The hematologic effects of vitamin B12 deficiency, when they result from pernicious anemia, are distinctive insofar as they usually result not from a dietary lack of vitamin B12 but from the failure to transfer minute amounts of this nutrient across the intestinal mucosa, “starvation in the midst of plenty,” as Castle aptly put it. This failure derives from the chronic absence of an intrinsic factor, which is secreted (along with hydrochloric acid) by the parietal cells of the gastric mucosa and transports cobalamin (“extrinsic factor”) to the ileum, where it is absorbed into the portal venous system. This is referred to as a conditioned deficiency, as it is conditional on the lack of an intrinsic factor. Minot and Murphy’s clinical experiment that showed the cure of the neurologic process by the feeding of liver, or parenteral liver extract that contained an “extrinsic factor” later found to be cobalamin, was a remarkable feat of translational medicine. A movie can be seen depicting this work at: http://bloodjournal .hematologylibrary.org/content/107/12/4970.1/suppl/DC1. It was Castle, experimenting on himself, who isolated the “intrinsic factor” that facilitates absorption of the vitamin.
The hematologic and neurologic manifestations of vitamin B12 deficiency often complicate many of the malabsorptive disorders, including poor nutrition in the elderly, especially those with atrophic gastritis, but also individuals of any age with celiac sprue; gastric or ileal resections; overgrowth of intestinal bacteria in “blind loops,” anastomoses, diverticula, and other conditions resulting in intestinal stasis; and infestation with cobalamin-metabolizing fish tapeworm (Diphyllobothrium latum). Uncommon instances of vitamin B12 deficiency are observed in lactovegetarians and in infants nursed by mothers deficient in vitamin B12; vitamin B12 deficiency may also be a result of a rare genetic defect of methylmalonyl-CoA mutase as discussed further on.
It should be further commented that interference with methionine synthetase, a methylcobalamin-dependent enzyme, can be produced by exposure to nitrous oxide. Chronic exposure can produce the entire subacute combined syndrome but more often, an individual is marginally deficient, often but not always elderly, and even short exposure may then induce symptoms. A megaloblastic anemic state, as well as the neurologic features of SCD, is thereby induced by the gas. This illness, cleverly named “anesthesia paresthetica” by Kinsella and Green, arises in operating room personnel (we have seen it in several anesthesia nurses), occasionally in dentists, and in abusers of the gas (whippets) to obtain a “high.” Their serum B12 levels are usually in the low-normal range, and measurements of methylmalonic acid are greatly elevated (see further on).
Symptoms of nervous system disease occur in the majority of patients with pernicious anemia and in most with B12 deficiency of other sources. The patient first notices mild general weakness and paresthesias consisting of tingling, “pins and needles” feelings, or other vaguely described sensations. The paresthesias involve the hands and feet, more often and first in the hands, and tend to be constant and steadily progressive and the source of much distress. As the illness progresses, the gait becomes unsteady and stiffness and weakness of the limbs, especially of the legs, develop. If the disease remains untreated, an ataxic paraplegia evolves with variable degrees of spasticity.