Ralph Carmel

Cobalamin (vitamin B₁₂) assays have been central to the diagnosis of clinical cobalamin deficiency such as pernicious anemia because the diagnostic sensitivities of older assays have been approximately 95%.¹ However, the competitive-binding luminescence assay (CBLA) replaced older microbiologic and radioisotope-dilution assays during the past decade. Few studies have compared these methods, and cobalamin CBLA has received less-focused scrutiny than older methods have received in the past. In 2000, a study showing that a CBLA failed to detect many low cobalamin levels² was disputed by the manufacturer.³ A later article attributed similar failure rates with the same CBLA to the diagnostic insensitivity of cobalamin to clinical cobalamin deficiency,⁴ without considering assay error.⁵ Since 2006, however, five case reports have identified false normal cobalamin levels in seven patients with pernicious anemia (see the Table in the Supplementary Appendix, available with the full text of this letter at NEJM.org), and some authors have proposed that CBLA failure to inactivate serum anti–intrinsic factor antibodies may be responsible.

This review focuses on recent developments and controversies in the diagnosis, consequences, and management of subclinical cobalamin deficiency (SCCD), which affects many elderly persons. Diagnosis of SCCD depends exclusively on biochemical tests whose individual limitations suggest that combinations of tests are needed, especially in epidemiologic research. The causes of SCCD are unknown in more than 60% of cases, which limits prognostic predictions and identification of health consequences. After years of varying, often inconclusive associations, new clinical trials suggest that homocysteine reduction by high doses of folic acid, cobalamin, and pyridoxine may reduce progression of structural brain changes and cognitive impairment, especially in predisposed individuals. The causative or contributory roles, if any, of SCCD itself in cognitive dysfunction require direct study. If the findings are confirmed, high-dose supplementation with three vitamins will probably be more effective than fortification of the diet. The story of SCCD, which is severalfold times more common in the elderly than clinical cobalamin deficiency but also differs from it in arising only infrequently from severe malabsorption and thus being less likely to progress, continues to evolve. Preventive benefits need to be confirmed and expanded, and will require fuller understanding of SCCD pathophysiology, natural history, and health consequences.

Cobalamin deficiency is relatively common, but the great majority of cases in epidemiologic surveys have subclinical cobalamin deficiency (SCCD), not

The success of folic acid fortification has generated consideration of similar fortification with cobalamin for its own sake but more so to mitigate possible neurologic risks from increased folate intake by cobalamin‐deficient persons. However, the folate model itself, the success of which was predicted by successful clinical trials and the known favorable facts of high folic acid bioavailability and the infrequency of folate malabsorption, may not apply to cobalamin fortification. Cobalamin bioavailability is more restricted than folic acid and is unfortunately poorest in persons deficient in cobalamin. Moreover, clinical trials to demonstrate actual health benefits of relevant oral doses have not yet been done in persons with mild subclinical deficiency, who are the only practical targets of cobalamin fortification because >94% of persons with clinically overt cobalamin deficiency have severe malabsorption and therefore cannot respond to normal fortification doses. However, it is only in the severely malabsorptive disorders, such as pernicious anemia, not subclinical deficiency, that neurologic deterioration following folic acid therapy has been described to date. It is still unknown whether mild deficiency states, which usually arise from normal absorption or only food‐bound cobalamin malabsorption, have real health consequences or how often they progress to overt clinical cobalamin deficiency. Reports of cognitive or other risks in the common subclinical deficiency state, although worrisome, have been inconsistent. Moreover, their observational nature proved neither causative connections nor documented health benefits. Extensive work, especially randomized clinical trials, must be done before mandatory dietary intervention on a national scale can be justified.

Summary: Transcobalamin (TC) I deficiency, like the function of TC I itself, is incompletely understood. It produces low serum cobalamin levels indistinguishable from those of true cobalamin deficiency. Diagnosis is especially elusive when TC I deficiency is mild. To provide new, more substantive definition, the TCN1 gene was examined in two well‐characterised families that included members with both severe and mild TC I deficiencies. A severely deficient proposita with undetectable TC I levels displayed compound heterozygosity for two mutations, each causing a premature stop codon. Relatives in both families who had mildly low or low‐normal plasma levels of TC I and cobalamin were heterozygous for one or the other of these mutations. An unrelated patient with mild TC I deficiency and unknown familial TC I and cobalamin status was then tested and found to be similarly heterozygous for one of the mutations. The two nonprivate mutations identify a genetic basis for TC I deficiency for the first time. They also add new approaches to studying mild and severe TC I deficiency and to reducing confusion of its low cobalamin levels with those of cobalamin deficiency and its often dramatically different prognosis and management.