Cobalamin Vitamin B12

Pathogenesis and Pathophysiology. Vitamin B12 deficiency produces neurological and hematological effects by impairing the function of two enzyme systems (Fig. 40-5 (Figure Not Available) ). y , y Methylcobalamin is a co-factor of methionine synthase, a cytosolic enzyme that catalyzes the conversion of homocysteine and methyltetrahydrofolate to produce methionine and tetrahydrofolate. Methionine is further metabolized to S-adenosylmethionine, which is necessary for methylation of myelin sheath phospholipids and proteins. Tetrahydrofolate is the required precursor for purine and pyrimidine synthesis. In the mitochondria, adenosylcobalamin catalyzes the conversion of L-methylmalonyl CoA to succinyl CoA.

In deficiency states, serum levels of homocysteine and methylmalonic acid rise. Although the mechanism of megaloblastic changes in both folate and cobalamin deficiency is reasonably well understood, the biochemical basis of the neurological damage that occurs in cobalamin deficiency remains uncertain. Of the two reactions that require cobalamin, the methionine synthase reaction is considered more likely to play a critical role in nervous system function. Rarely, neurological complications have also been reported in folate deficiency, because methionine synthase also requires this co-substrate. y It has been proposed that the accumulation of methylmalonate and propionate provide abnormal substrates for fatty acid synthesis, resulting in abnormal odd-carbon and branched-chain fatty acids, which may be incorporated into the myelin sheath and interfere with impulse conduction.

Vitamin B12 deficiency results in demyelination of the posterior columns, corticospinal tracts, and white matter of the cerebral hemispheres ( Fig 40-6 )■ [30] Less commonly, a sensorimotor and autonomic neuropathy that is axonal and demyelinating in nature may also be present. y These lesions lead to a constellation of symptoms, including cognitive and affective disorders, ataxia, spasticity, and paresthesias.

Epidemiology and Risk Factors. The total body store of cobalamin is 2000 to 5000 pg, half of which is stored in the liver. The recommended daily allowance is 6 pg/day, and the average diet provides 20 pg/day. Because the vitamin is tightly conserved through enterohepatic circulation, 2 to 5 years elapse before a subject develops cobalamin deficiency from malabsorption, and as long as 10 to 20 years are needed to induce a dietary deficiency from a strict vegetarian diet.

The most common cause of vitamin B12 deficiency is pernicious anemia or autoimmune parietal cell dysfunction ( .T§b]§.40-3 ).y The mean age of diagnosis is 60 years, and the female-to-male ratio is approximately 1.5:1. In white populations, the incidence of the disease increases with increasing age, peaking after age 65. In Hispanic and African populations, there is an overall younger age distribution, especially among women. When using radioassay-derived serum cobalamin levels below 200 pg/ml or elevated levels of homocysteine and methylmalonic acid as diagnostic criteria, the prevalence of B 12 deficiency from all causes ranges from 7 to 16 percent.^

Figure 40-5 (Figure Not Available) Intracellular vitamin-^ interactions. See the text for description. B indicates vitamin B2 (cyanocobalamin); MB2 , methylcobalamin; DBJ2 , deoxyadenosylcobalamin; TclI, transcobalamin II1B TcII, transcobalamin II-bound cobalamin; MTHF, methyltetrahydrofolate; THF, tetrahydrofolate; and CoA, coenzymefFrom Flippo TS, Holder WD Jr: Neurologic degeneration associated with nitrous oxide anesthesia in patients with vitamin B12 deficiency. Arch Surg 1993;128:1391-1395.)

Figure 40-6 Subacute combined degeneration of the spinal cord. A thoracic cord segment showing spongy degeneration of the white matter in a typical distribution (Weil's '.(From Okazaki H: Fundamentals of Neuropathology, 2nd ed. New York, Igaku Shoin, 1989, p 195.)

Other causes of B12 deficiency include ileal resection, parasitic infestations from Diphyllobothrium latum, Crohn's disease and other malabsorption states, short gut syndrome, veganism, chronic alcoholism with poor diet, and rare congenital enzyme deficiencies.

Clinical Features and Associated Disorders. Subacute combined degeneration of the spinal cord, peripheral nerve dysfunction, and cerebral dysfunction are classic features of the disorder. Many patients present without accompanying anemia or macrocytosis. Healton and associates reviewed 143 patients who had 153 episodes of cobalamin deficiency. y Seventy-four percent of the episodes presented with neurological symptoms, including paresthesias, numbness, gait ataxia, fecal incontinence, leg weakness, impaired manual dexterity, impaired memory, and impotence. Rarely, patients had orthostatic lightheadedness, anosmia, diminished taste, paranoid psychosis, and diminished visual acuity. The remaining 26 percent presented

_TABLE 40-3 -- CAUSES OF COBALAMIN DEFICIENCY__

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