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Summary

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. The majority of the body's choline is found in specialized fat molecules known as phospholipids, the most common of which is called phosphatidylcholine (1).

Function

Choline and compounds derived from choline (i.e., metabolites) serve a number of vital biological functions (Figure 1) (1).

Structural integrity of cell membranes

Choline is used in the synthesis of certain phospholipids (phosphatidylcholine and sphingomyelin) that are essential structural components of cell membranes. Phosphatidylcholine accounts for about 95% of total choline in tissues (2). This phospholipid can be synthesized from dietary choline via the cytidine diphosphocholine (CDP-choline) pathway or through the methylation of another phospholipid, phosphatidylethanolamine (Figure 2) (3). Sphingomyelin is a type of sphingosine-containing phospholipid (sphingolipid) that is synthesized by the transfer of a phosphocholine residue from a phosphatidylcholine to a ceramide (Figure 3). Sphingomyelin is found in cell membranes and in the fatty sheath that envelops myelinated nerve fibers.

Cell signaling

The choline-containing phospholipids, phosphatidylcholine and sphingomyelin, are precursors for the intracellular messenger molecules, diacylglycerol and ceramide. Specifically, sphingomyelinases (also known as sphingomyelin phosphodiestarases) catalyze the cleavage of sphingomyelin, generating phosphocholine and ceramide. Diacylglycerol is released by the degradation of phosphatidylcholine by phospholipases. Other choline metabolites known to be cell-signaling molecules include platelet activating factor (PAF) and sphingophosphocholine.

Nerve impulse transmission

Choline is a precursor for acetylcholine, an important neurotransmitter synthesized by cholinergic neurons and involved in muscle control, circadian rhythm, memory, and many other neuronal functions. Choline acetyltransferase catalyzes the acetylation of choline to acetylcholine, and acetylcholine esterase hydrolyzes acetylcholine to choline and acetate (4). CDP-choline administration was also found to stimulate the synthesis and release of a family of neurotransmitters derived from tyrosine (i.e., the catecholamines, including noradrenaline, adrenaline, and dopamine) (5). Of note, non-neuronal cells of various tissues and organ systems also synthesize and release acetylcholine, which then binds and stimulates cholinergic receptors on target cells (reviewed in 6).

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 in the bloodstream to extrahepatic tissues. Phosphatidylcholine synthesis by the phosphatidylethanolamine N-methyltransferase (PEMT) pathway is required for VLDL assembly and secretion from the liver (7, 8). Without adequate phosphatidylcholine, fat and cholesterol accumulate in the liver (see Deficiency).

Major source of methyl groups

Choline may be oxidized in the liver and kidney to form a metabolite called betaine via a two-step enzymatic reaction. In the mitochondrial inner membrane, flavin adenine dinucleotide (FAD)-dependent choline oxidase catalyzes the conversion of choline to betaine aldehyde, which is then converted to betaine by betaine aldehyde dehydrogenase in either the mitochondrial matrix or the cytosol (2). Betaine is a source of up to 60% of the methyl (CH 3 ) groups required for the methylation of homocysteine (9). Betaine homocysteine methyltransferase (BHMT) uses betaine as a methyl donor to convert homocysteine to methionine in one-carbon metabolism (Figure 4). The ubiquitous vitamin B 12 -dependent methionine synthase (MS) enzyme also catalyzes the re-methylation of homocysteine, using the folate derivative, 5-methyltetrahydrofolate, as a methyl donor (see Nutrient interactions). Elevated concentrations of homocysteine in the blood have been associated with increased risk of cardiovascular disease (10).

Osmoregulation

The conversion of choline to betaine is irreversible. Betaine is an osmolyte that regulates cell volume and protect cell integrity against osmotic stress (especially in the kidney). Osmotic stress has been associated with a reduced BHMT expression such that the role of betaine in osmoregulation may be temporarily prioritized over its function as a methyl donor (2).

Deficiency

Symptoms

Men and women fed intravenously (IV) with solutions that contained adequate methionine and folate but lacked choline have been found to develop a condition called nonalcoholic fatty liver disease (NAFLD) and signs of liver damage that resolved when choline was provided (11). The occurrence of NAFLD is usually associated with the co-presentation of metabolic disorders, including obesity, dyslipidemia, insulin resistance, and hypertension, in subjects with metabolic syndrome. NAFLD is estimated to progress to a more severe condition called nonalcoholic steatohepatitis (NASH) in about one-third of NAFLD patients, as well as to increase the risk of cirrhosis and liver cancer (12).

