The theory that megaloblastic anemia is not invariably present in clinically overt cobalamin deficiency was first proposed 90 years ago [1] and was roundly rejected at the time. It has since been well documented that anemia and macrocytosis are often absent in cobalamin deficiency [2-4]. Indeed, humans may be alone in the animal kingdom in developing any megaloblastic anemia at all when they are cobalamin deficient. Interestingly, the bone marrow cells of cobalamin-deficient monkeys regularly show metabolic evidence of cobalamin insufficiency and impaired thymidine synthesis with the deoxyuridine suppression test, even though the cells never assume a megaloblastic appearance [5]. This metabolic insufficiency at the cellular level has since been shown in bone marrow cells of those cobalamin-deficient humans who do not develop megaloblastic anemia [6-9], many of whom also lack neurologic symptoms.

These clinically silent deoxyuridine suppression abnormalities, which are reversible with cobalamin therapy [10], represent early deficiency in some of these patients; with time, the metabolic defect progresses and is translated into megaloblastic anemia. In other patients, however, such as the teenaged brothers with cblD mutation [6], clinical progression may be delayed or may not occur at all.

Metabolic evidence of subtle deficiency has since been shown to extend beyond the bone marrow cells [9, 11, 12]. Homocysteine methylation to methionine is often impaired enough to increase serum homocysteine levels in patients who have no overt clinical findings. Methylmalonyl CoA isomerization is also frequently impaired, and methylmalonic acid levels in the blood increase. These tests are useful as long as proper techniques are used and causes of falsely elevated metabolite levels, such as renal insufficiency, are not present.

Subtle, mild, or marginal cobalamin deficiency, thus defined as metabolic evidence of deficiency without the overt manifestations of anemia or neurologic disease, can now be shown by any of these metabolic tests [13], sometimes even without subnormal serum cobalamin levels [11]. Whether simply an early stage, a transient phenomenon, or a prolonged condition in its own right, subtle cobalamin deficiency is common. Certain groups or subpopulations, such as the elderly [11, 14], seem especially prone to it.

However, the metabolic abnormalities, although noteworthy, may not necessarily be clinically important or require treatment. It is this problem that Fata and colleagues [15] address in this issue. They show that elderly patients with low cobalamin levels have significantly worse antibody responses to pneumococcal polysaccharides than do controls with normal cobalamin levels. This intriguing observation parallels previous descriptions of impaired antibody responses in patients with more severe cobalamin deficiency. It suggests that subtle immunologic impairment may also occur in patients with subtle cobalamin deficiency.

As Fata and associates rightly point out, their findings are still preliminary. We do not know whether their patients with low cobalamin levels actually had metabolic evidence of deficiency; not all such patients do [9, 12]. We also do not know whether all of the controls with normal cobalamin levels were free of metabolic evidence of deficiency; again, this is not always the case [11]. Most importantly, we do not know whether mild deficiency caused the diminished antibody responses or simply coexisted with them. The antibody response in patients whose mild deficiency had been treated with cobalamin needs to be assessed.

If borne out, the findings of Fata and colleagues would provide a clinical reason for treating all mild or subtle cobalamin deficiencies that are diagnosed, at least in the elderly. To date, electroencephalographic, evoked potential and mild neurologic deficits such as neuropathy or memory impairment have been the only clinically relevant sequelae identified in some patients with subtle deficiency [12, 16]. Cobalamin therapy usually reverses these mild and often subclinical neurologic and electrophysiologic defects [12].

If we accept the plausible but unproven argument that biochemical abnormalities alone are not grounds for cobalamin therapy, under what circumstances should subtle cobalamin deficiency be treated? Three primary options are available: 1) Treatment can be withheld unless and until clinical abnormalities become obvious; 2) all patients found to have low cobalamin levels can be automatically treated; or 3) therapeutic decisions can be made after individual evaluation. Mild clinical defects, neurologic or otherwise, would be the clearest indication for treatment. Additional considerations could include any demonstration of underlying malabsorption of free [17] or food-bound cobalamin [18], because this would imply that the deficiency is not transient and will probably progress.

The first option is supported primarily by studies showing no benefits from treatment and no ill effects from withholding it [19, 20]. However, clinical assessment in these older studies was based on blood counts and other insensitive criteria. Subtle clinical dysfunction and subtle improvement could have escaped detection. Sometimes, patients themselves are unaware of mild neuropathy or mild memory deficits until they are treated [21].

The rationale for the second option is that cobalamin therapy is cheap and nontoxic, especially if given orally, and that it is simpler to treat everyone than to search for mild dysfunction. However, automatic treatment may encourage diagnostic attitudes that deemphasize the identification of underlying causes. Treatable underlying disorders or those that have important prognostic and other implications may be overlooked. Moreover, oral therapy may not be fully effective in the long run for patients who turn out to have underlying pernicious anemia, especially if the vitamin is taken haphazardly, as routine supplements often are. Oral therapy may also be excessive for persons who turn out to have no deficiency or only transient deficiency.

The third option most closely meets the clinical ideal of specific diagnosis as the basis for the most appropriate treatment of each individual person. This option, however, has several disadvantages. The clinical evaluation may be relatively costly, especially when one considers that millions of people are probably affected. An equally serious problem is that despite its high prevalence, we do not yet know enough about subtle deficiency, the most effective ways to evaluate it, what its clinical impact really is, and the benefits of therapy.

Indeed, the public health implications may extend beyond the usual clinical considerations. Other potential indications for therapy can be envisioned. One example is the issue of the possible cardiovascular benefits of decreasing the elevated homocysteine levels of cobalamin deficiency. Any subtle deficiency in young children raises developmental concerns. If fortification of the U.S. diet with folate is instituted to prevent some neural-tube defect births, cobalamin supplementation may need to be considered for all elderly persons and other persons who have increased risk for subtle cobalamin deficiency. We do not know whether the folate will render such persons susceptible to progression of the mild neurologic dysfunction that some of them have.

The answers to the many questions about subtle cobalamin deficiency are unknown. Given the high prevalence of the phenomenon, these questions must be addressed soon by careful studies. Projections from existing data suggest that millions of elderly Americans have low cobalamin levels or metabolic evidence of cobalamin deficiency.