Vitamin B12 Abstracts 5


Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations.
            (Alpers, 2016) Download
The systems involving folate and cobalamin have several features in common: 1) their dietary forms require luminal digestion for absorption; 2) intestinal bacteria in the upper intestine synthesize and utilize both vitamins, creating possible competition for the nutrients; 3) there is one major intestinal brush border protein essential for absorption; 4) both are subject to extensive entero-hepatic circulation. Finally, human mutations have confirmed the role of specific transporters and receptors in these processes. There are other features, however, that distinguish the metabolism of these vitamins: 1) upper intestinal bacteria tend to produce folate, while cobalamin (cbl) utilization is more common; 2) cbl absorption requires a luminal binding protein, but folate does not; 3) folate absorption can occur throughout the small bowel, but the cbl receptor, cubilin, is restricted to the distal half of the small bowel; 4) movement into cells uses transporters, exchangers, and symporters, whereas cbl is transferred by receptor-mediated endocytosis; 5) folate is carried in the blood mostly in red blood cells, whereas cbl is carried on specific binding-proteins; 6) folate can enter cells via multiple systems, but cbl uptake into all tissues use the transcobalamin receptor (TC-R), with the asialoglycoprotein receptor (ASGP-R) present in hepatocytes for uptake of haptocorrin-cbl (HC-cbl) complexes. In summary, the systems for absorption and distribution of folate and cobalamin are complex. These complexities help to explain the variable clinical responses after oral administration of the vitamins, especially when provided as supplements.

Vitamin B12 (cobalamin) deficiency in elderly patients.
            (Andrès et al., 2004) Download
Vitamin B12 or cobalamin deficiency occurs frequently (> 20%) among elderly people, but it is often unrecognized because the clinical manifestations are subtle; they are also potentially serious, particularly from a neuropsychiatric and hematological perspective. Causes of the deficiency include, most frequently, food-cobalamin malabsorption syndrome (> 60% of all cases), pernicious anemia (15%-20% of all cases), insufficient dietary intake and malabsorption. Food-cobalamin malabsorption, which has only recently been identified as a significant cause of cobalamin deficiency among elderly people, is characterized by the inability to release cobalamin from food or a deficiency of intestinal cobalamin transport proteins or both. We review the epidemiology and causes of cobalamin deficiency in elderly people, with an emphasis on food-cobalamin malabsorption syndrome. We also review diagnostic and management strategies for cobalamin deficiency.

Vitamin B12 and folate levels and lithium administration in patients with affective disorders.
            (Cervantes et al., 1999) Download
BACKGROUND:  It is unclear whether there is a relationship between lithium administration and vitamin B12 metabolism. METHODS:  We compared serum B12, serum folate, and red blood cell folate concentrations in patients receiving and not receiving lithium at two Mood Disorders Clinics. As the two centers differed in vitamin assay methods, data were first analyzed separately and then combined. To rule out an in vitro effect of lithium on the assays, we also added varying amounts of lithium to lithium-free blood samples and measured vitamin concentrations. RESULTS:  Mean serum B12 concentrations were approximately 20% lower in the lithium than in the nonlithium group at each center. This difference was statistically significant for each center and on combination (two-tailed p = .017, .021, and .0009). The parametric effect size for each center and the combined weighted mean effect size were moderate in magnitude (.605, .523, and .565). There was a nonsignificant trend toward an increased prevalence of assay-defined B12 deficiency in the lithium group at one center only, with no cases in either group at the other center and a nonsignificant combined relative risk. CONCLUSIONS:  Our data may represent a lithium-associated decrease in serum B12 concentration. The clinical significance of these findings is not yet clear.

Holotranscobalamin (HoloTC, Active-B12) and Herbert's model for the development of vitamin B12 deficiency: a review and alternative hypothesis.
            (Golding, 2016)  Download
The concentration of total vitamin B12 in serum is not a sufficiently sensitive or specific indicator for the reliable diagnosis of vitamin B12 deficiency. Victor Herbert proposed a model for the staged development of vitamin B12 deficiency, in which holotranscobalamin (HoloTC) is the first indicator of deficiency. Based on this model, a commercial immunoassay has been controversially promoted as a replacement for the total vitamin B12 test. HoloTC is cobalamin (vitamin B12) attached to the transport protein transcobalamin, in the serum, for delivery to cells for metabolism. Although there have been many published reports supporting the claims for HoloTC, the results of some studies were inconsistent with the claim of HoloTC as the most sensitive marker of vitamin B12 deficiency. This review examines the evidence for and against the use of HoloTC, and concludes that the HoloTC immunoassay cannot be used to measure vitamin B12 status any more reliably than total vitamin B12, or to predict the onset of a metabolic deficiency, because it is based on an erroneous hypothesis and a flawed model for the staged development of vitamin B12 deficiency. The author proposes an alternative model for the development of vitamin B12 deficiency.