Because phosphatidylcholine is required in the synthesis of very-low-density lipoprotein (VLDL) particles (see Function), choline deficiency results in impaired VLDL secretion and accumulation of fat in the liver (steatosis), ultimately leading to liver damage. Because low-density lipoprotein (LDL) particles are formed from VLDL particles, choline-deficient individuals also show reduced blood concentrations of LDL-cholesterol (13). Abnormally elevated biomarkers of organ dysfunction in the blood, including creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase, are corrected upon choline repletion. Choline deficiency-induced organ dysfunction has also been associated with increased DNA damage and apoptosis in circulating lymphocytes (14). In the liver, the accumulation of lipids is thought to impair mitochondrial function, thus reducing fatty acid oxidation and increasing the production of reactive oxygen species (ROS) that trigger lipid peroxidation, DNA damage, and apoptosis. Further, oxidative stress is thought to be responsible for prompting inflammatory processes that can lead to the progression of NAFLD to NASH and cirrhosis (end-stage liver disease) (15).

An intervention study in 57 healthy 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 (16). These signs of organ dysfunction resolved upon choline reintroduction in the diet. Because estrogen stimulates the endogenous synthesis of phosphatidylcholine via the phosphatidylethanolamine N-methyltransferase (PEMT) pathway, premenopausal women may be less likely to develop signs of choline deficiency in response to a low-choline diet compared to postmenopausal women (17, 18). Further, a notable single nucleotide polymorphism (SNP; rs12325817) of the PEMT gene, which may affect the expression and/or activity of the PEMT enzyme, is thought to increase the susceptibility to choline deficiency-induced organ dysfunction (17). Additional genetic polymorphisms occurring in choline and one-carbon metabolic pathways may alter the dietary requirement for choline and thus increase the likelihood of developing signs of deficiency when choline intake is inadequate (19-21). The composition of one’s intestinal microbiota has been recently identified as another potential predictor of susceptibility to choline deficiency-induced NAFLD (22). Of note, intestinal microbiota-dependent metabolism of dietary phosphatidylcholine might also be involved in the pathogenesis of cardiovascular disease (see Safety) (23, 24).

See Disease Prevention for more information on fatty liver diseases.

Nutrient interactions

Together with several B-vitamins (i.e., folate, vitamin B 12 , vitamin B 6 , and riboflavin), choline is required for the metabolism of nucleic acids and amino acids, and for the generation of the universal methyl group donor, S-adenosylmethionine (SAM) (see Figure 4 above). SAM is synthesized from the essential amino acid, methionine. Three molecules of SAM are required for the methylation reaction that converts phosphatidylethanolamine into phosphatidylcholine (see Figure 2 above). Once SAM donates a methyl group it becomes S-adenosylhomocysteine (SAH), which is then metabolized to homocysteine. Homocysteine can be converted back to methionine in a reaction catalyzed by vitamin B 12 -dependent methionine synthase, which requires 5-methyltetrahydrofolate (5-meTHF) as a methyl donor. Alternately, betaine (a metabolite of choline) is used as the methyl donor for the methylation of homocysteine to methionine by the enzyme, betaine-homocysteine methyltransferase (BHMT) (1). Homocysteine can also be metabolized to cysteine via the vitamin B 6 -dependent transsulfuration pathway (see Figure 4 above).

Thus, the human requirement for choline is especially influenced by the relationship between choline and other methyl group donors such as folate and S-adenosylmethionine. A low intake of folate leads to an increased demand for choline-derived metabolite, betaine. Moreover, the de novo synthesis of phosphatidylcholine is not sufficient to maintain adequate choline nutritional status when dietary intakes of folate and choline are low (25). Conversely, the demand for folate is increased when dietary supply for choline is limited (26).

The Adequate Intake (AI)

In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine established a dietary reference intake (DRI) for choline (27). The FNB felt the existing scientific evidence was insufficient to calculate an RDA for choline, so they set an Adequate Intake (AI; Table 1). The main criterion for establishing the AI for choline was the prevention of liver damage. Yet, common polymorphisms in genes involved in choline or folate metabolism alter one’s susceptibility to choline deficiency and thus may affect dietary requirements for choline (see Deficiency) (17, 19).

Table 1. Adequate Intake (AI) for Choline Life Stage Age Males

(mg/day) Females

(mg/day) Infants 0-6 months 125 125 Infants 7-12 months 150 150 Children 1-3 years 200 200 Children 4-8 years 250 250 Children 9-13 years 375 375 Adolescents 14-18 years 550 400 Adults 19 years and older 550 425 Pregnancy all ages - 450 Breast-feeding all ages - 550

Disease Prevention

Cardiovascular disease

Choline and homocysteine

A large body of research indicates that even moderately elevated levels of homocysteine in the blood increase the risk of cardiovascular disease (CVD) (10). The most common cause of a myocardial infarction or a stroke is the rupture of atherosclerotic plaques in arterial walls causing blood clot formation (thrombogenesis). High homocysteine concentrations may promote the development of atherosclerosis (atherogenesis) and thrombogenesis via mechanisms involving oxidative stress and endothelial dysfunction, inflammation, abnormal blood coagulation, and disordered lipid metabolism (reviewed in 28).

