Cobalamin metabolism is complex and requires many processes, any one of which, if not present, may lead to cobalamin deficiency.4,13,14,15
The causes of cobalamin deficiency are shown in and listed in .
Fig. 1: Cobalamin metabolism and corresponding causes of deficiency. Causes of cobalamin deficiency are shown in blue. The metabolic pathway starts when (1) dietary cobalamin (Cbl), obtained through animal foods, enters the stomach bound to animal proteins (more ...)
Once metabolized, cobalamin is a cofactor and coenzyme in many biochemical reactions, including DNA synthesis, methionine synthesis from homocysteine and conversion of propionyl into succinyl coenzyme A from methylmalonate, as shown in .
Fig. 2: A. Cellular uptake and processing of cobalamin. Cobalamin (Cbl) bound to the transport protein transcobalamin II (TCII) enters cells by means of transcobalamin II receptor-mediated endocytosis. Lysosomal enzymes degrade the transcobalamin II, (more ...)
A typical Western diet contributes 3–30 μg of cobalamin per day toward the estimated daily requirement of 2–5 μg that is recommended by the American Society of Geriatry,16
the US Food and Drug Administration and the Association Française de Sécurité Sanitaire des Aliments. Reserves, which are primarily hepatic, are significant (> 1.5 mg). The 5- to 10-year delay between the onset of insufficient intake and the development of clinical illness is a direct result of the hepatic stores and the enterohepatic cycle, whereby cobalamin is excreted in bile and then reabsorbed in the small intestine (see ).4,13
Between 1% and 5% of free cobalamin (and crystalline cobalamin) is absorbed along the entire intestine by passive diffusion, which explains the mechanism underlying oral treatment of deficiencies associated with pernicious anemia and food-cobalamin malabsorption.4,17,18
In a clinical setting, cobalamin absorption is examined (imperfectly) by the Schilling test.4,8
The test is currently performed as follows: patients are given 1000 μg of cyanocobalamin intramuscularly at day 1 to saturate the intestinal mucosal cells, followed by 1000 μg of free 58
Cocyanocobalamin orally on day 2. Excess cobalamin, which is not absorbed, is excreted, and the patient's urine is collected for 24 hours (from day 2 to day 3) and the percentage of labelled cyanocobalamin is determined. Abnormally low levels of cobalamin in the collected urine indicate cases of malabsorption or pernicious anemia; normal levels indicate dietary deficiency, food-cobalamin malabsorption or hereditary cobalamin metabolism deficiencies.