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12
Choline

SUMMARY

Choline functions as a precursor for acetylcholine, phospholipids, and the methyl donor betaine. The primary criterion used to estimate the Adequate Intake (AI) for choline is the prevention of liver damage as assessed by measuring serum alanine aminotransferase levels. The AI for adults is 550 mg/day of choline for men and 425 mg/day for women. There are no nationally representative estimates of the intake of choline from food or food supplements. Choline in the diet is available as free choline or is bound as esters such as phosphocholine, glycerophosphocholine, sphingomyelin, or phosphatidylcholine. The critical adverse effect from high intake of choline is hypotension, with corroborative evidence on cholinergic side effects (e.g., sweating and diarrhea) and fishy body odor. The Tolerable Upper Intake Level (UL) for adults is 3.5 g/day.

BACKGROUND INFORMATION

Choline is a dietary component that is important for the structural integrity of cell membranes, methyl metabolism, cholinergic neurotransmission, transmembrane signaling, and lipid and cholesterol transport and metabolism. Human cells grown in culture have an absolute requirement for choline (Eagle, 1955). When cells are deprived of choline, they die by apoptosis (Albright et al., 1996; Cui et al., 1996; Holmes-McNary et al., 1997; James et al., 1997; Shin et



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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 12 Choline SUMMARY Choline functions as a precursor for acetylcholine, phospholipids, and the methyl donor betaine. The primary criterion used to estimate the Adequate Intake (AI) for choline is the prevention of liver damage as assessed by measuring serum alanine aminotransferase levels. The AI for adults is 550 mg/day of choline for men and 425 mg/day for women. There are no nationally representative estimates of the intake of choline from food or food supplements. Choline in the diet is available as free choline or is bound as esters such as phosphocholine, glycerophosphocholine, sphingomyelin, or phosphatidylcholine. The critical adverse effect from high intake of choline is hypotension, with corroborative evidence on cholinergic side effects (e.g., sweating and diarrhea) and fishy body odor. The Tolerable Upper Intake Level (UL) for adults is 3.5 g/day. BACKGROUND INFORMATION Choline is a dietary component that is important for the structural integrity of cell membranes, methyl metabolism, cholinergic neurotransmission, transmembrane signaling, and lipid and cholesterol transport and metabolism. Human cells grown in culture have an absolute requirement for choline (Eagle, 1955). When cells are deprived of choline, they die by apoptosis (Albright et al., 1996; Cui et al., 1996; Holmes-McNary et al., 1997; James et al., 1997; Shin et