Once formed from dietary methionine, homocysteine can be catabolized to cysteine via the transsulfuration pathway or re-methylated to methionine (see Figure 4 above). Folate and choline are involved in alternate pathways that catalyze the re-methylation of homocysteine (see Nutrient interactions). Specifically, choline is the precursor of betaine, which provides a methyl group for the conversion of homocysteine to methionine via the enzyme, betaine-homocysteine methyltransferase (BHMT). While the amount of homocysteine in the blood is regulated by several nutrients, including folate and choline, conditions that cause damage to the liver like nonalcoholic steatohepatitis (NASH) may also affect homocysteine metabolism (29).

Dietary intakes of choline and betaine and CVD

Because both folate- and choline-dependent metabolic pathways catalyze the re-methylation of homocysteine, dietary intakes of both nutrients need to be considered when the association between homocysteine concentrations and cardiovascular disease is assessed. Yet, despite its relevance, the relationship of betaine and choline to homocysteine metabolism has been only lightly investigated in humans, essentially because the choline content of foods could not be accurately measured until recently. In preliminary intervention studies, pharmacologic doses of betaine (1,500 to 6,000 mg/day) were found to reduce blood homocysteine concentrations in a small number of volunteers with normal-to-mildly elevated homocysteine concentrations (30-33). Yet, in a cross-sectional analysis of a large cohort of 16,165 women (ages, 49-79 years), lower betaine doses in the range of dietary intakes were not found to be correlated with homocysteine concentrations (34). This study also showed that levels of choline intake were inversely associated with homocysteine concentrations in the blood. However, an eight-year follow-up study of the cohort failed to show any difference in cardiovascular risk between women in the upper versus bottom quartile of dietary choline intakes (>329 mg/day vs. ≤266 mg/day) (34). The prospective study of the Atherosclerosis Risk in Communities (ARIC) cohort found that the highest vs. lowest quartile (>486 mg/day vs. <298 mg/day) of total choline intakes from food was not significantly associated with the incidence of coronary artery disease in 14,430 middle-aged participants (35). Also, in a recent analysis of the Health Professionals Follow-up Study (HPFS) that enrolled 44,504 men for a period of 24 years, the risk of peripheral artery disease was positively correlated with homocysteine concentrations but neither with betaine nor choline levels of intake (36).

While further research is indicated, convincing evidence that increased dietary intake of choline or betaine could benefit cardiovascular health through lowering homocysteine concentrations in the blood is presently lacking.

Circulating concentrations of choline and betaine and CVD risk

A 1995 study had found that elevated blood homocysteine concentrations in patients who experienced a vascular occlusion were associated with higher urinary excretion of betaine, rather than with reduced intake of choline or betaine or diminished activity of BHMT (37). In a recent prospective study, high urinary betaine excretion was also associated with increased risk of heart failure in 325 nondiabetic subjects who have been hospitalized for acute coronary syndrome (38). In the same study, both top and bottom quintiles of plasma betaine concentrations were associated with an increased risk of secondary acute myocardial infarction. The findings of another prospective study (the Hordaland Health Study) that followed 7,045 healthy adults (ages, 47-49 years and 71-74 years) suggested that high choline and low betaine plasma concentrations were associated with an unfavorable cardiovascular risk profile (39). Indeed, plasma choline was positively associated with a number of cardiovascular risk factors, such as BMI, percentage body fat, waist circumference, and serum triglycerides, and inversely associated with HDL-cholesterol. On the contrary, plasma betaine was positively correlated to HDL-cholesterol and inversely associated with the above-mentioned risk factors as well as with systolic and diastolic blood pressure. More recent studies now suggest that the blood concentration of trimethylamine N-oxide (TMAO), generated from trimethylamine-containing nutrients like dietary choline, rather than that of choline, might influence the risk of cardiovascular events (see Safety).

It is not yet clear whether concentrations of choline, betaine, and/or TMAO in the blood can predict the risk for cardiovascular disease.

