Vitamin B12: Finding and treating the deficiency

Issue: April 1, 2003

ByRalph Green, MD, PhD, FRCPath

Ralph Green, MD [photo] ---Ralph Green, MD

Classical vitamin B12 deficiency is rarely seen today. Full-blown macrocytic anemia, with or without the neurological manifestations of combined system disease, is decidedly uncommon. Still, vitamin B12 deficiency has by no means disappeared. The face of the disease appears to have changed: manifestations are more subtle, and sometimes atypical. Examples of these “non-textbook” situations include patients with anemia but no macrocytosis and complete absence of hematological abnormalities (neuropathy or other nervous system abnormalities only).

Why the change?

Reasons for the change in spectrum of this intriguing deficiency disease are several. Judicious use of improved methods to identify B12 deficiency may allow for identification of more mild and certainly more unusual presentations. While the serum B12 assay itself continues to languish, beset by problems of sensitivity and specificity, the past decade has seen the advent of the metabolite assays involving measurement of plasma levels of homocysteine and methylmalonic acid, which rise in B12 deficiency. These assays have made it possible to detect early “preclinical” B12 deficiency that were therefore first heralded as the new “gold standard” for diagnosis of B12 deficiency. The glitter is, however, fading and doubts have now been raised about the reliability and infallibility of these measurements.

A newer approach involves measurement of the small fraction of circulating B12 (cobalamin) bound to the transport protein transcobalamin or TC (previously dubbed transcobalamin II). Typically, no more than 20% to 30% of the total B12 is on TC. The attraction of TC-B12 is that it is the fraction containing B12 being transported to tissues. Assays have been developed to measure this fraction, but they are not yet available for clinical use. It is still early days, and the assays have not yet been fully evaluated. Some argue that the precision of measurement of 30% or less of the serum B12 is lacking; time will tell. Recently, there have been reports to suggest that common genetic polymorphisms in TC may influence susceptibility to B12 deficiency.

Fast becoming a curiosity

Regarding assessment of B12 absorption, the time-worn urinary excretion test (Schilling’s test) is fast becoming a curiosity in North America. To a plethora of technical and interpretive problems has now been added the near-prohibitive consideration of radioisotope disposal with its attendant regulatory and cost considerations.

Because of these manifold problems in establishing a clear diagnosis of B12 deficiency, some make the ultimate nihilistic argument against approaching vitamin B12 deficiency as an exercise in diagnostic acumen. Since B12 does no harm and is relatively inexpensive (years of monthly B12 shots cost less than a serum methylmalonate), then why not simply treat a patient with suspected B12 deficiency? Academicians may cringe, but the pragmatic practitioner can shrug and turn to the next question: how to treat?

Traditionally, treatment regimens have been parenteral B12. Lifelong monthly intramuscular injections of 1,000 mg cyanocobalamin following an initial “topping up” with biweekly, (X 2 weeks) then weekly (X 4 weeks) of the same dose, or minor variations on this theme, remain the basic approach to managing a patient with confirmed B12 deficiency. The parenteral route of treatment derives from the knowledge that B12 deficiency is almost invariably the result of malabsorption. Consequently, oral replacement has been eschewed.

Caveat

photo and quote There is, however, an important qualifier to this dictum: some small decrement (perhaps 1%) of an oral dose of B12 is absorbed through passive diffusion, completely independent of the elegant and efficient mechanism of intrinsic factor-mediated absorption of the vitamin through receptor-mediated endocytosis. Inefficient as the passive absorptive mechanism is, with a large enough dose of, say, 1 mg to 2 mg daily, 10 mg to 20 mg of the precious nutrient can be absorbed, even without a functioning stomach. This is more than enough to satisfy the adult daily requirement for the vitamin of 2 mg to 3 mg recommended by the Institute of Medicine report on B-vitamins. The only problem is one of compliance. People, particularly older people, forget to take their pills.

The elderly are, undoubtedly, the target population most susceptible to developing B12 deficiency. The aging stomach inexorably loses its capacity to produce acid and pepsinogen, necessary to release B12 from its intimate embrace by food proteins. There is also failure to secrete intrinsic factor, the molecular chaperone for B12 as it traverses its perilous course down the intestinal tract and before it reaches safe haven in the terminal ileum.

With increasing age, food-B12 malabsorption sets in. This is aggravated in some by the ravages of Helicobactep. pylori and in a small minority with the predisposition for developing self-destructive autoantibodies, classical pernicious anemia.

Roughly 2% of the population over age 65 have pernicious anemia – a million people in the United States. Ten times as many have food-B12 malabsorption. The morbidity cost is difficult to estimate in terms of neurological and cardiovascular risk (from hyperhomocysteinemia). A looming problem is the potential hazard resulting from folic acid fortification of the food supply in the United States and elsewhere. Designed to prevent neural tube pregnancies, folic acid fortification poses the potential risk of masking the hematological complications of B12 deficiency in the elderly.

As a consequence, they remain vulnerable to progressive and possibly irreversible neurological damage.