2 mg.) Interestingly, the symptoms associated with the highest doses, while rare, include some MS-like tingling in the arms. The idea that an unrecognized inadequacy of vitamin B6 might be a factor in MS comes from just one study: “Serious dangers to health may be associated with undetected, lingering

12 subclinical deficiencies . . . This includes induction of and predisposition to diseases such as atherosclerosis and multiple sclerosis” (Kesel et al. 1999.)

Vitamin B12: Vitamin B12 levels have been low in MS patients in many studies. The significance of this is unclear. Is it related to poor absorption? Is it poorly utilized or kept in the wrong compartments in the body? (Goodkin, 1994) Low vitamin B12 status may increase vulnerability to the viral and immunologic processes which are suspected as being factors in causing MS. Certainly, adequacy of vitamin B-12 has critical importance to neurologic health (for everyone).

Some individuals are at special risk of poor vitamin B12 status. Some patients may be following strict vegetarian diets with inadequate vitamin B12, or using medications such as Glucophage (also called Metformin) for diabetes. Others take medications that block production of stomach acid called “proton pump inhibitors,” such as Prilosec, Prevacid, Protonix, Pepcid AC, and Nexium.

Any of these situations will increase the likelihood of impaired vitamin B-12 availability and/or absorption. Additionally, as we age, some people simply begin to produce much less acid in their stomachs. Inadequate stomach acid decreases our ability to absorb vitamin B12 from food sources. However, the form found in vitamin pills and fortified cereals is far more reliably absorbed in spite of these problems.

Because of this, 15-30% of the elderly are found to be deficient in this critical vitamin when their level is actually checked with a sensitive measure. (Waiting and watching for changes to appear in red blood cell size is not a sensitive measure because it is a very late-appearing symptom of vitamin B12 deficiency.) Assuring a generous intake of absorbable vitamin B-12 is not difficult or expensive. For most people simply taking a multivitamin supplement prevents this problem. In some studies described below, vitamin B12 administered with other therapeutic agents may have some benefit in MS, although a straightforward vitamin B12 deficiency is apparently not the reason. For more information about vitamin B-12 issues, please see my other hand-out “Aunt Cathy’s Guide to Vitamin B-12.” Here are some research regarding Vitamin B12 and MS. An annotated / abstract reference list follows at the end of this paper. Newer references are available but not in time for this publication

2006 Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006 Nov;5(11):949-60. Vitamin B12 and methionine synthesis: a critical review. Is nature's most beautiful cofactor misunderstood? Biofactors. 2006;26(1):45-57. Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):189-92. 2005 Vitamin B12, demyelination, remyelination and repair in multiple sclerosis J Neurol Sci. 2005 Jun 15;233(1-2):93-7. 2004 Attenuation of experimental autoimmune encephalomyelitis and nonimmune demyelination by IFN-beta plus vitamin B12: treatment to modify notch-1/sonic hedgehog balance. J Immunol. 2004 May 15;172(10):6418-26. 2003 Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler. 2003 Jun;9(3):239-45. Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis. Nutr Neurosci. 2003 Jun;6(3):189-96.

13 2002 Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B(12): mechanism of action and clinical importance: roles of the locus coeruleus and central noradrenergic systems. Med Hypotheses. 2002 Nov;59(5):594- 602. A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the "Cari Loder regime") in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002 Sep;73(3):246-9

Other B-vitamins and Iron: Regeneration of myelin requires both adequacy of iron and of B vitamins, especially vitamin B12 and folic acid. This situation is a good illustration of the problems inherent in evaluating the effects of manipulating or measuring a single nutrient to detect benefit. Many if not most important nutrient-related effects require the adequacy of several nutrients working together and so the common type of “single- nutrient research” will often fail to detect and identify important roles of that nutrient.

Hyperhomocysteinemia is associated with cognitive impairment in multiple sclerosis. J Neurol. 2008 Jan;255(1):64-9. Iron and the folate-vitamin B12-methylation pathway in multiple sclerosis. Metab Brain Dis. 2006 Sep;21(2-3):121-37. Some subjects with multiple sclerosis (MS) present with low blood iron parameters. Anecdotal reports and a single patient study suggest that iron supplementation may be beneficial in these subjects. Myelin is regenerated continually, but prerequisites for this process are iron and a functional folate-vitamin B12-methylation pathway. The aim of this study was to determine iron status, folate and homocysteine in MS subjects, and to evaluate the effect on MS symptoms if deficiencies were addressed. Results: In relapsing- remitting MS subjects, serum iron concentration correlated significantly with age at diagnosis (r=0.49; p=0.008). In Caucasian female MS subjects, serum iron and ferritin concentrations were significantly lower than in matched controls. In a 6-month pilot study, 12 subjects taking a regimen of nutritional supplements designed to promote myelin regeneration, improved significantly neurologically as measured by the Kurzke EDSS (Total Score means 3.50 to 2.45, 29.9%; p=0.021). These were significantly improved (p=0.002) compared to 6 control group patients taking multivitamins (Kurzke Score increased by 13.9% from 4.83 to 5.50). Both groups had significantly reduced homocysteine concentrations at 6 months, suggesting that methylation is necessary but not sufficient for myelin regeneration.

Magnesium: Magnesium (Mg) is involved in the activity of over 300 enzymes in the body, and it is very critical in neurologic health. As mentioned earlier, magnesium and vitamin B6 very often work together in this role. Stelmasiak et al. (1995), found a significant decrease of Mg concentration in red blood cells and no changes in blood plasma of MS patients compared with controls. This suggests the presence of changes in red blood cells which could be connected with their shorter life and impaired function in MS. Magnesium is known to be decreased in central nervous system (CNS) tissues of people with MS. Yasui & Ota (1992) note that with Mg depletion, pathologic changes are seen especially in white matter, and this may contribute to the development of MS.

Magnesium Adequacy: Inadequate Mg intake is common in the general population. In fact, a large national survey* of Americans done every ten years by the Center for Disease Control (the CDC) found that the majority of Americans obtain less than 2/3 of the Recommended Dietary Allowance for this nutrient. Certainly there is every reason to assure that the common dietary inadequacy of magnesium does not complicate problems for individuals with MS, since magnesium has so many important roles in neurologic function. (*NHANES – National Health And Nutrition Examination Survey.)

There is little MS-specific magnesium research being reported, but I found three items to include here:

14 Importance of magnesium depletion with hypofunction of the biological clock in the pathophysiology of headhaches with photophobia, sudden infant death and some clinical forms of multiple sclerosis. Magnes Res. 2004 Dec;17(4):314-26. … MS may be associated with primary disorders of BC Clinical forms of Mg depletion with hBC in MS present diurnal exacerbations and relapses during fair seasons….

The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses. 2001 Feb;56(2):163-70. …The very small probability that all the variables affecting Mg levels will behave favorably, results in a high probability of a gradually intensifying Mg deficiency. It is highly regrettable that the deficiency of such an inexpensive, low-toxicity nutrient result in diseases that cause incalculable suffering and expense throughout the world. The range of pathologies associated with Mg deficiency is staggering: hypertension (cardiovascular disease, kidney and liver damage, etc.), peroxynitrite damage (migraine, multiple sclerosis, glaucoma, Alzheimer's disease, etc.)

The effect of magnesium oral therapy on spasticity in a patient with multiple sclerosis. Eur J Neurol. 2000 Nov;7(6):741-4. The effects of magnesium glycerophosphate oral therapy on spasticity was studied in a 35-year-old woman with severe spastic paraplegia resulting from multiple sclerosis (MS). We found a significant improvement in the spasticity after only 1 week from the onset of the treatment on the modified Ashworth scale, an improvement in the range of motion and in the measures of angles at resting position in lower limbs. No side-effects were reported and there was no weakness in the arms during the treatment.

In view of the many roles of Mg (especially in the central nervous system) and the true likelihood that one’s diet may in fact provide too little magnesium, it is reasonable to take steps to assure that Mg intake at least meets RDA levels. Magnesium Food Sources: Best are nuts, peanuts and other legumes, whole grains, wheat germ and bran. If a person avoids these foods (e.g. out of concern about the fat content or the calories in nuts or peanut butter,) realize that a supplement is likely necessary to prevent inadequacy. Most general multivitamins have only 0-25% of the RDA, so read the label. For more information about magnesium, please see my other handout “Aunt Cathy’s Guide to Magnesium.”

One study suggested that phosphate adequacy may be a factor in MS:

Phosphate depletion is the link between growth, stress and diet in the aetiology of MS. Med Hypotheses. 2004;63(2):262-7. . . . Phosphate depletion results in demyelinization. Phosphate depletion (PD) can lead to neurological complications, which have been characterized in experimental & clinical studies. Hypophosphataemia, whether acute or chronic, induced by stress from accident, surgery or burns, by infection and/or undernutrition, is therefore an important etiological factor. Low SP levels have been reported in MS patients & the hypothesis that PD causes MS is presented here.

Carnitine Carnitine is a substance made by the body and also found in meats. It is important inside cells for converting fat into energy. There is currently a lot of interest in carnitine in a wide variety of medical applications. In MS, the applications have been aimed at helping with fatigue, as reported in these studies:

Levocarnitine administration in multiple sclerosis patients with immunosuppressive therapy-induced fatigue. Mult Scler. 2006 Jun;12(3):321-4. Nutritional factors and comedications are among the postulated causes of fatigue, a highly prevalent symptom in the multiple sclerosis (MS) population, with serious impact on patients' quality of life. Deficiency of carnitine may play a role by reducing energy production through fatty acid oxidation and numerous MS therapies can induce fatigue syndrome. The aim of this prospective open-labelled study was to collect and study serum carnitine levels in MS patients with and without disease-modifying treatment- induced fatigue syndrome. We investigated whether restoration of the carnitine pool might improve treatment-induced fatigue in MS

15 patients. In our study, there was no statistical difference in fatigue frequency between treated and untreated patients (P=0.5). Matched to age, gender and treatments, carnitine levels were lower for MS treated patients compared to untreated MS patients (P <0.05) or controls (P <0.001). Consecutive patients with low plasma carnitine levels who experienced fatigue were substituted. Treatment consisted of oral levocarnitine, 3-6 g daily. All patients achieved normal plasma carnitine levels. For 63% of patients treated with immunosuppressive or immunomodulatory therapies, oral levocarnitine adjunction decreased fatigue intensity, especially in patients treated with cyclophosphamide and interferon beta.

Treatment of multiple sclerosis-related fatigue: pharmacological and non-pharmacological approaches. Neurol Sci. 2006 Sep;27(Supplement 4):s297-s299. Fatigue is a common symptom in multiple sclerosis (MS). As fatigue includes a variety of aspects, its treatment is best approached in a multidisciplinary fashion that includes nonpharmacological interventions and medications. In individuals with mild fatigue non-pharmacological treatment including yoga, aerobic exercises, cooling therapy and energy conservation techniques might be considered. Several pharmacological treatments for patients with significant fatigue have proved to be effective. Among these agents, amantadine and aminopyridines are the most frequently used. More recently also aspirin and carnitine have been used to treat MS fatigue but they need to be confirmed in larger studies.

Comparison of the effects of acetyl L-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. J Neurol Sci. 2004 Mar 15;218(1-2):103-8. Treatment with acetyl L-carnitine (ALCAR) has been shown to improve fatigue in patients with chronic fatigue syndrome, but there have been no trials on the effect of ALCAR for treating fatigue in multiple sclerosis (MS)…Statistical analysis showed significant effects of ALCAR compared with amantadine for the Fatigue Severity Scale (p = 0.039). … The results of this study show that ALCAR is better tolerated and more effective than amantadine for the treatment of MS-related fatigue.

Nutrition problems due to MS and its treatment

• avoidance of “suspect” foods • dysphagia • weight / body composition • pressure ulcers (also called “bed sores”) • bladder infection • drug/nutrient interactions

Avoidance of “suspect” foods. Many people try a variety of dietary changes in the hope that it will help control the symptoms of MS. It is especially important in this situation that a knowledgeable person review the total intake picture to assure that important nutrients are not accidentally obtained in inadequate or excessive amounts.

Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice. …Our results indicate that oral flavonoids fail to beneficially influence the course of EAE in mice but, instead, suppress recovery from acute inflammatory damage. Biochem Pharmacol. 2005 Jul 15;70(2):220-8.

Exacerbation of protracted-relapsing experimental allergic encephalomyelitis in DA rats by gluten-free diet. … Here we study the effects of a gluten-free diet on the course of protracted-relapsing EAE in DA rats, serving as a preclinical model of human MS. The data show not only that this nutritional approach failed to ameliorate development of the disease but rather that it exacerbated the course. APMIS. 2004 Oct;112(10):651-5

Dysphagia Abnormal swallowing is common in MS although people often do not complained of it. It is associated with disordered brainstem/cerebellar function, overall disability, depressed mood and low vital capacity (Thomas & Wiles, 1999.) Assure that any textural manipulations to facilitate safe eating (such as thickening beverages) do not disrupt nutritional adequacy. For example, some people actually get a third of their calories just from the starchy thickeners. This will either result in excessive weight gain if they continue to eat the

16 same amount of food, or it will contribute to poor nutrient intake if the total food intake is cut back to avoid weight gain.

The best foods are those which have generous amounts of vitamins, minerals and beneficial phytochemicals relative to the number of calories they provide. These desirable foods are said to be “nutrient dense.” Starchy thickeners are not nutrient dense at all, and if a person must use them for safety of swallowing, appropriate nutrient supplementation will be even more important than usual. A few commercial thickening products are available that do contribute some vitamins and minerals, but most do not. If assuring adequate food/nutrient intake orally becomes a problem, it has been shown that a percutaneous gastrostomy tube can be very useful and improve quality of life significantly. (Acta Gastroenterol Latinoam 2004)

Weight / Body Composition: Many evaluations of nutritional status only look at Body Mass Index (BMI) or some other weight-related measure. It is important to consider the alterations in body composition that occur with increasing immobility. As mobility decreases, a person’s “Lean Body Mass” will also decrease, resulting in a lower requirement for total calories. Failure to adjust calories downward can contribute to overweight and increased mobility for people with MS. However, as described above, when caloric requirements and total intake decrease, there is an increased risk of missing out on essential nutrients. Supplementation is reasonable, and it will be necessary in almost all instances.

Pressure Ulcers: Weight influences on mobility can affect risk of pressure ulcers. However, although optimal protein and micronutrient nutrition is critical in preventing or healing pressure ulcers, they are often poorly provided when the calorie intake is low. Immobilization contributes to both the “pressure” and to the likelihood of inadequate intake of micronutrients. Again, supplementation will be necessary in almost all instances.

Bladder Infection: Cranberry juice may be helpful, not because of acidification of urine, but because of the effects of a natural substance in cranberries that helps make bacteria less likely to adhere to the bladder lining. A generous intake of fluids is also helpful. However, remember to watch the calories provided by beverages. For example, “cranberry juice cocktail” has a lot of sugar added because it is otherwise too tart. The result is a beverage with 20 calories per oz -- the same calories as whole milk! Using artificially sweetened cranberry juice provides the benefits of cranberry in a very small amount of calories.

Drug/Nutrition Interactions: Chronic use of antibiotics is known to impair folic acid absorption, and it also stops biotin and vitamin K production by intestinal bacteria. Several specific interactions were described in the section of vitamin B-12 earlier, and there are many other interactions of potential importance. Some medications can also affect appetite, swallowing, mouth dryness, and elimination patterns which indirectly influence the likelihood of obtaining appropriate nutrition. It is always important to evaluate the potential for drug/nutrient interactions, so ask your physician,

17 pharmacist or dietitian if there are any important issues with the particular medications you are taking.

Reproductive Health Note: Infant health of mothers with multiple sclerosis. West J Nurs Res. 2004 Oct;26(6):632-49. “Controversy surrounds whether mothers with multiple sclerosis (MS) who wish to breast-feed their infants should forego breast-feeding in order to resume immunomodulating therapy following birth even though breast- feeding has not been shown to have deleterious effects on these mothers. … Significantly more non-breast- fed than breast-fed infants experienced otitis media, lower respiratory illness, constipation, milk intolerance, & allergy during the 1st year. Study results support the need to encourage mothers with MS who wish to breast-feed their infants to do so and to delay immunomodulating therapy until breast-feeding cessation.”

IN SUMMARY:

My Best Guess (subject to change at any moment based on new research) about diet/nutrients to decrease risk of MS and/or decrease the rate of progression:

First: Try not to be Scottish, Irish, female, or to have lived up here in North Dakota when you were 15. Select your parents and other family members very carefully. [I realize, of course, that we have no control over these particular factors. However, recognizing these factors as important may help individuals to evaluate or even take steps to modify their own personal risk or the risk to others in the family.]

Second: Look Closely to Assure Adequacy of All Nutrients. This is true for everyone, of course. The diet should be “nutrient dense” (lots of nutrients per calorie, or per volume) because total food intake is often low. Realize that some people with MS are avoiding fat, milk and meat, so vitamin D, vitamin B6, calcium, zinc, iron and protein intake are all likely to be suspect.

Third: Specific Food and Nutrient Risk Issues Realize that to achieve adequacy of Vitamin D requires 2000 iu for many people up north – more than the usual RDA level-- and that inadequacy may be a factor in the development and/or progression of MS. Any people who are covered up, who have dark skin, who have old skin, who use sunscreen, or who often stay indoors should certainly aim for this amount of vitamin D from food and/or supplements. Interestingly, the same goes for people who have none of these risks . . . it may be protective against a number of serious health problems, and that amount is clearly safe even if one regularly sunbathes in the nude by the equator!

A multivitamin supplement will provide the RDA level of 400 iu. Milk is the major dietary source because it has been fortified with vitamin D in an effort to decrease the problem of rickets / bone deformity in children. One cup (8 oz) provides 100 iu. Until very recently there was no vitamin D in yogurt, cheese, ice cream, or in the calcium- fortified orange juice. Now some brands are beginning to add it. Again, look VERY

18 closely at this one! Some people are avoiding milk, and they may be injuring themselves substantially if vitamin D is not provided optimally in some other way. The only other generous food source is salmon and tuna . . . and as with milk, one would need to eat them frequently to count on these foods to prevent deficiency. Realize that one does not “have to” drink milk . . . one must simply recognize that if people drink little or no milk, they will definitely need some other reliable and generous vitamin D source . . . like a supplement. Assuring a reasonable calcium intake from non-milk sources will also be import, of course, but the calcium need not be in the same foods or supplements as the vitamin D provided. It will be well absorbed as long as the total amount of vitamin D is adequate, regardless of the timing.

Pending further research, if MS is diagnosed (or if it is especially severe), consider getting a one-time-only measure of 1,25-dihydroxyvitamin D level to rule out a metabolic problem converting the vitamin to its active form. If that kind of problem is found, the individual will need a special prescription form of active vitamin D called “calcitriol.” This kind of metabolic problem has now been found in at least some people with MS.

Check that calcium intake is at the recommended level for age (e.g. 1000-1500 mg). This can be especially difficult to achieve if one is avoiding dairy foods. In this situation (low dairy or low total calories,) a separate calcium supplement will likely be needed because most multivitamins with minerals provide only about 200 mg of calcium. A supplement that provides vitamin D along with the calcium is a very good idea in MS and up north, even with the 400 iu of vitamin D being provided in a multivitamin.

As a rule of thumb, (for everyone) it is a good idea to assure that the magnesium-to- calcium ratio is near the RDA ratio of 1-to-4. Supplementation of large amounts of calcium in the absence of adequate magnesium may increase risk of blood clots and stroke, and also bone fragility. Magnesium is often inadequate in the diets of Americans, so make sure it isn’t inadequate in yours. A person may need a supplement beyond a “multi with minerals” to achieve the RDA intake, depending on food choices. The RDA for Mg is 320 mg for women and 420mg for men. Do not take more than the RDA in supplement form without consulting your doctor. If a person does take the RDA amount as a supplement, and then also eats magnesium-rich foods, there is still no problem.

Selenium can be inadequate in low-protein diets especially, and there are other reasons (e.g geography) why many people have a poor intake. Low selenium intake has negative implications for cancer and diabetes as well as MS. An intake at 1-2 times the RDA seems reasonable for all. For example, a goal might be to provide a multi-vitamin with minerals that contains selenium (check the label) plus food content, for about 100-150 mcg total intake. As described earlier, the RDA = 60 mcg, the upper chronic intake limit = 600 mcg , and the toxic level = 800 mcg. If the multivitamin does not provide selenium, it is easy and inexpensive to simply add a small 50 mcg tablet.

A person who follows a strictly vegetarian diet may have a vitamin B-12 level that is seriously low. Other factors (such as a person’s age or using drugs that decrease stomach

19 acid) can impair absorption of vitamin B12 from food sources. Vitamin B-12 requirements may be higher than normal in MS. It is easy to provide a safe, generous, inexpensive and absorbable amount, such as the 25 mcg usually included in a “silver” type multivitamin. The RDA level = 2-3 mcg. The crystalline form of the vitamin provided in pills does not require stomach acid for absorption the way the form in food does.

Folic acid availability from foods is also known to be quite variable with measurable differences in health as a result. The best known and studied example of this is a gene called the methylenetetrahydrofolate reductase (MTHFR) gene that appears to decrease in the ability of dietary folate to to its job in preventing birth defects, depression and stroke. This gene is especially common among people of Irish and Scots heritage (also a group at higher risk of MS,) and most people who have it are unaware that they do. However, as with vitamin B12, providing folic acid in the form found in standard vitamin pills or fortified cereals has been shown to bypass the genetic problem and make folic acid available to do its job.

This is just one more reason why taking at least a standard multivitamin daily is a very good idea. (And remember . . . I am NOT selling anything! ☺) For one thing, the typically recommended levels of nutrients (RDAs and RDIs, etc.) are based on the needs of the “healthy” population. They were never intended to address the needs of people with serious health issues. The idea that a person should “just eat right” is no longer reasonable based on literally thousands of scientific studies.

In fact, as described above, it is actually potentially harmful advice to discourage a person from taking a standard multivitamin with minerals. Of course, a vitamin pill does not make up for a poor diet. Many important nutrients are not even provided by vitamin pills. A much more scientifically sound position today is: “Eat right AND take a daily multivitamin with minerals.” These are not mutually exclusive goals.

A generous “B-complex” supplement (e.g. “B-100”) in addition to a “multivitamin with minerals” may be helpful by raising the intake of vitamins B-6, B-12, folic acid and biotin in particular. The levels of all B-vitamins are safe at this intake level. Avoid taking more than one general “multivitamin with minerals” daily because the amount of iron, zinc and vitamin A (as retinol) may be too high.

Foods to Eat Less Of:

Choose a diet generally low in: • total fat and saturated fat, • dairy products; • meats that are smoked or preserved with nitrites. If you do eat cured meat, eat a vitamin C-rich food with it to decrease the formation of “nitrosamines” that are thought to contribute to cancer.

20 Foods to Eat More Of:

Of the dietary fat consumed, generally choose fats rich in omega-3 fatty acids (flax and especially fish) and high in PUFAs relative to other animal fat and saturated fat. Supplemental EPA/DHA fish oil or flax oil capsules may be helpful, especially if fish- eating is not desirable. The American Heart Association recommends eating fish twice a week if one has NO risk of cardiovascular disease . . . no high cholesterol, no diabetes, no family history, no smoking, etc. However, the higher than usual free radical production and inflammation associated with MS are certainly cardiovascular risk factors on their own. For people with some cardiovascular risk, a daily fish oil capsule is suggested:

Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA, May 21, 2005. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S. AHA Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-2757 “Supplements that provide about a gram (1000 mg) of omega-3 fat daily can benefit persons with cardiovascular disease. Higher dose (2–4 grams, or 2000-4000 mg) intakes appear to greatly improve high triglyceride levels in particular. The higher doses (over 3 grams daily) should be taken only with physician approval.”

For EVERYONE for MANY Reasons:

Assure a generous antioxidant intake relative to PUFAs. If a person has MS, an even more generous intake of antioxidants is needed because of increased free radical production. This increased need for antioxidant protection appears to be the case in many other autoimmune conditions as well, such as diabetes. Be aware that a “very low fat” diet naturally provides only minimal vitamin E as well. A good idea for all: a separate vitamin E supplement providing 200 iu and a vitamin C supplement that provides 200-500 mg. More may be added with a physician’s approval. Most multi-vitamins will provide only the RDA value of 30 iu of vitamin E and 60-100 mg of vitamin C. Again, the RDA levels, by definition, are based on the presumed needs of the “healthy population,” so additional consideration of specific health problems associated with MS often results in some departure from the RDA levels as a goal.

Aim for a generous intake of brightly colored fruits and vegetables. These foods are rich in nutrients and low in calories. They also provide lots of protective “phytochemicals” like lutein, lycopene, anthocyanins, carotenes, flavones, etc., which are very potent antioxidants. Other antioxidants may also be found to be helpful with new research (e.g. CoQ-10, new B-6 analogs, etc.)

Fourth: Troubleshooting other nutrition pitfalls for the individual with MS:

21 Watch for dysphagia problems in MS, and assure that manipulations of food texture do not disrupt nutritional balance or add excessive calories. If eating becomes too difficult to maintain nutritional status, consider a percutaneous gastrostomy as a tool.

Good nutrition helps prevent pressure ulcers; but if they develop, treat with aggressive, supportive nutrition (especially generous protein and zinc, copper, and vitamin C.)

Check for potential nutrition interaction effects of all medications, and make nutritional adjustments as necessary. This is not just a “take with food / don’t take with food” issue.

Remember to consider body composition and activity level changes in assessment of nutritional status and in making recommendations for calories, etc.: 1) weight:height ratio; 2) lean body mass-to-weight ratio; and 3) activity level..

Fifth: Stay tuned for new information!

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22 A COLLECTION OF ANNOTATED REFERENCES AND PARTIAL ABSTRACTSFOR THOSE WHO ARE INTERESTED:

------Vitamin D (2000-2007; selected annotated references)

2007 Risk assessment for vitamin D. Am J Clin Nutr. 2007 Jan;85(1):6-18. The objective of this review was to apply the risk assessment methodology used by the Food and Nutrition Board (FNB) to derive a revised safe Tolerable Upper Intake Level (UL) for vitamin D. New data continue to emerge regarding the health benefits of vitamin D beyond its role in bone. The intakes associated with those benefits suggest a need for levels of supplementation, food fortification, or both that are higher than current levels. A prevailing concern exists, however, regarding the potential for toxicity related to excessive vitamin D intakes. The UL established by the FNB for vitamin D (50 mug, or 2000 IU) is not based on current evidence and is viewed by many as being too restrictive, thus curtailing research, commercial development, and optimization of nutritional policy. Human clinical trial data published subsequent to the establishment of the FNB vitamin D UL published in 1997 support a significantly higher UL. We present a risk assessment based on relevant, well-designed human clinical trials of vitamin D. Collectively, the absence of toxicity in trials conducted in healthy adults that used vitamin D dose >/=250 mug/d (10 000 IU vitamin D(3)) supports the confident selection of this value as the UL.

2006 Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006 Dec 20;296(23):2832-8. Prospective, nested case- control study among more than 7 million US military personnel who have serum samples stored in the Department of Defense Serum Repository. Multiple sclerosis cases were identified through Army and Navy physical disability databases for 1992 through 2004, and diagnoses were confirmed by medical record review. Each case (n = 257) was matched to 2 controls by age, sex, race/ethnicity, and dates of blood collection. Vitamin D status was estimated by averaging 25-hydroxyvitamin D levels of 2 or more serum samples collected before the date of initial multiple sclerosis symptoms. Conclusion: The results of our study suggest that high circulating levels of vitamin D are associated with a lower risk of multiple sclerosis.

IL-10 signaling is essential for 1,25-dihydroxyvitamin D3-mediated inhibition of experimental autoimmune encephalomyelitis. J Immunol. 2006 Nov 1;177(9):6030-7. Conclusion: Thus, 1,25-(OH)(2)D(3) may be enhancing an anti-inflammatory loop involving hemopoietic cell-produced IL-10 acting on brain parenchymal cells and vice versa. If this interpretation is correct, and humans have a similar bidirectional IL-10-dependent loop, then an IL-10-IL-10R pathway defect could abrogate the anti-inflammatory and neuro- protective functions of sunlight and vitamin D(3). In this way, a genetic IL-10-IL-10R pathway defect could interact with an environmental risk factor, vitamin D(3) insufficiency, to increase MS risk and severity.

Dysfunction of the vitamin D endocrine system as common cause for multiple malignant and other chronic diseases. Anticancer Res. 2006 Jul-Aug;26(4A):2581-8. Extensive research on the CYP27B1-encoded 25-(OH)D-1alpha-hydroxylase has contributed much to our understanding about how locally produced 1,25-(OH)2D3 exerts tissue-specific control of cellular growth, differentiation and function. Because many types of epithelial, mesenchymal and immune cells express the 25-(OH)D-1alpha- hydroxylase, many organ functions are necessarily affected by changes in the activity of the enzyme. It is hypothesized that this is likely to occur under conditions of hypovitaminosis D, i.e., at serum 25-(OH)D levels below 30 nM, because extra-renal 25-(OH) D- 1alpha-hydroxylase activity is critically limited by the availability of its substrate. This can provide an explanation, on a molecular and cellular basis, for the many observations that significant associations exist between a compromised vitamin D status and the pathogenesis of frequent chronic diseases. In addition to skeletal disorders, vitamin D insufficiency is a risk factor for malignancies, particularly of the colon, breast and prostate gland, as well as for chronic inflammatory and autoimmune diseases (insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis, etc.).

New insights into the mechanisms involved in the pleiotropic actions of 1,25dihydroxyvitamin D3.Ann N Y Acad Sci. 2006 Apr;1068:194-203. Vitamin D functions to regulate calcium homeostasis in intestine, kidney, and bone. Vitamin D deficiency during bone development causes rickets and in adults vitamin D deficiency, which has been shown to be common in the elderly population, can cause secondary hyperparathyroidism that can result in osteomalacia and increased risk of fracture. Recent evidence has suggested that vitamin D can have numerous other physiological functions including protection against certain autoimmune diseases, such as diabetes and multiple sclerosis and inhibition of proliferation of a number of malignant cells including breast and prostate cancer cells. Exactly how vitamin D affects numerous different systems is a subject of continuing investigation. This article will review new developments related to the function and regulation of vitamin D target proteins in classic vitamin D target tissues that have provided novel insight into the mechanism of vitamin D action.

Epidemiology and natural history of multiple sclerosis: new insights. Curr Opin Neurol. 2006 Jun;19(3):248-54.PURPOSE OF REVIEW: The cause of multiple sclerosis remains elusive. We review recent epidemiological studies of genetic and environmental factors that influence susceptibility to the disease and its clinical course. RECENT FINDINGS: Genetic advances strengthen the association of multiple sclerosis with the human leukocyte antigen (HLA)-DRB1 allele and interferon-gamma polymorphisms and suggest that apolipoprotein E alleles play an important role. In the environmental realm, nested case-control studies show that prior Epstein-Barr virus exposure is overrepresented in multiple sclerosis. Smoking has been associated with both risk of multiple sclerosis and progressive disease. Vitamin D deficiency might tie together environmental clues with higher multiple sclerosis prevalence rates; dietary vitamin supplementation is also associated with reduced multiple sclerosis risk….

23 The role of vitamin D in multiple sclerosis. Ann Pharmacother. 2006 Jun;40(6):1158-61.OBJECTIVE: To evaluate the literature about the role of vitamin D in the prevention and treatment of multiple sclerosis (MS). DATA SOURCES: MEDLINE (1966-April 2006) and International Pharmaceutical Abstracts (1970-April 2006) searches were performed. In addition, pertinent references from identified articles were obtained. Key search terms included vitamin D, 25-hydroxyvitamin D, vitamin D deficiency, and multiple sclerosis. Data synthesis: Vitamin D supplementation prevented the development and progression of experimental autoimmune encephalitis, an animal model of MS, in mice. A large, prospective, cohort study found that vitamin D supplementation was associated with a 40% reduction in the risk of developing MS. Four small, noncontrolled studies suggested that vitamin D supplementation may decrease exacerbation of MS symptoms. CONCLUSIONS: Vitamin D supplementation may help prevent the development of MS and may be a useful addition to therapy. However, current studies are in small populations and are confounded by other variables, such as additional vitamin and mineral supplementation.

Vitamin D and autoimmune disease--implications for practice from the multiple sclerosis literature. J Am Diet Assoc. 2006 Mar;106(3):418-24. Recent studies and commentaries link vitamin D with several autoimmune diseases, including multiple sclerosis (MS). Adequate vitamin D intake reduces inflammatory cytokines through control of gene expression, thus inadequate vitamin D intake is suggested as a mechanism that could contribute to inflammation and, consequently, development of MS. Poor vitamin D status has been associated with increased risk for development of MS, and patients with MS may suffer consequences of vitamin D deficiency, such as bone loss. Animal studies and very limited human data suggest possible benefit from vitamin D supplementation in patients with MS. Based on the current state of research, a key principle for practicing dietetics professionals is to include vitamin D status in nutritional assessment. For those at risk for poor vitamin D status, intake can be enhanced by food-based advice and, when indicated, vitamin D supplementation.

[CB Note about the conclusion of the above citation – the “food-based advice” means that the vitamin D “should” be obtained from milk, salmon and some tuna. . . as there are very few other food sources. Interesting to me is the tendency for health professionals to be unaware of the fact that the vitamin D in milk is ADDED to it. It is not naturally rich in vitamin D. This kind of advice (that people “should” take their supplemental D preferentially in the form of a liquid dairy product) is not central to the fact that they simply must get enough vitamin D. Nutrition is not a religion . . . there are many ways to solve a problem. It is now known that many people require 1000-2000 iu of vitamin D daily to assure adequate levels in their blood. This is the amount provided by10 -20 cups of milk daily … clearly unreasonable and also poor nutrition as there would be room for nothing else. .Even if the milk is skim, this is rather a lot of calories (900-1800) especially for people with MS, and it obliges the displacement of other important foods. Clearly some supplemental vitamin D must be provided in a form other than “vitamin D added to milk.” A multivitamin provides 400 iu of vitamin D. An additional amount can be obtained from an inexpensive tablet (it comes in 400 iu, 1000 iu and 2000 iu and likely other strengths will become more common. It may also be obtained from vitamin D fortified calcium pills (usually 200-400 iu) or as 100 iu per cup of milk. Please see my vitamin D handout and “Top Five” handout for specific suggestions of many ways to be sure to obtain the right amount.]

The photobiology of vitamin D--a topic of renewed focus. Tidsskr Nor Laegeforen. 2006 Apr 6;126(8):1048-52. The sun is our most important source of vitamin D. Exposure to solaria, in sub-erythemogenic doses, also gives large amounts of this vitamin. The ultraviolet radiation in these sources converts 7-dihydrocholesterol to previtamin D3 in the skin. Furthermore, heat isomerization to vitamin D3 takes place, then transport to the liver and hydroxylation to calcidiol, which is transported to the kidneys and hydroxylated to the active hormone calcitriol. The vitamin D3 status of the body is supposed to be reliably imaged by calcidiol measurements. Calcidiol levels above 12.5 nmol/l prevent rickets and osteomalacia, but optimal levels are probably higher, in the range 100-250 nmol/l. A daily food intake of 100-200 microg vitamin D3 (50-100 g cod-liver oil), or a weekly exposure to two minimal erythemal doses of ultraviolet radiation (20 to 40 minutes whole body exposure to midday midsummer sun in Oslo, Norway), will give this level. An adequate supply of vitamin D3 seems to reduce the incidence rates or improve the prognosis of several cancer forms, including prostate, breast and colon cancer, as well as of lymphomas. Several other diseases are related to a low vitamin D3 status: heart diseases, multiple sclerosis, diabetes, and arthritis. The action mechanisms of vitamin D are thought to be mainly related to its known cell-differentiating and immuno-modulating effects. Even though most of the 250 annual death cases from skin cancer in Norway are caused by sun exposure, we should, in view of the health effects of ultraviolet radiation, consider modifying our restrictive attitude towards sun exposure and use of solaria.

[CB note on the last sentence of the above citation: Perhaps a multivitamin would be a bit safer intervention to suggest rather than ignoring the recognized risk of melanoma from sun exposure. It is also easier to do than the “weekly exposure to two minimal erythemal doses of ultraviolet radiation (20 to 40 minutes whole body exposure to midday midsummer sun in Oslo, Norway,)” especially for those of us who are shy about the whole-body exposure part.

Vitamin D physiology. Prog Biophys Mol Biol. 2006 Sep;92(1):4-8 … The active metabolite 1,25(OH)2D has an antiproliferative effect and downregulates inflammatory markers. Extrarenal synthesis of 1,25(OH)2D occurs under the influence of cytokines and is important for the paracrine regulation of cell differentiation and function. This may explain that vitamin D deficiency can play a role in the pathogenesis of auto-immune diseases such as multiple sclerosis and diabetes type 1, and cancer. In conclusion, the active metabolite 1,25(OH)2D has pleiotropic effects through the vitamin D receptor and vitamin D responsive elements of many genes and on the other side rapid non-genomic effects through a membrane receptor and second messengers. …

Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease. Prog Biophys Mol Biol. 2006 Sep;92(1):60-4 Autoimmune diseases like multiple sclerosis (MS) and inflammatory bowel disease (IBD) occur because of an inappropriate immune-mediated attack against self-tissue. Analyses of genetically identical twins shows that besides genetics there are

24 important environmental factors that contribute to MS and IBD development. Vitamin D availability due to sunshine exposure or diet may play a role in the development of MS and IBD. Compelling data in mice show that vitamin D and signaling through the vitamin D receptor dictate the outcome of experimental MS and IBD. Furthermore, the evidence points to the direct and indirect regulation of T cell development and function by vitamin D. In the absence of vitamin D and signals delivered through the vitamin D receptor, auto reactive T cells develop and in the presence of active vitamin D (1,25(OH)(2)D(3) ) and a functional vitamin D receptor the balance in the T cell response is restored and autoimmunity avoided.

1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNgamma axis leading to Th1 response in experimental allergic encephalomyelitis. J Neurosci Res. 2006 May 15;83(7):1299-309. … These findings highlight the fact that vitamin D modulates JAK-STAT signaling pathway in IL-12/IFNgamma axis leading to Th1 differentiation and further suggest its use in the treatment of MS and other Th1 cell-mediated autoimmune diseases.

Epidemiology of disease risks in relation to vitamin D insufficiency. Prog Biophys Mol Biol. 2006 Sep;92(1):65-79. Vitamin D from ultraviolet-B (UVB) irradiance, food, and supplements is receiving increased attention lately for its role in maintaining optimal health. Although the calcemic effects of vitamin D have been known for about a century, the non-calcemic effects have been studied intently only during the past two-three decades. The strongest links to the beneficial roles of UVB and vitamin D to date are for bone and muscle conditions and diseases. There is also a preponderance of evidence from a variety of studies that vitamin D reduces the risk of colon cancer, with 1000 IU/day of vitamin D or serum 25-hydroxyvitamin D levels >33 ng/mL (82 nmol/L) associated with a 50% lower incidence of colorectal cancer. There is also reasonable evidence that vitamin D reduces the risk of breast, lung, ovarian, and prostate cancer and non-Hodgkin's lymphoma. There is weaker, primarily ecologic, evidence for the role of vitamin D in reducing the risk of an additional dozen types of cancer. There is reasonably strong ecologic and case-control evidence that vitamin D reduces the risk of autoimmune diseases including such as multiple sclerosis and type 1 diabetes mellitus, and weaker evidence for rheumatoid arthritis, osteoarthritis, type 2 diabetes mellitus, hypertension and stroke. It is noted that mechanisms whereby vitamin D exerts its effect are generally well understood for the various conditions and diseases discussed here.

2005

Effects of alfacalcidol therapy on serum cytokine levels in patients with multiple sclerosis. Srp Arh Celok Lek. 2005 Dec;133 Suppl 2:124-8 The aim of our study was to investigate the immunomodulatory effect of alfacalcidol, a vitamin D analogue, on cytokine levels in RRMS patients in relapse. … Result: Alfacalcidol therapy in RRMS patients did not provoke any side effects. Vitamin D and its analogues, such as alfacalcidol, act as immunomodulatory agents, with potential therapeutic effects for patients with multiple sclerosis.

Why we should offer routine vitamin D supplementation in pregnancy and childhood to prevent multiple sclerosis. Med Hypotheses. 2005;64(3):608-18.... In areas of high MS prevalence, dietary supplementation of vitamin D in early life may reduce the incidence of MS. In addition, like folic acid, vitamin D supplementation should also be routinely recommended in pregnancy. Prevention of MS by modifying an important environmental factor (sunlight exposure and vitamin D level) offers a practical and cost- effective way to reduce the burden of the disease in the future generations.

A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005 Sep;76(9):1294-6. …Conclusions: Oral calcitriol is safe and well tolerated for up to one year by diet compliant relapsing-remitting MS patients. Further study of vitamin D related mechanisms is warranted in MS.

25-Hydroxyvitamin D levels in serum at the onset of multiple sclerosis. Mult Scler. 2005 Jun;11(3):266-71.…We conclude that the vitamin D stores in most MS patients are adequate for their normal bone metabolism. However, lower vitamin D levels during MS relapses than in remission suggest that vitamin D could be involved in the regulation of the clinical disease activity of MS. The optimal serum levels of vitamin D for the regulation of immune responses remain to be determined.

2004

Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood). 2004 Dec;229(11):1136-42. Low vitamin D status has been implicated in the etiology of autoimmune diseases such as multiple sclerosis, rheu-matoid arthritis, insulin-dependent diabetes mellitus, & inflammatory bowel disease. The optimal level of vitamin D intake required to support optimal immune function is not known but is likely to be at least that required for healthy bones. Experimentally, vitamin D deficiency results in the increased incidence of autoimmune disease. … This review discusses the accumulating evidence pointing to a link between vitamin D & autoimmunity. Increased vitamin D intakes might decrease the incidence & severity of autoimmune diseases and the rate of bone fracture.

Why the optimal requirement for Vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):575-9. The physiologic range for circulating 25-hydroxyvitamin D3 [25(OH)D; the measure of Vit. D nutrient status] concentration in humans & other primates extends to beyond 200 nmol/L (>80 ng/mL). This biologic "normal" value is greater than current population norms for 25(OH)D. Concentrations of 25-(OH)D that correlate with desirable effects extend to at least 70 nmol/L, with no obvious threshold. Randomized clinical trials using 20 mcg (800 IU) per day of Vit. D show that this suppresses parathyroid hormone, preserves bone mineral density, prevents fractures, lowers blood pressure & improves balance. Calcium absorption from diet correlates with 25(OH)D in the normal range. Health effects of Vita. D beyond osteoporosis are mostly supported by the circumstantial evidence of epidemiologic studies & laboratory research. These include prevention of cancer & the auto-immune diseases, insulin-dependent diabetes & multiple sclerosis. One mcg per day of Vit. D(3) (cholecalciferol) increases circulating 25(OH)D by about 1 nmol/L (0.4 ng/mL). A recommended dietary allowance (RDA) is the long-term daily intake level that meets the total requirements for the nutrient by nearly all healthy individuals (it would presume no

25 sunshine). If 70 nmol/L is regarded as a minimum desirable target 25(OH)D concentration, then current recommendations of 15 mcg per day do not meet the criterion of an RDA.

Multiple sclerosis and vitamin D: an update. Eur J Clin Nutr. 2004 Aug;58(8):1095-109. …The prevalence of MS is highest where environmental supplies of vitamin D are lowest. … Vitamin D deficiency is caused by insufficient sunlight exposure or low dietary vitamin D(3) intake. Subtle defects in vitamin D metabolism, including genetic polymorphisms related to vitamin D, might possibly be involved as well. Optimal 25OHD serum concentrations, throughout the year, may be beneficial for patients with MS, both to obtain immune-mediated suppression of disease activity, and also to decrease disease-related complications, including increased bone resorption, fractures, and muscle weakness.

Vitamin D intake and incidence of multiple sclerosis Neurology. 2004 Jan 13;62(1):60-5. … Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women: the Nurses' Health Study (NHS; 92,253 women followed from 1980 to 2000) and Nurses' Health Study II (NHS II; 95,310 women followed from 1991 to 2001). ... CONCLUSION: These results support a protective effect of vitamin D intake on risk of developing MS.

------Annotated References / Abstracts for FATS

Polyunsaturated fatty acids and neurological diseases. Mini Rev Med Chem. 2006 Nov;6(11):1201-11. This review summarizes the knowledge of the role of dietary PUFAs, especially omega-3, on normal brain function. Furthermore, it reports the evidence pointing to potential mechanisms of omega-3 fatty acids in development of neurological disorders and efficacy of their supplementation in terms of symptom management.

Erythrocyte membrane fatty acids in benign and progressive forms of multiple sclerosis J Neurol Sci. 2006 May 15;244(1- 2):123-6. Epub 2006 Mar 6. BACKGROUND: There is no good explanation why a proportion of patients with multiple sclerosis (MS) have a relatively benign form of the disease. An imbalance between saturated and unsaturated fatty acids (FA) might influence the disease course of MS. AIM: To assess whether the erythrocyte membrane fatty acid composition, which is a biological marker of long term dietary FA consumption, is different between patients with benign and progressive MS. METHODS: The erythrocyte membrane FA composition was measured by gas chromatography in 23 healthy controls, 27 patients with benign MS, 32 patients with secondary progressive MS and 23 patients with primary progressive MS. None of the patients was following a special diet. RESULTS: No significant differences in levels of saturated and unsaturated FA or in omega-3- and omega-6-polyunsaturated FA were found between controls and patients with the different subtypes of MS. Conclusion: Our data suggest that factors other than dietary fatty acid consumption are responsible for the different disease courses of MS.

Polyunsaturated fatty acid supplementation in MS. Int MS J. 2005 Nov;12(3):88-93. This article focuses on polyunsaturated fatty acid (PUFA) supplementation, which is a popular form of complementary and alternative therapy among people with MS. Owing to their popularity, clinicians should be knowledgeable about the PUFA supplements that are widely available, and the efficacy and safety data from clinical studies. Small-scale studies have demonstrated trends towards some beneficial effects. PUFA supplementation is generally well tolerated, although some specific supplements are best avoided and some clinical situations warrant caution. A review of the efficacy and safety data suggests that PUFA supplementation may be a promising approach. Large-scale trials are required to confirm the benefits.

Low fat dietary intervention with omega-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot Essent Fatty Acids. 2005 Nov;73(5):397-404. OBJECTIVES: To determine whether a low fat diet supplemented with omega-3 positively affects quality of life (QOL) in relapsing-remitting MS (RRMS) patients. In this 1-year long double-blind, randomized trial, patients were randomized to two dietary interventions: the "Fish Oil" (FO) group received a low fat diet (15% fat) with omega-3 FOs and the "Olive Oil" (OO) group received the AHA Step I diet (fat 30%) with OO supplements. The primary outcome measure was the Physical Components Summary Scale (PCS) of the Short Health Status Questionnaire (SF-36). Additional measures using MS specific QOL questionnaires, neurological status and relapse rate were obtained. RESULTS: 31 RRMS patients were enrolled, with mean follow up over 9-14 months. Clinical benefits favoring the FO group were observed on PCS/SF-36 and MHI. at 6 months. Reduced fatigue was seen on the OO diet at 6 months. The relapse rate decreased in both groups relative to the rates during the 1 year preceding the study: mean change in relapse rate in the FO group: -0.79 +/- SD 1.12 relapses/year vs. -0.69 +/- SD 1.11 in the OO group. This study suggests that a low fat diet supplemented with omega-3 PUFA can have moderate benefits in RRMS patients on modifying therapies.

Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting therapies.

26 Antioxidants in multiple sclerosis: do they have a role in therapy? CNS Drugs. 2006;20(6):433-41. Multiple sclerosis (MS) is an immune-mediated disease, with inflammation and neurodegeneration contributing to neuronal demyelination and axonal injury. Current therapies for MS are directed toward modulation of the immune response; however, there is increasing evidence that oxidative stress is an important component in the pathogenesis of MS. The inflammatory environment in demyelinating lesions is conducive to the generation of reactive oxygen species. When these species are generated in MS and animal models of MS, products such as peroxynitrite and superoxide are formed that are highly toxic to cells. There are several examples of potential beneficial effects from various antioxidants in animal models of MS, but the efficacy may vary between different agents and, in some instances, may yield deleterious effects. Despite these promising results in animal models, there is limited and conflicting evidence of potential therapeutic effects of antioxidants such as vitamins C and E in treating MS. However, clinical trials in MS patients with more potent antioxidants, identified in animal studies, have been initiated.

Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation. Curr Pharm Des. 2006;12(27):3521-33. Oxidative stress, in which production of highly reactive oxygen species (ROS) and reactive nitrogen species (RNS) overwhelms antioxidant defenses, is a feature of many neurological diseases and neurodegeneration. ROS and RNS generated extracellularly and intracellularly by various processes initiate and promote neurodegeneration in CNS. ROS and RNS can directly oxidize and damage macromolecules such as DNA, proteins, and lipids, culminating in neurodegeneration in the CNS. … We propose that combinations of agents which act at sequential steps in the neurodegenerative process can produce additive neuroprotective effects. A cocktail of multiple antioxidants with anti- inflammatory agents may be more beneficial in the prevention of neurodegenerative disease. A clearer appreciation of the potential therapeutic utility of antioxidants would emerge only when the complexity of their effects on mechanisms that interact to determine the extent of oxidative damage in vivo are more fully defined and understood.

Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Dec;59(12):1347-61. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligodendrocyte damage and subsequent axonal demyelination is a hallmark of this disease. Different pathomechanisms, for example, immune-mediated inflammation, oxidative stress and excitotoxicity, are involved in the immunopathology of MS. The risk of developing MS is associated with increased dietary intake of saturated fatty acids. Polyunsaturated fatty acid (PUFA) and antioxidant deficiencies along with decreased cellular antioxidant defence mechanisms have been observed in MS patients. Furthermore, antioxidant and PUFA treatment in experimental allergic encephalomyelitis, an animal model of MS, decreased the clinical signs of disease. Low-molecular-weight antioxidants may support cellular antioxidant defences in various ways, including radical scavenging, interfering with gene transcription, protein expression, enzyme activity and by metal chelation. PUFAs may not only exert immunosuppressive actions through their incorporation in immune cells but also may affect cell function within the CNS. Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.