Liver diseases

Fatty liver diseases

While a choline-deficient diet results in organ dysfunction and nonalcoholic fatty liver disease (NAFLD) (see Deficiency; 16), it is not known whether suboptimal dietary choline intakes in healthy subjects may contribute to an increased risk for NAFLD. A cross-sectional analysis of two large prospective studies conducted in China – the Shanghai Women’s Health Study and the Shanghai Men’s Health Study – including 56,195 people (ages, 40-75 years), was recently conducted to assess the association between dietary choline intakes and self-reported diagnosis of fatty liver disease (40). The highest versus lowest quintile of choline intake (412 mg/day vs. 179 mg/day) was associated with a 28% lower risk of fatty liver disease in normal-weight women, but no association was found in overweight or obese women or in men. Another cross-sectional study of 664 individuals with NAFLD or nonalcoholic steatohepatitis (NASH) also reported that disease severity was inversely correlated with dietary choline intakes in postmenopausal women, but not in premenopausal women, men, or children (41).

Liver cancer

In animal models, dietary choline deficiency has been associated with an increased incidence of spontaneous liver cancer (hepatocellular carcinoma) and increased sensitivity to carcinogenic chemicals (9). A number of mechanisms have been proposed to contribute to the cancer-promoting effects of choline deficiency: (1) enhanced liver cell regeneration and tissue sensitivity to chemical insults; (2) altered expression of numerous genes regulating cell proliferation, differentiation, DNA repair, and apoptosis due to improper DNA methylation; (3) increased likelihood of DNA damage caused by mitochondrial dysfunction-induced oxidative stress; and (4) activated protein kinase C-mediated cell-signaling cascade, eventually leading to an increase in liver cell apoptosis (2). Yet, it is not known whether choline deficiency can increase the susceptibility to cancer in humans (2).

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 (NTDs) (42). NTDs include various malformations, such as lesions of the brain (e.g., anencephaly, encephalocele) or lesions of the spine (spina bifida), which are devastating and usually incompatible with life (43). These defects occur between the 21st and 28th days after conception, a time when many women do not realize that they are pregnant (44). While the protective effect of folate against NTD is well established, only a few studies have investigated the role of other methyl group donors, including choline and betaine, in the occurrence of NTDs. A case-control study (424 NTD cases and 440 controls) found that women in the highest versus lowest quartile of periconceptual choline intake (>498.46 mg/day vs. ≤290.41 mg/day) had a 51% lower risk of an NTD-affected pregnancy (45). However, more recent studies failed to find an inverse relationship between maternal choline intake and risk of NTDs (46, 47). Another case-control study (80 NTD-affected pregnancy and 409 controls) in US women found that the lowest concentrations of serum choline (<2.49 mmol/L) during mid-pregnancy were associated with a 2.4-fold higher risk of NTDs (48). Finally, a more recent study, including 71 NTD-affected pregnancies, 214 pregnancies with non NTD malformations, 98 normal pregnancies in women with prior NTD-affected pregnancies, and 386 normal pregnancies, found no associations between maternal blood concentrations of choline during pregnancy, choline- and folate-related genetic variants, and risk of NTDs (49). However, it is important to note that circulating choline concentrations do not accurately reflect dietary intake of choline.

More research is needed to determine whether supplemental choline could add to the protective effect currently being achieved by periconceptual folic acid supplementation.

Cognitive health

Neuro-cognitive development

Increased dietary intake of cytidine 5’-diphosphocholine (CDP-choline or citicoline, a precursor of phosphatidylcholine; see Figure 2 above) very early in life can diminish the severity of memory deficits in aged rats (50). Choline supplementation of the mothers of unborn rats, as well as rat pups during the first month of life, led to improved performance in spatial memory tests months after choline supplementation had been discontinued (51). A 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 (52).

Because of the importance of DNA methylation in normal brain development, neuronal functions, and cognitive processes (53), methyl donor nutrients like choline are essential for optimal brain functioning. However, clinical evidence to determine whether findings in rodent studies are applicable to humans is currently limited. Recently, the analysis of the Seychelles Child Development Nutrition Cohort study reported a lack of an association between plasma concentrations of choline and its related metabolites and cognitive abilities in 256 five-year-old children. Only plasma betaine concentrations were found to be positively correlated with preschool language test scores (54). Yet, because circulating concentrations of choline are not directly related to dietary choline intakes, the study could not evaluate whether maternal choline intakes influence children’s brain development.

Project Viva is an ongoing prospective study that has examined the relationship between daily intakes of methyl donor nutrients in 1,210 women during pregnancy and child cognition at three and seven years postpartum. Maternal intake of choline during the first and/or second trimester of pregnancy was not correlated with measures of cognitive performance in children at age 3 years (55). Another report of the study indicated that upper vs. lower quartile of maternal choline intakes during the second trimester of pregnancy (median intakes, 392 mg/day vs. 260 mg/day) was significantly associated with higher visual memory scores in children aged 7 years old (56). Recently, a small randomized, double-blind, placebo-controlled trial in 99 pregnant women (ages, 21-41 years old) evaluated the effect of choline supplementation during pregnancy and lactation on infants’ cognitive function at ages 10 and 12 months (57). The results indicated that maternal choline supplementation (750 mg/day of choline in the form of phosphatidylcholine) from 18 weeks of gestation to 3 months’ postpartum provided no cognitive benefits in children regarding short-term visio-spatial memory, long-term episodic memory, and language and global development.

