Scientific Opinion on the substantiation of health claims related to choline
and contribution to normal lipid metabolism (ID 3186), maintenance of
normal liver function (ID 1501), contribution to normal homocysteine
metabolism (ID 3090), maintenance of normal neurological function
(ID 1502), contribution to normal cognitive function (ID 1502), and brain
and neurological development (ID 1503) pursuant to Article 13(1) of
Regulation (EC) No 1924/2006[sup]1[/sup]
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)2, 3
European Food Safety Authority (EFSA), Parma, Italy
Słowa kluczowe:
Choline
cognition
health claims
homocysteine
lipid metabolism
liver
neurological function
2. Znaczenie oświadczenia dla zdrowia człowieka
2.1. Udział w prawidłowym metabolizmie tłuszczów (ID 3186)
The claimed effect is “choline is needed for lipids metabolism”. The Panel assumes that the target population is the general population.
The Panel considers that contribution to normal lipid metabolism is a beneficial physiological effect.
2.2. Utrzymanie prawidłowego funkcjonowania wątroby (ID 1501)
The claimed effect is “maintaining healthy liver functioning”. The Panel assumes that the target population is the general population.
The Panel notes that the claimed effect refers to the maintenance of normal liver function.
The Panel considers that maintenance of normal liver function is a beneficial physiological effect.
2.3. Udział w prawidłowym metabolizmie homocysteiny (ID 3090)
The claimed effect is “reduction in homocysteine levels”. The Panel assumes that the target population is the general population.
In the context of the proposed wordings and the references provided, the Panel assumes that the claimed effect refers to the maintenance of normal blood concentrations of homocysteine by contributing to normal homocysteine metabolism.
The Panel considers that contribution to normal homocysteine metabolism is a beneficial physiological effect.
2.4. Utrzymanie prawidłowego funkcjonowania układu nerwowego (ID 1502)
The claimed effect is “cognitive, memory functioning; neurological functioning”. The Panel assumes that the target population is the general population.
The Panel considers that maintenance of normal neurological function is a beneficial physiological effect.
2.5. Udział w prawidłowym przebiegu procesów poznawczych (ID 1502)
The claimed effect is “cognitive, memory functioning; neurological functioning”. The Panel assumes that the target population is the general population.
Cognitive function includes memory, attention (concentration), learning, intelligence and problem solving. These are well defined constructs and can be measured by validated psychometric cognitive tests.
The Panel considers that contribution to normal cognitive function is a beneficial physiological effect.
2.6. Rozwój mózgu i układu nerwowego (ID 1503)
The claimed effect is “development”.
In the context of the proposed wordings and the clarifications provided by Member States, the Panel assumes that the claimed effect is related to brain and neurological development, which is interpreted by the Panel as children's development.
The Panel notes that claims related to children's development and health are outside the scope of Article 13 of Regulation (EC) No 1924/2006.
3. Naukowe uzasadnienia wpływu na zdrowie człowieka -
Choline is a dietary component which is also formed endogenously in the body by methylation of phosphatidylethanolamine using S-adenosylmethionine as the methyl donor. Choline functions as a precursor of acetylcholine, phospholipids and betaine, and plays a role in the structural integrity of cell membranes, in methyl metabolism, in cholinergic neurotransmission, and in lipid and cholesterol transport and metabolism. Demand for dietary choline is dependent on the metabolic methyl-group exchange relationships between choline and methionine, folate and vitamin B12. With this type of
nutrient interdependence, the designation of the essential nature of a nutrient will depend on whether de novo synthesis rates are adequate to meet the demand when other nutrients are available in amounts sufficient to sustain normal growth and function. In men with adequate folate and vitamin B12 status fed a choline-deficient diet, endogenous synthesis of choline may not be sufficient to cover needs, whereas little information is available with respect to other population subgroups (e.g. women, children and elderly subjects). The primary criterion to estimate adequate intakes of choline in the United States is the prevention of liver damage, as assessed by measuring serum alanine aminotransferase activity in the blood (IoM, 1998).
No dietary reference values for choline have been established in the EU. There are no reliable intake data, and no indications of inadequate choline intakes, available in the EU.
