Pioglitazone-associated fulminant hepatic failure

TO THE EDITOR: Actos (pioglitazone; Takeda Pharmaceuticals North America, Lincolnshire, IL) is a member of the new thiazolidinedione class of oral hypoglycemic agents. Two other members of this class, troglitazone and rosiglitazone, have been associated with hepatotoxicity (1–5). Troglitazone was recently withdrawn from the United States market after several cases of severe hepatotoxicity were reported, including fatal cases of liver failure. We report a case of severe hepatotoxicity associated with the use of pioglitazone. A 78-yr-old male with diabetes mellitus, hyperlipidemia, and coronary artery and peripheral vascular diseases presented with jaundice. He had no history of antecedent liver disease or exposure to known hepatotoxins. Pioglitazone (30 mg p.o. each day) had been prescribed 2 months before his presentation. Concurrent medications included metformin, furosemide, metolazone, magnesium oxide, venlafaxine, aspirin, and a multivitamin (one daily). Before initiation of therapy with pioglitazone, liver biochemical tests were normal. Approximately 2 months thereafter, the patient presented to our hospital with jaundice, which, within a few days, was followed by the onset of hepatic encephalopathy. There was no fever, rash, arthralgia, or eosinophilia. The liver biochemical test profile revealed a serum total bilirubin of 4.4 mg/dl (normal 0.0–1.0 mg/dl); direct bilirubin, 3.2 mg/dl (normal 0.0–0.3 mg/dl); ALP, 201 U/L (normal 50–136 U/L); AST, 2637 U/L (normal 12–32 U/L); and ALT, 2303 U/L (normal 20–65 U/L). The PT was 24 s (international normalized ratio 3.0). An abdominal CT scan and liver ultrasound examination with Doppler interrogation of the hepatic arterial and venous structures and the portal vein demonstrated a homogeneous liver without masses or ascites. Normal vascular flow characteristics were noted. Serological studies were negative for viral hepatitis A, B, and C. Serum antinuclear antibody testing was negative. All medications he had been taking before admission were discontinued and oral lactulose was administered. Despite these measures the serum total bilirubin rose to 12 mg/dl and his hepatic encephalopathy persisted (grade 3). A liver biopsy obtained by the transvenous route revealed swollen hepatocytes that contained finely granular eosinophilic cytoplasm and feathery degeneration with lobular infiltration of neutrophils and eosinophils, occasional binucleate hepatocytes, marked canalicular cholestasis with intact bile ducts, and no evidence of steatosis, portal inflammation, piecemeal necrosis, or fibrosis. A decision was made to proceed with an empirical course of corticosteroid treatment (prednisone, 20 mg/day p.o.). The patient improved over several weeks, the corticosteroids were tapered, and ultimately he made a complete hepatological recovery (including normalization of the liver biochemical tests). Drug rechallenge was not considered appropriate. The liver biopsy findings supported a drug reaction as the cause for this patient’s acute, reversible liver failure. Treatment with pioglitazone was temporally associated with the patient’s acute illness, and none of the other regularly ingested medications are considered common hepatotoxins. Evaluation of the fulminant hepatic failure in this case with serological and radiological imaging studies did not show any evidence of a viral, autoimmune, or hepatic malignant etiology. The clinical history did not suggest ischemic hepatopathy. Although improvement in the clinical course coincided with corticosteroid treatment, there was no evidence of autoimmune liver disease on a clinical, serological, or histological basis. The patient had subsequently done well after having the corticosteroids tapered and discontinued. According to the package insert for Actos (pioglitazone), in placebo-controlled trials conducted in the United States only four of 1526 patients (0.26%) treated with pioglitazone and two of 793 placebo-treated patients (0.25%) had ALT elevations greater than three times the upper limit of normal. The elevations were reversible and not clearly associated with the hypoglycemic agent. Despite the previous lack of any known association of pioglitazone therapy with hepatoxicity, given its structural similarity to the other thiazolidinediones, liver biochemical testing is recommended before initiating and periodically during therapy. The hepatotoxicity caused by troglitazone has been described as an idiosyncratic reaction. An idiosyncratic reaction is also possible in this case, and the time course would support this hypothesis. The specter of an immunoallergic-type injury is, however, raised, given the clinical improvement that coincided with the institution of corticosteroid therapy. Pioglitazone is now the third member of the thiazolidinedione class of hypoglycemic agents to be associated with hepatotoxicity. Despite the clinical improvement this patient enjoyed after institution of corticosteroid therapy, we believe it is important to highlight that this form of treatment has not clearly been shown to be beneficial in persons afflicted with drug hepatotoxicity. Our anecdotal experience does not alter this tenet. We encourage others to report hepatotoxic reactions that occur in association with pioglitazone treatment, as this may be a potentially serious adverse effect of this medication.