Edited by: José M. Alvarez-Suarez, University of the Americas, Ecuador
Reviewed by: Ella H. Haddad, Loma Linda University, United States; Mona Elena Popa, University of Agronomic Sciences and Veterinary Medicine, Romania
This article was submitted to Nutrition and Food Science Technology, a section of the journal Frontiers in Nutrition
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The EAT-Lancet commission recently suggested that transformation to healthy diets by 2050 will require a reduction of at least 50% in consumption of foods such as red meat and sugar, and a doubling in the global consumption of fruits, vegetables, nuts, and legumes. A diet rich in plant-based foods and with fewer animal source foods confers both improved health and environmental benefits. Notably, the risk of vitamin B12 deficiency increases when consuming a diet low in animal products. Humans are dependent on animal foods such as dairy products, meat, fish and eggs. Vitamin B12 deficiency is common worldwide, especially in populations with low consumption of animal foods because of low socioeconomic status, ethical reasons, or because of their lifestyle (i.e., vegans). According to the European Food Safety Authoroty, the recommended adequate intake of vitamin B12 is 4.0 μg/d for adults, and vitamin B12 requirements are higher during pregnancy and lactation. Infants and children from deficient mothers and elderly people are at risk for vitamin B12 deficiency. Diagnosis of vitamin B12 deficiency is hampered by low specificity of available biomarkers, and there is no consensus yet regarding the optimal definition of low vitamin B12 status. In general, a combination of at least two biomarkers is recommended. Therefore, this review presents an overview of vitamin B12 biochemistry and its biomarkers. We further summarize current recommendations of vitamin B12 intake, and evidence on the associations of vitamin B12 intake from different nutrient-dense animal foods with vitamin B12 status markers. Finally, potential consequences of low vitamin B12 status on different health outcomes for pregnant women, infants and elderly are presented.
Vitamin B12 (cobalamin) is an essential water-soluble micronutrient of microbial origin (
Vitamin B12 plays an important role in one-carbon metabolism. Dietary vitamin B12 is, once ingested, bound to haptocorin (an animal protein), which carries vitamin B12 to the stomach. In the stomach, HCl and pepsin are released which release vitamin B12 from animal proteins. Free vitamin B12 then binds to haptocorrin in the stomach after which it is transported into the intestine, where vitamin B12 is released by pancreatic enzymes after which vitamin B12 binds to intrinsic factor (IF) (
Vitamin B12 deficiency increased with age and is mostly due to malabsorption of the vitamin. In addition, low intake of animal food products—as outlined in chapter 3–and use of certain drugs may also result in vitamin B12 deficiency (
Causes of acquired vitamin B12 deficiency.
Gastric bypass | ↓ IF production |
Gastrointestinal infection with H. Pylori | ↓ IF production |
Ileal resection | ↓ Absorption of B12-IF |
Bacterial overgrowth | ↓ Absorption of B12-IF |
Intestinal disease (e.g., Crohn) | ↓ Absorption of B12-IF |
Pernicious anemia | Antibodies against IF or parital cells |
Difficulties in chewing foods | Releasing of B12 from food proteins |
Malnutrition | ↓ Vitamin B12 consumption |
Vegetarian or vegan diet | ↓ Intake of B12 containing animal products |
Proton-pump inhibitors | Defective release of B12 from food |
Metformin | ↓ Absorption of B12 |
Nitrous oxide | Inactivation of methionine synthase (in case of NO) |
Different derivatives of cobalamin exist of which methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl) are the physiological co-enzyme forms. MeCbl is a cofactor in the methionine-synthase dependent remethylation of homocysteine into methionine, which takes place into the cytosol. This remethylation reaction is an important step of the one-carbon metabolism, in which also reduction of folate derivatives takes place, which are important for DNA synthesis. In addition, methionine is an essential amino acid which is involved in formation of the universal methyl donor S-adenosylmethionine. Low dietary intake of vitamin B12 results in elevated homocysteine levels and might affect DNA synthesis and DNA methylation. AdoCbl is involved in the l-methylmalonyl-CoA-mutase-dependent conversion of methylmalonyl-CoA into succinyl-CoA, which takes place in the mitochondrium (
Several biomarkers (
Biomarkers of vitamin B12 status in serum or plasma.
