High Plasma Vitamin B12 and Cancer in Human Studies : A Scoping Review to Judge Causality and Alternative Explanations

Patients with cancer have been reported to show elevated plasma concentrations of vitamin B12, thus causing uncertainties regarding safety of vitamin B12. We conducted a systematic literature search and a scoping review of human studies published in PubMed between January 2005 and March 2022, to investigate the association between vitamin B12 (concentrations of B12 biomarkers, intake, and genetic determinants) and cancer. Except for liver cancer, the association between plasma vitamin B12 concentrations and cancer was not consistent across the studies. Vitamin B12 intake from food, or food and supplements, showed even less consistent associations with cancer. There was no evidence for temporality, coherence, or a biologically meaningful dose-response relationship between plasma vitamin B12 concentrations and cancer. Genetically determined high plasma vitamin B12 was likely to be associated with cancer. Available randomized controlled trials have used a high dose of multivitamin supplements and cancer was the unplanned outcome, thus the causality of B12 in cancer cannot be judged based on these trials. Additionally, low plasma vitamin B12 concentrations were common in patients with cancer. Therefore, there is not sufficient evidence to assume that high plasma vitamin B12, high B12 intake, or treatment with pharmacological doses of vitamin B12, is causally related to cancer. Low vitamin B12 status in patients with cancer needs to be diagnosed and treated in order to prevent the hematological and neurological sequela of the deficiency

The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway

Methyl groups are important for numerous cellular functions such as DNA methylation, phosphatidylcholine synthesis, and protein synthesis. The methyl group can directly be delivered by dietary methyl donors, including methionine, folate, betaine, and choline. The liver and the muscles appear to be the major organs for methyl group metabolism. Choline can be synthesized from phosphatidylcholine via the cytidine-diphosphate (CDP) pathway. Low dietary choline loweres methionine formation and causes a marked increase in S-adenosylmethionine utilization in the liver. The link between choline, betaine, and energy metabolism in humans indicates novel functions for these nutrients. This function appears to goes beyond the role of the nutrients in gene methylation and epigenetic control. Studies that simulated methyl-deficient diets reported disturbances in energy metabolism and protein synthesis in the liver, fatty liver, or muscle disorders. Changes in plasma concentrations of total homocysteine (tHcy) reflect one aspect of the metabolic consequences of methyl group deficiency or nutrient supplementations. Folic acid supplementation spares betaine as a methyl donor. Betaine is a significant determinant of plasma tHcy, particularly in case of folate deficiency, methionine load, or alcohol consumption. Betaine supplementation has a lowering effect on post-methionine load tHcy. Hypomethylation and tHcy elevation can be attenuated when choline or betaine is available

An exploratory study on the effect of choline and folate deficiency on levels of vascularization proteins and transcription factors in first trimester trophoblast HTR-8/SVneo cells

Aims: We studied the effect of choline and folate deficiencies on levels of predetermined placental proteins during early development. Methods: We incubated HTR-8/SVneo cells under choline and folate deficiency conditions and measured levels of some placental proteins using ELISA methods. Results: Concentrations of LRP2 protein in cell lysates were higher in cells incubated in choline and folate deficient media compared to the control media (mean [SD] = 2.95 [1.30] vs. 1.65 [0.27] ng/mg protein, p = 0.004). The levels of LRP2 protein in lysates of cells incubated in choline and folate deficient media were significantly higher than the concentrations in lysates of cells incubated in choline deficient but folate sufficient media (1.96 [0.28] ng/mg protein) or those incubated in choline sufficient but folate deficient media (1.77 [0.24] ng/mg protein) (p < 0.05 for both). The cellular levels of CDX2 protein were significantly higher in cells incubated in choline and folate deficient media compared to the control media (1.78 [0.60] vs. 0.99 [0.42] pg/mg protein, p = 0.002); and compared to CDX2 levels in cells incubated in choline deficient but folate sufficient media (0.87 [0.13] pg/mg protein, p < 0.001) or in choline sufficient but folate deficient media (0.96 [0.16] pg/mg protein, p < 0.001). The levels of sFLT-1 and IGF1 in culture media and that of EOMES in HTR-8/ SVneo cell lysates remained unchanged under all deficiency conditions. Discussion: LRP2 and CDX2 are likely to be molecular targets for early choline and folate deficiencies in human trophoblast cells. The results should be confirmed in animal models and in other models of placental cells

