Vitamin B12 Deficiency in the Elderly
12 Deficiency in the Elderly
Sudeep S. Gill, MD, FRCP(C), Research Fellow, Division of Geriatric Medicine, University of Toronto and Kunin-Lunenfeld Applied Research Unit, Baycrest Centre for Geriatric Care, Toronto, ON.
Shabbir M.H. Alibhai, MD, MSc, FRCP(C), Staff Physician, Department of Medicine, University Health Network, Toronto, ON.
Vitamin B12 deficiency is a common disorder in older adults, but its diagnostic work-up and management can be complex. In this article, we review the metabolic pathways involving vitamin B12 and the various pathologies that can interfere with these pathways. This discussion provides a framework to understand the following section, which outlines an approach to the clinical examination, laboratory evaluation and treatment of subjects with suspected vitamin B12 deficiency.
Key words: vitamin B12, folic acid, deficiency diseases, dementia, aging.
Introduction
Vitamin B12 deficiency is frequently suspected in older adults with a variety of neurologic and hematologic abnormalities. However, the diagnostic evaluation and management of such patients can be complex. Serum vitamin B12 concentrations alone have limited sensitivity and specificity in the elderly.1,2 Our goal in this article is to outline the physiology and pathophysiology of vitamin B12 metabolism, which will then permit a rational approach to the clinical examination, laboratory testing and treatment of vitamin B12 deficiency. An accompanying article (Folate Deficiency, Homocysteine and Dementia) discusses the interdependent metabolic pathways of folate. There is now increased interest in vitamin B12 and folate due to the potential role of homocysteine in a variety of cardiovascular3 and neurologic4 diseases.
Normal Physiology of Vitamin B12
Vitamin B12 is also known as cobalamin, and the terms are used interchangeably in this article. Different ligands can attach to produce chemically distinct cobalamins (e.g., cyanocobalamin, methylcobalamin), but they all share essentially identical nutritional properties.2 Foods of animal origin (such as meat and dairy products) are the primary dietary source of vitamin B12. The average North American diet contains 5-15mg/day of cobalamin, more than enough to meet the traditional recommended dietary allowance of 2mg/day.2 Furthermore, there are normally 2,000-5,000mg total body stores of cobalamin (which are found primarily in the liver). As a result, cobalamin deficiency on the basis of dietary insufficiency or malabsorption is rare and often takes years to develop.
Figure 1 illustrates the steps involved in vitamin B12 absorption. Dietary protein (or "extrinsic factor") binds to vitamin B12 in many foods. In the acidic environment of the stomach, vitamin B12 is dislodged from food protein and binds to salivary haptocorrin (previously called R binder protein). Haptocorrin prevents cobalamin from being degraded as it passes through gastric acid. As vitamin B12 enters the duodenum, the neutral pH environment and pancreatic enzymes facilitate the displacement of haptocorrin. Vitamin B12 then becomes attached to intrinsic factor, which is produced by parietal cells in the stomach. The cobalamin-intrinsic factor complex travels to the terminal ileum, where it is absorbed into mucosal cells via receptor-mediated endocytosis.2 Within the mucosal cells, cobalamin is picked up by transcobalamin II (TC II) and serum haptocorrins (formerly referred to as TC I and TC III), which are plasma proteins that carry cobalamin to the liver and other target organs. It is important to note that approximately 2% of vitamin B12 absorption occurs in the small bowel proximal to the terminal ileum, independent of intrinsic factor and its receptor.5 Studies have shown that high-dose oral vitamin B12 can be absorbed in significant quantities in the absence of intrinsic factor or an intact ileum.6
Two cobalamin-dependent biochemical