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline al., 1997; Zeisel et al., 1997). There is an endogenous pathway for the de novo biosynthesis of the choline moiety via the sequential methylation of phosphatidylethanolamine using S-adenosylmethionine as the methyl donor (Bremer and Greenberg, 1961) (see Figure 12-1). Thus, the demand for dietary choline is modified by metabolic methyl-exchange relationships between choline and three nutrients: methionine, folate, and vitamin B12 (lipotropes) (Zeisel and Blusztajn, 1994). With this type of nutrient interdependence, designation of the essential nature of a nutrient depends on showing that de novo synthesis rates are not adequate to meet the demand for the nutrient when the other nutrients are available in amounts sufficient to sustain normal growth and function. Healthy men with normal folate and vitamin B12 status fed a choline-deficient diet have diminished plasma choline and phosphatidylcholine concentrations and develop liver damage (Zeisel et al., 1991). For these individuals, de novo synthesis of choline was not adequate to meet the demand for FIGURE 12-1 Choline, folate, and methionine metabolism are closely interrelated. AdoHcy = S-adenosylhomocysteine, AdoMet = S-adenosylmethionine, B12 = vitamin B12, CDP-Choline = cytidine diphosphocholine, PtdEtn = phosphatidylethanolamine, THF = tetrahydrofolate. Reprinted with permission, from Zeisel and Blusztajn (1994). Copyright 1994 by Annual Reviews.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline the nutrient. Information about women, infants, children, and older adults is not sufficient to know whether choline is needed in the diet of these groups. Function Choline can be acetylated, phosphorylated, oxidized, or hydrolyzed. Several comprehensive reviews of the metabolism and functions of choline have been published (Kuksis and Mookerjea, 1978; Zeisel, 1981; Zeisel and Blusztajn, 1994). Choline accelerates the synthesis and release of acetylcholine, an important neurotransmitter involved in memory storage, muscle control, and many other functions (Cohen and Wurtman, 1975; Haubrich et al., 1974; Wecker, 1986). It is also a precursor for the synthesis of (1) phospholipids, including phosphatidylcholine (a membrane constituent important for the structure and function of membranes), for intracellular signaling (Exton, 1994; Zeisel, 1993) and hepatic export of very low-density lipoproteins (Yao and Vance, 1988, 1989); (2) sphingomyelin (another membrane constituent) for structural and signaling functions (Hannun, 1994); and (3) platelet activating factor, a potent messenger molecule (Frenkel et al., 1996). Choline is a precursor for the formation of the methyl donor betaine. Betaine is also required by renal glomerular cells, which use betaine and glycerophosphocholine as organic osmolytes to adapt to osmotic stress (Bauernschmitt and Kinne, 1993; Burg, 1995; Garcia-Perez and Burg, 1991; Grossman and Hebert, 1989). Physiology of Absorption, Metabolism, and Excretion Dietary choline is absorbed from the lumen of the small intestine via transporter proteins in the enterocyte (Herzberg and Lerner, 1973; Herzberg et al., 1971; Kuczler et al., 1977; Sheard and Zeisel, 1986). Before choline can be absorbed from the gut, some is metabolized by bacteria to form betaine (which may be absorbed and used as a methyl donor) and methylamines (which are not methyl donors) (Zeisel et al., 1983). No other component of the diet has been identified as competing with choline for transport by intestinal carriers. Choline is found in foods as free choline and as esterified forms such as phosphocholine, glycerophosphocholine, sphingomyelin, and phosphatidylcholine. Lecithin is a phosphatidylcholine-rich fraction prepared during commercial purification of phospholipids, and this term is often used interchangeably with phosphatidylcholine. Lecithin is often added to foods as an emulsifying agent.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Pancreatic enzymes can liberate choline from dietary phosphatidylcholine, phosphocholine, and glycerophosphocholine (Zeisel and Blusztajn, 1994). The free choline that is formed enters the portal circulation of the liver (Le Kim and Betzing, 1976) whereas phosphatidylcholine may enter via lymph in chylomicrons. All tissues accumulate choline by diffusion and mediated transport (Zeisel, 1981). A specific carrier mechanism transports free choline across the blood-brain barrier at a rate that is proportional to the serum choline concentration. In the neonate this choline transporter has an especially high capacity (Cornford and Cornford, 1986). The rate at which the liver takes up choline is sufficient to explain the rapid disappearance of choline injected systemically (Zeisel et al., 1980c). The kidney also accumulates choline (Acara and Rennick, 1973). Some of this choline appears in the urine unchanged but most is oxidized within the kidney to form betaine (Rennick et al., 1977). In the predominant pathway for phosphatidylcholine biosynthesis, choline is phosphorylated, converted to cytidine diphosphocholine, and then converted to phosphatidylcholine (Kennedy and Weiss, 1956; Vance, 1990) (Figure 12-1). In an alternative pathway, phosphatidylethanolamine is sequentially methylated to form phosphatidylcholine by the enzyme phosphatidylethanolamine-N-methyltransferase with S-adenosylmethionine as the methyl donor (Bremer and Greenberg, 1961; Vance and Ridgway, 1988). This is the major (perhaps only) pathway for de novo synthesis of the choline moiety in adult mammals. It is most active in the liver but has been identified in many other tissues (Blusztajn et al., 1979; Crews et al., 1981; Yang et al., 1988). Best estimates of in vivo activity of this enzyme, based on in vitro data, are that 15 to 40 percent of the phosphatidylcholine present in the liver is derived from the phosphatidylethanolamine-N-methyltransferase pathway, with the remainder coming from the cytidine diphosphocholine pathway (Bjornstad and Bremer, 1966; Sundler and Akesson, 1975). No estimates are available as to the relative extent of choline obtained from cell turnover. Dietary intake of phosphatidylcholine is approximately 6 to 10 g/day (Zeisel et al., 1991). A significant portion of choline is oxidized to form betaine in the liver and kidney (Bianchi and Azzone, 1964; Weinhold and Sanders, 1973). The methyl groups of betaine can be scavenged and reused in single-carbon metabolism (Finkelstein et al., 1982) (see “Nutrient-Nutrient Interactions”).