Cognitive function in older adults

Cognitive function, including the domains of memory, speed, and executive function, decline gradually with increasing age. The rate of cognitive decline is also influenced by modifiable risk factors like dietary habits. Deficiency in B-vitamins and elevated homocysteine concentrations in the blood have been associated with cognitive impairments in the elderly. Yet, a recent meta-analysis of 11 trials indicated that homocysteine lowering using B-vitamin supplementation fails to limit cognitive decline or improve cognitive performance in older adults (58). The cross-sectional data analysis of a subgroup of 1,391 volunteers (ages, 36-83 years) from the large Framingham Heart Study Offspring cohort has indicated that dietary choline intake was positively associated with specific cognitive functions, namely verbal memory and visual memory (59). Another cross-sectional study of 2,195 individuals (ages, 70-74 years) from the Hordaland Health Study examined cognitive abilities and blood concentrations of various determinants of circulating homocysteine, including choline and betaine (60). Unlike betaine, high vs. low plasma concentrations of free choline (>8.36 mcmol/L vs. ≤8.36 mcmol/L) were found to be significantly associated with a greater performance at cognitive tests assessing sensory motor speed, perceptual speed, executive function, and global cognition. However, in an earlier intervention study that enrolled 235 elderly individuals (mean age, 81 years old) with or without mild vitamin B 12 deficiency, baseline concentrations of betaine − but not choline − were found to be positively correlated to test scores evaluating the cognitive domains of construction, sensory motor speed, and executive function (61).

More research is needed to determine the effect of choline on the developing brain and whether choline intakes above the RDA may be useful in the prevention of memory loss or dementia in humans.

Disease Treatment

Cerebrovascular diseases

Cerebrovascular diseases (including stroke and sub-acute ischemic cerebrovascular disease) are the main cause of cognitive impairments in older people. Results from experimental studies have suggested that pharmacological doses of citicoline (CDP-choline) could enhance the metabolism of glucose and the biosynthesis of phospholipids and neurotransmitters, while limiting the degradation of phospholipids in neuronal membranes in models of ischemia and neurodegenerative diseases (reviewed in 62). Many short-term intervention studies in older individuals with vascular diseases have found that therapeutic doses of citicoline given either orally, by intramuscular injection, or by intravenous infusion, resulted in improvements in neuropsychological functions, including cognitive, emotional, and behavioral functions (reviewed in 5).

A six-month, multicenter observational study enrolled 197 stroke subjects (mean age, 81.5 years) with a progressive decline of their mental health and general confusion and/or stupor who were initially administered citicoline for 5 or 10 days (2,000 mg/day, by intravenous infusion) within a four-month period, and then for 21 days (1,000 mg/day, by intramuscular injection), repeated once after a seven-day washout period (63). Citicoline treatment was found to be associated with higher scores on cognitive and functional evaluation scales when compared to baseline measurements. However, only randomized controlled trials would be able to assess whether citicoline is protective against vascular damage and cognitive impairment in elderly adults with complex geriatric symptoms.

The International Citicoline Trial on acUte Stroke (ICTUS) is a multicenter and double-blind study that assessed the effect of supplementing 2,298 patients with acute ischemic stroke with citicoline (2,000 mg/day) or a placebo for six weeks on several functional and neurologic outcomes and on mortality rate (64). The results showed no difference between treatment groups after a 90-day follow-up period. Only subgroup analyses found significant benefits of citicoline in patients older than 70 years, in those with moderate rather than severe strokes, and in those not treated with recombinant tissue plasminogen activator (rtPA; standard-of-care treatment). An earlier meta-analysis of small randomized, placebo-controlled trials had reported a positive impact of citicoline (1,000 mg/day, administered for 28 days to 12 months) on memory and behavior in subjects with cognitive deficits associated with cerebrovascular disorders (65). The effect of citicoline was also evaluated in a recent multicenter, open-label, controlled trial (IDEALE trial) in Italian elderly adults (ages, 65-94 years) with evidence of vascular lesions on neuroradiology and mild-to-moderate cognitive deficits, as assessed by Mini-Mental State Examination (MMSE; scores ≥21) (66). Three hundred and forty-nine participants received oral citicoline (1,000 mg/day) or no treatment for nine months. MMSE scores in citicoline-treated individuals remained unchanged while they significantly deteriorated in untreated patients such that MMSE scores between groups were found to be significantly different after three and nine months of treatment. No significant effect was reported in measures of functional autonomy, mood, and behavioral disorders. Another recent open-label, randomized, controlled trial evaluated the effect of citicoline (1,000 mg/day for 12 months) in 347 subjects (mean age, 67.2 years) who suffered an acute stroke. The results demonstrated that citicoline significantly limited cognitive impairments in the domains of attention and executive functions and temporal orientation at 6 and 12 months post-stroke in treated compared to untreated patients (67).

