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Continuing Education

Elevating Awareness and Intake of An Essential for Public Health

Marie Caudill, PhD, RD Steven Zeisel, MD, PhD Kerry-Ann da Costa, PhD Betsy Hornick, MS, RD

Emerging science has revealed that choline plays important Choline is the newest roles in health throughout the life cycle with potentially essential nutrient. serious health consequences associated with inadequate choline intakes. Recent national consumption data indicate that the vast majority of Americans are falling short of recommended intakes. Increased education, including In 2009, the Choline Science Summit was held in Washington, District of Columbia, bringing together recommendations to consume more choline-rich foods, prominent scientists and researchers along with is needed to improve choline intakes for optimal health. leaders from organizations including the American Nutr Today. 2011;46(5):235–241 College of Obstetricians and Gynecologists, American Dietetic Association, American Society for Nutrition, International Life Sciences Institute, National WIC Association, and US Department of Agriculture (USDA). holine was discovered as a in 1862, The symposium addressed the latest science on choline but it was more than a century later that it and gathered insights for helping raise awareness Cwas recognized as an essential nutrient. It was and intake of this essential nutrient, especially among officially recognized as an essential nutrient by the vulnerable populations. It included discussions of Institute of Medicine (IOM) in 1998, and an adequate choline’s critical role in human health and development intake (AI) was established based on estimated throughout the life cycle, the role of genetics in dietary intakes and studies reporting damage determining choline requirements, and a closer look with lower choline intakes.1 Choline is essential for at the gaps in choline requirements compared with liver and brain function, , and for actual intakes. Participants also discussed strategies cellular membrane composition and repair.2 Recent for communicating choline recommendations and advances in the science and understanding of choline including choline in future public health education reveal that it plays a critical role in human health efforts. and development throughout the entire life cycle, A consensus was reached that choline deserves greater beginning with fetal brain and spinal cord recognition in nutrition guidance and public education. development.2,3 Participants agreed that a choline recommendation for Choline was not addressed in the 2005 Dietary special populations, specifically women who are of Guidelines for Americans because consumption childbearing age, pregnant, or lactating, is warranted, data were lacking. However, the development of a and the for choline should database of the choline content of foods now makes be reevaluated. In addition, they recognized that it possible to evaluate the choline content of diets.4 education among health professionals and consumers At the fourth meeting of the 2010 Dietary Guidelines is needed to elevate awareness of the important Advisory Committee, choline was proposed as a roles of choline and increase intake of this essential shortfall nutrient for certain subgroups.5 However, choline nutrient. The highlights of the Choline Science was not designated as a nutrient of concern in the 2010 Summit, including call-to-action conclusions, are Dietary Guidelines. presented here.