Lipoic acid in multiple sclerosis: a pilot study. Mult Scler. 2005 Feb;11(1):24-32. Lipoic acid (LA) is an antioxidant that suppresses and treats an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis. … We conclude that oral LA is generally well tolerated and appears capable of reducing serum MMP-9 and sICAM-1 levels. LA may prove useful in treating MS by inhibiting MMP-9 activity and interfering with T-cell migration into the CNS.

Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J Neuroimmunol 2002 Oct;131(1-2):104-14

Antioxidants and polyunsaturated fatty acids in multiple sclerosis. Eur J Clin Nutr. 2005 Aug 24.…Both dietary antioxidants and PUFAs have the potential to diminish disease symptoms by targeting specific pathomechanisms and supporting recovery in MS.

The role of methallothioneins in experimental autoimmune encephalomyelitis and multiple sclerosis. Ann N Y Acad Sci. 2005 Jun;1051:88-96. … In this review we summarize recent progress in understanding the regulation and function of methallothioneins during experimental autoimmune encephalomyelitis and MS. Ann N Y Acad Sci. 2005 Jun;1051:88-96.

Time-course expression of CNS inflammatory, neurodegenerative tissue repair markers and metallothioneins during experimental autoimmune encephalomyelitis. Neuroscience. 2005;132(4):1135-49. … suggest that metallothionein proteins are implicated in the clinical recovery of EAE and perhaps these antioxidant proteins may provide therapeutic benefits in MS. Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol. 2004 Nov 1;173(9):5794-800. … We show that the major green tea constituent, (-)-epigallocatechin- 3-gallate (EGCG), dramatically suppresses EAE induced by proteolipid protein 139-151. EGCG reduced clinical severity when given at initiation or after the onset of EAE by both limiting brain inflammation and reducing neuronal damage. …Because its structure implicates additional antioxidative properties, EGCG was capable of protecting against neuronal injury in living brain tissue induced by N-methyl-D-aspartate or TRAIL and of directly blocking the formation of neurotoxic reactive oxygen species in neurons. Thus, a natural green tea constituent may open up a new therapeutic avenue for young disabled adults with inflammatory brain disease by combining, on one hand, anti-inflammatory and, on the other hand, neuroprotective capacities. Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis. J Neurosci Res. 2004 Nov 1;78(3):362-70. We have demonstrated previously the ability of the antioxidant alpha lipoic acid (ALA) to suppress and treat a model of multiple sclerosis (MS), relapsing experimental autoimmune encephalo-myelitis (EAE). … These data, coupled with its ability to treat relapsing EAE, suggest that ALA warrants investigation as a therapy for MS.

Protective effects of caffeic acid phenethyl ester against experimental allergic encephalo-myelitis-induced oxidative stress in rats. Free Radic Biol Med. 2004 Aug 1;37(3):386-94. … Caffeic acid phenethyl ester (CAPE), an active component of honeybee

27 propolis, has been determined to have antioxidant, anti-inflammatory, antiviral, & anticancer activities. … Treatment with CAPE significantly inhibited reactive oxygen species (ROS) production induced by EAE, & ameliorated clinical symptoms in rats. These results suggest that CAPE may exert its anti-inflammatory effect by inhibiting ROS production at the transcriptional level through the suppression of nuclear factor kappaB activation, & by directly inhibiting the catalytic activity of inducible nitric oxide synthase.

The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004 Mar;251(3):261-8.Accumulating data indicate that oxidative stress (OS) plays a major role in the pathogenesis of multiple sclerosis (MS). Reactive oxygen species (ROS), leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelination and axonal damage in both MS and experimental autoimmune encephalomyelitis (EAE), its animal model. … treatment with antioxidants might theoretically prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several experimental studies have been performed to see whether dietary intake of several antioxidants prevents or reduces the progression of EAE. Although a few antioxidants showed some efficacy in these studies, little information is available on the effect of treatments with such compounds in patients with MS. Well-designed clinical studies using antioxidant intake, as well as investigations based on larger cohorts studied over a longer periods of time, are needed in order to assess whether antioxidant intake together with other conventional treatments, might be beneficial in treating MS.

Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004 Mar;148(1-2):146-53.Alpha-lipoic acid (alpha-LA) is a neuroprotective metabolic antioxidant that has been shown to cross the blood brain barrier. We tested whether alpha-LA is capable to prevent MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). … Our data indicate that alpha-LA can effectively interfere with the autoimmune reaction associated with EAE through mechanisms other than its antioxidant activity and supports further studies on the use of alpha-LA as a potential therapy for MS.

Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis: implications for the role of oxidative stress in the development of multiple sclerosis. J Neuroimmunol. 2003 Jun;139(1-2):27-35. Increasing evidence shows that oxidative stress plays an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Annotated References / Abstracts for Vitamin B12

Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006 Nov;5(11):949-60. There are many reasons for reviewing the neurology of vitamin-B12 and folic-acid deficiencies together, including the intimate relation between the metabolism of the two vitamins, their morphologically indistinguishable megaloblastic anaemias, and their overlapping neuropsychiatric syndromes and neuropathology, including their related inborn errors of metabolism. Folates and vitamin B12 have fundamental roles in CNS function at all ages, especially the methionine-synthase mediated conversion of homocysteine to methionine, which is essential for nucleotide synthesis and genomic and non-genomic methylation. Folic acid and vitamin B12 may have roles in the prevention of disorders of CNS development, mood disorders, and dementias, including Alzheimer's disease and vascular dementia in elderly people.

Vitamin B12 and methionine synthesis: a critical review. Is nature's most beautiful cofactor misunderstood? Biofactors. 2006;26(1):45-57. The mechanism by which Vitamin B12 prevents demyelination of nerve tissue is still not known. The evidence indicates that the critical site of B12 function in nerve tissue is in the enzyme, methionine synthase, in a system which requires S- adenosylmethionine. In recent years it has been recognized that S-adenosylmethionine gives rise to the deoxyadenosyl radical which catalyzes many reactions including the rearrangement of lysine to beta-lysine. Evidence is reviewed which suggests that there is an analogy between the two systems and that S-adenosyl methionine may catalyze a rearrangement of homocysteine on methionine synthase giving rise to iso- or beta-methionine. The rearranged product is readily degraded to CH3-SH, providing a mechanism for removing toxic homocysteine.

Plasma homocysteine levels in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2006 Feb;77(2):189-92. BACKGROUND: There is evidence that homocysteine contributes to various neurodegenerative disorders, and elevated plasma homocysteine levels have been observed in patients with multiple sclerosis (MS). OBJECTIVE: To investigate if and why plasma homocysteine levels are increased in MS, and whether they play a role in the disease course. METHODS: We compared plasma levels of homocysteine in 88 patients with MS and 57 healthy controls. In the MS group, 28 had a benign course, 37 were secondary progressive, and 23 primary progressive. To explore the underlying mechanisms, we measured serum levels of vitamins B6 and B12, folate, interleukin (IL)-12, tumour necrosis factor (TNF)-alpha, leukocyte nitric oxide production, and plasma diene conjugate levels (measure of oxidative stress). RESULTS: Mean (SD) plasma homocysteine concentration was higher in patients (13.8 (4.9) micromol/l) than in controls (10.1 (2.5) micromol/l; p<0.0001). However, there were no significant differences in homocysteine levels between the three clinical subgroups of MS. Serum concentrations of vitamin B6, vitamin B12, and folate were not different between patients with MS and controls. In the MS group, there were no correlations between plasma homocysteine levels and the serum concentrations of IL-12 or TNF-alpha, leukocyte nitric oxide production, or plasma diene conjugate levels. CONCLUSIONS: Elevated plasma homocysteine occurs in both benign and progressive disease courses of MS, and seems unrelated to immune activation, oxidative stress, or a deficiency in vitamin B6, vitamin B12, or folate.

Vitamin B12, demyelination, remyelination and repair in multiple sclerosis J Neurol Sci. 2005 Jun 15;233(1-2):93-7. Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and

28 suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.

Attenuation of experimental autoimmune encephalomyelitis and nonimmune demyelination by IFN-beta plus vitamin B12: treatment to modify notch-1/sonic hedgehog balance. J Immunol. 2004;172(10):6418-26. Interferon-beta is a mainstay therapy of demyelinating diseases, but its effects are incomplete in human multiple sclerosis & several of its animal models. In this study, we demonstrate dramatic improvements of clinical, histological, & laboratory parameters in in vivo mouse models of demyelinating disease through combination therapy with IFN-beta plus vitamin B(12) cyanocobalamin (B(12)CN) in nonautoimmune primary demyelinating ND4 (DM20) transgenics, and in acute and chronic experimental autoimmune encephalomyelitis in SJL mice. Clinical improvement (p values <0.0001) was paralleled by near normal motor function, reduced astrocytosis, and reduced demyelination. IFN-beta plus B(12)CN enhanced in vivo and in vitro oligodendrocyte maturation. In vivo & in vitro altered expression patterns of reduced Notch-1 & enhanced expression of sonic hedgehog & its receptor were consistent with oligodendrocyte maturation & remyelination. IFN-beta-B(12)CN combination therapy may be promising for the treatment of multiple sclerosis. Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid. Mult Scler. 2003 Jun;9(3):239-45. Objective: The aim of this study was to evaluate if multiple sclerosis (MS) is associated with vitamin B12 (cobalamin) deficiency. Methods: We measured serum vitamin B12, plasma folate, serum methylmalonic acid (MMA), plasma homocysteine (tHcy) and also cerebrospinal fluid (CSF) MMA and tHcy in 72 patients with MS and 23 controls. Results: The mean plasma tHcy level was significantly increased in MS patients (11.6 micromol/L) compared with controls (7.4 micromol/L) (P = 0.002). Seven patients showed low serum vitamin B12 levels but only one of them had concomitant high plasma tHcy. None of them showed high serum MMA. Plasma or blood folate levels did not differ between MS patients and controls. We found no significant differences in mean values or frequency of pathological tests of serum B12, serum MMA, mean corpuscular volume (MCV), haemoglobin concentration, CSF tHcy or CSF MMA between patients and healthy subjects. There were no correlations between CSF and serum/plasma levels of MMA or tHcy. Serum vitamin B12, serum MMA, plasma tHcy, CSF Hcy or CSF MMA were not correlated to disability status, activity of disease, duration of disease or age. Conclusions: The relevance of the increased mean value of plasma tHcy thus seems uncertain and does not indicate functional vitamin B12 deficiency. We can not, however, exclude the possibility of a genetically induced dysfunction of the homocysteine metabolism relevant for the development of neuroinflammation/degeneration. Our findings indicate that, regardless of a significant increase in plasma tHcy in MS patients, the MS disease is not generally associated with vitamin B12 deficiency since we did not find any other factors indicating vitamin B12 deficiency. Analysis of CSF MMA and CSF tHcy, which probably reflects the brain vitamin B12 status better than serum, are not warranted in MS. We conclude that B12 deficiency, in general, is not associated with MS.

Lipoprotein oxidation, plasma total antioxidant capacity and homocysteine level in patients with multiple sclerosis. Nutr Neurosci. 2003 Jun;6(3):189-96. Free radical-mediated peroxidation of biological molecules, especially of lipids, is implicated in the pathogenesis of a number of diseases like multiple sclerosis. Low concentration of antioxidant vitamins: beta carotene, retinol, alpha tocopherol and ascorbic acid have been observed in serum or cerebrospinal fluid of multiple sclerosis patients. On the basis of these observations, we studied the potential lipoprotein oxidation and total antioxidant capacity in the pathogenesis of multiple sclerosis. Lipoprotein oxidizability for plasma in vitro, serum levels of autoantibodies against oxidized low-density lipoproteins, plasma total homocysteine levels with vitamin B12 and folate, and plasma total antioxidant capacity were measured in twenty four patients with multiple sclerosis and twenty four healthy sex- and age-matched person as control. In multiple sclerosis patients during an attack, a significant increase in both in vitro lipid oxidizability for plasma and in the levels of autoantibodies against oxidized low-density lipoproteins, and a strong decrease in plasma total antioxidant capacity were detected. Plasma total homocysteine levels were significantly higher in multiple sclerosis patients whose plasma vitamin B12 and folate levels were lower but not statistically significant, than controls. The present study indicates that lipoprotein oxidation may be important factor in the course of multiple sclerosis and in vitro measurements of plasma oxidation kinetics as an indication for lipoprotein oxidation might be useful as an additional tool for the clinical diagnosis of multiple sclerosis. Treatment of multiple sclerosis with lofepramine, L-phenylalanine and vitamin B(12): mechanism of action and clinical importance: roles of the locus coeruleus and central noradrenergic systems. Med Hypotheses. 2002 Nov;59(5):594-602. In a randomized, placebo-controlled double-blind trial a combination of lofepramine, phenylalanine and vitamin B(12) was found to be effective in relieving the symptoms of multiple sclerosis (MS). The effect occurred within 2-4 weeks, and improved all types of symptoms in all types of MS. The combination was also effective in relieving symptoms in patients with chronic pain and chronic fatigue. We hypothesize that the action of this combined therapy may relate to activation of the noradrenergic locus coeruleus/lateral tegmentum (LC/LT) system which has the potential to influence the functioning of large areas of the brain and spinal cord. A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the "Cari Loder regime") in the treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002 Sep;73(3):246-9 OBJECTIVE: To determine whether combination therapy with lofepramine, L-phenylalanine, and intramuscular vitamin B-12 (the "Cari Loder regime") reduces disability in patients with multiple sclerosis. METHODS: A placebo controlled, double blind, randomised study carried out in five United Kingdom centres on outpatients with clinically definite multiple sclerosis, measurable disability on Guy's neurological disability scale (GNDS), no relapse in the preceding six months, and not on antidepressant drugs. Over 24 weeks all patients received vitamin B-12, 1 mg intramuscularly weekly, and either lofepramine 70 mg and L-phenylalanine 500 mg twice daily, or matching placebo tablets. Outcome was assessed using the GNDS, the Kurtzke expanded disability status scale; the Beck depression inventory, the Chalder fatigue scale, and the Gulick MS specific symptom scale. RESULTS: 138 patients were entered, and two were lost from each group. There was no statistically significant difference between the groups at entry or at follow up. Analysis of covariance suggested that treated patients had better outcomes on four of the five scales used. Both groups showed a reduction of 2 GNDS points within the first two weeks, and when data from all time points were considered, the treated group had a significant improvement of 0.6 GNDS points from two weeks onwards. CONCLUSIONS: Patients with multiple sclerosis improved by 2 GNDS points after starting vitamin B-12 injections. The addition of lofepramine and L-phenylalanine added a further 0.6 points benefit. More research is needed to confirm and explore the significance of this clinically small difference.

29 Sanford Medical Center 2011

Aunt Cathy’s Guide to Nutrition:

The Prader Willi Syndrome Cathy Breedon PhD, RD, CSP, FADA Association’s Food Guide Clinical/ Metabolic Nutrition Specialist Pyramid for Weight Control and Pediatric Nutrition Specialist (with some editorial Sanford Medical Center, Dept. of Pediatrics comments from me) University of North Dakota School of Medicine, Dept. of Pediatrics, Fargo, ND

Introductory comments from CB:

Children with a genetic condition called Prader Willi Syndrome usually struggle with their weight all of their lives. They appear to use up fewer calories each day, so just eating “normally” can still cause them to gain weight extremely fast. Losing weight is extremely difficult. The following is a 2003 Food Guide Pyramid that was designed for people with PWS, but potentially useful for any people with very low calorie requirements (such as people whose movement is impaired.) This pyramid has some helpful ideas (especially the suggestion to place vegetables as the “base” of the pyramid instead of the grains and cereals food group in the “regular” USDA Food Guide Pyramid.)

In addition to calorie concerns, however, I am very concerned about assuring that micronutrients (vitamins and minerals) and protein are provided in appropriate amounts in spite of the decreased total food intake. There are some other serious concerns as well. Unfortunately, there are some problems in that area in the 2003 Prader Willi Food Guide presented below. As it appears to continue to be used in practice in spite of these important issues, I have taken the liberty of interjecting my thoughts on this issue as you look over this otherwise helpful way of adjusting the base of the pyramid.

My comments are clearly delineated from those of the PWS Pyramid designer (Beverly Ekaitis, DTR, registered dietetic technician) by brackets [ ] and by bold print.

1 Start of the original 2003 article: ______

Prader-Willi Syndrome Association (USA)

A PRADER-WILLI FOOD PYRAMID

by Beverly Ekaitis, DTR, dietetic technician The Children's Institute of Pittsburgh (TRI) PWSA Editors’ Note: The USDA’s Food Guide Pyramid provides an appealing graphic tool for thinking about a day’s food portions, but it simply adds up to too much food for someone on a Prader-Willi diet. We asked the Children's Institute if they could adapt the new pyramid to the typical PW diet for families that might wish to use it as an alternative to the Exchange System, the Red-Yellow- Green (Stoplight) Diet, or other methods of counting calories. The Institute was glad to oblige but urges those who have been through the Institute’s program to continue using the Red-Yellow-Green Diet that they learned there. The Prader-Willi Food Pyramid that follows may not be appropriate for young children or for those on growth hormone therapy, and it should not be considered a substitute for individualized dietary guidance. Dietary guidance preferably should come from a nutritionist who is familiar with PWS.

2

The Food Pyramid Guide to Daily Food Choices, designed by the U.S. Department of Agriculture for adults who need 1,600 to 2,800 calories a day, represents the relative portions of foods to eat each day to maintain a healthy weight and body. To make the Food Pyramid usable for people with Prader-Willi syndrome, a few changes have to be made.

CB note : It is potentially useful for others with very low caloric requirements as well, with the same caveats described below.

The first change needed is to adjust the number of daily servings for each food group in order to reduce the total calorie level to 800 to 1,200 a day. These lower levels will provide for weight loss or maintenance for the adult or teenager with PWS, whose calorie needs are about 60 percent of those without PWS.

CB note:

Actual calorie goals for PWS and non-PWS individuals will vary considerably. Also, when establishing such a low calorie goal, consider that the daily values and other guidelines are usually based on a 2000 calorie diet. It is important to remember that such low calorie levels will invariably be inadequate in a number of nutrients unless careful supplementation is done. Failure to replace these nutrients is not benign.

Second, although the five main food groups—bread, vegetable, fruit, meat, and milk—remain the same, the positions of two of the groups need to be changed on the pyramid to reflect a change in the recommended number of servings. Each group has a specific number of servings that determines its position on the pyramid. The Food Groups The first USDA Food Pyramid (which had horizontal lines) has a base of the Bread group, which would provide the highest number of daily servings. The PW Pyramid, on the other hand, has as its base the Vegetable group, with 6-8 servings a day. For those familiar with the Red- Yellow-Green Diet, these would be "GO" foods, i.e., foods low in calories and fat. Making the vegetable group the base of the pyramid and the bulk of the diet will allow a large volume of food to be eaten without many additional calories.

3 The Bread group, which includes cereal, pasta, and rice, moves up the pyramid with a decrease in number of servings to three to five per day. We would also include starchy vegetables like corn, peas, and potatoes in this group because they have the same amount of calories per serving as breads.

CB note:

Try to use whole grains and foods that are naturally high in fiber whenever able to improve the micronutrient content of the diet (especially magnesium, chromium and natural forms of vitamin E) and to decrease the potential for insulin resistance problems.

(See my “Magnesium” and “Top Five Recommendations” handouts for more on this.)

The Fruit group includes fresh fruit, canned fruit, juice, and dried fruits. Many people think of fruit as a "free" food. While it is a good snack and a good source of fiber and vitamins, it does have calories that should be counted if one is on a restricted diet. The daily servings should be four—one at each meal and one for snack.

CB note:

Choose whole fruit as much as possible instead of juices. If you use canned fruit the juice-packed or water-packed are preferred over syrup-packed products. Liquid carbohydrate calories consumed may be less well recognized as calories consumed by the body of some individuals, and so additional calories may be accidentally taken in. Excessive juice and “regular” pop consumption is suspected of being contributory to increased weight gain in children in general.

The Milk group includes yogurt, milk, and cheese. To fit the needs of the person with PWS, the servings per day should be two, and the products chosen should be nonfat or low in fat. Fat- free, sugar-free frozen yogurt also can be used as a milk serving.

CB note: Be sure to provide additional calcium and vitamin D, as the amount provided by the serving number shown here is clearly inadequate for optimal health. MANY people (and over-weight individuals in particular) have been shown to require an intake of vitamin D well above the present RDA level. Now that blood levels are beginning to be checked more often, the very large number of people with inadequate vitamin D levels in their blood is being

4 identified, and inadequacy is now recognized as being very detrimental to heart health, muscle function, immune system function, prevention of cancer, autoimmune disorders, osteoporosis and bone pain More on vitamin D will be discussed later. Back to the specifics of the Pyramid: Note that the two cups of milk suggested will provide only 200 iu of vitamin D, but PWS individuals should be provided with at least 2000 iu daily simply to maintain levels associated with optimal health. Even more may be shown to be needed for individuals. Also, the 2000 iu is a maintenance level, not a level to treat deficiency, which could be much more than that. Most cheese, yogurt and other dairy products do not provide any vitamin D at all … and if some has been added in certain brands, it is still at the same too-low amount as is added to milk (i.e. 100 iu/cup.) Vitamin D deficiency is extremely common, generally unrecognized, and contributory to increased risk of cancer, muscle weakness, muscle pain, heart disease, MS, arthritis, diabetes, compromised immune function and more. It is now being described as an “unrecognized epidemic.” People who are overweight have an additional risk of vitamin D deficiency. A good plan would be to check the vitamin D level in the winter and if deficiency is found, the physician would then order a special high-dose catch-up amount (a “therapeutic dose”), which would be followed by an intake equivalent to at least a 2000 iu/daily maintenance level. One example of a therapeutic dose is 50,000 iu/week for 8 weeks, followed by a re-check and sometimes another round of that level of supplementation. The serum level that is associated with optimal health is 40 iu; the older lab sheets say that 25 is the lower end of normal, but that level has been shown to be insufficient for some of the known functions of vitamin D, such as cancer prevention and muscle strength. People with PWS have several additional risk factors for deficiency that lead me to recommend that it would be wise to get a vitamin D level measured annually in the winter (the lab to order is the “25-hydroxy vitamin D” measurement.)

(See my “Top Five Recommendations” handout for more information on vitamin D)

The Meat group includes meat, fish, poultry, eggs, peanut butter, and cooked dried beans. The USDA also includes nuts in this group, but due to their high fat content they should be eliminated from the PW Pyramid.

5 CB note:

Although nuts and peanut butter are higher in calories than some foods, they are also quite nutrient dense and they are among the richest source of dietary magnesium, a mineral that is often low in American diets, and which is extremely metabolically important.

In children and adults who are significantly overweight, magnesium may make a difference between whether or not one goes on to develop insulin resistant (type 2) diabetes. Additionally, magnesium inadequacy can contribute to obesity itself by making it hard to convert fuel from food into usable energy. (See “Magnesium” handout and “Top Five Recommendations” handout.)

The fat in nuts and legumes is of the more “heart friendly” type – rich in the type of fat called “monounsaturated” fat. Also, although fat has more calories per ounce than carbohydrate or protein, it is useful to note that in non- PWS individuals a more generous fat content per se does not seem to be associated with increased fatness or decreased weight loss as long as one stays within the target caloric level.

However, people with PWS appear to have difficulty doing anything with the fat they eat except store it. Restricting the proportion of calories from fat is reasonable, but as is discussed later, there are ways to help them use the fat more normally. In that situation, restricting fat specifically would become a much less important goal. Similarly, limiting consumption of fat does not prevent the production of fat from extra calories taken in from protein carbohydrate.

Nuts and peanuts also provide protein and the protein and fat content both contribute to a sense of satiety for most people. It helps them not get hungry again so soon, and it has been shown to be true for many other groups of people who are trying to “watch calories.” Whether this is true for people with PWS is not known … it appears that the drive to eat is controlled by a different mechanism than the sense of satiety associated with stomach fullness, as described below.

And the USDA suggests two to three meat servings per day of 2½-to-3-oz. portions. To decrease the calories for the PW meal plan, we changed the portion size to 2 oz. and suggest one to two servings a day. This means that a person on 800 calories could divide the 2 oz. serving to provide 1 oz. at lunch and 1 oz. at dinner, and a person on 1,200 calories could have 2 oz. at lunch and 2 oz. at dinner.

6 CB note : Dried beans and peas –kidney beans, navy beans, lentils, split peas, etc. – are terrific foods for people with weight problems. They are generous in magnesium, chromium and many other nutrients that help us use our calories appropriately, and they are also low in fat and high in fiber. They are a good source of protein, they are ‘filling,’ and their carbohydrate is in a form that has a low ‘glycemic index.’ Diets based on ‘low glycemic index’ foods appear to result in more weight loss than a “low fat” diet even when both diets provided the same number of calories. However … as before … these observations may not be that useful in coping with the metabolic problems of people with PWS. However, it may be helpful to people with PWS as well if it results in fewer episodes of elevated blood sugar after eating, perhaps by avoiding excessive stimulation of insulin. Hyperinsulinemia itself can be contributory to excessive weight gain. It is also reasonable to provide 1000 mg fish oil daily or to eat “fatty fish” twice weekly (as is recommended for everyone by the American Heart Association.) There are many reasons for this … please see my Top Five Recommendations paper for more general explanation. The reason it would be particularly reasonable in PWS is because missing part of a chromosome (or other metabolic conditions like diabetes) can affect production of many things we usually make for ourselves, such as the omega-3 fats EPA and DHA. These fats have many special roles in health, including eye health, brain development and decreasing inflammatory conditions. The ready-to-go form of EPA and DHA is in fish oil. The caloric contribution is very small compared to the health benefit. I standardly recommended it for all the children I work with who have metabolic problems … and also for all those who do not have any particular health problem. I take it myself and make my husband take it too. One additional caveat is that some people with PWS develop Type II diabetes and may be put on the medication Metformin/Glucophage. This medication has been shown to cause significant impairment of vitamin B12 status, which can cause neurologic injury. I recommend that anyone on this medication be monitored with an annual vitamin B12 level. Note that if the level is dropping even though still in the normal range, it suggests that they are using up stored vitamin B12 and are likely to develop deficiency even if it is not seen now. [Mean cell volume is a very late-appearing symptom of vitamin B12 deficiency. The changes in cell size occur because the person is no longer able to make DNA adequately … this should not be used as a screening test.] If generous oral vitamin B12 does not correct the problem, consider a vitamin B12 shot to bypass the intestinal impairment of vitamin B12 absorption

7 that is associated with use of this medication. Vitamin B12 deficiency is very dangerous. I have found it in several adolescents with PWS who were new to our clinic and whio had never had it evaluated. [Please see my “Vitamin B12” handout or my “Other Nutrition Issues in Diabetes” handout for more detail on this phenomenon, and some other monitoring issues.

Serving Sizes Except for the meat group, the serving sizes on our PW Pyramid are unchanged from the USDA Food Pyramid. They are as follows:

Vegetable: ½ cup cooked or 1 cup raw

Bread: 1 slice bread; ½ C. rice, pasta, or starchy vegetable; 1 oz. Cereal

Fruit: ½ C. canned, ½ C. or 1 piece fresh, 1/4 C. dried; ½ C. juice

Milk: 1 C. skim milk or lite yogurt, 1 oz. cheese, ½ C. frozen fat-free sugar-free yogurt

Meat: 2 oz. cooked lean meat, fish, poultry; 1 egg; ½ C. cooked dried beans; 2 T peanut butter

Fats, Oils, and Sweets The top of the USDA Pyramid shows fats, oils, and sweets. These are denoted by symbols that are concentrated in this area and dispersed throughout the other groups. The USDA suggests that these foods be used sparingly to add extra calories. These foods include butter, margarine, regular dressings, candy, sugars, sweets, fatty desserts, gravy, and fried foods, to name a few. The foods from this group add unwanted calories and few nutrients to the Prader- Willi diet. They should be limited to once a month for an 800-calorie plan and once a week for a 1,200-calorie plan. We have deleted the fat symbols throughout the PW Pyramid, because all foods chosen should be low in fat and sugar. Using this modified pyramid as a guide to weight loss and maintenance, in conjunction with a favorite exercise program, can be an easy way to ensure a healthy, nutritious diet for the person with Prader-Willi syndrome.

CB note: Following this plan will result in very poor micronutrient balance unless a number of vitamins and minerals are supplemented. This includes inadequacies of many nutrients that are not included in a standard multivitamin with minerals.

8 Another extremely important consideration is that is that there is clearly a metabolic component to weight issues in Prader Willi Syndrome. They are not being “piggy” or “lazy.” Something in their bodies is not working right and they are trying desperately to compensate for it … with predictable results: The well-recognized features of PWS include an intense drive to eat even when allowed to consume a very generous amount of food. Additionally, they often accumulate very generous body fat, and they tend to have hypotonia (low muscle tone) and very poor exercise endurance. These features of the syndrome make it necessary to look at more than severely cutting their calories and pushing for increase physical activity in an effort to avoid fatness. Restricting calories does not help the drive to eat at all, nor does it truly solve the excess fat accretion or muscle issues. This collection of symptoms can often reflect a metabolic problem that requires the person to be provided with a substance called carnitine, and our experience with children who have received carnitine supplementation has borne this out. Carnitine is normally made in ample amounts in one’s body, but there are a number of situations in which it is not made in normal amounts, or in which a person has much higher than usual needs. In a nutshell, carnitine has an important role in one’s ability to burn fat for fuel. Failure to efficiently burn fat for fuel means that fat will be stored but then it is unable to be made available for use as fuel. That means that for practical purposes, the fat consumed with a meal and the fat already stored in the body do not contribute to the job of running a person’s body. One’s brain then makes “getting some fuel” an extremely high priority … hence the intense food-seeking behavior even in the presence of clearly generous energy stores and a generous amount of food eaten. Maintaining normal muscle tone also requires carnitine because muscles preferentially burn fat for fuel, especially in endurance activities. Muscle weakness and poor exercise tolerance result from inability to burn fat fuel normally, which then impairs the pursuit of the physical activity encouraged as part of a weight management program. Further, the heart is a muscle … cardiomyopathy and hypotonia (low muscle tone) is often associated with carnitine insufficiency. When health care professionals only focus on the caloric restriction issue, they contribute to big problems for families. They often put the responsibility for preventing obesity on the shoulders of the caretakers with messages like “It’s your job to just tell her ‘no’ when she wants more food.” Consider that when health professionals say this kind of thing, they are asking a parent to consistently refuse food to a child who is begging and pleading for it.

9 Imagine the hungriest you have ever felt, and then imagine that people with PWS feel that way all the time. They experience intense discomfort from hunger … cutting their food intake down to half the amount other people get to eat does not solve this problem. It may prevent obesity to some degree, but it makes their discomfort worse and it can have a very negative on behavior and relationships. One promising non-nutritional intervention is the use of growth hormone. There are nutrition-related substances under investigation as potentially helpful in muscle operation in PWS as well, such as CoQ-10. In our clinic, we have seen tremendous benefit to individual babies and children from the combination of growth hormone, carnitine and CoQ-10. It has worked better in combination than with the (already standardly used) growth hormone therapy alone. The metabolic adjustment seems to make that expensive growth hormone more effective. The benefits include better lean body mass, BMI or weight-for-length, and muscle tone. It has significantly improved the classic intense food-seeking behavior. Severely hypotonic babies who started the carnitine and CoQ-10 upon diagnosis in the nursery have been able to suck well enough to go home without the gastrostomy tube placement often needed in early life. They move more vigorously. There is a lot more to learn, but the carnitine and CoQ-10 are very safe and very promising in some reports and small studies for children with PWS and other serious medical conditions with metabolic derangements. But large-scale long-term randomly-assigned prospective studies will take a long time to get. For that reason the use of carnitine and CoQ-10 in this application is not the official recommendation of large medical groups yet. Please note that I do not sell anything nor do I have any relationship with manufacturers of these substances. Additionally, I never go ANYWHERE near “scary” in my recommendations. But if it were MY child who had PWS I would surely do a trial on these substances while we await the long-term large research studies that are always needed. There are supportive preliminary reports in the scientific literature, and also anecdotal information from parents and from people like me who follow patients with PWS. For any particular child it will either help or it won’t, and I think it is certainly worth a trial. Stay tuned!

Summary about the use of the PWS Pyramid: The PWS pyramid above is a reasonable starting place for approaching a weight problem in general … it illustrates a simple way to identify the food groups with various calorie levels. However, the individual who put it together was a well-intentioned registered dietary technician and not a registered dietitian or licensed nutritionist. She was essentially only addressing the issue of calories, as she had been requested to do.

10 This discussion is not a criticism of her … she would not be expected to be aware of the other complex issues of nutrient inadequacy and metabolic disturbance such as those described above. She was asked to help with arranging a pyramid by the calorie content of food groups and she did that nicely. However, as pointed out in the boxes above, there are many other issues besides calories and weight in PWS. There is the potential for doing great harm by just cutting calories back when these other issues are not corrected. It is very important that the nutrition regimens of people with PWS be carefully evaluated by a health professional familiar with these problems.

11 MeritCare Medical Center

Aunt Cathy’s Guide to Nutrition: 2010

Why Are Children with Chronic Illnesses or Handicapping Conditions at High Risk of Aunt Cathy Receiving Suboptimal Nutrition? Cathy Breedon PhD, RD, CSP, FADA Pediatric and Clinical Nutrition Specialist, MeritCare Medical Center, Dept. of Pediatrics & A Quick Overview of Reasons: UND School of Medicine Dept. of Pediatrics Fargo, ND

1) Some children have higher than usual needs for energy (calories)

Sometimes this is because of the increased effort required for breathing in children with broncho-pulmonary dysplasia or congenital heart defects, or because of being especially physically active. Some children need to continually heal wounds. At the same time, they may have decreased ability to take food because of the effort required to eat or because a fluid limit is imposed. As a result, they often fail to grow optimally. Their intake of vitamins, minerals and protein can also be compromised, leading to: poor immune function, inadequate energy to explore and learn, poor skin integrity and wound healing and other problems.

Increasing the calories of formulas usually involves concentrating the product to make a higher caloric density. For example, using only 9 oz of water instead of the usual 13 oz when preparing a 13 oz can of infant formula concentrate will make the formula have 24 calories per ounce instead of the usual 20. The nice thing about this approach is that it provides ALL nutrients in higher amounts (not just calories,) it does not distort the ratios of nutrients per calorie, it contributes no additional cost, and it is safe to use.

Sometimes fat or carbohydrate calories will still need to be added, but these should generally be used only to add calories beyond the 24-26 calorie per ounce concentration. How to increase calories beyond the 24-26 calories per ounce should be determined with the help of a person familiar with these issues, as there are sometimes important reasons to use one additive over another in a particular child’s case.

Many of the substances added to foods or formulas to add calories can seriously distort the nutritional balance unless the protein, vitamins and minerals are carefully adjusted. For example, corn syrup, sugar, glucose polymers (like “Polycose ®” by Ross), butter/margarine, cream, regular vegetable oil, MCT oil ® (Mead Johnson/Novartis), and emulsified fat products like Microlipid and Intralipid all have one thing in common. They all just add empty calories. In small amounts there is no concern, but if a significant percentage of the child’s calories is contributed by these products there is potential for distorting the ratio of calories relative to the nutrients needed to metabolize them.

1 Some children will have higher needs for all nutrients in addition to calories. In this situation it is important to recognize that just adding protein and/or calories will not work well in the absence of the critically important vitamins and minerals that the body needs to convert fuel (calories) to make usable energy, and or to construct tissues. This is key in conditions that require extra production of tissue, such as wound healing and increased need for immune system activity. Failure to assure adequacy of micronutrients can make other efforts unsuccessful.

Unfortunately, this issue often does not get the attention it deserves and it is not uncommon for children to be given protein-only supplements without assuring adequacy of the necessary vitamins and minerals to use the protein. Also, giving just protein in the absence of adequate calories will result in the protein being burned as an energy source instead of using it for construction. Most nutrients have many important roles, some of which will be described further a bit later.

One should keep in mind that the usual recommended amounts of calories and nutrients such as the RDAs or RDIs or AIs are based on the needs of “most healthy people.” They do not address the needs of people with illness or other health conditions. The health care professionals will need to think through the particular challenges of a child’s situation and make adjustments in goals accordingly.

A good example is zinc, a mineral needed in over 200 different places in a person’s body. Every time we try to make a new cell, we need zinc to make the DNA in the center of it. That means that people who need to make a lot of new tissue will need a more generous intake of zinc. Poor zinc status impairs growth in children, and it limits the ability to heal wounds – another situation that requires a lot of new tissue formation. Recovery from wounds and staying healthy in general also depend on zinc because the production of T-cells of the immune system is very dependent on adequate zinc. At the same time, excessive amounts of zinc can cause problems. Determining the right amount requires a close look at the individual’s situation.

A generous intake of vitamin B12 and folic acid (another B vitamin) is also required for making DNA (for making all cells) and in particular for making new red blood cells. Sometimes anemia is not caused by inadequate iron but by a relative inadequacy of these nutrients, or others (like vitamin E) that are needed to keep red blood cells from being broken apart too soon. Vitamin C helps protect the white blood cells of the immune system to let them live longer to keep on killing germs. Vitamin C and copper are also players on the team that lets us build connective tissue for wound healing, and both are also required to use iron in the body.

And on and on. These are just a few of many examples of the critical role played by vitamins and minerals in health, and why this aspect of children’s nutrition cannot be ignored. For some specific additional information, please see my handouts on MeritCare’s website (www.meritcare.com) on folic acid, vitamin B12, magnesium, chromium, vitamin D, copper, zinc and iron. Just type my name in the key word box and then click “handouts.”

2 Another issue is cost. The “regular food” items are many times cheaper than the commercial additives. For example, consider fat additives commonly used: MCT oil ® is about $1 an ounce ($65 per quart) and the calories are about 5 calories less per teaspoon than most food fats. The advantage of using emulsified products is that they are better at staying mixed into formulas. But unless that is a major problem, it is useful to know that they are even higher in cost.

This is because they are primarily designed to be used in i.v. feedings. Microlipid ® is 88 cents per oz, but has only half the calories of other fats so you need to use twice as much. Compare these with the cost of canola oil (a good choice for a general vegetable oil.) Some other issues about the use of particular forms of fat will be discussed later.

Protein additives are also much more expensive than excellent quality protein in foods. At about 7 g protein per egg, egg protein costs about a penny a gram and it contains some additional nutritional value like choline and biotin. A can of “Resource Beneprotein ®” provides about 192 g protein per can (as whey protein,) and I found prices on line of $13-$15 per can, purchased as a case of 6 cans. That means that it can cost anywhere from 6.5 to 7.8 cents per gram of protein, or 6-8 times as much as egg protein.

The liquid pasteurized “no yolk” egg protein products available in grocery stores are more expensive than eggs, but cheaper than special additive products. “EggBeaters ®,” for example, provides 6 g protein per ¼ cup. They have the advantage of being pasteurized so they can be added to foods that are not intended to be cooked, such as a smoothie or eggnog, or in a tube feeding. Powdered milk is another very inexpensive product, with 1.5 g protein per tablespoon, and some calcium and other nutrients provided with it.

Glucose polymers (such as “Polycose ®” by Ross) are simply starch in solution and they have no advantage over regular food carbohydrates like sugar or food starch. They are designed primarily as a carbohydrate that can be added to beverages without adding a sweet taste. There is usually no reason to avoid sweetness in children’s feedings. The risk of tooth decay is identical because any carbohydrate fed orally is food for bacteria in the mouth. The main factors that increase risk of tooth decay are frequency of carbohydrate-containing feedings and contact time of carbohydrate with the teeth. Whether the carbohydrate is in the form of sugar (mono- or di-saccharides) or starch (polysaccharide) appears to make little difference.

Similarly, there is not a significant difference in osmolality (the number of particles per amount of fluid) because the starch is digested very promptly to the sugars maltose and glucose once it reaches the small intestine. That means that it is not less likely to contribute to loose stools.

There is no danger of causing a “sweet tooth” to be developed in the child. Children just come that way . . . human milk is sweet and it is all part of the design to make babies want to nurse. I have found that using regular table sugar can often make many foods and formulas more palatable for children, and therefore it is more effective because they eat more. And, of course, the dental and sweet tooth concerns are even less of a concern when the child is fed through a tube instead of orally.

3 A teaspoon of sugar weighs 4 grams and adds 16 “empty calories” from carbohydrate;

A teaspoon of glucose polymer products weighs 2 grams and provides only 8 “empty calories” from carbohydrate.

That means you need only half as much sugar to get the same calories. A 12.3 oz (350 grams) can of a glucose polymer product costs about $8.30 from one of the cheapest on- line sources. Compare that with table sugar. Nutritionally and calorically they are the same.

In most circumstances there is no need to use these expensive special products at all. MCT oil ®, for example, is designed for special needs related to certain liver diseases or intestinal malabsorption problems such as Cystic Fibrosis. It is often inappropriate for other uses because besides being very costly, it is all saturated fat (from coconut oil) and so it provides no “essential” fats or any omega-3 and omega-6 polyunsaturated fats at all . . . just calories. I have found that using regularly available food products also has the psychological advantage of “de-medicalizing” at least one part of the child’s care.

Sometimes health care professionals are not familiar with these issues, because they have to know so much about everything else. So, it might be beneficial to show this paper to them if these very costly products are suggested in order to use them only when regular carbohydrates and fats available at the grocery store will not do. And in addition, remember that just adding fat or carbohydrate calories or just protein from any source will contribute no other nutrients and so should be used as a small part of the child’s higher calorie feeding regimen.

And finally, it may be necessary to use other feeding routes in order to achieve appropriate growth and the best possible health. This may involve feeding through a tube from the nose to the tummy (an NG tube – a “naso-gastric” tube.) Sometimes tubes are placed through the skin to go directly into the tummy. They are called a PG tube, a PEG tube, or other variations. PG stands for “Percutaneous” (through the skin) “gastrostomy” (through an opening into the stomach.) Sometimes it is positioned into the jejunum of the small intestine instead. The health care professionals will know the benefits and problems associated with using one approach over another for a particular child.

At times it may be necessary to feed the child through the veins (i.v.) and bypass the usual feeding route completely. This is called TPN (Total Parenteral Nutrition”) or some variant. Sometimes it is called PPN (Partial Parenteral Nutrition) if it is used to supplement a feeding that uses the intestines. [The word “enteral” means using the intestines; “parenteral” is short for “para enteral,” which means the feeding route is outside of or along side (but not by way of) the intestines.] This kind of feeding is not done if the stomach and intestines are able to be used well enough to meet the child’s nutrition needs.

4 2) Some children have physical eating problems.

Poor head control, chewing, swallowing, mouth control, or mouth sores, etc., can also lead to poor nutrition. Children may receive an inadequate intake because of the time and effort required to eat even a small volume of food. Sometimes they get enough calories but inadequate protein, vitamins and minerals because of textural manipulations that can seriously limit the amount and variety of foods eaten.

Children with neurologic injury (such as cerebral palsy) may continue to struggle with infant feeding reflexes that do not fade away. “Tongue thrust” is an example of the reflexive pushing of food out of the mouth. Poor lip closure, an excessive or absent gag reflex, a “bite reflex,” and dental problems (such as “malocclusion” and difficulty providing appropriate dental care) are other common problems that make oral feeding difficult. Unfortunately, careful analysis of the diet is often not undertaken and the diet is assumed to be appropriate and adequate as long as some food is found that can be easily/safely fed and the child’s weight seems to be adequate.

For some neurologically impaired children with unrecognized dysphagia (poor control of swallowing,) even the safety of oral feeding may not be considered, and aspiration pneumonia can result from food going into the lungs. Also, texture adjustments for dysphagia themselves can cause nutritional imbalance. The diet can easily be too high in starchy thickeners and too low in foods that provide other nutrients such as protein, vitamins and minerals. Careful adjustment of the diet can minimize these problems. “Video fluoroscopy” is test to be sure that the child is not swallowing unsafely. Speech pathologists have programs to help children gain eating skills or to become less “orally defensive”(being very resistant to being fed by mouth.)

If increasing the caloric density of the feeding is a goal, the same cautions involved in Section 1 above will also apply here. Sometimes a tube feeding is necessary to provide some or all of the child’s nutrition. If swallowing is unsafe, it will need to provide all of it. The timing of tube feedings can be planned to fit inbest with the family’s schedule or situation. For example, all tube feedings might be given during the day, or some (or all) may be administered by a pump overnight. The latter approach can be especially helpful when one wants the child to be most interested in working on eating skills during the day, or if the child is very intolerant of high volume intakes at feedings. If the child can eat but just cannot eat enough, the tube feeding can be an excellent help because it allows the child to be passively fed as needed. It can also help administer medications. Bad tasting medications certainly do not help a child just learning to eat look forward to taking anything by mouth.

This combination approach also lets the child continue to work on eating skills, to eat just preferred or safe foods, and the rest of the nutrition can be easily fed passively. I think of this as contributing to another important feeding issue: “the happiness factor.” Check the part of Section 1 above: (“Some children will have higher needs for all nutrients in addition to calories”) as the vitamin and mineral issues will be important here as well.

3) Some children are unable to perceive hunger or satiety, or they may perceive it but be unable to communicate it to the caretaker.

Some children behave as if they are simply uninterested in eating, or unaware of eating in general, or they may limit their food choices to only a very few items. In such cases, there can be great pressure on the caretaker to “just get SOMETHING into the child,” and so serious

5 imbalances in nutrition can easily occur even when calories are adequate and effort is huge. Many children with autism present problems of this kind. And with so many major issues for the caretakers to deal with, nutritional adequacy may be pretty far down on the list of things that grab their attention. In such cases, individual problem solving with a nutrition professional familiar with these issues would be especially helpful.

After infancy, most children with Prader-Willi Syndrome (PWS) have the opposite problem: They behave as if they are ALWAYS hungry and in search of food. They seem to be “driven to eat” and they tend to eat many more than their bodies appear to need. However, new understanding of the metabolism problems in this genetic condition helps explain the reasons for this particular behavior and have provided some new approaches that are very helpful. Recent research suggests that there are ways to help with this specific serious problem associated with PWD, including the supplementation of carnitine and CoQ10 and treatments that involve growth hormone. Discussion of carnitine continues in the next section.

4) Some children have markedly decreased energy needs

This may be because of very low energy expenditure and/or low muscle tone (e.g. spina bifida, Down Syndrome, muscular dystrophy, Prader-Willi Syndrome (PWS) and “general hypotonia”). They may need a very low calorie intake to prevent debilitating obesity. Excessive fat accumulation can make it much harder for the child to develop mobility skills . . . it’s like trying to learn to crawl with weak muscles and a ten-pound weight on your back. It makes it harder for the caretakers to safely lift the child, and it can also result in more frequent adjustments of braces, wheel chairs, car seats and other equipment.

The child with less muscle mass because of less physical activity can often appear to receive adequate-but-not-excessive calories when actual calories taken in are much higher than needed. This is because we are looking at arms and legs with certain general assumptions about how much is muscle, how much is bone and how much is fat. An overly fat child who has low muscle and/or bone mass will often have fairly normal limb contours and appearance. The excessive fat the child has to deal with in terms of extra weight to move around, etc., can be hidden.

That is one reason why other measurements besides height and weight can be very helpful in assessing the nutritional appropriateness of feeding plans for children with non-average body composition. By measuring fat on the arm and back with a caliper, for example, one can see if the child has fat stores that are too low, too high or just right. These measures are also helpful when we are making adjustments in feedings of children who are unable to express hunger or satiety. As a rule-of-thumb, the less typical a child’s mobility or muscle tone, the less likely standard weight and height growth charts will provide the key information needed.

Interestingly, for some types of low muscle tone, supplemental carnitine has been shown to help very much. Carnitine is usually made in an adequate amount in our bodies, but certain medical conditions or medication use can result in a general inadequacy of this important substance. This situation is a bit similar to the fact that although most people make plenty of insulin, children with diabetes can’t make enough, and it simply has to be provided to them.

The carnitine helps the child move fat into the furnaces in the cells of the muscles so it can be burned for fuel. Having too little carnitine can result in low muscle tone from inadequate fat fuel to the muscles, very poor exercise endurance, lethargy, excessive sleepiness, hunger and unwanted high-fat weight gain because it can’t be used for fuel normally.

6 Some medications interfere accidentally with carnitine adequacy, and these symptoms show up as side effects of the drug. More will be discussed about carnitine in the section on drug/nutrient interactions later in this paper. However, if these descriptions describe your child, you may want to download my handout on this topic to learn a bit more about this important substance. It’s called:

“By Request: A Short Carnitine Discussion that Might Be Helpful”

It has now been shown that vitamin D inadequacy can be an important cause of muscle weakness as well, with many consequences including increased risk of falls and even congestive heart failure, a type of heart problem in which the heart muscle is too weak to pump blood normally. Inadequacy of vitamin D at present is actually extremely common even in the general population. It has now been identified as a previously unrecognized epidemic! The failure to recognize deficiency was because, until very recently, it was simply not checked as part of a normal doctor’s visit. We all just assumed it was fine.

In the population of children with special medical problems, the likelihood of inadequacy is even greater, in part because of certain medications (e.g. seizure medications) or being unable to be outside enough even in sunny summer weather. The vitamin D issue is discussed in much greater detail in my downloadable handout called:

“Aunt Cathy’s Guide: My Current Top Five Easy Ways to Improve Your Family’s Nutrition (subject to change at any moment! ☺)”

In general, children with low caloric requirements or low volume intake for any reason will benefit from careful micronutrient supplementation. Simply adding a standard vitamin drop will not solve the problem, nor will just adding the standard “complete type” children’s chewable vitamin with minerals. There are still big holes in the diet regimen. Intake of essential nutrients is inadequate on very low calorie diets unless the health professional looks closely at the feeding plan and makes adjustments to replace inadequate nutrients. Check the part of Section 1 above because the vitamin/mineral issues will be important here as well.

5) Some children have troubles with constipation, including some of those whose caloric needs are low and some whose caloric needs are high.

For children with lower caloric requirements: Children with lower-body paralysis like those with spina bifida or other spinal cord injury, or those with a surgically- correctible condition called Hirschprung’s disease, may experience constipation because of difficulty moving things along in the intestines. Some children may also have problems with bladder infection. A number of the traditional dietary interventions (such as corn syrup, cranberry or prune juice, etc.) contribute an unacceptably high number of calories for this group of children. Cranberries may have a role in decreasing recurrence of bladder infection (as was shown in a study of elderly women) but an artificially sweetened product may be needed.