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Clinical Effects of Inadequate Intake Humans Although choline is clearly essential to life, there is only one published study examining the effects of inadequate dietary intake in healthy men. That study reported decreased choline stores and liver damage (elevated alanine aminotransferase) when men were fed a choline-deficient diet containing adequate methionine, folate, and vitamin B12 for 3 weeks (Zeisel et al., 1991) (Figures 12-2 and 12-3). Another study, in which men were fed a choline- and methyl-deficient diet, reported decreased choline stores but did not report on liver function (Jacob et al., 1995). Individuals fed with total parenteral nutrition (TPN) solutions devoid of choline but adequate for methionine and folate develop fatty liver and liver damage as assessed by elevated alanine aminotransferase; in some individu FIGURE 12-2 Plasma choline in healthy men ingesting a control (500 mg/day of choline) or choline-deficient (13 mg/day of choline) diet. *Difference from day 7 value: p < 0.01. Reprinted with permission, from Zeisel et al. (1991). Copyright 1991 by the Federation of American Societies for Experimental Biology.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline FIGURE 12-3 Serum alanine aminotransferase (ALT) activity in men ingesting a control or choline-deficient diet. Serum ALT was determined by using an automated spectrophotometric assay. Data are expressed as mean activity ± standard error of the mean. *Difference from day 7 value: p < 0.05. Reprinted with permission, from Zeisel et al. (1991). Copyright 1991 by the Federation of American Societies for Experimental Biology. als, this is resolved when a source of dietary choline is provided (Buchman et al., 1992, 1993, 1995; Chawla et al., 1989; Shapira et al., 1986; Sheard et al., 1986). In a double-blind protocol, investigators administered lecithin (30 percent phosphatidylcholine) orally to patients receiving TPN twice daily for 6 weeks. At the end of this time, plasma choline had risen by more than 50 percent in the lecithin group whereas in the placebo group it had decreased by 25 percent. In the treated group, liver fat decreased by 30 percent (Buchman et al., 1992). In another small clinical study (Buchman et al., 1995), four patients who had low plasma concentrations of free choline after treatment with TPN (which contained no additional choline) were given 1 to 4 g/day of choline chloride for 6 weeks. During choline administration, plasma choline concentration