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Choline in the Diet Table 2. Dietary Reference Intakes for Choline Choline is often grouped with the vitamin B complex. Life Stage Group Adequate Intake, mg/d It is available in the diet as free choline, a water-soluble Y form, or it may be bound as -soluble esters, such 0 6 mo 125 7Y12 mo 150 as , or . Although the Y human body can produce a limited supply of choline, 1 3 y 200 4Y8 y 250 consuming choline-rich foods is necessary to meet the Y body’s requirements. 9 13 y 375 Females Choline is found in a wide variety of foods; liver, Y eggs, , and are among the richest sources. One 14 18 y 400 19Y70+ y 425 450 Table 1. Selected Food Sources of Choline Lactation 550 Males Choline, 14Y70+ y 550 Food mg/Serving 1 Beef, liver, cooked (3 oz) 355 Source: Food and Nutrition Board, Institute of Medicine. Egg, whole, raw, fresh (1 large) 125 Beef steak, bottom round, cooked (3 oz) 111 egg supplies 125 mg of choline, about one-third to Pork, loin chop, cooked (3 oz) 94 one-half of the daily recommendation.6 Other sources Salmon, chinook, smoked (3 oz) 76 of choline include poultry, salmon, germ, , , breast, cooked (3 oz) 73 nuts, , and some (Table 1). Data Beef, ground, 85% , cooked (3 oz) 70 from the Nurses’ Health Study found animal products, Turkey, light , roasted (3 oz) 70 including eggs, milk, chicken, beef, and pork, to be the Salmon, sockeye, cooked (3 oz) 56 largest sources of choline in the diet.7 Choline is Wheat germ, toasted, plain (2 tbsp) 50 available in supplement form, but many Milk, 1% low fat, with added A 43 and prenatal vitamins do not currently contain choline. and D (1 cup) Baked , canned (½ cup) 40 Pork, Canadian-style (2 slices) 37 Choline Intake Versus Requirements Lima beans, cooked, boiled, 33 Based on estimated dietary intakes and studies reporting drained (½ cup) liver damage with lower choline intakes, the IOM set the , low fat, fruited (8 oz) 32 AI for choline at 425 mg/d for women 19 years or older, , cooked, boiled, drained (½ cup) 31 450 mg/d for pregnant women, and 550 mg/d for lactating , baked, flesh and skin (1) 30 women and for men 19 years or older (Table 2).1 Evidence , cooked, boiled (½ cup) 24 was insufficient to set an estimated average requirement sauce, canned (1 cup) 24 (EAR) and recommended dietary allowance (RDA). Thus, , green, frozen, cooked, 22 the AI serves as a goal for choline intake of individuals, drained (½ cup) and intakes less than this level will not necessarily result , dry roasted (1 oz) 20 in deficiency. Bacon, pork, cured, cooked (2 pieces) 20 , creamy (2 tbsp) 20 Corn, sweet, cooked (½ cup) 18 (1 oz) 15 Increased choline requirements due Frankfurter, beef (1) 15 (1 oz) 12 to genetic variations are more , raw (1) 12 common than we previously thought. , pearled, cooked (½ cup) 10

Source: US Department of Agriculture Database for the Choline Content of Common Foods, Release 2,4 and US Department of Agriculture 6 National Nutrient Database for Standard Reference, Release 22. These When the AI was established in 1998, it was assumed values may vary slightly depending on the method of processing and preparation. that less than 5% of the population was affected by genetic differences that may result in increased choline

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requirements. However, recent research examining Choline in Human Health common variations in genes involved in choline metabolism reveals that a significant proportion of the population Choline’s role in human health begins prenatally carries genetic variants that may increase their requirement and extends into adulthood and old age. Its functions for choline above current recommendations.8,9 Based on this are complex and include synthesis research, it has been proposed that as much as 50% of the (), cell-membrane signaling (), population may have genetic variations that increase their lipid transport (), and methyl-group metabolism 2 choline requirements above current recommendations.9,10 ( conversion to ). In humans, In 2004, a USDA Special Interest Database for choline in dietary deficiency of choline results in liver and muscle foods was created to provide researchers and consumers damage. A more detailed review of choline’s wide-ranging with the means to estimate choline intake; a second roles in human health is published elsewhere.2,3 The release of the database in 2008 provides data for more following overview of key research presented at the summit than 630 foods.4 The database contains values for total emphasizes the role of choline across the life cycle. choline and 6 metabolites of choline: , free choline, glycerophosphocholine, , Pregnancy and Lactation phosphatidylcholine, and sphingomyelin. In 2005, total Demand for choline is especially high during pregnancy choline was included for the first time in the dietary intake 12 and lactation. Recent evidence suggests that pregnancy data collected by ‘‘What We Eat in America’’ (National and lactation present specific windows of opportunity in Health and Nutrition Examination Survey). This survey which adequate choline intake may help improve data revealed that only 10% of individuals had intakes pregnancy outcomes and promote lifelong beneficial at or greater than their AI for choline (A. Moshfegh, 13Y15 effects on and learning. Choline Science Summit, September 10, 2009). Several subpopulations were found to have mean usual intakes well less than the AI, including children 9 years or older; men, especially older men; women; and pregnant women (Figure 1).11 Among males and females, 2 years Choline needs rise in pregnancy or older, mean daily intake of choline was 316 mg/d, and lactation. significantly less than the AI of 425 to 550 mg/d for adults.11 Suboptimal intakes of choline, coupled with evidence that a significant proportion of the population carry genetic variations that may raise choline requirements to levels Large amounts of choline are delivered to the fetus greater than the AI, reinforce the need for intervention across the , and choline concentration in strategies to increase intake of choline-rich foods. is 10-fold greater than that present in

Figure 1. Average daily intake of choline.

