Recurrence and Accelerated Progression of Hepatitis C following Liver Transplantation

CASE REPORT

A 68-year-old woman underwent orthotopic liver transplantation (OLT) in July 1998 for hepatocellular carcinoma, which developed in an HCV related cirrhotic liver. The tumor had been previously chemoembolized. Hepatitis C was diagnosed in 1982, but had never been treated.

During the immediate postoperative period, she developed severe hypoxia, successfully treated by almitrine. On day 8, she was extubated. She received a classical triple immunotherapy regimen including tacrolimus, azathioprine and prednisolone and additional prophylactic anti -CMV treatment. She was transiently put on insulin and a carbohydrate diet to control diabetes which appeared post-operatively. On day 13, liver function tests were grossly normal (Table [1]). On day 25 postOLT, she was discharged, free of insulin. On that day, mild elevation of serum transminases were noted for the first time (Table [1]).

Thereafter, several clinical and biological abnormalities were observed during follow-up (Table [1]): episodes of hyperglycemia with or without ketoacidosis, which required insulin; arterial hypertension, which was treated, and a persistent rise in serum transaminases and a mild elevation in conjugated bilirubin starting 2 months postoperatively. Azathioprine was stopped on day 29, and tacrolimus was replaced by cyclosporine on day 210.

Differential Diagnosis

A rise in serum transaminases and a mild elevation in bilirubin starting 2 months postoperatively could be due to several etiologies. First, it was important to look systematically for the following causes, which could require specific treatment. There was no obvious endothelialitis and interlobular bile ducts were normal on liver biopsies ruling out the diagnosis of acute and chronic rejection. The absence of bile duct proliferation on biopsies and the absence of dilatation of the intrahepatic biliary tree on MR-cholangiogram rule out the diagnosis of biliary obstruction. Doppler ultrasound was normal making the diagnosis of vascular obstruction unlikely. Finally, the patient was not exposed to known drugs that could explain the biochemical and pathological data.

In favor of the diagnosis of recurrent hepatitis C were the following arguments:

• initial drop, then rise, in serum viral load reaching 1,500,000 and 4,600,000 copies/mL on postoperative day 44 and 314, respectively.

• pathological lesions compatible with a cholestatic form of recurrent hepatitis C and detection of viral proteins on frozen sections of the graft biopsies by immunohistochemistry.

Pathological Findings The first post OLT liver biopsy on day 44 showed normal lobular architecture. There were portal stellate fibrosis with moderate pericellular fibrosis surrounding ductular-like structures, moderate portal inflammation, and mild piecemeal necrosis, moderate disorganization of hepatocytic plates with ballooned hepatocytes mainly in centrolobular zones, numerous acidophilic bodies surrounded by aggregates of lymphocytes and canalicular cholestasis, mostly centrolobular with occasional bile thrombi (Fig. 1A-C). The second liver biopsy on day 101 showed basically the same changes of cholestatic hepatitis with a higher grade (severe activity) and stage (beginning of fibrous septum formation) corresponding to a METAVIR score A3/F2, and ductular proliferation. In addition, features of hepatocellular regeneration and bile thrombi were observed. The third liver biopsy on day 314 showed extension of portal fibrosis with septa and obvious pericellular fibrosis involving the entire lobule, ductular proliferation and prominent cholestasis. A thin rim of fibrosis was seen around centrolobular veins. The disease activity was unchanged, but lymphoid aggregates were present in 1/3 of portal tracts (METAVIR score: A3 - F2/F3) (Fig.2A).

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