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Although choline is not by strict definition a vitamin, it is an essential nutrient. Despite the fact that humans can synthesize it in small amounts, choline must be consumed in the diet to maintain health (1). The majority of the body's choline is found in specialized fat molecules known as phospholipids, the most common of which is called phosphatidylcholine or lecithin (2).
Structural integrity of cell membranes
Choline is used in the synthesis of the phospholipids, phosphatidylcholine and sphingomyelin, which are structural components of all human cell membranes.
The choline-containing phospholipids, phosphatidylcholine and sphingomyelin, are precursors for the intracellular messenger molecules, diacylglycerol and ceramide. Two other choline metabolites, platelet activating factor (PAF) and sphingophosphorylcholine, are also known to be cell-signaling molecules.
Nerve impulse transmission
Lipid (fat) transport and metabolism
Fat and cholesterol consumed in the diet are transported to the liver by lipoproteins called chylomicrons. In the liver, fat and cholesterol are packaged into lipoproteins called very low density lipoproteins (VLDL) for transport through the blood to tissues that require them. Phosphatidylcholine is a required component of VLDL particles. Without adequate phosphatidylcholine, fat and cholesterol accumulate in the liver (see Deficiency).
Major source of methyl groups
Choline may be oxidized in the body to form a metabolite called betaine. Betaine is a source of methyl (CH3) groups required for methylation reactions. Methyl groups from betaine may be used to convert homocysteine to methionine. Elevated levels of homocysteine in the blood have been associated with increased risk of cardiovascular diseases (5).
Men and women fed intravenously (IV) with solutions that contained adequate methionine and folate but lacked choline have developed a condition called "fatty liver" and signs of liver damage that resolved when choline was provided (3). Choline is required to form the phosphatidylcholine portion of very low density lipoprotein (VLDL) particles. VLDL particles transport fat from the liver to the tissues (see Function). When the supply of choline is inadequate, VLDL particles cannot be synthesized and fat accumulates in the liver, ultimately resulting in liver damage. Because low density lipoprotein (LDL) particles are formed from VLDL particles, choline-deficient individuals also have reduced blood levels of LDL cholesterol (6). Healthy male volunteers with adequate folate and vitamin B12 nutrition developed elevated blood levels of a liver enzyme called alanine aminotransferase (ALT) when fed a choline-deficient diet. Elevated ALT activity is a sign of liver damage. More recently, a study in 57 adults who were fed choline-deficient diets under controlled conditions found that 77% of men, 80% of postmenopausal women, and 44% of premenopausal women developed fatty liver, liver damage, and/or muscle damage (7). These signs of organ dysfunction resolved when choline was replaced in the diet. Premenopausal women may be relatively resistant to choline deficiency, because estrogen induces endogenous synthesis of choline via the phosphatidylethanolamine N-methyltransferase (PEMT) enzyme (8). Further, recent studies have identified a small number of very common genetic polymorphisms that predict the risk for developing symptoms of organ dysfunction when deprived of dietary choline (9, 10). In choline deficiency, liver damage appears to be the result of increased liver cell death because cell culture studies have shown liver cells initiate programmed cell death (apoptosis) when deprived of choline (3). A recent study in 51 men and women reported that a choline-deficient diet induced DNA damage and apoptosis in peripheral lymphocytes (11).
The human requirement for choline is affected by its relationships with other methyl group donors, such as folate and S-adenosyl methionine (SAM). See diagram. The methyl group donor (SAM) is synthesized from the amino acid, methionine. Three molecules of SAM are required for the three methylations of phosphatidylethanolamine needed to synthesize phosphatidylcholine. Once SAM donates a methyl group it becomes S-adenosyl homocysteine, which is metabolized to homocysteine. Homocysteine can be converted to methionine in a reaction that requires 5-methyl tetrahydrofolate (THF) and a vitamin B12-dependent enzyme. Alternately, betaine (a metabolite of choline) may be used as the methyl donor for the conversion of homocysteine to methionine (2). For a more thorough discussion of the relationships between homocysteine levels and nutrient intake see the Linus Pauling Institute Newsletter article: The Vascular Toxicity of Homocysteine and How to Control It.
A study of 21 men and women fed diets with varied folate and choline content indicated that choline is used as a methyl group donor when folate intake is low, and that the de novo synthesis of phosphatidylcholine is not sufficient to maintain adequate choline nutritional status when dietary folate and choline intakes are low (12).
In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine established a dietary reference intake (DRI) for choline (4). The FNB felt the existing scientific evidence was insufficient to calculate a RDA for choline, so they set an Adequate Intake level (AI). The main criterion for establishing the AI for choline was the prevention of liver damage (see Deficiency). Recent studies have found that polymorphisms in genes involved in choline (9) or folate (10) metabolism alter one's susceptibility to choline deficiency and thus may affect dietary requirements for choline.
