Clinical and pathological features of a prolonged type of acute intrahepatic cholestasis

We examined the clinical and pathological features of drug-induced acute intrahepatic cholestasis (AIC) to elucidate the pathogenesis of prolonged cases.

Twenty-six cases of drug-induced AIC were divided into prolonged and non-prolonged groups. Serum bilirubin levels and other biochemical data were compared between the two groups. Biopsy liver specimens were examined by light and electron microscopy. The localization of multidrug resistance protein 2 (MRP2) was immunohistochemically assessed by the Envision technique.

The causative drugs of four prolonged cases were found to be tiopronin, chlorpromazine and diclofenac. Two of the patients either died or underwent liver transplantation. The maximal total bilirubin levels (35.2 +/-> 13.8 mg/dL) were significantly higher and a half-life of total bilirubin (78.8 +/-> 69.6 days) was markedly longer in the prolonged cases, in comparison to the non-prolonged cases (16.8 +/-> 8.1 mg/dL, 22.1 +/-> 12.7 days, respectively). The liverbiopsy specimens revealed canalicular cholestasis and a slight degree of lobular inflammation. In the prolonged cases, liver cell injury and cholestasis was marked, and the interlobular bile ducts disappeared in the portal triads. The reaction products of MRP2, recognized on the bile canaliculi in a control liver, were weakened and found in the pericanalicular vesicles in AIC.

These results indicated disturbances in the canalicular bilirubin transport through MRP2 in the prolonged cases, resulting from severe cholestasis, liver cell injury and vanishing bile ducts. The histological findings of the liver at the acute icteric phase may be important to understand the pathogenesis and to predict the prognosis in AIC.