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Adequate dietary intake of choline by the pregnant mother and later by the infant is believed to directly affect brain development, possibly enhancing memory and learning functions that endure across the life span. Chemical structure of choline. Extrapolating from animal studies, human sensitivity to the developmental effects of dietary choline could maternal blood.16 Because human milk is rich in choline, continue from to 4 years of age.26 lactation further increases maternal demand.1 Maternal choline supply is critical to support fetal growth, Adulthood including brain development. Although endogenous production of choline increases during pregnancy, the Elevated levels of homocysteine have been associated demand appears to exceed the supply, and dietary in some studies with greater risk for cardiovascular choline is critical to meet the increased requirements.17 disease, , cognitive decline, and bone fractures. Low intakes of choline are associated with elevated levels Choline supplementation, as phosphatidylcholine, was of homocysteine, which may be an important risk factor found to be as effective as folic acid in lowering for several adverse pregnancy outcomes, including homocysteine levels, suggesting that choline may also preeclampsia, prematurity, and very low birth weight.13 play a role in reducing cardiovascular risk.27 Findings Given the similar role played by choline and in from the ATTICA study and the Nurses’ Health Study the conversion of homocysteine to methionine, research revealed that subjects whose diets were rich in choline suggests that choline is also important for neural tube and betaine, a choline metabolite, had improved levels closure.16,18 In a study of maternal periconceptional of several inflammatory markers, including C-reactive intakes of choline and its influence on neural tube defect .28,29 Elevated C-reactive protein has recently risk, researchers found that women in the lowest quartile been recognized by the National Heart, Lung, and Blood for dietary choline intake had 2 times the risk of giving Institute as a useful marker for cardiovascular risk.30 birth to a child with a neural tube defect, compared with High dietary intakes of choline have also been recently women in the highest quartile.15 associated with a decreased risk for certain . In a Recent studies in animal models show that choline case-control study, low dietary choline was associated supplementation during critical periods of fetal/neonatal with increased breast cancer risk and mortality.31 development can have long-term beneficial effects on memory and attention and may help protect against age-related cognitive impairment.19Y22 In rodents, Choline Call to Action: Conclusions choline availability during later periods of pregnancy From the Choline Science Summit and after birth influences the formation of neural stem cells in the memory center of the brain (hippocampus), Our knowledge and understanding of choline have causing lifelong changes in brain structure and function. increased exponentially over the past decade. Recognition Rodent offspring exposed to extra choline in utero did not of the mounting evidence linking inadequate choline show a typical decline in memory with age, suggesting that intake to public health consequences coupled with choline deficiency during pregnancy may be linked to evidence of suboptimal intakes in high-risk populations long-term cognitive impairment.23 Preliminary studies also provided the foundation for bringing together choline suggest that dietary intervention with choline may reduce experts and nutrition leaders for the Choline Science the severity of some fetal effects and may protect Summit. Following presentations of the cutting-edge against damage associated with epileptic seizures.24,25 science on choline, Summit participants convened into Itremainstobeseeniftheseresultsalsoapplytohumans. breakout sessions to begin an important dialogue. The Evidence of the critical role of choline in pregnancy goal of these sessions was to achieve consensus on future coupled with data suggesting inadequate intake of choline strategies to (1) elevate awareness of this essential nutrient in women suggests a need for intervention to ensure among health professionals and consumers and (2) close optimal intake of choline during pregnancy. Women who the gap between actual and recommended intakes. The are of childbearing age, pregnant or lactating should be following summarizes the conclusions from these sessions. advised of the benefits of consuming a diet rich in choline. Choline Is a ‘‘Nutrient of Concern’’ That Merits Childhood Specific Nutrition Guidance In humans, the hippocampus continues to develop after Participants agreed that a public health recommendation birth, resembling the adult structure by 4 years of age. for choline is particularly warranted for special