3.1. Udział w prawidłowym metabolizmie tłuszczów (ID 3186)
The six references provided in the consolidated list were one textbook and five narrative reviews on the metabolic effects of choline deficiency, on the absolute choline dependence of cultured cells, and on the dietary requirements of choline.
It is well established that choline functions as a precursor of phospholipids, and plays a role in the structural integrity of cell membranes (IoM, 1998). Phosphatidylcholine is the predominant phospholipid (>50 %) in the cell membranes. It is also well established that choline plays a role in lipid and cholesterol transport and metabolism. Dietary choline deficiency is associated with liver damage (elevated serum alanine aminotransferase activity) and the development of fatty liver (hepatosteatosis) in humans fed choline-deficient total parenteral nutrition solutions, as well as in men and post-menopausal women (but not in pre-menopausal women) fed choline-deficient diets (da Costa et al., 2005; Fischer et al., 2007; IoM, 1998; Kohlmeier et al., 2005; Zeisel, 2006). These effects can be reversed by the administration of dietary choline (Buchman et al., 1992; 1995; da Costa et al., 2005). Most of the choline-deficient diets used in these studies were adequate for methionine and folate, and for vitamin B12 in some cases. The effect of choline-deficient diets on lipid transport and metabolism, assessed by the amount of fat accretion in the liver, appears to depend on genetic variations of, for example, the 5,10-methylenetetrahydrofolate dehydrogenase, the phosphatidylethanolamine N-methyltransferase, and/or the choline dehydrogenase genes, as well as on oestrogen status (i.e. de novo choline synthesis of phosphatidylcholine is up-regulated by oestrogen) (da Costa et al., 2006; Kohlmeier et al., 2005).
No studies on specific effects of supplemental choline on lipid metabolism were included in the references provided.
The Panel concludes that a cause and effect relationship has been established between the consumption of choline and contribution to normal lipid metabolism.
3.2. Utrzymanie prawidłowego funkcjonowania wątroby (ID 1501)
It is well established that choline deficiency is associated with liver damage (elevated serum alanine aminotransferase activity) and the development of fatty liver (hepatosteatosis) in humans fed choline- free total parenteral nutrition solutions, as well as in men and post-menopausal women (but not in pre- menopausal women) fed choline-deficient diets (Kohlmeier et al., 2005) or a choline-deficient diet with adequate amounts of methionine, folate and occasionally vitamin B12 (da Costa et al., 2005; Fischer et al., 2007; IoM, 1998; Zeisel, 2006). These effects can be reversed by the administration of dietary choline (Buchman et al., 1992; 1995; da Costa et al., 2005). The effect of choline-deficient diets on fat accretion in the liver appears to depend on genetic variations of, for example, the 5,10-methylenetetrahydrofolate dehydrogenase, the phosphatidylethanolamine N-methyltransferase,
and/or the choline dehydrogenase genes, as well as on oestrogen status (i.e. de novo choline synthesis of phosphatidylcholine is up-regulated by oestrogen) (da Costa et al., 2006; Kohlmeier et al., 2005).
Prevention of elevated serum alanine aminotransferase activities and/or fat accretion in the liver, assessed by appropriate imaging techniques (computed tomography, magnetic resonance imaging), have been proposed as the primary criterion to estimate adequate intakes for choline (IoM, 1998).
The Panel concludes that a cause and effect relationship has been established between the consumption of choline and maintenance of normal liver function.
3.3. Udział w prawidłowym metabolizmie homocysteiny (ID 3090)
It is well established that choline can function as a precursor for the formation of betaine, and that betaine can act as a methyl donor in the remethylation of homocysteine in the liver by the enzyme betaine-homocysteine methyltransferase (IoM, 1998).
A claim on betaine and contribution to normal homocysteine metabolism has already been assessed with a favourable outcome (EFSA Panel on Dietetic Products Nutrition and Allergies (NDA), 2011).