Release of vitamin binding proteins from granulocytes by lithium: vitamin B12 and folate binding proteins.
            (Herbert and Colman, 1980) Download

Staging vitamin B-12 (cobalamin) status in vegetarians.
            (Herbert, 1994) Download
When one stops eating vitamin B-12 (cobalamins), one passes through four stages of negative cobalamin balance: serum depletion [low holotranscobalamin II, ie, low vitamin B-12 on transcobalamin II (TCII)], cell depletion (decreasing holohaptocorrin and low red cell vitamin B-12 concentrations), biochemical deficiency (slowed DNA synthesis, elevated serum homocysteine and methylmalonate concentrations), and, finally, clinical deficiency (anemia). Serum vitamin B-12 is on two proteins: the circulating vitamin B-12 delivery protein, TCII, and the circulating vitamin B-12 storage protein, haptocorrin. Because TCII is depleted of vitamin B-12 within days after absorption stops, the best screening test for early negative vitamin B-12 balance is a measurement of vitamin B-12 on TCII (holoTCII). HoloTCII falls below the bottom of its normal range long before total serum vitamin B-12 (which is mainly vitamin B-12 on haptocorrin) falls below the bottom of its normal range.

Vegetarian lifestyle and monitoring of vitamin B-12 status.
            (Herrmann and Geisel, 2002) Download
Vegetarians are at risk to develop deficiencies of some essential nutrients, especially vitamin B-12 (cobalamin). Cobalamin occurs in substantial amounts only in foods derived from animals and is essential for one-carbon metabolism and cell division. Low nutritional intake of vitamin B-12 may lead to negative balance and, finally, to functional deficiency when tissue stores of vitamin B-12 are depleted. Early diagnosis of vitamin B-12 deficiency seems to be useful because irreversible neurological damages may be prevented by cobalamin substitution. The search for a specific and sensitive test to diagnose vitamin B-12 deficiency is ongoing. Serum vitamin B-12 measurement is a widely applied standard method. However, the test has poor predictive value. Optimal monitoring of cobalamin status in vegetarians should include the measurement of homocysteine (HCY), methylmalonic acid (MMA), and holotranscobalamin II. Vitamin B-12 deficiency can be divided into four stages. In stages I and II, indicated by a low plasma level of holotranscobalamin II, the plasma and cell stores become depleted. Stage III is characterized by increased levels of HCY and MMA in addition to lowered holotranscobalamin II. In stage IV, clinical signs become recognizable like macroovalocytosis, elevated MCV of erythrocytes or lowered haemoglobin. In our investigations, we have found stage III of vitamin B-12 deficiency in over 60% of vegetarians, thus underlining the importance of cobalamin monitoring in this dietary group.

Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells.
            (Moreira et al., 2011) Download
Superoxide (O(2)(•-)) is implicated in inflammatory states including arteriosclerosis and ischemia-reperfusion injury. Cobalamin (Cbl) supplementation is beneficial for treating many inflammatory diseases and also provides protection in oxidative-stress-associated pathologies. Reduced Cbl reacts with O(2)(•-) at rates approaching that of superoxide dismutase (SOD), suggesting a plausible mechanism for its anti-inflammatory properties. Elevated homocysteine (Hcy) is an independent risk factor for cardiovascular disease and endothelial dysfunction. Hcy increases O(2)(•-) levels in human aortic endothelial cells (HAEC). Here, we explore the protective effects of Cbl in HAEC exposed to various O(2)(•-) sources, including increased Hcy levels. Hcy increased O(2)(•-) levels (1.6-fold) in HAEC, concomitant with a 20% reduction in cell viability and a 1.5-fold increase in apoptotic death. Pretreatment of HAEC with physiologically relevant concentrations of cyanocobalamin (CNCbl) (10-50nM) prevented Hcy-induced increases in O(2)(•-) and cell death. CNCbl inhibited both Hcy and rotenone-induced mitochondrial O(2)(•-) production. Similarly, HAEC challenged with paraquat showed a 1.5-fold increase in O(2)(•-) levels and a 30% decrease in cell viability, both of which were prevented with CNCbl pretreatment. CNCbl also attenuated elevated O(2)(•-) levels after exposure of cells to a Cu/Zn-SOD inhibitor. Our data suggest that Cbl acts as an efficient intracellular O(2)(•-) scavenger.