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline increased into the normal range but decreased back to baseline when choline supplementation was discontinued. Fatty liver was resolved completely during choline supplementation but steatosis (fatty liver) recurred in one patient after 10 weeks of return to choline-free TPN. The available data support the provisional conclusion that de novo synthesis of choline is not always sufficient to meet human requirements for choline. Animals Supporting animal studies (in many species, such as the baboon) also found that a choline-deficient diet resulted in decreased choline stores and liver dysfunction (Hoffbauer and Zaki, 1965; Sheard et al., 1986; Tayek et al., 1990; Yao and Vance, 1990). The following animals fed a choline-deficient diet may be susceptible to developing growth retardation, renal dysfunction and hemorrhage, or bone abnormalities: baboon (Hoffbauer and Zaki, 1965), chicken (Blair et al., 1973; Ketola and Nesheim, 1974), dog (Best and Huntsman, 1932; Hershey, 1931), guinea pig (Tani et al., 1967), hamster (Handler, 1949), pig (Blair and Newsome, 1985; Fairbanks and Krider, 1945), quail (Ketola and Young, 1973), rat (Newberne and Rogers, 1986), and trout (Ketola, 1976). SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR CHOLINE Markers of Liver Dysfunction The liver is damaged when humans consume an otherwise adequate diet that is deficient in choline, resulting in elevated alanine aminotransferase levels in blood (Burt et al., 1980; Tayek et al., 1990; Zeisel et al., 1991). Fatty infiltration of liver also occurs in choline deficiency but is difficult to use as a functional marker without special liver imaging techniques (Buchman et al., 1992). Hepatic choline and choline metabolite concentrations have been shown to decrease during choline deficiency in the rat (Zeisel et al., 1989). Phosphocholine concentration in liver is highly correlated with dietary choline intake, decreasing to 10 to 20 percent of control values after 2 weeks on a diet sufficient in methionine, folate, and vitamin B12 but deficient in choline (Pomfret et al., 1990). Hepatic phosphocholine concentration was most sensitive to modest dietary choline deficiency, decreasing to 10 to 20 percent of control values after 2 weeks of a deficient diet (Pomfret et al., 1990). This

