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Letters to the Editor |
Department of Medicine, New York Methodist Hospital, 506 Sixth Street, Brooklyn, NY 11215 and Weill Medical College of Cornell University, New York, NY, Fax 718-780-6333, e-mail rac9001{at}nyp.org
To the Editor:
Based on analyses in cobalamin-deficient patients before and after therapy, Morkbak and colleagues (1) confirm our finding that cobalamin concentrations correlate with haptocorrin (HC; transcobalamin I) (2) but propose that HC concentrations are regulated by cobalamin status rather than being genetically determined, which they mistake as my view. In fact, no exclusive theory of HC regulation is likely. Many things affect HC synthesis, release, and clearance, and HC concentrations are altered in many varied disorders (3). Moreover, cobalamin changes often follow, rather than precede, such HC changes because HC’s long half-life disproportionately influences retention of its attached cobalamin (holo-HC). In addition, highly variable release of leukocytic apo-HC (cobalamin-free HC) frequently occurs whenever serum is tested instead of plasma (4); critical effects of this artifact on Morkbak’s vegan serum data cannot be dismissed merely because leukocyte counts did not change after therapy.
Statistical associations between cobalamin and HC concentrations require no complicated theories. The 75% or greater identity between circulating cobalamin and holo-HC, which in turn also constitutes 80% or more of total HC, guarantees significant associations and renders most alternative interpretations speculative. Nor should too much be made of the probably nonindependent statistical associations of methylmalonic acid and homocysteine with HC, given HC’s confounding near-identity with cobalamin.
Morkbak’s claims that HC was "decreased" in cobalamin deficiency and that cobalamin deficiency may explain much HC deficiency are undercut by her data: most patients with low cobalamin (<200 pmol/L) actually had total HC concentrations well within the reference interval (>240 pmol/L). Closer study of those few exceptions with total HC <240 pmol/L [see Fig. 1A in (1)] might have proved enlightening; postreatment values in Table 1 of (1) imply that some very low HC concentrations persisted after cobalamin therapy, casting doubt on their relation to cobalamin status. Inattention to individually important patients, especially those who do not quite conform to group expectations, is unfortunately commonplace in contemporary studies of cobalamin status, which too often focus exclusively on overall group statistics.
Further weakening Morkbak’s thesis is the likelihood that the disparity in posttherapy HC changes between cobalamin-deficient and nondeficient patients had much more to do with the grossly disparate cobalamin regimens the 3 study groups received than with differences in their cobalamin status. Excessive cobalamin doses were given to the cobalamin-deficient vegan group (5 mg orally daily) and the group suspected of deficiency (1 mg intramuscularly every week). As a result, mean cobalamin concentrations rose massively from 97 to 1016 pmol/L in the first group (947% increase) and from 281 to 960 pmol/L in the second (242% increase). Compare these with the nondeficient group, who received only 0.4 mg orally daily and whose mean cobalamin therefore rose just 51%, from 350 to 527 pmol/L. Small wonder that the first group showed significant increases in serum holo-HC and total HC—holo-HC because of apo-HC saturation by massive cobalamin doses and total HC possibly from leukocytic HC release because serum was tested instead of plasma—and the second group showed only the holo-HC increase in plasma as massive cobalamin injections converted apo-HC to holo-HC, whereas the third group showed neither plasma HC saturation nor increase because relatively modest amounts of new cobalamin entered the bloodstream. Nor do HC data stratified by MMA response to therapy prove the claimed influence of metabolic cobalamin status on HC concentrations. The 2 groups whose MMA concentrations responded to therapy were those also confounded by massive cobalamin doses and serum testing, unlike the nonresponsive controls. Proof of HC dependence on cobalamin status awaits studies with uniform treatment regimens and uniform testing of plasma.
To dispel potential diagnostic confusion and Morkbak’s concerns about assuming HC deficiency simply from low circulating cobalamin concentrations, the apparently underappreciated diagnostic criteria for primary HC deficiency (as fulfilled in all our published cases save one unusually inaccessible subgroup) bear reemphasis: low HC and cobalamin along with absence of clinical, metabolic, or malabsorptive signs of cobalamin deficiency are required. These and additional published features, including nonresponsiveness of HC to cobalamin therapy, established that the low cobalamin concentrations in such patients are caused by HC deficiency, not the other way around (5)(6). Many cases also display familial patterns, but we have cautioned that some may not be genetic in origin (6).
Although low cobalamin caused by cobalamin deficiency may occasionally be accompanied by low total HC, Morkbak’s Fig. 1A supports my report that only 5% of patients with proven cobalamin deficiency had low HC concentrations (6). Subnormal total HC is clearly the exception rather than the rule in cobalamin deficiency. Because primary HC deficiency may be far from rare (6), diagnostic care is needed to avoid confusing its low cobalamin concentrations with those of cobalamin deficiency. The clinical ramifications are important.
References
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