Regular “cranberry juice cocktail” or prune juice provides about 20 calories per ounce, which is equal to the calories in whole milk. Corn syrup provides 60 “empty” sugar calories per tablespoon. Well-intentioned interventions to solve one problem can make another problem much worse. Low/non-calorie approaches to helping with constipation (e.g. milk of magnesia, lactulose, etc.) are available and some of these are discussed below.

7 Contrary to popular belief, simply increasing water or other fluids will not resolve constipation unless inadequate fluid intake was a contributing problem. Extra fluid is clearly needed if fiber is being added, but in the absence of added fiber any additional fluid is simply absorbed from the intestine and excreted via the kidney.

In addition, adding fiber may not be a helpful approach to constipation for a child whose neurologic ability to push food through the lower intestinal tract may be impaired. In fact, it may actually contribute to bowel obstruction. Some types of fiber actually slow transit time through the intestine instead of moving things along. Extra fluids are also beneficial for decreasing risk of bladder infections and kidney stones, but for the child with low calorie needs, it is important that the calories from the added fluids do not contribute to weight problems. Additional information about constipation issues in general is included in the section below.

For children with constipation problems for whom a nutrient-dense high-calorie diet is needed: In contrast to the issues described above, it is useful to know that there are pretty generous calories in some of the foods and beverages we commonly use for constipation or kidney health. Examples include cranberry juice (“cocktail”) or prune juice (20 calories per ounce – as high as whole milk,) and corn syrup (60 kcal per Tablespoon.) When trying to increase fluids for this child, remember that juices are 99.9% water. That means that they contribute the same amount of fluid as plain water would, but they have the advantage of adding some calories, some beneficial phytochemicals and a few nutrients. It makes little sense to concentrate a child’s formula and then feed plain water . . . it just re-dilutes the feeding.

Consider whether some of the ways we add extra calories are possible contributors to the constipation. For example, “casein” is a curd-forming milk protein that can be quite constipating for some people. Whey protein is not curd-forming, and therefore it is generally less constipating. There are several commercial nutritional beverage products used for children that are readily available, such as Boost ® or KinderCal ® (by Mead Johnson), Carnation Instant Breakfast ® or Nutren Jr. ® (by Nestle), or PediaSure ® (by Abbott.)

If using these products, check the label to see if the protein is primarily in the form of casein. You may see the word “caseinate” on the label. This is a perfectly fine protein source for growth, but for the chronically constipated child it would be worth trying one that had less casein. Powdered products added to milk (like instant breakfast products) often include powdered milk as the protein source, so the protein would still be 82% casein.

This is also an issue in infant feeding. Mother’s milk is very useful for MANY reasons, including fat blend, immune-boosting factors and better absorbability of many nutrients. In addition to these great benefits, it is unusual for babies to be constipated when exclusively fed breastmilk. However, some children’s health situations can result in a degree of constipation even when fed with mother’s milk.

Soy formulas are milk-free and so they have no casein, although for some children soy is constipating, too. Of the milk-based products, a variety of protein sources are available: Nestle Good Start Supreme ® is all whey (no casein) and the whey is partly chopped up. This product has been helpful for use with chronically constipated babies. Standard Enfamil Lipil ® (Mead Johnson) and Similac Advance ® (Abbott) products have adjusted the casein-to whey ratio from 82%-to-18% (regular milk) to an easier to digest 40% to 60% ratio in an effort to try to approach the ratios in human milk.

8 The protein in all the “lactose free” milk-based formulas is 100% casein. Enfamil’s “GentleEase ®” product has less lactose than their standard Enfamil Lipil ® and it has both casein and whey in the same ratio (40% casein to 60% whey.) The difference is that they have hydrolyzed (chopped up) both of these proteins. This may be helpful for constipation. Similac’s lactose free infant formula recently had a name change to “Similac Sensitive ®.” It still has 100% of the protein as casein.

Dairy fat (butterfat) can also be quite constipating. Butterfat is the form of fat in cream, whole and 2% milk, butter and cheese. In addition to the constipation issue, it is a very saturated fat and (like MCT oil ®) it always a very poor source of the essential fatty acids, including any type of omega-3 or omega-6 polyunsaturated fats. In spite of this, some diets, such as the ketogenic diet for seizure control, may contain a very high amount of cream.

The ketogenic diet is (not surprisingly) constipating for many children. Using other forms of fat in place of at least some of the cream can help a lot, both for constipation relief and for good nutrition. The heavy cream is used in that diet because it is more palatable when the child has to be fed orally. However, for the tube-fed child ketogenic diet, it is much easier to provide a more nutritious and less constipating feeding, starting with a base product like Abbott Nutrition’s “RCF ®” formula (“Ross Carbohydrate Free.”) It has all the nutrition of a standard infant formula except the carbohydrate is omitted, including a standard fat blend.

Some iron sources can contribute to constipation, and it is not uncommon to find that the heavily iron-fortified infant cereal can contribute to the problem. High doses of “inorganic” iron (that is, the “ferrous” or “ferric” forms found in plants or in pills) can be constipating and since they are also far less well-absorbed, they are actually not the best route to improving iron deficiency in an individual. Iron in breastmilk is “organic” and it is not constipating and it is very well absorbed. The standard amount of inorganic iron in formulas is not constipating. For example, “Nestle Good Start Supreme ®” formula (a whey based product) is often useful for helping constipated babies and it only comes with iron. [Note that none of the standard infant formulas are made in “low iron” versions anymore because it was not useful for constipation and it was also nutritionally incomplete.]

Highly absorbable and non-constipating “organic” iron is also the kind found in meat. It is called “heme” iron, and there is also a substance in meat called “Meat Protein Factor” that improves the absorption of the inorganic iron in the meal as well. For more detail on solving iron problems, please download my handout called:

“Aunt Cathy’s Guide to: Nutrition Support of Iron Deficiency”

Products to relieve constipation: Both Milk of Magnesia ® (magnesium hydroxide) and MiraLax ® (polyethylene glycol) attract water to the bowel by osmosis and so they can be useful for keeping stools from hardening. This is especially helpful when intestinal transit time is slower than average … the slow transit time gives the large intestine more time to extract water, contributing to harder stools.

Both of these products contribute no calories. Prune juice and corn syrup add considerable calories, but they act the same way (an osmotic effect,) and the prune juice naturally has additional phytochemical substances that encourage defecation. The prunes themselves are helpful . . . not just the juice.

9 Glycerol suppositories can act locally at the rectum to ease passage of stools, but they do not prevent the formation of dry/hard stools. Other products such as those containing senna can work by means of irritating the bowel to stimulate activity. Others can interfere with the absorption of nutrients. For this reason it is important to talk with your pharmacist or other health care provider about the usefulness or safety of any constipation products or approaches for your child.

6) There are many pediatric conditions that greatly alter nutrient requirements and metabolism such as cystic fibrosis, diabetes, inborn metabolic errors (such as PKU) and inflammatory bowel disease.

The health care professional must examine diet alterations for children with these conditions. As always, adjustments of the child's diet must not only correct the obvious problem (such as glucose control in diabetes,) but it is also essential to examine the feeding plan to be sure it provides adequate and appropriate levels of all of the other nutrients. This step is often overlooked. Different patterns of growth and body composition associated with certain conditions must also be considered in the nutrition plan.

Increased nutrient excretion or turnover, or decreased absorption will also alter nutrient requirements so that the "normal" guidelines of adequacy or safety (such as the "RDA" or “RDI” or “AI” level) or expected patterns of “normal” growth rates may not apply. They may not apply for other reasons as well, such as altered body composition or the effects of medications. Most guidelines only address intake goals and growth expectations for "healthy" people.

In many cases, special levels of certain nutrients can greatly affect the risk of complications and worsening of chronic conditions. One area of encouraging micronutrient research is diabetes and antioxidants such as vitamins E and C, minerals like selenium and zinc, and a number of brightly colored plant pigments described later. Other substances that look promising are the B vitamins (all, but especially B6 and biotin,) magnesium, carnitine, alpha- lipoic acid, and gamma linolenic acid.

The same patterns are emerging for many conditions that feature altered metabolism and/or inflammation. Please see my handouts specifically focusing on each of certain conditions for more information: Diabetes, Hemochromatosis, Multiple Sclerosis (MS,) Epidermolysis Bullosa (EB – a severe skin condition) and Celiac Disease are currently available.

A) Antioxidants

For diabetes and many other autoimmune diseases like lupus, juvenile rheumatoid arthritis, and inflammatory bowel disease, and for genetic conditions like Down Syndrome and apparently many others, the medical condition itself (or the therapy) results in increased production of damaging free radicals. This leads to increased frequency and severity of complications beyond those due to the condition or medication use alone. For this reason, appropriate generous antioxidant supplementation is advisable.

10 In addition to vitamin/mineral antioxidants, there are many potent antioxidants available in brightly colored fruits and vegetables. The food pigments themselves are often antioxidants. Examples include orange colored “beta-carotene” in carrots and squash, red “lycopene” in tomatoes and watermelon, green “lutein” in dark leafy greens, red/blue “anthocyanins” in blueberries and beets, yellow xeazanthin in corn and kale, and white/yellow “flavones” in onions and garlic.

This class of substances is usually called “phytochemicals,” which simply means “plant chemicals.” [Note that all “plant chemicals” are NOT heath-promoting. Poison ivy comes right to mind as an example of a phytochemical that is not friendly.] Many vegetables and fruits have a wide variety of phytochemicals that have benefits in addition to the antioxidant content, so children’s diets (and the diets of adults) should be as generous in these foods as possible. A great example: Lycopene, the red pigment in tomatoes, is 200 times as potent as a protective antioxidant than vitamin E. There is much to be gained from including brightly colored fruits and vegetables in the diets of everyone in the family.

I have had some success using pureed fruits and vegetables that are frozen in an ice-cube tray and then popped out and stored in a freezer bag. These are then quick and easy to add to strongly-flavored foods like soups, spaghetti sauce, chili, meatloaf, etc. For a tube-fed child, any combination of fruits and vegetables can be pureed all together with formula or other nutritious liquids (e.g. prune juice) and frozen as described. Blenderizing the “veggie cubes” with the formula to be fed will usually thin it down enough, but it can also be strained if there is a concern about clogging the tube.

This sounds time-consuming, but it can be done all at once for a month’s supply. One can use canned, frozen or fresh (use low sodium vegetables if using the canned type.) Some folks have a routine of freezing any leftover fruits and vegetables immediately after a meal in a freezer bag and then blenderizing them all at once when a good amount has been stored up. Also, many Grandmas or friends who keep asking how they can help are often very happy to take on this kind of project. For everyone, of course, clean and safe food-handling techniques are very important.

Another option is to add readily available fruit and/or vegetable juices (e.g. carrot juice, cranberry juice, prune juice, low sodium “V-8” type) as part of the liquid used to reconstitute infant formula. Variety is very important because the various beneficial phytochemicals are not all in the same food. There are many new products out there to investigate now that the public is becoming aware of the importance of these phytochemicals for health. Some are powders, juice concentrates or combinations of vegetable and fruit juice. For the latter, be sure to check the calories, and whether or not they are additionally sweetened when choosing. More information on this topic is available in my handouts:

“Aunt Cathy’s Guide to: Nutrition and Eye Health”

“Aunt Cathy’s Guide: My Current Top Five Easy Ways to Improve Your Family’s Nutrition (subject to change at any moment! ☺)”

and

“Aunt Cathy’s Guide to: Some Ideas for Trying to Eat More of Those Terrific Antioxidant Phytochemicals. . . and Liking It.”

11 B) Omega-3 / Omega-6 Oils

Along with antioxidant supplementation, manipulation of the inflammatory response by altering the ratio of omega-3 to omega-6 fatty acids is also looking very promising in the autoimmune and inflammatory diseases in particular. This ratio also appears to be very important in other areas of health research as well, such as risk of heart disease, cancer, HIV, depression, epilepsy, cognitive function, and degenerative eye diseases.

In each case, the direction of change that shows benefit is increasing the proportion of dietary fats that are rich in oils of the omega-3 family in relation to the intake of fats from the omega-6 family. Vegetable oils that are high in “omega-6” (such as corn oil) contribute to a strong inflammatory response. Adjusting the intake of dietary fat to displace some omega-6 oils with oils from the omega-3 family can significantly reduce the strength of an inflammatory response. This is particularly important in conditions characterized by excessive inflammation.

Compared with corn oil, other vegetable oils like canola oil, flaxseed oil, walnut oil and soy oil (only if non-hydrogenated) contribute to a much better balance of omega –3 to omega-6 oils. Ground flax seeds, soybeans, walnuts and other nuts and seeds have other nutritional benefits that the oil alone will not have. Additionally, displacing some omega-6 fat with oils rich in a form of fat called monounsaturated oils (like peanut oil or olive oil) will have a favorable effect on the omega-3 to omega-6 ratio.

At present, the relative ratio of these fats is an area of some difference in the general pediatric oral/tube-feeding complete nutrition products. For example, Nutren Jr. ® (Nestle) has a lower ratio of omega-6 to omega-3 fats compared with PediaSure (Ross Labs) and Kindercal ® (Mead Johnson.) This might be a consideration especially in conditions with a strong inflammation component. Some products are being especially designed to provide fats with a less inflammatory potential, such as Modulen IBD ® for inflammatory bowel disease (Nestle.) New products and reformulations will likely be forthcoming as this aspect of nutrition receives greater attention.

As mentioned above, olive oil and peanut oil are mostly “friendly” monounsaturated oils. They are not rich in either omega-3 or omega-6 polyunsaturated oils, but if they replace the high omega-6 corn oil in the typical US diet, they can have a big beneficial effect on the ratio of the remaining omega-6 to omega-3 oils. This contributes to decreasing the strength of inflammatory substances that the body makes out of these two families of oil. It has the added advantage of displacing some of the less beneficial fats in the diet, like the saturated fats in coconut oil, palm oil and butterfat. All these oils have about the same number of calories … about 9 per gram.

Fish oils contain a generous amount of the omega-3 oils, and they are in a form that is especially easily utilized in the effort to control inflammation. It is becoming very clear that many individuals benefit greatly from having the fish oil form in particular provided because it contains “ready-to-use” EPA and DHA.

These two fats (EPA and DHA) have direct anti-inflammatory effects, and DHA is a critical fat of the brain tissue. Newer forms of supplements are appearing on the market which can facilitate their use by children. More information is available in my handout on “lipids” … the family of substances that includes fats and oils and cholesterol:

“Aunt Cathy's Guide To: All Those Lipids: Recommendations for Using Different Types of Vegetable Oils (Omega-3, Omega-6 and Monounsaturated Oils)”

12 7) Therapeutic diets that eliminate certain foods or entire food groups are in need of careful attention to the nutritional adequacy provided by the foods remaining.

This includes special diets for allergies, celiac disease (“gluten-sensitive enteropathy”), autism, inborn metabolic errors, diabetes or the ketogenic diet for seizure control. It is critical that the nutritional adequacy of the diet is not compromised. Sometimes small adjustments in the foods offered can solve any problems caused by food group limitation, but in the more restrictive diets it is virtually impossible to obtain appropriate levels of vitamins and minerals without careful supplementation.

As the nutrient content of supplement products on the market can be quite variable, it is reasonable to have the diet and supplement plan evaluated carefully by a credentialed nutrition professional (e.g. an RD – a Registered Dietitian) using a computer analysis program. [Some RDs are also “Certified Specialists in Pediatric Nutrition.” Those with this credential will have the letters CSP in addition to the RD after their names.]

Such computer programs for nutrient analysis are available in many hospitals and clinics and in many university settings. They allow for the clinician and the family to be very sure that there are no accidental nutrient inadequacies or excesses in the feeding regimen that could harm the child’s overall health. Most computer programs in stores that sell health products and vitamin supplements are inadequate for the kind of careful micronutrient assessment that is needed in this situation, and in addition, they are often primarily programmed to promote and increase sales of particular nutrition products.

8) Many children are maintained on medications with important nutritional implications.

Here are a few examples:

Chronic use of seizure medications [like phenobarbital, valproate (Depekene®,) phenytoin (Dilantin®,) Tegretol®, and many others] can cause increased turnover of vitamin D, contributing to osteoporosis and fractures, among other problems. This is a special concern now that the epidemic nature of vitamin D deficiency even among healthy people is becoming recognized; people with health problems are at even higher risk for many reasons.

Vitamin D inadequacy has been found to be quite common especially in the northern half of the country (but all over in the south as well.) It is common among people with dark skin, those whose skin is often covered up or injured, or old, and those who are frequently indoors. It increases risk of developing arthritis, MS, diabetes, muscle weakness, muscle pain, lung problems, cardiovascular disease and several types of cancer.

Other nutrients are also affected by these medications. Health professionals need to consider the influence of the medications when assessing the adequacy of nutrient intake, and they may need to provide a different level of supplementation to safely assure adequacy. Again, for lots more information on this topic and specific recommendations, please see my handout:

“Aunt Cathy’s Guide: My Current Top Five Easy Ways to Improve Your Family’s Nutrition (subject to change at any moment! ☺)”

13 Phenytoin (Dilantin®) also interacts in a complex way with folic acid and several other vitamins, and its absorption is altered by the presence of food. When folate is found to be inadequate and then supplements are given to people on this medication to correct the deficiency, breakthrough seizures can occur. This does not happen when their folate level is never allowed to be depleted in the first place.

Chronic users of this medication often have low erythrocyte (red blood cell) folate levels. Inadequate folic acid is also associated with depression, poor response to antidepressants, and risk of heart disease, stroke, colon cancer, and Alzheimer’s disease. In pregnancy, the relatively poor folate status increases risk of significant birth defects. It is recommended that anyone starting to use Dilantin should automatically receive supplementation at the RDA level of folic acid to prevent serious difficulties. If the drug is already in use, the physician should carefully correct the deficiency, possibly by using a temporary increase in the drug during the adjustment period to prevent breakthrough seizures.

Valproic acid (Depakene®) specifically interacts with carnitine and can cause metabolic disturbances including severe hypoglycemia and lethargy that impairs the child’s ability to function. It also severely impairs endurance. One reason is that it can inhibit production of carnitine in the body, increasing dependence on external sources. Valproic acid also seems to require carnitine for optimal drug effectiveness. Therefore, inadequate carnitine increases the amount of drug required for seizure control and it is associated with “break-through seizures” and a much greater risk of serious liver toxicity from the drug.

Carnitine is usually made by a person’s liver and kidneys in adequate amounts so it has not been thought of as an “essential” substance. (“Essential” in nutrition means that you have to take it in ready-made from outside either in foods or in supplements.) However, it is now clear that in circumstances like this, carnitine can become “essential.” You may see carnitine described as a “conditionally essential” nutrient for that reason. Relative carnitine inadequacy (unrelated to medications) has also been found to be a factor in many conditions involving low muscle tone, poor endurance, and/or disturbed metabolism, including diabetes.

Other Common Nutrition/Medication Interactions:

Methotrexate also interacts with folic acid. This drug is used as a chemotherapy drug for cancer, but it is also an important medication in treatment of psoriasis and juvenile rheumatoid arthritis. Assuring adequacy of folic acid has been shown to help the patient tolerate the use of the medication. Inadequate folic acid status is associated with having to stop using methotrexate because of discomfort even when it is clearly helping treat the disease.

Hydrocortisone (an anti-inflammatory) can cause growth failure, increase excretion of nitrogen and zinc, and decrease absorption of calcium and phosphorus. Vitamin D status is also a factor here.

Sulfasalazine (Azulfidine®) an antibiotic used for inflammatory bowel disease impairs absorption of folic acid, and diets of people with this condition are often also low in fruits and vegetables because of bowel discomfort. Their diet may also be lacking in dairy foods and high fiber foods by doctor’s order. The risk of multi-nutrient inadequacy is great due to the combination of dietary limitation, drug-induced nutrient absorption problems, high needs for healing the intestine and high losses of nutrients via gut “weeping.”

14 It is not surprising that these children need help to grow normally. There is evidence that the thrombotic (blood clots / strokes) and affective problems (mood issues) and higher risk of colon cancer all noted in this population may be related to the very common folic acid inadequacy.

Any antibiotics when used chronically can compromise status of biotin, vitamin K (which can cause bleeding and bone, kidney and blood pressure problems,) and significantly impair folic acid absorption. Antibiotics can also induce a chronic diarrhea (and this may in turn be treated inappropriately with a clear liquid diet or half-strength feedings, resulting in further malnutrition.)

Many people are commonly maintained on chronic antibiotics, including those with spinal cord injury (to prevent bladder infection), cystic fibrosis, acne, certain heart conditions, HIV or other immune-compromised individuals. Some antibiotics contribute to gastrointestinal distress such as stomach pain and diarrhea.

Theophyllin (a broncho-dilator) absorption is influenced significantly by the timing of its administration in relation to food intake.

Acid control medications: Zantac®, Tagamet®, (the “H2 blockers”) and especially Prilosec®, Nexium®, Pepcid® Protonix® and Prevacid® (all PPI’s: “Proton Pump Inhibitors”) are drugs that decrease acid production in the stomach. Loss of stomach acid can impair absorption of vitamin B12 from natural food sources because stomach acid is required for getting it into a form that can be absorbed.

This means that eating a “well balanced diet” will fail to provide adequate vitamin B12 when these medications are used. Vitamin B12 deficiency is very serious, so this issue should not be ignored. However, absorption of the form found in vitamin supplements is NOT affected by loss of acid, so this problem can easily be avoided with the regular use of a multivitamin product.

Because of increasing use of the PPI medications in infants as an attempt to treat gastroesophageal reflux (throwing up after feedings,) it is useful to know that a breastfed baby maintained on these drugs will need a vitamin drop that contains vitamin B12 in addition to assuring a vitamin D drop. Any standard drop will do and it can contain both easily. A formula-fed infant is already receiving vitamin B12 in a crystalline form that does not require acid for its absorption. [They will still need the extra vitamin D drop, of course.]

One other consideration with PPI’s is they decrease the effectiveness of infant formula products like Enfamil AR ®. This is a standard infant formula that includes rice as part of the carbohydrate. It is designed to help with decreasing gastroesophageal reflux in infants with this problem by causing the formula to thicken and form a gel in the tummy after the baby drinks it. This thickening is accomplished via exposure to stomach acid, however, so the formula product will not do its gel-forming tricks if the baby is also being treated with a PPI.

Metformin (Glucophage®) is a medication for people with Type II (insulin resistant) diabetes. It also interferes with vitamin B12 absorption. The mechanism is different from the acid-reducing effects described above. This form of diabetes (Type II) has generally not been a pediatric problem in the past, but the incidence of “adult type” diabetes is increasing markedly along with increased incidence of obesity in children.

15 For more information on the vitamin B12 issue, please see my handouts:

“Aunt Cathy's Guide to Nutrition: A Vitamin B12 Update”

and

“Aunt Cathy’s Guide to: Thinking About OTHER Nutrition Issues in Diabetes”

Serotonin Re-uptake Inhibitors (such as Zoloft®) are used both for depression and for inflammatory bowel disease, especially of the primarily constipation type. This class of drug does not work well when an individual has a poor intake of folic acid. This is an example of how careful attention to nutrition can improve the clinical response to a drug, thus avoiding the potential side effects due to raising the drug dosage or changing to a stronger drug.

Many drugs (including “herbal” drugs) can also affect intake by causing nausea, vomiting, constipation, taste changes, lethargy, or altered appetite. For example, Methylphenidate (Ritalin®) for attention deficit disorders may impair appetite enough to slow growth, although there is some evidence now that this may be less of a problem than originally thought. Narcotic pain medications often cause constipation and decreased appetite.

“Herbal remedies” are not nutrients but many people have been given the impression that they are. They are often marketed as “dietary supplements” because by law, the people selling them do not have to prove that their product is safe or effective. It is a loophole in the Food and Drug Administration’s laws that many people are unaware of.

People assume that in America a company could not package and sell health products that were inadequately tested (or not tested at all.) But although labeled as “dietary supplements” in order to avoid having to test them, these products are actually in the category of drugs and medications. This is because whether they are in a natural state or packaged as a pill, the goal of using them is to achieve some pharmacologic reaction.

For children with complex medical conditions and especially those who must use medications of various types, there can be significant and dangerous interactions when unknown to the physician, herbal products (or any “over-the-counter” products) are added to the mix.

As one example, the herbal supplement “St. John’s Wort” which has been promoted as a “natural antidepressant with no side effects” actually interacts with a wide variety of medications and causes the medications to stop working sooner than they should. This effect of St. John’s Wort has been found with medications for heart disease, HIV/AIDS, birth control pills, and drugs that prevent the rejection of transplanted organs. Serious injury has resulted.

This is just one example of why it is very important to discuss the use of ANY herbal product or other over-the-counter product with the child’s physician. “Natural” products certainly CAN have side effects – after all, some of the most potent (and also dangerous) drugs come from plants. For example, digitalis (an important heart medicine) comes from the foxglove plant, and even heroin, cocaine and marijuana are “herbal” products.

16 Summary:

Providing optimal nutrition for the child with special health needs can:

• optimize physical, intellectual and psychological development.

• prevent serious complications like fractures and medication toxicity.

• optimize immune function to reduce the incidence/severity of illness.

• decrease pain due to inflammation or nutritional inadequacy.

• optimize the safety and effectiveness of any medications used.

• facilitate the care of the individual.

• improve the quality of life of the child and the caretakers.

These goals will only be realized when health professionals are able to take a close look at this important aspect of the child’s care.

17

MeritCare Medical Center’s

Aunt Cathy’s Guide to: A Top Ten Nutrition Aunt Cathy Plan for Optimizing Cathy Breedon PhD, RD, CSP, FADA Clinical Nutrition Specialist Pregnancy Outcome Perinatal/Pediatric Nutrition Specialist (Subject to Change at Any Moment ☺) MeritCare Health Systems, Fargo, ND and UND School of Medicine

An important note to the reader: This is a quick summary of my main conclusions on nutrition in pregnancy based on the current medical literature (as of date shown). My workshops include considerable detail describing the research leading to these conclusions, and the complete bibliography is far too large to include here. Some pertinent references are cited, however. This “Top Ten” list was designed at the request of health professionals in practice who have attended a workshop at which the supporting literature was presented because they felt a quick “bottom line” summary would assist in applying the research to patient care. Readers who have not attended the workshops will be viewing this list of suggestions out of context. References regarding a particular suggestion can be provided if you send an e-mail requesting it to the address above.

And now, the current “Top Ten”:

1. The physician or other primary health care person should emphasize the importance of eating a good variety of foods and taking appropriate supplements.

This is in addition to the support of other health care professionals (nurses, dietitians, etc.) who may be encouraging good nutrition. Reason: many patients believe that if the doctor does not mention diet and nutrition, it must not be very important. Patients are more likely to take the issue seriously when the point is reinforced by all the team members, including the team leader especially.

2. Establish a simple nutrition screening protocol and refer women for appropriate nutrition counseling.

Utilize settings other than pregnancy visits to optimize effectiveness in birth defects prevention. For example, evaluate nutrition at other OB visits for birth control or for annual exams, and provide advice to help correct nutrition problems before a pregnancy is established

3. Start supplementation with a multivitamin with minerals and begin providing nutrition advice preconceptionally.

It used to be standard practice to postpone nutrition discussions and/or nutrient supplementation until the first pregnancy visit, which was often scheduled at the end of the first trimester. It is now well documented that nutritional status in the preconceptional period and throughout the entire pregnancy is truly critical for optimizing outcome. Similarly, the old practice of discontinuing vitamin/mineral supplements because of nausea in early pregnancy is no longer recommended because (in addition to concerns about nutrient inadequacy during critical construction periods) research shows that the supplements (minus the high-dose iron) can actually decrease nausea, vomiting and vertigo in pregnancy. The discomfort associated with taking prenatal vitamins appears to be more related to the extremely high iron content of some prenatal products. Such a high amount of extra iron is contributory to GI distress and it is not needed in early pregnancy. Additionally, the form of iron in supplements (i.e, inorganic ferrous and ferric iron) is clearly not the most efficient or biologically absorbable form at any time. Most are far less than 2% absorbed, which is substantially less than the 20% iron absorption from “heme” iron forms in meat, for example. [Please see my “Nutrition Support of Iron Deficiency” handout for more on this topic.]

[J Obstet Gynaecol Can. 2007 Dec;29(12):1003-26. Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2007 Dec;29(12):1003-26. J Obstet Gynaecol Can. 2006 Aug;28(8):680-9. Prenatal multivitamin supplementation and rates of congenital anomalies: a meta- analysis. J Obstet Gynaecol Can. 2006 Aug;28(8):680-9. Relationship between vitamin use, smoking, and nausea and vomiting of pregnancy. Acta Obstet Gynecol Scand. 2003 Oct;82(10):916-20. Prevalence and severity of nausea and vomiting of pregnancy and effect of vitamin supplementation. Clin Invest Med. 1999 Jun;22(3):106-10. Periconceptional folic acid containing multivitamin supplementation. Eur J Obstet Gynecol Reprod Biol. 1998 Jun;78(2):151-61.]

The EXTRA folic acid in prenatal products (800 mcg instead of 400 mcg) is also generally not needed in EARLY pregnancy. In preconception and early pregnancy, 400 mcg of folic acid in supplement form appears to be is sufficient to prevent neural tube defects in most situations, and the fetus has priority for this nutrient over the mother’s needs. A fetus sequesters folic acid for its own use and then “leaves town” with it, potentially leaving the mother folate deficient after delivery unless intake is sufficient to meet both of their needs. The EXTRA 400 mcg in the prenatal vitamin is to prevent the mother from becoming depleted as the pregnancy progresses, both for her own health and to prevent birth defects should a pregnancy occur within a few months of delivery of the present infant.

Toward this end, a STANDARD vitamin/mineral product can be very helpful, especially for women who eat poorly at this time due to nausea (or general poor diet) and are therefore obtaining suboptimal amounts of vitamins and minerals. A standard product (which generally provides about 18 mg iron) is also less constipating than the very high iron products. Most research now suggests that the very high iron products are more problematic than they are helpful – other interventions improve iron status more effectively without the unpleasant side effects. If providing 800 mcg of folic acid is preferred, simply add a small and inexpensive OTC 400 mcg folic acid tablet. Folic acid adequacy is also now recognized to be a factor in decreasing risk of miscarriage, depression, stroke and cancer of the colon and breast, so our advice to women to take a multivitamin during childbearing years should be expanded to all of a woman’s life. The use of this kind of product is now generally regarded as “prudent for most adults.”

Recently a large epidemiologic study suggested that use of a general multivitamin in the periconceptional period may actually decrease risk of developing pre-eclampsia. Because the report is quite new at the time of this update, and the topic is so important, I am including the abstract below. Periconceptional Multivitamin Use Reduces the Risk of Preeclampsia. Am J Epidemiol. 2006 Jun 13; The objective was to assess the independent effect of regular periconceptional multivitamin use on the risk of preeclampsia. Pregnant women (n = 1,835) enrolled in the Pregnancy Exposures and Preeclampsia Prevention Study (Pittsburgh, Pennsylvania, 1997-2001) at less than 16 weeks' gestation were asked whether they regularly used multivitamins or prenatal vitamins in the past 6 months. Women were classified as users or nonusers. The unadjusted prevalence of preeclampsia was 4.4% in nonusers and 3.8% in users. After adjustment for race/ethnicity, marital status, parity, prepregnancy physical activity, and income in a multiple logistic regression model, regular use of multivitamins was associated with a 45% reduction in preeclampsia risk compared with nonuse (odds ratio (OR) = 0.55, 95% confidence interval (CI): 0.32, 0.95). Prepregnancy overweight modified this effect. After confounder adjustment, lean multivitamin

2 users had a 71% reduction in preeclampsia risk compared with lean nonusers (OR = 0.29, 95% CI: 0.12, 0.65). In contrast, there was no relation between multivitamin use and preeclampsia among overweight women (OR = 1.08, 95% CI: 0.52, 2.25). A sensitivity analysis for unmeasured confounding by fruit and vegetable intake supported these conclusions. If confirmed by others, these results suggest that regular use of a multivitamin supplement in the periconceptional period may help to prevent preeclampsia, particularly among lean women.

Similarly interesting in regard to nutrition and pre-eclampsia prevention (and deserving of the “box- of-its-own”) is a new report from the Cochrane Database: Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. [Cochrane Database Syst Rev. 2006 Jul 19;3:CD001059.]

The authors concluded: “Calcium supplementation appears to almost halve the risk of pre- eclampsia, and to reduce the rare occurrence of the composite outcome 'death or serious morbidity'. There were no other clear benefits, or harms.” This observation is particularly noteworthy because the Cochrane Database group has a mandate to be very picky and skeptical; it takes quite a lot of consistency among reports of what they regard as quality studies for this organization to conclude something other than “there is not enough evidence” to come to any conclusions.

[Multivitamin use and the risk of preterm birth. Am J Epidemiol. 2004 Nov 1;160(9):886-92. A role for supplements in optimizing health: the metabolic tune-up. Arch Biochem Biophys. 2004 Mar 1;423(1):227-34. Vitamins for chronic disease prevention in adults: clinical applications. JAMA. 2002 Jun 19;287(23):3127-9. Eat Right and Take a Multivitamin NEJM 338 (15):1060-1061 1998], and particularly so for any who may become pregnant. [Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet. 2004 Feb 15;125C(1): 12-21. Impact of folic Acid fortification in the United States: markedly diminished high maternal serum alpha-fetoprotein values. Obstet Gynecol. 2004 Mar;103(3):474-9. The use of folic acid for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2003 Nov;25(11):959-73. Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J Nutr. 2004 Jan;134(1):162-6.]

Assume that at least some nutrients are NOT adequate unless you have actually checked that they are. Just as one example, the most recent National Health and Nutrition Examination Survey of the CDC found that the majority of Americans obtain less than 2/3 of the RDA for magnesium. As magnesium is known to be a critical cofactor in over 300 metabolic pathways, it is a very key nutrient in perinatal health and suboptimal intake of this nutrient is a very serious problem. [More on magnesium will be discussed later.] In general, choose a multivitamin/mineral supplement product that is as complete as possible but inexpensive. Generics are fine. A complete-type “prenatal” product that is not of the very high-iron type can also be helpful.

It seems prudent during pregnancy in particular to choose a vitamin/mineral supplement product with no more than the RDA for vitamin A. Preferably one should be selected which provides some (at least 25-50%) of the vitamin A in the precursor form “as ß-carotene” instead of providing it all as retinyl palmitate or retinyl acetate, since the retinol (hormonal) form in high amounts is a risk factor for birth defects.

A closer look at vitamin A: Vitamin A has important functions in cell differentiation, and similar types of birth defects are associated with both vitamin A deficiency and vitamin A excess. This is an area of considerable interest at present. Opinions differ regarding the teratogenicity of various forms of vitamin A. For example, one group of researchers concluded “the available human data suggest that threshold concentrations of these retinoids resulting in teratogenesis were unlikely to be exceeded following vitamin A supplements of 25,000 IU/day.” Another study found no association between periconceptional vitamin A exposure at doses >8000 IU or >10,000 IU per day and malformations in general, cranial neural crest defects, or neural tube defects. They concluded that if vitamin A is a teratogen, the minimum teratogenic dose appeared to be well above the level consumed by most women during organogenesis.

3

[Model predicting the teratogenic potential of retinyl palmitate, using a combined in vivo/in vitro approach. Teratology 1998 Sep-Oct;58(3-4): 113-23. Vitamin A and birth defects. Am J Obstet Gynecol 1997 Jul;177(1):31-6.]

However, other maternal factors may result in increased risk of teratogenicity. For example, hyperglycemia increases embryonic susceptibility to the teratogenic effects of vitamin A in diabetic mice, and normalization of blood sugar completely the erased increased susceptibility. The damaging effects of high dose retinol can also be affected by folate and methionine status, and genetic predisposition.

[Hyperglycaemia potentiates the teratogenicity of retinoic acid in diabetic pregnancy in mice. Diabetologia. 2004 Feb 14. Antagonism of hypervitaminosis A-induced anterior neural tube closure defects with a methyl-donor deficiency in murine whole-embryo culture. J Nutr. 2003 Nov;133(11):3561-70. Combination therapy with folic acid and methionine in the prevention of retinoic acid-induced cleft palate in mice. Birth Defects Res Part A Clin Mol Teratol. 2003 Mar;67(3):168-73. Increased susceptibility to retinoid-induced teratogenesis in TGF-beta2 knockout mice. Reprod Toxicol. 2002 Nov-Dec;16(6):741-7. Maternal diabetes increases the risk of caudal regression caused by retinoic acid. Diabetes. 2002 Sep;51(9):2811- 6. Retinoids and cardiovascular developmental defects. Cardiovasc Toxicol. 2002;2(1):25-39. Vitamin A during pregnancy. Nutr Health. 2001;15(3- 4):237-43. All-trans-retinoic acid-mediated modulation of p53 during neural differentiation in murine embryonic stem cells. Cell Biol Toxicol. 2002;18(4):243-57. Teratogenic effects of chronic ingestion of high levels of vitamin A in cats. J Anim Physiol Anim Nutr (Berl). 2003 Feb;87(1- 2):42-51.Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study. Teratology 2000 Oct;62(4):214-26. Vitamin A teratogenicity and risk assessment in the macaque retinoid model. Reprod Toxicol 2000 Jul-Aug;14(4):311-23. Dietary vitamin A and teratogenic risk: European Teratology Society discussion paper. Eur J Obstet Gynecol Reprod Biol 1999 Mar;83(1):31-6. Prevention of congenital abnormalities by vitamin A. Int J Vitam Nutr Res 1998;68(4):219-31. Safety of vitamin A: recent results. Int J Vitam Nutr Res 1998;68(6):411-6. Periconceptional vitamin A use: how much is teratogenic? Reprod Toxicol 1998 Jan-Feb;12(1):75-88. Teratogenic effects of vitamin A and its derivates Arch Pediatr 1997 Sep;4(9):867-74.]

It also appears that the FORM of vitamin A used can greatly alter the toxicity of supplements in addition to the dichotomy between beta-carotene (the vitamin A precursor) and a variety of the hormonal forms of vitamin A in foods and supplements (retinol, retinoic acid and retinyl esters.) It was shown that the degree of toxicity of vitamin A also depends greatly on whether it is provided in a oil-based preparation, or as water-miscible, emulsified, or solid preparation. The results of a recent important animal study were as follows: “Chronic hypervitaminosis A is induced after daily doses of 2 mg retinol/kg in oil-based preparations for many months or years. In contrast, doses as low as 0.2 mg retinol. kg(-1). d(-1) in water-miscible, emulsified, and solid preparations for only a few weeks caused chronic hypervitaminosis A. Thus, water-miscible, emulsified, and solid preparations of retinol are approximately 10 times as toxic as are oil-based retinol preparations. The safe upper single dose of retinol in oil or liver seems to be approximately 4-6 mg/kg body wt. These thresholds do not vary considerably with age.” Another form of vitamin A (a metabolite called isotretinoin – the drug Accutane) is well recognized as causing birth defects. And as a rule, because it is a very rich source of the hormonal forms of vitamin A, some researchers have raised concerns about frequent consumption of liver during pregnancy. Positions taken on “the liver question” vary greatly in the official recommendations of experts in various nations, ranging from alarm to unconcern.

[Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations. Am J Clin Nutr. 2003 Dec;78(6):1152- 9. A call for action--prevention of fetal exposure to isotretinoin. A position paper by The Organization of Teratology Information Services Public Affairs Committee.Reprod Toxicol. 2001 Nov-Dec;15(6):729. Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol. 2001 Nov;45(5):S183-7. The problem of a high content of vitamin A in the liver of calves, cattle, sheep and swine for the consumer. Amount of accumulation and mechanism of teratogenic effect (review article). Berl Munch Tierarztl Wochenschr. 1994 Oct;107(10):342-7. Survey of animal livers for vitamin A content. Food Addit Contam. 1992 May-Jun;9(3):237-42. A survey of vitamin A concentrations in the liver of food-producing animals. Food Addit Contam. 1998 Jan;15(1):10-8. Health risks related to high content of vitamin A in liver Nord Med. 1990;105(5):149-50, 153. Evaluation of vitamin A toxicity. Am J Clin Nutr. 1990 Aug;52(2):183-202.]

Use a children’s chewable version (one daily) if needed or desired for people who have trouble with pills or for those with nausea. Use the regular dosage of one tablet per day, (the standard dose for people ages 4-to-adult). Do not suggest taking two tablets (“because the product is designed for children”) because the vitamin A (retinol) content would then be higher than is desirable during pregnancy, and as noted above, in early pregnancy this could increase the risk of birth defects. If most of the vitamin A is provided in the form

4 of beta carotene, the risk of contributing to birth defects is much less. In general, children’s products are quite similar to those formulated for adults.

Choose a product with at least 400-800 mcg folic acid. If the mother previously had a child with a neural tube defect (NTD), providing the usually recommended amount of folic acid preconceptionally may be adequate. However, for some women it may not be adequate for genetic reasons (e.g. some women who have high homocysteine levels that are unresponsive to the usual intake levels of folic acid) or those who are chronic users of antibiotics, certain epilepsy medications or alcohol (all of which impair folic acid absorption or metabolism.) In some unusual cases, up to 4000 mcg/day (4 mg) may be needed to normalize folic acid- dependent metabolism.

If a genetic or other medical condition that greatly increases requirements for folic acid is suspected, the physician can order a one-time “methionine-load homocysteine” level in the mother when not pregnant to determine if her folic acid needs are higher than usual. This test is unnecessary in the vast majority of situations, however, as even for those with the MTHFR gene (known to affect folic acid metabolism), provision of the RDA level in a vitamin pill form (i.e. the crystalline well-absorbed form) almost always corrects the problem. Identifying those with higher than average requirements will both protect her future babies from birth defects and it will also significantly reduce her own risk of stroke, DVT, depression and cancer. High-dose folic acid can also help those with a family history of cleft lip or palate (one study used 10 mg/day), NTD-affected previous pregnancy or family history, insulin-dependent diabetes, epilepsy treatment with valproic acid, phenytoin or carbamazepine.

A recent summary of recommendations of the major association of obstetricians in Canada was that for these women “high-dose folic acid (4.0 mg-5.0 mg daily) supplementation is recommended. This should be taken as folic acid alone, not in a multivitamin format, due to risk of excessive intake of other vitamins such as vitamin A.” Other seizure medications can increase folic acid requirements as well, such as phenytoin (Dilantin), which when taken during pregnancy has been associated with cleft lip/palate and heart and uro- genital defects. Norwegian experts make the following recommendations: “Valproate and carbamazepine have been associated with neural tube defects and phenytoin with cleft lip/palate and heart and urogenital defects. All women taking valproate and carbamazepine are advised to take 4 mg/day of folic acid at least one month before pregnancy and during the first trimester. Other women with epilepsy in fertile age are recommended to take 0.4 mg/day. Vitamin K 10 mg/day should be given the last 4 weeks to women on liver enzyme-inducing AEDs.”[Anti-Epilepsy Drugs] Ideally, women taking phenytoin would already be receiving folic acid supplementation since the time that she began to use the drug “because of the hypothesized cofactor mechanism, decreased adverse effects associated with folate deficiency, and better seizure control with no perturbation of phenytoin pharmacokinetics.” However, if this has not been done (and it may not have been) it is important to increase folic acid intake gradually and under the physician’s supervision, as a sudden increase in intake could have a negative effect on seizure control in this situation.

[A sample of some references on this very large topic: The use of folic acid for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2003 Nov;25 (11):959-73. Folic acid and homocysteine affect neural crest and neuro-epithelial cell outgrowth and differentiation in vitro. Dev Dyn. 2003 Jun;227(2):301-8. Vitamin and homocysteine status of mothers and infants and the risk of nonsyndromic oro- facial clefts. Am J Obstet Gynecol. 2003 Oct;189(4):1155-60. Is there more to folates than neural-tube defects? Proc Nutr Soc. 2003 Aug;62(3): 591-8. The use of folic acid for the prevention of neural tube defects and other congenital anomalies. J Obstet Gynaecol Can. 2003 Nov;25(11): 959-73. Pregnancy and birth in women with epilepsy. Tidsskr Nor Laegeforen. 2003 Jun 12;123(12):1695-7. Management issues for women with epilepsy: neural tube defects and folic acid supplementation. Neurology. 2003 Sep 1;61(6 Suppl 2):S23-6. The effects of folic acid in the prevention of neural tube development defects caused by phenytoin in early chick embryos. Spine. 2003 Mar 1;28(5):442-5. Primary prevention of neural-tube defects and some other major congenital abnormalities: recommendations for the appropriate use of folic acid during pregnancy. Paediatr Drugs. 2000 Nov-Dec;2 (6):437-49. Nonsyndromic orofacial clefts: association with maternal hyperhomocysteinemia. Teratology. 1999 Nov;60(5):253-7. Folic acid for the prevention of congenital anomalies. Eur J Pediatr. 1998 Jun;157(6):445-50. Neural tube and craniofacial defects with special emphasis on folate pathway genes. Crit Rev Oral Biol Med. 1998;9(1):38-53. Reduced recurrence of orofacial clefts after periconceptional supplementation with high- dose folic acid and multivitamins. Teratology. 1995 Feb;51(2):71-8. Phenytoin-folic acid interaction. Ann Pharmacother. 1995 Jul;29 (7-8):726-35. Regarding dietary sources of folate, it is often not recognized that many popular fruits and vegetables do not even contain folate (e.g. apples and grapes have none), and that not all food sources of folate are equally

5 well absorbed or utilized. The form in vitamin pills, fortified grains and cereals (“folic acid”) IS well absorbed. In view of the importance of assuring folic acid adequacy at this critical phase of fetal development and the studies showing that the most reliable way to assure an adequate intake of a bioavailable form of folic acid is via supplementation, it is prudent to simply provide a multivitamin. Interestingly, several countries have attempted to improve women’s preconceptional folic acid intake via ad campaigns urging supplement use. In several cases it has been quite unsuccessful, not because the supplements did not prevent birth defects, but because women simply have still not adopted the practice of reliably taking the supplements. As a result, there is considerable pressure in several countries at present to establish a folic acid food-fortification program such as that initiated in 1998 in the US.

Since January 1998, folic acid (in a well-absorbed form) has been added to grains in the U.S. The results of this large public health undertaking were recently reported. Compared with the incidence before fortification, the supplementation of grains has decreased the incidence of neural tube defects by an astounding 70%. During the same period, stroke and stroke deaths have declined by an impressive 15%. [Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006 Mar 14;113(10):1335-43.] No problems were identified as a result of the fortification.

In several studies throughout Europe, it has been found that although there is clear evidence for NTD prevention by assuring adequacy of periconceptional folic acid, it continues to be found that public health messages urging women to take folic acid supplements have been ineffective in bringing about the kind of changes observed with food fortification with folic acid. The reason is that with supplementation of food, one does not need awareness of the issue nor the motivation to plan ahead. Further, there are no limitations of willingness/ablilty to purchase supplements limits. [Example: Promotion of folate for the prevention of neural tube defects: who benefits? Paediatr Perinat Epidemiol. 2005 Nov;19(6):435-44.]

Studies continue to show that the simple use of a multivitamin can decrease risk of quite a number of birth defects besides the well-documented neural tube defects of spina bifida and anencephaly. For example, periconceptional intake of thiamine, niacin and pyridoxine seems to contribute to the prevention of oral-facial clefts. A multivitamin will also decrease risk of birth defects associated with vitamin B12 deficiency, which has been shown to occur in unsupplemented vegans and also (surprisingly) among people with gastro- esophageal reflux problems (GERD) who use medications that decrease stomach acid production (such as Prilosec®, Prevacid ®, Nexium®, Protonix® and others.) Low stomach acid production impairs absorption of vitamin B12 from food, but it is easily corrected by providing the crystalline form of vitamin B12 found in vitamin supplements. Glucophage® (Metformin) is a medication for diabetes that has been shown to negatively affect absorption of vitamin B12.[For more information on these issues, please see “Aunt Cathy’s Guide to Nutrition: New Discoveries about Folic Acid and Health.” And “Aunt Cathy’s Guide to Nutrition: a Vitamin B12 Update.”]

Folic acid supplementation, fortification and/or multivitamin supplementation has been associated with significant reduction of risk for many anomalies besides neural tube defects. 1) incidence of all birth defects overall; 2) cardiovascular anomalies, 3) orofacial clefts; 4) limb deficiencies ; 5) urinary tract defects; 6) nonsyndromic omphalocele; 7) imperforate anus; and 8) incidence of pediatric cancers. [Prenatal supplementation with multivitamins and the incidence of pediatric cancers: clinical and methodological considerations. Pediatr Blood Cancer. 2008 Feb;50(2 Suppl):487-9. Prenatal multivitamin supplementation and rates of pediatric cancers: a meta-analysis. Clin Pharmacol Ther. 2007 May;81(5):685-91. Periconceptional folates and the prevention of orofacial clefts: role of dietary intakes in France Rev Epidemiol Sante Publique. 2005 Sep;53(4):351-60. Vitamin supplements and the risk for congenital anomalies other than neural tube defects. Am J Med Genet. 2004;125C(1): 12-

6 21. Maternal dietary B vitamin intake, other than folate, and the association with orofacial cleft in the offspring. Eur J Nutr. 2004;43(1):7-14. Maternal myo-inositol, glucose, and zinc status is associated with the risk of offspring with spina bifida. Am J Obstet Gynecol. 2003;189(6): 1713-9. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2003;254(5):455-63. The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients. Eur J Intern Med. 2003;14(4):221-226. Should we screen diabetic patients using biguanides for megaloblastic anemia? Aust Fam Physician. 2003;32(5):383-4. Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002 28;162(19):2251-2. Side effects: Calcium supplements help metformin users absorb vitamin B12. Treatment update. 2000;12(7):6-7. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23(9): 1227-31. Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy. Ann Pharmacother. 2003;37(4): 490-3. Changes in gastric mucosa and luminal environment during acid-suppressive therapy: a review in depth. Dig Liver Dis. 2001;33(8):707-19. Maternal periconceptional vitamins: interactions with selected factors and con-genital anomalies? Epidemiology. 2002;13(6):625-30. Maternal multivitamin use and orofacial clefts in offspring. Teratology. 2001;63(2):79-86. Neural tube defects associated with maternal periconceptional dietary intake of simple sugars and glycemic index. Am J Clin Nutr. 2003;78(5):972-8. Oral clefts and vitamin supplementation. Cleft Palate Craniofac J. 2001;38(1):76-83. Maternal diet during pregnancy and risk of brain tumors in children. Int J Cancer Suppl. 1998;11:23-5. Neural tube defects associated with maternal periconceptional dietary intake of simple sugars and glycemic index. Am J Clin Nutr. 2003;78(5):972-8. Effects of retinoic acid on the neural crest-controlled organs of fetal rats. Pediatr Surg Int. 2003;19(5):-355-8. Marginal biotin deficiency is teratogenic in ICR mice. J Nutr. 2003;133(8: 2519-25. Folic acid and neural tube defects in pregnancy: a review. J Perinat Neonatal Nurs. 2003;17(4): 268-79.]