Total vitamin B12 | Global vitamin B12 status | ↓ In vitamin B12 deficiency |
Holo-transcobalamin | Vitamin B12-bound to transcobalamin or active B12 | ↓ In vitamin B12 deficiency |
Methylmalonic acid | Functional marker of vitamin B12 deficiency | ↑ Vitamin B12 deficiency |
Homocysteine | Functional marker of vitamin B12 deficiency | ↑ Vitamin B12 deficiency |
Regarding biomarkers of vitamin B12 there is a need to establish reference intervals of total vitamin B12 in pregnancy as these levels decrease during pregnancy. In addition, better biomarkers are necessary to determin vitamin B12 deficiency as total B12 and active B12 hamper diagnostic specificity.
Several organizations have followed different approaches to set the dietary reference values for vitamin B12 (
Maintenance of heamatological markers in patients with pernicious anemia in a remission phase (i.e., correcting hemoglobin, mean corpuscular volume, and reticulocyte).
Maintenance of the total body stores of vitamin B12 (≈2–3 mg) by adjusting the daily requirements for the daily loss of the vitamin. The absorption efficacy of vitamin B12 from foods is assumed to be 40% and the daily loss is between 2 and 6 μg/d (biliary loss or transfer to the fetus or infant (via the placenta or the breastmilk).
Maintenance of normal serum levels of vitamin B12 markers (total vitamin B12, MMA, holoTC, and Hcy).
Dietary reference values for vitamin B12 (in μg/d) in different age and sex groups as suggested by different organizations.
Age | 7Mo−6y | 4–12Mo | 6–11Mo | 7–12Mo | 6–11Mo | 7–12Mo | 6–11Mo | 7–12 Mo |
Reference value | 1.5 μg/d | 0.8 μg/d | 0.5 μg/d | 0.7 μg/d | 0.5 μg/d | 0.5 μg/d | 0.5 μg/d | 0.4 μg/d |
Age | 1–4 y | 1–2 y | 1–3 y | 1–3 y | 1–3 y | 1–3 y | 1–3 y | |
Reference value | 1.0 μg/d | 0.6 μg/d | 0.9 μg/d | 0.7 μg/d | 0.9 μg/d | 0.7 μg/d | 0.5 μg/d | |
Age | 4–7 y | 2–5 y | 4–6 y | 4–8 y | 4–8 y | 4–6 y | 4–6 y | |
Reference value | 4.5 μg/d | 0.8 μg/d | 1.2 μg/d | 1.3 μg/d | 1.2 μg/d | 0.9 μg/d | 0.8 μg/d | |
Age | 7–10 y | 7–10 y | 6–9 y | 7–9 y | 9–13 y | 9–13 y | 7–10 y | 7–10 y |
Reference value | 2.5 μg/d | 1.8 μg/d | 1.3 μg/d | 1.8 μg/d | 2.0 μg/d | 1.8 μg/d | 1.0 μg/d | 1.0 μg/d |
Age | 11–14 y | 10–13 y | 10–17 y | 10–18 y | 10–18 y | 14–18 y | 11–14 y | 11–14 y |
Reference value | 3.5 μg/d | 2.0 μg/d | 2.0 μg/d | 2.4 μg/d | 2.8 μg/d | 2.4 μg/d | 1.3 μg/d | 0.2 μg/d |
Age | 15–17 y | 13–19 y | 15–17 y | 15–18 y | ||||
Reference value | 4.0 μg/d | 3.0 μg/d | 1.4 μg/d | 1.5 μg/d | ||||
Adults (M+F), > 18 y | 4.0 μg/d | 3.0 μg/d | 2.0 μg/d | 2.4 μg/d | 2.8 μg/d | 2.4 μg/d | 1.4 μg/d | 1.5 μg/d |
Pregnant women | 4.5 μg/d | 3.5 μg/d | 2.0 μg/d | 2.6 μg/d | 3.2 μg/d | 2.6 μg/d | 1.6 μg/d | 1.5 μg/d |
Lactating women | 5.0 μg/d | 4.0 μg/d | 2.6 μg/d | 2.8 μg/d | 3.8 μg/d | 2.8 μg/d | 1.9 μg/d | 2.0 μg/d |
Approximately 1% of a high oral vitamin B12 dose (i.e., derived from supplemental cyanocobalamin) crosses the intestinal barrier into the blood via simple diffusion (
In a study among 98 Danish post-menopausal women Bor et al. (
The association between vitamin B12 markers and intake was generally weaker in studies in elderly people (
A meta-analysis on the association between vitamin B12 intake and biomarkers Dullemeijer et al. estimated that doubling the intake of vitamin B12 is associated with 11.0% (95% CI: 9.4%, 12.5%) higher serum vitamin B12 concentration (
The increase in plasma vitamin B12 and the decrease in functional markers appear to depend on population characteristics (mainly age and accompanying diseases), duration of the intervention, starting plasma concentrations of the vitamin, and the administered dose of crystalized cyanocobalamin, even in non-therapeutic ranges. In general, a daily intake of free cyanocobalamin as low as 1.5–2.5 μg provided for approximately 4–6 months may increase plasma vitamin B12 by 50–100 pmol/L.
