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Home , Folate deficiency, Vitamin deficiency

■ clinical review The Role of Folic Acid in Deficiency States and Prevention of Disease

Randall A. Swain, MD, and Linda St. Clair, MS, RD Charleston, West Virginia

Folic acid, a water-soluble , has been used the assumption that supplements may prevent since the 1940s to treat some cases of macrocytic ane­ heart disease, stroke, and peripheral arterial disease. mia without neurologic disease. is Controlled trials should take place before widespread best diagnosed with folate levels along supplementation with folate is carried out on a with macrocytosis and/or megaloblastic . In large scale because of the possibility of outbreaks of addition to reversing overt deficiency, the vitamin may permanent Bi2-related neurologic damage in those reduce the incidence of neural tube defects by 45% in with undiagnosed pernicious anemia. Flowever, if a women who receive 400 gg per day. It is recommend­ patient has a premature cardiovascular event and has ed that all women of childbearing age take 400 gg of minimal risk factors, ordering a test to determine folate per day. Elevations in levels, a homocysteine level may be advisable, and if elevated, metabolite intimately associated with folate, are also treating with folic acid supplement as long as B12 defi­ being found with increasing regularity in those with car­ ciency does not coexist. diovascular diseases. Flomocysteine levels are reduced KEY WORDS. Folic acid; primary prevention; homo­ by folic acid administration. Therefore, there is some cysteine; atherosclerosis; neural tube defects. (J Frn biologic plausibility, but not currently direct proof, for Pract 1997:44:138-144)

olic acid or pteroylglutamic acid was first normality is about 50 pg. The results o f a 1961 synthesized and named in the 1940s. study1 concluded that 50 pg per day o f folate would Cases o f macrocytic anemia that ulti­ meet the minimum daily requirement (M D R ). The mately responded to yeast (in which study was conducted at a Boston hospital using a folate is present in large amounts) were synthetic diet devoid o f folic acid. On this diet, describedF shortly thereafter. Since that time folate patients developed overt has kept a relatively low profile while other within a few days. When patients were given 50 fig such as the antioxidants have been touted for dis­ per day o f folate orally, the deficiency resolved ease prevention and treatment. Recently, however, along with the anemia. medical findings are thrusting this important vitamin There is a difference between the MDR and the into the “prevention spotlight.” In this article, basic recommended daily allowance (RDA). The MDR, as information about folic acid and deficiency states mentioned above, is 50 tolOO pg per day, while the are reviewed, and the newer concepts of the use of RDA is set at 200 pg per day for adult men and 180 folate for prevention o f neural tube defects and car­ pg per day for adult women. The RDA for folate is diovascular disease are presented. arbitrarily set at a level that is neither the MDR nor necessarily the optimal level o f intake, but the level FOLIC ACID BASICS o f intake that, on the basis o f scientific knowledge, is judged to be adequate to meet the known needs The minimum daily requirement or the amount of o f almost all healthy persons.2 folate from exogenous sources needed to sustain The World Health Organization has also recom­ mended an intake of around 200 pg per day.3 This Submitted, revised, December 26, 1996. would provide about a 3- to 4-month supply in the From the Department o f Family and Sports Medicine, West Virginia University-Charleston Division, and Lifefit Diet event o f zero intake. Americans usually take in only Modification Center, Corporate Health Services, Charleston, 200 to 300 pg per day, according to the US West Virginia. Requests fo r reprints should be addressed to Department of Health and Human Services. This Randall A. Swain, MD, Department o f Family and Sports Medicine, West Virginia University—Charleston Division, was substantiated in the third National Health and 1201 Washington St East, Suite 108, Charleston, WV 25301. Nutrition Examination Survey (NHANES) study,

