The popularity of metformin has renewed interest in biguanide hypoglycemic agents. The association between phenformin and fatal lactic acidosis, particularly in patients with renal failure, led to the withdrawal of phenformin from the U.S. market in 1977 [1]. We describe a patient who recently died of phenformin-associated lactic acidosis.

A 64-year-old Haitian woman with diabetes, hypertension, and consequent renal insufficiency presented with profound lactic acidosis (pH, 7.15; bicarbonate level <5.0 mmol/L; lactic acid level, 54.5 mmol/L). She had been hospitalized on four previous occasions for unexplained severe lactic acidosis. After recovery from such an episode, muscle biopsy had disclosed normal structure on light and electron microscopy and normal in vitro mitochondrial enzymatic function (pyruvate dehydrogenase complex, dihydrolipoamide dehydrogenase, and electron transport chain complexes I to IV). Mitochondrial DNA contained no rearrangements or known point mutations.

During this final hospitalization, we discovered that the patient had been taking Bidiabe (Laboratori Guidotti, Pisa. Italy), a combination of chlorpropamide (125 mg) and phenformin hydrochloride (30 mg). Despite treatment with antibiotics, sodium bicarbonate, insulin, and hemodialysis, the patient died. The patient's serum phenformin concentration was 649 µg/L at admission and 42 µg/L at autopsy. Our patient had obtained Bidiabe without prescription in Haiti and had been taking it without the knowledge of her physicians for several years.

It is not known why some patients develop lactic acidosis while taking phenformin. We found no enzyme deficiency to explain recurrent acidosis in our patient. However, skeletal-muscle electron microscopy done at autopsy revealed hyperplasia of mitochondria that had normal size. internal structure, and distribution (Figure 1). Hepatocyte mitochondrial hyperplasia might reflect an early compensatory response to adverse environmental stimuli, as has been hypothesized in other settings [2].

View larger version (120K): [in this window] [in a new window]   Figure 1. Electron µgraph obtained at autopsy shows hepatocyte cytoplasm densely filled with mitochondria (asterisks). The latter are of normal size, shape, and internal structure. Arrow demarcates luminal space, and the bar represents 1.9 µm.

The availability of metformin, a drug that has similar efficacy but is associated with a lower risk for lactic acidosis, now renders phenformin obsolete [3]. Physicians, especially those serving immigrant communities, must remain aware of the availability of phenformin.