Elsevier

Biochimie

Volume 95, Issue 5, May 2013, Pages 1002-1007
Biochimie

Review
Vitamin B12 absorption: Mammalian physiology and acquired and inherited disorders

https://doi.org/10.1016/j.biochi.2012.11.004Get rights and content

Abstract

Background

Vitamin B12 (cobalamin) is a cobalt-containing compound synthesized by bacteria and an essential nutrient in mammals, which take it up from diet. The absorption and distribution of dietary vitamin B12 to the organism is a complex process involving several gene products including carrier proteins, plasma membrane receptors and transporters. Disturbed cellular entry, transit or egress of vitamin B12 may lead to low vitamin B12 status or deficiency and eventually hematological and neurological disorders.

Objective

The aim of this review is to summarize the causes leading to vitamin B12 deficiency including decreased intake, impaired absorption and increased requirements. Under physiological conditions, vitamin B12 bound to the gastric intrinsic factor is internalized in the ileum by a highly specific receptor complex composed by Cubilin (Cubn) and Amnionless (Amn). Following exit of vitamin B12 from the ileum, general cellular uptake from the circulation requires the transcobalamin receptor CD320 whereas kidney reabsorption of cobalamin depends on Megalin (Lrp2).

Whereas malabsorption of vitamin B12 is most commonly seen in the elderly, selective pediatric, nondietary-induced B12 deficiency is generally due to inherited disorders including the Imerslund-Gräsbeck syndrome and the much rarer intrinsic factor deficiency. Biochemical, clinical and genetic research on these disorders considerably improved our knowledge of vitamin B12 absorption.

This review describes basic and recent findings on the intestinal handling of vitamin B12 and its importance in health and disease.

Highlights

► Dietary vitamin B12 absorption is a multistep process. ► Intestinal uptake of B12 requires Cubilin and Amnionless. ► B12 malabsorption results in a low vitamin status or a frank deficiency. ► A low vitamin B12 status increases the risk for deficiency. ► Frank B12 deficiency leads to hematological and neurological defects.

Introduction

The significance of vitamin B12 (cobalamin) adequate nutritional status throughout life span is established and the adverse effects of vitamin B12 deficiency in human health are currently recognized [1], [2], [3]. In addition to the well-described reversible hematological and often irreversible neurological changes of severe vitamin B12 deficiency, epidemiological studies revealed a more common condition, the low vitamin B12 status particularly in elder and pregnant women [4], [5], [6]. Because vitamin B12 is essential for DNA synthesis and cellular energy production, a low vitamin B12 status may be a risk factor for altered cellular metabolism and age-related diseases including cognitive decline and cardio-vascular disease [7]. The developing embryo may be particularly susceptible to vitamin B12 deficiency and a low maternal B12 status is believed to increase 2–4 fold the risk of neural tube closure defects [7], [8]. In this review we summarize current knowledge on the physiological and pathological aspects of vitamin B12 absorption in the ileum and its consequences on vitamin B12 status.

Section snippets

Vitamin B12

Vitamin B12 (a generic term for all cobalamins biologically active in man) is a water-soluble vitamin, with a molecular weight of 1355.4 Da [9]. It is made up by a central cobalt atom and a planar corrin ring (Fig. 1A). Cobalt is the functional part of vitamin B12. Diversity of the molecule that binds to the cobalt atom on the upper part of the corrin ring, including cyanide-, methyl- or deoxyadenosyl-groups gives rise to the various forms of vitamin B12 cyanocobalamin, methylcobalamin and

Vitamin B12 absorption

Mammals do not synthesize vitamin B12. Its presence in animal products is due to microbial synthesis and dietary intake of these products is the only natural source for man. The selective vitamin B12 absorption is a multistep process that involves the stomach, pancreas and small intestine (Fig. 1B). It is mediated by two carriers haptocorrin (HC) and intrinsic factor (IF), homologous proteins each carrying a single vitamin B12 molecule [16]. Malabsorption of vitamin B12 due to a dysfunction at

Causes of vitamin B12 deficiency

Assessing vitamin B12 status is challenging. The two biomarkers generally used are serum vitamin B12, which does not necessarily reflect tissue concentrations of the vitamin, and methylmalonic acid, a functional indicator of vitamin B12 status, which accumulates in the blood in the absence of adequate cobalamin levels. Despite its use to monitor vitamin B12 status, total serum homocystein levels are not in principle exclusively vitamin B12-dependent [46]. With the caveat that the levels of the

Conclusion

Biochemical and genetic approaches helped us to identify most of the gene products involved in the intestinal absorption of vitamin B12. Future research will show whether the same gene products, including the intestinal receptors of vitamin B12 CUBN and AMN and/or LRP2 are also involved in vitamin B12 transport in the central nervous system and/or the placenta. However, because ∼20% of the currently known cases with inherited intestinal vitamin B12 malabsorption remain unexplained additional

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      Inadequate dietary intake and poor absorption are common causes of vitamin B12 deficiency, which can lead to hematological and neurological disorders such as megaloblastic anemia, paresthesia, ataxia, and cognitive dysfunction [1–5]. CD320, also known as transcobalamin receptor, is the receptor responsible for cellular uptake of vitamin B12 in tissues [1,2,6–8]. Following the absorption in the intestine, vitamin B12 enters intercellular fluid and the circulation, where it forms a complex with its carrier protein, transcobalamin 2 (TCN2).

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