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populations, especially for women who are of where requirements may vary from established childbearing age, pregnant, or lactating. Research dietary reference intakes.32 Choline offers an excellent confirms that choline is an essential nutrient vital to opportunity to study the impact of nutrigenetics on fetal brain development and neural tube closure. Like establishing gene-based nutrient requirements. folate, adequate choline intake is critical even before a woman may know she is pregnant. Yet, intake data from National Health and Nutrition Examination Survey There Is a Critical Need to Increase Awareness 2005Y2006 reveal that the mean daily intake of choline and Intake of Choline Through Public and during pregnancy is 337 mg, and only 14% of pregnant Professional Education women have usual intakes at or greater than their AI (A. Moshfegh, Agricultural Research Service, USDA, With only an estimated 10% of Americans achieving written communication, December 16, 2009). The lack AIs and compelling evidence of negative health of focus on this essential nutrient may be jeopardizing outcomes associated with low choline intakes, the the health of mother and child. Increasing dietary intakes summit participants agreed there is a need to increase of choline is a simple tactic that may further aid in awareness of the public health consequences of promoting healthy pregnancy outcomes. suboptimal choline intakes and provide education Preliminary recognition of choline as a shortfall regarding the richest food sources of choline. There nutrient by the 2010 Dietary Guidelines Advisory is also evidence of a lack of understanding about choline Committee acknowledged the evidence that choline plays among both health professionals and consumers. A a critical role in human health and that public health recent survey found that 74% of mothers are not at all implications can ensue with continued suboptimal intakes. familiar with the benefits of choline, and 78% cannot 33 Continued studies on choline may provide additional identify food sources of choline. Among health evidence to identify it as a nutrient of concern for the professionals, including registered dietitians and population at large in future nutrition guidance. physicians, knowledge and awareness of choline are low. Choline ranked last among common nutrients as a nutrient to recommend in a . Only about 10% of those AI Levels for Choline Should Be Reevaluated With surveyed indicated they were moderately familiar with Consideration of Establishing an EAR and RDA choline and likely to recommend choline-containing foods Study of the potential health implications of suboptimal to their patients. Among obstetricians and gynecologists, choline intakes is still in the early stages, yet the evidence only about 6% were likely to recommend foods containing to date is compelling enough to suggest that AI levels choline for healthy pregnant women.33 may be too low for some subgroups. A significant finding Clearly, there is a need to increase awareness of in the past decade is the discovery of variation in the choline’s role in healthVfor both consumers and health dietary requirements for choline that can be explained professionalsVand provide education regarding by genetic differences between individuals. Summit choline-rich foods, such as eggs, lean beef, and pork. A participants agreed that this evidence should be sample menu was displayed to participants to illustrate presented to the IOM for consideration of establishing how current choline requirements can be met by a varied the EAR for choline, or the average daily choline intake diet that includes choline-rich foods while following level estimated to meet the requirements of half of the daily food plan recommendations. A challenge recognized healthy individuals in a particular life stage and sex by participants is that current dietary guidance from group. This would likely mean establishing the RDA at a variety of health organizations recommends limiting a level greater than the current AIs to meet the intake of to less than 300 mg/d, less than requirements of nearly all healthy individuals in a 200 mg for those with existing . particular life stage and sex group. Summit participants This dietary advice may have had the unintended acknowledged this would require increased education consequence of restricting choline-rich foods, such as on choline’s role in human health and delineation eggs, meat, and milk. of choline-rich foods to help ensure AIs. The summit participants agreed that enlisting the Another consideration discussed by the summit support of professional organizations representing participants was the possibility of establishing separate registered dietitians, pediatricians, family physicians, recommendations for specific genotypes. Although this obstetricians, gynecologists, nurse practitioners, would require genetic testing, the future of nutrigenetics, and midwives should be a priority in helping to educate or the study of the effects of genetic variation on nutrient health professionals. Professional seminars, continuing metabolism, may allow for personalized nutrient education programs, and educational tool kits were recommendations in the future for choline and other identified as examples of strategies for reaching health