Neurodegenerative diseases

Dementia

Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson’s disease (PD), are characterized by progressive cognitive decline and dementia. Dysfunctions in neurotransmitter signaling, affecting cholinergic and dopaminergic pathways in particular, have been involved in the occurrence of cognitive impairments. Deficits in acetylcholine and abnormal phospholipid metabolism have been reported in postmortem studies of the brains of AD patients (11). For these reasons, inhibitors of (acetyl) cholinesterase (which catalyzes the breakdown of acetylcholine) and large doses of lecithin (phosphatidylcholine) have been used to treat patients with dementia due to AD in hopes of raising the amount of acetylcholine available in the brain. While cholinesterase inhibitors have shown positive effects on cognitive functions and measures of clinical global state (68), a systematic review of randomized controlled trials did not find lecithin to be more beneficial than placebo in the treatment of patients with cognitive impairment, vascular dementia, AD, or mixed dementia (69). Limited data are available to assess whether citicoline (CDP-choline) might improve cognitive performance in subjects with AD (70). No recent trial has investigated the effect of citicoline in PD patients.

Glaucoma

Optic neuropathies, including glaucoma, are associated with damage of the optic nerve and loss of visual function. In glaucoma, the progressive deterioration of the optic nerve is caused by loss of a specific neuronal population known as retinal ganglion cells (RGC), such that the condition has been classified as a neurodegenerative disease (71). In a small, double-blind, placebo-controlled study, the effect of citicoline was assessed in 24 subjects affected by open-angle glaucoma and treated with β-blockers. Patients were randomized to follow a therapeutic cycle for a total period of eight years: citicoline (1,000 mg/day, by intramuscular injection) or placebo (β-blockers alone) for a two-month period followed by a four-month washout period (72). Electrophysiological examinations were used to assess the extent of visual dysfunctions, including the simultaneous recordings of Pattern ElectroRetinoGrams (PERG) and Visual Evoked Potentials (VEP). Citicoline was found to enhance retinal function and neural conduction along post-retinal visual pathways, such that responses of the visual cortex to stimuli were significantly improved compared to placebo.

In a similar pilot trial, citicoline efficacy was assessed in 26 volunteers (mean age, 65.4 years) affected by another type of optic neuropathy known as non-arteritic anterior ischemic optic neuropathy (NAION). Oral citicoline (1,600 mg/day) was given for 60 days followed by 60 days of washout, and the therapeutic cycle was repeated once. Compared to placebo, citicoline was found to improve retinal function and post-retinal neural conduction, evidenced by PERG and VEP measures (73). Oral citicoline (four cycles of 500 mg/day for four months followed by a two-month washout period) was also found to significantly reduce the rate of visual field loss and the level of intraocular pressure in 41 patients with progressive glaucoma (74). Larger randomized controlled trials are needed to establish whether citicoline supplementation could be included in the medical treatment of glaucoma.

Traumatic brain injury

For decades, pre-clinical and small clinical studies have investigated the effect of citicoline in the management of patients sustaining a traumatic brain injury (TBI). A systematic review of clinical data suggested that citicoline could hasten the resorption of cerebral edema and improve the recovery of consciousness and neurologic disorders in severe TBI cases (classified by Glasgow Coma Scale [GCS] scores of ≤8). Citicoline also appeared to limit memory deficits and the duration and severity of other post-traumatic symptoms (e.g., headache, dizziness, attention disorder) in TBI patients with mild-to-moderate injuries (GCS scores, 9-15) (reviewed in 5). Although citicoline is currently included in TBI therapeutic regimen in 59 countries, only one multicenter, randomized, double-blind, placebo-controlled trial has recently been conducted in the US. The CiticOline Brain Injury Trial (COBRIT) has enrolled 1,213 patients with mild-to-severe TBI and assessed the effect of enteral or oral citicoline (2,000 mg/day, for 90 days) on functional and cognitive outcomes (measured by components of the TBI Clinical Trials Network Care Battery) (75). No significant benefits of citicoline supplementation over placebo were found at 90 days (end of treatment period) and 180 days. A Cochrane review of the effect of citicoline in the treatment of TBI should be available soon (76).