Adequate Intake (AI) for Choline
|Adults||19 years and older||550||425|
A large body of research indicates that even moderately elevated levels of homocysteine in the blood increase the risk of cardiovascular diseases (5). For more information on homocysteine and cardiovascular diseases, see the article on Folic Acid. Choline, when oxidized in the body to form betaine, provides a methyl group for the conversion of homocysteine to methionine by the enzyme, betaine-homocysteine methyltransferase (BHMT). See diagram. Despite its relevance, the relationship of betaine and choline to homocysteine metabolism has been only lightly investigated in humans. Methodological problems make betaine and BHMT difficult to measure. One study found higher urinary excretion of betaine and its metabolites in patients with vascular disease and elevated homocysteine levels compared to control subjects, suggesting that elevated blood homocysteine levels were not related to reduced intake of choline or betaine or diminished activity of BHMT (13). In preliminary studies, pharmacologic doses of betaine (1.7 to 6 grams/day) were found to reduce blood levels of homocysteine in a small number of patients with vascular disease and elevated homocysteine levels. Additionally, a small study in 26 healthy men reported that choline supplementation decreased plasma homocysteine concentrations (14). However, a prospective cohort study in 14,430 middle-aged men and women participating in the Atherosclerosis Risk in Communities study found that dietary choline or dietary choline and dietary betaine, together, was not associated with coronary heart disease (15). Although further research is indicated, convincing evidence that increased dietary intake or blood levels of choline or betaine affect homocysteine levels and cardiovascular disease risk in humans is presently lacking.
In rats, dietary choline deficiency is associated with an increased incidence of spontaneous liver cancer and increased sensitivity to carcinogenic chemicals. A number of mechanisms have been proposed to explain the cancer-promoting effects of choline deficiency: (a) choline deficiency causes liver damage and regenerating liver cells are more sensitive to the effects of carcinogenic chemicals; (b) choline deficiency results in decreased methylation of DNA, resulting in abnormal DNA repair; (c) choline deficiency results in increased oxidative stress in the liver, increasing the likelihood of DNA damage; (d) choline deficiency may stimulate changes in the programmed cell death (apoptosis) of liver cells, contributing to the development of liver cancer; and (e) choline deficiency activates the potent cell-signaling molecule, protein kinase C, which creates a cascade of effects that is still being investigated (2, 3). The implications for choline deficiency on human susceptibility to cancer remain unclear.
Neural Tube Defects
It is known that folate is critical for normal embryonic development, and maternal supplementation with folic acid decreases the incidence of neural tube defects (NTD) (16). NTD result in either anencephaly or spina bifida, which are devastating and sometimes fatal birth defects. These defects occur between the 21st and 27th days after conception, a time when many women do not realize that they are pregnant (17). While folate's protective effect against NTD is well recognized, the effects of other methyl group donors, including choline and betaine, are not known. A case-control study (424 NTD cases and 440 controls) found that women in the highest quartiles of choline and betaine intake, in combination, had a 72% lower risk of a NTD-affected pregnancy (18). More recently, a case-control study (80 NTD-affected pregnancy and 409 controls) in U.S. women found that the lowest levels of serum choline during mid-pregnancy were associated with a 2.4-fold higher risk of NTD (24). Yet, more research is needed to determine whether choline is involved in the etiology of NTD.
Cognitive functioning (memory)
Increased dietary intake of choline very early in life can diminish the severity of memory deficits in aged rats. Choline supplementation of the mothers of unborn rats, as well as rat pups during the first month of life, leads to improved performance in spatial memory tests months after choline supplementation has been discontinued (2). A recent review by McCann et al. discusses the experimental evidence from rodent studies regarding the availability of choline during prenatal development and cognitive function in the offspring (19). It is not clear whether findings in rodent studies are applicable to humans. More research is needed to determine the role of choline in the developing brain and whether choline intake is useful in the prevention of memory loss or dementia in humans.
Alzheimer's disease has been associated with a deficit of the neurotransmitter, acetylcholine, in the brain (20). One possible cause for the acetylcholine deficit is a decrease in the expression of an enzyme that converts choline into acetylcholine in the brain. Large doses of lecithin (phosphatidylcholine) have been used to treat patients with dementia associated with Alzheimer's disease in hope of raising the amount of acetylcholine available in the brain. However, a systematic review of the randomized trials did not find lecithin to be more beneficial than placebo in the treatment of patients with dementia or cognitive impairment (21).
De novo synthesis (biosynthesis)
Humans can synthesize choline in small amounts by converting the phospholipid, phosphatidylethanolamine, to phosphatidylcholine. This is referred to as de novo synthesis of choline. Three methylation reactions are required, each using the compound S-adenosyl methionine (SAM) as a methyl group donor. Because phosphatidylcholine can be synthesized and metabolized to provide choline, choline was not previously considered an essential nutrient (3). However, more recent research indicates that humans cannot synthesize enough choline to meet their metabolic needs (see Deficiency).