A total intake of vitamin B12 from the diet between 4 and 7 μg/d is associated with normal plasma vitamin B12 and MMA and thus appears to be adequate to maintain body vitamin B12 status in adults. This intake might be insufficient if people have difficulties in chewing foods, releasing the vitamin from its food binding, and/or absorbing it due to disorders as shown in
In addition to supplements or fortified cereals as potential sources of vitamin B12, this paper focusses on vitamin B12 intake from natural food products, e.g., animal foods. In total, 19 observational studies were identified addressing associations of vitamin B12 containing aminal food items with plasma or serum vitamin B12 biomarkers. These studies were performed among infants (
Main characteristics and results of observational studies addressing the relation between dietary intake and vitamin B12 status biomarkers among different age categories.
Dagnelie et al. ( |
10–20 months | Macrobiotic diet ( |
vitamin B12 (pmol/L) | Geometric mean ± coefficient of variation in: Marcobiotic group: 149 ± 21.6 Control group: 404 ± 15.6 P for difference < 0.001 | None of the macrobiotic fed children had ever received animal produces or vitamin B12 supplements, except for 10 out of 47 infants who had received small amounts of dairy products at some time in their live. | Plasma B12 among macrobiotic fed infants significantly lower than among the control group | |
Van Dusseldorp et al. ( |
12 [9–15] | List of 6 food groups, including intake of cheese, pasteurized milk, buttermilk and yogurt. | Vitamin B12 (pmol/L) MMA (μmol/L) Hcy (μmol/L) | Correlation coefficients ( |
The group of macrobiotic fed children had received a macrobiotic diet until 6 y of age and had then switched to a lactovegetarian, lacto ovovegetarian, or omnivorous diet (macrobiotic adolescents). The group of macrobiotic fed children switched to a diet containing dairy products (200 g milk or yogurt and 22 g cheese/d (supplying on average 0.95 mg cobalamin/d), and fish, meat, or chicken 2–3 times/wk. In girls, meat consumption contributed more to vitamin B12 status than the consumption of dairy products, whereas in boys these food groups were equally important. | Moderate consumption of animal products after cessation of a macrobiotic diet is insufficient to restore low vitamin B12 status among adolescents | |
Villamor et al. ( |
8.7 [5–12] | 38 item FFQ obtained by mothers to assess dietary intake among children | Vitamin B12 (pmol/L) | P for trend across quartiles of plasma B12 with: Animal protein pattern: 0.003 Cheap protein pattern: 0.75 Traditional/starch pattern: 0.45 Snacking pattern: 0.84 Adjusted differences (95%CI, P for trend) in B12 concentrations of high vs. low/no intake of: Meat: 24 (1 to 48, 0.04) Dairy: 32 (5 to 95, 0.06) Fish: 17 (−7 to 41, 0.16) Cow liver: 5 (−17 to 28, 0.08) Egg: −25 (−50 to 1, 0.12) Supplement: 9(−8 to 27, 0.31) | PCA derived patterns:Animal protein (beef/ pork/veal/lamb, chicken/turkey, milk, cheese) Cheaper protein (cow tripe/liver, spleen, chicken giblets) traditional/starch (rice, potato, plantain), snacking (candy, ice cream, packed fried snacks, soda, fruit punch). Analyses adjusted for sex, age, frequency of meat, dairy, fish, cow liver, and supplement intake. | Strong dose–dependent positive association between a pattern including frequent consumption of beef, chicken, and dairy products and plasma vitamin B12. | |
Hay et al. ( |
2 [2–2] | 7–day food records. Diary, liver pate, meat (products), fish (products). | Vitamin B12 (pmol/L) and holoTC (pmol/L) | Spearman correlations of Serum Vitamin |