4. Assure adequate magnesium, calcium, vitamin D and iodine intake in particular; these are nutrients that are often inadequate in the diets of Americans and they are often needed in amounts beyond that provided by most multivitamin/mineral supplements.

Maternal magnesium status has been shown to be related to pregnancy outcome. Dietary magnesium inadequacy has been demonstrated to be quite common among American women, although it is rarely recognized or evaluated. Consider a magnesium supplement at about the RDA levels (e.g. 250-500 mg) especially if the woman has any of the following conditions: • a magnesium-poor diet (not uncommon) • a need for generous calcium supplements (to maintain a normal Mg:Ca ratio) • preeclampsia, • a medication that causes magnesium loss (e.g. thiazide diuretics). • leg cramps, • diabetes, or • PMS when not pregnant

The best dietary sources include: peanuts, bran, wheat germ, nuts, legumes. If a supplement is used, try Mg oxide or chloride instead of sulfate or hydrochloride for better absorption and less of a laxative side-effect. Most prenatal vitamins contain only 10-25% of the RDA for magnesium. Please see “Aunt Cathy’s Guide to Nutrition: Magnesium” for more detail.

Some researchers feel that prenatal magnesium adequacy has a higher priority than even iron supplementation because of the over 300 enzyme systems in the body that depend on magnesium to function properly. Several measures of pregnancy outcome such as higher frequency of spontaneous abortions (miscarriage), fetal growth retardation, maternal hospitalizations, preterm delivery, SIDS and referrals to NICUs have been found to be associated with poor magnesium status in pregnancy. These issues are related to general nutrition and are quite separate from issues related to the acute therapeutic i.v. magnesium sometimes used in the treatment of pre-eclampsia or premature labor, and even from the magnesium levels as measured in blood tests. The laboratory values often do not reflect cellular levels at all, primarily reflecting the ability of the kidney to hormonally regulate magnesium levels in the blood.

Other studies have shown a benefit of assuring magnesium adequacy (i.e. providing the RDA level of magnesium) in the reduction of leg cramps in pregnancy. Pregnant women with diabetes need special attention to adequacy of magnesium intake because of the potential for increased losses and the common finding of poor magnesium status among people with diabetes in particular. In addition, inadequacy of magnesium is a risk factor for the development of gestational diabetes as well as Type II diabetes. One

7 contributing factor may be the role magnesium plays in ATP production in the TCA Cycle, and another is very likely its key role in the functioning of insulin receptors.

[Magnesium intake and risk of type 2 diabetes in men and women. Diabetes Care. 2004;27(1):134-40. Role of cellular magnesium in health and human disease. Front Biosci. 2004 1;9:262-76. Dietary magnesium intake in relation to plasma insulin levels and risk of type 2 diabetes in women. Diabetes Care. 2004;27(1):59-65. Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit. 2002 May;8(5):CR326-30.Interventions for leg cramps in pregnancy. Cochrane Database Syst Rev. 2002;(1):CD000121; Magnesium in drinking water and the risk of delivering a child of very low birth weight. Magnes Res. 2002;15(3-4):207-13; Magnesium deficit and sudden infant death syndrome (SIDS): SIDS due to magnesium deficiency and SIDS due to various forms of magnesium depletion: possible importance of the chronopathological form. Magnes Res. 2002;15(3-4):269-78. Gestational diabetes and its impact on the neonate” Neonatal Netw. 2001;20(6):17-23. The apparent impact of gestational magnesium (Mg) deficiency on the sudden infant death syndrome (SIDS). Magnes Res. 2001;14(4):291-303. Micronutrients in pregnancy. Br J Nutr. 2001;85 Suppl 2:S193-7. Gestational magnesium deficiency is deleterious to fetal outcome. Biol Neonate. 1999;76(1):26-32. Nutritional and antimicrobial interventions to prevent preterm birth: an overview of randomized controlled trials. Obstet Gynecol Surv. 1998;53(9):575-85.Vitamin and mineral deficiencies which may predispose to glucose intolerance of pregnancy.J Am Coll Nutr. 1996;15(1):14-20. The effect of oral magnesium substitution on pregnancy-induced leg cramps. Am J Obstet Gynecol. 1995;173(1):175-80.]

Calcium and vitamin D intake status. Be sure that AT LEAST the RDA level is usually provided for calcium. Give dietary guidance to correct inadequacy (see “Aunt Cathy’s Guide to Nutrition: Calcium Supplements” for more detail.) Supplement with calcium and vitamin D if unable to meet goals with foods (ideally without using bone meal, dolomite, or oyster shell calcium.) Remember that the RDA for vitamin D (400 iu) appears to be inadequate for people in the northern latitudes or for those whose skin is dark or covered; some researchers are now suggesting that 1000 - 2000 iu may be needed by these people in order to maintain appropriate blood levels. Interestingly, after years of continually increasing recommendations for calcium intake, it appears that the old RDA level of 800 mg calcium may well be adequate IF the adequacy of vitamin D is assured.

The critical point is that “assuring adequacy” is quite different from “assuring an intake at the RDA level.” There is now a large effort on the part of experts in this field around the world to induce an increase in the officially recommended intake levels. Such things are notoriously slow to become official, but the data is very clear that such a change is needed.

The role of vitamin D inadequacy and risk of perinatal problems is now beginning to be explored. Remember that the amount of vitamin D currently included in a standard prenatal vitamin is 400 iu … the same as in a standard vitamin for when one is not pregnant. This is clearly an amount insufficient to meet the needs of both Mom and Baby. Here are some new reports:

J Clin Endocrinol Metab. 2007 Sep;92(9):3517-22. Maternal vitamin d deficiency increases the risk of preeclampsia. … Results: Adjusted serum 25(OH)D concentrations in early pregnancy were lower in women who subsequently developed preeclampsia compared with controls [geometric mean, 45.4 nmol/liter, and 95% confidence interval (CI), 38.6-53.4 nmol/liter, vs. 53.1 and 47.1-59.9 nmol/liter; P < 0.01]. There was a monotonic dose-response relation between serum 25(OH)D concentrations at less than 22 wk and risk of preeclampsia. After confounder adjustment, a 50-nmol/liter decline in 25(OH)D concentration doubled the risk of preeclampsia (adjusted odds ratio, 2.4; 95% CI, 1.1-5.4). Newborns of preeclamptic mothers were twice as likely as control newborns to have 25(OH)D less than 37.5 nmol/liter (adjusted odds ratio, 2.2; 95% CI, 1.2-4.1). Conclusions: Maternal vitamin D deficiency may be an independent risk factor for preeclampsia. Vitamin D supplementation in early pregnancy should be explored for preventing preeclampsia and promoting neonatal well-being.

J Nutr. 2007 Feb;137(2):447-52. High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates.

8 In utero or early-life vitamin D deficiency is associated with skeletal problems, type 1 diabetes, and schizophrenia, but the prevalence of vitamin D deficiency in U.S. pregnant women is unexplored. We sought to assess vitamin D status of pregnant women and their neonates residing in Pittsburgh by race and season. Serum 25-hydroxyvitamin D (25(OH)D) was measured at 4-21 wk gestation and predelivery in 200 white and 200 black pregnant women and in cord blood of their neonates. Over 90% of women used prenatal vitamins. Women and neonates were classified as vitamin D deficient [25(OH)D<37.5 nmol/L], insufficient [25(OH)D 37.5-80 nmol/L], or sufficient [25(OH)D>80 nmol/L]. At delivery, vitamin D deficiency and insufficiency occurred in 29.2% and 54.1% of black women and 45.6% and 46.8% black neonates, respectively. Five percent and 42.1% of white women and 9.7% and 56.4% of white neonates were vitamin D deficient and insufficient, respectively. Results were similar at <22 wk gestation. After adjustment for prepregnancy BMI and periconceptional multivitamin use, black women had a smaller mean increase in maternal 25(OH)D compared with white women from winter to summer (16.0+/-3.3 nmol/L vs. 23.2+/-3.7 nmol/L) and from spring to summer (13.2+/-3.0 nmol/L vs. 27.6+/-4.7 nmol/L) (P<0.01). These results suggest that black and white pregnant women and neonates residing in the northern US are at high risk of vitamin D insufficiency, even when mothers are compliant with prenatal vitamins. Higher-dose supplementation is needed to improve maternal and neonatal vitamin D nutriture. The vitamin D research has critical implications for pregnancy as well as neonatal health and a wide range of health problems. For example, recently, vitamin D deficiency was shown to be associated with increased risk of death from ALL causes.

Arch Intern Med. 2007;167:1730-1737. (Sept. 10) Vitamin D Supplementation and Total Mortality: A Meta-analysis of Randomized Controlled Trials Arch Intern Med. 2007;167:1709-1710. (Sept. 10) Can Vitamin D Reduce Total Mortality?

Recently it has been suggested that the vitamin D deficiency during pregnancy may be related to the increasing prevalence of autism. This is certainly just a very interesting hypothesis at this stage, but because assuring adequacy has MANY other benefits during pregnancy and throughout life, it is reasonable to simply assure (not assume) adequacy among pregnant women … and everyone else. There are likely many benefits that have not yet been recognized related to preventing vitamin D deficiency.

Here’s an abstract of a paper that describes why this issue worth looking into:

Med Hypotheses. 2008;70(4):750-9. Autism and Vitamin D. Any theory of autism's etiology must take into account its strong genetic basis while explaining its striking epidemiology. The apparent increase in the prevalence of autism over the last 20 years corresponds with increasing medical advice to avoid the sun, advice that has probably lowered vitamin D levels and would theoretically greatly lower activated vitamin D (calcitriol) levels in developing brains. Animal data has repeatedly shown that severe vitamin D deficiency during gestation dysregulates dozens of proteins involved in brain development and leads to rat pups with increased brain size and enlarged ventricles, abnormalities similar to those found in autistic children. Children with the Williams Syndrome, who can have greatly elevated calcitriol levels in early infancy, usually have phenotypes that are the opposite of autism. Children with vitamin D deficient rickets have several autistic markers that apparently disappear with high-dose vitamin D treatment. Estrogen and testosterone have very different effects on calcitriol's metabolism, differences that may explain the striking male/female sex ratios in autism. Calcitriol down- regulates production of inflammatory cytokines in the brain, cytokines that have been associated with autism. Consumption of vitamin D containing fish during pregnancy reduces autistic symptoms in offspring. Autism is more common in areas of impaired UVB penetration such as poleward latitudes, urban areas, areas with high air pollution, and areas of high precipitation. Autism is more common in dark-skinned persons and severe maternal vitamin D deficiency is exceptionally common the dark- skinned. Conclusion: simple Gaussian distributions of the enzyme that activates neural calcitriol combined with widespread gestational and/or early childhood vitamin D deficiency may explain both

9 the genetics and epidemiology of autism. If so, much of the disease is iatrogenic, brought on by medical advice to avoid the sun. Several types of studies could easily test the theory. ------Other related recent reports: Prevalence of autism in children born to Somali parents living in Sweden: a brief report. Dev Med Child Neurol. 2008 Aug;50(8):598-601. Increased occurrence of autism among Somali children-- does vitamin D deficiency play a role? Tidsskr Nor Laegeforen. 2008 Sep 11;128(17):1986-7. Stay tuned!

For more on vitamin D issues please see my on-line handouts “Vitamin D: It’s Not Just for Bones Anymore!” and “My Current Top Five Easy Ways to Improve Your Family’s Nutrition.”

Vitamin D is added to milk and for many people it is not well known that it is rarely added to other dairy products. Only in the recent past has vitamin D begun to be added to a few brands of yogurt, cheese, and calcium-fortified orange juice [Fortification of orange juice with vitamin D: a novel approach for enhancing vitamin D nutritional health. Am J Clin Nutr. 2003;77(6):1478-83.] Because the amount of vitamin D added to milk is 100 iu/cup, it is quite unrealistic to expect that most people would obtain that the RDA for vitamin D from food. Also, note that the Food Guide Pyramid suggests 3 servings daily “from the dairy group.” Women following that pattern would not be likely to obtain the RDA of 400 iu of vitamin D, much less the higher amounts suggested in the north or among those with dark skin.

Unfortunately, many people (including health professionals) are unaware of these fine points, and for this reason (when it is actually checked) serum vitamin D levels are often found to be inadequate even when calcium intake is appropriate and the RDA for vitamin D is provided. The new version of the Food Guide Pyramid fails to address the problem. It shows a sample2000 kcal diet that provides the (too low) RDA for vitamin D obtained in a week only by being heavily weighted with fortified milk and salmon. There is no caveat included regarding supplementation being important especially for those who do not drink a lot of milk or eat salmon . . . quite a lot of folks. The problem is completely ignored because of the simple fact that the pyramid planners chose not to even list vitamin D at all on the list of essential nutrients! [Vitamin K – another nutrient of increasing concern because of its newly discovered role in bone formation and the poor utilization of the form we have relied on from intestinal bacteria -- is not on the list either.]

Poor vitamin D status is now identified as a risk factor for such diverse conditions as pre-eclampsia, breast cancer, prostate cancer, colon cancer, multiple sclerosis, diabetes (both Type I and Type II), depression, rheumatoid arthritis, osteoarthritis, osteoporosis, impaired fetal development, schizophrenia, myopathy (muscle damage, including heart muscle damage), lupus, increased absorption of lead, schizophrenia and fibromyalgia. This is due to the fact that vitamin D is activated by converting it into a key steroid hormone (the 1,25dihydroxychole-calciferol form) that is structurally very similar to estrogen and testosterone. Inadequacy has great potential for serious health consequences. So far, over 200 different tissues throughout the body have been determined to have receptors for vitamin D hormone.

A few of the many references on this topic: Vitamin D deficiency in recently pregnant women. Rev Med Liege. 2008 Feb;63(2):87-91. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007 Sep;92(9):3517-22.Vitamin D supplementation during the first year of life and risk of schizophrenia: a Finnish birth cohort study. Schizophr Res. 2004 1;67(2-3):237-45. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost. 2004;91(2):373-80. Vitamin D deficiency in early life accelerates Type 1 diabetes in non-obese diabetic mice. Diabetologia. 2004 31. Maternal blood lead concentration, diet during pregnancy, and anthropometry predict neonatal blood lead in a socioeconomically disadvantaged population. Environ Health Perspect. 2003;111(2):195-200. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79(3):362-71. Vitamin D status of middle-aged women at 65-71 degrees N in relation to dietary intake and exposure to ultraviolet radiation. Public Health Nutr. 2004;7(2):327-35. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. The prostate 25-hydroxyvitamin D-1{alpha}-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D. Carcinogenesis. 2004 Jan 16. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62(1):60-5. The pleiotropic actions of vitamin D. Bioessays. 2004;26(1):21-8. Vitamin D and vitamin D analogs as cancer chemopreventive agents. Nutr Rev. 2003;61(7):227-38. The potential benefits of dietary and/or supplemental calcium and vitamin D. Urol Oncol. 2003;21 (5):384-91. Can vitamin D

10 supplementation in infancy prevent type 1 diabetes? Nutr Rev. 2002 60(4):118-21. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358(9292):1500-3. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr. 2003;78(6):1128-34. Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age. Am J Clin Nutr. 2003;78(6):1053-67. In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care. 2003;26(12):3237-42. Nutrition. The vitamin D deficit. Science. 2003 12;302(5652):1886-8. Vitamin D status as a determinant of peak bone mass in young Finnish men. Arthritis Rheum. 2004;50(1):72-7. J Clin Endocrinol Metab. 2004;89(1):76-80. Vitamin D insufficiency in Greenlanders on a westernized fare: ethnic differences in calcitropic hormones between Greenlanders and Danes. Calcif Tissue Int. 2004;74(3):255-63. High prevalence of vitamin D insufficiency in healthy elderly people living at home in Argentina. Eur J Clin Nutr. 2004;58(2):337-42. Vitamin D and prostate cancer prevention and treatment. Trends Endocrinol Metab. 2003;14(9):423-30. Vitamin D: its role and uses in immunology. FASEB J. 2001;15(14):2579-85.. Vitamin D levels in women with systemic lupus erythematosus and fibromyalgia. J Rheumatol. 2001;28(11):2535-9. Preeclampsia is associated with low circulating levels of insulin-like growth factor I and 1,25-dihydroxyvitamin D in maternal and umbilical cord compartments. J Clin Endocrinol Metab. 2000;85(5):1828-33.]

Because of the explosion of information on the critical functions of vitamin D hormone, adequacy is an issue that must be looked at carefully both for a healthy pregnancy and for the long-term health of the mother and child. This is also behind the 2008 recommendation of the American Academy of Pediatrics that all infants and children should receive at least 400 iu vitamin D daily starting soon after birth, and that breast- fed infants in particular are at risk of inadequacy without supplementation. This is in part a reflection of the newly recognized reality that many babies are actually born vitamin D deficient because of inadeqacy during pregnancy. Whether or not the disease relationships described above are confirmed by subsequent research, it does illustrate the potentially broad implications of inadequacy (or excessive intake) of this important hormone, and suggests that it would be prudent to assess maternal intake carefully. [Prevention of rickets and vitamin D deficiency in infants, children and adlescents. Pediatrics October 13, 2008. 2008;122:1142-1152. The Canadian recommendation is 400 iu for infants. Vitamin D-deficiency rickets among children in Canada. CMAJ. 2007 Jul 17;177(2):161-6. Bones and beyond: an update on the role of vitamin D in child and adolescent health in Canada. Appl Physiol Nutr Metab. 2007 Aug;32(4):770-7.]

A newly recognized problem with perinatal iodine deficiency in the US (and elsewhere) with serious reproductive consequences:

Iodine deficiency is a nutrition problem with well-known potential to harm fetal and infant neurologic development. Since salt was iodized in the US it has been assumed that this problem was eradicated and it has essentially gone off our radar screen. Emerging research (beginning in 2005) is demonstrating that this problem continues to be a very serious threat. The issue is new enough and important enough that I have put together a separate paper with current recommendations and descriptions of some key research.about this critical topic.

Please see “Aunt Cathy’s Guide to Nutrition: New Attention to an Old Problem: Iodine Deficiency in Pregnancy and Lactation. 2009”

5. Evaluate the ratio of a woman’s intake of omega 6: omega 3 fatty acids, with a ratio of 4:1 as a goal, and consider providing a generous amount of the omega-3 fatty acids as pre-formed EPA and DHA.

Most Americans consume these fats in a 10:1 ratio. A considerable body of research suggests that as a start there are major health advantages associated with consuming these fats at a 4:1 ratio. The ratio appears to be very important in areas such as risk of heart disease, cancer, HIV, depression, epilepsy, and degenerative eye diseases. In each case, the direction of change that shows benefit is increasing the proportion of dietary fats that are rich in oils of the omega-3 family in relation to the intake of fats from the omega-6 family. In addition to the ratio of these two families of fat, consumption of some of them as preformed 20-22 carbon long chain fatty acids appears to have special benefit in general and in pregnancy in particular. The long chain omega-3 fats (EPA = eicosapentaenoic acid; DHA = docosahexa-enoic acid) are found in fish and fish oil supplements.

11 Various advisories regarding hazardous levels of mercury or other toxins in certain fish have made it more difficult to recommend fish consumption in general, especially during pregnancy. However, a recent report on EPA-DHA (NOT on cod-liver oil, which is different in a number of ways) supplements available in the U.S. appeared in Consumer Reports (2003.Jul;68(7): 30-2.) They evaluated the safety of products on the market (e.g. related to mercury concerns, etc.,) the actual content of each product, and the price. The good news is that they found all to be safe, and all products contained what the label said was in there. However the price per 300 mg of supplemental fish oil ranged from 6 to 60 cents each!

[FDA warns on mercury in tuna. JAMA. 2004 Jan 14;291(2):171. Toxicology. Salmon survey stokes debate about farmed fish. Science. 2004 Jan 9;303(5655):154-5. Weighing health benefit and health risk information when consuming sport-caught fish. Risk Anal. 2003 Dec;23(6):1185-97. Decline in fish consumption among pregnant women after a national mercury advisory. Obstet Gynecol. 2003 Aug;102(2):346-51.]

Oils rich in omega-3 fatty acids appear to have important implications in pregnancy and infant nutrition in particular. DHA (a 22 carbon omega-3 fatty acid) is a major fat of the brain, and the research is growing that suggests that providing some pre-formed DHA is often advantageous. In a study over infants in various parts of the world, values of arachidonic acid and docosahexaenoic acid showed two-fold variability in cord blood of full term infants. The highest values of docosahexaenoic acid were observed in countries with apparently higher consumption of dietary fat from sea fish. DHA is also known to be essential for retinal development in infants.

Maternal essential fatty acid status declines during pregnancy, and as a result, neonatal concentrations of docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) may not be optimal. Importantly, maternal supplementation with the essential fatty acids linoleic and alpha linolenic acid did not promote neonatal DHA+AA status. Maternal DHA supplementation significantly increases maternal DHA status and limits the last trimester decline in maternal status, aiding preferential transfer of DHA from mother to fetus. Long-chain PUFA (EPA, DHA, ARA) are therefore conditionally essential substrates during early life that are related to the quality of growth and development. The amount of DHA in human milk varies widely and is positively correlated with visual and language development in breast-fed infants. A dietary supply during pregnancy, lactation, and early childhood that avoids the occurrence of LC-PUFA depletion is desirable, as was recently recommended by an expert consensus workshop of the Child Health Foundation. Fetal growth requires n-3 docosahexaenoic acid (DHA), which is derived from the n-3 fatty acids in the maternal diet. Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships. DHA can be formed in the liver from alpha linolenic acid, but it is unclear if the rate of DHA synthesis in humans is sufficient to support optimal brain and retinal development.

Differences in DHA status between women both in the non-pregnant state and in pregnancy may reflect variations in metabolic capacity for DHA synthesis. One group of researchers noted that available estimates suggest that 67 mg DHA/d is accumulated by the fetus during the third trimester of gestation. Human milk concentrations of DHA have been noted to decrease in recent years and a low intake of DHA among some pregnant women has been observed. The balance between the n-6 and n-3 PUFA in the maternal diet rather than amount of n-6 or n-3 PUFA per se could be important for adipose tissue growth and for maintaining adequate serum leptin levels in the offspring. In multiple pregnancies, fetal demand for ‘- docosahexaenoic acid may not be entirely satisfied. It may be that a greater maternal intake of docosahexaenoic acid should be encouraged for optimal tissue perfusion. Omega-3 fats are also associated with decreased risk of premature delivery. As premature delivery is the most common cause of low infant birth weight, and infant morbidity and mortality, this is a very important observation.

There may be a role for omega-3 fatty acids in allergy development, and possibly beneficial effects of n - 3 PUFAs in diabetic pregnancy and in the prevention and treatment of long-term metabolic abnormalities associated with macrosomia. It has also been reported that maternal alcohol intake can alter fatty acid transport by the human placenta, decreasing fetal availability of polyunsaturated fats in general and of DHA

12 especially. It may be that this decreased DHA transport is one of the (many) mechanisms of FAS (Fetal Alcohol Syndrome.)

There is not an official pregnancy-specific recommendation as yet, but the following recommendations from the American Heart Association provide an idea of the range suggested in yet another health condition for which these issues are being found to be important:

American Heart Association Recommendations for Omega-3 Fat Intake (2002)

People without Eat a variety of (preferable oily) fish at least twice a week. documented heart disease Include oils and foods rich in alpha-linolenic acid (flaxseed, canola and soybean oils; flaxseeds; and walnuts. People with Eat about a gram of EPA+DHA daily. This can come from oily documented heart disease fish or from fish-oil supplements.* People with high Take 2-4 grams of EPA+DHA provided as fish oil supplements.* triglycerides

*As always, you should discuss this with your physician, since in certain situations (like people on certain medications) there may be reasons to do things differently.

Rev Obstet Gynecol. 2008 Fall;1(4):162-9. Omega–3 Fatty Acid supplementation during pregnancy.

Omega-3 fatty acids are essential and can only be obtained from the diet. The requirements during pregnancy have not been established, but likely exceed that of a nonpregnant state. Omega-3 fatty acids are critical for fetal neurodevelopment and may be important for the timing of gestation and birth weight as well. Most pregnant women likely do not get enough omega-3 fatty acids because the major dietary source, seafood, is restricted to 2 servings a week. For pregnant women to obtain adequate omega-3 fatty acids, a variety of sources should be consumed: vegetable oils, 2 low-mercury fish servings a week, and supplements (fish oil or algae-based docosahexaenoic acid).

Some references on this topic: [Fish oil supplementation in pregnancy and lactation may decrease the risk of infant allergy. Acta Paediatr. 2009 Jun 1.Systematic review of fatty acid composition of plasma phospholipids of venous cord blood in full-term infants. Eur J Nutr. 2002;41(3):125-31. Effect of alpha-linolenic acid supplementation during pregnancy on maternal and neonatal polyun-saturated fatty acid status and pregnancy outcome. Am J Clin Nutr. 2004;79(2):251-60. Maternal docosahexaenoic acid supplementation and fetal accretion. Br J Nutr. 2003;90(1):135-45. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age. Pediatrics 2003; 111(1):e39-44; Maternal docosahexaenoic acid supplementation during pregnancy and visual evoked potential development in term infants: a double blind, prospective, randomised trial. Arch Dis Child Fetal Neonatal Ed.2003;88(5):F383-F390. Long chain polyunsaturated fatty acids improve cognitive development. Perinatal biochemistry and physiology of long- chain polyunsaturated fatty acids. J Pediatr. 2003;143(4 Suppl) :S1-8. J Fam Health Care. 2002;12(6 Suppl):5. Higher maternal plasma docosahexaenoic acid during pregnancy is associated with more mature neonatal sleep-state patterning. Am J Clin Nutr. 2002;76(3):608-13. Neuroprotective effect of developmental docosahexaenoic acid supplement against excitotoxic brain damage in infant rats. Neuroscience. 2003;119(4):999-1012. Determinants of polychlorin-ated biphenyls and methylmercury exposure in Inuit women of childbearing age. Environ Health Perspect. 2001;109(9):957-63. Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation. Am J Clin Nutr. 2000;71(1 Suppl):307S-11S. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J Pediatr. 2003;143(4 Suppl):S1-8. Synaptic lipid signaling: significance of polyunsaturated fatty acids and platelet-activating factor. J Lipid Res. 2003;44(12):2221-33. Effect of dietary n-3 fatty acids on the composition of long- and very-long-chain polyenoic fatty acid in rat retina. J Nutr Sci Vitaminol (Tokyo). 2003;49(3): 210-3. Protective effect of docosahexaenoic acid on oxidative stress-induced apoptosis of retina photoreceptors. Invest Ophthalmol Vis Sci. 2003;44(5):2252-9. Visual acuity and retinal function in infant monkeys fed long-chain PUFA. Lipids. 2002;37(9):839-48. Scotopic electroretinogram in term infants born of mothers supplemented with docosahexaenoic acid during pregnancy. Invest Ophthalmol Vis Sci.2003;44(8):3685-9. Docosahexaenoic and arachidonic acid influence on preterm baboon retinal composition and function. Invest Ophthalmol Vis Sci. 2003;44(10):4559-66. Retinal sensitivity loss in third- generation n-3 PUFA-deficient rats. Lipids. 2002;37(8):759-65. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J Pediatr. 2003; 143(4 Suppl):S1-8.] Perinatal supply and metabolism of long-chain polyunsaturated fatty acids: importance for the early development of the nervous system. Ann N Y Acad Sci. 2002;967:299-310. Pediatr Res. 2002;52(5):750-5. Conversion of alpha-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. Br J Nutr. 2002 88(4):411-20. Supplementing lactating women with flaxseed oil does not increase docosahexaenoic acid in their milk. Am J Clin Nutr. 2003;77(1):226-33. Intakes of essential n-6 and n-3 polyunsaturated fatty acids among pregnant Canadian women. Am J Clin Nutr. 2003;77(2):473-8. Leptin levels in rat offspring are modified by the ratio of linoleic to alpha-linolenic acid in the maternal diet. J Lipid Res. 2002 Oct;43(10):1743-9. Maternal and umbilical cord erythrocyte omega-3 and omega-6 fatty acids and

13 haemorheology in singleton and twin pregnancies. Arch Dis Child Fetal Neonatal Ed. 2003;88(2):F134-8. A randomized trial of docosahexaenoic acid supplementation during the third trimester of pregnancy. Obstet Gynecol. 2003;101(3):469-79. J Nutr.2003133(5 Suppl 2): 1606S-1625S. Exp Biol Med (Maywood).2001;(226(6):498-506; BMJ.2002;324(7335): 447; Obstet Gynecol Serv.2001;56(5 Suppl 1):S1-S13; Pediatrics. 2001;108(2):359- 71; Obstet Gynecol Surv. 2001;56(5 Suppl 1):S1-13; Pediatr Clin North Am.2001;48(1):173-88; BJOG.2000;107 (3):382-95.) [Maternal and umbilical cord erythrocyte omega-3 and omega-6 fatty acids and haemorheology in singleton and twin pregnancies. Arch Dis Child Fetal Neonatal Ed. 2003;88(2):F134-8. Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol. 2003;112(6):1178-84. Implication of lipids in macrosomia of diabetic pregnancy: can n-3 polyunsaturated fatty acids exert beneficial effects? Clin Sci (Lond). 2003;105(5):519-29.] Fish oil supplementation of rats during pregnancy reduces adult disease risks in their offspring. J Nutr. 2003;133(10):3170-4. Decline in fish consumption among pregnant women after a national mercury advisory. Obstet Gynecol. 2003;102(2):346-51 Maternal docosahexaenoic acid supplementation during pregnancy and visual evoked potential development in term infants: a double blind, prospective, randomised trial. Arch Dis Child Fetal Neonatal Ed. 2003;88(5):F383-90. Effects of n-3 polyunsaturated fatty acid supplementation in pregnancy on maternal and fetal erythrocyte fatty acid composition. Eur J Clin Nutr. 2004;58(3):429- 37. The effect of maternal smoking and ethanol on fatty acid transport by the human placenta. Br J Nutr. 2002;87(3):247-52. The role of docosahexaenoic acid in brain development and fetal alcohol syndrome. Biochem Soc Trans. 1998;26(2):246-52. Dietary fatty acids and alcohol: effects on cellular membranes. Alcohol Alcohol. 1993;28(5):607-8. Effects of prenatal ethanol and long-chain n-3 fatty acid supplementation on development in mice. 1. Body and brain growth, sensorimotor development, and water T-maze reversal learning. Alcohol Clin Exp Res. 1990;14(3):405-12. Effects of prenatal ethanol and long-chain n-3 fatty acid supplemen-tation on development in mice. 2. Fatty acid composition of brain membrane phospholipids. Alcohol Clin Exp Res. 1990;14(3):413-20.

Because the omega-3 PUFAs contain a greater number of double bonds, a generous antioxidant intake is advisable. In addition to the well-known nutrient antioxidants (vitamins C and E, selenium, etc.) the pigments of brightly colored fruits and vegetables are now known to be especially potent antioxidants. These include lycopene in tomatoes, lutein in leafy greens, anthocyanins in beets and raspberries, beta-carotene in orange-colored foods, allicin and SAC in garlic, and many others. Because conditions like diabetes (or other conditions involving altered metabolism, auto-immunity or inflammation) result in a greatly increased production of free radicals, generous antioxidant intake is also recommended in these situations. It appears to be protective at least against the increased risk of fetal damage due to the free radical component. There are, of course, many additional health benefits for everyone associated with a generous intake of brightly colored fruits and vegetables as well. See “Aunt Cathy’s Guide: Nutrition in Eye Health” for some specifics about antioxidant sources and amounts.

Oxidative and antioxidative status in pregnant women with either gestational or type 1 diabetes. Clin Biochem. 2004;37(4):293-8. Changes in plasma lipids and markers of oxidative stress in normal pregnancy and pregnancies complicated by diabetes. Clin Sci (Lond). 2004;106(1):93-8. Glutathione metabolism and oxidative stress in neonatal rat tissues from streptozotocin-induced diabetic mothers. Diabetes Metab Res Rev. 2004;20(1):72-8. Ascorbic acid, glycation, glycohemoglobin and aging. Med Hypotheses. 2004;62(2):275-9. Antioxidant, antidiabetic, antihyperlipidemic, reproduc-tion stimulatory properties and safety of essential oil of Satureja Khuzestanica in rat in vivo: a oxicopharmacological study. Med Sci Monit. 2003;9 (9):BR331-5Reduced SOD activity and increased neural tube defects in embryos of the sensitive but not of the resistant Cohen diabetic rats cultured under diabetic conditions. Birth Defects Res Part A Clin Mol Teratol. 2003;67(6):429-37.Lipid peroxidation and vitamin E status in gestational diabetes mellitus. J Obstet Gynaecol Res. 2003;29(5):300-4. Circulating biomarkers of oxidative stress in complicated pregnancies. Arch Gynecol Obstet. 2003;267(4):189-95. Maternal diabetes in vivo and high glucose in vitro diminish GAPDH activity in rat embryos. Diabetes. 2003;52(5): 1222- 8. The role of reactive oxygen species in diabetes-induced anomalies in embryos of Cohen diabetic rats. Int J Exp Diabetes Res. 2002;3(4):247-55. gamma-Linoleic acid and ascorbic acid ameliorate the effects of experimental diabetes on electrolyte and bone homeostasis in pregnant rats. J Endocrinol. 2002;173(2):273-84.Effects of ergothioneine on diabetic embryopathy in pregnant rats. Food Chem Toxicol. 2002;40(12):1751-5. Com- bined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatr Res. 2001;49(6):755-62.Vitamins C and E improve rat embryonic antioxidant defense mechanism in diabetic culture medium. Teratology. 2001;64(1):33- 44. Lipid peroxidation and scavenging enzyme activity in streptozotocin-induced diabetes. Acta Diabetol. 2000;37(4):179-83. Antioxidant therapy and streptozotocin-induced diabetes in pregnant rats. Acta Diabetol. 1999;36(3):113-7. Lipoic acid prevention of neural tube defects in offspring of rats with streptozocin-induced diabetes. Am J Obstet Gynecol. 1999;180(1 Pt 1):188-93.Role of reactive oxygen species (ROS) in the diabetes-induced anomalies in rat embryos in vitro: reduction in antioxidant enzymes and low-molecular-weight antioxidants (LMWA) may be the causative factor for increased anomalies. Teratology. 1999;60(6):376-86. Teratogenic effects of diabetes mellitus in the rat. Prevention by vitamin E. Diabet-ologia. 1996;39(9):1041-6.Dietary vitamin E prophylaxis and diabetic embryopathy: morphologic and biochemical analysis. Am J Obstet Gynecol. 1996;175(4 Pt 1):793-9. Maternal antioxidant treatments prevent diabetes-induced alterations of mitochondrial morphology in rat embryos. Anat Rec. 1998;251(3):303-15The effect of vitamin E on antioxidant tissue activity in pregnant rats with streptozocin-induced diabetes Przegl Lek. 1998;55(6): 320-4. Prevention of diabetic embryopathy in offspring of diabetic rats with use of a cocktail of deficient substrates and an antioxidant. Am J Obstet Gynecol. 1997;176(4):790-7Vitamin E decreases the occurrence of malformations in the offspring of diabetic rats. Diabetes. 1997;46(6):1054-61. Congenital malformations in experimental diabetic pregnancy: aetiology and antioxidative treatment. Minireview based on a doctoral thesis. Ups J Med Sci. 1997;102(2):61-98.Antioxidant status and lipid peroxidation in diabetic pregnancy. Br J Nutr. 1997;78(4):523-32.Vitamin C supplement-ation of the maternal diet reduces the rate of malformation in the offspring of diabetic rats. Diabetologia. 1997;40(12):1416-24.6):320-4.

6. If blood pressure begins to go up in the second half of pregnancy: Do not automatically decrease sodium intake, and never recommend a diet restricted to 2 g sodium/day or less during pregnancy unless special conditions like renal disease or congestive heart failure are involved and the physician has a special reason for needing such a low level. In women with pre-eclampsia, a severe sodium restriction can actually

14 precipitate a seizure. Puffy feet and ankles in pregnancy are not caused by diet. With physician approval, increase calcium to 2000 mg supplement (in addition to diet) and give magnesium at the RDA Ca:Mg ratio (e.g. about 400 mg, since the RDA ratio is 300 mg Mg to 1200 mg Ca, the ratio with supplemental calcium described above = 400 Mg : 2000 Ca.) High dose calcium in the absence of adequate magnesium may increase risk of thrombotic events. In addition, remember to assure adequacy of vitamin D in order for the calcium to be absorbed appropriately. This plan may or may not be helpful in the prevention or control of PIH based on conflicting results from studies, but some individuals may respond favorably, and the intervention appears to be benign. And since prevention is always preferable to treatment, there is evidence [described earlier] that nutrition issues in the periconceptional period may also play a role in risk of development of pre- eclampsia later in pregnancy.

7. For nausea/hyperemesis problems, have M. Erick’s video “Morning Sickness: All Day and All Night” (Lemon-Aid Films), and book “No More Morning Sickness” available for clients. In addition, the following ideas may be helpful (many of which were initially published by Ms. Erick.)

• Continued use of a multivitamin (they actually decrease nausea), and as described earlier, since the prenatal type is not necessary in early pregnancy and they can be harder to tolerate, a standard multi- vitamin with minerals or a children’s chewable product taken with food is the best choice. If she is “gun shy” about iron or vitamins in general because of poor tolerance of her prenatal vitamin, the psychological advantage of a children’s vitamin can help (“It’s so gentle it’s for little children!”) as can the use of a “silver” type product with little or no iron. In general, remember that the woman having problems with eating is precisely the woman who is most in need of supplemental vitamins and minerals, so it is all the more important to help her find one she can tolerate. Do not advise her to “just skip it until you feel better.”

• Ms Erick found that sniffing lemons and eating citrus foods (grapefruit, lemonade, etc.) often have a marked diminishing effect on the feeling of nausea, especially among women whose nausea is triggered by increased sensitivity to odors. Avoiding strong smells is helpful, so eating outdoors in nice weather is pleasant, as is having someone else do the cooking while she goes for a walk. Cold foods usually are less aromatic than hot foods. Even cooking smells that are normally pleasant (coffee brewing, sauces simmering, etc.) can induce nausea in many pregnant women. And, of course, things that are unpleasant under any circumstances can be even worse (garbage, the cat box, dirty diapers, etc.) so these are excellent tasks for significant others who want to help. ☺)

• Do not restrict the diet or advocate “clear liquids” as a treatment. For many women, liquids like water, juice and pop are the most difficult to keep down. However, many can tolerate lemonade, and for some ginger ale or ginger tea are helpful. Ginger appears to be safe in the amounts tested in hyperemesis patients, and studies have supported that it apparently helps in some cases. In a survey of obstetricians, 51.8% reported using ginger in this context. “The most commonly cited herbs for morning sickness were ginger, chamomile, peppermint and raspberry leaf (55, 37, 44 and 63% cited respectively). There was no consensus in the popular literature about whether or not each of these herbs was safe for use in pregnancy. Seven sources (6%) cited chamomile and peppermint as unsafe, while 16 (12%) cited the use of ginger and 11 (15%) the use of raspberry leaf as unsafe during pregnancy.” Another survey of 300 non-medical sources studied 75 cited the use of herbs in pregnancy.

[A randomized comparison of ginger and vitamin B6 in the treatment of nausea and vomiting of pregnancy. J Med Assoc Thai. 2003 Sep;86(9): 846-53. A survey on the management of nausea and vomiting in pregnancy by obstetrician/gynecologists. Prim. Care Update Ob Gyns. 2001 Mar; 8(2):69-72.] [What do we know about herbal morning sickness treatments? A literature survey. Midwifery. 2000 Sep;16(3):224-8.]

15 • Vitamin B6 (pyridoxine) and antihistamines have been shown to be helpful in some women, and the research available suggests that these interventions are safe. However, the amount of vitamin B6 in multi- vitamins is only the RDA level (2 – 2.5 mg) and not the therapeutic level. Oral therapeutic levels used range from 25-100 mg/day, and sometimes pyridoxine is administered as an injection. In any case, these interventions during pregnancy require the approval of the physician or other primary care professional. However, this level of intake IS available over the counter in the form of “B-100 Complex” supplements.

[Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2003;(4): CD000145. Nausea and vomiting of pregnancy. Am Fam Physician. 2003 Jul 1;68(1):121-8. Comparison of three outpatient regimens in the management of nausea and vomiting in pregnancy. J Perinatol. 2003 Oct;23(7):531-5. Bendectin and birth defects. II: Ecological analyses. Birth Defects Res Part A Clin Mol Teratol. 2003 Feb;67(2):88-97. Overview of nausea and vomiting of pregnancy with an emphasis on vitamins and ginger. Am J Obstet Gynecol. 2002 May;186(5 Suppl Understanding):S253-5. The use of CAM by women suffering from nausea and vomiting during pregnancy. BMC Complement Altern Med. 2002 May 17;2(1):5. Health risks over the Internet: advice offered by "medical herbalists" to a pregnant woman. Wien Med Wochenschr. 2002;152(7-8):190-2. A survey on the management of nausea and vomiting in pregnancy by obstetrician/gynecologists. Prim. Care Update Ob Gyns. 2001 Mar;8(2):69-72.]

• Do not presume that her nausea has a psychological etiology. A few years back it was common in the medical literature to find that the woman was blamed for the puzzle of hyperemesis gravidarum. (“She is expressing her subconscious ambivalence about the pregnancy”, etc.) Old textbooks may still refer to this sort of theory. The evidence that it was “all in her head” was sometimes based on her rapid improvement when hospitalized and hooked up to i.v. glucose, which was described as a placebo. (“She responded to simply getting attention.”) However, in this situation, the i.v. glucose was definitely not a placebo, but an interruption of the fasting/nausea pattern. The glucose arriving in the bloodstream shuts off ketone production, which may be one of the triggers of nausea in pregnancy. Note that once the glucose has decreased the nausea, she needs to be told to begin “grazing” regularly on carbohydrate (and to eat other foods, too, of course, as able) and to avoid fasting.

• “Grazing,” (eating a little bit frequently and especially keeping the carbohydrate coming in) is an important concept. It encourages small servings, which may be helpful, but it is the “frequent feedings” aspect that seems to be the most beneficial. Old advice like “eat 6 small dry meals with 6 servings of liquids half an hour after each meal” has been standardly given out and it can be helpful. However, it appears that its usefulness is related less to the specific juggling of liquids and solids than it is to the fact that she is taking in small meals of carbohydrate 12 times a day! Some women even set an alarm to go off every two hours to make sure that carbohydrate is provided regularly because they feel nauseated once they fast longer than that. The old advice about eating crackers or dry toast half an hour before getting out of bed is probably helpful in the sense that it sends some carbohydrate down. Interestingly, there are no studies showing a special benefit of dry toast or crackers at the bedside instead of any other carbohydrate- containing food, but this particular advice is regularly included in materials given to pregnant women. Instead of just the old “cracker” advice, give her a larger “menu” of carbohydrate-containing food suggestions. This is especially important if she is somewhat dehydrated; soda crackers can be unpleasant when the mouth feels dry. In this regard, even the “avoid high fat food” advice often given may have been useful (when it was helpful) primarily because if she ate isocalorically she would necessarily increase carbohydrate intake by displacing fat. Plus, the presence of fat in food decreases the speed of stomach emptying, thus delaying the absorption of carbohydrate and the shut-off of ketone production.

• As a rule, do not tell her to automatically avoid particular foods, because (for example) even though some women find greasy foods less palatable, others have good luck with them. In fact, one of the most well tolerated foods is potato chips. In some cases reported, consuming a small bag of potato chips about half an hour before supper significantly improved the women’s ability to eat the meal. Interestingly, potato chips are less “empty calories” than one might expect . . . they provide carbohydrate (“Yes!!”), sodium,

16 potassium, a little vitamin C, and energy to a woman desperately in need of all. At the very least, the chips are better than not keeping anything down! Wash them down a little later with some lemonade!

• Instead of telling her to avoid large numbers or types of foods, find out what foods she thinks she can eat, and then find ways to make them available to her. In addition to chips, many women report tolerating spaghetti, hard cooked eggs, chocolate milk, etc. At this stage the foods do not have to be particularly “nutritious” . . . breaking the fasting/nausea cycle is the goal. Good nutrition is the focus a bit later.

• Be aware of the potential serious danger from micronutrient deficiency (e.g. Wernicke’s encephalopathy and other overt deficiency diseases have been documented), especially when primarily glucose or other carbohydrates are provided via i.v. or “clear liquid’ diet without concomitant vitamin and mineral supplementation in a woman who has been unable to eat well. At least 12 cases of this unfortunate outcome have been reported in the literature, and all would have been prevented simply by the regular provision of a multivitamin (oral or added to the i.v.)

[Memory loss and ataxia after hyperemesis gravidarum: a case of Wernicke-Korsakoff syndrome. Eur J Obstet Gynecol Reprod Biol. 2002 Apr 10;102(1):100-1. Hyperemesis gravidarum complicated by Wernicke's encephalopathy. Obstet Gynecol. 2002 May;99(5 Pt 2):875-7.]

• For heartburn, chewing gum has been shown to be helpful because it increases saliva production and helps neutralize stomach acid. Sugar-free gum is the choice from a dental perspective, but if a sugar-containing gum is found to help a woman suffering from nausea and vomiting to control it by “grazing” on carbohyd- rates, that would likely be the preferred product. The “acid bath” from regular vomiting would certainly be at least as detrimental to the tooth enamel as gum. There are also some new “antacid” gums available that utilize calcium carbonate. An expert panel in the Netherlands recommended calcium/ magnesium-based antacids as the treatment of choice for pregnant women because of their good safety profile.

[Contemporary understanding and management of reflux and constipation in the general population and pregnancy: a consensus meeting. Aliment Pharmacol Ther. 2003 Aug 1;18(3):291-301 Clinical effectiveness of a new antacid chewing gum on heartburn and oesophageal pH control. Aliment Pharmacol Ther. 2002 Dec;16(12):2029-35. Effects of gum chewing on pharyngeal and esophageal pH. Ann Otol Rhinol Laryngol. 2001 Dec;110(12):1117-9. Walking and chewing reduce postprandial acid reflux. Aliment Pharmacol Ther. 2001 Feb;15(2):151-5.]

8. Advise women to avoid:

• Caffeine: Caffeine may increase risk of miscarriage and may affect fetal growth, although data are conflicting. There are many phytochemical substances in coffee besides caffeine, so there is quite a lot of sorting out to do. To the surprise of most people, several recent studies reported some benefits of both substances in relation to health conditions like diabetes and parkinsonism. In pregnancy, the prudent course is (and has been for some time) to “limit” intake of both substances. One recent publication had this to say: “Currently available evidence suggests that it may be prudent for pregnant women to limit coffee consumption to 3 cups/d providing no more than 300 mg/d of caffeine to exclude any increased probability of spontaneous abortion or impaired fetal growth.” [Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr. 2006;46(2):101-23. Association of maternal caffeine consumption with decrements in fetal growth. Am J Epidemiol. 2003 Mar 1;157(5):456-66. Maternal serum caffeine metabolites and small-for-gestational age birth. Am J Epidemiol. 2002 Jan 1;155(1):32-7.]

• Alcohol: Alcohol is the number one preventable cause of mental retardation in America. Note that the nutritional status of the mother is a critical variable in the degree to which exposure to potential teratogens damages the fetus. For example, exposure to alcohol is significantly more damaging to the fetus when the mother also has poor zinc status (a common finding among heavy users of alcohol). It also appears that providing a generous antioxidant intake may decrease some of the toxic effects. (References cited earlier.) Avoiding alcohol is the best advice, of course, but there is good that can be done

17 with nutrition interventions, even among those who are unable to stop drinking. Many “problem drinkers” WILL take nutritional supplements especially when the benefits to the fetus are explained. As a rule, regular heavy drinkers are frequently found to have poor nutrition status with extremely detrimental results, in particular in relation to zinc, folic acid, and thiamin. Folic acid absorption is specifically inhibited by chronic alcohol use. Many other nutrients are often inadequate as well, but they are less commonly recognized.

To optimize the care of this woman, don’t WONDER if she might be poorly nourished . . . ASSUME that she is poorly nourished and ACT on it. If you are wrong and her nutritional status is actually excellent, no harm will be done by providing levels of nutrients at the levels usually regarded as appropriate for a healthy pregnant woman (i.e. RDA, RDI, etc.). But if she IS poorly nourished, there is the potential to do great good by implementing relatively small, simple, safe and inexpensive interventions. (For more information, see “Aunt Cathy’s Guide to Nutrition: Fetal Alcohol Syndrome”)

• Smoking: Smoking exposes the fetus to carbon monoxide, nicotine, lead, cadmium, and to transport of carcinogens. It reduces transport of nutrition and oxygen to the fetus, increasing risk of being born “small- for Gestational age” (SGA.) A recent study “found that moderate smoking mothers deliver neonates with decreased birth weight and highly correlated to placental cadmium concentration. Decreased metal nutrient/pollutant ratios, a condition here found in smokers, may indicate a placental dysfunction, contributing to impair birth weight.” [Metals content in placentas from moderate cigarette consumers: correlation with newborn birth weight. Biometals. 2005 Jun;18(3):233-41.]

Cigarette smoking during pregnancy generates free radicals (as it always does regardless of pregnancy status) and it has been implicated in oxidative cellular damage in fetuses. Two recent studies measured vitamin E in maternal and cord blood of smokers and nonsmokers (as a marker of antioxidants available to quench free radicals.) The women who smoked during pregnancy and the cord blood of their newborns had a lower concentration of vitamin E in plasma and in erythrocytes as compared with group of non- smoking women. The same researchers also measured malondialdehyde levels (a marker of lipid peroxidation.) They found that malondialdehyde was higher in plasma and in erythrocytes of mothers and babies in the “smoking” dyad, and concluded that smoking during pregnancy promotes free radical damage in growing fetus and newborns and stimulates metabolic disorders dependent on oxidative stress. This is likely an indication that antioxidant intake from vitamins, minerals and phytochemicals needs special attention in these women. [The effect of tobacco smoking during pregnancy on concentration of malondialdehyde in blood of mothers and in umbilical cord blood Ginekol Pol. 2005 Dec;76(12):960-5 The effect of tobacco smoking during pregnancy on concentration of vitamin E in blood of mothers and their newborns in umbilical cord blood Ginekol Pol. 2006 Apr;77(4):263-8.]

