To the Editor:
Although massive doses of oral cobalamin seem to work well in a research setting with compliant, motivated patients, the study by Kuzminski et al1 is misleading in important ways. The question surrounding oral therapy has always concerned its effectiveness in patients with defective absorption. Unfortunately, that is not who was tested by the investigators. Almost certainly, 12 of their 18 patients treated orally had normal absorption of cobalamin from pills. Patients with dietary cobalamin deficiency, atrophic gastritis, or acid-suppressive therapy have adequate intrinsic factor-mediated absorption, with the latter two unable to absorb only food-bound cobalamin. All 12 patients, and certainly those with a presumed dietary basis for deficiency, would probably have responded even to 5 μg pills and, thus, provide no useful information.
Moreover, the higher serum cobalamin levels and lower homocysteine and methylmalonic acid levels at the end of 4 months in the orally treated patients seem explainable more by the dose schedule than by the route. The response curves for the first month of therapy, when injections were administered weekly or more often, show equal or better response in the patients treated by injection. Only later, when injection frequency was reduced to once monthly, while massive oral doses continued daily, did the response to oral treatment seem to overtake that of parenteral treatment.
In fact, the 4-month serum values at the end of the study are themselves misleading. By then, the parenterally treated patients had been left untreated for 30 days (the last day of injection was day 90), whereas the orally treated patients continued taking their pills up to the day of final testing.
The study only proved that patients, most of whom had unimpaired absorption of cobalamin in pill form, will respond to large doses taken daily. Great caution must be exercised in extrapolating this to patients with defective intrinsic factor-mediated absorption, and especially so in the real world, where life-long compliant ingestion of huge doses every day is unlikely.
Response
Dr Carmel fails to appreciate the well-established fact, which is discussed and referenced extensively in our report1-1 and elsewhere,1-2 that oral cobalamin at a dose of ≥1 mg/d is effective therapy for all causes of cobalamin deficiency, because approximately 1% of oral cobalamin is absorbed by diffusion regardless of the functional status of the gastrointestinal tract. For example, in a comprehensive Swedish study1-3 published 30 years ago, 64 patients with well-documented cobalamin deficiency (including 55 with lack of intrinsic factor due to pernicious anemia, 4 with ileal resection, and 1 with total gastrectomy) all had sustained neurologic and hematologic remissions when treated with oral cobalamin at 1 mg/d and followed for up to 5 years (61 of 64 for >3 years). In addition, all 64 patients maintained normal serum cobalamin levels. Interestingly, studies of this kind have not been performed for various parenteral regimens, although we are not aware of evidence that incomplete neurologic and hematologic remissions occur with the most commonly used parenteral regimen, in which 1 mg of cobalamin is administered intramuscularly on a monthly basis.
Our study was also performed in patients with well-documented cobalamin deficiency1-1 and is the first randomized, controlled trial of oral cobalamin (2 mg/d) versus parenteral cobalamin (1 mg administered intramuscularly on 7 occasions in the first month and once monthly thereafter). As expected, excellent and indistinguishable neurologic and hematologic responses were observed in both groups and all (18/18) evaluable patients in the oral group had normal serum cobalamin levels at 1, 2, and 4 months. Serum cobalamin levels were normal in all (15/15) evaluable patients in the parenteral group at 1 month, but 3 of 15 and 4 of 14 evaluable patients had low values at 2 and 4 months, respectively. Elevated levels of serum methylmalonic acid and total homocysteine, which are the most sensitive indicators of cobalamin status,1-4,1-5 decreased markedly in both groups, and the mean values were not significantly different at 1 month. However, at 4 months, the mean values for serum methylmalonic acid and homocysteine were lower in the oral group, and the difference was statistically significant for methylmalonic acid. These differences may become even greater at treatment times greater than 4 months (both regimens must be continued for life in almost every patient) and may be very important clinically, because serum total homocysteine is an independent graded risk factor without threshold for all forms of vascular disease1-6 and appears to be a particularly strong predictor of cardiovascular mortality.1-7 Metabolic control could be improved in the maintenance portion of the parenteral regimen by administering weekly or biweekly injections, but this would be burdensome.
Dr Carmel also fails to appreciate the fact, which is also discussed and referenced extensively in our report1-1 and elsewhere,1-2 that compliance is a comparable problem for both oral and parenteral cobalamin regimens, because most cobalamin injections today are administered in nonmedical settings. Compliance is easily assessed in patients receiving oral therapy, because compliant patients will have normal serum cobalamin levels.1-1,1-3 This is not true with respect to the parenteral regimen, where approximately one quarter or more of compliant patients will still have low serum cobalamin levels.1-1
Dr Carmel refers to 2 mg of cobalamin as a “large,” “huge,” and “massive” amount, but it is important to note that 2 mg of cobalamin readily fits into a single small tablet or capsule. This results in a simple and convenient treatment regimen that is also inexpensive, free of side effects, and cost effective.1-2
In summary, we believe that a number of studies, including ours, have demonstrated that oral cobalamin therapy is safe and effective for all causes of cobalamin deficiency and is the treatment of choice for most patients. Oral cobalamin therapy has been used commonly and success-fully in Sweden for many years,1-2 and its use is already increasing in the United States.1-8
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