Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin.
A 68-year-old woman, with type 2 diabetes mellitus, hypercholesterolemia, and prior long-term simvastatin therapy, self-resumed troglitazone after running out of metformin. She developed an acute severe hepatitis with microvesicular steatosis and mysositis. There was subsequent resolution of the myositis but progression of the hepatitis to symptomatic cirrhosis over a period of 12 weeks. Both troglitazone and simvastatin are metabolized by cytochrome P-450 3A4. Troglitazone typically induces metabolism of drugs metabolized by this cytochrome so that simple simvastatin toxicity seems less likely to have been involved. The association with myositis, the severity of the hepatitis with progression to cirrhosis, and the presence of microvesicular steatosis suggests altered mitochondrial metabolism, which has been described with each agent, as the underlying pathogenic mechanism. Although troglitazone (Rezulin) has been withdrawn from the market, other similar agents are available for therapy of type 2 diabetes mellitus. Increased awareness of a potential interaction between these two classes of drugs is warranted.
Department of Internal Medicine, University of Virginia, Charlottesville, USA.
S H
SH
Caldwell
E E
EE
Hespenheide
R W
RW
von Borstel
D000368:Aged; D000924:Anticholesteremic Agents / Q000009:adverse effects*; D000975:Antioxidants / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D002839:Chromans / Q000009:adverse effects*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000188:drug therapy*; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications* / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000175:diagnosis / Q000188:drug therapy; D009220:Myositis / Q000139:chemically induced* / Q000175:diagnosis / Q000188:drug therapy; D019821:Simvastatin / Q000009:adverse effects*; D013844:Thiazoles / Q000009:adverse effects*; D045162:Thiazolidinediones; D000077288:Troglitazone
D000924:Anticholesteremic Agents; D000975:Antioxidants; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D019821:Simvastatin; D000077288:Troglitazone