138 The Journal o f Family Practice, Vol. 44, No. 2 (Feb), 1997 THE ROLE OF FOLIC ACID

which documented that in a sample size of over Stage 1: Early negative folate balance with 14,000 subjects, men ate a mean o f 317 pg per day decreased serum folate levels but normal (median, 266 pg per day) o f folate while women ate folate stores as indicated by a normal red a mean of 236 pg per day (median, 195 pg per day).4 blood cell (RBC) folate level. Herbert5 found that the percentage o f total folate in , yeast, and egg yolk that is absorbed is very Stage 2: Folate depletion both in serum values high; but the absorbability of the forms of folate in and RBC folate levels. most other is probably in the range o f 10%. - ♦ The Food and Nutrition Board reported that the Stage 3: Folate-deficient red cell production bioavailability o f folate in the typical US diet is resulting in increasing but not yet gross­ about one half o f crystalline (in vitamins) folic acid, ly abnormal red cell indices and hyper­ which is efficiently absorbed. The average amount segmentation o f neutrophils. of folate stored in the body is 5 to 10 mg, one half of which is present in the liver. Enterohepatic circula­ Stage 4: Clinical folate deficiency with macrocyt­ tion is thought to play a role in the maintenance o f ic anemia. folate levels. ingestion, however, interferes with this process and usually causes a negative A diagnosis o f deficiency is based on findings o f folate balance. macrocytosis with or without anemia or on a sus­ Folic acid is abundantly present in most food pected deficiency based on high likelihood (Table groups. Foods with the highest amounts o f folate 1). Unlike B12 deficiency, folic acid deficiency does include yeast, fresh green vegetables, organ not usually cause neurologic damage. Rare reports meats, and some fresh fruits. Unfortunately, have indicated that folate deficiency may lead to a folate is highly susceptible to destruction, up to subacute spinal cord syndrome with gait distur­ 50% by cooking or processing.67 Retention of bance, , and loss of position sense.8 folate is basically the same whether foods are Serum folate levels are notoriously unreliable, as cooked in a m icrowave or on a conventional they may fluctuate from day to day because of range.7 In general, cooking recommendations for dietary changes. The RBC folate level is a much retention of folate are similar to those for any better indicator o f folate status. Deficiency states water-soluble vitamin: minimal contact o f the are best treated by a daily oral dose of 1 mg per day vegetable with the cooking water reduces loss o f o f folic acid. Doses larger than this are excreted in due to the solution.7 Using a small the . with folic acid administration is amount of cooking water when a vegetable is exceedingly rare. Although doses of 15 mg intra­ boiled is recom m ended fo r this reason. venously in a nonconvulsive patient have been Vegetables should be cooked only until crisp-ten­ reported to be without known problems,9 some der (barely done). in a steamer or in a sources have noted that intravenous doses over 15 pressure cooker also reduces contact with the mg may cause epileptiform activity in humans.10 No water. The vitamin is absorbed from food sources such findings have been noted to date with large by the proximal third of the small intestine. The oral doses of folate. The mechanism of this inter­ manner in which the vitamin is transferred to the action may be that folate competes with anti­ circulation is not w ell understood. epileptic agents for binding positions in both the intestine and the brain.10 MACROCYTIC ANEMIA AND FOLATE Folate deficiency will often be found in the elder­ ly, alcoholics, the poor, patients Like all nutritional deficiencies, folate deficiency receiving long-term therapy, and AIDS may be caused by a number of factors, including patients using sulfa drugs or pentamidine for pneu- inadequate ingestion, inadequate absorption, inad­ mocystis prophylaxis. Previous articles have stated equate utilization, increased requirement, that alcohol abuse is the most common cause of increased excretion, or increased destruction. This folate deficiency in this country.11 Studies on the process of deficiency may be divided into four pro­ cause o f macrocytosis with or without anemia have gressive clinical stages. provided conflicting evidence. In two studies the

The Journal o f Family Practice, Vol. 44, No. 2 (Feb), 1997 1 39 THE ROLE OF FOLIC ACID

leading cause was found to be vitamin B 12 or folate refuted this.15 Patients taking both 5 mg and 27.5 mg deficiency, followed closely by alcohol abuse.12,13 In per week of folate had significantly less toxicity another study, however, an overwhelming prepon­ than their counterparts on placebo. Investigators derance o f alcohol abuse was revealed to be the noticed no deceased efficacy, however. cause, followed by .14 The most common cause most likely differs according to the THE RELATIONSHIP OF B12 AND patient population being seen. FOLATE Any patient at risk for vitamin deficiency with significant macrocytosis with or without anemia Folic acid and cobalmin () are closely should have a serum B 12 and RBC folate determina­ related, as the latter helps recycle folic acid for tion. If both the RBC folate and the B12 levels are reuse in the homocysteine-to- reaction. abnormal, further metabolic testing with serum or They both serve as cofactors in this important urine determination of homocysteine and methyl­ cycle. Both RBC folate levels16 and serum folate malonic acid levels may be necessary. Elevations in levels17 are reduced by cobalmin deficiency. homocysteine levels and borderline or low RBC Despite this, these levels are reduced much more folate levels usually indicate folate deficiency as by folic acid deficiency. Homocysteine levels and long as B12 levels are above 350 pg/mL. Those being methylmalonic acid levels may be combined with treated with the above-mentioned medications on a RBC folate and serum B12 levels to effectively diag­ long-term basis should be given prophylactic folic nose both deficiency states (Table 2). It is essential acid at a dose o f 1 mg per day. Although methotrex­ to diagnose the correct deficiency state because ate was thought to exert its anti-rheumatic effects the treatment of cobalmin deficiency with folate by folic acid antagonism, recent studies have may result in an inappropriate improvement in