Habitual Choline Intakes across the Childbearing Years: A Review

Choline is an important nutrient during the first 1000 days post conception due to its roles in brain function. An increasing number of studies have measured choline intakes at the population level. We collated the evidence focusing on habitual choline intakes in the preconceptual, pregnancy, and lactation life stages. We conducted a review including studies published from 2004 to 2021. Twenty-six relevant publications were identified. After excluding studies with a high choline intake (>400 mg/day; two studies) or low choline intake (<200 mg/day; one study), average choline intake in the remaining 23 studies ranged from 233 mg/day to 383 mg/day, even with the inclusion of choline from supplements. Intakes were not higher in studies among pregnant and lactating women compared with studies in nonpregnant women. To conclude, during the childbearing years and across the globe, habitual intakes of choline from foods alone and foods and supplements combined appear to be consistently lower than the estimated adequate intakes for this target group. Urgent measures are needed to (1) improve the quality of choline data in global food composition databases, (2) encourage the reporting of choline intakes in dietary surveys, (3) raise awareness about the role(s) of choline in foetal–maternal health, and (4) consider formally advocating the use of choline supplements in women planning a pregnancy, pregnant, or lactating

Association between neuropathy and B-vitamins: A systematic review and meta-analysis

Background Peripheral neuropathy (PN) is common in patients with diseases that are in turn associated with deficiency of the B-vitamins, and vitamin treatment has shown mixed results. Methods This systematic review and meta-analysis studied the association between PN/pain and B-vitamin biomarkers and investigated whether vitamin treatment can ameliorate the symptoms. PubMed and Web of Science were searched according to the study protocol. Results A total of 46 observational and seven interventional studies were identified and included in the data synthesis. The presence of PN was associated with lowered B12 levels (pooled estimate [95% CIs] = 1.51 [1.23–1.84], n = 34, Cochran Q Test I2 = 43.3%, p = 0.003) and elevated methylmalonic acid (2.53 [1.39–4.60], n = 9, I2 = 63.8%, p = 0.005) and homocysteine (3.48 [2.01–6.04], n = 15, I2 = 70.6%, p < 0.001). B12 treatment (vs. the comparators) showed a non-significant association with symptom improvement (1.36 (0.66–2.79), n = 4, I2 = 28.9%). Treatment with B1 was associated with a significant improvement in symptoms (5.34 [1.87–15.19], n = 3, I2 = 64.6%, p = 0.059). Analysis of seven trials combined showed a non-significant higher odds ratio for improvement under treatment with the B-vitamins (2.58 [0.98–6.79], I2 = 80.0%, p < 0.001). Conclusions PN is associated with lowered plasma vitamin B12 and elevated methylmalonic acid and homocysteine. Overall, interventional studies have suggested that B-vitamins could improve symptoms of PN. Available trials have limitations and generally did not investigate vitamin status prior to treatment. Well-designed studies, especially in non-diabetes PN, are needed. This meta-analysis is registered at PROSPERO (ID: CRD42020144917)

Folate status and health: challenges and opportunities

AbstractEach year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 μg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (&gt;18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia.</jats:p

Glucose and Fat Tolerance Tests Induce Differential Responses in Plasma Choline Metabolites in Healthy Subjects

Plasma choline shows associations with plasma glucose and lipids. We studied changes of choline metabolites after oral glucose tolerance test (OGTT) and fat tolerance test (OFTT). Eighteen healthy subjects (mean age 54.3 years; BMI 26.8 kg/m2) underwent 2 tests. First, OFTT (80 g fat) was applied and blood was collected at baseline and 4 h after OFTT. Seven days later, 75 g glucose was applied and blood was collected at baseline and 2 h after OGTT. Plasma concentrations of choline, betaine, trimethylamine N-oxide (TMAO), dimethylglycine, S-adenosylmethionine (SAM), lipids and glucose were measured. After OFTT, plasma choline declined (10.6 to 9.2 µmol/L; p = 0.004), betaine declined (33.4 to 31.7 µmol/L; p = 0.003), TMAO slightly increased (4.1 to 5.6 µmol/L; p = 0.105), glucose declined (5.39 to 4.98 mmol/L; p < 0.001), and triglycerides increased (1.27 to 2.53 mmol/L; p < 0.001). After OGTT, plasma choline increased (10.1 to 11.1 µmol/L; p < 0.001), TMAO declined (4.0 to 3.5 µmol/L; p = 0.029), dimethylglycine declined (2.0 to 1.7 µmol/L; p = 0.005), SAM declined (103 to 96 nmol/L; p = 0.041), but betaine, glucose, and SAM were unchanged. In conclusion, OFTT lowered plasma betaine and choline and caused heterogeneous changes in plasma TMAO. OGTT reduced the flow of methyl groups and plasma TMAO

