Vitamin B12 deficiency

Ryan Jacobson MD (Dr. Jacobson of Loyola University Chicago Stritch School of Medicine has no relevant financial relationships to disclose.)
Zachary N London MD, editor. (Dr. London of the University of Michigan has no relevant financial relationships to disclose.)
Originally released October 6, 1999; last updated October 9, 2017; expires October 9, 2020

This article includes discussion of vitamin B12 deficiency, cobalamin deficiency, and Addison-Biermer disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

B12 deficiency may cause an extraordinary variety of progressive neurologic syndromes. In this article, the author describes the well-established manifestations of B12 deficiency as well as more controversial associations with macular degeneration, cerebrovascular disease, and dementia. In addition, although severe B12 deficiency has long been known to cause severe developmental delay, this update includes emerging information suggesting that a relative B12 deficiency may cause a common metabolic syndrome in infancy that is potentially linked to subtle developmental problems.

Key points

 

• B12 deficiency should be suspected in any patient with otherwise unexplained peripheral neuropathy, myelopathy, optic neuropathy, dementia, ataxia, movement disorder, or psychiatric disturbance.

 

• Serum B12 level should be determined in any patient with suspected B12 deficiency; abnormal blood cell indices are neither sensitive nor specific for B12 deficiency.

 

• In cases of borderline low B12 levels, or when B12 deficiency is strongly suspected despite reported normal levels from an automated assay, elevated serum methylmalonic acid and homocysteine levels may confirm a physiological deficiency.

 

• Daily, high-dose oral B12 supplementation appears as effective as parenteral therapy, and is substantially less costly. A brief parenteral course of therapy may still be needed for patients with significant neurologic signs of B12 deficiency.

 

• Modest elevations in serum methylmalonic acid and homocysteine levels are common in breastfed infants and may represent a physiologically significant B12 deficiency.

Historical note and terminology

Improvements in histological technique in the late 19th century led to the recognition of pernicious anemia, also called Addison-Biermer disease, as a distinct diagnostic entity with hematologic, gastrointestinal, and neurologic features (Chanarin 2000). Osler, among many others, provided harrowing accounts of the then mysterious and lethal progressive condition (Osler and Bell 1877; Gardner and Osler 1877). The first accurate description of spinal cord pathology associated with certain types of anemia was by Ludwig Lichtheim (Lichtheim 1887). Russell and colleagues coined the term "subacute combined degeneration of the spinal cord" in their definitive study of the neuropathological abnormalities commonly associated with pernicious anemia (Russell et al 1900). In 1926, Minot, Murphy, and Whipple showed that a factor present in calf liver could rapidly restore red blood cell counts in pernicious anemia, and in 1934, they were awarded the Nobel Prize for this discovery. Later efforts by Folker and Todd led to the isolation of the active anti-anemic factor in liver, vitamin B12. Kass has written an excellent short history of the early research on B12 deficiency, a field in which the Nobel Prize has twice been awarded (Kass 1976).

In general, the term "vitamin B12" refers to any of the biologically active molecules related to cyanocobalamin, the form of vitamin B12 originally isolated from the liver.

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