Ketoconazole-induced hepatic injury: Report of 4 cases

Ketoconazole appears to be a well-tolerated and safe antifungal drug with minimum toxicity. The incidence of symptomatic hepatic injury associated with the use of ketoconazole is estimated to be about 1 in 10000 treated cases. We report on four cases diagnosed as ketoconazole-induced symptomatic hepatitis after exclusion of the possibility of viral or autoimmune hepatitis. The patients included one man and three women with a the mean age of 49 (range 43-53 years). The symptoms of malaise and jaundice developed 67 (range 7- 130) days after ketoconazole intake (200mg/day). Liver biochemistry tests revealed conjugated hyperbilirubinemia in all four cases (range of indirect/total bilirubin: 10-12/19-27mg/dl), elevation of the alanine aminotransferase (ALT) level of more than 10 times normal (40U/L) in three cases (range 460-1176 U/L), and mild elevation of alkaline phosphatase in all four cases (range 112-165 U/L, normal < 94U/L). Three patients had an elevated alfa-fetoprotein level (55-98 ng/ml, normal < 20 ng/ml). Liver biopsies in two of these four patients showed diffuse inflammation of the liver parenchyma with bridging hepatic necrosis. In each case, the clinical symptoms improved and the liver biochemistry tests returned to normal 1 to 2.5 months after withdrawal of the drug.