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professionals. Other organizations and programs, of the 2010 Dietary Guidelines Advisory Committee. including March of Dimes; the Special Supplemental November 4Y5, 2009. http://www.cnpp.usda.gov/ Nutrition Program for Women, Infants, and Children; DGAsMeeting4.htm. Accessed December 7, 2009. and USDA’s Daily Food Plan for Moms, can help to 6. US Department of Agriculture, Agricultural Research reinforce this education with public health initiatives and Service. 2009. USDA National Nutrient Database for Standard Reference, Release 22. http://www.ars.usda.gov/ teaching materials. With education and understanding ba/bhnrc/ndl. Accessed December 7, 2009. that adequate choline intake before and during pregnancy 7. Chiuve S, Giovannucci E, Handkinson S, et al. The can have lifelong effects on a child’s health, increasing association between betaine and choline intakes and the intake of choline-rich foods becomes a simple change with plasma concentrations of homocysteine in women. a significant impact. However, to facilitate these changes, Am J Clin Nutr. 2007;86:1073Y1081. a specific recommendation in future nutrition guidance for 8. da Costa KA, Kozyreva OG, Song J, Galanko JA, Fischer pregnant and lactating women to increase consumption LM, Zeisel SH. Common genetic polymorphisms affect the of choline-rich foods is an important first step in bringing human requirement for the nutrient choline. Faseb J. Y greater attention and awareness for this essential nutrient. 2006;20:1336 1344. The Choline Science Summit was supported by the 9. Kohlmeier M, da Costa KA, Fischer LM, Zeisel SH. Genetic variation of folate-mediated one-carbon transfer pathway Choline Coalition, which includes the Egg Nutrition Center, predicts susceptibility to choline deficiency in humans. Balchem Corporation, National Pork Board, and The Beef Proc Natl Acad Sci USA. 2005;102:16025Y16030. Checkoff. 10. Niculescu M, Zeisel S. Diet, methyl donors and DNA : interaction between dietary folate, methionine, and choline. JNutr. 2002;132(suppl):S2333YS2335. 11. US Department of Agriculture, Agricultural Research Marie Caudill, PhD, RD, is an associate professor, Division of Nutritional Service. 2008. Nutrient Intakes From Food: Mean Amounts Sciences and Genomics at Cornell University, Ithaca, New York. Consumed per Individual, One Day, 2005Y2006. http:// Kerry-Ann da Costa, PhD, is a research assistant professor, Department www.ars.usda.gov/SP2UserFiles/Place/12355000/pdf/0506/ of Nutrition at the University of North Carolina at Chapel Hill. Table_1_NIF_05.pdf. Accessed December 22, 2009. Steven Zeisel, MD, PhD, is a Kenan Distinguished University Professor in 12. Caudill MA. Pre- and postnatal health: evidence of increased Nutrition and Pediatrics, University of North Carolina at Chapel Hill, and choline needs. J Am Diet Assoc. 2010;110:1198Y1206. Director of the University of North Carolina Research Institute, Kannapolis. 13. Vollset S, Refsum H, Irgens L, et al. Plasma total Betsy Hornick, MS, RD, is a nutrition writer and consultant in private homocysteine, pregnancy complications, and adverse practice, specializing in food, nutrition and health communications, pregnancy outcomes: the Hordaland Homocysteine Study. Poplar Grove, Illinois. Am J Clin Nutr. 2000;71:962Y968. This work was supported by the Egg Nutrition Center and American 14. Rees W, Wilson F, Maloney C. Egg Board. metabolism in pregnancy: the impact of methionine in the The authors have no conflicts of interest to disclose. maternal diet. J Nutr. 2006;136:1701SY1705S. Correspondence: Betsy Hornick, MS, RD, 3016 Fairchild St, Poplar Grove, 15. Shaw GM, Carmichael SL, Yang W, Selvin S, Schaffer DM. IL 61065 ([email protected]). Periconceptional dietary intake of choline and betaine DOI: 10.1097/NT.0b013e31822dff64 and neural tube defects in offspring. Am J Epidemiol. 