Adjusted for sex and energy intakeMMA and Hcy were not associated with animal food intake. | In this unfortified toddler population, vitamin B12 status was strongest associated with dairy intake, and with a lesser extend to liver pate' | |
Christian et al. ( |
9.5 [9–10] | 136 item Semi quantitative FFQ, including amongst others minced meat, fish, chicken, mutton, meat and fish, eggs, non–vegetarian, curd foods, milk and dairy | Vitamin B12 (pmol/L) | B (95%CI) T3 vs. T1 of intake with plasma B12: Minced meat: 0.011 (−0.077 to 0.100) Fish: 0.052 (−0.031 to 0.134) Chicken: −0.003 (−0.112 to 0.105) Mutton: 0.101 (−0.007 to 0.209) Meat & fish: 0.126 (0.041 to 0.212) Eggs: −0.031 (−0.122 to 0.061) Non–vegetarian: 0.124 (0.044 to 0.203) Curd (yogurt) foods: −0.075 (−0.157 to 0.007) Milk/dairy: −0.029 (−0.110 to 0.053) | Adjusted for age, sex, BMI, height, SLI score, maternal education, other food groups in the table except traditional fermented foods and raw vegetables, and pregnancy plasma B12 concentrations. | Meat and fish are most important animal derived B12 sources among Indian children | |
Manioset al. ( |
11 [9–13] | Three 24 h dietary recalls (2 week days, 1 weekend day) | Hcy (μmol/L) | Adjusted for age, sex, and total vitamin B12 intake from other food sources Vitamin B12 intake from red meat and cheese were not associated with Hcy concentrations. | High vitamin B12 intake from milk was associated with lower Hcy concentrations | ||
Denissen et al. ( |
32.6 ± 3.8 | 200 item semi–quantitative FFQ, including dairy products (28 items), meat (29 items), (shell)fish (7 items), eggs (1 item) | Vitamin B12 (pmol/L) holoTC (pmol/L) MMA (μmol/L) | %difference (95%CI) Q5 vs. Q1: Dairy–B12: 29 (21 to 37) Dairy–HoloTC: 53 (41 to 66) Dairy–MMA: −21 (−27 to −14) Meat–B12: 15 (8 to 23) Meat–HoloTC: 20 (10 to 30) Meat–MMA: −16 (−23 to −9) Fish–B12: 7 (0.5 to 13) Fish– HoloTC: 15 (7 to 24) Fish– MMA: −15 (−21 to −8) Eggs– B12: 1 (−5 to 7) Eggs– HoloTC: 9 (1 to 17) Eggs– MMA: −5 (−12 to 2) | Multivariable adjusted proportional difference in geometrical means of highest quintile relative to lowest quintile of intake. Values obtained by multiple linear regression analyses adjusted for recruitment group, age, prepregnancy BMI, education, smoking, vitamin B−12 intake from supplements, alcohol use, energy intake, vitamin B−12 intake from mixed dishes, as well as for vitamin B−12 intake from dairy, meat, fish and eggs (except for the food group of interest) | ||
Tuckeret al. ( |
53.6 [26–83] | 126 item Semi quantitative FFQ. Vitamin B12 intake was calculated from individual food sources. Food contributions to total vitamin B−12 was calculated, and total vitamin B12 intake was divided into vitamin B12 intake from supplements, breakfast cereals, meat, poultry, fish, dairy sources, and all other foods | vitamin B12 (pmol/L) | Prevalence of |
Adjusted for age and sex Adjusted for age, sex, total energy intake, total vitamin B12 intake Dietary patterns were derived from cluster analysis. | Milk appears to protect against lower vitamin B12 concentrations. Participants in all food intake groups were significantly more likely to have B12 concentrations <185 pmol/L compared to subjects in the supplement group. Only the meat group differed significantly from the supplement group in having vitamin B12 concentrations <148 pmol/L. | |
Gao et al. ( |
42 [35–49] | 170 item FFQ from which intake of Fruit and milk, Red meat, and refined cereals were composed | vitamin B12 (pmol/L) Hcy (μmol/L) | OR (95%CI) of having |
