Dr. Ron’s Research Review – November 16, 2011

This week’s research review: Diagnosing and Treating B12 Deficiency

Guidelines for diagnosing and treating cobalamin (B12) deficiency were published in Blood by Ralph Carmel, MD. (Carmel 2008)

I always begin with intramuscular cobalamin to bypass potential barriers to immediate effectiveness. A single injection, whether as an experimental 1- to 2-µg dose or the more usual 1000-µg dose, suffices to correct the anemia. The 1000-µg dose also begins repletion of stores (up to 150-µg is retained from that injection by most patients).

 Cyanocobalamin, a pharmacologic preparation requiring conversion to metabolically active cobalamins, is the form commonly available in the United States, whereas hydroxocobalamin, which requires less frequent injections, is preferred in parts of Europe. Methylcobalamin, a light-sensitive form, is rarely used.

The daily requirement for cobalamin is so small relative to stores that deficiency typically takes years to develop in adults and only infrequently reaches the depletion point necessary for clinical consequences.

Whether given parenterally or orally, 1000-µg doses are needed to accommodate wide variations in diffusion and retention among patients.1 The variations cannot be predicted but tend to remain consistent. Some patients describe feeling tired before the month is up; its attribution to “fast clearing” of cobalamin requires further study. Injection intervals can be titrated or oral doses can be used as a bridge. I usually provide 8 to 10 injections over the first 2 to 3 months before considering monthly injections. Hydroxocobalamin injections can be spaced at twice the interval for cyanocobalamin.

Some patients discontinue cobalamin once they feel better, often because they misunderstand the nature of their disease, but sometimes it is the physician who fails to think beyond the first shot. Relapse in patients with IF-related malabsorption occurs within 1 to 2 years.

Either MMA or homocysteine is a better monitoring tool than serum cobalamin and provides early warning of relapse if measured annually.

Unfortunately, NHANES stopped measuring vitamin B-12-related biomarkers after 2006. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. The use of serum vitamin B-12 and plasma methylmalonic acid would provide continuity with past NHANES.  (Yetley, Pfeiffer et al. 2011) (Yetley, Coates et al. 2011)


Abstracts

How I treat cobalamin (vitamin B12) deficiency

            (Carmel 2008) Download

The challenges in medical management of cobalamin deficiency lie in attention to the unique pathophysiology that underlies cobalamin deficiency, more than in the mechanics of therapy. The central physiologic principles are that clinically important deficiency is more likely to occur (and progress) when intrinsic factor-driven absorption fails than when diet is poor and that most causes take years to produce clinically obvious deficiency. Transient defects have little clinical impact. The key management principle is the importance of follow-up, which also requires knowing how the deficiency arose. The virtues of these principles are not always fully appreciated. Recent developments have made diagnosis and management more difficult by diminishing the ability to determine cobalamin absorption status. Clinicians must also grapple with premature medicalization of isolated, mild biochemical changes that added many asymptomatic cases of still undetermined medical relevance to their caseload, often expanded by inflated cobalamin level criteria. The potential for misattribution of cobalamin-unrelated presentations to nongermane cobalamin and metabolite abnormalities has grown. Pathophysiologically based management requires systematic attention to each of its individual components: correctly diagnosing cobalamin deficiency, reversing it, defining its underlying cause, preventing relapse, managing the underlying disorder and its complications, and educating the patient.

Biomarkers of vitamin B-12 status in NHANES: a roundtable summary

            (Yetley, Pfeiffer et al. 2011) Download

A roundtable to discuss the measurement of vitamin B-12 (cobalamin) status biomarkers in NHANES took place in July 2010. NHANES stopped measuring vitamin B-12-related biomarkers after 2006. The roundtable reviewed 3 biomarkers of vitamin B-12 status used in past NHANES--serum vitamin B-12, methylmalonic acid (MMA), and total homocysteine (tHcy)--and discussed the potential utility of measuring holotranscobalamin (holoTC) for future NHANES. The roundtable focused on public health considerations and the quality of the measurement procedures and reference methods and materials that past NHANES used or that are available for future NHANES. Roundtable members supported reinstating vitamin B-12 status measures in NHANES. They noted evolving concerns and uncertainties regarding whether subclinical (mild, asymptomatic) vitamin B-12 deficiency is a public health concern. They identified the need for evidence from clinical trials to address causal relations between subclinical vitamin B-12 deficiency and adverse health outcomes as well as appropriate cutoffs for interpreting vitamin B-12-related biomarkers. They agreed that problems with sensitivity and specificity of individual biomarkers underscore the need for including at least one biomarker of circulating vitamin B-12 (serum vitamin B-12 or holoTC) and one functional biomarker (MMA or tHcy) in NHANES. The inclusion of both serum vitamin B-12 and plasma MMA, which have been associated with cognitive dysfunction and anemia in NHANES and in other population-based studies, was preferable to provide continuity with past NHANES. Reliable measurement procedures are available, and National Institute of Standards and Technology reference materials are available or in development for serum vitamin B-12 and MMA.

Overview of a roundtable on NHANES monitoring of biomarkers of folate and vitamin B-12 status: measurement procedure issues

            (Yetley, Coates et al. 2011) Download

A roundtable dialogue to discuss "NHANES Monitoring of Biomarkers of Folate and Vitamin B-12 Status" took place in July 2010. This article provides an overview of the meeting and this supplement issue. Although the focus of the roundtable dialogue was on the measurement of folate and vitamin B-12 status biomarkers in NHANES, this article also describes the relevance and importance of these issues for clinical and research laboratories. The roundtable identified the microbiological assay (MA) as the gold standard for measurement of serum and red blood cell folate concentrations. The roundtable noted that differences in results between the Bio-Rad Quantaphase II procedure (Bio-Rad Laboratories, Hercules, CA) that NHANES 1991-1994 and 1999-2006 used and the MA that NHANES 2007-2010 used will require adjustment equations to evaluate time trends. The roundtable found that the close agreement between the serum results for the MA and liquid chromatography-tandem mass spectrometry (LC-MS/MS) procedures supported the conversion to LC-MS/MS for serum folate in future NHANES. The roundtable recognized the uncertainty about whether subclinical vitamin B-12 deficiency is a public health concern but encouraged reinstatement of at least one circulating vitamin B-12 measure and one functional vitamin B-12 status measure in future NHANES. The use of serum vitamin B-12 and plasma methylmalonic acid would provide continuity with past NHANES. The roundtable supported the continued use of the National Institute of Standards and Technology (NIST) reference materials in NHANES biomarker analyses and the further development of additional reference materials by the NIST.


References

Carmel, R. (2008). "How I treat cobalamin (vitamin B12) deficiency." Blood 112(6): 2214-21.

Yetley, E. A., P. M. Coates, et al. (2011). "Overview of a roundtable on NHANES monitoring of biomarkers of folate and vitamin B-12 status: measurement procedure issues." Am J Clin Nutr 94(1): 297S-302S.

Yetley, E. A., C. M. Pfeiffer, et al. (2011). "Biomarkers of vitamin B-12 status in NHANES: a roundtable summary." Am J Clin Nutr 94(1): 313S-321S.