Very little information is available on the choline content of foods (4). Most choline in foods is found in the form of phosphatidylcholine. Milk, eggs, liver, and peanuts are especially rich in choline. Phosphatidylcholine, also known as lecithin, contains about 13% choline by weight. Presently, national surveys do not provide any information on the dietary intake of choline, but it has been estimated that the average intake by adults is between 730 and 1,040 mg/day (2). Lecithins added during food processing may increase the daily consumption of choline by about 115 mg/day (4). Strict vegetarians who consume no milk or eggs may be at risk of inadequate choline intake. The total choline contents of some choline-rich foods are listed in milligrams (mg) in the table below (22).
|Food||Serving||Total Choline (mg)|
|Beef liver, pan fried||3 ounces*||355|
|Wheat germ, toasted||1 cup||172|
|Atlantic cod, cooked||3 ounces||71|
|Beef, trim cut, cooked||3 ounces||67|
|Brussel sprouts, cooked||1 cup||63|
|Broccoli, cooked||1 cup, chopped||62|
|Shrimp, canned||3 ounces||60|
|Milk, skim||8 fl oz.||38|
|Peanut butter, smooth||2 tablespoons||20|
|Milk chocolate||1.5-ounce bar||20|
*A three-ounce serving of meat or fish is about the size of a deck of cards.
Choline salts, such as choline chloride and choline bitartrate are available as supplements. Phosphatidylcholine supplements also provide choline; however, they are only 13% choline by weight. Therefore, a supplement providing 4,230 mg (4.2 grams) of phosphitidyl choline would provide 550 mg of choline. Although the chemical term "lecithin" is synonymous with phosphatidylcholine, commercial lecithin preparations may contain anywhere from 20-90% phosphatidylcholine. Thus, lecithin supplements may contain even less than 13% choline (23).
High doses (10 to 16 grams/day) of choline have been associated with a fishy body odor, vomiting, salivation, and increased sweating. The fishy body odor results from excessive production and excretion of trimethylamine, a metabolite of choline. Taking large doses of choline in the form of phosphatidylcholine (lecithin) does not generally result in fishy body odor, because its metabolism results in little trimethylamine. A dose of 7.5 grams of choline/day was found to have a slight blood pressure lowering (hypotensive) effect, which could result in dizziness or fainting. Choline magnesium trisalicylate at doses of 3 grams/day has resulted in impaired liver function, generalized itching, and ringing of the ears (tinnitus). However, it is likely that these effects were a result of the salicylate, rather than the choline in the preparation (4).
In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine established the tolerable upper intake level (UL) for choline at 3.5 grams/day for adults. This recommendation was based primarily on preventing hypotension (low blood pressure) and secondarily on preventing the fishy body odor due to increased excretion of trimethylamine. The UL was established for generally healthy people, and the FNB noted that individuals with liver or kidney disease, Parkinson's disease, depression, or a genetic disorder known as trimethylaminuria might be at increased risk of adverse effects when consuming choline at levels near the UL (4).
|Tolerable Upper Intake Level (UL) for Choline|
|Age group||UL (g/day)|
|Infants 0-12 months||Not possible to establish*|
|Children 1-8 years||1.0|
|Children 9-13 years||2.0|
|Adolescents 14-18 years||3.0|
|Adults 19 years and older||3.5|
*Source of intake should be food and formula only.
Methotrexate, a medication used in the treatment of cancer, psoriasis, and rheumatoid arthritis, inhibits the enzyme dihydrofolate reductase and therefore limits the availability of methyl groups donated from folate derivatives. Rats given methotrexate have shown evidence of diminished nutritional status of choline, including fatty liver, which can be reversed by choline supplementation (2). Thus, individuals taking methotrexate may have an increased choline requirement.
Little is known regarding the amount of dietary choline required to promote optimum health or prevent chronic disease in humans. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 550 milligrams (mg)/day for adult men and 425 mg/day for adult women. A varied diet should provide enough choline for most people, but vegetarians who consume no milk or eggs may be at risk of inadequate choline intake.
Older adults (65 years and older)
Little is known regarding the amount of dietary choline most likely to promote optimum health or prevent chronic disease in older adults. At present, there is no evidence to support a different intake of choline from that of younger adults (550 mg/day for men and 425 mg/day for women).
Written in November 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Updated in January 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed in January 2008 by:
Steven H. Zeisel, M.D., Ph.D.
Professor and Chair of Nutrition
School of Public Health
The University of North Carolina, Chapel Hill
Last updated 8/18/2009 Copyright 2000-2013 Linus Pauling Institute
The Linus Pauling Institute Micronutrient Information Center provides scientific information on the health aspects of dietary factors and supplements, foods, and beverages for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.
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