Adjusted for age, sex, total energy intake, BMI, smoking, alcohol use, income and education level. | The pattern high in fruits and milk was associated with a significantly lower risk of having Hcy >11 or 12 μmol/L and of having B12 <221 pmol/L compared to the pattern of refined cereals. Pattern of red meat did not differ in risk of high Hcy or low B12 compared to the fruit and milk pattern. | |
Koebnick et al. ( |
46 [25–64] | 7 day food records including 12 food groups | vitamin B12 (pmol/L) Hcy (μmol/L) | Median (P25, P75) concentrations according to type of raw food consumption: Vitamin |
Unadjusted analyses Mixed raw food diet included raw meat and fish | Individuals who consumed a mixed raw food diet had highest vitamin B12 and lowest Hcy concentrations whereas those consuming a stricht vegan diet had lowest vitamin B12 and highest Hcy concentrations. | |
Hao et al. ( |
49 [35–64] | Semi quantitative FFQ. Animal–based foods were classified in dairy, egg, animal meat and fish. | vitamin B12(pmol/L) | Adjusted OR (95%CI, P for trend) for having vitamin B12 deficiency (<185 pmol/L): T3 vs. T1 dairy: 0.5 (0.4 to 0.7, <0.001) Q5 vs. Q1 egg: 0.8 (0.6 to 1.1, 0.196) Q5 vs. Q1 meat: 1.0 (0.7 to 1.4, 0.163) Q5 vs. Q1 fish: 0.4 (0.3 to 0.5, <0.001) | Intake food source divided in tertiles (dairy) or quintiles (egg, animal meat, fish) Adjusted for region, area (urban, rural), gender, age, season | Higher consumption of dairy and fish was associated with a lower likelyhood of having B12 concentrations <185 pmol/L compared to low or intermediate consumption. | |
Vogiatzoglou et al. ( |
[47–49] | 169 item FFQ | Vitamin B12 (pmol/L) | Adjusted mean (95%CI) plasma vitamin B12 concentrations in Q4 vs. Q1 B12 intake from: dairy: 385 (376 to 395) vs. 323 (314 to 332) milk: 388 (379 to 397) vs. 331 (324 to 338) Cheese: 370 (362 to 378) vs. 346 (338 to 335) Meat: 362 (354 to 369) vs. 355 (344 to 366) (shell) fish: 375 (366 to 385) vs. 339 (331 to 346) Eggs: 358 (349 to 366) vs. 356 (350 to 363) P for trend <0.001, except for meat ( |
Adjusted for sex, energy, use of B vitamin containing supplements, total intake of other food groups | Dairy and fish are significant contributors to plasma vitamin B12. Vitamin B12 appears to be more bioavailable from dairy products than from other animal products. | |
Yakub et al. ( |
32.4 [18–60] | 15 item food group frequency questionnaire composing dietary patterns | Vitamin B12 (pmol/L) Hcy (μmol/L) | Adjusted mean plasma vitamin B12 concentrations in Q4 vs. Q1 (P diff) intake from: Prudent diet: 322 vs. 317 (P diff = 0.85) High animal protein diet: 335 vs. 312 (P diff = 0.56) High plant protein diet: 325 vs. 326 (P diff = 0.80) Adjusted mean plasma Hcy in Q4 vs. Q1 (P diff) intake from: Prudent diet: 13.97 vs. 15.78 (P diff = 0.26) High animal protein diet: 18.58 vs. 13.29 (P diff <0.001) High plant protein diet: 12.50 vs. 18.40 (P diff <0.001) | Adjusted for age and sex Patterns identified by factor analyses: Prudent pattern: high intake of eggs, fish, uncooked vegetables, juices, and bananas and other fruits. High animal–protein pattern: high intake of meat, chicken, wheat, bananas, and tea with milk. High plant–protein pattern: high intake of cooked vegetables and legumes and a small intake of meat | Patterns high in animal and plant proteins were associated with lower Hcy, but not with vitamin B12 concentrations. | |
Murakami et al. ( |