• Unsafe Food and Water: Undercooked meat, unpasteurized milk products, unpasteurized apple cider, raw oysters, swordfish, etc., are potential sources of listeria, E. Coli O:157, toxoplasma gondii, mercury and others organisms and substances that are especially dangerous in pregnancy. Avoid frequent consumption of liver during pregnancy due to the finding that the retinol content is much higher than was previously believed. Have well water checked for lead and other contaminants, along with the presence of submersible pumps or faucets with bronze fittings that can leach lead into the water. The EPA Safe Drinking Water Hotline has specific information about these issues: 1-800-426-4791. Poor nutrition also plays a part because it compromises the ability of the immune system to protect against infection, it impairs detoxification of harmful agents (e.g. by affecting the functioning of the cytochrome P450 system), and it also leads to greater absorption of certain toxic substances.

9. Encourage weight gains within the currently accepted ranges (25-35 lbs for the “average” woman, etc.) Weight gain in the first trimester has only recently been found to be very contributory to birth weight, so helping women avoid significant weight loss due to nausea may be more important than was realized earlier. This has huge public health implications, because low birth weight, specifically “small for

18 gestational age” (SGA), appears to be a significant predictor of risk of several chronic diseases of adulthood (diabetes, heart disease, etc.). This relationship is referred to as the “Fetal Origins Hypothesis” or the “Barker Hypothesis.”

This topic has been the subject of a huge amount of research in the past few years, and just a small amount some is noted below. Basically, it is quite clear that prenatal nutrition and other factors that affect the growth and metabolism of the fetus can contribute to a number of very significant health problems in later life. Some of the most studied relationships have been related to SIZE of babies as a predictor of later health. At present the central research focus is teasing out exactly what factor is doing what to whom and when. This is an onerous task, however, as the factors do not operate in isolation. It is clear that being either a large- for-gestational age infant or a small-for-gestational age infant is at higher risk of several negative outcomes in the long term. Why this is so is a tremendously complex question. For example, if an effect is seen with excessive caloric intake in pregnancy, is it a function of:

• the amount of calories? • the particular substances used to provide the excessive calories? • the timing of the exposure to excessive calories in relation to a critical fetal development period? • the genetic peculiarities of the study subjects? • the underlying health conditions of the subjects such as the mother’s metabolic state? • a disruption of the ratios of calories to the nutrients needed to appropriately metabolism them? • an interaction with other related factors? • the resultant size of the infant, or is size just a marker for some other problem?

How can we tell? Most studies can only chip away at a few questions at a time. However, we will need to keep working to determine some answers to these kinds of questions or we may embark on promotion of prenatal goals and policies that are not only unhelpful but potentially injurious.

Some references about the “Fetal Origins Hypothesis” concept: [Folate supplementation during pregnancy improves offspring cardiovascular dysfunction induced by protein restriction. Hypertension. 2006 May;47(5):982-7. Nutritional control of fetal growth. Nutr Rev. 2006 May;64(5 Pt 2):S50-1; discussion S72-91. Normal and abnormal fetal growth. Horm Res. 2006;65 Suppl 3:19-27. The late effects of fetal growth patterns. Arch Dis Child Fetal Neonatal Ed. 2006 Jul;91(4):F299-304. Wheezing & eczema in relation to infant anthropometry: evi-dence of developmental programming of disease in childhood. Matern Child Nutr. 2006 Jan;2(1):51-61. The developmental origins of adult disease. Matern Child Nutr. 2005 Jul;1(3):130-41. Metabolic syndrome in childhood: association with birth weight, maternal obesity, & gestational diabetes mellitus. Pediatrics. 2005 Mar;115(3):e290-6. Experimental models of developmental programming: consequences of exposure to an energy rich diet during development. J Physiol. 2005 May 15;565(Pt 1). Life-long echoes--a critical analysis of the developmental origins of adult disease model. Biol Neonate. 2005;87(2):127-39. 39. Blood pressure, serum lipids, fasting insulin, & adrenal hormones in 12-year-old children born with maternal preeclampsia. J Clin Endocrinol Metab. 2003;88(3):1217-22. Maternal dietary ethanol consumption is associated with hyper-triglyceridemia in adult rat offspring. Alcohol Clin Exp Res. 2002;26(6):848-55. Impaired glucose tolerance & elevated blood pressure in low birth weight, nonobese, young South African adults: early programming of cortisol axis. J Clin Endocrinol Metab. 2000;85 (12):4611-8. Does birth weight predict adult serum cortisol concentrations? 24-hour profiles in the United kingdom 1920-1930 Hertfordshire Birth Cohort. J Clin Endocrin-ol Metab. 2002;87(5):2001-7. Striking variation in the sex ratio of pups born to mice according to whether maternal diet is high in fat or carbohydrate. Proc Natl Acad Sci. 2003;100(8):4628-32. Low birth weight & weight in infancy are associated with adult insulin resistance & type 2 diabetes. A proposed mechanism is programming of the hypothalamic-pituitary-adrenal axis by intrauterine undernutrition, leading to persistently elevated cortisol concentrations. Long-term programming of blood pressure by maternal dietary iron restriction in the rat. Br J Nutr. 2002 88(3): 283-90. Maternal blood lead concentration, diet during pregnancy, & anthropometry predict neonatal blood lead in a socioeconomically disad-vantaged population. Environ Health Perspect. 2003;111(2):195-200. Increased systolic blood pressure in rats induced by a maternal low-protein diet is re- versed by dietary supplementation with glycine. Clin Sci (Lond). 2002;103(6):633-9. Gender-linked hypertension in offspring of lard-fed pregnant rats. Hypertension. 2003;41(1):168-75. Maternal energy stores & diet composition during pregnancy program adolescent blood pressure. Circula- tion. 2001;104(9):1034-9 Maternal nutrition during gestation & blood pressure in later life. J Hypertens. 2001;19(1):29-34. Size at birth, gestational age & cortisol secretion in adult life: foetal programming of both hyper- & hypocortisolism? Clin Endocrinol (Oxf). 2002;57 (5):635-41. A deficient maternal calcium intake during pregnancy increases blood pressure of the offspring in adult rats. BJOG. 2002;109(5): 540- 5. Insulin resistance in

19 adult rat offspring associated with maternal dietary fat & alcohol consumption. J Endocrinol. 2002;173(1): 63-71. Diet in late pregnancy & glucose- insulin metabolism of the offspring 40 years later. BJOG. 2000;107(7):890-5. Maternal consumption of a high-meat, low-carbohydrate diet in late pregnancy: relation to adult cortisol concentrations in the offspring. J Clin Endocrinol Metab. 2003;88(8): 3554-60. Whole body insulin resistance in rat offspring of mothers consuming alcohol during pregnancy or lactation: com-paring prenatal & postnatal exposure. J Appl Physiol.2004; 96(1):167-72. Olive oil consumption during pregnancy & lactation in rats influences mammary cancer development in female offspring. Nutr Cancer. 2003;46(1):59-65. Effects of maternal ethanol consumption on hematopoietic cells in the rat fetal liver. Alcohol. 2002;28(3):151-6.]

Be wary of nutritionally inadequate weight loss diets undertaken prior to conception in order to be at a “healthier” weight going into pregnancy. Weight may be more “ideal” but nutrient stores could be severely compromised at a time when the fetus is most vulnerable to inadequacy.

For example, there is a higher risk of neural tube defects (NTDs) seen among the offspring of obese women. However, it is unlikely to be corrected by a diet that provides inadequate folic acid, vitamin B-12, vitamin B-6 and selenium, all of which have been shown to have a role in the prevention of NTDs. Some studies find the folic acid – NTD relationship to be quite different among overweight mothers. This may be because several other threats to a healthy pregnancy have not been corrected. Preconceptional weight loss is not contraindicated, but it must be undertaken with careful attention to nutritional adequacy, and appropriately planned vitamin/ mineral supplementation is advisable.

Another related issue is pregnancy after gastric bypass surgery. As this “bariatric” [weight reduction] surgery is becoming more common, subsequent pregnancy is becoming a much larger issue. Serious micronutrient inadequacies are appearing in the scientific literature in this population, including devastating conditions like Wernicke’s encephalopathy from thiamine deficiency (multiple references cited below.) Wernicke’s Encephalopathy has very overt symptoms and it is therefore far more recognizable than deficiencies of many other nutrients. I believe the multiple cases reported of overt thiamine deficiency after gastric bypass to be the “canary in the mine-shaft” -- it is likely a marker for other serious problems that are much less visible. Bottom line: careful consideration of micronutrient intake levels and absorption factors are especially critical in pregnancy post-bypass.

It is also useful to note that research is just in its infancy (no pun intended) regarding understanding of the issues involved in post-bariatric surgery pregnancy and of bariatric surgery in general. Some reports indicate that after weight-loss surgery certain pregnancy complications were indeed less than those found in control groups of women similarly obese but not undergoing surgery. Obesity is well known to be associated with an increase in many risks to a successful pregnancy, such as diabetes, pre-eclampsia, diabetes complications and c-section. However, reports describing pregnancy after bariatric surgery as “safe” have so far only compared those immediate pregnancy complications as the outcome measurement of the study. Additionally, the number of cases studied in this way is still quite small, and the women were (by definition) those receiving prenatal health care. Its “safety” in terms of the optimal health and development of the fetus and the continued health of the mother in terms of nutrient adequacy (and not just changes in degree of fatness) is only beginning to be investigated.

A recent report demonstrated that individuals who are morbidly obese and planning gastric bypass surgery are ALREADY deficient in a number of nutrients before the surgery takes place. [Preoperative Nutritional Status of Patients Undergoing Roux-en-Y Gastric Bypass for Morbid Obesity. J Gastrointest Surg. 2006 Jul- Aug;10(7):1033-7.] One might reasonably extrapolate from this situation as well to question whether the overall nutritional status of other seriously obese individuals might be similarly affected (whether planning surgery or not,) and to consider what might be done to correct things prior to conception.

Again, the first critical step is simply recognizing that:

• micronutrient inadequacies in the general public are not uncommon;

20 • women are generally at higher risk; • people who battle with overweight could easily be at additional risk because of a history of food restricting weight-loss attempts, and the use of medications or purging to induce weight loss; • “malnutrition” includes micronutrient inadequacy and not just calories and protein; in America malnutrition is not at all limited to people who are underweight.

Some additional references on this topic: Pregnancy after bariatric surgery: a comprehensive review. Arch Gynecol Obstet. 2008 May;277(5):381-8. Reproductive Considerations and Pregnancy after Bariatric Surgery: Current Evidence & Recommendations. Obes Surg. 2008 Apr 8. Pregnancy Following Gastric Bypass Surgery for Morbid Obesity: Maternal & Neonatal Outcomes. Obes Surg. 2008 Mar 4. Pregnancy outcomes after laparoscopic Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2008 Jan-Feb;4(1):39-45. Reproductive implications of bariatric surgery: pre- & postoperative considerations for extremely obese women of childbearing age. Curr Diab Rep. 2007 Aug;7(4):281-8. Effect of Body Mass Index on pregnancy outcomes in nulliparous women delivering singleton babies. BMC Public Health. 2007 Jul 24;7(147): 168 Nutritional consequences of bariatric surgery. Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):489-496. Acute psychotic disorder after gastric bypass surgery: differential diagnosis & treatment. Am J Psychiatry. 2006 Jan;163(1):15-9. Wernicke encephalopathy after bariatric surgery: losing more than just weight. Neurology. 2005 Dec 27;65(12):1987. Eating avoidance disorder & Wernicke-Korsakoff syndrome following gastric bypass: an under- diagnosed association. Obes Surg. 2005 Sep;15(8):1207-10. Wernicke encephalopathy--an emerging trend after bariatric surgery. Am J Med. 2004 Nov 15;117(10):804-5. Wernicke's encephalopathy after Roux-en-Y gastric bypass. Obes Surg. 2004 Sep;14(8):1135-7. Stroke & seizure following a recent laparoscopic Roux-en-Y gastric bypass. Obes Surg. 2004 Jun-Jul;14(6):857-60. Acute Wernicke's encephalopathy following bariatric surgery: clinical course & MRI correlation. Obes Surg. 2004 Jan;14 (1):129-32. Rapid onset of Wernicke's encephalopathy following gastric restrictive surgery. Obes Surg. 2003 Aug;13(4):661-2. .A cluster of polyneuropathy and Wernicke-Korsakoff syndrome in a bariatric unit. Obes Surg. 2002 Jun;12(3):328-34. Wernicke encephalopathy in non-alcoholic patients. Am J Med Sci. 2002 Feb;323(2):107-11. Wernicke's syndrome after bariatric surgery. Clin Nutr. 2000 Oct;19(5):371-3. Wernicke-korsakoff encephalopathy & polyneuropathy after gastroplasty for morbid obesity: report of a case. Arch Neurol. 2000 Sep;57(9): 1356-9. A rare complication of adjustable gastric banding: Wernicke's encephalopathy. Obes Surg. 2000 Jun;10(3):274-5. A case of Wernicke-Korsakoff syndrome with dramatic improvement in consciousness immediately after intravenous infusion of thiamine No To Shinkei. 2000 Jan;52(1):59-63. Alcohol & poor compliance as factors in Wernicke's encephalopathy diagnosed 13 years after gastric bypass. Can J Surg. 1998 Oct;41(5):389-92. Starvation injury after gastric reduction for obesity. World J Surg. 1998 Sep;22(9):1002-7. Wernicke's encephalopathy developed several years after total gastrectomy. Report of 2 cases Rinsho Shinkeigaku. 1997 Nov;37(11):1027-9. Wernicke's encephalopathy after vertical banded gastroplasty for morbid obesity. Eur J Surg. 1997 Jun;163(6):473-4. Wernicke's encephalopathy after vertical banded gastroplasty for morbid obesity. BMJ. 1996 Feb 17;312(7028):434. ]

10. Pregnant women with metabolic conditions such as diabetes (Type I or II or gestational), Lupus, Crohn’s disease, Celiac disease, MS, Epilepsy or multiple allergies have special nutrition problems that are often unrecognized.

These include altered requirements for specific nutrients, and drug/nutrient interactions of special concern in pregnancy. These metabolic conditions result in significantly more inflammation and a greater production of injurious free radicals.

It has been shown that women with diabetes can decrease the risk of birth defects and other complications by maintaining good glycemic control prior to and throughout pregnancy. However, careful attention to micronutrients such as providing generous antioxidants, an appropriate omega-3 to omega-6 ratio, and adequacy of vitamins and minerals (e.g. selenium and magnesium) has been shown to further decrease the risk.

B vitamin adequacy appears to be even more important in women with insulin resistance / gestational diabetes in regulating homocysteine levels. As there are pregnancy complications specifically associated with elevated homocysteine in women with gestational diabetes, attention to this interaction may be very important. [Total plasma homocysteine correlates in women with gestational diabetes. Arch Gynecol Obstet. 2008 Jan 31. Teratogenicity associated with pre-existing and gestational diabetes. J Obstet Gynaecol Can. 2007 Nov;29(11):927-44.]

Other examples and references were included earlier (such as epilepsy control medications and their interactions with folic acid, vitamin D, vitamin K and carnitine.)

21

Here are a few additional references regarding nutrition and epilepsy treatment: [Carnitine status of pregnant women: effect of carnitine supplementation and correlation between iron status and plasma carnitine concentration. Eur J Clin Nutr. 2009 Jun 3. Importance of monotherapy in women across the reproductive cycle. Neurology. 2007 Dec 11;69(24 Suppl 3):S10-6. Pregnancy and epilepsy : Retrospective analysis of 118 patients. Nervenarzt. 2008 Apr 4. Antiepileptic drug use, folic acid supplementation, and congenital abnormalities: a population-based case-control study. BJOG. 2008 Jan;115(1):98-103. Management of epilepsy in women of childbearing age: practical recommendations. CNS Drugs. 2006;20(5):373-87. Valproic acid in epilepsy : pregnancy-related issues. Drug Saf. 2006;29(1):1-21. Recent advances on neural tube defects with special reference to Valproic Acid. Endocr Metab Immune Disord Drug Targets. 2006 Mar;6(1):25- 31.Antiepileptic drugs: a case report in a pregnancy with a neural tube defect. Pediatr Neurol. 2006 Apr;34(4):323-4. Best practice guidelines for the management of women with epilepsy. Epilepsia. 2005;46 Suppl 9:117-24.]

Note that the standard recommended nutrient intakes for pregnant women are (by definition) based on the needs of “98% of the healthy population” and they simply cannot be relied upon to meet the needs of women who are not members of that group. Carefully assessing and adjusting the diet or supplement regimen can significantly improve outcomes for these women and their babies, especially when any necessary adjustments are made prior to conception.

Stay Tuned!

22 MeritCare Medical Center Aunt Cathy’s Guide: My Current Top Five Aunt Cathy Easy Ways to Improve Cathy Breedon PhD, RD, CSP, FADA Your Family’s Nutrition Prenatal/Pediatric Nutrition Specialist Clinical/Metabolic Nutrition Specialist (subject to change at any moment! ☺) MeritCare Medical Center, Fargo, ND

This is a quick summary of some things in the nutrition news that can make a big difference in people’s health. Although references are not provided in this brief version, all the suggestions are based on reports in the legitimate scientific literature and the references are available on my more thorough papers that are also on this website (see page 10.) The recommendations are not based on goofy things found on the internet. When “researching” a topic on the internet, it is important to consider the reliability of the source. After all, there is no law against fiction in America! People can pretty much print anything. For example, websites that end in .edu (colleges and universities) tend to be more reliable than sites designed primarily to sell you something. And of course, none of the following suggestions are intended to take the place of the advice of your health care provider.

1. Eat lots of brightly colored fruits and vegetables. There are many beneficial phytochemicals (plant chemicals) that have been found to have a potentially protective role against a variety of common health problems such as cancer, heart disease, diabetes, MS, birth defects, and macular degeneration (a form of blindness.) Some of them act as protective “antioxidants,” but they have many other benefits as well.

Some of the beneficial substances are actually the pigments that give the plants their color. Some examples are: lutein in green leafy vegetables, lycopene in tomatoes and watermelon, beta-carotene in peaches and carrots, anthocyanin in blueberries and beets and zeaxanthin in corn. It turns out that white is a color too, in terms of phytochemicals. Apples for example, have quercetin, a flavonol phytochemical with a number of potentially beneficial effects.

An example of other beneficial substances in fruits and vegetables is sulforaphane in broccoli, which appears to decrease risk of colon cancer especially. Compared with meats, and high fat dairy foods, they are much lower in fat and calories. We tend to eat way too little of these terrific foods, and it hurts us.

To get the best of all of them, eat a wide variety of fruits and vegetables of many colors, and aim for 9 servings a day (an amount that has been shown to be beneficial in some studies.) Some expert groups suggest even more. My official recommendation is “Eat all the brightly colored vegetables and fruits that you can get your hands on!”

1 Nine servings seems like a lot to most folks, since many people eat very few. In fact, the french fry is the most commonly eaten vegetable in America. Hmmmm. Not an ideal pattern. Start by adding a couple servings and working up. Throw some chopped green pepper and dried tomatoes on the pizza. Keep those ready-to-eat baby carrots on hand. Make it EASY for us to grab the healthier snack as we run out the door.

Canned, frozen or fresh fruits and vegetables all count because the brightly colored antioxidants are not destroyed by heat! If you use canned veggies, watch out for the salt they often can them with. Choose low sodium versions, or at least rinse them off. This is not an issue with fruits, or with frozen veggies except if they are packed in some kind of sauce. Remember that color is a big deal, so choosing only iceberg lettuce won’t provide the dark green lutein found more generously in romaine or spinach. Color variety is key.

Check out “Aunt Cathy’s Ideas for Trying to Eat More of Those Terrific Antioxidant Phytochemicals . . . and Liking It” for ideas for adding them to our diet. This and many other nutrition topics are available at meritcare.com, including any mentioned throughout this paper as having more information on a topic. Information on how to find them is included at the end of this paper.

The dark leafy veggies are also terrific sources of vitamin K, a nutrient just now being recognized as critical to decrease risk of osteoporosis, cardiovascular disease, kidney stones, liver and colon cancer and arthritis. It is also a nutrient found to be low in the diets of many Americans. It appears that the elderly need more than the current RDA of 90-120 mcg/day. This information is so new that vitamin K is not even included in most multivitamins currently on the market, and many health professionals will not yet have heard about these new issues.

[Vitamin K: The coagulation vitamin that became omnipotent. Thromb Haemost. 2007 Jul;98(1):120-5.]

If you are taking medications to prevent blood clots, be sure to show this information to your doctor before adding a lot of vegetables to your diet. New research on the relationship between vitamin K and these drugs will result in changes in how we do things. But because the information in support of these changes is very new, it will also be new to many healthcare providers, so I have put a ‘Vitamin K” handout on line that includes all the scientific references and detail that your doctor will want to see before making any changes in diet or medication. Your doctor can also contact me for the most recent reports on this topic.

2. When you eat grains, try to use whole grain whenever possible. The “germ” (the part that becomes the baby plant) and the bran (the fibrous coating) of grains are removed in processing when grains are “refined.” These are the parts that would have contributed the most magnesium, chromium, vitamin E, fiber and many other nutrients. Magnesium and chromium have important roles in using the rest of the grain (the starchy part) for energy and for avoiding diabetes.

Large national studies (such as NHANES by the National Center for Disease Control in Atlanta) have shown that the majority of Americans have a diet too low in these minerals.

2 This inadequacy contributes to weight problems, diabetes, heart disease and some neurologic problems that are too common in our society.

“Enriched” grain products have only a few nutrients replaced (vitamins B1, B2, B3, and iron) out of all the nutrients that are removed when refining grain. This label can be confusing because the word “enriched” sounds like something was made to be even better. Instead, it means “not as nutritious as whole grain.” If you don’t like whole grain bread and pasta, you can still add back the nutrients they contain by adding wheat germ and bran to other foods. Check out “Aunt Cathy’s Industrial Strength ‘Instant’ Oatmeal Recipe” for some ideas.

3. Nuts, seeds, peanuts and dried beans/peas are terrific nutrient-rich foods because they are essentially the germ of new plants. For example, in one study from Harvard, eating an ounce of nuts or peanuts four times a week or more was shown to be related to 25% less likelihood of developing diabetes. This appears to be associated with the generous magnesium in these foods. They also have more “satiety value” – you feel like you actually ATE something” -- and they are terrific nutritious snacks including for people who are watching their weight or who have diabetes.

Although all fats have about 9 calories per gram, the forms of fat in nuts and peanuts (mostly “monounsaturated” and “omega-3” fats) are less contributory to heart disease than many other forms of fat. Also they are rich in nutrient content so they are not an “empty calorie” food. So, although they do have calories, I think of these forms of fat as potentially “Dangerous to your butt, but not to your heart!” Additionally, dried beans and peas are also very low in fat and high in fiber. It looks like that means chili beans, lima beans, split peas, chick peas, navy beans, lentils, pinto beans, etc., are “health foods!”

These foods, and assuring adequacy of magnesium (and chromium, another key mineral in the same foods) in general, are especially beneficial for people who appear to be genetically (or for whatever reason) at greater risk of developing diabetes. This includes people who have family members with diabetes, people who are overweight, and some ethnic groups who appear to be disproportionately at risk.

For example, serious health problems related to diabetes have been found to be causing much more injury to Native Americans and African Americans than to some other groups of folks. There are many contributing factors, of course, but assuring adequacy of magnesium and chromium (another key mineral in the same foods) is one factor that can be easily corrected if people just hear about it. [Vitamin D is another, as discussed later.]

4. Another important form of fat to include in our diet is called “omega-3” fat. A lot of research shows that it is associated with a decreased risk of cancer, heart disease, inflammatory disease, depression, pregnancy problems, and much more. We Americans tend to eat too much of another family of fat called omega-6 fat, such as that found in corn oil. To improve the balance in the American diet, flax, canola and walnuts are great plant sources of omega-3 fat.

3 Additionally, there is a huge amount of research showing that the special forms of omega-3 fats found in fish and fish-oil supplements (EPA and DHA) have certain very important advantages for many people. EPA decreases inflammation in a wide range of inflammatory diseases like MS, cardiovascular disease and arthritis. I think of EPA (whose real name is eicosapentaenoic acid) should be thought of as “Environmental Protection Agency” instead, because it seems to be very protective against a number of health problems.

DHA in particular appears to be very important for the development of the brain and the retina of the eye, so it is critical during pregnancy and infancy. It has also been shown to be helpful in the continued good operation of the brain (e.g. in possibly helping to ward off age-related problems like alzheimers and other forms of dementia,) and for decreased risk of, or progression of, depression, blindness due to macular degeneration, attention deficit disorder and Parkinson’s disease.

More research is ALWAYS needed, of course, but the cumulative results of a great many studies have been in the same direction. Assuring an adequate intake of these fats looks like a VERY good idea. Additionally, it is now recognized that for some people it is difficult to efficiently convert the plant omega-3 oils (like those in canola, flax and walnuts) into the important EPA and DHA oils that are found ready-made in the fish oil. This may be a factor in a broad range of inflammatory conditions and critical in pregnancy.

The American Heart Association recommends 1000 mg of fish oil for most people with risk of heart disease. People at risk include those who smoke, who have disturbed blood lipids (too much LDL cholesterol or triglycerides, or too little HDL cholesterol,) who are overweight or sedentary, or who have high blood pressure, diabetes, or a family history of heart disease. Other factors contribute to heart disease risk as well.

[Omega-3 fatty acids and coronary heart disease risk: Clinical and mechanistic perspectives. Atherosclerosis. 2007 Dec 24 n-3 Fatty Acids: Recommendations for Therapeutics and Prevention. Proceedings of a symposium, New York, New York, USA, May 21, 2005. Am J Clin Nutr. 2006 Jun;83(6 Suppl):1451S-1538S.]

Saturated fats have long been on our list of “foods to eat less of.” These include lard/meat fat, butter/dairy fat, and “hydrogenated” (solidified) oils like shortening or margarine. None of these is a good source of omega-3 fat. Eating less of them and choosing foods that are more generous in their omega-3 fat content is a very good idea.

Some shortenings and margarines accidentally contain “trans” fat, another “good-to- avoid” form of fat that must be shown on the nutrition labels of foods if there is more than ½ gram per serving. It is usually in food because the oil was “partially hydrogenated” to make it solid at room temperature like margarine or shortening. It is gradually being removed from our food supply because it is quite unhealthy. The biggest source at present is in baked goods made with shortening. Some margarines and shortenings are now made that have no trans fat in them, and they usually note this on the label because it is such a good thing.

4 5. Increase your regular intake of vitamin D to assure an intake that averages at least 1000 iu per day (for some folks 2000) and take a multivitamin with minerals daily in addition to “eating right.” This is a markedly different recommendation because new research shows that older recommendations of 200-400 iu of vitamin D were simply too low to assure adequacy. Some researchers have found that even 1000 iu may be too little for some people in terms of optimizing health and minimizing disease risks, especially among people with dark skin or who live up north. In certain situations, 2000 iu appears to be needed. (More on that later.) In the northern third of the country vitamin D deficiency is now being described as “an unrecognized epidemic.” [See map on p. 12]

It is now known that inadequate vitamin D status is very common, and that it is associated with increased risk of diabetes, lupus, scleroderma, fibromyalgia, multiple sclerosis, cancer of the breast, colon, prostate, endometrium and pancreas, heart disease, muscle pain, osteoporosis, rheumatoid arthritis, osteoarthritis, obesity, muscle weakness and poss preserving cognitive function in older adults.

Other associations of inadequate vitamin D are now beginning to be explored such as increased risk of parkinsons disease, autism, asthma, impairment of the immune system, pre-eclampsia and cancer of the lung. This is not surprising because it has now been recognized that vitamin D actually functions as a key steroid hormone -- one that your body would make as needed … if you just give it enough of the material to do the job. Over 200 different body tissues have been identified so far that have receptors for the vitamin D hormone, and they need it in order to work properly. “Vitamin D is a unique vitamin. Its metabolic product, calcitriol, is a profound secosteroid hormone that has impact on over 1000 genes in the human body.” Modern concepts in the diagnosis and treatment of vitamin D deficiency and its clinical consequences. J Environ Pathol Toxicol Oncol. 2009;28(1):1-4.

[Vitamin D and aging. J Steroid Biochem Mol Biol. 2009 Mar;114(1-2):78-84. Vitamin D and type 2 diabetes Is there a link? Prim Care Diabetes. 2009 Apr 21. Behavioural and physical characteristics associated with vitamin D status in women. Bone. 2009 Jun;44(6):1085-91 Hypovitaminosis D is Associated with Greater Body Mass Index and Disease Activity in Pediatric Systemic Lupus Erythematosus. J Pediatr. 2009 May 14. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):722-9. Sex-specific association of serum vitamin D levels with physical function in older adults.Osteoporos Int. 2009 May;20(5):751-60. Vitamin D status and muscle function in post-menarchal adolescent girls. J Clin Endocrinol Metab. 2009 Feb;94(2):559-63. 25. Vitamin D Supplementation and Reduced Risk of Preeclampsia in Nulliparous Women. Epidemiology. 2009 May 15. Association of 25-Hydroxyvitamin D With Blood Pressure in Predominantly 25- Hydroxyvitamin D Deficient Hispanic and African Americans. Am J Hypertens. 2009 May 14. Effect of vitamin D supplementation in the institutionalized elderly. J Bone Miner Metab. 2009 May 15. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009 Feb 23;169(4):384- 90. Nutrition and health: guidelines for dental practitioners.Oral Dis. 2009 May 15. Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season. Metabolism. 2008 Feb;57(2):183-91. 25- Hydroxyvitamin D and Risk of Myocardial Infarction in Men A Prospective Study Arch Intern Med. 2008;168(11):1174-1180. Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother. 2008 Jan;9(1):107-118. Vitamin D in Health and Disease. Clin J Am Soc Nephrol. 2008 Jun 4. Monthly ambient sunlight, infections and relapse rates in multiple sclerosis. Neuroepidemiology. 2008;31(4):271-9]

Another emerging area of research is the role of vitamin D inadequacy as a factor in heart disease. Cardiovascular disease is the most common cause of death in the US, so this is a very important issue. In a “meta-analysis” (looking at data of many studies at once) published recently the risk for mortality (death) from all causes was found to be significantly less among people taking an ordinary dose of a vitamin D supplement compared with those who did not. Another prospective study concluded that a low vitamin D level in the blood was associated with a higher risk of death from all causes, and specifically with heart attack as well.

5 [Circulating calcitriol concentrations and total mortality. Clin Chem. 2009 Jun;55(6):1163-70. Vitamin D and cardiovascular disease. Pharmacotherapy. 2009 Jun;29(6):691-708.Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis. Atherosclerosis. 2009 Jun 6. Prospective Study of Serum 25-Hydroxyvitamin D Level, Cardiovascular Disease Mortality, and All-Cause Mortality in Older U.S. Adults. J Am Geriatr Soc. 2009 Jun 22 Increased Levels of 25 Hydroxyvitamin D and 1,25-Dihydroxyvitamin D After Rosuvastatin Treatment: A Novel Pleiotropic Effect of Statins? [Crestor] Cardiovasc Drugs Ther. 2009 Jun 20. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008:168(12):1340-1349. Vitamin D and cardiovascular disease risk. Curr Opin Clin Nutr Metab Care. 2008 Jan;11(1):7-12. Macro- and micronutrients in patients with congestive heart failure, particularly African-Americans. Vasc Health Risk Manag. 2007;3(5):743-7. Vitamin D supplementation & total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007 10;167:1730-7]

Can we make adequate vitamin D in our skin?

We can make adequate vitamin D in our skin, but only 1. if we live where the angle of the sun is more directly overhead (i.e. not up north,) 2. if we are not covered up with clothes or sunscreen most of the time, 3. if our skin is not old or darkly pigmented, 4. if we do not take anti-seizure medications and 5. if we are not severely overweight. Even at the equator there are many reports of people being found to have serious vitamin D deficiency simply because they are covered up much of the time. Some are covered up for religious reasons, some to prevent skin cancer (melanoma) and some of us are just covered up as a public service! ☺ We all need to be sure to get adequate vitamin D some other way. People who work nights also need to think about this. It is estimated that about 50% of the earth’s population is at risk of vitamin D deficiency.

[Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S.]

Did you know that the men at greatest risk of prostate cancer are older African- American men living in the north? African-American women living in the north also have a higher incidence of breast cancer, which appears to also be associated with low vitamin D status. Many researchers believe that we can lower the risk by correcting the inadequacy of vitamin D that is so common among people up north and among people of color.

For example, recently blood tests evaluating the ACTUAL vitamin D status of African- American mothers and their newborns in Pittsburgh found that over half in each group was vitamin D deficient, even if prenatal vitamins were regularly used. This has many very serious implications, but it could be remedied by more generous supplementation of this key vitamin. Attention to this is long overdue. About a third of white mothers and babies in the same northern study were also found to be deficient.

In another new report it was found that a daily intake of 2000 iu of vitamin D assured that dark-skinned northern women maintained a desirable blood level of greater than 50 ng/ml. Another study found that 2000 iu daily could raise the storage form of vitamin D in blood to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer in observational studies. Ironically, 2000 iu daily had long been set as the presumed upper level of safety for vitamin D intake. Many experts have expressed the opinion that the upper level of safety should be changed to a chronic intake of 10,000 iu daily.

What serum (blood) levels of vitamin D are associated with good health?

6

A recent report found evidence suggesting that higher vitamin D intakes beyond current recommendations may be associated with better health outcomes. They looked at a number of studies related to bone mineral density (BMD), lower extremity function, dental health, risk of falls, admission to nursing homes, fractures, cancer prevention and hypertension (high blood pressure.)

Their conclusion: “For all endpoints, the most advantageous serum levels for 25(OH)D appeared to be at least 75 nmol/l (30 ng/ml) and for cancer prevention, desirable 25(OH)D levels are between 90-120 nmol/l (36-48 ng/ml). An intake of no less than 1000 IU (25 mcg) of vitamin D3 (cholecalciferol) per day for all adults may bring at least 50% of the population up to 75 nmol/l. Thus, higher doses of vitamin D are needed to bring most individuals into the desired range. While estimates suggest that 2000 IU vitamin D3 per day may successfully and safely achieve this goal, the implications of 2000 IU or higher doses for the total adult population need to be addressed in future studies.” [Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.]

[Diagnosis and treatment of vitamin D deficiency. Expert Opin Pharmacother. 2008 Jan;9(1):107-118. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med. 2008:162(6):505-512 Hypovitaminosis D among healthy children in the United States. .Arch Pediatr Adolesc Med. 2008:162(6):513-519. Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency. J Perinatol. 2007 Sep;27(9):568-71. Dose response to vitamin D supplementation among postmenopausal African American women. Am J Clin Nutr. 2007 Dec;86(6):1657-62. The urgent need to recommend an intake of vitamin D that is effective. Am J Clin Nutr. 2007 Mar;85(3):649-50. Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol. 2007;103(3-5):708-11]

Clearly a lot more research is needed … it is ALWAYS needed …but these new reports are a great illustration of the emerging broad importance of this issue. The 1000 iu level is safe in general and the 2000 iu level is safe (and may be necessary) in some cases . . . what is clearly NOT safe is allowing a person to have a low vitamin D level.

[Vitamin D Status: Measurement, Interpretation, and Clinical Application. Ann Epidemiol. 2008 Mar 8. Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? Adv Exp Med Biol. 2008;624:1-15. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S.]

Taking in this amount of vitamin D will require using a supplement. The primary supplemented food in our diet is fortified milk with 100 iu/cup, but ten cups of milk is not reasonable, and it is also not good nutrition. One would have no room left for other foods. Start with a regular multivitamin with minerals. That provides 400 iu. If you drink a lot of milk, that combination may be adequate. Otherwise, you can easily add a tiny, easy-to- swallow inexpensive 400 –2000 iu vitamin D capsule, or a calcium supplement with a similar amount of vitamin D. There are even tiny 1000 iu “gummi”-type vitamin D products available.

Vitamin D can be stored well in the body, so some people prefer taking a week’s worth of extra vitamin D all on one day. There are few foods naturally high in vitamin D – really just salmon, tuna and cod-liver oil – which are problem foods for many people. We will begin to see more foods being supplemented now that the public is becoming aware of the problem. Some yogurt and cheese now have a little vitamin D added, and the calcium- fortified orange juices are now supplemented as well. Other foods will likely be fortified in the coming years. However, if you are in an at-risk group (e.g. dark skin, living up north, etc.) it is likely necessary to take an additional vitamin D supplement even if you do drink a lot of milk and take a multivitamin. Note also that milk “straight from the cow” does not contain any vitamin D, so some of our farm families get none and are quite unaware if it.

7 Some people are hesitant to take supplements for one reason or another. So, just for fun, I have put together four daily meal plans that would provide 1000-2000 iu various ways:

Four Daily Meal Plans that Would Provide 1000-2000 iu Vitamin D

Plan 1 -- The “I love milk plan”: 1 multivitamin 400 iu 4 cups milk 400 iu 1,000 iu vitamin D supplement Total = 1800

Plan 2 -- The “I hate milk and salmon plan”: 1 multivitamin 400 iu 0 cups milk 0 iu 1,000 vitamin D supplement Total = 1400

Plan 3 – The “I insist on getting my vitamin D only in the form of fortified foods and not from pills” plan: 0 vitamin supplements 0 iu 4 oz daily salmon (110 iu/oz) 440 iu 10 cups of milk (WHATTTT???) Total = 1440

Plan 4 – The “I insist on getting my vitamin D only in the form naturally occurring in the foods I eat and not from any fortification or pills” plan: 0 vitamin supplements 0 iu 0 cups milk 0 iu 14 oz daily salmon (110 iu/oz) 1540 iu Total = 1540 iu

As you can see, one cannot realistically get there from here without supplementation.

Vitamin D Inadequacy in Breastfeeding Alert

Interestingly, mother’s milk is an amazingly nutritious food and breastfeeding is certainly encouraged. However, the milk does not contain vitamin D. This is probably because when people were invented nobody lived in Fargo. As an adaptation to live well up here, we need to have a furnace, a coat, really good mittens and vitamin D. It is that simple.

Because of the finding of serious vitamin D deficiency in many breast-fed babies, in 2003 the American Academy of Pediatrics recommended that breastfed babies be given “at least 200 iu of vitamin D by two months of age.” In 2008 that recommendation was changed to 400 iu/day for all infants and they recommended starting it right away because many babies were actually born with inadequate stores of vitamin D because their mothers were deficient during pregnancy (in spite of taking prenatal vitamins.) This change brings US recommendations in line with those of their Canadian colleagues who have recommended 400 iu for babies, and at least 800 iu for everyone else up there for several years now. Here are some details of the kind of research that led to this change in recommendation:

A recent study in Boston of 380 healthy infants and toddlers who were seen for a routine health visit found that the prevalence of vitamin D deficiency (<20 ng/mL) was 12% (44 of 365 children), and 146 children (40%) had levels below an accepted optimal threshold (<30 ng/mL.*)

8 [Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512. Neonatal vitamin D status at birth at latitude 32 degrees 72': evidence of deficiency. J Perinatol. 2007 Sep;27(9):568-71.]

The same Boston authors studied the therapeutic amounts of vitamin D supplementation needed to correct the low vitamin D status of the children. They concluded that these two approaches were effective for bringing low vitamin D levels into the range of >30 ng/mL* within a 6 week treatment period:

Daily 2000 IU vitamin D2 or D3 or Weekly 50,000 IU vitamin D2

[Prevalence of Vitamin D Deficiency Among Healthy Infants and Toddlers Arch Pediatr Adolesc Med. 2008;162(6):505-512. Treatment of Hypovitaminosis D in Infants and Toddlers. J Clin Endocrinol Metab. 2008 Apr 15.]

*However, note that a report described earlier suggested that the healthiest ranges of serum vitamin D may in fact be above this “optimal threshold” of >30 ng/mL, and that it might be in the range of 36-48 ng/mL.

[Optimal serum 25- hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.]

Take that multivitamin with minerals for other important reasons as well.

Besides the welcome 400 iu of vitamin D, multivitamins provide folic acid and vitamin B12 in forms that are easier to absorb and use by people taking certain common medications, those who have certain genetic traits, and people who experience some age-related changes in the stomach.

For example, some people take “proton pump inhibitor” medications (strong blockers of stomach acid production for heartburn or “gastro-esophageal reflux.”) They can be unable to obtain vitamin B12 from normal food sources because the process requires the presence of acid in the stomach. However, they CAN absorb the vitamin B12 in the vitamin pill form. Similarly, a third of the elderly are found to be vitamin B12 deficient when the most sensitive tests are used. That’s a lot of people! Often it happens for the same reason …an age-related decreased production of stomach acid.

Both of these invisible vitamin B12 absorption situations can cause very serious health problems … and both are prevented by simply taking a regular multivitamin! So, without having to know if you are personally at risk or a family member is at risk, the simple use of the multivitamin will prevent a number of serious problems. The problems to be avoided in this way include nerve damage, cancer, depression, stroke and birth defects.

However, some other causes of vitamin B12 deficiency will NOT be corrected just by the multivitamin (although people should still take one for other reasons, of course.) For example, the diabetes medication Metformin (Glucophage) also can also have a negative effect on vitamin B12 status. This is also true of a very serious vitamin B12 deficiency condition called “pernicious anemia.” These are both caused by factors other than the changes in stomach acid. Vitamin B12 issues with Metformin or pernicious anemia will need to be monitored and corrected by your health care provider, as the simple multivitamin will not solve those problems. (For more information on vitamin B12 issues and monitoring vitamin B12 status, please see my vitamin B12 handout.)

I do not sell anything. I just think that the evidence is quite clear that taking a multivitamin is a very good idea for everyone, and more and more professional health

9 associations are of the same opinion. A low cost product is just fine, contrary to the claims of people who are trying to sell you a pricier “pyramid scheme” product.

Children’s chewable vitamins are very similar to adult products, and they can be very useful for people with trouble taking pills or who have concerns about the vitamin’s ability to dissolve and be well absorbed in the intestine. Most product labels say for ages under four give ½ tablet daily, and for ages four-through-adult, take a whole one daily. Read the label.

Note that many children’s and adult vitamins are not very complete. Some very popular products like some “gummi” vitamin products are actually quite incomplete and therefore not the best choice for a multivitamin. It is a good idea to pick a product that says “Complete” on the label (even though NONE of the vitamins on the market are actually complete.) The labels show that some products clearly provide nutrients that other products (including others by the same manufacturer) have left out. Some products will advertise some special feature to make them stand out in the crowd, and it is often an unimportant distinction. For the most part, just a complete-type generic is just fine, and much less costly.

Another nutrient problem that has recently been found to need more attention is IODINE DEFICIENCY. In many parts of the world (including the US --- see map on p. 12) iodine deficiency is common, and the traditional international approach to solving it has been to add iodine to salt. However, it appears that the amount obtained from iodized salt is actually not sufficient during pregnancy, and that even in areas that have been thought to have corrected iodine deficiency many women obtain too little.

Iodine deficiency is the number one cause of preventable mental retardation in the world. Iodine deficiency can also result in a serious lack of energy in anyone affected because it impairs the function of the thyroid gland. The World Health Organization is now increasing the recommendation for iodine intake, especially in pregnancy.

Back home in America, many people are unaware that they should select “iodized salt” …the packaging is often very similar and they are side-by-side on the shelf at the store. Most specialty salts that are popular now, like sea salt or exotic salts, are also not iodized. Additionally, we frequently are advised to cut back on salt for other health reasons, which can further limit iodine intake. The choice of salt as the way to supplement iodine was made well before ideas of sodium restriction were common for health reasons.

Because it has long been assumed that the iodine deficiency problem was “solved” in the US, at present many vitamin pills contain no iodine at all, including many prenatal vitamins. So, this is one more nutrient that a person should check for when they select a multivitamin. Choose iodized salt if you use salt, and people who use little salt should be sure to find an iodine supplement especially if they live in the northern half of the country. The problem of iodine deficiency has simply not been in our radar for many years. This is a very newly recognized and extremely important health problem that needs attention.

10 [Iodine Content of prenatal multivitamins in the United States. NEJM. 2009;360:939-940. Iodine deficiency in pregnancy and the effects of maternal iodine supplementation on the offspring: a review. Am J Clin Nutr. 2009 Feb;89(2):668S-72S. Iodine status of the U.S. population, National Health and Nutrition Examination Survey 2003- 2004. Thyroid. 2008 Nov;18(11):1207-14.]

And finally:

Of course, taking a multivitamin does not take the place of eating healthy foods. Do I have to say this? For example, the vitamin pills contain no protein, no omega-3 fats, and little or no beneficial phytochemicals, potassium, magnesium, selenium, chromium, calcium, phosphorus, etc. The people who design the pills assume that taking a multivitamin does not take the place of eating healthy foods. It is up to us to eat more of the really great nutritious foods as described in this paper. For people who say that they “don’t believe in” taking a vitamin, I usually try to point out that nutrition is not a religion, so belief is not really a central issue. It’s a biological / biochemical science. At this time in history, the science indicates that it is advantageous to take a multivitamin, some fish oil, and for some folks additional vitamin D, vitamin K and iodine IN ADDITION TO eating lots of healthy nutritious foods.

Bottom line:

Eat lots of healthy foods including plenty of brightly colored fruits and vegetables, nuts, legumes, seeds and whole grains

AND

Take a multivitamin with minerals. Many people will also need extra vitamin D (some will need quite a bit more), vitamin K and iodine.

AND

For many people, for many reasons, fish oil supplements are advisable.

For additional information on these and other topics you can go to MeritCare’s website (www.meritcare.com) and find other articles in the “Aunt Cathy’s Guide to Nutrition” series.

Just type Cathy Breedon in the “search box” and a page comes up where you can click “Cathy Breedon’s Handouts.”

Topics there include information and references especially for people interested in:

Specific health problem issues as diabetes, celiac disease, cancer, eye health, multiple sclerosis, hemochromatosis, epidermolysis bullosa and the nutrition needs

11 of children with several types of chronic health issues.

Pregnancy and infant nutrition issues

Nutrient-specific summaries providing much more detail about nutrients discussed here, such as magnesium, iron, chromium, iodine, vitamins D, K and B12 and different kinds of fat and oil.

12 MAPS of INTEREST: VITAMIN D and IODINE Cathy Breedon

VITAMIN D: https://www.health.harvard.edu/newsweek/images/latitude-vitaminD.jpg Except during the summer months, the skin makes little if any vitamin D from the sun at latitudes above 37 degrees north (in the United States, the shaded region in the map) or below 37 degrees south of the equator. People who live in these areas are at relatively greater risk for vitamin D deficiency.

(Actually, that’s where I live … but you can see why it’s a really big deal Up North!”)

IODINE: Map showing spatial correlation between the former "Goiter Belt*" in the northern U.S. and areas where the iodine content of drinking water is naturally low. www.uwsp.edu/gEo/faculty/ozsvath/images/goiter_belt.htm [*Goiter is an abnormal enlargement of the thyroid gland, often due to iodine deficiency.]

13 MeritCare Health System 9/2009

Aunt Cathy's Guide to Nutrition: Aunt Cathy A Vitamin B12 Update Cathy Breedon PhD, RD, CSP, FADA Perinatal/Pediatric Nutrition Specialist MeritCare Health Systems and UND School of Medicine Full Reference Version

Vitamin B12 is needed in only tiny amounts, and unlike most B vitamins, it is stored well in the body. Most Americans eat foods that provide lots of it. So there shouldn't be any problem with vitamin B12, right? This is a Trick Question of course; if there were no problem I would not be here talking about it! ☺

Most references for the information provided here are included at the end. A few newer ones are sprinkled around in the text. As always, this handout is not intended to take the place of your physician or health care provider. It is simply a summary of the most recent information available in the scientific literature on this topic as of the date shown.

What does B12 do?

1. B12 is involved in making important chemical messengers and myelin in the brain and nervous system, so some of the major symptoms of deficiency are neurologic problems.

2. B12 is involved in the making DNA, the genetic center of every cell in the body. It is especially important during periods of growth (pregnancy, infancy and childhood), and in tissues that continually make a lot of new cells (red blood cells and the armies of cells in the immune system.)

What happens if B12 is too low?

Besides serious nerve damage and mental confusion, B12 deficiency damages the retina of the eye, and may play a role in conditions such as heart disease, stroke, Alzheimer's disease, incontinence and loss of hearing. When deficiency is severe, people can have unusually high heart rates and

1 have trouble breathing. Vitamin B12 deficiency causes changes in testicular tissues in men, and it may be related to increased risk of breast cancer in older women.

During pregnancy, inadequate B12 causes birth defects such as neural tube defects and brain damage. A new study suggests that underlying vitamin B12 deficiency may be involved in the development of HELLP Syndrome, a serious complication of pregnancy. [HELLP syndrome-like by vitamin B12 Deficiency: Report of seven cases. J Gynecol Obstet Biol Reprod (Paris). 2009 Mar 20]

What foods have B12?

The only natural food sources are animal products like meat, poultry, fish, milk, cheese and eggs. Other foods may have it added.

Who is at risk of low B12 status?

1. People with inadequate B12 in their diet.

Strict Vegans (people who use no animal products) and their breast-fed babies are at high risk unless they take a B12 supplement. Some people just eat a really poor diet that happens to be very low in both meats and dairy foods.

2. Some people do not absorb B12 well in spite of an adequate diet.

Stomach problems that may decrease B12 absorption: Gastrectomy (stomach removal); Gastric surgery for weight loss [Anemia after bariatric surgery: more than just iron deficiency. Nutr Clin Pract. 2009] Low stomach acid production or atopic gastritis (both common problems among the elderly); Infection with H. Pylori, a bacteria that causes ulcers and gastritis; Genetic factors causing low levels of "Intrinsic Factor," a B12 carrier made in the stomach.