2004;160:102Y109. 16. Zeisel S, Niculescu M. Perinatal choline influences brain REFERENCES structure and function. Nutr Rev. 2006;64:197Y203. 1. Food and Nutrition Board, Institute of Medicine. Dietary 17. Molloy AM, Mills JL, Cox C, et al. Choline and Reference Intakes for Thiamin, , , , homocysteine interrelations in umbilical cord and maternal Y Folate, , , , and Choline. plasma at delivery. Am J Clin Nutr. 2005;82(4):836 842. Washington, DC: National Academy Press; 1998:390Y422. 18. Fisher MC, Zeisel SH, Mar MH, Sadler TW. Perturbations 2. Zeisel SH. 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22. Mellott TJ, Williams CL, Meck WH, Blusztajn JK. 29. Fargnoli JL, Fung TT, Olenczuk DM, Chamberland JP, Prenatal choline supplementation advances hippocampal Hu FB, Mantzoros CS. Adherence to healthy eating development and enhances MAPK and CREB activation. patterns is associated with higher circulating total and FASEB J. 2004;18(3):545Y547. high-molecular-weight adiponectin and lower resistin 23. Meck WH, Williams CL. Metabolic imprinting of choline concentrations in women from the Nurses’ Health Study. by its availability during gestation: implications for Am J Clin Nutr. 2008;88:1213Y1224. memory and attentional processing across the lifespan. 30. US Department of Health and Human Services, National Neurosci Biobehav Rev. 2003;27(4):385Y399. Institutes of Health, National Heart, Lung, and Blood 24. Thomas J, Biane J, OBryan K, O’Neill T, Dominguez H. Institute (statement from Elizabeth G. Nabel, MD, Director, Choline supplementation following third-semester-equivalent National Heart, Lung, and Blood Institute on New Findings alcohol exposure attenuates behavioral alterations in rats. on the Role of Inflammation in Prevention of Coronary Behav Neurosci. 2007;121:120Y130. Heart Disease). http://www.nih.gov/news/health/nov2008/ 25. Wong-Goodrich SJ, Mellott TJ, Glenn MJ, Blusztajn JK, nhlbi-10.htm. Accessed December 8, 2009. Williams CL. Prenatal choline supplementation attenuates 31. Xu X, Gammon MD, Zeisel SH, et al. Choline metabolism neuropathological response to status epilepticus in the and risk of breast cancer in a population-based study. adult rat hippocampus. Neurobiol Dis. 2008;30:255Y269. FASEB J. 2008;22:2045Y2052. 26. Zeisel S. The fetal origins of memory: the role of dietary 32. Solis C, Veenema K, Ivanov AA, et al. Folate intake at choline in optimal brain development. J Pediatr. 2006; RDA levels is inadequate for Mexican American men with 149:131SY136S. the methylenetetrahydrofolate reductase 677TT genotype. 27. Olthof M, Brink E, Katan M, Verhoef P. Choline J Nutr. 2008;138:1Y6. supplemented as phosphatidylcholine decreases fasting and 33. StrategyOne Health Professionals Survey, March 2007. postmethionine-loading plasma homocysteine concentrations Online study among 252 health care professionals from in health men. Am J Clin Nutr. 2005;82:111Y117. Harris Interactive’s Physicians and Specialty Health 28. Detopoulou P, Panagiotakos DB, Antonopoulou S, Pitsavos C, Professionals Panels. Sponsored by American Egg Board/ Stefanadis C. Dietary choline and betaine intakes in relation Egg Nutrition Center. http://www.cholineinfo.org/ to concentrations of inflammatory markers in healthy adults: healthcare_professionals/overview.asp. Accessed the ATTICA study. Am J Clin Nutr. 2008;87:424Y430. December 7, 2009.

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