20 [18–22] | Diet history questionnaire including 17 foods | Hcy (μmol/L) | Adjusted geometric mean (95%CI) Hcy concentrations were significantly lower in Q5 vs. Q1 dairy intake (P for trend 0.02). Hcy did not differ across quintiles of (shell)fish, meats, and egg consumption | Adjusted for survey year, region, municipality level, current smoking, current alcohol drinking, supplement use, physical activity, BMI, energy intake, intakes of other foods. | High consumption of dairy products was associated with lower Hcy concentrations | |
Kwan et al. ( |
76.5 [60–93] | Semi qualitative FFQ. Total vitamin B12 intake divided into vitamin B12 intake from supplements, breakfast cereals, dairy sources, eggs, meat, poultry, fish, and all other foods | Vitamin B12 (pmol/L) | Proportions of B12 <185 pmol/L of vitamin B12 intake from: Hispanics: Dairy: 15.8 (T1), 14.2 (T2), 23.6 (T3), P for diff>0.05 Meat: 15.5 (T1), 15.6 (T2), 22.0 (T3), P for diff>0.05 |
Adjusted for age, sex, and energy intake. | Dairy and meat consumption are not significantly related to vitamin B12 status | |
Lasheras et al. ( |
Men: 73.3 women: 74.2 [60–80] | FFQ for dietary intake, individual foods vegetables, legumes, fruit, cereals, potatoes, fish, meat, eggs, milk and dairy, other foods. | Hcy (μmol/L) | Multiple linear regression with beta (95%CI) for Hcy and intake of: Meat: −0.083 (−0.035 to 0.010) Milk and dairy products: 0.004 (−0.020 to 0.021) Total dietary score: −0.156 (−0.545 to −0.015) | Adjusted for sex, age, and serum creatinine Total diet score based on quartiles of the intakes (grams per day) of main food groups contributing to intake of B–vitamins: i.e., meat, fish, milk, dairy, fruit, and vegetables. | Only the dietary pattern characterized by high intakes of B vitamin–rich foods was associated with lower Hcy concentrations and lower proportion of high Hcy. | |
Ledikwe et al. ( |
76.5 [66–80] | 24 h recall, 2 months interval during 10 months, categorized 6 main food sources; High nutrient dense; vegetables, fruit, milk, poultry fish. Low nutrient dense; dairy desserts, meat | Vitamin B12 (pg/mL) | Least Square Mean (95%CI) vitamin B12 (pg/mL): Low–nutrient dense pattern: 455 (406–504) High–nutrient dense pattern: 556 (493–618) P for difference 0.03 Least Square Mean (95%CI) Hcy (μmol/L): Low–nutrient dense pattern: 9.9 (9.1–10.7) High–nutrient dense pattern: 9.9 (8.9–10.8) P for difference 0.981 OR (95%CI) of having B12 <350 pg/mL while consuming low nutrient dense pattern group compared to high nutrient dense pattern: 2.15 (0.93–4.96) | Significance tests adjusted for energy intake, age, sex, tobacco use, alcohol use Low–nutrient–dense pattern: higher intake of breads, sweet breads/desserts, dairy desserts, processed meats, eggs, and fats/oils High–nutrient– dense pattern: higher intake of cereals, dark green/yellow vegetables, other vegetables, citrus/ melons/berries, fruit juices, other fruits, milks, poultry, fish, and beans | Consumption of a high–nutrient–dense dietary pattern was associated with higher vitamin B12 concentrations compared to a low nutrient dense dietary pattern. Hcy concentrations did not differ between high and low nutrient dense diets. | |
Vogiatzoglou et al. ( |
[71–74] | 169 item FFQ | Vitamin B12 (pmol/L) | Adjusted mean (95%CI) plasma vitamin B12 concentrations in Q4 vs. Q1 B12 intake from: Dairy: 358 (348,368) vs. 318 (309, 328) Milk: 357 (347,367) vs. 317 (307, 327) Cheese: 343 (332,355) vs. 337 (328, 347) meat & meat products: 342 (332, 354) vs. 340 (332, 349) Fish and shellfish: 359 (350, 369) vs. 321 (311, 330) eggs: 334 (324, 344) vs. 339 (331,347) P for trend <0.01, except for cheese ( |