Sources

De novo synthesis (biosynthesis)

Humans can synthesize choline moieties in small amounts by converting phosphatidylethanolamine into phosphatidylcholine (see Figure 2 above). Three methylation reactions catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT) are required, each using S-adenosylmethionine (SAM) as a methyl group donor. Choline is generated endogenously when the methylation of phosphatidylethanolamine is coupled with the catabolism of newly formed phosphatidylcholine by phospholipases. This is referred to as de novo synthesis of choline. The substitution of choline by serine in the synthesis of phosphatidylserine from phosphatidylcholine by phosphatidylserine synthase-1 also releases choline (4). Because phosphatidylcholine metabolism is a source of endogenous choline, the nutrient was not initially classified as essential (1). Yet, de novo choline synthesis in humans is not sufficient to meet their metabolic needs such that healthy humans fed choline-deficient diets develop fatty liver, liver damage, and/or muscle damage (see Deficiency).

Food sources

In the US, mean dietary intakes of choline are well below the recommended AI. According to a US national survey, NHANES 2007-2008, mean dietary intakes of choline were approximately 260 mg/day for women and 396 mg/day for men (77). In a 14-year US prospective study, including over 14,000 middle-aged participants, mean daily intakes of choline were 294 mg and 332 mg in women and men, respectively (35). Eggs, liver, and peanuts, are especially rich in choline (27). Major contributors to choline in the American diet are meat, poultry, fish, dairy foods, pasta, rice, and egg-based dishes (77). Spinach, beets, wheat, and shellfish are also good sources of the choline metabolite, betaine (78). Betaine cannot be converted back to choline but can spare some choline requirements for homocysteine remethylation (1). Phosphatidylcholine, which contains about 13% choline by weight, is the main form of choline in dietary products (79). Lecithin extracts, which comprise a mixture of phosphatidylcholine and other phospholipids, are often added during food processing. Lecithins in processed food have been estimated to increase the daily consumption of phosphatidylcholine by about 1.5 mg/kg of body weight for adults (27).

Strict vegetarians, who consume no meat, milk, or eggs, may be at risk for inadequate choline intake. The total choline contents of some choline-containing foods are listed in milligrams (mg) in Table 2. For more information on the nutrient content of specific foods, search the USDA food composition website or the USDA documentation on the choline content of common foods.

Table 2. Some Food Sources of Choline Food Serving Total Choline (mg) Beef liver, pan fried 3 ounces* 356 Wheat germ, toasted 1 cup 202 Egg 1 large 147 Beef, trim cut, cooked 3 ounces 97 Scallop, cooked, steamed 3 ounces 94 Salmon, pink, canned 3 ounces 75 Chicken, breast, cooked, roasted 3 ounces 73 Atlantic cod, cooked 3 ounces 71 Shrimp, canned 3 ounces 69 Brussel sprouts, cooked, boiled 1 cup 63 Broccoli, cooked, boiled 1 cup, chopped 63 Milk, skim 8 fluid ounces 38 Peanut butter, smooth 2 tablespoons 20 Milk chocolate 1.5-ounce bar 20 Peanuts 1 ounce 15 *A three-ounce serving of meat or fish is about the size of a deck of cards.

Supplements

CDP-choline (citicoline) and choline salts, such as choline chloride and choline bitartrate, are available as supplements. Phosphatidylcholine supplements also provide choline; however, choline comprises only about 13% of the weight of phosphatidylcholine (79). Therefore, a supplement containing 4,230 mg (4.23 grams) of phosphatidylcholine would provide 550 mg of choline. Although the term "lecithin" is synonymous with phosphatidylcholine when used in chemistry, commercial lecithins are usually prepared from soybean, sunflower, and rapeseed, and may contain anywhere from 20%-90% of phosphatidylcholine. Egg yolk lecithin is a more unlikely source of lecithin in dietary supplements. Moreover, the nature of phosphatidylcholine-containing fatty acids depends on whether lecithin is produced from vegetable, animal, or microbial sources. In particular, soybean lecithin is richer in polyunsaturated fatty acids than egg yolk lecithin (80).

Safety

Toxicity

High doses (10,000 to 16,000 mg/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. In the inherited condition, primary trimethylaminuria (also known as “fish odor syndrome”; see the article on Riboflavin), a defective flavin containing monooxygenase 3 (FMO3) enzyme results in impaired oxidation of trimethylamine in the liver. Disease management includes the use of choline-restricted diets in affected individuals (81).

