Subtle Cobalamin Deficiency

As physicians, we tend to think of deficiency states in terms of their classic, generally florid features. In the case of cobalamin (vitamin B₁₂) deficiency, these features include, first and foremost, megaloblastic anemia and neurologic dysfunction. Of course, all dividing cells are affected, but the sequelae outside the bone marrow and the nervous system are usually not clinically apparent.

The theory that megaloblastic anemia is not invariably present in clinically overt cobalamin deficiency was first proposed 90 years ago [1] and was roundly rejected at the time. It has since been well documented that anemia and macrocytosis are often absent in cobalamin deficiency [2-4]. Indeed, humans may be alone in the animal kingdom in developing any megaloblastic anemia at all when they are cobalamin deficient. Interestingly, the bone marrow cells of cobalamin-deficient monkeys regularly show metabolic evidence of cobalamin insufficiency and impaired thymidine synthesis with the deoxyuridine suppression test, even though the cells never assume a megaloblastic appearance [5]. This metabolic insufficiency at the cellular level has since been shown in bone marrow cells of those cobalamin-deficient humans who do not develop megaloblastic anemia [6-9], many of whom also lack neurologic symptoms.

These clinically silent deoxyuridine suppression abnormalities, which are reversible with cobalamin therapy [10], represent early deficiency in some of these patients; with time, the metabolic defect progresses and is translated into megaloblastic anemia. In other patients, however, such as the teenaged brothers with cblD mutation [6] …