Lithium in scalp hair of adults, students, and violent criminals. Effects of supplementation and evidence for interactions of lithium with vitamin B12 and with other trace elements.
            (Schrauzer et al., 1992) Download
The lithium content of human hair shows an approximately linear response to extradietary lithium supplementation at dosage levels of up to 2000 micrograms/d. From the mean hair lithium concentration of 0.063 micrograms/g in 2648 predominantly American adults, and the reference hair lithium concentrations determined in the present study, the mean lithium intakes were calculated to be 730 micrograms/d. Hair lithium concentrations were extremely low in nearly 20% of the American samples, and in samples collected in Munich, Germany and Vienna, Austria. Hair lithium levels are low in certain pathological conditions, e.g., heart disease, in learning-disabled subjects, and in incarcerated violent criminals. The highest levels were observed in samples of a lithium-treated psychiatric patient. A statistically highly significant direct association was observed between the hair lithium and cobalt concentrations, which suggests a role of lithium in the transport and distribution of vitamin B12. Interactions of lithium with other trace elements are also discussed.

The biochemical and genetic basis for the microheterogeneity of human R-type vitamin B12 binding proteins.
            (Yang et al., 1982) Download
R-type vitamin B12 binding proteins (R proteins) from human granulocytes, erythrocytes, plasma, and other body fluids were characterized by isoprotein banding patterns on autoradiograms after resolution via thin-layer polyacrylamide isoelectric focusing (IEF) gel electrophoresis. R proteins obtained from various tissue sources in a given individual show tissue-specific electrophoretic patterns. The desialated R proteins obtained following in vitro treatment with neuraminidase are, however, the same for any given individual and do not show tissue specificity. The differences seen in native R proteins (i.e., transcobalamin I, III, and others) obtained from different tissues are due to variations only in the sialic acid content. Granulocytes from patients with chronic myelogenous leukemia (CML) contain both TC I and TC III, and these R proteins can be released in vitro by lithium stimulation. Normal granulocytes contain only TC III. Differences in desialated R proteins from individual to individual are due to a genetic polymorphism controlled by a single genetic locus (designated TCR) with two alleles, 1 and 2, which are found to be codominantly expressed in heterozygous individuals. The allelic variants of the desialated R proteins found in different blood cells and body fluids are controlled by only one genetic locus.



Alpers, DH (2016), ‘Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations.’, Biochimie, 126 52-56. PubMed: 26586110
Andrès, E, et al. (2004), ‘Vitamin B12 (cobalamin) deficiency in elderly patients.’, CMAJ, 171 (3), 251-59. PubMed: 15289425
Cervantes, P, AM Ghadirian, and S Vida (1999), ‘Vitamin B12 and folate levels and lithium administration in patients with affective disorders.’, Biol Psychiatry, 45 (2), 214-21. PubMed: 9951569
Golding, PH (2016), ‘Holotranscobalamin (HoloTC, Active-B12) and Herbert’s model for the development of vitamin B12 deficiency: a review and alternative hypothesis.’, Springerplus, 5 (1), 668. PubMed: 27350907
Herbert, V and N Colman (1980), ‘Release of vitamin binding proteins from granulocytes by lithium: vitamin B12 and folate binding proteins.’, Adv Exp Med Biol, 127 61-78. PubMed: 6996457
Herbert, V (1994), ‘Staging vitamin B-12 (cobalamin) status in vegetarians.’, Am J Clin Nutr, 59 (5 Suppl), 1213S-22S. PubMed: 8172125
Herrmann, W and J Geisel (2002), ‘Vegetarian lifestyle and monitoring of vitamin B-12 status.’, Clin Chim Acta, 326 (1-2), 47-59. PubMed: 12417096
Moreira, ES, NE Brasch, and J Yun (2011), ‘Vitamin B12 protects against superoxide-induced cell injury in human aortic endothelial cells.’, Free Radic Biol Med, 51 (4), 876-83. PubMed: 21672628
Schrauzer, GN, KP Shrestha, and MF Flores-Arce (1992), ‘Lithium in scalp hair of adults, students, and violent criminals. Effects of supplementation and evidence for interactions of lithium with vitamin B12 and with other trace elements.’, Biol Trace Elem Res, 34 (2), 161-76. PubMed: 1381936
Yang, SY, PS Coleman, and B Dupont (1982), ‘The biochemical and genetic basis for the microheterogeneity of human R-type vitamin B12 binding proteins.’, Blood, 59 (4), 747-55. PubMed: 6949616