Most of the references provided in the consolidated list were narrative reviews from textbooks and scientific journals referring to the biochemical functions and metabolism of choline, or human and animal studies addressing the effects of choline depletion or supplementation relative to the status of other methyl donors (e.g. folate, vitamin B12 and betaine) on health outcomes other than homocysteine concentrations or metabolism (e.g. liver steatosis, muscle function and cancer).
Two human intervention studies on the effects of choline supplementation on blood concentrations of homocysteine were provided (da Costa et al., 2005; Olthof et al., 2005).
In a placebo-controlled cross-over study, Olthof et al. (2005) investigated the effect of supplemental choline (2.6 g/day as phosphatidylcholine) for two weeks on plasma homocysteine concentrations after an overnight fast, as well as after an oral methionine load in 26 men with mildly elevated
homocysteine concentrations (14.7 3.4 mol/L). Phosphatidylcholine supplementation for two weeks
significantly decreased mean fasting plasma homocysteine concentrations by 18 % (-3.0 mol/L;
95 % CI: -3.9, -2.1 mol/L). A single dose of phosphatidylcholine containing 1.5 g choline
significantly reduced the postmethionine-loading increase in homocysteine by 15 % (-4.8 mol/L;
95 % CI: -6.8, -2.8 mol/L) on the first day of supplementation, and phosphatidylcholine supplementation for two weeks significantly reduced the postmethionine-loading increase in
homocysteine by 29 % (-9.2 mol/L; 95 % CI: -11.3, -7.2 mol/L). All changes were relative to placebo. The Panel notes that the doses of choline used in this study are several times above the proposed conditions of use.
In one small (pilot) depletion study, eight men were fed a “choline-sufficient” diet providing 550 mg choline per day for 10 days followed by a choline-deficient diet (<50 mg/day) for 42 days, or until the subjects were clinically judged to be choline deficient (i.e. evaluated as the development of hepatic steatosis assessed by magnetic resonance imaging), whichever came first (da Costa et al., 2005). Plasma concentrations of homocysteine were assessed in fasting and four hours after an oral methionine load (100 mg/kg body weight) on day 10 of the diet containing 550 mg choline per day, and after 42 days of the choline-deficient diet (or when deficiency was diagnosed). The diets met or exceeded the estimated average requirement for methionine plus cysteine and the daily reference intake for vitamin B6, vitamin B12, and folate (400 dietary folate equivalents per day). Four subjects developed hepatic steatosis during the choline depletion phase, and four subjects did not by day 42. In all eight human subjects, plasma choline and betaine concentrations fell 30 % and 47 %, respectively, at the end of the depletion phase (P<0.005). Subjects who were judged to be clinically depleted had
decreases in plasma choline and betaine concentrations which were not different from those observed in subjects not deemed to be clinically depleted. At the end of the depletion phase, plasma concentrations of homocysteine at fast and four hours after an oral methionine load significantly increased only in subjects clinically choline-depleted, as compared to the “choline sufficient” phase.
Two human observational studies addressed the association between dietary choline and blood concentrations of homocysteine (Cho et al., 2006; Dalmeijer et al., 2008).
In a cohort of the Framingham Offspring Study (Cho et al., 2006) an inverse association was observed between choline, betaine, and choline plus betaine intakes measured by validated food frequency questionnaires (FFQ) and plasma total homocysteine concentrations in 1,960 subjects (1,040 women) independent of age, sex, smoking, alcohol intake, caffeine intake, hypertensive medication use, serum creatinine concentrations and intakes of folate, vitamin B6 and vitamin B12. The energy-adjusted mean (±SD) intakes of choline and betaine were 313±61 mg/day (314 mg per day for women and 312 mg per day for men) and 208±90 mg per day (216 mg per day for women and 200 mg per day for men), respectively.
In a prospective cohort study (Dalmeijer et al., 2008) which investigated the association between dietary intakes of folate, betaine and choline and the risk of cardiovascular disease (CVD) in a cohort of 16,165 women, aged 49-70 years, without prior CVD, intakes of folate, betaine and choline were assessed using a validated FFQ at baseline. Median follow-up period was 97 months. Homocysteine concentrations were assessed in the blood of a randomly selected sample of women (n=910). High folate and choline intakes were statistically significantly associated with lower homocysteine concentrations, whereas no statistically significant association was observed for betaine. Mean intakes
of betaine, choline and folate were 214 74, 300 51 and 195 40 mg/day, respectively.
