HEPATITIS C VIRUS-RELATED FIBROSING CHOLESTATIC HEPATITIS AFTER RENAL TRANSPLANTATION

Abstract

Fibrosing cholestatic hepatitis is a well-described syndrome in patients with immunodeficiency and chronic hepatitis B. It is clinically, biologically, and histologically characterized by rapidly progressive hepatic failure, a mildly elevated serum aminotransferase level, an extensive periportal fibrosis associated with intense cholestasis, mild inflammatory cellular infiltrate, no cirrhosis, and a high hepatocellular level expression of B viral antigens. This syndrome reflected a direct hepatocytopathic injury linked to high intrahepatic viral antigen expression. Because the syndrome of fibrosing cholestatic hepatitis has not been described in chronic hepatitis C, we report the first well-characterized case in a renal transplant patient with chronic hepatitis C and discuss the clinical and pathogenic implications of such a syndrome in this setting.

Fibrosing cholestatic hepatitis (FCH^*) is a recently described syndrome that occurs in patients with chronic hepatitis B and immunodeficiency due to human immunodeficiency virus infection ⁽¹⁾ and in transplant patients as a result of immunosuppression ⁽²⁾. It is characterized by a rapidly progressive hepatic failure with fatal outcome, mildly elevated serum aminotransferase activity, and high viral replication. At the histologic level, extensive periportal fibrosis is associated with marked cholestasis, mild inflammatory cellular infiltrate, and an absence of cirrhosis. A high hepatocellular level expression of B viral antigens in the endoplasmic reticulum is observed in relation to an enhancement of hepatitis B virus (HBV) replication ⁽³⁾, and may explain this unusual direct hepatotoxicity of HBV.

We report herein the first case, to the best of our knowledge, of FCH in a renal transplant recipient with chronic hepatitis C infection, and we discuss the clinical and pathogenic implications of such a syndrome in this setting.

A 40-year-old man was admitted to Hôpital Necker in November 1995 for progressive anorexia and jaundice. He had been chronically hemodialyzed since 1985 for megaoligonephrony; antibodies against hepatitis C virus (HCV) were detected in 1990. He underwent renal transplantation in June 1992, with anti-leukocyte function-associated antigen-1 antibodies as immunosuppressive induction treatment. After transplantation, two acute graft rejection episodes were treated by steroid bolus and antithymoglobulin serum in February and June 1993, respectively. He was then given standard immunosuppressive therapy with prednisolone (10 mg/day), cyclosporine (250 mg/day), and azathioprine (100 mg/day). Hepatic laboratory tests, including alanine aminotransferase and γ-glutamyltransferase activities and serum bilirubin level, were normal in 1992 and 1993.

In May 1995, he had a first liver biopsy for evidence of mild, elevated liver function test that revealed chronic hepatitis of moderate activity with a Knodell score of 4 (Fig. 1). In September 1995, a cholecystectomy was performed for a clinical suspicion of cholecystitis, which was not confirmed by pathological examination of the gallbladder. Liver biopsy during surgery revealed extension of fibrosis as compared with the first biopsy. Azathioprine was stopped in October 1995 because serum activities of alkaline phosphatase and γ-glutamyl transpeptidase continued to rise.

On admission, the patient was afebrile and had jaundice, ascites, and hepatomegaly. Laboratory tests revealed a white blood cell count of 11.0×10⁹/L, a prothrombin time of 89% of the normal value, and a serum-conjugated bilirubin level of 60 μmol/L; enzymic activities were as follows: alanine aminotransferase, 90 IU/L (normal range, 5-40 IU/L); alkaline phosphatase, 340 IU/L (normal range, 30-90 IU/L); and γ-glutamyltransferase, 800 IU/L (normal range, 8-38 IU/L). The creatinine level was 160 μmol/L. Ascitic fluid contained 25 g/L of protein and 100 cells/μl. Culture of ascitic fluid was negative. Abdominal ultrasonography and tomodensitometry showed no abnormality, except homogeneous hepatomegaly and ascites.

The patient had antibodies against hepatitis B surface and core antigens, but none against hepatitis D virus or human immunodeficiency virus. Serum HBV DNA and cytomegalovirus antigenemia tests were negative. Autoantibodies (anti-nuclear, anti-liver kidney microsome, anti-smooth muscle, antimitochondria) were negative. He had no chronic alcohol consumption.

Quantitative HCV viremia, as assessed by the commercially available Monitor test (Roche Diagnostic Systems, Neuilly sur Seine, France), was at a titer of 12×10⁶ copies/ml, the highest titer we have ever observed by this procedure in our entire population of immunocompetent as well as immunocompromised patients. The HCV genotype was 1b according to the Innolipa (Innogenetics, Gent, Belgium) procedure. Because the patient was experiencing accelerated liver failure, a transjugular liver biopsy was performed in December 1995. This showed extensive periportal fibrosis without cirrhosis, intense cholestasis, and a sparse neutrophilic cellular infiltrate, all consistent with the so-called diagnosis of FCH.

