Absorption And Transport

The daily requirement of cobalamin is about 3.0 micrograms. Absorption takes place mainly in the terminal ileum, and it is carried in plasma bound to proteins. Some 90% of recently absorbed or administered cobalamin is carried on transco-balamin II an important transport protein which is rapidly cleared from the circulation (t'/2 6-9 minutes). Hereditary deficiency of transcobalamin II causes severe cobalamin deficiency. About 80% of all circulating cobalamin is bound to transcobalamin I (t1/, 9-12 days) which is possibly a plasma storage form (hereditary deficiency of which is of no consequence). Cobalamin in its reduced form cob(I)alamin functions as a coenzyme for methionine synthase in a reaction that generates tetrahydrofolate, and is critical for DNA and RNA synthessis.

Cobalamin is not significantly metabolised and passes into the bile (there is enterohepatic circulation which can be interrupted by intestinal disease and hastens the onset of clinical deficiency), and is excreted via the kidney. Body stores amount to about 5 mg (mainly in the liver) and are sufficient for 2-4 years if absorption ceases.


Indications for administration are the prevention and cure of conditions due to its deficiency. Hydroxocobalamin is preferred for clinical use.

Pernicious (Addisonian) anaemia. The atrophic gastric mucosa is unable to produce intrinsic factor (and acid) due to an autoimmune reaction to gastric parietal cells and intrinsic factor itself, there is failure to absorb vitamin B12 in the terminal ileum so that deficiency results. Despite its name (given when no treatment was known and it was believed to be a neoplastic disorder due to the appearance of the megaloblastic bone marrow), the prognosis of a patient with uncomplicated pernicious anaemia, properly treated with hydroxocobalamin, is little different from that of the rest of the population. The neurological complications, particuarly spasticity, develop only after prolonged severe deficiency but may be permanent; they are rarely seen today. Total removal of the stomach or atrophy of the mucous membrane in a postgastrectomy remnant may, after several years, lead to a similar anaemia.

Malabsorption syndromes. In stagnant loop syndrome (bacterial overgrowth which competes for the available cobalamin and can be remedied by a broad-spectrum antimicrobial), ileal resection, Crohn's disease and chronic tropical sprue affecting the terminal ileum, vitamin B12 deficiency is common although megaloblastic anaemia occurs only relatively late. The fish tape worm Diphyllobothrum latum which can infest humans who eat raw or partially cooked freshwater fish roe can grow up to 10 meters in the gut and competes for ingested cobalamin.

Tobacco amblyopia has been attributed to cyanide intoxication from strong tobacco which interferes with the coenzyme function of vitamin B12; hydroxocobalamin (not cyanocobalamin) may be given.


The serum concentration of vitamin B12 is low (normal 170-925 nanogram/1). In severe deficiency there is pancytopenia, the blood film shows anisopoikilocytosis with oval macrocytes and hyper-segmented neutrophils; the marrow is megaloblastic. In many patients with pernicious anaemia antibodies to intrinsic factor can be identified in the serum.

Absorption of radioactive vitamin B12 (Schilling test) helps to distinguish between gastric and intestinal causes.

First: the patient is given a small dose of radioactive vitamin B12 orally, with a simultaneous large dose of nonradioactive vitamin B12 intramuscularly. The large injected dose saturates binding sites so that any of the oral radioactive dose that is absorbed cannot bind and will be eliminated in the urine where it can easily be measured (normally > 10% of the administered dose appears in urine collected for 24 h, if renal function is normal). In pernicious anaemia and in malabsorption, gut absorption and therefore subsequent appearance of radioactivity in the plasma (measured 8-12 h later) and urine are negligible.

Second: the test is repeated with intrinsic factor added to the oral dose. The radioactive vitamin BJ2 is now absorbed in pernicious anaemia (but not in intestinal malabsorption) and is detected in plasma and urine. Both stages of the test are needed to maximise reliability of diagnosis of pernicious anaemia.


Inconclusively diagnosed anaemia is an important contraindication. Therapy of pernicious anaemia must be both adequate and lifelong, so that accurate diagnosis is essential. Even a single dose of vitamin B12 interferes with the haematological picture for weeks (megaloblastic haematopoiesis reverts to normal within 12 hours), although the Schilling test remains diagnostic.

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