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Choline

CHOLINE

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).

FUNCTION

Choline and compounds derived from choline (metabolites) serve a number of vital biological functions (2-4).

Structural integrity of cell membranes: Choline is used in the synthesis of the phospholipids, phosphatidylcholine and sphingomyelin, structural components of all human cell membranes.

Cell signaling: 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: Choline is a precursor for acetylcholine, an important neurotransmitter, involved in muscle control, memory, and many other functions.

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.

DEFICIENCY

Symptoms: 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 (4). 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 normal folate and vitamin B-12 nutritional status fed a choline deficient diet developed elevated blood levels of a liver enzyme called alanine aminotransferase (ALT). Elevated ALT activity is a sign of liver damage. Liver damage appears to be the result of increased liver cell death. In cell culture, liver cells initiate programmed cell death (apoptosis) when deprived of choline (4).

De novo synthesis: Choline can be synthesized by humans 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, it was not previously considered an essential nutrient (4).  However, recent research indicates that humans cannot synthesize enough choline to meet their metabolic needs (see Deficiency).

Nutrient interrelationships: 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 required 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 methyl tetrahydrofolate (THF) and a vitamin B-12-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 recent study of 21 men and women fed diets that varied in 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 (5).

The RDA: In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine established a dietary reference intake (DRI) for choline (3). The FNB felt the existing scientific evidence was insufficient to calculate an 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).

    The AI for adult men, aged 19 and over: 550 milligrams (mg)/day
    The AI for adult women, aged 19 and over: 425 mg/day

DISEASE PREVENTION

Cardiovascular diseases: A large body of research indicates that even moderately elevated levels of homocysteine in the blood increase the risk of cardiovascular diseases (7). For more information on homocysteine and cardiovascular diseases, see 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 than in control subjects, suggesting that elevated blood homocysteine levels were not related to reduced intake of choline or betaine or diminished activity of BHMT (8). 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. Although further research is indicated, convincing evidence that increased dietary intake or blood levels of choline or betaine affect homocysteine levels in humans is presently lacking (9).

Cancer: 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 are still being investigated (2,4).  The implications for choline deficiency on human susceptibility to cancer remain unclear.

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). The significance of these findings to humans is not yet known. 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.

DISEASE TREATMENT

Dementia (Alzheimer's disease): Alzheimer's disease has been associated with a deficit of the neurotransmitter, acethylcholine, in the brain (10). One possible cause is a decrease in the 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 (11).

FOOD SOURCES

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 (3). Strict vegetarians who consume no milk or eggs may be at risk of inadequate choline intake. Approximate values for the choline content of some foods are listed in milligrams (mg) in the table below.

Food Serving Choline (mg)
Egg 1 large 200-300
Beef liver, cooked 3 ounces 453
Beef, cooked 3 ounces 59
Cauliflower, cooked 1 cup 55
Peanut butter 2 tablespoons 26
Grape juice, canned 8 ounces 13
Potato, baked 1 medium 18
Milk, whole 8 ounces 10
Tomato 1 medium 7
Orange 1 medium 10
Whole wheat bread 1 slice 4

SAFETY

Toxicity: 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 (3).

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. 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, and a genetic disorder known as trimethylaminuria might be at increased risk of adverse effects when consuming choline at levels near the UL (3)

Drug interactions: Methotrexate, a medication used in the treatment of cancer, psoriasis, and rheumatoid arthritis, limits the availability of methyl groups donated from folate derivatives by inhibiting the enzyme, dihydrofolate reductase. Rats given methotrexate have show evidence of diminished choline nutritional status including fatty liver, which can be reversed by choline supplementation (2). Thus, individuals taking methotrexate may have an increased choline requirement.

THE LINUS PAULING INSTITUTE RECOMMENDATION

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. Currently, choline is not routinely included in common multivitamin-mineral supplements, so those who are interested in supplementing their dietary intake of choline may need to take a separate supplement. Lecithin (phosphatidylcholine), a choline supplement, is only 13% choline by weight, so a lecithin supplement providing 4,230 mg (4.2 grams) of phosphitidyl choline would provide 550 mg of choline.

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).

REFERENCES

1.  Blusztajn, J.K. Choline, a vital amine. Science. 1998; volume 281: pages 794-795. (PubMed)

2. Zeisel, S.H. Choline and phosphatidylcholine. In Shils, M. et al. Eds. Nutrition in Health and Disease, 9th Edition. Baltimore: Williams & Wilkins, 1999: pages 513-523.

3.  Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998: pages 390-422. (National Academy Press)

4.  Zeisel, S.H. Choline: an essential nutrient for humans. Nutrition. 2000; volume 16: pages 669-671.

5.  Jacob, R.A. et al. Folate nutriture alters choline status of women and men fed low choline diets. Journal of Nutrition. 1999; volume 129: pages 712-717. (PubMed)

6.  Zeisel, S.H. & Blusztajn, J.K. Choline and human nutrition. Annual Review of Nutrition. 1994; volume 14: pages 269-296. (PubMed)

7.  Gerhard, G.T. & Duell, P.B. Homocysteine and atherosclerosis. Current Opinion in Lipidology. 1999; volume 10: pages 417-428. (PubMed)

8.  Lundberg, P. et al. 1H NMR determination of urinary betaine in patients with premature vascular disease and mild hyperhomocysteinemia. Clinical Chemistry. 1995; volume 41: pages 275-283. (PubMed)

9.  Blom, H. Determinants of plasma homocysteine. American Journal of Clinical Nutrition. 1998; volume 68: pages 919-921. (PubMed)

10.  Whitehouse, P.J. The cholinergic deficit in Alzheimer's disease. Journal of Clinical Psychiatry. 1998; volume 59 (supplement 13): pages 19-22. (PubMed)

11.  Higgins, J.P. & Flicker, L. Lecithin for dementia and cognitive impairment. Cochrane Database of Systematic Reviews. 2000. 2:CD001015. (PubMed)