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline measurement is not easily undertaken in humans, although magnetic resonance spectroscopy does makes it possible (Cohen et al., 1995). Plasma Concentrations Plasma choline concentration varies in response to diet and is found in the water-soluble fraction as free choline (Buchman et al., 1993; Burt et al., 1980; Chawla et al., 1989; Sheard et al., 1986; Zeisel et al., 1991). It decreases approximately 30 percent in subjects fed a choline-deficient diet for 3 weeks (Zeisel et al., 1991). Plasma choline concentration can increase twofold after a meal high in choline content and three- or fourfold after a supplemental choline dose (Zeisel et al., 1980b). Fasting plasma choline concentrations vary from 7 to 20 µmol/L, with most subjects having concentrations of 10 µmol/L. The disadvantage of using plasma choline as a functional indicator is that these concentrations do not appear to decline below approximately 50 percent of normal, even when subjects fast for more than 1 week (Savendahl et al., 1997). Perhaps this is because membrane phospholipids, which are a large storage pool for choline, are hydrolyzed to maintain plasma choline concentration above this minimal level. Fasting plasma phosphatidylcholine concentrations (mostly as part of plasma lipoproteins) are approximately 1 to 1.5 mmol/L (Aquilonius et al., 1975; Zeisel et al., 1980b, 1991). Plasma phosphatidylcholine concentration also decreases in choline deficiency (Zeisel et al., 1991) but is also influenced by factors that change plasma lipoprotein levels. Reduction of Risk of Chronic Disease Dementia Studies in rodents suggest that dietary intake of choline early in life can diminish the severity of memory deficits in aged animals (Bartus et al., 1980; Meek and Williams, 1997a, b, c). Most available human studies have used choline-containing compounds to treat rather than prevent the symptoms of dementia and therefore did not address whether dementias could be prevented. In the absence of food composition data, epidemiological studies on the association of choline intake with dementia are not available. More human studies are needed to determine whether dietary choline intake is useful in the prevention of dementia.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Cardiovascular Disease The choline-containing phospholipid phosphatidylcholine (lecithin) has been used as a treatment to lower cholesterol concentrations because lecithin-cholesterol acyltransferase has an important role in the removal of cholesterol from tissues. In humans phosphatidylcholine ingestion is associated with a modest reduction in plasma cholesterol (Hirsch et al., 1978; Wood and Allison, 1982; Zeisel et al., 1991). In addition, choline or betaine treatment has been used to lower high plasma homocysteine concentrations (Anonymous, 1997; Dudman et al., 1987; Wendel and Bremer, 1984; Wilcken et al., 1983, 1985), and choline-deficient rodents have elevated plasma homocysteine concentrations (Varela-Moreiras et al., 1995) (see Chapter 8, “Vascular Disease”). Wendel and Bremer (1984) reported that betaine treatment was more effective than folate treatment in normalizing plasma homocysteine and methionine concentrations of a child with homocystinuria, a genetic disease caused by 5,10-methylenetetrahydrofolate reductase deficiency (choline is the precursor for betaine, which itself is found in sugar beets and wine). Therefore, dietary choline intake might be correlated with cardiovascular disease risk. More human studies are needed before conclusions can be drawn about whether dietary choline intake is useful in preventing cardiovascular disease. Cancer In rodents dietary choline deficiency is associated with increased incidence of liver cancer and increased sensitivity to carcinogenic chemicals (Newberne and Rogers, 1986). The mechanisms of the carcinogenic actions of choline deficiency are not known but may be mediated by changes in protein kinase C activity (da Costa et al., 1993, 1995). There are no human data; studies in humans are needed to assess the role of dietary choline in the prevention of cancer. FACTORS AFFECTING THE CHOLINE REQUIREMENT Nutrient-Nutrient Interactions Any consideration of the requirements for choline and methionine needs to include the close interrelationships with other methyl donors. Choline, methionine, and folate metabolism interact at the point that homocysteine is converted to methionine.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Betaine-homocysteine methyltransferase catalyzes the methylation of homocysteine using betaine as the methyl donor (see Figure 12-1) (Finkelstein et al. 1982; Mudd and Poole, 1975; Wong and Thompson, 1972). In an alternative pathway, 5-methyltetrahydrofolate-homocysteine methyltransferase regenerates methionine by using a methyl group derived de novo from the single-carbon pool (Finkelstein et al., 1982, 1988). Methionine adenosyltransferase converts methionine to S-adenosylmethionine (the active methylating agent for many enzymatic methylations, including the methylation of phosphatidylethanolamine to form phosphatidylcholine [Ridgway and Vance, 1988]). Perturbing the metabolism of one of the methyl donors reveals the intermingling of these metabolic pathways. Total hepatic folate content decreased by 31 to 40 percent in rats after 2 weeks on a choline-deficient diet (Selhub et al., 1991; Varela-Moreiras et al., 1995). This effect was reversed by refeeding choline (Varela-Moreiras et al., 1995). Rats fed diets deficient in both methionine and choline for 5 weeks had hepatic folate concentrations that were half of those present in controls (Home et al., 1989). Tetrahydrofolate deficiency in rats, induced by treatment with methotrexate (Barak and Kemmy, 1982; Barak et al., 1984; Freeman-Narrod et al., 1977; Pomfret et al., 1990; Svardal et al., 1988) or by dietary folate deficiency (Kim et al., 1994) resulted in diminished hepatic total choline, with the greatest decrease occurring in hepatic phosphocholine concentrations. During choline deficiency in rats, hepatic S-adenosylmethionine concentrations also decreased by as much as 50 percent (Barak et al., 1982; Poirier et al., 1977; Shivapurkar and Poirier, 1983; Zeisel et al., 1989). In rats choline deficiency for 2 weeks doubled plasma homocysteine levels (Varela-Moreiras et al., 1995). See Chapters 7 and 8 for more information on plasma homocysteine. Gender Males may have a higher choline requirement than do females. Female rats are less sensitive to choline deficiency than are male rats (Tessitore et al., 1995), perhaps because of females’ enhanced capacity to form the choline moiety de novo. Females rats have greater phosphatidylethanolamine-N-methyltransferase activity in liver than do males (Arvidson, 1968; Bjornstad and Bremer, 1966; Lyman et al., 1971). Estimates of the amount of increased activity vary between 10 (Lyman et al., 1971) and 50 percent (Bjornstad and Bremer, 1966). A woman’s capacity to form the choline moiety