In weighing the evidence, the Panel took into account that choline can be a precursor for the formation of betaine, that betaine can act as a methyl donor in the remethylation of homocysteine in the liver by the enzyme betaine-homocysteine methyltransferase, that choline depleted diets tend to increase plasma concentrations of homocysteine, that a human intervention study showed a significant decrease in plasma concentrations of homocysteine following choline administration, and that two observational studies supported the inverse association between dietary choline and blood concentrations of homocysteine.
The Panel concludes that a cause and effect relationship has been established between the consumption of choline and contribution to normal homocysteine metabolism.
3.4. Utrzymanie prawidłowego funkcjonowania układu nerwowego (ID 1502)
The references provided included narrative reviews and textbooks which did not provide any original data for the scientific substantiation of the claimed effect, and conference abstracts which did not provide sufficient detail for a scientific evaluation. A number of the remaining references did not address relevant endpoints (e.g. choline metabolism, memory and attention) or did not evaluate choline (e.g. citicoline and phosphatidylserine). The Panel considers that no conclusions can be drawn from these references for the scientific substantiation of the claimed effect.
The Panel notes that no human studies have been provided from which conclusions can be drawn for the scientific substantiation of the claimed effect.
Ten animal studies provided primary data to substantiate the claimed effect. These studies evaluated the effects of choline supplementation and deprivation on choline plasma concentrations, acetylcholine synthesis and release, and nicotinic receptor regulation. The Panel considers that while effects shown in animal studies may be used as supportive evidence, human studies are required for
the substantiation of a claim, and that evidence provided in animal studies alone is not sufficient to predict the occurrence of an effect of choline consumption on the maintenance of normal neurological function in humans.
The Panel concludes that a cause and effect relationship has not been established between the consumption of choline and the maintenance of normal neurological function.
3.5. Udział w prawidłowym przebiegu procesów poznawczych (ID 1502)
The references provided included narrative reviews which did not provide any original data, and conference abstracts which did not provide sufficient detail for a scientific evaluation. A number of the remaining references did not report on relevant endpoints (e.g. choline metabolism and functions, choline uptake into the brain, and deficiency symptoms unrelated to cognition) or did not evaluate choline (e.g. citicoline and phosphatidylserine). Some of the human intervention studies provided used lecithin preparations. The Panel notes that these interventions did not control for dietary compounds other than choline (e.g. phospholipids and fatty acids) which could contribute to the claimed effect. The Panel notes that no conclusions can be drawn from these references for the scientific substantiation of the claimed effect.
The study by Sitaram et al. (1978) evaluated the effect of a single dose of choline chloride (10 g) against placebo (not defined but matched for colour and taste) given in random order on two separate days on a serial learning test and a selective reminding test in 10 healthy male and female volunteers. The Panel notes that the dose of choline which was used in the study was much greater than the minimum dose of 20 mg, the indicated “therapeutic” dose of 300 mg, or the “excess” consumption of 3.5 g per day given in the conditions of use. The Panel considers that no conclusions can be drawn from this reference for the scientific substantiation of the claimed effect.
The study by Buchman et al. (2001) was a pilot study in patients (n=11) receiving long-term parenteral nutrition (more than 80 % of their nutritional needs). The effect of choline supplementation on verbal and visual memory was evaluated after 24 weeks of parenteral nutrition regimen supplemented with 2 g of choline chloride (n=5) vs. no supplementation (n=6). The Panel notes that 24 endpoints were tested in this pilot study and that no correction was made for multiple testing. The Panel considers that no conclusions can be drawn from this small pilot study for the scientific substantiation of the claimed effect.
Nine of the animal studies provided evaluated the effect of choline supplementation on various memory tests in rats. The Panel considers that evidence provided in animal studies is not sufficient to predict the occurrence of an effect of choline consumption on contribution to normal cognitive function in humans.
The Panel concludes that a cause and effect relationship has not been established between the consumption of choline and contribution to normal cognitive function.