TABLE 1

Causes of Folate Deficiency

Cause of Deficiency Specific Examples in Humans

Inadequate ingestion and poor intake of fresh uncooked fruits and vegetables (rare in U.S. except in cases of ethanol abuse)

Inadequate absorption Disease Gluten enteropathy; sprues; congenital enzyme deficiency Drugs ; ethanol; ; cholestyramine; azulfidine, oral contraceptives

Inadequate utilization Metabolic blocks Folic acid antagonists Methotrexate; ; ; pentamidine; some anticonvulsants Enzyme deficiency Congenital or due to liver diseases Decreased folate uptake Alcohol deficiency

Increased requirements Extra demand , cancer, lactation Infancy Increased red cell production

Increased excretion Kidney or B 12 deficiency

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TABLE 2

Meaning of Laboratory Results in Folate or B12 Deficiency

Laboratory Test Folic Acid Deficiency B12 Deficiency

Serum folate Reduced or Normal Normal or mildly reduced Serum B12 Normal Reduced or normal MCV on CBC Increased or normal Increased or normal Homocysteine Increased Increased or normal RBC folate Reduced Normal Methylmalonic acid Normal unless renal insufficiency Increased often rarely normal Antibody to parietal cell or Absent Present if due to pernicious anemia intrinsic factor Serum gastrin Normal Increased most often but can be normal

MCV on CBC denotes mean corpuscular volume on .

hematologic levels but may also cause deteriora­ chance of NTDs by 48% and higher dosages are tion in the neurologic status of the patient.1819 If estimated not to be any more effective.27 after testing a determination cannot be made about Many researchers and health officials have stated which deficiency exists, only one specific vitamin that increasing foods high in folate in the diet would should be given, and the homocysteine and methyl­ also reduce the incidence of NTDs. This does not malonic acid levels should be followed serially to seem to be true. In a recent British trial, eating an determine which vitamin is causing the deficiency. additional 0.4 mg per day o f folic acid naturally Patients in whom cobalmin deficiency should be found in food was compared with foods fortified suspected include the elderly, patients on anti­ with similar amounts o f folate and with folate sup­ ulcer medication, AIDS patients, vegetarians, plements.28 In these three groups, effects on RBC patients who have undergone bow el surgery, and folate were monitored over 3 months. There was no patients with . A recent review on B12 significant change in levels in those assigned to the deficiency has been published in this journal if fur­ natural source group, while those in the other two ther information is o f interest.20 groups had significant elevations in their levels. Therefore, it seems most prudent to advise supple­ FOLATE AND PREVENTION OF NEURAL mentation for all women of childbearing age. TUBE DEFECTS The reason folate is effective in reducing the inci­ dence o f NTDs is not clear. It may be due to a subtle The effectiveness of multivitamins in preventing folate deficiency during early pregnancy when the neural tube defects (NTDs) was reported in 1991 is forming neural tissue. It is known that the by the Medical Research Council21 and again in fetal and uterine placental units require much larger 1992 by Czeizel and Dudas.22 Other studies have amounts o f the coenzyme folate than the nonpreg­ showed that folic acid alone may prevent both nant woman.29 Up to one third o f all first-time occurrence o f NTD and recurrent worldwide are complicated by folate deficiencies, NTDs.23'27 Investigators and several while US pregnancies are only affected 1% to 4% of bodies have recommended that all women of child­ the time.30 The incidence is increased up to eight bearing age should receive a 0.4-mg supplement times by multiple gestations, teenaged pregnancies, per day of folate. Women who have had a previous and closely spaced successive pregnancies.30 These child with an NTD should receive 4 to 5 mg per day low folate levels have been found with increased fre­ as near to the time o f conception as possible and quency in those mothers with NTD babies as com­ during early pregnancy. Following these recom­ pared with controls.31 mendations has been postulated to reduce the A recent case-control study may point to a sec-