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline de novo may decrease after menopause (Lindblad and Schersten, 1976), because estrogens increase hepatic phosphatidylethanolamine-N-methyltransferase activity in rats (Drouva et al., 1986; Young, 1971). Exercise Strenuous physical activity in trained athletes reduced the plasma choline concentration by approximately 40 percent, from 14.1 to 8.4 µmol/L (Conlay et al., 1986). A choline supplement given to marathon runners modestly enhanced performance (Sandage et al., 1992). In 10 top-level triathletes who were given either a placebo or lecithin at 0.2 g/kg body mass 1 hour before each type of exercise, plasma choline concentrations in all the triathletes decreased on average by 16.9 percent after the bicycle exercise when placebo was taken before the race but did not do so when lecithin was given (Von Allworden et al., 1993). Bioavailability No estimates are available for percentage absorption of the various forms of choline in humans. The water-soluble choline-derived compounds (choline, phosphocholine, and glycerophosphocholine) are absorbed via the portal circulation whereas the lipid-soluble compounds (phosphatidylcholine and sphingomyelin) present in foods are absorbed into lymph as chylomicrons via the thoracic duct. This results in differential delivery and kinetics of distribution to tissues (Cheng et al., 1996; Zeisel et al., 1980b). FINDINGS BY LIFE STAGE AND GENDER GROUP Data are not sufficient for deriving an Estimated Average Requirement (EAR) for choline. The two published studies in healthy humans used male subjects only and tested a single level of choline intake. For these reasons only an Adequate Intake (AI) can be estimated. This amount will be influenced by the availability of methionine and folate in the diet. It may be influenced by gender, pregnancy, lactation, and stage of development. Although AIs are set for choline, it may be that the choline requirement can be met by endogenous synthesis at some of these stages. To date, all studies have used choline-free diets and compared them with choline-containing diets; no intermediate levels of defi-

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline about the infant’s ability to handle excess amounts. The only source of intake for infants should be from food or formula to prevent high levels of intake. There are no data to suggest that during pregnancy or lactation increased susceptibility to developing cholinergic effects or fishy body odor from excess choline intake would occur. Therefore, the UL of 3.5 g/day is also set for pregnant and lactating women. The UL of 3.5 g/day for adults was adjusted for children and adolescents on the basis of relative body weight as described in Chapter 3, with the use of reference weights from Chapter 1, Table 1-2. Values have been rounded down. Choline UL Summary, Other Life Stage Groups UL For Infants 0–12 months Not possible to establish; source of intake should be formula and food only UL for Children 1–3 years 1 g/day of choline 4–8 years 1 g/day of choline 9–13 years 2 g/day of choline UL for Adolescents 14–18 years 3 g/day of choline UL for Pregnancy 14–18 years 3 g/day of choline 19 years and older 3.5 g/day of choline UL for Lactation 14–18 years 3 g/day of choline 19 years and older 3.5 g/day of choline Special Considerations Individuals with the following conditions may be at risk of adverse effects with choline intakes at the UL: trimethylaminuria, renal disease, liver disease, depression, and Parkinson’s disease. Intake Assessment National surveys do not provide data on the dietary intake of choline. The UL applies to the weight of the choline moiety in the compound; for example, choline chloride contains more choline by weight than does choline bitartrate. Dietary supplements containing choline are available; however, reliable estimates of the

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline amount of these supplements consumed in the United States and Canada are unavailable. Risk Characterization Because there is no information from national surveys on choline intakes or on supplement usage, the risk of adverse effects within the United States or Canada can not be characterized. RESEARCH RECOMMENDATIONS FOR CHOLINE High Priority Recommendations Sufficient human data are not available for determining whether choline is essential in the human diet, how much is required if it is essential, and the public health impact of poor choline nutriture. For this reason, research that could provide such human data is assigned the highest priority: Examination of the effects of the use of graded levels of dietary intake of choline on parameters of health. This would include assessing plasma and tissue choline compounds and metabolites; plasma cholesterol and homocysteine concentrations; erythrocyte folate; and liver, renal, brain, and other organ function. To facilitate this process, food composition data are needed for choline, phosphocholine, glycerophosphocholine, sphingomyelin, phosphatidylcholine, and betaine and the analytic sensitivity and specificity of methods for analysis of food composition need to be validated. Human studies on interrelationships among requirements for choline, methionine, folate, vitamin B6, and vitamin B12 to compare the homocysteine-lowering effects of combinations of these nutrients. Other Research Areas Two additional topics also merit attention: The relative effectiveness of different choline-containing compounds in the diet in promoting health and determination of the sparing effect of endogenous synthesis of choline. It will be important to conduct studies on the bioavailability of choline and choline compounds and on the rate of de novo synthesis of choline in vivo. Studies using increasing levels of dietary intake designed to assess toxicity for all organ systems, including heart, liver, brain and

