Abstract / Summary
Vitamin B12 (cobalamin) deficiency affects an estimated 6% of adults under 60 and nearly 20% of those over 60 in developed countries; prevalence exceeds 70-80% in developing countries. Despite these numbers, the diagnosis is easily missed. Neurological impairment – including subacute combined degeneration of the spinal cord, peripheral neuropathy, and cognitive decline – can develop and progress even in the absence of anemia or macrocytosis. The assays have well-documented blind spots, and the early symptoms are nonspecific: fatigue, paresthesia, gait unsteadiness, and cognitive slowing are readily attributed to aging, diabetic neuropathy, or depression. The result is a common condition that remains undiagnosed in a substantial proportion of affected individuals. The clinical understanding of B12 deficiency has undergone a quiet but profound transformation over the past five decades. Several observations were made independently and confirmed repeatedly, which forced the medical field to abandon its older, simpler version. First, neurological disease from B12 deficiency frequently occurs without anemia or macrocytosis - in one landmark series of 141 patients with neurologic disease from B12 deficiency, more than a quarter had a normal hematocrit, and one in six had neither anemia nor macrocytosis. Second, the assays most laboratories used for decades measured not only true B12 but also biologically inactive cobalamin analogs, generating normal results in patients who were, in fact, deficient – false negatives that could delay diagnosis by years. Third, Pernicious anemia, long considered the prototypical cause, accounts for only a minority of cases; food-cobalamin malabsorption driven by the atrophic gastritis of aging is the dominant mechanism in the elderly. Fourth, metformin and proton pump inhibitors -two of the most widely prescribed medications worldwide, especially in high-income countries - reliably lower serum B12 over time, a risk factor that is rarely discussed when these medications are prescribed. Fifth, high-dose oral B12, absorbed by mass action, is as effective as intramuscular injections for most patients, a practical reality that has yet to fully penetrate clinical practice. This review synthesizes the current evidence on the pathophysiology, epidemiology, clinical spectrum, diagnostic approach, and management of vitamin B12 deficiency. It is written for the clinician who must decide which patient with fatigue, paresthesia, cognitive complaints, or a borderline-low B12 level actually has tissue deficiency requiring treatment, and who must then choose between oral and injectable therapy, determine the dosing schedule, and know when the patient can simply stop.