The Journal of Family Practice, Vol. 44, No. 2 (Feb), 1997 1 41 THE ROLE OF FOLIC ACID

ond possible cause. These authors studied 41 moth­ were found to have the highest levels of fatal ers who gave birth to babies with NTDs and com­ myocardial infarction. This group had an overall pared them with 50 controls.32 In this study the risk 1.69 times that o f those with the highest folate metabolite homocysteine, which uses folate as a levels. cofactor in its conversion, was studied. Previous Homocystinemia does not appear to be a risk fac­ studies had shown that homocysteine levels in nor­ tor solely for ischemic heart disease either. A recent mal pregnancies in healthy women tend to cross-sectional study involving over 1000 elderly decrease.33 The women with NTD births all had high­ patients from the Framingham cohort was per­ er baseline homocysteine levels or had increased formed to analyze the risk o f strokes.39 Forty-three homocysteine levels with a methionine load. This percent o f the men and 34% o f the women had more makes the elevated homocysteine levels a possible than a 25% stenosis o f the carotid arteries. Of these source of increased risk of NTDs through the mech­ subjects, those who had high homocysteine levels anism of as yet unknown congenital biochemical were twice as likely to have this degree o f stenosis defects. Unrelated studies on folic acid and homo­ as their counterparts with lower homocysteine lev­ cysteine have shown that folate administration els. Plasma folate levels and intake o f dietary folate alone or in combination with reduces were both inversely associated with the degree of homocysteine levels. (See discussion below on carotid artery stenosis. Another study on stroke risk homocysteine levels and premature cardiovascular was performed with data from the First National disease.) It is not currently recommended by any Health and Nutrition Examination Survey by Giles medical organization that routine folate or homo­ et al.40 This study showed that those patients with cysteine levels be obtained, since all women who low folic acid levels were 1.4 times more likely to are pregnant should be treated with at least 400 pg have a stroke than their counterparts with higher o f folate supplementation. Most prenatal vitamins folic acid levels. Two other studies have had con­ contain this amount of folate. RBC folate levels flicting outcomes. One study using data from the should be obtained in those pregnant women with Physician’s Health Study reported that men with macrocytic anemia or macrocytosis. higher homocysteine levels had 1.2 times the risk of a stroke compared with those with lower homocys­ HOMOCYSTEINE LEVELS AND teine levels.41 Conversely, another study showed no PREMATURE CARDIOVASCULAR such increased risk with elevations in the homocys­ DISEASE teine levels.42 Elevations in the homocysteine levels have also Homocystinuria, which is a rare been postulated to be a risk factor for deep venous associated with very high homocysteine levels, has thrombosis (DVT). Two early studies showed that been known to cause premature atherosclerosis.34 there was a possible association between DVT and Other conditions that are much more common, homocysteine levels both in patients younger than however, including folate deficiency, may elevate age 4043 and in the older population.44 Finally, in a homocysteine levels to a lesser extent.36 Early ret­ case-control format, 269 patients with DVT and 269 rospective case-control studies indicated a possi­ controls had their plasma homocysteine levels deter­ ble relationship of these milder homocysteine ele­ mined.45 Twenty-eight o f 269 patients with DVT had vations and atherosclerotic vascular disease.35,36 A high levels o f homocysteine as compared with only prospective case-control study was later published 13 o f 269 controls. in 1992 that also suggested this assoc­ What can we conclude from all these data? iation.37 This study revealed a mild increase in Homocysteine levels may be just a marker or even a serum levels o f homocysteine in men with myocar­ major risk factor for many forms o f vascular disease. dial infarctions. These increased levels could be A meta-analysis o f 21 studies46 recently was complet­ responsible for a threefold increased incidence of ed to analyze homocysteine. It estimated a risk 1.6 i myocardial infarction after other factors were con­ times greater for heart disease in men and 1.8 for trolled for. A retrospective cohort study recently women for each increase of 5 pmol/L in the homo­ published by Morrison et al38 revealed that those cysteine level. The authors estimated that 10% of the with the lowest ranges of serum folic acid levels population’s risk for coronary artery disease (CAD)

142 The Journal o f Family Practice, Vol. 44, No. 2 (Feb), 1997 THE ROLE OF FOLIC ACID

appears related to elevations in this metabolite. It tal agencies are recommending folate enrichment also seemed to be an independent risk factor for for some foods. Unfortunately, widespread supple­ cerebrovascular disease, as those with high homo­ mentation of food with folate alone may cause out­ cysteine levels were 1.5 times more likely to experi­ breaks of neurologic damage in those with undiag­ ence stroke than those with lower levels. A similar nosed pernicious anemia. effect was seen in peripheral vascular disease. REFERENCES Folate supplementation, according to statistical 1. Zulusky R, Herbert V. Megaloblastic anemia in with analysis, was theorized to be able to prevent 13,500 response to 50 micrograms o f folic acid daily. N Engl J Med to 50,000 CAD deaths per year in the United States. 1961; 265:1033-8. 2. Committee on Dietary Allowances. Recommended dietary To date, it is unclear whether homocysteine is allowances. 10th ed. 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