Conditions that affect the part of the small intestine where it joins the large intestine (called the "terminal ileum"):

2 Surgical removal of that part of the intestine; Crohn's disease (inflammatory bowel disease) or celiac disease; Overgrowth of the intestine surface by bacteria or parasites such as giardia. This is especially common among adults older than 70 who have chronic diarrhea, loss of appetite, or nausea.

[Vitamin B12 status, methylmalonic acidemia, and bacterial overgrowth in short bowel syndrome. J Pediatr Gastroenterol Nutr. 2009 Apr;48(4):495-7.]

Some medications interfere with absorption of B12 from food.

Medications probably account for the surprisingly greater number of younger adults now being found to be deficient in B12. Drugs that block stomach acid production (like Tagamet, Zantac and especially “proton pump inhibitors” like Prilosec, Nexium, Previcid and Protonics) and the diabetes drug Metformin (Glucophage) all interfere with B12 absorption. Additionally, people with low vitamin B12 status are at great risk if nitrous oxide anesthesia is used.

People with autoimmune disorders such as insulin-dependent diabetes, celiac disease, multiple sclerosis, and certain thyroid disorders have a higher risk of deficiency for several reasons.

Sometimes it is related to nutrient malabsorption related to intestinal damage from poorly controlled celiac disease. However, as another autoimmune disorder, the severe vitamin B12 deficiency called pernicious anemia is also more common in this population. In some people with celiac disease, neurologic symptoms are not uncommon … it is important to monitor their B12 levels carefully.

In insulin dependent diabetes or multiple sclerosis, however, neurologic symptoms of pernicious anemia are often missed because they are written off as likely due to neurologic damage from those overriding conditions. An adult friend of mine with type 1diabetes experienced extremely debilitating neurologic symptoms because of having developed the autoimmune disease pernicious anemia. She could no longer walk and the pain was severe. Her symptoms were ascribed to complications of diabetes, and I am sorry to report that it took quite a lot of pressure and several months

3 to get the health care professionals involved in her care to check her vitamin B12 level.

She has improved greatly on vitamin B12 shots since then, but the painful neurologic damage will never be completely gone. Pernicious anemia has been documented in adolescents with diabetes, celiac disease, and autoimmune thyroid disorders as well as in adults, especially among those already identified as having two or more autoimmune diseases. [ Pernicious anemia in an adolescent with type 1 diabetes mellitus. Arch Pediatr Apr;16(4):357-9]

Interestingly, parenteral vitamin B12 does look like it can be helpful in diabetic neuropathy, whether related to underlying pernicious anemia or not. [Vitamin B12 may be more effective than nortriptyline in improving painful diabetic neuropathy. Int. J. Food Sci 2009 Feb 12:1-6)]

How is B12 deficiency recognized?

Most commonly it is recognized when a blood test called a CBC shows red blood cells that are very large ("macrocytic anemia.") Unfortunately, this is a very late-appearing symptom and some nerve damage will have already happened by the time the problem is recognized. It takes up to three years for symptoms of deficiency to develop, so people often fail to associate the symptoms with a change in diet or health (such as having had stomach surgery, starting to use a certain medication, or deciding to follow a vegan diet.)

Some researchers estimate that as many as 30% of elderly people have unrecognized B12 deficiency, often due to changes in the stomach and intestine caused by aging. This can contribute to symptoms such as confusion and other mental changes; correcting B12 inadequacy often results in great improvement.

Doctors can check B12 levels in the blood, and there are other markers called homocysteine and methylmalonic acid (MMA). This testing is not commonly done unless symptoms or risk factors suggest that there is a problem. However, it is impractical, expensive and unnecessary to do these tests regularly on everyone.

What should be done?

4 Quite a lot can be done to decrease the likelihood of B12 deficiency ever developing. Why risk possible inadequacy? Assuring adequacy is by far more cost-effective, health-protective and safe than waiting to act until symptoms of inadequacy become apparent.

1. An inexpensive generic standard multivitamin with minerals is likely a very good investment for most people. These provide the adult RDA of 2 mcg of well-absorbed B12. Products designed for older adults ("Silver"-type multivitamins) often have 25 mcg. Some have quite a lot more, as do some “B- 100 complex” supplements. Some researches now recommend >50 mcg/day. B12 is a very safe vitamin and overdose is extremely unlikely. For some of the conditions (such as low stomach acid), simply taking a generous amount of vitamin B12 in a supplement form can solve the problem.

2. For other conditions (such as surgical removal of the stomach or part of the intestine or autoimmune-related pernicious anemia), prescription B12 shots are often needed to assure that there is enough in the body. New techniques include nasal inhalers, sub-lingual (under the tongue) versions, or extremely high oral doses of B12. As always, it is extremely important to monitor the effectiveness of any of these methods.

Summary:

Vitamin B12 deficiency is not uncommon (although it is often unrecognized) and it is very dangerous.

Certain diet patterns or health conditions increase the risk of unrecognized B12 deficiency. People with any of the risk factors described above should be sure to ask their doctors about this issue. Sharing this column with the doctor may be helpful.

The problem of unrecognized vitamin B12 deficiency is just one of the many reasons why it is regarded as “prudent” for all adults to take a daily multivitamin. (Journal of the American Medical Association, June 2002.)

(Some references, abstracts and comments follow.) ------

5 Some references for vitamin B12 and the elderly, proton pump inhibitors and/or metformin

Jensen RT.Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):4-19. Proton pump inhibitors are being increasingly used and for longer periods of time, especially in patients with gastroesophageal reflux disease. Each of these trends has led to numerous studies and reviews of the potential risk-benefit ratio of the long-term use of proton pump inhibitors. Both long-term effects of hypergastrinaemia due to the profound acid suppression caused by proton pump inhibitors as well as the effects of hypo- /achlorhydria per se have been raised and studied. Potential areas of concern that have been raised in the long-term use of proton pump inhibitors, which could alter this risk-benefit ratio include: gastric carcinoid formation; the development of rebound acid hypersecretion when proton pump inhibitor treatment is stopped; the development of tolerance; increased oxyntic gastritis in H. pylori patients and the possibility of increasing the risk of gastric cancer; the possible stimulation of growth of non-gastric tumours due to hypergastrinaemia; and the possible effect of the hypo/achlorhydria on nutrient absorption, particularly iron and vitamin B12. Because few patients with idiopathic gastro-oesophageal reflux disease/peptic ulcer disease have been treated long-term (i.e., >10 years), there is little known to address the above areas of potential concern. Most patients with gastrinomas with Zollinger-Ellison syndrome have life-long hypergastrinaemia, require continuous proton pump inhibitors treatment and a number of studies report results of >5-10 years of tratment and follow-up. Therefore, an analysis of Zollinger-Ellison syndrome patients can provide important insights into some of the safety concerns raised above. In this paper, results from studies of Zollinger-Ellison syndrome patients and other recent studies dealing with the safety concerns above, are briefly reviewed.

Liu KW, Dai LK, Jean W. Metformin-related vitamin B12 deficiency. Age Ageing. 2006 Mar;35(2):200-1. Metformin is an invaluable hypoglycaemic agent. We report two cases who had symptomatic vitamin B12 deficiency related to metformin use; the mechanisms are discussed. The clinician must be aware of the possibility of metformin-associated B12 deficiency in users who suffer cognitive impairment, peripheral neuropathy, subacute combined degeneration of the cord or anaemia.

Kilicdag EB, Bagis T, Tarim E. Administration of B-group vitamins reduces circulating homocysteine in polycystic ovarian syndrome patients treated with metformin: a randomized trial. Hum Reprod. 2005 Jun;20(6):1521-8. Background: The aim of the current study was to assess the effects of B-group vitamins and folic acid administration on serum levels of homocysteine (Hcy) in patients with polycystic ovarian syndrome (PCOS) on short-term metformin treatment. Methods: Patients were randomly assigned to one of three treatment groups. Group 1 patients (n = 20) received metformin (850 mg twice daily); group 2 patients (n = 20) received metformin (850 mg twice daily) and B-group vitamins (vitamin B1, 250 mg; vitamin B6, 250 mg; vitamin B12, 1000 microg twice daily); and group 3 patients (n = 20) received metformin (850 mg twice daily) and folic acid (174 microg twice daily). In all groups, lipid profiles and plasma total Hcy, vitamin B12, folic acid and glucose levels were recorded at baseline and at 3 months. Results: A 26.5% increase in Hcy levels was seen after 12 weeks of metformin therapy, while 21.17 and 8.33% decreases in Hcy levels were detected when B-group vitamins or folic acid plus metformin were given respectively. There were no statistically significant differences recorded in insulin sensitivity using homeostasis model assessment in the three groups. Conclusion: These findings suggest that B-group vitamins and folic acid administration counteract the Hcy- increasing effect seen with metformin therapy.

Elphick DA, Chew TS, Higham SE, Small bowel bacterial overgrowth in symptomatic older people: can it be diagnosed earlier? Gerontology. 2005 Nov-Dec;51(6):396-401. Background/Objectives In older people, small bowel bacterial overgrowth syndrome may be a common, but under-diagnosed, cause of diarrhoea and nutrient malab-sorption. We aim to determine which clinical features and baseline laboratory investigations indicate a high likelihood of small bowel bacterial overgrowth as defined by a positive glucose breath test. Methods: A retrospective analysis of records for all patients referred for glucose breath test over a 6-year period to a teaching hospital. Results: Out of 197 referrals, 168 patient records were located and analysed (62 male, 106 female; median age 65). Patient characteristics predictive of a positive glucose breath test were: increasing age (p < 0.01), low serum vitamin B12 (p = 0.02), low serum albumin (p = 0.03), previous partial gastrectomy (p < 0.01), previous right hemi-colectomy (p < 0.01), presence of small bowel diverticulae (p = 0.01) and concurrent use of a proton pump inhibitor (p < 0.01). 52.5% (n = 21/40) of patients studied who were over 75 years old versus 21.8% (n = 28/128) of those under 75 years old had a positive glucose breath test (p < 0.01). The median time to diagnosis, from first hospital visit to positive glucose breath test, was 39 weeks. Conclusions: There is often a significant delay in diagnosis of small bowel bacterial overgrowth. We suggest that this diagnosis should be considered earlier in the investigative algorithm in older patients with indicative symptoms and a predisposing factor (including previous partial gastrectomy, previous right hemi-colectomy, small bowel diverticulae or use of a proton pump inhibitor) or concurring laboratory indices (low vitamin B12 or albumin). Wiersinga WJ, de Rooij SE, Huijmans JG. Diagnosis of vitamin B12 deficiency revised Ned Tijdschr Geneeskd. 2005 Dec 10;149(50):2789-94.Vitamin B12 (cobalamin) deficiency is a common disorder with potential irreversible haematological and neurological consequences. Currently used diagnostic tests such as the evaluation of serum vitamin B12 and the Schilling test are insufficient, e.g. the positive predictive value of a low serum vitamin B12 level for actual vitamin B12 deficiency (i.e. tissue deficiency) is low. Insufficient availability of vitamin B12 will lead to the accumulation of methylmalonic acid and homocysteine in the body. Nearly all patients with vitamin B12 deficiency also have substantially increased levels of methylmalonic acid and homocysteine. New tests of serum methylmalonic acid and homocysteine are highly sensitive for vitamin B12 deficiency and may obviate the need for the somewhat cumbersome Schilling test.

6 Wolters M, Strohle A, Hahn A. Cobalamin: a critical vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66. Vitamin B(12) deficiency is a common problem in elderly subjects. If a serum cobalamin level of about 150 pmol/L (200 pg/mL) is considered normal, 10-15% of the elderly are deficient. Today, however, a threshold of 220-258 pmol/L (300-350 pg/mL) is recognized as desirable in the elderly, or else sensitive markers like the blood concentration of homocysteine or methylmalonic acid (MMA) are used. Then the prevalence of cobalamin deficiency rises to up to 43%. In the elderly, this high prevalence of poor cobalamin status is predominantly caused by atrophic gastritis type B. Atrophic gastritis results in declining gastric acid and pepsinogen secretion, and hence decreasing intestinal absorption of the cobalamin protein complexes from food. About 20-50% of the elderly are affected. Furthermore, the reduced acid secretion leads to an alkalinization of the small intestine, which may result in bacterial overgrowth and thus to a further decrease of the bioavailability of the vitamin. In addition, some drugs such as proton pump inhibitors or H2 receptor antagonists inhibit the intestinal absorption of vitamin B(12). An already moderately reduced vitamin B(12) level is associated with vascular disease and neurocognitive disorders such as depression and impaired cognitive performance. Furthermore, a poor vitamin B(12) status is assumed to be involved in the development and progression of dementia (e.g., Alzheimer's dementia). This is especially observable if the folic acid status is reduced as well. Due to the insecure supply, the cobalamin status of elderly persons (>/=60 years) should be regularly controlled and a general supplementation with vitamin B(12) (>50 microg/day) should be considered.

Pongchaidecha M, Srikusalanukul V, Chattananon A. Effect of metformin on plasma homocysteine, vitamin B12 and folic acid: a cross-sectional study in patients with type 2 diabetes mellitus. J Med Assoc Thai. 2004 Jul;87(7):780-7. .OBJECTIVE: To determine the effect of metformin on the levels of plasma homocysteine (Hcy), serum vitamin B12 and folic acid in patients with type 2 diabetes mellitus and the relationship between cumulative metformin exposure and levels of plasma homocysteine (Hcy). MATERIAL AND METHOD: The cross sectional study was conducted to assess the effect of metformin treatment on plasma homocysteine (Hcy), serum vitamin B12 and folic acid in 152 type 2 diabetic out-patients aged between 35-65 years old at the Diabetes Clinic of The Makaruk Hospital, Kanchanaburi, Thailand Among those, 88 and 64 patients were categorised to the metformin and non-metformin group according to their records of receiving metformin treatment for a period of a minimal 6 consecutive months before the study. Fasting blood was drawn from each patient and analysed for plasma homocysteine using the Fluorescence Polarization Immunoassay (FPIA) method (IMX Analyzer), and serum vitamin B12 and folic acid using the radioimmunoassay method RESULTS: The plasma Hcy levels showed no significant difference (p = 0.544) among patients in the metformin group compared with those in the non-metformin group (10.6+/-5.8 mol/L vs 10.4+/-4.0 mol/L). There was a significant difference (p = 0.011) in the levels of serum vitamin B12 among patients in the metformin group and among those in the non-metformin group (318.0+/-192.2 pg/mL vs 434.3+/-300.7 pg/mL). However, there was no significant difference (p = 0.090) in serum folic acid levels between patients in the metformin and those in the non-metformin group (8.8+/-5.1 ng/mL vs 7.7+/-3.8 ng/mL). The plasma Hcy levels showed a significant correlation with the duration of metformin treatment (p = 0.014) and the amount of metformin received (p = 0.015) with the Spearman correlation coefficient of 0.260 and 0.258 respectively. CONCLUSION: Even though the direct effect of metformin treatment on the plasma Hcy could not be concluded from the present study, it was found that there was a significant depletion of level of serum vitamin B12 among patients who had been on long-term metformin treatment. Therefore, vitamin B12 supplement is suggested for diabetic patients who are receiving metformin medication.

Buvat DR. Use of metformin is a cause of vitamin B12 deficiency. Am Fam Physician. 2004 Jan 15;69(2):264; 264, 266. No abstract available.

Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004 Apr;57(4):422-8 Objective: Acid- suppressant drugs are commonly prescribed for elderly patients, a population in which vitamin B(12) deficiency is a common disorder. The purpose of this study was to examine the possible association between use of prescription histamine H-2 receptor antagonists (H2RA) or proton pump inhibitors (PPI) and vitamin B(12) deficiency in older adults. Study Design and Setting: This was a case-control study in a University-based geriatric primary care setting. Among patients aged 65 years or older with documented serum vitamin B(12) studies between 1990 and 1997, 53 vitamin B(12)-deficient cases were compared with 212 controls for past or current use of prescription H2RA/PPI according to information in subjects' medical records. Results: Controlling for age, gender, multivitamin use, and Helicobacter pylori infection, chronic (#10878;12 months) current use of H2RA/PPI was associated with a significantly increased risk of vitamin B(12) deficiency (OR 4.45; 95% CI 1.47-13.34). No association was found between past or short-term current use of H2RA/PPI and vitamin B(12) deficiency. Conclusion: These findings support an association between chronic use of H2RA/PPI by older adults and development of vitamin B(12) deficiency. Additional studies are needed to confirm these findings.

Force RW, Meeker AD, Cady PS.Ambulatory care increased vitamin B12 requirement associated with chronic acid suppression therapy. Ann Pharmacother. 2003 Apr;37(4):490-3. Background: Assimilation of vitamin B(12) from dietary sources requires gastric acid. By decreasing acid production, the proton pump inhibitors (PPIs) and histamine(2) (H(2))-blockers may reduce vitamin B(12) absorption. Objective: To determine whether chronic acid suppression therapy is associated with the initiation of vitamin B(12) supplementation, we conducted a retrospective case-control study using a state-wide Medicaid population. Methods: Case patients were identified as those who initiated vitamin B(12) supplementation during the study period. Four control patients were age- and gender-matched to each case. Patients (n = 109 844) with a paid claim between September 27, 1995, and September 27, 1997, were eligible for inclusion. Chronic acid suppression therapy was defined as treatment with H(2)-blockers or PPIs for >/=10 of the 12 months prior to the first vitamin B(12) injection. Comparisons were made between the case and control groups regarding exposure to chronic acid suppression therapy. Results: One hundred twenty-five cases were matched to 500 controls. Twenty-three patients

7 (18.4%) had been exposed to chronic acid suppression therapy compared with 55 (11.0%) of the control group (p = 0.025; OR 1.82; 95% CI 1.08 to 3.09). Conclusions: Initiation of vitamin B(12) supplementation was associated with chronic gastric acid suppression therapy.

Wulffele MG, Kooy A, Lehert P. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2003 Nov;254(5):455-63. Objective: Metformin is a key treatment option in type 2 diabetes. However, metformin may decrease vitamin B12 levels and increase levels of homocysteine, a cardiovascular risk factor. We investigated whether 16 weeks of treatment with metformin affects serum concentrations of homocysteine, folate and vitamin B12 in subjects with type 2 diabetes treated with insulin. Design: Placebo-controlled, randomized trial. Measurements: at baseline and 16 weeks later. Setting : This trial was conducted in the outpatient clinics of three general hospitals in The Netherlands. Subjects: A total of 745 patients with type 2 diabetes, treated with insulin and not known with a contraindication for the use of metformin, were approached; 390 gave informed consent and entered the study. Thirty-seven subjects dropped out (12 placebo and 25 metformin users). Intervention: Addition of metformin or placebo to insulin therapy. Primary Outcome Parameters: Serum homocysteine, folate, vitamin B12, indices of glycaemic control and body weight. Results: Amongst those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of 4% (0.2 to 8; P=0.039) and with decreases in folate [-7% (-1.4 to -13); P=0.024] and vitamin B12 [-14% (-4.2 to -24); P<0.0001]. In addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12. Conclusion: In patients with type 2 diabetes, 16 weeks of treatment with metformin reduces levels of folate and vitamin B12, which results in a modest increase in homocysteine. The clinical significance of these findings remains to be investigated.

Schubert ML.Gastric secretion. Curr Opin Gastroenterol. 2003 Nov;19(6):519-25. Purpose of review: Gastric acid facilitates the digestion of protein and the absorption of iron, calcium, and vitamin B12. It also protects against bacterial overgrowth and enteric infection, including prion disease. When homeostatic mechanisms malfunction, the volume and concentration of acid may overwhelm mucosal defense mechanisms, leading to duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease. This article reviews recent knowledge contributing to understanding of the regulation of gastric acid secretion at the central, peripheral, and intra-cellular levels. Recent Findings: The vagus nerve contains afferent fibers that transmit sensory information from the stomach to the nucleus of the solitary tract. Input from the nucleus of the solitary tract is relayed to vagal efferent neurons that originate from two brain stem nuclei: the nucleus ambiguus and the dorsal motor nucleus of the vagus. The latter is also influenced by thyrotropin-releasing hormone neurons that act centrally to stimulate acid secretion. The main peripheral stimulants of acid secretion are the hormone gastrin and the paracrine amine histamine. Gastrin stimulates acid secretion directly and, more importantly, indirectly by releasing histamine from fundic entero-chromaffin- like cells. Gastrin also exerts trophic effects on various tissues, including the gastric and intestinal mucosa. The main inhibitor of acid secretion is somatostatin. Somatostatin, acting via ssTR2 receptors, exerts a tonic paracrine inhibitory influence on the secretion of gastrin, histamine, and acid secretion. Calcitonin gene-related peptide, adrenomedullin, amylin, atrial natriuretic peptide, and pituitary adenylate cyclase-activating polypeptide all stimulate somatostatin secretion and thus inhibit acid secretion. HK-ATPase, the proton pump of the parietal cell, is stored within cytoplasmic tubulovesicles during the resting state, but during stimulation, it is shuttled to the canalicular membrane by a poorly understood mechanism that probably involves soluble N-ethylmaleimid- sensitive factor attachment protein receptor proteins. The proton pump inhibitor, pantoprazole, is unique in that it binds cysteine 822, located deep within the membrane domain of the alpha-subunit. The difficulty that reducing agents, such as glutathione, have in reaching cysteine 822 may be responsible for the longer half- time for acid recovery observed with pantoprazole. Hypergastrin-emia, induced by proton pump inhibitors, enhances expression of cyclooxygenase-2 and hence prostaglandins within parietal cells, a feedback pathway that may protect the stomach against acid-induced damage. Summary: In the past year, significant advances have been made in understanding of the regulation of gastric acid secretion. Ultimately, these advances should lead to improved therapies to prevent and treat acid-related disorders. Gastric acid secretion must be precisely controlled at a variety of levels to prevent disease caused by hyperchlorhydria and hypochlorhydria. The mechanisms include neural (central and peripheral), hormonal, paracrine, and intracellular pathways that operate in concert to switch acid secretion on during ingestion of a meal and off during the interdigestive period. A better understanding of the physiology of acid secretion in health and disease should eventually lead to improved therapies to prevent and treat acid-related disorders.

Andres E, Perrin AE, Demangeat C. The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients. Eur J Intern Med. 2003 Jul;14(4):221-226. Background: To date, only case reports or small studies have documented the syndrome of food-cobalamin malabsorption in specific populations of patients or situations. In this paper, we present the data from 80 unselected patients with cobalamin deficiency related to food-cobalamin malabsorption. Methods: We studied 80 patients with well-established food-cobalamin malabsorption who were extracted from an observational cohort study (1995-2000) of 127 consecutive patients with cobalamin deficiency and who were followed in a department of internal medicine. Results: The median age of patients was 66 years and the female to male ratio was 1.2. The mean hemoglobin level was 113+/-27 g/l (range 32-159 g/l) and the mean erythrocyte cell volume was 95.4+/-12.3 fl (range 55-140 fl). Mean serum vitamin B12 and homocysteine levels were 153+/-74 pg/ml (range 35-200 pg/ml) and 20.6+/-15.7 mumol/l (range 8-97 mumol/l), respectively. The main clinical findings noted were peripheral neuropathy (46.2%), stroke (12.5%), confusion or dementia (10%), asthenia (18.7%), leg edema (11.2%), and digestive disorders (7.5%). The commonest associated conditions were atrophic gastritis (39%) with evidence of Helicobacter pylori infection (12.2%) and alcohol abuse (13.7%). Three patients had Sjogren's syndrome and one had systemic sclerosis. Ten percent of all patients were on long-term metformin (10%) and 7.5% on acid-suppressive drugs. Correction of the serum vitamin B12 levels and hematological abnormalities was achieved equally well in all patients treated with either intramuscular or oral crystalline cyanocobalamin. Conclusion: This study suggests that food-cobalamin malabsorption may be the leading cause of vitamin B12 deficiency in adults. As other studies have also reported, the condition is often associated with neuro-psychiatric findings and with several other conditions. Oral and parenteral cobalamin appear to be equally effective in correcting serum B12 levels and hematological abnormalities and, in many cases, they also relieve symptoms.

8 Filioussi K, Bonovas S, Katsaros T. Should we screen diabetic patients using biguanides for megaloblastic anaemia? Aust Fam Physician. 2003 May;32(5):383-4. Background: Patients taking biguanides on a continuous basis sometimes develop vitamin B12 deficient megaloblastic anaemia. The prevalence of this side effect has not been estimated. Methods: We screened 600 patients with type 2 diabetes treated with biguanides (phenformin or metformin) for a mean of 11.8 years (SD: 3.6 years) with complete blood counts, red cell indices and red cell morphology. If this showed macrocytosis, we measured total serum vitamin B12 and antiparietal cells antibodies (APCA). Patients with macrocytosis and low serum vitamin B12 levels were treated with cyanocobalamin 1 mg injection daily for seven days. Results: 54 (9%) of the patients had megaloblastic anaemia with low serum total vitamin B12 levels, only three (0.5%) also had abnormally raised APCA. All 54 patients responded to cyanocobalamin with a reticulocyte increase within 10 days. Conclusion: Annual screening for megaloblastic anaemia in patients on long term treatment with biguanides may be worthwhile. The anaemia is easily remediable and does not necessitate withdrawal of the drug.

Fujita H, Narita T, Yoshioka N, Hosoba M, Ito S. A case of megaloblastic anemia due to vitamin B12 deficiency precipitated in a totally gastrectomized type II diabetic patient following the introduction of metformin therapy. Endocr J. 2003 Aug;50(4):483-4. No abstract available.

Andres E, Noel E, Kaltenbach G, Perrin AE, Vinzio S, Goichot B, Schlienger JL,.Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002 Oct 28;162(19):2251-2. No abstract available

Heine RJ. Does the vitamin B12 deficiency caused by metformin disappear again after stopping this drug? Ned Tijdschr Geneeskd. 2002 Nov 16;146(46):2213-4. Dutch. No abstract available.

Desouza C, Keebler M, McNamara DB, Fonseca V. Drugs affecting homocysteine metabolism: impact on cardiovascular risk. Drugs. 2002;62(4):605-16.

Gilligan MA. Metformin and vitamin B12 deficiency. Arch Intern Med. 2002 Feb 25;162(4):484-5. No abstract available. Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother. 2002 May;36(5):812-6. Objective: To report a case of vitamin B(12) deficiency associated with long-term use (approximately 4 1/2 y) of histamine(2) (H(2))-receptor antagonists and a proton-pump inhibitor (PPI) in a patient with gastroesophageal reflux. Case Summary: A 78-year-old nonvegetarian white woman with symptomatic gastroesophageal reflux (GER) was started on cimetidine 300 mg 4 times daily in February 1990 and took various other antisecretory medications over the course of the next 4 1/2 years. She had a normal serum vitamin B(12) concentration of 413 pg/mL in August 1992. In June 1994, her serum vitamin B(12) concentration was found to be in the low normal range at 256 pg/mL. Biochemical markers of vitamin B(12)-dependent enzyme activity were measured at that time, and methylmalonic acid (MMA) and homocysteine (HCYS) were elevated at 757 nmol/L and 27.3 micromol/L, respectively. Serum folate was within the normal range at 4.9 ng/mL, and serum creatinine was slightly elevated at 1.4 mg/dL. MMA and HCYS concentrations decreased dramatically with oral replacement of vitamin B(12) 1000 microg/d, which confirmed vitamin B(12) deficiency. Oral replacement also demonstrated that the woman was able to adequately absorb nonprotein-bound vitamin B(12) from the gastrointestinal tract, suggesting that her deficiency was a result of food- cobalamin malabsorption. The accumulation of MMA and HCYS was not a consequence of renal dysfunction, since both metabolites dramatically decreased with vitamin B(12) replacement. Discussions: Malabsorption of dietary protein-bound vitamin B(12) has been demonstrated with the use of H(2)-receptor antagonists and PPIs. One previous case report of vitamin B(12) deficiency resulting from long-term use of omeprazole has been published. The malabsorption of dietary vitamin B(12) is thought to be a result of its impaired release from food protein, which requires gastric acid and pepsin as the initial step in the absorption process. Conclusions: The use of H(2)-receptor antagonists and/or PPIs may impair the absorption of protein-bound dietary vitamin B(12) and could contribute to the development of vitamin B(12) deficiency with prolonged use. Patients taking these medications for extended periods of time, particularly >4 years, should be monitored for vitamin B(12) status.

CB comment: Italics above are mine. I would have suggested moving to simply prevent it with appropriate supplementation of B12, since monitoring regularly misses large numbers of deficient people.

Mitchell SL, Rockwood K. The association between antiulcer medication and initiation of cobalamin replacement in older persons. J Clin Epidemiol. 2001 May;54(5):531-4. As chronic use of antiulcer medications might predispose older persons to cobalamin deficiency, we studied participants (> 65 years) in the clinical examination of the Canadian Study of Health and Aging to test the association between the use of an antiulcer medication (histamine-2 blocker or proton pump inhibitor) at baseline with initiation of cobalamin replacement during the 5 year follow-up period. Of 1054 eligible subjects, 125 (11.7%) were taking an antiulcer medication at baseline. At follow-up, 49 (4.6%) had started cobalamin replacement. Antiulcer medication use at baseline was significantly associated with the initiation of cobalamin therapy (odds ratio 2.56, 95% confidence interval 1.30-5.05), even after adjusting for age, gender and institutional residence (odds ratio 2.61, 95% confidence interval 1.31- 5.23). There is an independent association between the use of antiulcer medication and initiation of cobalamin therapy. While the relationship is not unambiguously causal, this finding underscores the need for judicious prescribing of antiulcer medications for older persons.

9 CB comment: Italics above are mine. While judicious prescribing is always appropriate it does not prevent B12 deficiency in the folks who are (judiciously) found to need to use proton pump inhibitors. Why can’t we mention the idea of preventing the problem with appropriate supplementation?

Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002 Oct 28;162(19):2251-2. No abstract available. ter Heide H, Hendriks HJ, Heijmans H. Are children with cystic fibrosis who are treated with a proton-pump inhibitor at risk for vitamin B(12) deficiency? J Pediatr Gastroenterol Nutr. 2001 Sep;33(3):342-5. Background: In a recent study, the authors demonstrated the beneficial effect of proton-pump inhibitors (PPI) on fat malabsorption and bone mineral content in children with cystic fibrosis (CF). Prolonged use of PPI could result in vitamin B(12) deficiency as a consequence of impaired release of vitamin B(12) from food in a nonacid environment. The aim of this study was to evaluate the vitamin B 12 status of CF patients either treated with a PPI or not by measuring vitamin B(12) and homocysteine blood levels, the latter being a sensitive indicator of vitamin B(12) deficiency. Methods: The study population consisted of 20 CF patients, 11 patients treated with a PPI for at least 2 years and 9 patients not treated with a PPI, and 10 healthy, age-matched control participants. Homocysteine blood levels were measured by high-performance liquid chromatography, and vitamin B(12) levels were measured by a competitive protein-binding assay. Results: Vitamin B(12) levels were significantly higher in both CF groups compared with the control participants (PPI+, P = 0.02; PPI-, P = 0.009). There was no significant difference in vitamin B(12) levels between both CF groups. Homocysteine levels were normal and similar in all groups. Conclusions: Cystic fibrosis patients treated with a PPI for at least 2 years show no signs of vitamin B(12) deficiency.

CB comment: Italics above are mine. It would have been very surprising to have found B12 deficiency in this situation, since children with CF are routinely supplemented with higher dose supplemental vitamins. So, rather than being interpreted as evidence that the proton pump inhibitors do not impair vitamin B12 absorption from food, it should be interpreted as showing that adequate provision of vitamin B12 in supplement form can protect against deficiency among persons using these medications.

Jolobe OM. Prevalence of hypochromia (without microcytosis) vs microcytosis (without hypochromia) in iron deficiency. Clinical & Laboratory Haematology. 22(2):79-80, 2000 Apr. The usefulness of hypochromia (MCH deficiency was examined in 365 geriatric patients aged 67-96 years with either one or both or these characteristics. Of these, 201 proved to be iron deficient with a serum ferritin of 18 mcg/l. There was a highly significant difference (P < 0.001) between the proportion of iron deficient patients with a mean corpuscular haemoglobin (MCH) < 26 pg (in the presence of a mean corpuscular volume (MCV) > 80 (fl) vs. counterparts with MCV < 80 fl (in the presence of MCH >26 pg). Fifteen per cent of the 201 iron deficient subjects were also shown to have coexisting vitamin B12 deficiency. There was a comparable (16%) prevalence of this haematinic deficiency in the subgroup of 31 iron deficient patients with MCH < 26 pg in the presence of MCH >80 fl.

CB comment: Italics above are mine. This study shows that megaloblastic anemia as a marker of B12 deficiency can be masked by a concomitant iron deficiency, thus making its usefulness as a marker even less reliable. It is a very poor measure to use for screening in any case, since megaloblastic anemia is a very late-appearing symptom of vitamin B12 deficiency, and significant harm can be done long before the red cell size is affected.

Side effects.Calcium supplements help metformin users absorb vitamin B12. Treatmentupdate. 2000 Oct;12(7):6-7. No abstract available.

Bauman WA, Shaw S, Jayatilleke E. .Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000 Sep;23(9):1227-31.

Pautas E. Cherin P. De Jaeger C. Godeau P. Vitamin B 12 deficiency in the aged. Presse Medicale. 28(32):1767-70, 1999 Oct 23. A COMMON CONDITION: Vitamin B12 deficiency is common in the elderly. Search for deficiency should be undertaken whenever the clinical situation could lead to vitamin deficiency whether macrocytic anemia is present or not as its development may come late. PATHOPHYSIOLOGICAL IMPLICATIONS: The potential relationships between degenerative neuropsychiatric disorders and cerebrovascular or cardiovascular disease, mainly via hyperhomocysteinemia, emphasize the importance of searching for vitamin B12 deficiency in the elderly. SPECIFIC CAUSES: In the elderly, it is important to recognize specific causes of vitamin B12 deficiency, mainly resulting from vitamin malabsorption.

10 Bopp-Kistler I. Ruegger-Frey B. Grob D. Six P. Vitamin B12 deficiency in geriatrics. Schweizerische Rundschau fur Medizin Praxis. 88(45):1867-75, 1999 Nov 4. Cobalamin deficiency increases with advancing age. The cut-off point of serum concentration should be raised, because many elderly people with "normal" serum vitamin B12 concentrations are metabolically deficient in cobalamin. The measurement of the metabolites homocysteine and/or methylmalonic acid is recommended. Cobalamin deficiency may result in a variety of atypical symptoms. Hematological changes typical of megaloblastic anemia are absent in a majority of patients with neuropsychiatric disorders. Generally underlying pernicious anemia is not the main cause of cobalamin deficiency in the elderly. Protein- bound cobalamin malabsorption due to atrophic gastritis with hypo- or achlorhydria is a common cause of cobalamin deficiency in elderly people. An important manifestation of cobalamin deficiency is cognitive impairment. Much controversy exists on the subject of the association of dementia of the Alzheimer type with cobalamin deficiency. In several studies dementia has been related to low serum cobalamin levels. Physicians should be liberal of cobalamin therapy. The window of opportunity for effective intervention may be as short as one year from the onset of medical symptoms. At last a compilation of recommendations is given.

Bradford GS. Taylor CT. Omeprazole and vitamin B12 deficiency. Annals of Pharmacotherapy. 33(5):641-3, 1999 May. The mainstay for cobalamin deficiency is correction of the underlying disorder and replacement therapy. Because the defect is often one of absorption, parenteral or intranasal routes are recommended. In most cases, replacement therapy is all that is needed. The vitamin preparation most commonly used is cyanocobalamin (also called vitamin B12), which has no known physiologic role but instead is converted to a biologically active form before it can be used by tissues. The studies reviewed in this article clearly show that omeprazole therapy will decrease the absorption of vitamin B12 by preventing its cleavage from dietary proteins. However, these data are insufficient to infer that clinically significant deficiency will occur over time. In fact, some of the studies suggest that the simple addition of juices or other acidic drinks into the diet may dramatically increase cobalamin absorption. Clearly, well-designed clinical trials are needed to evaluate this theory over an extended follow-up period to determine the clinical significance of omeprazole-associated vitamin B12 deficiency and possibly identify patients at risk for deficiency. In conclusion, the possibility of dietary vitamin B12 malabsorption should be considered in patients receiving chronic omeprazole treatment and presenting with signs and symptoms of deficiency. All healthcare workers should be made aware of the potential clinical complications of omeprazole-associated vitamin B12 deficiency since it may go unrecognized and is easily corrected. This is particularly relevant for elderly patients with poor dietary intake of vitamin B12, impaired vitamin B12 stores, and certain gastrointestinal disorders.

CB comments from an earlier version of references regarding the above report:

I see a problem with this plan. 1. They note that B12 deficiency often goes unrecognized. 2. In spite of this, the action suggested is to “watch for signs and symptoms of deficiency” before doing anything, since not everyone may be in fact deficient. 3. This is going to miss a bunch of folks. Also, some of the “signs and symptoms” are relatively late- appearing symptoms like macrocytosis. By then, one can no longer efficiently make DNA, and some neurologic damage may not be totally reparable. 4. Why not simply assure adequacy by suggesting that patients on this drug simply take vitamin B12 in a cheap and readily available form that dos not require acid for absorption (e.g. in a multivitamin – no protein molecule attached) and prevent the whole thing? It is cheap, safe and helpful in a bunch of other situations at the same time. I don’t get it. 5. They note that they will have to wait a number of years to see how many people actually become deficient, so the “present study” cannot answer this question. True. But just because this study is unable to measure a potentially seriously negative clinical outcome, I am not sure that waiting to see how many people are injured down the road before suggesting benign supplementation is the moral high ground here. Prevention is a snap and the potential injury associated with deficiency is too great.

Baik HW. Russell RM. Vitamin B12 deficiency in the elderly, Annual Review of Nutrition. 19:357-77, 1999. Vitamin B12 deficiency is estimated to affect 10%-15% of people over the age of 60, and the laboratory diagnosis is usually based on low serum vitamin B12 levels or elevated serum methylmalonic acid and homocysteine levels. Although elderly people with low vitamin B12 status frequently lack the classical signs and symptoms of vitamin B12 deficiency, e.g. megaloblastic anemia, precise evaluation and treatment in this population is important. Absorption of crystalline vitamin B12 does not decline with advancing age. However, compared with the younger population, absorption of protein-bound vitamin B12 is decreased in the elderly, owing to a high prevalence of atrophic gastritis in this age group. Atrophic gastritis results in a low acid-pepsin secretion by the gastric mucosa, which in turn results in a reduced release of free vitamin B12 from food proteins. Furthermore, hypochlorhydria in atrophic gastritis results in bacterial overgrowth of the stomach and small intestine, and these bacteria may bind vitamin B12 for their own use. The ability to absorb crystalline vitamin B12 remains intact in older people with atrophic gastritis. The 1998 recommended daily allowance for vitamin B12 is 2.4 micrograms, but elderly people should try to obtain their vitamin B12 from either supplements or fortified foods (e.g. fortified ready-to-eat breakfast cereals) to ensure adequate absorption from the gastrointestinal tract. Because the American food supply is now being fortified with folic acid, concern is increasing about neurologic exacerbation in individuals with marginal vitamin B12 status and high-dose folate intake.

11 Shaw JT, McWhinney B, Tate JR. Plasma homocysteine levels in indigenous Australians. Med J Aust. 1999 ;170(1):19- 22. Nutrition & Health. 12(4):215-26, 1998. Vitamin B12 deficiency damages nerve cells and aggravates nervous system disorders even in the absence of evidence of anaemia. Prevalence of B12 deficiency increases with age especially over 65 and is frequently associated with Alzheimer's disease. Recent American surveys record a higher prevalence of B12 deficiency and of undiagnosed and untreated pernicious anaemia in the elderly than reported earlier. B12 deficiency is also reported to be a risk factor for heart disease, stroke and accelerated ageing.

Nilsson-Ehle H. Age-related changes in cobalamin (vitamin B12) handling. Implications for therapy. Drugs & Aging. 12(4):277-92, 1998 Apr Cobalamin (vitamin B12) deficiency is more common in the elderly than in younger patients. This is because of the increased prevalence of cobalamin malabsorption in this age group, which is mainly caused by (autoimmune) atrophic body gastritis. Cobalamin supplementation is affordable and nontoxic, and it may prevent irreversible neurological damage if started early. Elderly individuals with cobalamin deficiency may present with neuropsychiatric or metabolic deficiencies, without frank macrocytic anaemia. An investigation of symptoms and/or signs includes the diagnosis of deficiency as well as any underlying cause. Deficiency states can still exist even when serum cobalamin levels are higher than the traditional lower reference limit. Cobalamin-responsive elevations of serum methylmalonic acid (MMA) and homocysteine are helpful laboratory tools for the diagnosis. The health-related reference ranges for homocysteine and MMA appear to vary with age and gender. Atrophic body gastritis is indirectly diagnosed by measuring serum levels of gastrin and pepsinogens, and it may cause dietary cobalamin malabsorption despite a normal traditional Schilling's test. The use of gastroscopy may also be considered to diagnose dysplasia, bacterial overgrowth and intestinal villous atrophy in healthy patients with atrophic body gastritis or concomitant iron or folic acid deficiency. Elderly patients respond to cobalamin treatment as fully as younger patients, with complete haematological recovery and complete or good partial resolution of neurological deficits. Chronic dementia responds poorly but should, nevertheless, be treated if there is a metabolic deficiency (as indicated by elevated homocysteine and/or MMA levels). Patients who are at risk from cobalamin deficiency include those with a gastrointestinal predisposition (e.g. atrophic body gastritis or previous partial gastrectomy), autoimmune disorders [type 1 (insulin- dependent) diabetes mellitus and thyroid disorders], those receiving long term therapy with gastric acid inhibitors or biguanides, and those undergoing nitrous oxide anaes-thesia. To date, inadequate cobalamin intake has not proven to be a major risk factor. Intervention trials of cobal-amin, folic acid and pyridoxine (vitamin B6) in unselected elderly populations are currently under way. [Ref: 165]

Aarsand AK, Carlsen SM. Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment. J Intern Med. 1998 Aug;244(2):169-74.

Riordan SM. McIver CJ. Wakefield D.. Small intestinal bacterial overgrowth in the symptomatic elderly. American Journal of Gastroenterology. 92(1):47-51, 1997 Jan. OBJECTIVE: 1) To determine the prevalence of small intestinal overgrowth with colonic-type bacteria in symptomatic elderly subjects, particularly those without important "clues" such as clinically apparent predisposition or vitamin B12 deficiency, and 2) to investigate defense mechanisms such as gastric acidity, small intestinal motility, and luminal IgA in this setting. METHODS: Fifty-two symptomatic subjects without vitamin B12 deficiency or clinically apparent predisposition to bacterial overgrowth or disturbed mucosal immunity, including 22 subjects > or = 75 yr old, underwent culture of small intestinal luminal secretions. Indicator paper was used to measure fasting gastric pH. The presence of bacteria of confirmed nonsalivary origin in small intestinal secretions served as an index of small intestinal dysmotility. Small intestinal luminal IgA concentrations were measured by radial immunodiffusion. RESULTS: Small intestinal overgrowth with colonic-type flora was not present in any subject investigated for dyspepsia, irrespective of age. In subjects with chronic diarrhea, anorexia, or nausea, overgrowth with colonic-type flora (Enterobacteriaceae) was present in 0/12 (0%), 1/10 (10.0%), and 9/14 (64.3%) subjects aged < 50 yr, 50-74 yr, and > or = 75 yr, respectively. Enterobacteriaceae were not concurrently recovered from saliva of any subject > or = 75 yr old with small intestinal overgrowth with these bacteria. Fasting hypochlorhydria was present in only 1/9 (11.1%) such subjects. Luminal IgA concentrations were significantly greater in subjects > or = 75 yr old with bacterial overgrowth than in culture-negative subjects (p < or = 0.003). CONCLUSIONS: Small intestinal overgrowth with colonic-type bacterial should be considered in subjects > or = 75 yr old with chronic diarrhea, anorexia, or nausea, even in the absence of clues such as clinically apparent predisposition or vitamin B12 deficiency. Small intestinal dysmotility, rather than fasting hypochlorhydria or mucosal immunosenescence, probably is responsible for the prevalence of bacterial overgrowth in this group.

12 Sanford Medical Center

Aunt Cathy's Guide To: Aunt Cathy Vitamin B12 Absorption Cathy Breedon PhD, RD, CSP, FADA Clinical/Metabolic Nutrition Specialist (not scientifically correct) Sanford Medical Center and UND School of Medicine, Fargo, ND

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Health situations that can impair vitamin B12 absorption:

1. Having inadequate stomach acid due to aging (achlorhydria) or the use of PPI acid blocking medications for gastroesophageal reflux means that the protein glob cannot be removed and the B12 is too big to absorb. Solution: The form in vitamin pills is just the vitamin B12 without the protein glob, so the problem is eliminated.

2. Failure to make or use intrinsic factor in the stomach (as in the genetic condition pernicious anemia or in people with stomach removal, stomach damage or gastric bypass surgery.) Solution: The “handle” is not available to efficiently absorb B12 regardless of the molecular size. This requires an alternate route of administration, such as B12 shots or supplement forms that are inhaled or sublingual.

3. The diabetes medication Metformin (Glucophage) impairs vitamin B12 absorption in the intestine. Solution: A generous intake can help, but vitamin B12 levels should be monitored for anyone on this medication, especially with long term use. Again, looking at “Mean Cell Volume” on a blood test will not detect a problem soon enough. At least a vitamin B12 serum level should be monitored.

4. Injury to terminal ileum can impair absorption as well: bacterial overgrowth, inflammatory bowel disease, poorly controlled celiac disease, surgical removal, etc. Solution: This may require an alternate route of administration, such as B12 shots or supplement forms that are inhaled or sublingual. MeritCare Medical Center 10/2010

Aunt Cathy’s Guide:

Vitamin D: A Quick Review Aunt Cathy Cathy Breedon PhD, RD, CSP, FADA of Forms, Labs and Other Prenatal/Pediatric Nutrition Specialist Things People Have Asked Clinical Nutrition Specialist MeritCare Medical Center, Fargo, ND Me About Recently and UND School of Medicine

I regularly get questions about some of the confusing aspects about nutrition information in the news. Vitamin D issues can be especially complex and crazy- making. But there is a new understanding of the international epidemic nature of vitamin D deficiency. Additionally, we have a rapidly-expanding understanding of its critical role in the functioning of over 200 tissues and its role as a factor in an ever increasing number of serious health problems (like cancer, heart disease, diabetes, arthritis, multiple sclerosis, lupus, fibromyalgia, immune compromise and more.) Health care professionals need to have this sorted out more now than ever.

[Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008 Apr;87(4):1080S-6S. Hypovitaminosis D among healthy children in the United States: a review of the current evidence. Arch Pediatr Adolesc Med. 2008 Jun;162(6):513-9. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med. 2008 Jun;162(6):505-12. Lots more references are in my other papers.]

This little paper evolved from a question emailed to me recently from a dietitian. As I was typing away with an answer, it occurred to me that other health professionals might find this information helpful as well. And so … a new handout is born!

For more information about vitamin D or other nutrition issues, just Google my name and something pops up that says “Cathy Breedon’s Handouts” on the Sanford Health website. opics will pop up, including:

“My Current Top Five Easy Ways to Improve Your Family’s Nutrition (subject to change at any moment! ☺)” This paper addresses vitamin D as one of the Top Five issues, but in much less detail than the Vitamin D paper described above. It is designed for those who want just a cut-to-the-chase version of why this matters so much and what are we supposed to do about it.

As always, my handouts are intended to provide some summarizing of interesting nutrition information in the news. They are not intended to take the place of the guidance and recommendations of an individual’s health care providers.

1 And of course everything is way more complicated than my descriptions suggest, but this is just an attempt at a nice simplified discussion trying to sort things out sufficiently to give direction in thinking about functional applications and doing some good.

Here was the original inspiring question:

“What are all those different forms of vitamin D, what factors affect absorption or utilization, what are the right tests to order and how should they be interpreted … etc. etc.” My rambling response:

First, here are two areas of two big distinctions each in the vitamin D world.

(So what is NOT confusing about all this?!):

1. There are two major forms of vitamin D that come into the body as food or supplements: Cholecalciferol (D3) Ergocalciferol (D2)

2. There are two major forms of vitamin D floating around in the body: 25-hydroxycholecalciferol (25-hydroxyD) and 1, 25-dihydroxycholecalciferol (1,25-dihydroxyD)

Here’s a look at all four:

1. Food and Supplement Vitamin D 2. Forms of Vitamin D Floating Sources Coming in from Outside Around in the Body

Ergocalciferol Vitamin D-2 25-hydroxycholecalciferol

in plants and some supplements also called Calcidiol; a storage form of circulating non-activated vitamin D

Cholecalciferol Vitamin D-3 1,25-dihydroxycholecalciferol

in animal foods and some supplements. also called Calcitriol; the active steroid This is also the kind one makes in the hormonal form of vitamin D skin from exposure to ultraviolet light.

2 The difference between the plant source vs animal source (ergocalciferol D2 vs cholecalciferol D3)

The kind we make (out of 7-dehydrocholesterol in the skin + UV light) and the kind we use in the body is the chole type (because we are animals.) But we can make chole out of ergo so the questions are NOT about ABSORPTION (i.e. getting it into the body from out there in the intestinal lumen) but about whether the same number of mg or iu's of ergo is equal to the same amount of chole.

At the moment there is no official differentiation, but there have been reports that the chole form may be superior in certain instances especially. For example, in a recent study of elderly people with vitamin D deficiency, the cholecalciferol and ergocalciferol forms were compared as agents to correct the deficiency. They found that cholecalciferol was almost twice as potent as ergocalciferol in raising serum 25(OH)D, when administered either by mouth or as an injection. [Short and Long Term Variations in Serum Calciotrophic Hormones after a Single Very Large Dose of Ergocalciferol (Vitamin D2) or Cholecalciferol (Vitamin D3) in the Elderly. J Clin Endocrinol Metab. 2008 May 20. ]

Other studies have shown correction of vitamin D deficiency using very high dose ergocalciferol supplements, but they generally are not studied in terms of efficacy in comparison with using chole … just whether or not they correct the deficiency. Since the ergocalciferol must be converted to cholecalciferol, the simple solution -- in my non-opinionated opinion ☺ -- is to just get the “chole” type and quit worrying about that particular issue. Very high-dose ergocalciferol is effective for correcting vitamin D deficiency in children and young adults with cystic fibrosis. J Cyst Fibros. 2009 May 14.

