The Disappearance of Cobalamin Absorption Testing: A Critical Diagnostic Loss

Abstract

An appreciation of the physiological peculiarities of cobalamin (vitamin B-12) is indispensable to understanding cobalamin deficiency. Almost alone among B vitamins, cobalamin deficiency is very often linked to failures of absorption (1,2). Adults rarely become symptomatic or anemic just because of poor dietary intake. One peculiarity is how tightly the complicated, high-affinity binding proteinand receptor-dependent absorptive process built around gastric intrinsic factor (IF), and around other binding proteins throughout the body, controls every aspect of cobalamin transport and transfer (2). The IF system assures both delivery from limited animal-derived dietary sources and reabsorption of biliary cobalamin, partially explaining the often muted clinical impact of poor intake. Yet the saturable system’s own somewhat limited capacity and subtly restrictive, even exclusionary features (perhaps meant to exclude nonfunctional cobalamin analogs) also create inefficiencies that are not always obvious. Barely .1 mg of cobalamin is made available from most meals no matter their cobalamin content, and then only if the IF-mediated process functions properly (2,3). The greatest weakness, however, also lies in the heavy dependence of absorption, and thus cobalamin status, on the IFbased system, whose sole back-up, a nonsaturable but dismally inefficient carrier-free diffusion, can transport only 1% of presented cobalamin. Should IF secretion be lost (‘‘pernicious anemia’’) or its delivery of cobalamin to IF receptors fail (intestinal malabsorption), it cannot be compensated dietarily except with cobalamin intake so massive as to be unavailable in nature. As much as 1000 mg would need to be ingested daily to compensate for the failure of both absorption and enterohepatic reabsorption by the IF system, but very few food items contain .1–2 mg/ 100 gm portion (3). The carrier-mediated and carrier-free absorption processes of most other B vitamins, such as folate, are more effective. An important saving grace derives from another peculiarity of cobalamin, its slow turnover. Except for rare defects of cellular utilization, whatever causes cobalamin deficiency in adults must persist for several years to deplete body stores (which exceed daily intake 1000-fold) to the point of clinical consequences. Many potential disturbances, whether malabsorptive or not, are too transitory to produce clinical cobalamin deficiency or often even subclinical deficiency, which consists of biochemical changes without apparent clinical consequences (2,4). Absorption testing Because a clinical diagnosis of cobalamin deficiency, with hematologic or neurologic changes, implies the presence of long-standing gastrointestinal disease until proven otherwise (1), absorption testing has always been an essential task for clinicians and investigators. The traditional Schilling test, designed in 1953, identifies malabsorption by the poor urinary excretion of an orally administered cobalamin dose. When repeated along with a dose of IF, the test also distinguishes between gastric and intestinal defects. If malabsorptive processes stay undiagnosed, management decisions and vitamin replacement strategies tend to be haphazard and incomplete (Table 1). In 1973, Doscherholmen and Swaim (5) expanded the scope of malabsorption to include food-cobalamin malabsorption (FCM), an inability to release food-bound cobalamin and make it available to gastric IF. FCM cannot be diagnosed with the Schilling test, whose radiolabeled test dose of free cobalamin bypasses the need to release food-bound cobalamin. Work from many laboratories in the 1980s and early 1990s established that FCM was associated with 30–50% of all low cobalamin levels, a frequency at least 10-fold that of the more clinically ominous malabsorption of free cobalamin that occurs when gastric IF secretion or its uptake by intestinal IF receptors fails (6). However, the individual impact of FCM on cobalamin status is typically milder and more delayed. That is because FCM affects only a preparatory step and thus compromises rather than abrogates the final IF-mediated steps of absorption (and presumably does not impair reabsorption of biliary cobalamin). Pernicious anemia, the absence of IF, was originally lethal and even now carries the risk of neurologic deterioration if not properly diagnosed and treated (2,3), whereas most persons with FCM have asymptomatic, subclinical cobalamin deficiency or sometimes no deficiency at all (6,7). Numerous studies explored absorption testing methods and the mechanisms of FCM, as reviewed elsewhere (6). It became evident that the mechanisms were more diverse than initially suspected, that FCM does not always require atrophic gastritis and achlorhydria, and that our understanding of FCM and its implications was incomplete (5–7). As one poorly understood example, the intriguing reversal of FCM after antibiotic treatment has been attributed separately to Helicobacter pylori and facultative anaerobes, although neither organism’s role was identified or directly proven (4,7–10). FCM testing never became clinically available and much work remains to be done (6,7). 1 Author disclosures: R. Carmel, no conflicts of interest. * To whom correspondence should be addressed. E-mail: rac9001@nyp.org.