Jaundice developing in a patient with hepatitis C 4 months after liver transplantation

Abstract

A 52-year-old man underwent liver transplantation (LT) for hepatitis C virus (HCV)-related cirrhosis. Before LT, he had a Model for End-Stage Liver Disease score of 32 and had been hospitalized with spontaneous bacterial peritonitis and hepatorenal syndrome requiring hemodialysis. He was infected with genotype 1A with a viral load of 1,800,000 IU and previously did not respond to interferon. He received a liver from a 66-year-old donor with 9 hours of cold ischemia time. The liver suffered mild ischemia-reperfusion injury and the post-LT course was complicated by renal failure requiring dialysis. Steroid-free immunosuppression was used with interleukin-2 antagonist induction, mycophenolate, and tacrolimus. All liver tests normalized, and the patient was discharged after 3 weeks. ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCV, hepatitis C virus; LT, liver transplantation. Tacrolimus trough levels were maintained at 10-12 μg/L with gradual normalization of renal function. Liver tests remained normal but the ascites never totally resolved. The patient became jaundiced 4 months after LT with aspartate aminotransferase (AST) 110 U/L, alanine aminotransferase (ALT) 127 U/L, alkaline phosphatase 390 U/L, and direct bilirubin 6.2 mg/dL. Doppler ultrasonography showed no ductal dilatation and the hepatic artery was patent. Magnetic resonance imaging cholangiography showed no evidence of biliary stricture. He was afebrile with hemoglobin 11.6 g/dL, platelets 80,000/μL, and creatinine 2.1 mg/dL. Cytomegalovirus was undetectable by polymerase chain reaction and HCV RNA 18,500,000 IU. A liver biopsy was performed and showed the following: Low-power magnification showing cholestasis with feathery degeneration of hepatocytes (arrows) and minimal inflammation is seen in portal areas (Fig. A). A ductular reaction is noted (arrow heads). Trichrome stain of one representative portal tract shows fibrous tissue and delicate fibrous septa extending into periportal sinusoids and occasionally enclosing hepatocytes (arrows; Fig. B). These features are consistent with the cholestatic variant of recurrent HCV.1 Treatment with pegylated interferon-α2a and ribavirin was initiated, but the jaundice and ascites worsened. The AST, ALT, and alkaline phosphatase decreased minimally and the direct bilirubin increased to 17.1 mg/dL. The HCV RNA decreased to 1,500,000 IU 6 weeks into treatment, but the patient developed gradual renal failure and severe anemia requiring cessation of antiviral treatment; he soon developed enterococcal bacteremia and died. The cholestatic variant of recurrent HCV is typified by cholestatic liver tests and an extremely high HCV viral load occurring early after LT. It occurs infrequently and generally results in graft failure, carrying a high mortality rate.1 Its histological findings are in contradistinction to typical acute recurrent HCV (Fig. C) in which there is more necroinflammation, absence of cholestasis, and less fibrosis. Acidophilic bodies (arrowheads), lobular inflammatory infiltrates, and spotty necrosis are seen. Response to interferon therapy is poor, and retransplantation may be required. Its pathogenesis is poorly understood with risk factors being older donor age, significant HCV viremia, and strong immunosuppression.2 It has also been described in human immunodeficiency virus, after renal and cardiac transplantation, and after chemotherapy in patients with HCV or HBV.3, 4 A similar histologic syndrome is well-described in patients with recurrent HBV after LT.5 The early post-LT differential diagnosis of abnormal liver tests in this patient included drug hepatotoxicity, biliary obstruction or hepatic artery thrombosis, cytomegalovirus infection, acute/chronic rejection, as well as recurrent HCV. Definitive histopathologic diagnosis of cholestatic HCV recurrence may be problematic because more than one of the above processes may be present in the same biopsy. Appropriate exclusion of other diagnoses and provision of clinical and laboratory information to the pathologist is essential.