Biomarkers of cobalamin (vitamin B-12) status in the epidemiologic setting: a critical overview of context, applications, and performance characteristics of cobalamin, methylmalonic acid, and holotranscobalamin II

Abstract

Cobalamin deficiency is relatively common, but the great majority of cases in epidemiologic surveys have subclinical cobalamin deficiency (SCCD), not classical clinical deficiency. Because SCCD has no known clinical expression, its diagnosis depends solely on biochemical biomarkers, whose optimal application becomes crucial yet remains unsettled. This review critically examines the current diagnostic concepts, tools, and interpretations. Their exploration begins with understanding that SCCD differs from clinical deficiency not just in degree of deficiency but in fundamental pathophysiology, causes, likelihood and rate of progression, and known health risks (the causation of which by SCCD awaits proof by randomized clinical trials). Conclusions from SCCD data, therefore, often may not apply to clinical deficiency and vice versa. Although many investigators view cobalamin testing as unreliable, cobalamin, like all diagnostic biomarkers, performs satisfactorily in clinical deficiency but less well in SCCD. The lack of a diagnostic gold standard limits the ability to weigh the performance characteristics of metabolic biomarkers such as methylmalonic acid (MMA) and holotranscobalamin II, whose specificities remain incompletely defined outside their relations to each other. Variable cutoff selections affect diagnostic conclusions heavily and need to be much better rationalized. The maximization of reliability and specificity of diagnosis is far more important today than the identification of ever-earlier stages of SCCD. The limitations of all current biomarkers make the combination of ≥2 test result abnormalities, such as cobalamin and MMA, the most reliable approach to diagnosing deficiency in the research setting; reliance on one test alone courts frequent misdiagnosis. Much work remains to be done.

FIGURE 1.

Schematic illustration of the diverse courses that cobalamin deficiency states may follow, depending on their underlying causes. The fields represent, from top to bottom, the normal cobalamin state, subclinical deficiency (mild metabolic abnormalities without clinical signs or symptoms), and clinical deficiency (mild and then progressively more severe hematologic and/or neurologic signs and symptoms). The thick arrow (upper left) marks the onset of gradual cobalamin depletion whose progressions are arbitrarily represented as linear. Line 1: the depletion produced by severe, permanent malabsorption typified by pernicious anemia. Line 2: the less complete, less inexorable disruption of cobalamin balance (eg, dietary insufficiency or a malabsorption limited to food-bound cobalamin). Based on various published direct or indirect (but nonsystematic) observations, the diagram posits a slower course of unknown duration that also increases the time spent transiting through subclinical cobalamin deficiency (SCCD), which may explain why SCCD is more common. At some point, this course may (a) eventually progress sufficiently to produce clinical, symptomatic deficiency, (b) remit completely for reasons that may or may not be known, (c) accelerate and reach clinical deficiency more quickly (eg, chronic gastritis transforms into pernicious anemia as intrinsic factor secretion disappears), or (d) fluctuate indefinitely between normal and mildly subclinical deficiency states. Modified and expanded from reference .

FIGURE 2.

The influence of higher cutoffs for serum cobalamin concentrations on the frequency of true deficiency in the cases labeled as “deficient” by each cutoff. True deficiency was defined by each study's abnormal methylmalonic acid and homocysteine results. Results of 4 surveys with metabolic data that provided the frequencies (or permitted their calculations) are shown here. This figure summarizes the cobalamin concentrations and cutoffs in ng/L ranges in the top line and in pmol/L in smaller font in the second line (1 ng = 0.738 pmol), which closely approximate the different points in all 4 studies. The arrowheads that bracket the frequency rates of metabolically defined deficiency in the center box (201–350 ng/L) delineate the relevant ranges of cobalamin values. The further data breakdowns available in reference 23 provide more discrete subset rates (italicized in smaller font). ¹Reference 47, ²Reference 23, ³Reference 46, ⁴Reference 24.