This month, Marilyn Telen, MD, discusses management of a patient with long-term B12 deficiency.
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I have a 42-year-old female patient who has had very low B12 levels for at least a decade. This is the first time she has seen a hematologist. She does not have persistent anemia or red cell macrocytosis. She has no neurologic symptoms. Her methylmalonic acid levels and B12-binding capacity have been normal. She has had a lot of gastrointestinal issues and, at various times, small bowel Crohn disease as well as small intestine bacterial overgrowth, which have required therapy. At this time, she is not on any treatment other than dietary restrictions and desipramine. Serology for pernicious anemia and bowel biopsies looking for celiac disease have been normal.
In the past her B12 level has increased moderately when given supplementation, but she does not tolerate parenteral, oral, or nasal supplementation so stopped them. As far as she knows, there is no family history of B12 issues. My best guess is that she has some form of B12-binding protein abnormality that is not of any functional consequence. I tried to find a way to assay for transcobalamin 1 but have not had success. Any suggestions regarding further testing, if needed, or management are welcomed.
A longstanding "low" B12 level in the absence of signs and symptoms of B12 deficiency presents an interesting dilemma. Methylmalonic acid (MMA) level and B12 binding capacity (unsaturated transcobalamin) levels that are not elevated support the conclusion that the patient is not functionally B12 deficient. That she does not have anemia or even macrocytosis also suggests that your patient is not functionally B12 deficient, as confirmed by her normal MMA. In general, MMA is a much more reliable test for functional B12 deficiency than a B12 level. You could also get a homocysteine level if you want to reassure your patient further. The negative personal or family history of pernicious anemia or related autoimmune disorders also fits with the conclusion that your patient is not truly B12 deficient.
There are a variety of B12 assays that use different methodologies, but none have proven entirely reliable clinically, although they tend to correlate with each other. Thus, a normal serum B12 concentration does not reliably rule out a functional B12 deficiency, the assessment of which is better served by homocysteine or MMA measurement. Conversely, your patient's results imply that low levels also do not entirely reliably indicate true functional B12 deficiency.
I doubt that your patient has an inherited abnormality of transcobalamin, given that she seems relatively healthy and has a normal unsaturated transcobalamin level. Most transcobalamin deficiency is caused by mutations in the TCN2 (transcobalamin 2) gene and lead to a complete or near-complete deficiency of transcobalamin. Most patients with inherited transcobalamin disorders are detected due to anemia and even failure to thrive when they are quite young. All such patients appear to have low results in assays of B12-binding capacity. There are some links to available testing for transcobalamin 2 (see the NIH Genetics and Rare Diseases Information Center), but I do not think such testing is indicated for your patient.
All that being said, inability to tolerate B12 supplements of any sort is rare. B12 is, in my experience, among the best-tolerated medicines I have ever prescribed. However, some people may experience adverse reactions, including headache, gastrointestinal distress (nausea, diarrhea), pruritus, and nervousness or anxiety. It would be reasonable to encourage her to eat B12-rich foods, such as fish, meat, poultry, eggs, milk, and milk products. Continued surveillance for functional B12 deficiency (such as annual MMA measurement) might also be reasonable, given the sometimes serious consequences of true B12 deficiency.
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