One other concern would be the healthiness of the liver, since the conversion occurs there. If a person has a very sick liver or a very immature one (like preterm infants), it would be prudent to provide the form that does not require conversion.)

Absorption is not usually the major problem with vitamin D unless a person has a condition that makes one have significant fat malabsorption ... like steatorrhea in Cystic Fibrosis, as a major example. Anything that makes people malabsorb fat will make them malabsorb the fat soluble vitamins (A, D, E and K) as well.

For other people, in some comparisons the gel caps and liquids have somewhat better absorption than solid tablets, and in general, taking the supplements daily appears to be more effective than weekly or monthly supplementation regimens.

3 Taking the vitamin D supplements with the largest meal of the day also appears to enhance absorption. However, in general, if the amount provided is generous these last two issues become far less important. The biggest problem is not these gradations of efficiency of absorption but simply failure to provide a generous amount sufficient to assure adequacy.

The biggest problems with supplementation regimens are that:

1) the amount of vitamin D being supplemented is often far too low to correct deficiency, let alone bring about rapid correction of deficiency; and

2) people simply don’t take them reliably.

Because of the poor adherence to therapeutic or maintenance regimens, some other approaches are being tried. For example, a one-time dose of 300,000 iu has been shown to be effective in correcting severe deficiency without negative effects.

Taking vitamin D with the largest meal improves absorption and results in higher serum levels of 25-hydroxyvitamin D. J Bone Miner Res. 2010 Feb 8. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009 Oct 1;339:b3692. Efficacy and safety of oral continuous low-dose versus short-term high-dose vitamin D: a prospective randomised trial conducted in a clinical setting. Med J Aust. 2010 Jun 21;192(12):686-9. Are commonly recommended dosages for vitamin D supplementation too low? Vitamin D status and effects of supplementation on serum 25-hydroxyvitamin D levels-an observational study during clinical practice conditions. Osteoporos Int. 2010 Jun 17. Clinical responses to a mega-dose of vitamin D3 in infants and toddlers with vitamin D deficiency rickets. J Trop Pediatr. 2010 Feb;56(1):19-26. Vitamin D: what is an adequate vitamin D level and how much supplementation is necessary? Bone. 2009 Oct;45(4):747-9. Best Pract Res Clin Rheumatol. 2009 Dec;23(6):789-95. Combination of bolus dose vitamin D with routine vaccination in infants: a randomised trial. Singapore Med J. 2010 May;51(5):440-5. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010 Jun 8;74(23):1852-9. Cholecalciferol loading dose guideline for vitamin D-deficient adults. Eur J Endocrinol. 2010 Apr;162(4):805-11. Vitamin D insufficiency and effect of cholecalciferol in children with chronic kidney disease. Pediatr Nephrol. 2010 Sep 25. Effect of high dose ergocalciferol in chronic kidney disease patients with 25-hydroxyvitamin D deficiency. J Med Assoc Thai. 2010 Aug;93(8):885-91.Low vitamin D status: definition, prevalence, consequences, and correction. Endocrinol Metab Clin North Am. 2010 Jun;39(2):287-301 Vitamin D intake needed to maintain target serum 25-hydroxyvitamin D concentrations in participants with low sun exposure and dark skin pigmentation is substantially higher than current recommendations. J Nutr. 2010 Mar;140(3):542-50. A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases. Cancer. 2010 Jan 15;116(2):284-91.Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol. Bone. 2009 Nov;45(5):870-5. Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents. Osteoporos Int. 2008 May;19(5):663-71.

I am including an abstract here of a very important recent report that evaluated randomized double blind studies and addressed the question of how much vitamin D supplementation was needed to achieve health targets for risk of falls, fractures, cardiovascular disease and color cancer. It also addresses the issue of the safety of these levels. The authors are all very well known and respected researchers:

4 Benefit-risk assessment of vitamin D supplementation. Osteoporos Int. 2009 Dec 3. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC.

Current intake recommendations of 200 to 600 IU vitamin D per day may be insufficient for important disease outcomes reduced by vitamin D. INTRODUCTION: This study assessed the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any associated risk.

METHODS AND RESULTS: Based on double-blind randomized control trials (RCTs), eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant dose-response relationship between higher-dose and higher achieved 25(OH)D and greater fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for 700 to 1000 IU vitamin D per day or mean 25(OH)D between 75 and 110 nmol/l (30-44 ng/ml).

Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110 nmol/l).

In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000 IU per day or achieved 25(OH)D up to 643 nmol/l. Mean levels of 75 to 110 nmol/l were reached in most RCTs with 1,800 to 4,000 IU vitamin D per day without risk.

CONCLUSION: Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000 IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the population.

In the world of renal disease and chemotherapy adjuncts, however, there are other specialized vitamin D analogs available and questions in the professional literature about the relative efficacy of various injectable forms of D2 vs D3, etc. This is beyond the scope of this brief discussion about the most typical nutrition-related issues encountered by health professionals.

1. The difference between two lab values: 25-hydroxy D vs 1,25-dihydroxy D. This is not about any food forms or any of that business in #1 above. It is about what one does with vitamin D in the body.

The 25-hydroxy form is the non-activated-yet-but-stored-and-available-to-be- used form. (And that’s just its nickname!) It is made in the liver from cholecalciferol

5 (obtained from any source: food, supplement, skin production) by attaching a hydroxyl group (an OH group) at the #25 carbon of the molecule.

This form (25-hydroxycholecalciferol or 25-hydroxyD,) is the storage form that we ordinarily test to check for plain old “deficiency vs adequacy” in the person's body. (I am using the simple letter D to stand for the word cholecalciferol in more and more of these descriptions because it is tedious to keep writing it out.)

As you know, we health professional types need to begin a habit of regularly checking this in everybody because just counting up the amount we think people took in misses the boat in most circumstances. I think an automatic 'standing orders' scenario would be very informative and helpful. I just found eight more people this week who were overtly deficient in spite of what "should have been enough" vitamin D. You can only know for sure by checking their blood.

When we need the active hormonal form (for one of the 200 different tissues with vitamin D receptors that are looking for it,) the 25-hydroxyD storage form is sent to the kidney and another hydroxyl group is attached there at the #1 carbon on the molecule. The product ... the active hormonal form of vitamin D ... is 1,25- dihydroxycholecalciferol.

This is not something one would ordinarily check as a blood test unless the person had some sort of potentially vitamin-D related symptoms in spite of a good intake of vitamin D. It would usually be done to identify people with kidney disease who have lost the ability to make the 1,25 vitamin D. There is also a much smaller group of people who have an inborn error of vitamin D metabolism that results in the same problem. While this is likely to be rare, I have found this situation to exist in five out of five people for whom I asked to have it checked.

I certainly check this when their symptoms are unusual, such as extremely severe or rapidly progressing MS (e.g. in a 10-year-old.) Another time I might ask to have it checked is if the person has vitamin D deficiency symptoms but it has already been shown that their blood 25-hydroxyD level is OK. In that situation I know it is not simple inadequacy that is contributing to any problems.

Additionally, there are certain genetic factors that impair the utilization of vitamin D. For example, there are “polymorphisms” (different forms) of vitamin D receptors found on some people’s cells that contribute to having vitamin D related problems in spite of a good vitamin D intake and normal ability to activate it to the

6 active form. In other words, vitamin D hormone knocks on the door of a cell with a message but nobody answers the door. But this kind of metabolism problem is only a tiny part of the problem of vitamin D adequacy. Most folks just aren’t getting enough sun or enough vitamin D supplementation, so that is where we need to look first in order to identify problems and do some serious good.

7 So, a good order of thinking about this for a patient is:

First Get a regular 25-hydroxy D level (for EVERYBODY!!!) --- ideally annually in the winter -- and if it is low give them a therapeutic supplemental amount of vitamin D to get them up to normal. Then figure out a maintenance dose to switch to once subsequent tests show that the low level has been corrected. Also, it is wise not to assume it has been corrected after some prescribed number of doses. We really need to check it.

For many people, getting the level during the winter is most likely to pick up any inadequacy issues. A level drawn any time of year will help identify problems for people who are not regularly in the sun even in the summer. This includes a large number of people, for a variety of reasons.

I continue to hear every week from a surprising number of health professionals (including dietitians, physicians, pharmacists and nurses) who have had their levels checked after hearing me go on and on about the vitamin D deficiency problem. They had been startled to find that they were themselves vitamin D deficient. This is in spite of “eating right” and taking a multivitamin! What would be the likelihood of non–health-care-professionals also having this kind of problem?

Second If the person has good blood levels of 25-hydroxyD but still looks “suspicious” in terms of vitamin D-related conditions, then one might get a 1,25 D level to see if they have a metabolic defect in hydroxylation in the kidney or some other condition like kidney disease that is impairing production of the hormonal form. In that situation, one would utilize a special prescription form of supplemental vitamin D to get around the problem: the ready-to-go form of the active hormone 1,25-dihydroxyD which is usually ordered as calcitriol.

This problem is much less common than the problem of simple inadequacy of vitamin D, but I have found four individuals with this as the unrecognized basis of some very severe symptoms. These people were not kidney patients. That tells me that the problem is likely more common than we think but generally unrecognized.

Here is an example to illustrate why I think doing this in the order described above is potentially useful:

8 1. It was recently found in an observational study that pre-dialysis kidney patients who start earlier on calcitriol supplementation may have improved survival and quality of life, etc. (Arch Intern Med. 2008;168:397-403) compared with those who began to use it later. By early, they appeared to mean not waiting for severe deficiency symptoms to show up before providing it, or not waiting until the person had to go on dialysis because of kidney failure. This meshes nicely with another recent finding of an association between increased risk of death from all causes and low vitamin D status, including cardiovascular disease, and contribution of adequate vitamin D in decreasing the risk of progression to kidney disease in people with diabetes.

[E.g.: Vitamin D and chronic kidney disease. Ethn Dis. 2009 Autumn;19(4 Suppl 5):S5-8-11.Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD. Clin J Am Soc Nephrol. 2009 Sep;4(9):1523-8. 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008 Jun 9;168 (11):1174-80. Low serum levels of 25-hydroxyvitamin D predict fatal cancer in patients referred to coronary angiography. Cancer Epidemiol Biomarkers Prev. 2008 May;17(5):1228-33. Vitamin D, cardiovascular disease, and survival in dialysis patients. J Bone Miner Res. 2007 Dec;22 Suppl 2:V95-9. Can vitamin D reduce total mortality? Arch Intern Med. 2007 Sep 10;167(16):1709-10, 1730-37. ]

Interestingly, in the pre-dialysis study described above, apparently plain old 25- hydroxy D levels were not regularly evaluated, so although calcitriol was shown to be helpful in many ways for preventing deficiency consequences, it may NOT have been a kidney-related hydroxylation problem that needed the earlier intervention. It may have been just the same old unrecognized common inadequacy of vitamin D intake that was the limiting factor for many of these folks.

For many people with serious kidney disease, foods like milk and salmon are restricted. As these are about the only reliable and rich sources of vitamin D in our diet, simple inadequacy of vitamin D should not be an unexpected finding … if we check for it. This possibility was not addressed in the study, but I think it has important implications for patient care:

Although giving calcitriol (a significantly more expensive and prescription- only pharmacy product) was clearly associated with benefit in this situation, assuring vitamin D adequacy with generous plain old cheap vitamin D supplementation may have done the trick just as well for many of the people involved.

This is another argument for a regular planned 25-hydroxy D level check for everybody. We could save the big guns (calcitriol) for those who really need it. Additionally, as described in the report below, there is evidence that even folks for whom calcitriol IS actually needed, there are other roles for 25-hydroxy vitamin D

9 and therefore good reason to maintain that level in the safe and adequate range at the same time as providing ready-made calcitriol.

Vitamin D in Health and Disease. Clin J Am Soc Nephrol. 2008 Jun 4.

“Vitamin D functions in the body through both an endocrine mechanism (regulation of calcium absorption) and an autocrine mechanism (facilitation of gene expression). The former acts through circulating calcitriol, whereas the latter, which accounts for more than 80% of the metabolic utilization of the vitamin each day, produces, uses, and degrades calcitriol exclusively intracellularly.

In patients with end-stage kidney disease, the endocrine mechanism is effectively disabled; however, the autocrine mechanism is able to function normally so long as the patient has adequate serum levels of 25(OH)D, on which its function is absolutely dependent.

For this reason, calcitriol and its analogs do not constitute adequate replacement in managing vitamin D needs of such patients. Optimal serum 25(OH)D levels are greater than 32 ng/mL (80 nmol/L). The consequences of low 25(OH)D status include increased risk of various chronic diseases, ranging from hypertension to diabetes to cancer.

The safest and most economical way to ensure adequate vitamin D status is to use oral dosing of native vitamin D. (Both daily and intermittent regimens work well.) Serum 25(OH)D can be expected to rise by about 1 ng/mL (2.5 nmol/L) for every 100 IU of additional vitamin D each day. Recent data indicate that cholecalciferol (vitamin D3) is substantially more potent than ergocalciferol (vitamin D2) and that the safe upper intake level for vitamin D3 is 10,000 IU/d.”

The levels described as “normal” in many research studies set the level of insufficiency and deficiency at significantly lower levels than what appears to be needed for optimal health benefit. This accounts for some of the confusing research outcomes. For example, a study finding no benefit of supplemental vitamin D on some outcome in a population would not be surprising if only low levels of supplementation were tested. In most cases, blood levels were most often not evaluated to determine the success of the supplementation for achieving “adequacy.” Additionally, the ranges perceived to be “normal” were often set too low so that true comparisons of adequacy vs inadequacy did not take place…only gradations of inadequacy. In fact, one of my old books actually had two sets of “normal values” to evaluate vitamin D adequacy. The cut-off to use in winter was much lower because it was “average” and “expected” to have a much lower level during those months. It 10 is a classic illustration that just because something is average or expected does not mean it is good or safe. Live and learn … Here’s another report with some information about what serum vitamin D levels might be better indicators of adequacy:

Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.

“Recent evidence suggests that higher vitamin D intakes beyond current recommendations may be associated with better health outcomes. In this chapter, evidence is summarized from different studies that evaluate threshold levels for serum 25(OH)D levels in relation to bone mineral density (BMD), lower extremity function, dental health, risk of falls, admission to nursing home, fractures, cancer prevention and incident hypertension. For all endpoints, the most advantageous serum levels for 25(OH)D appeared to be at least 75 nmol/l (30 ng/ml) and for cancer prevention, desirable 25(OH)D levels are between 90-120 nmol/l (36-48 ng/ml). An intake of no less than 1000 IU (25 mcg) of vitamin D3 (cholecalciferol) per day for all adults may bring at least 50% of the population up to 75 nmol/l. Thus, higher doses of vitamin D are needed to bring most individuals into the desired range. While estimates suggest that 2000 IU vitamin D3 per day may successfully and safely achieve this goal, the implications of 2000 IU or higher doses for the total adult population need to be addressed in future studies

2. The risk of injury from overdose in an individual is much higher if the active hormone form is given instead of just a precursor form. This is analogous to the higher potential for injury from giving high dose retinol (an active hormonal form of vitamin A primarily in liver and some supplements) compared with high doses of the pre-cursor form of vitamin A, the orange pigment beta-carotene in fruits, vegetables and some supplements. [Remember that the upper level of safety of “regular” vitamin D is now described as a chronic intake of 10,000 iu/day. It is WAY less toxic than most of us were taught. “Therapeutic” levels to correct deficiency are often something like 50,000 iu/week for 8 weeks, or as described earlier, a one-time dose of 300,000 iu.]

2. Regularly monitoring 1,25-dihydroxyD levels would be a reasonable plan for folks with kidney disease so we can catch them when production just starts to decrease. That way we can intervene BEFORE they suffer the multiple severe consequences associated with inadequacy of this vital steroid hormone. I would also like to see a one-time-only 1,25-dihydroxy D level for people with autoimmune diseases like MS, arthritis, lupus, diabetes, etc., for reasons beyond the scope of this paper. (Details are available in the other handouts listed earlier.)

11

For additional information on these and other topics you can go to MeritCare’s website (www.meritcare.com) and find other articles in the “Aunt Cathy’s Guide to Nutrition” series.

Just type Cathy Breedon in the “search box” and a page comes up where you can click “Cathy Breedon’s Handouts.” -General nutrition for health (“Top Five Easy Ways to Improve Your Family’s Nutrition”)

-Specific health problems (such as diabetes, celiac disease, cancer, multiple sclerosis, hemochromatosis, epidermolysis bullosa, and others.)

-Pregnancy and infant nutrition

-Summaries providing much more detail about specific nutrients (such as iron, magnesium, vitamin D, vitamin K, B-vitamins, and different kinds of fat and oil.

12 MeritCare Medical Center

Aunt Cathy’s Guide to: 2/2010

Vitamin K -- Focus on the Vitamin K

and Warfarin/Coumadin Cathy Breedon PhD, RD, CSP, FADA Anticoagulant Drugs Issue Prenatal/Pediatric Nutrition Specialist Clinical Nutrition Specialist MeritCare Medical Center, Fargo, ND and UND School of Medicine This paper is in response to the many questions I get from health care professionals about the problem of actual vitamin K insufficiency in many people already using these drugs. It is a follow-up clarification of the drug-nutrient interaction issue only, and it is intended only for health care professionals who have read my more complete paper on many aspects of the vitamin K inadequacy problem:

“Aunt Cathy’s Guide to: Vitamin K --New Issues in Cardiovascular Health, Osteoporosis, Cancer of the Liver and Colon, Diabetes, Pregnancy & Varicose Veins.

—------Question 1:

“What should we tell people already on Coumadin/warfarin regarding vitamin K?”

My Answer:

Here's our problem ... overt vitamin K deficiency is (unfortunately) common in this population and quite often unrecognized because it is rarely evaluated, either by lab tests or dietary evaluations. A great many multivitamin supplements do not even include vitamin K because (until recently) it had been assumed to be provided in adequate amounts by intestinal bacteria. It is not even included in the list of nutrients in the “mypyramid.gov” diet information. It is not on our radar.

Many health professionals are totally unaware of this. Some automatically tell patients to quit taking their multivitamins without checking to see if the product even contains any vitamin K. This is clearly not benign for many reasons, many of which are explained in another paper:

“Aunt Cathy’s Guide: My Current Top Five Easy Ways to Improve Your Family’s Nutrition (subject to change at any moment! ☺)” Back to the topic: Normally dietitians and nurses are dead-set against allowing any actual vitamin deficiency diseases in their patients, and now that we know it is such a big problem, we want to fix it. But we are usually not in control of this situation.

It needs to be corrected because vitamin deficiency hurts people in several different ways, both related to the coagulation issue and also related to a number of other serious complications of inadequacy (arteriocalcinosis, liver and colon cancer, osteoporosis, diabetes, arthritis, etc.)

However, if patients are already on this drug AND they are vitamin K deficient, the doctor (or PA or NP) has to be the one in charge of incrementally improving the vitamin K status.

This can be accomplished most effectively (because of consistency) with a regular (daily) supplement. A daily supplement providing the advisable intake is actually recommended by many researchers as a way to minimize the problem of volatility of blood coagulation for people on these medications. It should be pretty easy to do ... just walk the amount up incrementally and monitor coagulation while doing it and adjusting the dosage of medication. But if the doctor doesn't "believe in" this new research there is not a thing we can do about it. We can't tell patients to add a bunch (even a "consistent" bunch) of vitamin K because it might cause problems for a person whose coagulation balance was calculated counting on a baseline vitamin K deficiency state.

Question 2:

“What if the person is not yet on Coumadin/warfarin but he/she may be put on this medication?”

If a person is contemplating going on Coumadin, it is of course safe to beef up their vitamin K intake "up front" to a consistent "assured adequacy" amount. Then the person prescribing it simply sets the new drug prescription based on the underlying consistent and adequate vitamin K status. That would be ideal. (Actually, ideal would be a situation in which nobody had vitamin K insufficiency to begin with. ☺)

Nutrition folks and other health care professionals need to have a clear understanding that vitamin K is not a scary nutrient. It is just that there is an important drug/nutrient interaction that needs attention when people are put on that particular drug. We also need to be very aware that low vitamin K can also increase the dangerous volatility of a warfarin patient's blood coagulation. (This is another reason why vitamin K deficiency is NOT benign.)

Vitamin K is only a safety issue in relation to folks on this medication. Vitamin K does not "make you" coagulate your blood. It's just a tool (a vitamin cofactor) that needs to be there for normal coagulation to take place. (Other things set coagulation into motion.) There is no upper level of safety even established for this vitamin in its natural forms (vitamin K-1 philoquinone and vitamin K-2 menaquinone) because no problems have ever been seen apart from the altered situation that exists when a person is prescribed a warfarin/ Coumadin type of anticoagulant medication. They are of a class called “vitamin K antagonists” because they exert their influence on the vitamin K piece of the process of coagulation.

However, all we can really do about vitamin K for people on warfarin or those about to start warfarin is to share this new information with the people in charge of prescribing their medications.

An additional note:

This discussion is only about the importance of simple nutritional adequacy of vitamin K in relation to warfarin use. It is not addressing therapeutic applications of high-dose vitamin K as a treatment for warfarin overdose or drug-related bleeding. That intervention is not a nutrition-related use of vitamin K but a pharmacologic use in an acute situation. It is outside of the scope of this discussion.

Another additional note:

There are other types of medications sometimes used to decrease risk of inappropriate blood clotting that do not interact with vitamin K, such as “antiplatelet agents” (some are listed below.) This is mentioned here to be sure that health care people recognize that inducing vitamin K inadequacy by restricting intake is especially inappropriate when the medication does not operate as a vitamin-K antagonist at all.

Antiplatelet Agents

Generic Name Trade Names Clopidogrel Plavix Ticlopidine Ticlid Dipyridamole Persantine Dipyridamole ER plus aspirin (25mg) Aggrenox

Yet another additional note: Similarly, the nutritional intervention of decreasing the ratio of omega-6 to omega-3 fats in the diet has the ability to decrease clotting time because it alters the strength of thromboxanes produced. Again, vitamin K is not involved in this effect. Thromboxanes made from the omega-6 fatty acid arachidonic acid (ARA) are much more aggregatory than are those made from the omega-3 fat eicosapentaenoic acid (EPA.) [A good way to remember this is that “the bigger number (that is 6, which is bigger than 3) is associated with the bigger aggregation effect.”]

The American diet typically provides about 10 to 20 omega-6 fats for every omega-3 fat. In societies that regularly have intake ratios of about 4 omega-6 fats per omega-3 fat (such as those eating the “Mediterranean Diet,”) the problem of excessive and inappropriate clotting is much less common. It benefits other health parameters as well. While change in the 4:1 ratio direction has been shown to be an excellent idea overall for general health (including cardiovascular health,) this form of intervention needs to be discussed with physicians/Pas/NPs if they are treating a person with any anti-clotting medication. Actually, the dietary change can sometimes make it unnecessary to be on anti-clotting medications at all, but as before, incorporating this kind of diet change also needs to be managed by the person prescribing the medication.

FYI: Here's the recommendation from page 2 of my "Top Five" handout about this:

"The dark leafy veggies are also terrific sources of vitamin K, a nutrient just now being recognized as critical to decrease risk of osteoporosis, cardiovascular disease, kidney stones, liver cancer and arthritis. It is also a nutrient found to be low in the diets of many Americans. It appears that the elderly need more than the current Advisable Intake of 90-120 mcg/day. This information is so new that vitamin K is not even included in many multivitamins currently on the market, and many health professionals will not yet have heard about these new issues. [Vitamin K: The coagulation vitamin that became omnipotent. Thromb Haemost. 2007 Jul;98(1):120-5.]

If you are taking medications to prevent blood clots, be sure to show this information to your doctor before adding more vitamin K–rich vegetables to your diet or taking any vitamin K supplements. New research on the relationship between vitamin K and these drugs will result in changes in how we do things. But because the information in support of these changes is very new, it will also be new to many healthcare providers, so I have put a ‘Vitamin K” handout on line that includes all the scientific references and detail. Your doctor would want to read more about it before he/she decides to make any changes in your personal diet or medication regimen."

References for this and many other emerging health issues related to vitamin K are included in my paper on MeritCare’s website described earlier:

Vitamin K --New Issues in Cardiovascular Health, Osteoporosis, Cancer of the Liver and Colon, Diabetes, Pregnancy & Varicose Veins.

Sanford Medical Center

11/2010 Aunt Cathy’s Guide to:

Vitamin K --New Issues in Cardiovascular Health,

Renal Health, Osteoporosis, Cathy Breedon PhD, RD, CSP, FADA Liver & Colon Cancer, Prenatal/Pediatric Nutrition Specialist Clinical Nutrition Specialist Diabetes, Pregnancy & Sanford Medical Center, Fargo, ND Varicose Veins (Short Version) and UND School of Medicine

1. Overview/Summary: Vitamin K Top Ten

2. Some Vitamin K Facts and Figures

(All the important useful information is on pp. 1-9)

3. References from the Scientific Literature:

Inadequacy of Vitamin K and:

I. Contribution to Cardiovascular Disease and Arterial and Renal Calcinosis

II. Contribution to Unsafe Variability of Anticoagulation Therapy

III. Contribution to Osteoporosis and Osteoarthritis and Rheumatoid Arthritis

IV. Potential Issues in Liver Cancer and Colorectal Cancer

V. Miscellaneous Health Issues: Non-warfarin-related hemorrhage, cholestasis, diarrhea, celiac disease, cystic fibrosis, short bowel syndrome, pregnancy, and odds and ends

This is the short form of this paper with just the references at the end. Another version is available that includes the abstracts of the referenced articles. As always, this paper is a review of new issues in the scientific literature and not intended to take the place of your personal health care provider.

In particular, individuals using anticoagulant medications like Coumadin/warfarin must not make changes in their vitamin K intake without consulting their physician/PA/NP.

A separate paper for health professionals is available that discusses this issue in more detail.

1 Overview/Summary: Vitamin K Issues

1. Vitamin K has been found to be involved in carboxylation reactions in various tissues. As a result, it is now recognized as playing a critical role in bone health, growth, diabetes, pregnancy, cardiovascular health, renal health, and certain cancers, in addition to its well- known role in blood coagulation. Allowing (or inducing) vitamin K deficiency for any reason is clearly not benign.

2. Foods that are generous in vitamin K1 are also excellent sources of beneficial antioxidant phytochemicals. This includes lutein, a pigment in leafy greens that appears to have an additional unique potential benefit in the prevention or the slowing of the progression of blindness due to macular degeneration. These foods are also very low in calories and rich in other vitamins and minerals as well. However, many Americans eat very few of these foods and as a result, relative vitamin K inadequacy is not at all uncommon when it is actually checked. (It is currently only very rarely checked.) The most generous dietary vitamin K2 sources include bacterially fermented foods. One of the richest is natto … a strong flavored soy bean product popular in Japan but considerably less so in the US.

3. Elderly people appear to require a regular intake of vitamin K above the 2001 “Adequate Intake” (AI) level in order to assure adequacy. Note that the recommended amounts for everyone (AIs, RDI, RDA, etc.) were set at a time when it was assumed that intestinal bacteria provided about half of one’s requirements. As this source has been found to be more unreliable than was thought, it is very reasonable to aim toward an intake that is generous. People using the drug Coumadin need to discuss this issue with their physician as described below in #6 and #8 because of a drug/nutrient interaction. However, except for this well-known drug/nutrient interaction, there is no upper level of safety for vitamin K and foods rich in vitamin K are rich in many other nutrients as well.

4. Vitamin K as phylloquinone (K1) and menaquinone (K2) are not toxic, and for that reason there is no “Upper Limit of Safety” established for this vitamin. In contrast, menadione (K3) is potentially harmful and it is generally no longer used as a vitamin K supplement. It was previously assumed that about half of a person’s vitamin K requirements were met via production by intestinal bacteria. It is now clear that healthy people are in fact MUCH more dependent on vitamin K from foods and/or supplements to assure adequacy than we thought.

5. Misunderstanding about recommendations for vitamin K intake for people on anticoagulant therapy has resulted in many people avoiding all sources of vitamin K (instead of taking in a CONSISTENT but ADEQUATE amount of vitamin K as recommended by the drug manufacturers.) One result, for example, is the association seen between anticoagulant use and increased risk of osteoporosis and cardiac and renal calcification . Initially it was thought to be due to the drug itself, but it turned out to be related to the far too common inappropriate excessive restriction of vitamin K.

2 6. It appears that dangerous VARIABILITY of blood clotting among some patients taking anticoagulants can be controlled significantly by assuring a consistent daily intake of an adequate amount of vitamin K. Coagulation variability is a much greater problem among patients whose usual vitamin K status is low. Those are the people most greatly affected by fluctuations in vitamin K content of diet or supplements. Persons with a reliable adequate intake level are far less affected by additional intake in vitamin K.

7. Vascular calcification, a known cardiovascular risk factor, is another side effect related to the problem of inducing low vitamin K status in patients on anticoagulants and among the population at large. Failure to activate the hormone osteocalcin because of inadequate vitamin K results in failure to move calcium from the bloodstream into bone. Instead, calcium is deposited inappropriately in other tissues, such as blood vessel walls and the kidneys. This results in arteriocalcinosis (an independent risk factor for cardiovascular disease.) It also results in renal calcinosis because increased calcium needs to be excreted.

8. Vitamin K inadequacy is now being identified even among healthy children when vitamin K status is evaluated …however, at present it is only very rarely evaluated. People with conditions that result in malabsorption are at very high risk of deficiency. This includes conditions like cystic fibrosis, poorly controlled celiac disease, Crohn’s disease (inflammatory bowel disease or IBD,) biliary atresia, short bowel syndrome and intractable diarrhea.

Others at particular risk of inadequacy of vitamin K include people using drugs that interfere with vitamin K such as salicylates (e.g. aspirin) and many seizure-control medications. Similarly, some renal medications used to bind phosphate in the intestine (e.g. sevelamer-HCl) can greatly impair vitamin K absorption. [Metal ion and vitamin adsorption profiles of phosphate binder ion-exchange resins. Clin Nephrol. 2010 Jan;73(1):30-5.

Assuring vitamin K adequacy in pregnant and breast-feeding women is an important new focus. Vitamin K inadequacy in pregnancy has recently been identified as a risk factor for pregnancy complications like hyperemesis gravidarum, pre-eclampsia, intracranial bleeding in the infant, and excessive blood loss at delivery. Although vitamin K transfer across the placenta is noted to be poor, relative inadequacy in pregnancy can also contribute to poor nutrient stores in infants.

Whether more generous maternal stores of vitamin K might enhance the transfer to the fetus has not been evaluated. The recommendation of the American Academy of Pediatrics is to provide vitamin K to newborns. Additionally, breast-fed babies are noted to be at higher risk of inadequacy apparently for the same reason … low vitamin K content of mother’s milk. Again, whether relative maternal vitamin K inadequacy is a factor in the breastmilk vitamin K content has not been evaluated yet. [American Academy of Pediatrics Policy Statement: Controversies Concerning Vitamin K and the Newborn Committee on Fetus and Newborn Pediatrics Vol. 112 No. 1 July 2003, pp. 191-192]

3 9. New roles of vitamin K are being recognized. For example, failure to activate osteocalcin because of inadequate vitamin K appears to have a negative effect on energy metabolism, including insulin metabolism. A possible role of vitamin K inadequacy in diabetes and obesity is just beginning to be examined. This is in addition to the cardiovascular, bone, and renal health issues.

Assuring vitamin K adequacy appears to be a factor in some aspects in the prevention or treatment of cancers of the liver, colon/rectum, prostate, pancreas and ovaries. Other recent areas of investigation include a role of vitamin K inadequacy in hypertension (high blood pressure) and inflammatory diseases such as arthritis. Dietary vitamin K appears to have a role in sulfatide metabolism, myelin structure and behavior functions.

10. All of the health concerns described above are made less severe by the same intervention:

Assure adequacy of vitamin K status for everyone from foods and/or supplements. (Do not ASSUME adequacy.)

If a person is on the anticoagulant medication Coumadin*, assure that the vitamin K is administered in a consistent manner each day and that the physician has approved any adjustments of vitamin K intake.

Remember that inducing a vitamin K deficiency is common in this context, makes the drug use more dangerous, and causes damage to the cardiovascular system, the renal system, bone health and increases risk of certain cancers.

*Note that many anticoagulants do not involve vitamin K in their function as Coumadin does, so it makes even less sense to restrict vitamin K with these medications.

Adjust intake recommendations to compensate for conditions associated with malabsorption and the effects of aging.

4

Some Vitamin K Facts and Figures

Adequate Intake (AI) for Vitamin K

Life Stage Age mcg/day

Infants 0-6 months 2.0

Infants 7-12 months 2.5

Children 1-3 years 30

Children 4-13 years 55

Adolescents 14-18 years 75 Males 120 Adults 19 years and older * Females 90 Pregnancy or Breastfeeding 18 years and younger 75

Pregnancy or Breastfeeding 19 years and older 90

Food and Nutrition Board, Institute of Medicine. Vitamin K. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington D.C.: National Academy Press; 2001:162-196.

*Older adults [for sure] may benefit from higher regular intakes than are listed in the the Advisable Intakes (AIs.) These were developed with the assumption that intestinal production of usable vitamin K provided a more significant amount. Current AIs for other age groups have not been re-evaluated since the discovery that the intestinal bacterial sources are far less available than was believed, so it is not just the elderly who may be at risk. The rest have not been checked yet.

Vitamin K status in the elderly. Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):20-3.

5 Sources

Leafy Vegetable Food Sources

Phylloquinone (vitamin K1) is a major dietary form of vitamin K, and the major food source is leafy green vegetables. Not all green vegetables are good sources . . . it’s the darker leafy ones that have the most! Additional benefits of these foods are the extremely low calories and the generous provision of other vitamins (such as vitamin C and vitamin A as beta carotene) and potent antioxidant phytochemicals such as lutein.

There are many excellent reasons to include these foods in one’s diet. This is also true for people using anticoagulation medications like Coumadin (warfarin.) As described earlier, the goal is to assure both an adequate intake of vitamin K and a consistent level of intake. No one benefits from vitamin K deficiency.

Food Serving Vitamin K1 (mcg)

Seaweed, dulse dried 100g (3.5 oz) 1700

Kale, raw 1 cup (chopped) 547

Broccoli, cooked 1 cup (chopped) 420

Parsley, raw 1 cup (chopped) 324

Swiss chard, raw 1 cup (chopped) 299

Green tea, dried 1 oz (28 g) 199 Spinach, raw 1 cup (chopped) 120

Leaf lettuce, raw 1 cup (shredded) 118

Iceberg lettuce 1 leaf (20 g) 22

Watercress, raw 1 cup (chopped) 20-85 (various refs) Pennington, JA. Bowes & Church’s Food Values of Portions Commonly Used, Ed. 16 Phil: Lippincott Co., 1994

Some is available in vegetable oils as shown on the next page, but they contribute far less vitamin K than leafy green vegetables. And, it is fairly impractical and also unwise to suggest that people attempt to meet their vitamin K requirements by increasing fat intake substantially. Additionally, hydrogenation of vegetable oils may decrease the absorption and biological effect of dietary vitamin K.

(Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr. 2001;74(6):783-790.)

6

Oil Food Sources:

Food Serving Vitamin K1 (mcg)

Soybean oil 1 Tablespoon 26 – 76 (various refs)

Canola oil 1 Tablespoon 20

Mayonnaise 1 Tablespoon 12

Corn oil 1 Tablespoon 0 - 7 (various refs)

Olive oil 1 Tablespoon 8

Animal Food Sources:

Food Serving Vitamin K1 (mcg)

Meat 3.5 oz 4

Raw Beef Liver (others less) 3.5 oz 104

Milk 8 oz 10

Egg Yolk 1 large 25

Fermented Food Sources:

Food Serving Vitamin K2 (mcg)

Natto (fermented soybeans) 1 oz 245

Curd Cheese 1 oz 20

Non-Food Sources: Intestinal Bacteria

Bacteria that normally colonize the large intestine synthesize menaquinones (vitamin K2), which are active forms of vitamin K. Until recently it was thought that up to 50% of the human vitamin K requirement might be met by this bacterial synthesis. Recent research

7 indicates that the contribution of intestinal bacterial synthesis is much less than previously thought, although the exact contribution remains unclear. Most of our menaquinones we actually make ourselves from phylloquinone. The likelihood is that even healthy people are more dependent on food sources of vitamin K than we previously believed. Individuals taking chronic antibiotics are far more dependent on food or supplement sources, of course, because these “friendly” colonic bacteria are killed by the medication as well.

(Suttie JW. The importance of menaquinones in human nutrition. Annu Rev Nutr. 1995;15:399-417.)

Non-Food Sources: Supplements

In the U.S. vitamin K1 is available without a prescription in multivitamin and other supplements in doses that generally range from 10-120 mcg per dose. Vitamin K2 supplements are also available now. (PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.)

The amount of vitamin K associated with a decreased risk of hip fracture in the Framingham Heart Study was about 250 mcg/day. This can be obtained from a little more than 1/2 cup of chopped broccoli or a large salad of mixed greens every day. A multivitamin with minerals that provides at least the AI level of vitamin K would also be an excellent idea, and the label should be checked closely because vitamin K is notoriously variable between various products.

Many vitamin supplement products contain none because of the earlier assumptions about the GI bacterial sources providing a significant amount. Some chewable calcium supplements provide some vitamin K and vitamin D. Again, check the label. A form of vitamin K2, menatetrenone (MK-4) has been used to treat osteoporosis in Japan and is currently under study in the U.S National Institutes of Health. K2 as MK-7 is the form produced in natto.

Many earlier references state that vitamin K inadequacy is extremely unusual in adults. Testing for vitamin K inadequacy is also generally rare because inadequacy is assumed to not be a problem. Traditionally testing involves measuring prothrombin time. However, it appears that this hematological manifestation of inadequacy may not reflect adequacy of vitamin K for other functions. For example, newer studies use undercarboxylated osteocalcin or other measures as a marker of vitamin K inadequacy in bone and cardiovascular applications in particular.

Vitamin K adequacy has not been in the public health radar … or the radar of health care professionals. Consider, for example, the mypyramid.gov guidelines*, which are an effort to help people achieve an advisable intake of all nutrients over two weeks in 2000 kcals/day. Vitamin K is simply not included in the analysis. Vitamin D is missing as well. Apparently these nutrients are assumed to be adequate because “you can make your own.” In the case of vitamin D, this assumed adequacy is now being discarded because of the overwhelming evidence that vitamin D deficiency is actually a huge but previously unrecognized public health problem. It is possible that the assumption of vitamin K adequacy may turn out to be

8 similarly suspect. In any case, with the clear safety of generous vitamin K in normal circumstances, it would be advisable to simply assure adequacy rather than to assume it. *(http://www.mypyramid.gov/downloads/sample_menu.pdf)

Vitamin K Nomenclature

Older nomenclature IUPAC (abbreviation)

K1 Phylloquinone (K)

K 2(n) Menaquinone-n (MK-n)

K2(4) Menatetrenone (MK-4)

K2(35) Menaquinone-7 (MK-7)

K3 Menadione

From Machlin, LJ. Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects. New York: Marcel Dekker, Inc.,1984

Toxicity Issues

There is no known toxicity associated with high doses of phylloquinone (vitamin K1), or menaquinone (vitamin K2) forms of vitamin K.

No tolerable upper level (UL) of intake of these forms of vitamin K has been established.

(Food and Nutrition Board, Institute of Medicine. Vitamin K. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington DC: National Academy Press; 2001:162-196.)

The same is not true for menadione (vitamin K3) and its derivatives. Menadione can interfere with the function of glutathione, one of the body's natural antioxidants, resulting in oxidative damage to cell membranes. Menadione given by injection has induced liver toxicity,

9 jaundice, and hemolytic anemia (due to the rupture of red blood cells) in infants, and is no longer used for treatment of vitamin K deficiency.

Contrary to popular belief, the fat-soluble status of vitamin K does NOT make it more likely to be toxic than water soluble vitamins.

The toxicity traditionally ascribed somewhat globally to the fat soluble vitamins is in fact due to the fact that two of them (vitamins A and D) have actual hormonal messenger roles in the body. For this reason, relative inadequacy or excess of the active hormonal form of these two vitamins can actually induce metabolic changes to occur. The other two fat soluble vitamins (E and K) and the water soluble vitamins (C and the B vitamins) are much less likely to be toxic because they exert no hormonal influence on tissues.

The fact that a substance dissolves in butter is not a measure of its potential toxicity, although most of us were taught that it is. This is an important big change in our understanding

Mnemonic Devices:

I always find it hard to keep these kinds of terms and numbers straight, so I usually make up a little mnemonic device to help me out. Here’s the one I use for remembering which form of vitamin K comes from which source, and which is K1 and which is K2 (Feel free to disregard this section and make up your own if you find these unhelpful. ☺)

Phylloquinone starts with a P … as in “Plants.”

(“Leafy greens” vitamin K is Phylloquinone)

I think of the kind made in people’s intestines by bacteria or made in man from phylloquinone is menaquinone … that is, the kind made “in men.”

(The kind of vitamin K made in men is menaquinone. Women too, of course.)

Because we convert phylloquinone to menaquinone for many of its uses, I think of

phylloquinone (the spinach one) coming first (K1) and menaquinone (the kind made

in man out of K1) as coming along secondarily (K2)

10 References by Topic:

(A version with abstracts of these references is also available.)

I. Inadequacy of Vitamin K:

Contribution to Cardiovascular Disease: Arterial Calcinosis, Renal Calcinosis, Diabetes, Inflammation and Hypertension

2010 Clin J Am Soc Nephrol. 2010 Feb 4. The circulating inactive form of matrix GLA Protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. J Nutr Biochem. 2010 Feb 8. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor kappaB through the repression of IKKalpha/beta phosphorylation. Clin J Am Soc Nephrol. 2010 Feb 18 Vitamins K and D status in stages 3-5 chronic kidney disease. Kidney Int. 2010 Oct 20. The dualistic role of vitamin D in vascular calcifications. Clin J Am Soc Nephrol. 2010 Apr;5(4):568-75. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Thromb Haemost. 2010 Oct;104(4):811-22. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Urol Int. 2010 Jul;85(1):94-9. Activity and expression of vitamin K-dependent gamma-glutamyl carboxylase in patients with calcium oxalate urolithiasis. Thromb Haemost. 2009 Apr;101(4):706-13. Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification. Clin J Am Soc Nephrol. 2010 Apr;5(4):590-7 Vitamins K and D status in stages 3-5 chronic kidney disease Kidney Int. 2010 Sep 22 Recent progress in the treatment of vascular calcification. Clin Nephrol. 2010 Jan;73(1):30-5. Metal ion and vitamin adsorption profiles of phosphate binder ion- exchange resins.

2009

Clin Exp Immunol. 2009 Dec 17. Vitamin K(3) attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappaB activation. J Mal Vasc. 2009 Apr 2. Origin of the mediacalcosis in kidney failure Nephrol Dial Transplant. 2009 Jul;24(7):2095-101. Association of kidney function and uncarboxylated matrix GLA protein: data from the Heart and Soul Study. J Thromb Haemost. 2009 Feb;101(2):359-66. Uncarboxylated matrix GLA protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. J Thromb Haemost 2009;Sept 28. Warfarin use and the risk of valvular calcification. Int J Artif Organs. 2009 Feb;32(2):67-74. Coagulation meets calcification: The vitamin K system. J Bone Miner Res. 2009 Vitamin k and bone: past, present, and future. Br J Nutr. 2009 Apr 1:1-16 Minerals and vitamins in bone health: the potential value of dietary enhancement.

11 Osteoporos Int. 2009 Mar 12Prior treatment with vitamin K(2) significantly improves the efficacy of risedronate. J Bone Miner Metab. 2009;27(3):333-40.Short-term menatetrenone therapy increases gamma- carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomized prospective study. Bioorg Med Chem Lett. 2009 Feb 15;19(4):1054-7. Elucidation of the mechanism producing menaquinone-4 in osteoblastic cells. J Bone Miner Res. 2009 Jun;24(6):983-91.Vitamin k treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal north american women. J Mal Vasc. 2009 Apr 2. Origin of the mediacalcosis in kidney failure.

2008 Am J Clin Nutr. 2008 Jul;88(1):210-5. Phylloquinone intake, insulin sensitivity, and glycemic status in men and women. Atherosclerosis. 2008 Jul 19Thromb Res. 2008;122(3):411-7. High dietary menaquinone intake is associated with reduced coronary calcification. Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification. J Vasc Res. 2008 Apr 10;45(5):427-436. The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification. Arterioscler Thromb Vasc Biol. 2008 Apr;28(4):771-6. Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism and aortic calcification: the Rotterdam Study. Am J Epidemiol. 2008 Feb 1;167(3):313-20. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Clin J Am Soc Nephrol. 2008 May 21. Vitamin K-dependent Proteins, Warfarin, and Vascular Calcification. Am J Clin Nutr. 2008 Jul;88(1):210-5. Phylloquinone intake, insulin sensitivity, and glycemic status in men and women. Cell Cycle. 2008 Jun;7(11):1575-9. Does the absence of ABCC6 (multidrug resistance protein 6) in patients with Pseudoxanthoma elasticum prevent the liver from providing sufficient vitamin K to the periphery? J Pharm Pharmacol. 2008 Jul;60(7):889-93. Mechanisms underlying the biphasic effect of vitamin K1 (phylloquinone) on arterial blood pressure. Curr Opin Lipidol. 2008 Feb;19(1):39-42. Vitamin K intake and atherosclerosis.

2007 J Atheroscler Thromb. 2007 Dec;14(6):317-24. Treatment with vitamin k(2) combined with bisphosphonates synergistically inhibits calcification in cultured smooth muscle cells. Nat Clin Pract Nephrol. 2007 Oct;3(10):522-3. Vascular calcification in chronic kidney disease: the role of vitamin K. Rhinology. 2007 Sep;45(3):208-13. Vitamin D3, vitamin K2, and warfarin regulate bone metabolism in human paranasal sinus bones. Thromb Haemost. 2007 Jul;98(1):120-5. Vitamin K: The coagulation vitamin that became omnipotent. Exp Anim. 2007 Jul;56(4):273-8. Vitamin K Deficiency of Germfree Mice Caused by Feeding Standard Purified Diet Sterilized by gamma-Irradiation. . Nutr Metab Cardiovasc Dis. 2007 Jan;17(1):58-62. Phylloquinone intake and risk of cardiovascular diseases in men.

12 2005-2006

Blood. 2006 Nov 30; Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats. Am J Health Syst Pharm. 2005 Aug 1;62(15):1574-81 Vitamin K in the treatment and prevention of osteoporosis and arterial calcification Eur J Clin Nutr. 2005 Feb;59(2):196-204 Phylloquinone intake as a marker for coronary heart disease risk but not stroke in women. Nutr Res. 2009 Apr;29(4):221-8. High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature.

II. Inadequacy of Vitamin K:

Contribution to Unsafe Variability of Anticoagulation Therapy

2010 Br J Haematol. 2010 Feb 11. Influence of dietary vitamin K intake on subtherapeutic oral anticoagulant therapy.

2009 Am J Transl Res. 2009 Jul 15;1(4):381-92.Activated protein C: a potential cardioprotective factor against ischemic injury during ischemia/reperfusion. J Manag Care Pharm. 2009 Apr;15(3):244-52. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. Blood Coagul Fibrinolysis. 2009 Apr 3. Erythrocyte folate and 5-methyltetrahydrofolate levels decline during 6 months of oral anticoagulation with warfarin.

2008 Hamostaseologie. 2008 Feb;28(1-2):44-50 New insight in therapeutic anticoagulation by Coumarin Derivatives. J Thromb Haemost. 2008 Jul;6(7):1226-8. Vitamin K epoxide reductase complex subunit 1 (VKORC1 ) polymorphism influences the anticoagulation response subsequent to vitamin K intake: a pilot study Vitam Horm. 2008;78:265-79 Vitamin K and thrombosis.

2007 J Thromb Haemost. 2007 Oct;5(10):2043-8..Daily vitamin K supplementation improves anticoagulant stability. Thromb Haemost. 2007 Jul;98(1):120-5. Vitamin K: The coagulation vitamin that became omnipotent. INRJ Thromb Thrombolysis. 2007 Feb 24; Prospective study of supplemental vitamin K therapy in patients on oral anticoagulants with unstable international normalized ratios. J Am Diet Assoc. 2007 Nov;107(11):2022.Vitamin K: what are the current dietary recommendations for patients taking coumadin? Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):1-5. Dietary vitamin K intake & anticoagulation in elderly patients.

13 2006 Blood. 2006 Nov 16 Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Int J Vitam Nutr Res. 2006 Mar;76(2):65-74. Dietary vitamin K variability affects International Normalized Ratio (INR) coagulation indices.

2004-2005 Pharmacotherapy. 2005 Dec;25(12):1746-51. Low-dose vitamin K to augment anticoagulation control. Am J Cardiovasc Drugs. 2004;4(1):43-55. The use of vitamin K in patients on anticoagulant therapy: a practical guide.

III. Inadequacy of Vitamin K:

Contribution to Osteoporosis, Osteoarthritis, Bone Development, Rheumatoid Arthritis, and Related Conditions

2010 Transplantation. 2010 Feb 27;89(4):458-464. Dietary vitamin K2 supplement improves bone status after lung and heart transplant. Proc Nutr Soc. 2010 Feb;69(1):25-33. Session 2:Other diseases: Dietary management of osteoporosis throughout the life course.

2009 J Bone Miner Metab. 2009 Dec 19. Hop rho iso-alpha acids, berberine, vitamin D(3) and vitamin K(1) favorably impact biomarkers of bone turnover in postmenopausal women in a 14-week trial. Clin Calcium. 2009 Dec;19(12):1815-21. Clinical implications of undercarboxylated osteocalcin. Clin Calcium. 2009 Dec;19(12):1805-14Anti-fracture efficacy of vitamin K. Clin Calcium. 2009 Dec;19(12):1797-804. Effect of vitamin K on bone material properties. Clin Calcium. 2009 Dec;19(12):1788-96.Biological effects of vitamin K2 on bone quality. Clin Calcium. 2009 Dec;19(12):1779-87. In vivo metabolism of vitamin K: in relation to the conversion of vitamin K1 to MK-4. Clin Calcium. 2009 Dec;19(12):1770-8.Vitamin K function mediated by activation of steroid and xenobiotic receptor Curr Osteoporos Rep. 2009 Dec;7(4):111-7. Osteoporosis prevention and nutrition. J Orthop Sci. 2009 Nov;14(6):687-92 Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: dieary survey in a population-based cohort of the ROAD study. Nutr Res. 2009 Apr;29(4):221-8. High-dose vitamin K supplementation reduces fracture incidence in postmenopausal women: a review of the literature. Br J Nutr. 2009 May 19:1-8. The effect of menaquinone-7 (vitamin K2) supplementation on osteocalcin carboxylation in healthy prepubertal children. J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):15-21. Effect of low dose vitamin K2 (MK-4) supplementation on bio-indices in postmenopausal Japanese women.