Adjusted for sex, energy, use of B vitamin containing supplements, total intake of other food groups | Dairy and fish are significant contributors to plasma vitamin B12. Vitamin B12 appears to be more bioavailable from dairy products than from other animal products. | |
Brouwer– Brolsma et al. ( |
72 [>65] | 190 item FFQ including meat, fish and shell fish, eggs and dairy products. | Vitamin B12 (pmol/L) | Probability (95%CI) of having serum B12 > 200 pmol/L (T3 vs. T1). B12 intake from: Total vitamin B12 intake: 1.20 (1.06, 1.35) Meat: 1.22 (1.08, 1.37) (Shell)fish: 1.16 (1.04, 1.30) Eggs: 1.05 (0.93, 1.18) Dairy: 1.24 (1.10, 1.39) | Adjusted for age, sex, BMI, education, alcohol intake, physical activity, smoking, creatinine, total energy intake, intake of other vitamin B12 containing food items. | Higher intakes of dairy, meat, and fish and shellfish were significantly associated with higher vitamin B12 concentrations, with meat and dairy (predominantly milk were the most potent sources) |
Two case-control studies among infants (
In contrast to following a well-defined dietary regime, a Colombian study identified 4 dietary patterns derived from an 28-item FFQ based on principal component analysis. Patterns included diets rich in (1) animal protein (e.g., beef/pork/veal/lamb, chicken/turkey, milk, cheese), (2) cheaper protein (e.g., cow tripe/liver, spleen, chicken giblets), (3) traditional/starch (e.g., rice, potato, plantain), and (4) snacking products (e.g., candy, ice cream, packed fried snacks, soda, fruit punch). Only the pattern rich in animal protein was significantly positively associated with plasma vitamin B12 (P for trend = 0.003). This study also studied individual animal food groups, and fully adjusted differences in plasma vitamin B12 for low vs. high consumers were significant only for meat, but not for dairy, fish, cows liver, and eggs (
When considering different animal products within individual studies among children, differences in vitamin B12 concentrations were most pronounced when comparing high vs. low intake of dairy products, followed by meat and fish intake (
Only one study among pregnant women (
Those studies addressing specific animal products revealed that high dairy consumption was associated with significantly lower prevalences of vitamin B12 concentrations <185 pmol/L (
A number of studies described vitamin B12 intake or vitamin B12 biomarkers among omnivores, vegetarians and vegans. All studies consistently observed that vitamin intake was lowest, intermediate and highest among vegans, vegetarians and meat-eaters, respectively (
Five observational studies were identified among elderly (average age population >65 y), out of which 4 focussed on specific animal products (
A dietary pattern characterized by high intakes of foods rich in B-vitamins, such as meat, fish, milk, dairy, fruit, and vegetables, was associated with lower mean Hcy concentrations (
Dairy consumption seems to be the strongest determinant of vitamin B12 concentrations. However, when comparing the magnitude of the relation of dairy, meat, fish or egg consumption with vitamin B12 status it is essential to adjust statistical analyses for vitamin B12 intake from other animal food products, which was done in 5 studies (
This section addresses the associations between low vitamin B12 intake or status (defined by abnormal biomarkers) and several health outcomes from epidemiological studies performed in vulnerable population groups.
