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Metformin-induced Vitamin B12 Deficiency Presenting as a Peripheral Neuropathy

Posted: Tuesday, May 04, 2010

Chronic metformin use results in vitamin B12 deficiency in 30% of patients. Exhaustion of vitamin B12 stores usually occurs after twelve to fifteen years of absolute vitamin B12 deficiency.

Vitamin B12 deficiency, which may present without anemia and as a peripheral neuropathy, is often misdiagnosed as diabetic neuropathy, although the clinical findings are usually different. Failure to diagnose the cause of the neuropathy will result in progression of central and/or peripheral neuronal damage which can be arrested but not reversed with vitamin B12 replacement.

Metformin has been available in the United States for approximately fifteen years. Vitamin B12 deficiency, which may present without anemia and as a peripheral neuropathy, is often misdiagnosed as diabetic neuropathy, although the clinical findings are usually different. Failure to diagnose the cause of the neuropathy will result in progression of central and/or peripheral neuronal damage which can be arrested but not reversed with vitamin B12 replacement.

Metformin is now recommended as initial therapy for Type 2 diabetes. Because of this, metformin used either as monotherapy or in combination with other antidiabetic oral agents and insulin has become the most widely utilized antidiabetic oral agent.

Metformin's best known and most feared side effect, i.e. lactic acidosis almost never occurs if metformin is not used inappropriately. The common side effects of metformin are gastrointestinal and can be overcome by initiating metformin therapy at a lower dose and slowly increasing the dose, by giving metformin after meals, or by utilizing a slow-release metformin preparation.

However, a common, potentially damaging, and well-documented complication of metformin -- vitamin B12 malabsorption -- is poorly recognized and not screened for or treated prophylactically by the majority of physicians who prescribe metformin. This is unfortunate since a correctable cause of irreversible damage to the central and peripheral nervous system may be overlooked.

That malabsorption of vitamin B12 occurs with metformin in 30% of diabetic subjects has been recognized for many years. This potentially debilitating side-effect of metformin was not well recognized in the United States when metformin was first approved in 1994 or when the use of metformin increased dramatically following the United Kingdom Prospective Diabetes Study (UKPDS) study, which showed that metformin decreased diabetes-related chronic complications (including cardiovascular complications) and death in overweight subjects. Vitamin B12 malabsorption was not well recognized when both the American Diabetes Association and the European Association for the Study of Diabetes recommended metformin as first line therapy for Type 2 diabetes. It was not until 2006 that the increased risk of vitamin B12 deficiency with metformin was rediscovered through a case-control study of Chinese patients which showed a correlation between the dose and duration of metformin use with vitamin B12 deficiency.

While vitamin B12 deficiency is associated with a macrocytic and megaloblastic anemia, the anemia is often preceded by the development of neuropathy. While the anemia of vitamin B12 deficiency is reversible, the progress of the neuropathy is only arrested and not reversed with initiation of vitamin B12 therapy. In the nervous system, vitamin B12 deficiency causes demyelination followed by axonal degeneration and neuronal death -- not only in peripheral nerves but also in the posterior and lateral columns of the spinal cord and the cerebrum. Clinically, the earliest manifestations are numbness and paresthesias in the feet, which, unless the vitamin B12 deficiency is corrected, can be followed by weakness, ataxia, sphincter disturbance, and changes in mental status.

The mechanism of vitamin B12 deficiency with metformin is undoubtedly due to malabsorption of vitamin B12 at its absorption site in the terminal ileum. Initially, it was believed that metformin caused proliferation of bacteria in the small bowel either due to an effect on intestinal motility or an increased intestinal glucose level. However, the current and more likely explanation for metformin-induced vitamin B12 malabsorption and deficiency is that metformin has an effect on calcium-dependent membrane action in the terminal ileum. Absorption of the vitamin B12-intrinsic factor complex is calcium dependent and metformin interferes with this absorption. In support of this hypothesis is evidence that dietary calcium supplementation reverses metformin-induced vitamin B12 malabsorption.

The risk of adverse effects from metformin-induced vitamin B12 malabsorption will increase with the time of exposure to metformin since, after partial gastrectomy and removal of intrinsic factor, it takes twelve to fifteen years for vitamin B12 levels to become deficient. Therefore, in those patients who have been on long-term metformin, an annual vitamin B12 level should be obtained. Perhaps a more practical and cost-effective approach would be to give every patient on metformin an annual 1000 microgram injection of vitamin B12 which is sufficient to cover vitamin B12 needs for at least a year. An alternative therapy would be to prophylactically administer calcium carbonate (1.2 grams daily) which may also correct the "loose stools" associated with metformin therapy.
Practice Pearls:

    * Thirty percent of patients on metformin malabsorb vitamin B12.
    * Vitamin B12 deficiency can present as reversible megaloblastic anemia or nonreversible central and/or peripheral neuronal lesions.
    * With an absolute vitamin B12 deficiency, it takes twelve to fifteen years to totally deplete pre-existing vitamin B12 stores.
    * Since metformin has been available for fifteen years in the United States, we may be approaching an epidemic of metformin-induced vitamin B12 deficiency.
    * Metformin-induced vitamin B12 deficiency could be avoided with annual estimates of serum vitamin B12 levels or an annual vitamin B12 injection.

References:

Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2008;31:173–175.                                                                                                                                                    

Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycaemia in Type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193–203.

Source: http://www.diabetesincontrol.com/index.php?option=com_content&view=article&id=9254&catid=53&Itemid=8, David S.H. Bell, MD; Southside Endocrinology and Division of Diabetes, Endocrinology, and Metabolism, University of Alabama Medical School, Birmingham, AL, "Metformin-induced Vitamin B12 Deficiency Presenting as a Peripheral Neuropathy," South Med J. 2010;103(3):265-267.

 
 
 
 
 
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