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline kidney; fishy body odor; and possible growth suppression in children from observational data and as determined by experimental studies in animal models. REFERENCES Acara M, Rennick B. 1973. Regulation of plasma choline by the renal tubule: Bidirectional transport of choline. Am J Physiol 225:1123–1128. Acara M, Rennick B, LaGraff S, Schroeder ET. 1983. Effect of renal transplantation on the levels of choline in the plasma of uremic humans. Nephron 35:241– 243. Albright CD, Liu R, Bethea TC, da Costa KA, Salganik RI, Zeisel SH. 1996. Choline deficiency induces apoptosis in SV40-immortalized CWSV-1 rat hepatocytes in culture. FASEB J 10:510–516. Al-Waiz M, Ayesh R, Mitchell SC, Idle JR, Smith RL. 1988. Trimethylaminuria (“fishodour syndrome”): A study of an affected family. Clin Sci 74:231–236. Al-Waiz M, Ayesh R, Mitchell SC, Idle JR, Smith RL. 1989. Trimethylaminuria: The detection of carriers using a trimethylamine load test. J Inherit Metab Dis 12:80– 85. Anonymous. 1997. Betaine for homocystinuria. Med Lett Drugs Ther 39:12. Aquilonius SM, Ceder G, Lying-Tunell U, Malmlund HO, Schuberth J. 1975. The arteriovenous difference of choline across the brain of man. Brain Res 99:430– 433. Arvidson GA. 1968. Biosynthesis of phosphatidylcholines in rat liver. Eur J Biochem 5:415–421. Barak AJ, Kemmy RJ. 1982. Methotrexate effects on hepatic betaine levels in choline-supplemented and choline-deficient rats. Drug Nutr Interact 1:275–278. Barak AJ, Tuma DJ, Beckenhauer HC. 1984. Methotrexate hepatotoxicity. J Am Coll Nutr 3:93–96. Bartus RT, Dean RL, Goas JA, Lippa AS. 1980. Age-related changes in passive avoidance retention: Modulation with dietary choline. Science 209:301–303. Bauernschmitt HG, Kinne RK. 1993. Metabolism of the “organic osmolyte” glycerophosphorylcholine in isolated rat inner medullary collecting duct cells. I. Pathways for synthesis and degradation. Biochim Biophys Acta 1148:331–341. Best CH, Huntsman ME. 1932. The effects of the components of lecithine upon deposition of fat in the liver. J Physiol 75:405–412. Bianchi G, Azzone GF. 1964. Oxidation of choline in rat liver mitochondria. J Biol Chem 239:3947–3955. Bjornstad P, Bremer J. 1966. In vivo studies on pathways for the biosynthesis of lecithin in the rat. J Lipid Res 7:38–45. Blair R, Newsome F. 1985. Involvement of water-soluble vitamins in diseases of swine. J Anim Sci 60:1508–1517. Blair R, Whitehead CC, Bannister DW, Evans AJ. 1973. Involvement of diet in fatty liver and kidney syndrome in broiler chickens. Vet Rec 92:118–119. Blusztajn JK, Zeisel SH, Wurtman RJ. 1979. Synthesis of lecithin (phosphatidylcholine) from phosphatidylethanolamine in bovine brain. Brain Res 179:319– 327. Boyd WD, Graham-White J, Blackwood G, Glen I, McQueen J. 1977. Clinical effects of choline in Alzheimer senile dementia. Lancet 2:711.

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