Vitamin B12 deficiency can cause megaloblastic anemia/pernicious anemia (
The metabolisms of vitamin B12 and folate interact. Supplementation of folic acid before pregnancy and in the first pregnancy trimester reduces the risk of neural tube defects (NTDs) in the child. An inverse association has been reported between NTDs risk and vitamin B12 status or polymorphisms in vitamin B12 metabolizing enzymes (
Maternal vitamin B12 status determines vitamin B12 status of the child at birth and thereafter. Vitamin B12 in neonates at birth is higher than that in plasma of the mother, but it generally declines in the infants after birth. In a nested case-control study, concentrations of vitamin B12, Hcy, and MMA were assessed in healthy pregnant women (
Prolonged breastfeeding is related to food insecurity and represent a problem in many parts of the world where the mothers have multiple micronutrient deficiencies. In Indian children (mean age 16 months) from families of low to middle socioeconomic status, prolonged breastfeeding was associated with stunting, anemia, low weight, or wasting (low weight-for-length) in the child (
Several epidemiological studies reported associations between vitamin B12 biomarkers and brain health, cognitive function, or bone health [reviewed in (
In a 6-y follow up study in Swedish elderly men (
In general, the evidence from homocysteine-lowering trails by B-vitamins on cognition or bone fracture is mixed and there are several negative studies (
There is some concern about supplementing high doses of folic acid to women of reproductive age with low vitamin B12 intake. Supplementing folic acid >1 mg/d is common in many parts of the world where low vitamin B12 is endemic, thus causing unbalanced intake and status of the two B-vitamins. Vitamin B12 deficiency is common in pregnant women from many countries such as Colombia (
Due to low animal source foods, Indian women are a good example of a population with imbalanced folate-to-B12 ratio. A small observational study including Indian women at 36 weeks of gestation and their newborn children within 24 h after birth reported a negative association between folate-to-B12 ratio and birth weight, birth length, and head and chest circumferences (
In UK pregnant women, both folate and vitamin B12 status showed inverse associations with maternal BMI (
High dietary intake of vitamin B12 has not been shown to be disadvantageous. Supplemental forms of vitamin B12 are considered safe and there is no evidence-based Tolerable Upper Intake Level for vitamin B12. However, elevated plasma concentrations of vitamin B12 (often defined as plasma vitamin B12 levels >600, >800, or >1,000 pmol/L) in individuals not receiving supplemental vitamin B12 have been described in studies in patients with different cancers, liver diseases, or type 2 diabetes (
Elevated plasma vitamin B12 has been shown to predict future cancer (
Notably, a causal role for vitamin B12 in future diseases or mortality cannot be assumed based on the presence of elevated plasma vitamin B12 levels. High vitamin B12 test results could be due to supplementation (i.e., long storage time), release from damaged tissues, or reduced kidney excretion. In all instances high plasma vitamin B12 levels are likely to be too unspecific to be used as a screening test for existing tumors or to predict future health outcomes. The likelihood of detecting cancer in patients with high vitamin B12 test has not been studied. Considering the high rate of false positive results (with seriously negative impact on patients), there is currently no evidence to initiation of further cancer diagnostic tests in subjects with plasma vitamin B12 levels >600 pmol/L.
Studies reporting on the relationship between vitamin B12 intake and health outcomes have limitations due to methodological variations related to quantifying the intake, differences in population characteristics and to the fact that clinical outcomes such as anemia or neuropathy are late manifestations of the deficiency and are not specific for vitamin B12 deficiency.
The current recommendation is to decrease consumption of animal foods and increase consumption of plant foods, as recently suggested by the EAT-Lancet commission (
When considering specific animal food products, dairy consumption seemed to be a stronger determinant of vitamin B12 concentrations than meat, fish and eggs. However, nutritional composition of different dairy (milk, yogurt, cheese, curd cheese), meat (chicken, pork, veal), and fish (lean vs. fatty) differs considerably, and bioavailability of vitamin B12 from these different animal food products together with potential interactions between vitamin B12 and other nutrients from these nutrient-dense animal products are unclear. Therefore, nutrient-density or well-known interactions between nutrients, such as folate and vitamin B12, should also be considered when studying the relations of intake on status or health.
SE, RO, SH, and MV substantial contributions to the conception or design of the work. All authors drafting the work or revising it critically for important intellectual content. All authors provide approval for publication of the content. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SE, RO, SH, and MV selected extracted relevant papers of this manuscript. SE, RO, and SH wrote the manuscript. SE had primary responsibility for final content. All authors read and approved the final manuscript.
EvdH was employed by company FrieslandCampina. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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intrinsic factor
holotranscobalamin
methylmalonic acid
total homocysteine
neural tube defects.