Can Imurel (azathioprine) cause a histopathological image of pericholangitis?/nA 26-year-old man re

Fråga: Can Imurel (azathioprine) cause a histopathological image of pericholangitis?

A 26-year-old man received a renal transplant six years ago. Since then he has had treatment with azathioprine 50 mg daily and Sandimmun (ciclosporine) 75 mg daily. His liver test results have been stable with transaminases within the normal range and a slight elevation of alkaline phosphatase (ALP) and bilirubin. Eleven months ago the patient developed jaundice and abdominal pain. Liver function tests showed slight elevation of transaminases, ALP 5 ukat/L and bilirubin 200 umol/L. Abdominal ultrasound and endoscopic retrograde cholangiopancreaticography (ERCP) were unremarkable. Serological examination for viral hepatitis was negative as well as the search for antinuclear and antimitochondrial antibodies. Liver biopsy showed pericholangitis with enlarged portal tracts infiltrated with lymphocytes, plasma cells and granulocytes. Azathioprine-induced toxicity was suspected and the drug was withdrawn. Soon thereafter the patient recovered. In addition to the drugs mentioned above the patient also has treatment with Furix (furosemide) 40 mg daily and Prednisolone 10 mg daily.

Sammanfattning: Hepatotoxicity attributed to azathioprine covers a broad spectrum of clinical, biochemical and histological manifestations. In most reported cases the changes have been reversible on drug withdrawal, but severe irreversible changes have been described.

Svar: Horesman et al have reported a case that bears resemblance to the present case (1). It was a 67-year-old man with primary polymyositis who was treated with azathioprine (100-150 mg/day). Three months after initiation of azathioprine therapy he developed jaundice. Biochemical examination showed a slight elevation of transaminases, marked increase in alkaline phosphatase and moderate hyperbilirubinemia. Abdominal ultrasound and upper abdominal computed tomography were unremarkable. Serological examination was negative. Liver biopsy showed enlarged portal tracts, infiltrated with lymphocytes, histiocytes and neutrophiles, which were mainly observed in the close vicinity of bile ducts. Bile duct epithelium appeared multilayered and infiltrated by neutrophiles. Because of the suspicion of drug-induced liver toxicity, azathioprine was discontinued. Liver function tests progressively improved, reaching normal values three months later and remaining normal during the following year of follow-up. Rechallenge was not attempted.

The clinical and pathological features of azathioprine hepatotoxicity are still not well defined. Numerous case reports of possible azathioprine-related liver damage exist. Hepatotoxicity attributed to azathioprine covers a broad spectrum, including asymptomatic elevation of liver tests, mild cholestasis, more severe forms of cholestatic hepatitis, cholestasis with bile duct injury, venoocclusive disease with portal hypertension, peliosis hepatis and nodular regenerative hyperplasia (2,3). Reversal of hepatotoxicity and/or positive rechallenge has been observed in several cases (1,2,4). Nonreversibility of azathioprine-induced hepatotoxicity after withdrawal has also been reported (2). It has been suggested that at least some of the different histopathological changes may represent the same pathophysiological entity, but at different stages (2).

The mechanism behind azathioprine-induced hepatotoxicity remains unclear. Renal transplantation and male gender appear to be significant risk factors, particularly to vascular lesions (3). In dogs azathioprine is a dose-dependent hepatotoxin, but in humans liver injury is less clearly related to the dose (3).

In Swedis there are 64 reports of liver and biliary tract adverse drug reactions and azathioprine (5).

We recommend that this case be reported to the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). 1 Horsmans Y, Rahier J, Geubel P. Reversible cholestasis with bile duct injury following azathioprine therapy. A case report. Liver 1991;11:89-93. 2 Sterneck M, Wiiesner R, Ascher N, Roberts J, Ferrell L, Ludwig J, Lake J. Azathioprine hepatotoxicity after liver transplantation. Hepatology 1991;14:806-810. 3 Farrell GC. Drug-induced liver disease: Churchill Livingstone; 1994. p. 468-470 4 Romagnuolo J, Sadowski DC, Lalor E, Jewell L, Thomson ABR. Cholestatic hepatocellular injury with azathioprine: A case report and review of the mechanisms of hepatotoxicity. Can J Gastroenterol 1998;12:479-483. 5 Swedis (The Swedish Drug Information System)