STUDIES OF CHRONIC HEPATITIS IN THE LIVER ALLOGRAFT. IS THIS A FORM OF CHRONIC REJECTION?  

Index

S.G.Hubscher

Department of Pathology, University of Birmingham, Birmingham B15 2TT, UK

Several studies have described inflammatory changes resembling chronic hepatitis in biopsies obtained from liver allograft recipients surviving long-term following liver transplantation. In some cases these changes can be attributed to a known cause (e.g. chronic viral hepatitis), but there remain many cases in which the aetiology is uncertain. The clinical significance and natural history of "idiopathic" post-transplant chronic hepatitis (PTCH) also require further elucidation. From January 1989 to December 1994, protocol liver biopsies were obtained from all long-term survivors in the Birmingham Liver Transplant Programme as part of a routine annual review. A smaller number of biopsies were taken to investigate clinically apparent graft dysfunction. A total of 1140 biopsies were obtained from 459 patients 12 months post-transplant. Histological assessments were carried out using a detailed proforma and the data were subsequently entered into a database. Excluding 47 biopsies from known hepatitis B virus (HBV) or hepatitis C virus (HCV) positive cases, 491 of 1093 biopsies (45%) had a histological diagnosis of chronic hepatitis. Features used to make a diagnosis of chronic hepatitis were the presence of a predominantly mononuclear portal inflammatory infiltrate associated with interface hepatitis and/or parenchymal inflammation with hepatocyte necrosis. The degree of necroinflammatory activity in portal/periportal regions and in the liver parenchyma was graded semiquantitatively on a scale of 0(absent) to 3 (severe). Individual scores were combined to produce an overall inflammatory grade of mild, moderate or severe. Inflammatory activity was graded as mild in 84.1% of biopsies, moderate in 10.3% and severe in 5.6%. Fibrosis was staged on a scale of 0 (no fibrosis) to 3 (cirrhosis). Aetiological factors which have been considered in cases of PTCH include viral agents, recurrent autoimmune disease, drugs and a modified form of rejection. No evidence for acquired HBV or HCV infection has been found in the great majority of cases where specific viral testing has been carried out. In a consecutive series of 41 PTCH cases only 2 (5%) were found to be HCV-RNA positive by PCR analysis. The prevalence of chronic hepatitis was found to be higher in biopsies obtained from patients with autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis), all of which may be associated with a chronic hepatitic picture in the non-transplanted liver and can recur following liver transplantation, than in those obtained from patients with diseases not associated with chronic hepatitis and/or not recurring in the liver allograft (e.g alcoholic liver disease, metabolic liver disease, drug-induced liver failure). This suggests that some cases of PTCH may be related to recurrent autoimmune disease, in which other diagnostic features are lacking. In a small number of cases, the histological finding of PTCH has coincided with the de novo appearance of autoantibodies, suggesting a diagnosis of acquired autoimmune hepatitis. A higher incidence of chronic hepatitis has been observed in patients transplanted for fulminant seronegative hepatitis (71%) than in those transplanted for other non-recurring causes of acute liver failure (31%), raising the possibility of persistent or recurrent disease in the former group. No definite drug aetiology can be implicated for the great majority of cases. By definition, typical features of acute (cellular) rejection or chronic (ductopenic) rejection are not seen in cases diagnosed as chronic hepatitis. However, some biopsies with predominantly hepatitic features have other changes raising the possibility of rejection. Previous studies have suggested that late cellular rejection may be associated with histological features different to those typically seen in early acute rejection. These include less conspicuous venous endothelial inflammation and more prominent lobular inflammation, producing a hepatitis-like picture. Features of chronic hepatitis have also been incorporated into one grading scheme proposed for chronic rejection. In the absence of any other obvious cause, it is possible that some cases of PTCH may represent a form of late cellular rejection. The majority of patients with a diagnosis of chronic hepatitis in a protocol biopsy are clinically well with normal or near normal liver biochemistry. Median AST levels at the time of biopsy were as follows : mild CH = 29 (range 9-393), moderate CH = 40 (range 19-298) , severe CH = 43 (range 16-316). Some patients who have become symptomatic with significant transaminitis, have been treated with corticosteroids resulting in clinical and biochemical improvement. A small number of cases have been unresponsive to immunosuppression progressing to graft failure requiring retransplantation. Seven of 281 patients (2.5%) from whom serial biopsies were obtained at intervals of up to 5 years had severe fibrosis amounting to cirrhosis in their latest biopsy. In conclusion, chronic hepatitis of unknown aetiology continues to be a common diagnosis in biopsies obtained from liver allograft recipients surviving more than 12 months following liver transplantation. Most cases appear to have little impact on graft function or patient survival. However some symptomatic cases require additional immunosuppression and a few are associated with progressive fibrosis resulting in cirrhosis. Further studies are required to determine the aetiology of this lesion, including its relationship with rejection, and the behaviour of chronic hepatitis over a longer period of follow up.

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