14 2008 Calcif Tissue Int. 2008 Aug;83(2):121-8. Effects of vitamin k(2) and risedronate on bone formation and resorption, osteocyte lacunar system, & porosity in the cortical bone of glucocorticoid- treated rats. Ann Rheum Dis. 2008 Jul 14 Vitamin K in hand osteoarthritis: results from a Randomized Clinical Trial. Bone. 2008 Aug;43(2):230-7. Uptake of postprandial lipoproteins into bone in vivo: Impact on osteoblast function. Br J Nutr. 2008 Feb 18:1-7. Vitamin K status is associated with childhood bone mineral content. J Bone Miner Metab. 2008;26(3):260-4. Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. Am J Clin Nutr. 2008 May;87(5):1513-20. Vitamin K1 intake is associated with higher bone mineral density and reduced bone resorption in early postmenopausal Scottish women: no evidence of gene-nutrient interaction with apolipoprotein E polymorphisms. J Pharmacol Sci. 2008 Apr;106(4):530-5. Pharmacological topics of bone metabolism: recent advances in pharmacological management of osteoporosis. Proc Nutr Soc. 2008 May;67(2):163-76.Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment. J Biol Regul Homeost Agents. 2008 Jan-Mar;22(1):35-44. Vitamin K and D association stimulates in vitro osteoblast differentiation of fracture site derived human mesenchymal stem cells. Arch Pediatr. 2008 Mar;15(3):301-12. Recommendations for the management of bone demineralization in cystic fibrosis J Clin Endocrinol Metab. 2008 Apr;93(4):1217-23. Effect of vitamin K supplementation on bone loss in elderly men and women. Clin Calcium. 2008 Feb;18(2):224-32. Genomic approaches to bone and joint diseases. New insights into molecular mechanisms underlying protective effects of vitamin K on bone health Eur J Epidemiol. 2008;23(3):219-25. Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and vitamin K. J Cyst Fibros. 2008 Jul;7(4):307-12. Undercarboxylated osteocalcin and bone mass in 8-12 year old children with cystic fibrosis. J Nutr. 2008 Jan;138(1):172S-177S. The balance of bone health: tipping the scales in favor of potassium-rich, bicarbonate-rich foods. J Bone Miner Metab. 2008;26(1):79-85. Low plasma phylloquinone concentration is associated with high incidence of vertebral fracture in Japanese women. J Bone Miner Metab. 2008;26(1):9-12. Steroid and xenobiotic receptor mediates a novel vitamin K2 signaling pathway in osteoblastic cells. Br J Nutr. 2008 Jan;99(1):198-205. Nutrition and bone health projects funded by the UK Food Standards Agency: have they helped to inform public health policy? Clin Exp Rheumatol. 2008 May-Jun;26(3):484-91. Extremes in vitamin K status of bone are related to bone ultrasound properties in children with juvenile idiopathic arthritis.

2007 Mayo Clin Health Lett. 2007 Nov;25(11):4. Vitamin K linked to bone strength. Pediatr Res. 2007 Mar;61(3):366-70 Pronounced elevation of undercarboxylated osteocalcin in healthy children. J Nutr Sci Vitaminol (Tokyo). 2007 Dec;53(6):464-70. Vitamin K content of foods and dietary vitamin K intake in Japanese young women. J Nutr Sci Vitaminol (Tokyo). 2007 Oct;53(5):419-25. Nutritional effects of gamma-glutamyl carboxylase gene polymorphism on the correlation between the vitamin K status and gamma- carboxylation of osteocalcin in young males.

15 Clin Calcium. 2007 Nov;17(11):1752-60. Experience of vitamin K2 in Thailand Clin Calcium. 2007 Nov;17(11):1709-16. Clinical application of undercarboxylated osteocalcin Clin Calcium. 2007 Nov;17(11):1702-8. Measurement of serum undercarboxylated osteocalcin by ECLIA with the "Picolumi ucOC" kit. Osteoporos Int. 2007 Jul;18(7):963-72. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Int J Cardiol. 2007 Jun 12;118(3):338-44. Fracture risk in users of oral anticoagulants: a nationwide case-control study. Thromb Haemost. 2007 Jul;98(1):120-5. Vitamin K: The coagulation vitamin that became omnipotent. Curr Rheumatol Rep. 2007 Apr;9(1):85-92. Not just calcium and vitamin D: other nutritional considerations in osteoporosis. Curr Opin Clin Nutr Metab Care. 2007 Jan;10(1):20-3. Vitamin K status in the elderly. Int J Cardiol. 2007 Jun 12;118(3):338-44. Fracture risk in users of oral anticoagulants: a nationwide case-control study. Comp Biochem Physiol B Biochem Mol Biol. 2007 May 29; Vitamin K deficiency inhibits mineraliz- ation & enhances deformity in vertebrae of haddock (Melanogrammus aeglefinus L.) Br J Nutr. 2007 Apr;97(4):661-6. Serum percentage undercarboxylated osteocalcin, a sensitive measure of vitamin K status, and its relationship to bone health indices in Danish girls. Exp Anim. 2007 Apr;56(2):103-10. Additive effect of vitamin K2 and risedronate on long bone mass in hypophysectomized young rats. J Bone Miner Metab. 2007;25(1):46-53. Effect of vitamin K2 and growth hormone on the long bones in hypophysectomized young rats: a bone histomorphometry study. Am J Kidney Dis. 2007 Mar;49(3):432-9. Subclinical vitamin K deficiency in hemodialysis patients. J Nutr Sci Vitaminol (Tokyo). 2007 Jun;53(3):219-24. vitamin K2 (menaquinone-4) on intestinal alkaline phosphatase activity in rats.

2006 Curr Drug Saf. 2006 Jan;1(1):87-97Role of vitamin K2 in the treatment of postmenopausal osteoporosis. Clin Calcium. 2006 Sep;16(9):106-14 and Nutrition. 2006 Jul-Aug;22(7-8):845-52. (same article in both journals) Protective effects of vitamin K against osteoporosis and its pleiotropic actions J Nutr Sci Vitaminol (Tokyo). 2006 Oct;52(5):307-15. Beneficial effect of pretreatment and treatment continuation with risedronate and vitamin K2 on cancellous bone loss after ovariectomy in rats: a bone histomorphometry study. Arthritis Rheum. 2006 Apr;54(4):1255-61. Low vitamin K status is associated with osteoarthritis in the hand and knee. Calcif Tissue Int. 2006 Nov;79(5):318-25. Synergistic effect of vitamin K2 and prostaglandin E2 on cancellous bone mass in hypophysectomized young rats. Clin Calcium. 2006 Dec;16(12):2017-25. Present knowledge in nutritional aspects of fracture. Am J Clin Nutr. 2006 Feb;83(2):380-6. Vitamin K status of healthy Japanese women: age-related vitamin K requirement for gamma-carboxylation of osteocalcin. Int J Vitam Nutr Res. 2006 Nov;76(6):385-90. A preliminary assessment of vitamin K1 intakes and serum undercarboxylated osteocalcin levels in 11-13 year old Irish girls. Br J Nutr. 2006 May;95(5):982-8 Phylloquinone (vitamin K1) intakes and serum undercarboxylated osteocalcin levels in Irish postmenopausal women.

2004-2005 Am J Health Syst Pharm. 2005 Aug 1;62(15):1574-81 Vitamin K in the treatment and prevention of osteoporosis and arterial calcification. Curr Pharm Des. 2004;10(21):2557-76. Effects of vitamin K2 on osteoporosis.

16 IV. Inadequacy of Vitamin K:

Cancer: Liver, Colorectal, Prostate, Ovarian, Pancreatic and Cancer Risk in General

2010 Am J Clin Nutr. 2010 Mar 24. Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg). Int J Cancer. 2010 Feb 15;126(4):992-1003. Antioxidant intake from fruits, vegetables and other sources and risk of non-Hodgkin's lymphoma: the Iowa Women's Health Study. J Cell Physiol. 2010 Mar 18. Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways.

2009 Gastroenterol Hepatol. 2009 Nov 19. Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway. Endocr J. 2009;56(7):843-9. Epub 2009 Jun 24. Vitamin K2 suppresses proliferation and motility of hepatocellular carcinoma cells by activating steroid and xenobiotic receptor. J Gastroenterol Hepatol. 2009 Nov 19. Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway. Nutr Res. 2009 Sep;29(9):676-83. Prevalence of vitamin K and vitamin D deficiency in patients with hepatobiliary and pancreatic disorders. Am J Clin Nutr. 2009 Oct;90(4):889-907. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? J Hepatol. 2009 Aug;51(2):315-21. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. Int J Toxicol. 2009 Jan-Feb;28(1):33-42.Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells. Cancer Chemother Pharmacol. 2009 Dec;65(1):143-50. The potential of vitamin K3 as an anticancer agent against breast cancer that acts via the mitochondria-related apoptotic pathway. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):227-32. Antiproliferative action of menadione and 1,25(OH)2D3 on breast cancer cells. Curr Med Chem. 2009;16(15):1821-30 In situ modulation of oxidative stress: a novel and efficient strategy to kill cancer cells. Int J Mol Med. 2009 Jun;23(6):709-16. Growth inhibitory effects of vitamin K2 on colon cancer cell lines via different types of cell death including autophagy and apoptosis. Jpn J Clin Oncol. 2009 Apr;39(4):251-9..Effect of cell differentiation for neuroblastoma by vitamin k analogs. J Gastroenterol. 2009;44(3):228-35. Involvement of hepatoma-derived growth factor in the growth inhibition of hepatocellular carcinoma cells by vitamin K(2). Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):49-56. Serum undercarboxylated osteocalcin as biomarker of vitamin K intake and risk of prostate cancer: a nested case-control study in the Heidelberg cohort of the European prospective investigation into cancer and nutrition. Apoptosis. 2009 Jan;14(1):108-23. Arsenic induced apoptosis in malignant melanoma cells is enhanced by menadione through ROS generation, p38 signaling and p53 activation.

17 2008 Anticancer Res. 2008 Sep-Oct;28(5A):2727-32 Altered deoxyribonuclease activity in cancer cells and its role in non toxic adjuvant cancer therapy with mixed vitamins C and K3. Am J Clin Nutr. 2008 Apr;87(4):985-92. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC- Heidelberg). Biol Pharm Bull. 2008 Jun;31(6):1270-3. An attempt to evaluate the effect of vitamin K3 using as an enhancer of anticancer agents. Vitam Horm. 2008;78:435-42 Hepatocellular carcinoma and vitamin K. Am J Clin Nutr. 2008 Apr;87(4):985-92. Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC- Heidelberg). Cancer Sci. 2008 May;99(5):1040-8. DNA polymerase gamma inhibition by vitamin K3 induces mitochondria-mediated cytotoxicity in human cancer cells. Cancer Lett. 2008 May 8;263(1):53-60. Vitamin K2 suppresses malignancy of HuH7 hepatoma cells via inhibition of connexin 43. Anticancer Res. 2008 Jan-Feb;28(1A):45-50. The utility of vitamin K3 (menadione) against pancreatic cancer. J Clin Pathol. 2008 Apr;61(4):537-40. A study of the prevalence of vitamin K deficiency in patients with cancer referred to a hospital palliative care team and its association with abnormal haemostasis. J Cancer Res Clin Oncol. 2008 Jul;134(7):803-12. Induction of apoptosis in PA-1 ovarian cancer cells by vitamin K(2) is associated with an increase in the level of TR3/Nur77 and its accumulation in mitochondria and nuclei.

2007 Hepatogastroenterology. 2007 Oct-Nov;54(79):2073-7. Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma. Clin Calcium. 2007 Nov;17(11):1693-9. Clinical application of vitamin K for hepatocellular carcinoma. Int J Mol Med. 2007 Dec;20(6):801-8. Vitamin K2-induced cell growth inhibition via autophagy formation in cholangiocellular carcinoma cell lines. Int J Oncol. 2007 Aug;31(2):323-31. Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells. Hepatol Res. 2007 Sep;37 Suppl 2:S303-7. Potential role of vitamin K(2) as a chemopreventive agent against hepatocellular carcinoma. Hepatol Res. 2007 Sep;37 Suppl 2:S299-302. Chemoprevention of liver carcinogenesis with retinoids: Basic and clinical aspects. World J Gastroenterol. 2007 Jun 21;13(23):3259-61. Combined treatment of vitamin K(2) and angiotensin-converting enzyme inhibitor ameliorates hepatic dysplastic nodule in a patient with liver cirrhosis. Intern Med. 2007;46(11):711-5. Hepatocellular carcinoma with peritoneal dissemination which was regressed during vitamin K2 and vitamin E administration. Am J Surg. 2007 Apr;193(4):431-7. A review of the prognostic factors in patients with recurrence after liver resection for hepatocellular carcinoma. J Gastroenterol Hepatol. 2007 Apr;22(4):518-22. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection. Int J Oncol. 2007 Aug;31(2):323-31.Vitamins K2, K3 and K5 exert antitumor effects on established colorectal cancer in mice by inducing apoptotic death of tumor cells. Cancer Sci. 2007 Mar;98(3):431-7. Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells.

18 Clin Cancer Res. 2007 Apr 1;13(7):2236-45. Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. J Gastroenterol Hepatol. 2007 Apr;22(4):518-22. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection.

2006 Clin Calcium. 2006 Sep;16(9):106-14 and Nutrition. 2006 Jul-Aug;22(7-8):845-52. (same article in both journals) Protective effects of vitamin K against osteoporosis and its pleiotropic actions Cancer. 2006 Feb 15;106(4):867-72. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence & survival in patients with hepatocellular carcinoma after curative treatment: a pilot study.

Miscellaneous

Vitamin K Deficiency Associated with Intestinal Malabsorption Problems

2010 Am J Clin Nutr. 2010 Sep;92(3):660-7. Suboptimal vitamin K status despite supplementation in children and young adults with cystic fibrosis. Thromb Res 2010 Jan 3. Small intestinal bacterial overgrowth and warfarin dose requirement variability.

2009 Gastroenterology. 2009 Nov;137(5 Suppl):S105-18. Vitamin K in parenteral nutrition. Pediatr Clin North Am. 2009 Oct;56(5):1035-53. Nutritional deficiencies during normal growth. Clin Calcium. 2009 Dec;19(12):1779-87. In vivo metabolism of vitamin K: in relation to the conversion of vitamin K1 to MK-4.

2008 Pediatrics. 2008 Nov;122(5):1014-20. Prevalence of low bone mass and deficiencies of vitamins D and K in pediatric patients with cystic fibrosis from 3 Canadian centers. J Cyst Fibros. 2008 May 27. Efficacy of high dose phylloquinone in correcting vitamin K deficiency in cystic fibrosis. Arch Pediatr. 2008 Mar;15(3):301-12. Epub 2008 Mar 5. Recommendations for the management of bone demineralization in cystic fibrosis J Cyst Fibros. 2008 Jul;7(4):307-12. Undercarboxylated osteocalcin and bone mass in 8-12 year old children with cystic fibrosis. Nutrition. 2008 Apr;24(4):330-9. Nutrient intake from habitual oral diet in patients with severe short bowel syndrome living in the southeastern United States.

2007 Tohoku J Exp Med. 2007 Jul;212(3):335-9. Vitamin K-deficient intracranial hemorrhage as the first symptom of cytomegalovirus hepatitis with cholestasis. Masui. 2007 Feb;56(2):181-5.Suspicious case of epidural hematoma due to coagulopathy caused by vitamin K deficiency associated with antibiotics. J Hum Nutr Diet. 2007 Dec;20(6):605-10. Vitamin K prescribing patterns and bone health surveillance in UK children with cystic fibrosis. Bone. 2007 Dec;41(6):965-72. Shwachman-Diamond syndrome is associated with low-turnover

19 osteoporosis. Adv Ther. 2007 Nov-Dec;24(6):1286-9 Celiac disease with diffuse cutaneous vitamin K-deficiency bleeding. J Child Neurol. 2007 Jan;22(1):114-5.Cerebral hemorrhage as the initial manifestation of cystic fibrosis. Gastroenterol Clin Biol. 2007 Jun;31(6-7):614-5. Severe vitamin K deficiency during a drug wash-out procedure with cholestyramine. 2006 Adv Ther. 2006 May-Jun;23(3):469-74. Evaluation of vitamin K deficiency in children with acute and intractable diarrhea. Pediatr Neurosurg. 2006;42(6):362-7 Intracranial hemorrhage and vitamin K deficiency associated with biliary atresia: summary of 15 cases and review of the literature.

Odds and Ends:

2010 Cochrane Database Syst Rev. 2010 Jan 20;(1):CD000229. Vitamin K prior to preterm birth for preventing neonatal periventricular hemorrhage. Early Hum Dev. 2010 Jan 28. Vitamin K the basics-What's new? Early Hum Dev. 2010 Jan 25. Vitamin K prophylaxis for preterm infants.

2009 Acta Paediatr. 2009 Dec 3. Evaluation of the acceptability of a new oral vitamin K prophylaxis for breastfed infants. Hematol Oncol. 2009 Dec;31(12):985-8. Third trimester fetal intracranial hemorrhage owing to vitamin K deficiency associated with hyperemesis gravidarum.

2008 Eur J Pediatr. 2008 Feb;167(2):165-9. Incidence of late vitamin K deficiency bleeding in newborns in the Netherlands in 2005: evaluation of the current guideline. Pediatrics. 2008 Apr;121(4):e857-63.Prevention of vitamin K deficiency bleeding in breastfed infants: lessons from the Dutch and Danish biliary atresia registries. Prenat Diagn. 2008 Jan;28(1):59-61. Vitamin K deficiency in hyperemesis gravidarum as a potential cause of fetal intracranial hemorrhage and hydrocephalus.

2007 J Matern Fetal Neonatal Med. 2007 Sep;20(9):661-7. Preeclampsia is associated with low concentrations of protein Z. Am J Med Genet A. 2007 Jan 15;143(2):200-4. Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: a complication of hyperemesis gravidarum induced vitamin K deficiency? Neurology. 2007 Dec 11;69(24 Suppl 3):S10-6. Importance of monotherapy in women across the reproductive cycle. [Seizure Medications] J Am Diet Assoc. 2007 Dec;107(12):2091-9. Poor nutrient intakes during 1-year follow-up with community-dwelling older adults with early-stage Alzheimer dementia compared to cognitively intact matched controls. Arch Dis Child. 2007 May 23; Vitamin K deficiency bleeding: the readiness is all. N Engl J Med. 2007 Jan 11;356(2):174-82. Case records of the Massachusetts General Hospital. Case

20 1-2007. A 40-year-old woman with epistaxis, hematemesis, and altered mental status. Arch Dis Child. 2007 May 30; Vitamin K deficiency bleeding in the Great Britain and Ireland; British Paediatric Surveillance Unit Surveys, 1993 - 94 and 2001 - 02. Pediatrics. 2006 Dec;118(6):e1657-66Vitamin K prophylaxis for preterm infants: a randomized, controlled trial of 3 regimens.

Some Basic Science References: some recent study topics.

2010 J Nutr Biochem. 2010 Jan 19. Age- and brain region-specific effects of dietary vitamin K on myelin sulfatides. Transplantation. 2010 Feb 27;89(4):458-464. Quantitative determination of plasma vitamin K1 byHPLC coupled isotope-dilution tandem mass spectrometry. 2008 Bioelectrochemistry. 2008 May 12. Direct and indirect methods for the determination of vitamin K(3) using differential pulse polarography and application to pharmaceuticals Biochemistry. 2008 Jun 17;47(24):6301-10. Transmembrane domain interactions and residue proline 378 are essential for proper structure, especially disulfide bond formation, in the human vitamin K- dependent gamma-glutamyl carboxylase. J Biol Chem. 2008 Jun 27;283(26):17991-8 001. Periostin, a member of a novel family of vitamin K- dependent proteins, is expressed by mesenchymal stromal cells. Vitam Horm. 2008;78:185-209. Vitamin K-dependent actions of Gas6. Vitam Horm. 2008;78:131-56. Vitamin K-dependent carboxylation. Vitam Horm. 2008;78:103-30. Structure and function of vitamin K epoxide reductase. Vitam Horm. 2008;78:85-101. Quinone oxidoreductases and vitamin K metabolism. Bioorg Med Chem Lett. 2007 Nov 15;17(22):6383-6. Effects of quinones on free-radical processes of oxidation and fragmentation of hydroxyl-containing organic compounds. Vitam Horm. 2008;78:63-84. Structure, function, and mechanism of cytosolic quinone reductases. Vitam Horm. 2008;78:35-62. The vitamin K cycle. Vitam Horm. 2008;78:23-33. VKORC1 and the vitamin K cycle. Vitam Horm. 2008;78:1-22. Determinants of vitamin K status in humans. Vitam Horm. 2008;78:XIX-XX. Vitamin K. Preface. Methods Mol Biol. 2008;446:85-94. gamma-Glutamate and beta-hydroxyaspartate in proteins. J Nutr. 2008 Mar;138(3):492-6. Age and dietary form of vitamin K affect menaquinone-4 concentrations in male Fischer 344 rats. J Biol Chem. 2008 Apr 25;283(17):11270-9. Conversion of phylloquinone (Vitamin K1) into menaquinone-4 (Vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice.

21 MeritCare Medical Center 9/2010

Aunt Cathy’s Guide to Nutrition: Carnitine Aunt Cathy Cathy Breedon PhD, RD, CSP, FADA Some Sorted References from the Prenatal/Pediatric Nutrition Specialist Clinical/Metabolic Nutrition Specialist Scientific Literature: MeritCare Medical Center, Fargo, ND 2006 to Sept. 2010 (plus one from 1989 of particular interest as noted in my accompanying paper on carnitine.)

Altern Med Rev. 2010 Apr;15(1):76-83. Acetyl-L-carnitine. Monograph.

Cancer-related:

2010

Clin Cancer Res. 2010 Jun 18. Metabolic Approach to the Enhancement of Antitumor Effect of Chemotherapy: A Key Role of Acetyl-L-Carnitine.

J Pediatr Hematol Oncol. 2010 Apr;32(3):e114-7. Vincristine-induced peripheral neuropathy in a neonate with congenital acute lymphoblastic leukemia.

Eur Rev Med Pharmacol Sci. 2010 Apr;14(4):292-301. Randomised phase III clinical trial of 5 different arms of treatment on 332 patients with cancer cachexia.

J Pediatr Hematol Oncol. 2010 Mar;32(2):e61-9. Serum carnitine levels in childhood leukemia.

Oncologist. 2010;15(2):200-11. Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia.

J Biol Chem. 2010 Feb 26;285(9):6275-84. The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine analogue bleomycin-A5.

Nutr Metab (Lond). 2010 Apr 16;7:30. Role of carnitine in disease.

1 2009

J Pediatr Hematol Oncol. 2009 Sep;31(9):664-9. Carnitine plasma levels and fatigue in children/adolescents receiving cisplatin, ifosfamide, or doxorubicin.

Nutrition. 2009 Nov-Dec;25(11-12):1193-201. In vitro studies on the inhibition of colon cancer by butyrate and carnitine.

Cell Tissue Res. 2009 Aug;337(2):269-80. Carnitine reduces testicular damage in rats treated with etoposide in the prepubertal phase.

J Pain Symptom Manage. 2009 Apr;37(4):622-31. L-carnitine supplementation in patients with advanced cancer and carnitine deficiency: a double- blind, placebo-controlled study.

Gynecol Oncol. 2009 Mar;112(3):631-6. Effect of acetyl-l-carnitine on ovarian cancer cells' proliferation, nerve growth factor receptor (Trk- A and p75) expression, and the cytotoxic potential of paclitaxel and carboplatin.

2008

Curr Opin Support Palliat Care. 2008 Sep;2(3):180-6. Fatigue in chronically ill patients.

Int J Cancer. 2008 Sep 15;123(6):1227-39. Impact of antioxidant supplementation on chemotherapeutic toxicity: a systematic review of the evidence from randomized controlled trials.

Eur J Cancer. 2008 Jul;44(11):1507-15. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies.

2007

Cancer Biol Ther. 2007 Oct;6(10):1606-13. Carnitine palmitoyltransferase I in human carcinomas: a novel role in histone deacetylation?

CNS Drugs. 2007;21 Suppl 1:39-43; discussion 45-6. Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short review.

Aging/Neuodegenerative Conditions/ Eye:

2010 Chem Biol Interact. 2010 Mar 30;184(3):346-51. Regulatory effect of acetyl-l-carnitine on expression of lenticular antioxidant and apoptotic genes in selenite-induced cataract.

2

Mech Ageing Dev. 2010 Jul-Aug;131(7-8):473-9. Epub 2010 Apr 24. Optimal micronutrients delay mitochondrial decay and age-associated diseases.

Rejuvenation Res. 2010 Apr-Jun;13(2-3):148-51. Acetyl-L-carnitine supplementation to old rats partially reverts the age- related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha-dependent mitochondrial biogenesis.

Methods Mol Biol. 2010;610:285-308. Redox homeostasis and cellular stress response in aging and neurodegeneration.

Geriatr Gerontol Int. 2010 Jul;10 Suppl 1:S99-106. Acetyl-L-carnitine improves aged brain function.

Aging Cell. 2010 Aug;9(4):570-9. Epub 2010 Jun 9. Acetyl-L-carnitine protects yeast cells from apoptosis and aging and inhibits mitochondrial fission.

J Psychiatr Pract. 2010 Jan;16(1):5-14. Clinical outcomes and low-dose levocarnitine supplementation in psychiatric inpatients with documented hypocarnitinemia: a retrospective chart review.

Methods Mol Biol. 2010;610:285-308. Redox homeostasis and cellular stress response in aging and neurodegeneration.

Invest Ophthalmol Vis Sci. 2010 Jan;51(1):430-6. Epub 2009 Aug 13. Involvement of OCTN2 in the transport of acetyl-L-carnitine across the inner blood-retinal barrier.

Arq Bras Endocrinol Metabol. 2010 Feb;54(1):37-44.

3 Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson's disease.

J Altern Complement Med. 2010 Mar;16(3):235-49. Alternative medical interventions used in the treatment and management of myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia.

J Neurochem. 2010 Apr 1;113(2):515-29. Altered brain phospholipid and acylcarnitine profiles in propionic acid infused rodents: further development of a potential model of autism spectrum disorders.

IUBMB Life. 2010 May;62(5):357-62. Acetyl-l-carnitine increases artemin level and prevents neurotrophic factor alterations during neuropathy.

Ageing Res Rev. 2010 Mar 17. Mechanistic contribution of carnitine deficiency to geriatric frailty.

Nutr Metab (Lond). 2010 Apr 16;7:30. Role of carnitine in disease.

Schizophr Bull. 2010 May 21. [Epub ahead of print] Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents.

2009 J Neurol Sci. 2009 Aug 15;283(1-2):199-206. The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease.

Nutr Res. 2009 Jan;29(1):70-4. Dietary supplementation with a combination of alpha-lipoic acid, acetyl-L-carnitine, glycerophosphocoline, docosahexaenoic acid, and phosphatidylserine reduces oxidative damage to murine brain and improves cognitive performance.

J Biol Chem. 2009 Aug 21;284(34):22840-52. Epub 2009 Jun 24. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control.

Exp Brain Res. 2009 Aug;197(3):287-96. Epub 2009 Jun 30. Early nerve ending rescue from oxidative damage and energy failure by L: -carnitine as post- treatment in two neurotoxic models in rat: recovery of antioxidant and reductive capacities.

Ann Clin Psychiatry. 2009 Oct-Dec;21(4):213-36. Novel and emerging treatments for autism spectrum disorders: a systematic review.

Mol Vis. 2009 Jul 31;15:1485-91.

4 Evaluation of lenticular antioxidant and redox system components in the lenses of acetyl-L-carnitine treatment in BSO-induced glutathione deprivation.

Altern Ther Health Med. 2009 Jul-Aug;15(4):34-43. Syndrome of allergy, apraxia, and malabsorption: characterization of a neurodevelopmental phenotype that responds to omega 3 and vitamin E supplementation.

Optom Vis Sci. 2009 Feb;86(2):E132-8. L-carnitine and short chain ester in tears from patients with dry eye.

Front Biosci. 2009 Jan 1;14:376-97. Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative diseases.

Exp Eye Res. 2009 May;88(5):938-44. The effect of acetyl-L-carnitine on lenticular calpain activity in prevention of selenite-induced cataractogenesis.

Vestn Oftalmol. 2009 Sep-Oct;125(5):34-7. Stress protection therapy in the prevention of macular morphological lesions in patients with diabetes mellitus at cataract microsurgery.

2008 Drugs R D. 2008;9 Suppl 1:3-14. The aging eye and the role of L-carnitine and its derivatives.

Expert Opin Investig Drugs. 2008 Jun;17(6):827-43. Acetyl-L-carnitine and alpha-lipoic acid: possible neurotherapeutic agents for mood disorders?

J Neurochem. 2008 May;105(3):677-89. Epub 2008 Jan 10. Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects of L-carnitine.

Clin Exp Pharmacol Physiol. 2008 Feb;35(2):168-73. Changes in redox ratio and protein glycation in precataractous lens from fructose-fed rats: effects of exogenous L-carnitine.

Neurosurg Rev. 2008 Apr;31(2):205-13; discussion 213. Vitamin E and L-carnitine, separately or in combination, in the prevention of radiation-induced brain and retinal damages.

Arch Gerontol Geriatr. 2008 Mar-Apr;46(2):181-90. Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue.

Altern Med Rev. 2008 Jun;13(2):85-115. Alzheimer's disease, amnestic mild cognitive impairment, and age-associated memory impairment: current understanding and progress toward integrative prevention.

Drugs R D. 2008;9 Suppl 1:15-22 Ocular disorders secondary to systemic disease and the potential role of carnitines.

Drugs R D. 2008;9 Suppl 1:23-32. Inherited ocular disorders, ophthalmic procedures and carnitines.

Drugs R D. 2008;9 Suppl 1:15-22.

5 Ocular disorders secondary to systemic disease and the potential role of carnitines.

2007 Neuromolecular Med. 2007;9(3):264-9. Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine on cognitive performance and aggression in normal mice and mice expressing human ApoE4.

Am J Clin Nutr. 2007 Dec;86(6):1738-44. L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial.

Orv Hetil. 2007 Dec 2;148(48):2259-68. Metabolic therapy for early treatment of age-related macular degeneration

Curr Eye Res. 2007 Nov;32(11):961-71. Acetyl-L-carnitine prevents selenite-induced cataractogenesis in an experimental animal model.

6 Curr Eye Res. 2007 Jun;32(6):575-84. L-carnitine protects human retinal pigment epithelial cells from oxidative damage.

Neuromolecular Med. 2007;9(3):264-9. Effects of dietary supplementation with N-acetyl cysteine, acetyl-L-carnitine and S-adenosyl methionine on cognitive performance and aggression in normal mice and mice expressing human ApoE4.

Reproduction:

Free Radic Biol Med. 2010 Aug 15;49(4):674-81. Effect of oxidative stress during repeated ovulation on the structure and functions of the ovary, oocytes, and their mitochondria.

J Endocrinol Invest. 2010 Apr 22. Acetyl-L-Carnitine (ALC) administration positively affects reproductive axis in hypogonadotropic women with functional hypothalamic amenorrhea.

EXS. 2010;100:397-460. Pro-inflammatory and oxidative stress pathways which compromise sperm motility and survival may be altered by L-carnitine.

Nutr Metab (Lond). 2010 Apr 16;7:30. Role of carnitine in disease.

Cell Tissue Res. 2009 Aug;337(2):269-80. Carnitine reduces testicular damage in rats treated with etoposide in the prepubertal phase.

Hum Reprod. 2008 Jul;23(7):1602-6. Serum total L-carnitine levels in non-obese women with polycystic ovary syndrome.

Cell Biochem Funct. 2007 Nov-Dec;25(6):611-8. Protective effect of L-carnitine on testicular ischaemia-reperfusion injury in rats.

Zhonghua Nan Ke Xue. 2006 Aug;12(8):726-9. Carnitines and male reproduction

Cardiovascular/Diabetes/Respiratory:

2010

Endocr Res. 2010 May;35(2):51-8.

7 Inspiratory muscle strength is correlated with carnitine levels in type 2 diabetes.

Diabetologia. 2010 Jun;53(6):1210-6. Epub 2010 Mar 9. Type 2 diabetes impairs pulmonary function in morbidly obese women: a case-control study.

Intern Med. 2010;49(16):1717-25. Epub 2010 Aug 13. Sibutramine and L-carnitine compared to sibutramine alone on insulin resistance in diabetic patients. Nutr Metab (Lond). 2010 Apr 16;7(1):30. Role of carnitine in disease.

Metabolism. 2010 Apr 26. [Epub ahead of print] Effects of combination of sibutramine and l-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients.

Endocr J. 2010 Jul 30. [Epub ahead of print] Orlistat and L-carnitine compared to orlistat alone on insulin resistance in obese diabetic patients.

JPEN J Parenter Enteral Nutr. 2010 May-Jun;34(3):295-9. Caloric restriction and L-carnitine administration improves insulin sensitivity in patients with impaired glucose metabolism.

Diabetes. 2010 Aug 3. [Epub ahead of print] Increased ROS production and lower abundance of complex I subunits and carnitine palmitoyltransferase 1B protein despite normal mitochondrial respiration in insulin resistant human skeletal muscle.

Eur J Clin Invest. 2010 Jul 29. [Epub ahead of print] Effects of acetyl-L-carnitine and oxfenicine on aorta stiffness in diabetic rats.

8 Schizophr Bull. 2010 May 21. [Epub ahead of print] Atypical Antipsychotics Rapidly and Inappropriately Switch Peripheral Fuel Utilization to Lipids, Impairing Metabolic Flexibility in Rodents.

Endocr Res. 2010 May;35(2):51-8. Inspiratory muscle strength is correlated with carnitine levels in type 2 diabetes.

Toxicol In Vitro. 2010 Apr 3. Natural Antioxidants and Hypertension: Promise and Challenges.

Cardiovasc Ther. 2010 Mar 29. The therapeutic prospects of using l-carnitine to manage hypertension-related organ damage.

Arq Bras Endocrinol Metabol. 2010 Feb;54(1):37-44. The supplementation of L-carnitine does not promote alterations in the resting metabolic rate and in the use of energetic substrates in physically active individuals.

J Cell Mol Med. 2010 Jan;14(1-2):215-25. Clinical efficacy of intravenous L-carnitine in patients with right-sided heart failure induced by pulmonary arterial hypertension.

2009

Diabetes Metab Res Rev. 2009 Sep;25 Suppl 1:S45-9. Carnitine and type 2 diabetes.

Diabetol Metab Syndr. 2009 Oct 16;1(1):17. Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats.

World J Pediatr. 2009 Feb;5(1):60-2. Serum total and free carnitine levels in children with asthma.

Hypertension. 2009 Sep;54(3):567-74. Epub 2009 Jul 20. Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy.

Curr Clin Pharmacol. 2009 Jan;4(1):4-37. State of the art clinical efficacy and safety evaluation of N-acetylcarnosine dipeptide ophthalmic prodrug. Principles for the delivery, self-bioactivation, molecular targets and interaction with a highly evolved histidyl-hydrazide structure in the treatment and therapeutic management of a group of sight-threatening eye diseases.

J Biol Chem. 2009 Aug 21;284(34):22840-52. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control.

Diabetes. 2009 Mar;58(3):550-8. Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance.

9 J Physiol Biochem. 2009 Sep;65(3):225-33. Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress.

Curr Med Res Opin. 2009 Sep;25(9):2223-8. Effect of propionyl-L-carnitine, L-arginine and nicotinic acid on the efficacy of vardenafil in the treatment of erectile dysfunction in diabetes.

Hypertension. 2009 Sep;54(3):567-74.. Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy.

Expert Opin Pharmacother. 2009 Aug;10(12):1875-82. Effects of simvastatin and carnitine versus simvastatin on lipoprotein(a) and apoprotein(a) in type 2 diabetes mellitus.

Metabolism. 2009 Nov;58(11):1618-23. Effect of L-carnitine on the size of low-density lipoprotein particles in type 2 diabetes mellitus patients treated with simvastatin.

Am J Clin Nutr. 2009 Jan;89(1):71-6. L-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes.

Nutr Metab (Lond). 2009 Jun 2;6:25. Effect of oral acetyl L-carnitine arginate on resting and postprandial blood biomarkers in pre- diabetics.

Pathophysiology. 2009 Jun;16(1):53-56.. Effect of short term treatment of L-carnitine on tissue ACE activity in streptozotocin-induced diabetic rats.

Am J Clin Nutr. 2009 Jan;89(1):71-6. Epub 2008 Dec 3. L-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes.

J Nutr. 2009 Jun;139(6):1073-81. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women.

Diabetes Metab Res Rev. 2009 Sep;25 Suppl 1:S45-9. Carnitine and type 2 diabetes.

Diabetol Metab Syndr. 2009 Oct 16;1(1):17. Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats.

2008

Asia Pac J Clin Nutr. 2008;17 Suppl 1:306-8. Effects of L-carnitine on obesity, diabetes, and as an ergogenic aid.

10 Ann Pharmacother. 2008 Nov;42(11):1686-91.. Role of acetyl-L-carnitine in the treatment of diabetic peripheral neuropathy.

Clin Drug Investig. 2008;28(8):495-500. Thioctic acid and acetyl-L-carnitine in the treatment of sciatic pain caused by a herniated disc: a randomized, double-blind, comparative study.

Urol Int. 2008;81(3):340-6. L-carnitine treatment partially restores urinary bladder function of streptozotocin diabetic rats.

Pharmacol Ther. 2008 Nov;120(2):149-56. Carnitine in metabolic disease: potential for pharmacological intervention.

Ann Nutr Metab. 2008;52(4):335-8. Effect of oral L-carnitine administration on insulin sensitivity and lipid profile in type 2 diabetes mellitus patients.

Eur J Pharmacol. 2008 Jul 7;588(2-3):213-6.. Preventive effect of acetyl-L-carnitine on the thermal hypoalgesia in streptozotocin-induced diabetic mice.

2007

Diabetologia. 2007 Apr;50(4):824-32. Carnitine revisited: potential use as adjunctive treatment in diabetes.

1989 Am J Dis Child. 1989 Nov;143(11):1337-9. Relative carnitine insufficiency in children with type I diabetes mellitus.

Valproic Acid:

Pharm Res. 2010 Apr 13. Participation of lipid transport and fatty acid metabolism in valproate sodium-induced hepatotoxicity in HepG2 cells.

Altern Med Rev. 2010 Mar;15(1):76-83. Drugs and pharmaceuticals: management of intoxication and antidotes.

Am J Ther. 2010 Mar 11. Valproate-Induced Hyperacute Hyperammonemic Coma in a Patient With Hypocarnitinemia.

Nutr Metab (Lond). 2010 Apr 16;7:30. Role of carnitine in disease.

Clin Toxicol (Phila). 2009 Feb;47(2):101-11. Carnitine in the treatment of valproic acid-induced toxicity.

Epilepsy Res. 2009 Sep;86(1):32-41. The risk of asymptomatic hyperammonemia in children with idiopathic epilepsy treated with valproate: relationship to blood carnitine status.

11

J Gen Intern Med. 2008 Feb;23(2):210-3. Hyperammonemic encephalopathy caused by carnitine deficiency.

Dig Dis Sci. 2008 Nov;53(11):3018-25. Acetyl-L-carnitine treatment in minimal hepatic encephalopathy.

Dig Dis Sci. 2008 Sep;53(9):2330-3. Is oral L-acyl-carnitine an effective therapy for hepatic encephalopathy? Review of the literature.

J Am Board Fam Med. 2007 Sep-Oct;20(5):499-502. Valproate-associated hyperammonemic encephalopathy.

Hum Exp Toxicol. 2007 Dec;26(12):967-9. Two cases of valproic acid poisoning treated with L-carnitine

Klin Padiatr. 2006 Sep-Oct;218(5):260-3. Asymptomatic carnitine depletion on ketogenic diet in patients with pharmacoresistant epilepsies.

Miscellaneous:

Zhonghua Xin Xue Guan Bing Za Zhi. 2010 Feb;38(2):152-5 Quantitative Measurement of Plasma 3-Hydroxyisovaleryl Carnitine by LC-MS/MS as a Novel Biomarker of Biotin Status in Humans.

Anal Chem. 2010 Apr 16. Enhanced Bioavailability of L-Carnitine After Painless Intradermal Delivery vs. Oral Administration in Rats.

Drug Discov Today. 2010 Apr 2. Acetyl-L-carnitine - monograph.

Curr Opin Pharmacol. 2010 Mar 29. Enzymology of the carnitine biosynthesis pathway.

Oxid Med Cell Longev. 2009 Apr;2(2):73-81. Metabolic myopathies: the challenge of new treatments.

J Physiol Biochem. 2009 Sep;65(3):225-33. Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress.

12

Here are the 310 carnitine references that have appeared since January 1 of this year. They are not sorted … just a PubMed search. Cathy B.

1. Effect of oxidative stress during repeated ovulation on the structure and functions of the ovary, oocytes, and their mitochondria. Miyamoto K, Sato EF, Kasahara E, Jikumaru M, Hiramoto K, Tabata H, Katsuragi M, Odo S, Utsumi K, Inoue M. Free Radic Biol Med. 2010 Aug 15;49(4):674-681. Epub 2010 Jun 8.PMID: 20621580 [PubMed - as supplied by publisher]Related citations

2. Effects of trans-10,cis-12 CLA on liver size and fatty acid oxidation under energy restriction conditions in hamsters. Lasa A, Simón E, Churruca I, Fernández-Quintela A, Macarulla MT, Martínez JA, Portillo MP. Nutrition. 2010 Jul 8. [Epub ahead of print]PMID: 20619605 [PubMed - as supplied by publisher]Related citations

3. Ethylene Glycol Monomethyl Ether-Induced Toxicity is Mediated through the Inhibition of Flavoprotein Dehydrogenase Enzyme Family. Takei M, Ando Y, Saitoh W, Tanimoto T, Kiyosawa N, Manabe S, Sanbuissho A, Okazaki O, Iwabuchi H, Yamoto T, Adam KP, Weiel JE, Ryals JA, Milburn MV, Guo L. Toxicol Sci. 2010 Jul 8. [Epub ahead of print]PMID: 20616209 [PubMed - as supplied by publisher]Related citations

4. Synthesis and biological evaluation of cyclic nitrogen mustards based on carnitine framework. Leiris S, Lucas M, Dupuy d'Angeac A, Morère A. Eur J Med Chem. 2010 Jun 9. [Epub ahead of print]PMID: 20615582 [PubMed - as supplied by publisher]Related citations

5. NPY neuron-specific Y2 receptors regulate adipose tissue and trabecular bone but not cortical bone homeostasis in mice. Shi YC, Lin S, Wong IP, Baldock PA, Aljanova A, Enriquez RF, Castillo L, Mitchell NF, Ye JM, Zhang L, Macia L, Yulyaningsih E, Nguyen AD, Riepler SJ, Herzog H, Sainsbury A. PLoS One. 2010 Jun 29;5(6):e11361.PMID: 20613867 [PubMed - in process]Free PMC ArticleFree textRelated citations

6. Dilated cardiomyopathy in epidermolysis bullosa: a retrospective, multicenter study. Lara-Corrales I, Mellerio JE, Martinez AE, Green A, Lucky AW, Azizkhan RG, Murrell DF, Agero AL, Kantor PF, Pope E. Pediatr Dermatol. 2010 May;27(3):238-43.PMID: 20609141 [PubMed - in process]Related citations

7. [Expressions of sperm-specific genes in carnitine-cultured testis sperm of obstructive azoospermia patients] Shi JZ, Zhang SS, Zhang Z, Liang Q, Shi Y, Hua JL, Sun T. Zhonghua Nan Ke Xue. 2010 Jun;16(6):504-9. Chinese. PMID: 20608353 [PubMed - in process]Related citations

8. Cannabinoid receptor 1 and 2 agonists increase lipid accumulation in hepatocytes. De Gottardi A, Spahr L, Ravier-Dall'antonia F, Hadengue A. Liver Int. 2010 Jun 29. [Epub ahead of print]PMID: 20602678 [PubMed - as supplied by publisher]Related citations

9. Functional Expression of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in mouse small intestine and liver. Sugiura T, Kato S, Shimizu T, Wakayama T, Nakamichi N, Kubo Y, Iwata D, Suzuki K, Soga T, Asano M, Iseki S, Tamai I, Tsuji A, Kato Y. Drug Metab Dispos. 2010 Jul 2. [Epub ahead of print]PMID: 20601551 [PubMed - as supplied by publisher]Related citations

10. Molecular characterization of a gilthead sea bream (Sparus aurata) muscle tissue cDNA for carnitine palmitoyltransferase 1B (CPT1B). Boukouvala E, Leaver MJ, Favre-Krey L, Theodoridou M, Krey G. Comp Biochem Physiol B Biochem Mol Biol. 2010 Jun 23. [Epub ahead of print]PMID: 20601065 [PubMed - as supplied by publisher]Related citations

11. Metformin selectively attenuates mitochondrial H(2)O(2) emission without affecting respiratory capacity in skeletal muscle of obese rats. Kane DA, Anderson EJ, Price JW 3rd, Woodlief TL, Lin CT, Bikman BT, Cortright RN, Neufer D. Free Radic Biol Med. 2010 Jun 28. [Epub ahead of print]PMID: 20600832 [PubMed - as supplied by publisher]Related citations

12. Why We Should be Vigilant: Drug Cytotoxicity Observed with In Vitro Transporter Inhibition Studies. Zheng X, Diao L, Ekins S, Polli JE. Biochem Pharmacol. 2010 Jun 23. [Epub ahead of print]PMID: 20599790 [PubMed - as supplied by publisher]Related citations

13. Crystal structure of human gamma-butyrobetaine hydroxylase. Tars K, Rumnieks J, Zeltins A, Kazaks A, Kotelovica S, Leonciks A, Saripo J, Viksna A, Kuka J, Liepinsh E, Dambrova M. Biochem Biophys Res Commun. 2010 Jul 1. [Epub ahead of print]PMID: 20599753 [PubMed - as supplied by publisher]Related citations

14. AMPK activation represses the human gene promoter of the cardiac isoform of acetyl-CoA carboxylase: Role of nuclear respiratory factor-1. Adam T, Opie LH, Essop MF. Biochem Biophys Res Commun. 2010 Jul 1. [Epub ahead of print]PMID: 20599696 [PubMed - as supplied by publisher]Related citations

15. Acetyl-L-Carnitine for Alcohol Craving and Relapse Prevention in Anhedonic Alcoholics: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial. Martinotti G, Reina D, Di Nicola M, Andreoli S, Tedeschi D, Ortolani I, Pozzi G, Iannoni E, D'Iddio S, Janiri L. Alcohol Alcohol. 2010 Jun 30. [Epub ahead of print]PMID: 20595193 [PubMed - as supplied by publisher]Related citations 16. L-carnitine for acute valproic Acid overdose: a systematic review of published cases. Perrott J, Murphy NG, Zed PJ. Ann Pharmacother. 2010 Jul-Aug;44(7-8):1287-93. Epub 2010 Jun 29.PMID: 20587742 [PubMed - in process]Related citations

17. Clinical correlates of low serum carnitine levels in hospitalized psychiatric patients. Cuturic M, Abramson RK, Moran RR, Hardin JW, Hall AV. World J Biol Psychiatry. 2010 Jun 29. [Epub ahead of print]PMID: 20586533 [PubMed - as supplied by publisher]Related citations

18. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Musso G, Gambino R, Cassader M, Pagano G. Hepatology. 2010 Jul;52(1):79-104.PMID: 20578268 [PubMed - in process]Related citations

19. Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency. Li FY, El-Hattab AW, Bawle EV, Boles RG, Schmitt ES, Scaglia F, Wong LJ. Hum Mutat. 2010 Jun 22. [Epub ahead of print]PMID: 20574985 [PubMed - as supplied by publisher]Related citations

20. [Effects of carnitine on peripheral blood mitochondrial DNA copy number and liver function in non- alcoholic Fatty liver disease.]

22. Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan. Niu DM, Chien YH, Chiang CC, Ho HC, Hwu WL, Kao SM, Chiang SH, Kao CH, Liu TT, Chiang H, Hsiao KJ. J Inherit Metab Dis. 2010 Jun 22. [Epub ahead of print]PMID: 20567911 [PubMed - as supplied by publisher]Related citations

23. Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications. Al-Hassnan ZN, Imtiaz F, Al-Amoudi M, Rahbeeni Z, Al-Sayed M, Al-Owain M, Al-Zaidan H, Al-Odaib A, Rashed MS. J Inherit Metab Dis. 2010 Jun 22. [Epub ahead of print]PMID: 20567907 [PubMed - as supplied by publisher]Related citations

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25. Checks before bolus epidural injection. Wildsmith JA. Anaesthesia. 2010 Jun;65(6):650; author reply 650-1. No abstract available. PMID: 20565404 [PubMed - indexed for MEDLINE]Related citations

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61. Metabolism of acetyl-l-carnitine for energy and neurotransmitter synthesis in the immature rat brain. Scafidi S, Fiskum G, Lindauer SL, Bamford P, Shi D, Hopkins I, McKenna MC. J Neurochem. 2010 May 13. [Epub ahead of print]PMID: 20477950 [PubMed - as supplied by publisher]Related citations

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108. Stevia rebaudiana Bertoni extract supplementation improves lipid and carnitine profiles in C57BL/6J mice fed a high-fat diet. Park JE, Cha YS. J Sci Food Agric. 2010 May;90(7):1099-105.PMID: 20393989 [PubMed - in process]Related citations

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217. L-carnitine modulates blood platelet oxidative stress. Saluk-Juszczak J, Olas B, Wachowicz B, Glowacki R, Bald E. Cell Biol Toxicol. 2010 Aug;26(4):355-65. Epub 2010 Jan 13.PMID: 20069352 [PubMed - in process]Related citations

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