Imbalanced Folate and Vitamin B12 in the Third Trimester of Pregnancy and its Association with Birthweight and Child Growth up to 2 Years

Scope: Folic acid supplementation during pregnancy may lead to an imbalance when vitamin B12 intake is low (folate trap) and may affect child’s growth. Methods: The authors study the association between third trimester maternal intakes of folate and B12 and birthweight and postnatal growth of 2632 infants from the KOALA Birth Cohort Study. Plasma vitamin biomarkers are measured in 1219 women. Results: Imbalanced total intakes (folate > 430 µg day−1 combined with B12 < 5.5 µg day−1) are not associated with birthweight [ adj (95% CI) = –14.87 (–68.87, 39.13)] compared with high intakes of both. Imbalanced intake is associated with a lower z score of weight at 1–2 years [ adj = –0.14 (–0.25, –0.03)]. Having red blood cell folate > 745 nmol L−1 and plasma B12 < 172 pmol L−1 is not associated with birthweight [ adj = –7.10 (–97.90, 83.71) g]. Maternal dietary B12 intake [ adj = –9.5 (–15.6, –3.3)] and plasma methylmalonic acid [ adj = 234 (43, 426)] are associated with birthweight. Conclusion: Low maternal dietary B12 intake and elevated methylmalonic acid rather than imbalanced vitamins are associated with higher birthweight, suggesting that low maternal B12 can predispose the infants for later obesity

Infants’ Folate Markers and Postnatal Growth in the First 4 Months of Life in Relation to Breastmilk and Maternal Plasma Folate

Background: Human milk is the sole source of folate in exclusively breastfed infants. We investigated whether human milk folate or maternal plasma folate are associated with infants’ folate status and postnatal growth in the first 4 months of life. Methods: Exclusively breastfed infants (n = 120) were recruited at age < 1 month (baseline). Blood samples were available at baseline and at the age of 4 months. Plasma and breastmilk samples were available from the mothers at 8 weeks postpartum. The concentrations of (6S)-5-methyltetrahydrofolate (5-MTHF) and different folate status markers were measured in samples of the infants and their mothers. The z-scores of weight, height, and head circumference of the infants were measured five times between baseline and 4 months. Results: Women with 5-MTHF concentrations in breastmilk <39.9 nmol/L (median) had higher plasma 5-MTHF compared to those with milk 5-MTHF concentrations >39.9 nmol/L (mean (SD) plasma 5-MTHF = 23.3 (16.5) vs. 16.6 (11.9) nmol/L; p = 0.015). At the age of 4 months, infants of women who were higher suppliers of 5-MTHF in breastmilk had higher plasma folate than those of low-supplier women (39.2 (16.1) vs. 37.4 (22.4) nmol/L; adjusted p = 0.049). The concentrations of breastmilk 5-MTHF and maternal plasma folate were not associated with infants’ longitudinal anthropometric measurements between baseline and 4 months. Conclusions: Higher 5-MTHF in breastmilk was associated with higher folate status in the infants and the depletion of folate in maternal circulation. No associations were seen between maternal or breastmilk folate and infants’ anthropometrics. Adaptive mechanisms might counteract the effect of low milk folate on infant development

Natural Choline from Egg Yolk Phospholipids Is More Efficiently Absorbed Compared with Choline Bitartrate; Outcomes of A Randomized Trial in Healthy Adults

Choline is a vitamin-like essential nutrient, important throughout one’s lifespan. Therefore, choline salts are added to infant formula, supplements and functional foods. However, if choline is present in a natural form, e.g. bound to phospholipids, it may be more efficiently absorbed. The study’s aim was to evaluate if choline uptake is improved after consumption of an egg yolk phospholipid drink, containing 3 g of phospholipid bound choline, compared to a control drink with 3 g of choline bitartrate. We performed a randomized, double blind, cross-over trial with 18 participants. Plasma choline, betaine and dimethylglycine concentrations were determined before and up to six hours after consumption of the drinks. The plasma choline response, as determined by the incremental area under the curve, was four times higher after consumption of the egg yolk phospholipid drink compared with the control drink (p < 0.01). Similar outcomes were also observed for choline’s main metabolites, betaine (p < 0.01) and dimethylglycine (p = 0.01). Consumption of natural choline from egg yolk phospholipids improved choline absorption compared to consumption of chemically produced choline bitartrate. This information is of relevance for the food industry, instead of adding choline-salts, adding choline from egg yolk phospholipids can improve choline uptake and positively impact health