Bilirubin and γ-glutamyltransferase levels increased rapidly and were 500 μmol/L and 1500 IU/L, respectively, at the beginning of January 1996. Alanine aminotransferase activity remained at about twofold the normal value. Despite the withdrawal of an immunosuppressive regimen as early as October 1995 and supportive therapy, the patient died in a context of liver failure with hepatic coma. Postmortem examination confirmed the same pattern of liver lesions (Fig. 1) and showed no malignancy or particular infectious disease.

To the best of our knowledge, we report the first case of FCH related to HCV infection in a kidney transplant recipient. FCH is a peculiar syndrome described in renal and liver transplant recipients as well as in patients with acquired immune deficiency syndrome (AIDS) with chronic hepatitis B ^{(1, 2)}. This syndrome is associated with a high, if not constant, mortality and is thought to reflect direct cytopathic injury linked to a high intrahepatic viral antigen expression. This direct cytopathic effect has been suggested in transgenic mice and HBV-transfected cell models and contrasts with the usual immune-induced hepatotoxicity of HBV.

Mechanisms of HCV pathogenicity have not been clearly elucidated ⁽⁴⁾. An immune-mediated mechanism of liver injury is suggested by the intrahepatic lymphoid follicles and peripheric and intrahepatic CD4 and CD8 lymphocytes directed against C viral antigen, which seem to correlate with severity of liver lesions. Conversely, some evidence has been found of direct cytopathic liver damage, such as relative paucity of cellular infiltrate, and severe outcome of chronic hepatitis C, especially with rapid evolution to cirrhosis in immunodeficiency situations such as AIDS. High levels of viremia and the more severe liver injury have been reported in patients with chronic hepatitis C and various immunodeficiency situations, such as AIDS, liver and renal transplantation, and immunosuppressive therapy ^{(5, 6)}. Similarly, subfulminant hepatic failure caused by HCV acquired via transplantation of a heart from an HCV-infected donor has been reported: the very high serum and tissue levels of HCV RNA suggested that HCV was directly cytopathic to the hepatocytes ⁽⁷⁾. Furthermore, among 149 patients with end-stage HCV-related liver disease who received liver transplantation, three cases of HCV-related severe cholestatic hepatitis were observed: serial liver biopsies demonstrated a rapid progression from acute lobular hepatitis to diffuse hepatocytic ballooning with severe intrahepatic cholestasis ⁽⁸⁾. An immune-mediated mechanism for hepatocyte damage in HCV infection has been suggested recently by a case of fulminant hepatitis after withdrawal of chemotherapy in carriers of HCV with low serum HCV RNA levels ⁽⁹⁾.

There are strong and numerous similarities between our observation and the classically described FCH: first, a clinical outcome with rapid and fatal progressive liver failure within a few months, without evidence of other liver disease; second, a particular cholestatic course of hepatitis with mildly elevated aminotransferase levels; third, a high level of viremia (12×10⁶ genomes/ml)-the highest viremia we have ever observed in our overall population, which includes 151 anti-HCV-positive renal transplant recipients; and fourth, an extensive fibrosis without cirrhosis associated with intense cholestasis and mild cellular infiltrate at liver biopsy.

We cannot exclude the possibility that the particularly strong potent immunosuppressive therapy, before and early after transplantation (especially antithymoglobulin serum and anti-leukocyte function-associated antigen-1 antibodies), did not contribute to such an evolution. On the other hand, this syndrome may reflect nonexclusive intrinsic viral characteristics, including genotype, the replicative ability, or a defective export of HCV proteins that could be related to a specific mutation, as described in FCH associated with HBV ⁽¹⁰⁾. Indeed, the genotype 1b is reportedly associated with severe liver injury.

Such FCH raises the question of implementing an early reinforced antiviral therapy associated with a discontinuation of the immunosuppressive regimen, especially in renal transplantation, where hemodialysis is an efficient alternative if the kidney allograft is lost. Antiviral therapy was not discussed in this patient because, in our experience, α-interferon is not an efficient therapy for HCV infection in kidney recipients, and we have not had success in treating HBV-related FCH in three kidney recipients (unpublished data).

Acknowledgments. The authors thank Dr. M-L. Chaix for HCV quantitation, Prof. C. Bréchot for genotype determination, Prof. P. Berthelot for constructive criticism, and Prof. H. Kreis and Prof. J-P Soulillou for participating in their patient's care.

Figure 1: Photomicrograph shows evolution of liver histology from May 1995 (A) to January 1996 (B). Enlarged portal tracts (arrows) without lobular fibrosis (A) and with extensive intralobular fibrosis (B) can be seen (Masson's trichrome, ×75).