Vitamin B12 deficiency - A 21st century perspective

Abstract

Vitamin B12 deficiency is a common condition which can present with non-specific clinical features, and in severe cases with neurological or haematological abnormalities. Although classically caused by pernicious anaemia, this condition now accounts for a minority of cases and vitamin B12 deficiency occurs most often due to food-bound cobalamin malabsorption. Since missing the diagnosis can result in potentially severe complications, including degeneration of the spinal cord and pancytopaenia, vitamin B12 deficiency must be diagnosed early and managed appropriately. Intramuscular injections have been the mainstay of treatment, but oral replacement therapy can be effective in many cases. There is accumulating evidence that high vitamin B12 levels (values varied from 350-1,200 pmol/l) are associated with haematological and hepatic disorders, in particular with malignancy. This review focuses on the developments in the clinical features and management of vitamin B12 deficiency over the last decade.

Keywords: B12; cobalamin; deficiency; vitamin.

Fig 1.

Pictorial representation of the absorption of vitamin B₁₂ (cobalamin). Dietary vitamin B₁₂ is found in association with food proteins, and must be released on exposure to the low pH within the gastric lumen to facilitate absorption in the small bowel. Once liberated, vitamin B₁₂ is immediately bound by haptocorrin (transcobalamin I) and remains attached until proteolytic cleavage of the complex in the duodenum. Here, it is available to bind intrinsic factor (IF), a second carrier protein, synthesised by the parietal cells of the gastric mucosa. IF is necessary for uptake of vitamin B₁₂ in the terminal ileum. On traversing the brush border, vitamin B₁₂ dissociates from IF, and enters the circulation where it binds transcobalamin II or haptocorrin. Transcobalamin II and haptocorrin are responsible for delivery of cobalamin to peripheral tissues and the liver, respectively. Cbl = cobalamin; HC = haptocorrin; IF = intrinsic factor; PA = pernicious anaemia; PPI = proton pump inhibitor; TCII  = trancobalamin II.

Fig 2.

Intracellular metabolism of vitamin B₁₂. Following transport to peripheral tissues, free vitamin B₁₂ is generated. In the cytosol, vitamin B₁₂ (Cbl) is used as a cofactor by MS to react homocysteine with N⁵-MeTHF to produce methionine and THF. Synthesis of THF affords the downstream generation of purines and pyrimidines required for DNA and RNA synthesis, explaining the clinical features of deficiency. The only other vitamin B₁₂-dependent reaction is the conversion of methylmalonyl CoA to succinyl CoA by methylmalonyl CoA mutase, occurring in the mitochondria. Cbl = cobalamin; MCM = methylmalonyl-CoA mutase; MS = methionine synthase; N⁵-MeTHF = N⁵-methyltetrahydrofolate; TCII = transcobalamin II; TCII-R = transcobalamin II receptor; THF = tetrahydrofolate.