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 7,500 mg/day of choline was found to have a slight blood pressure lowering (hypotensive) effect, which could result in dizziness or fainting. Choline magnesium trisalicylate at doses of 3,000 mg/day has resulted in impaired liver function, generalized itching, and ringing of the ears (tinnitus). However, it is likely that these effects were caused by the salicylate, rather than the choline in the preparation (27).

In 1998, the Food and Nutrition Board (FNB) of the Institute of Medicine established the tolerable upper intake level (UL) for choline at 3,500 mg/day for adults (Table 3). 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 inherited trimethylaminuria might be at increased risk of adverse effects when consuming choline at levels near the UL (27).

Table 3. Tolerable Upper Intake Level (UL) for Choline Age Group UL (mg/day) Infants 0-12 months Not possible to establish* Children 1-8 years 1,000 Children 9-13 years 2,000 Adolescents 14-18 years 3,000 Adults 19 years and older 3,500 *Source of intake should be food and formula only.

Do high choline intakes and/or phosphatidylcholine supplements increase the risk for cardiovascular disease?

Oral supplementation with phosphatidylcholine (250 mg of total choline from food plus 250 mg of supplemental phosphatidylcholine) has been found to result in detectable concentrations of trimethylamine and trimethylamine N-oxide (TMAO) in the blood (23). The intestinal microbiota is directly implicated in the generation of trimethylamine from dietary choline, phosphatidylcholine, and carnitine. Trimethylamine is subsequently converted into TMAO by flavin-containing monooxygenases in the liver. The prospective study that followed 4,007 individuals,with or without cardiovascular disease (CVD) for a three-year period found baseline concentrations of circulating TMAO to be positively correlated with incidence of death, nonfatal myocardial infarction, and stroke − described as major adverse cardiac events (MACE) (23). In the same cohort, MACE risk was found to be about 30% higher in individuals in the highest vs. lowest quartile of choline or betaine plasma concentrations (82). However, depending on gut microbiota composition, the risk of having an adverse cardiovascular event may be lower in individuals with low vs. high circulating TMAO even though choline and/or betaine concentrations in the blood are elevated (82).

Elevated TMAO concentrations have been reported in subjects at increased risk of CVD, such as those with diabetes mellitus (83) or end-stage renal disease (chronic kidney failure) (84), and in patients with cardiac insufficiency (chronic heart failure) (85). Yet, in the latter patients, high plasma concentrations of choline, betaine, and TMAO were not associated with a poorer survival rate after five years of follow-up (85). Finally, supplementation with choline, TMAO, or betaine was found to result in the formation of macrophage-derived foam cells in atherosclerosis-prone mice (24). Foam cells are known to contribute to the development of atherosclerotic lesions (i.e., atherogenesis) by accumulating excessive amounts of lipids within the arterial walls and triggering the secretion of pro-inflammatory cytokines.

Further research is needed to understand how the composition of intestinal microbiota influences the metabolic fate of ingested choline. At present, there is no evidence that dietary choline increases the risk of cardiovascular events.

Drug interactions

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 and greater drug adverse reactions due to liver dysfunction (11, 86). Thus, individuals taking methotrexate may have an increased choline requirement. Treatments with a family of lipid-lowering drugs known as fibrates (e.g., fenofibrate, bezofibrate) have been associated with an increased excretion of betaine in the urine and a rise in homocysteine concentration in the blood of patients with diabetes mellitus or metabolic syndrome (87, 88). If the benefits of fibrate therapy are indeed mitigated by fibrate-induced betaine deficiency, the use and safety of supplementing patients with betaine would need to be considered (89).

Linus Pauling Institute Recommendation

Little is known regarding the amount of dietary choline required to promote optimum health or prevent chronic diseases in humans. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 550 mg/day for adult men and 425 mg/day for adult women. A varied diet should provide enough choline for most people, but strict vegetarians who consume no milk or eggs may be at risk of inadequate choline intake.

Older adults (>50 years)

Little is known regarding the amount of dietary choline most likely to promote optimum health or prevent chronic diseases in older adults. At present, there is no evidence to support a different recommended intake of choline from that of younger adults (550 mg/day for men and 425 mg/day for women).

Authors and Reviewers

Originally written in 2000 by:

Jane Higdon, Ph.D.

Linus Pauling Institute

Oregon State University

Updated in May 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

Updated in August 2009 by:

Victoria J. Drake, Ph.D.

Linus Pauling Institute

Oregon State University

Updated in January 2015 by:

Barbara Delage, Ph.D.

Linus Pauling Institute

Oregon State University

Reviewed in February 2015 by:

Steven H. Zeisel, M.D., Ph.D.

Professor and Chair of Nutrition

School of Public Health

The University of North Carolina, Chapel Hill

Copyright 2000-2020 Linus Pauling Institute

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