Recurrent Hepatitis C in Liver Allografts: Prospective Assessment of Diagnostic Accuracy, Identification of Pitfalls, and Observations About Pathogenesis

Hepatitis C virus (HCV)-induced cirrhosis is the leading indication for liver transplantation throughout the world.32 Unfortunately, reinfection is nearly universal and recurrent disease occurs in a majority of recipients. HCV replication can be detected in the RNA-positive recipients within days after transplantation.27 Allograft dysfunction can occur as early as 1 week following transplantation in patients with high viral loads before transplantation,6 but the majority of HCV-positive recipients usually first show signs of recurrent disease between 2 and 3 months.11,31 Distinguishing among recurrent viral hepatitis and AR and CR and other causes of allograft dysfunction is based primarily on liver biopsy evaluation, Guidelines to recognize individual syndromes were proposed more than a decade ago, 13,16 but experience has shown the distinction to be problematic.1,19,25 Steatosis is an early nonspecific finding in recurrent HCV5; spotty hepatocyte necrosis, lobular disarray, and Kupffer’s cell hypertrophy are more reliable features that specifically point toward recurrent HCV as the cause of allograft injury.31,33 Later in the course of recurrent HCV, predominantly mononuclear portal inflammation with variable interface activity and low-grade bile duct damage signal the transition from acute to chronic hepatitis. Chronic HCV is characterized by mononuclear portal inflammation that is frequently arranged into nodular aggregates and mild bile duct damage that is neither as severe nor as widespread as is seen in acute rejection (AR) or chronic rejection (CR).31 Interface activity, including a type II ductular reaction, is also more common in hepatitis than in rejection. Retrospective analysis of case material to determine whether specific histopathologic criteria are useful in distinguishing among recurrent HCV and other causes of allograft dysfunction is fraught with pitfalls. The Electronic Data Interface for Transplantation (EDIT)15 software simultaneously creates an information portal for patient management and populates a research database. Real-time entry of all pertinent treatment, laboratory, and histopathology data into this software has enabled us to accomplish our primary goal. This objective was to prospectively and rigorously test our ability to distinguish among recurrent HCV, rejection, and other various causes of liver allograft dysfunction in HCV RNA-positive recipients enrolled in a recent “immunosuppression minimization protocol.”36 A secondary goal was to retrospectively analyze errors and determine how they might be avoided. The treatment protocol used in this patient population is based on the concept that alloantigen migration to the central lymphoid tissues of the recipient early after transplantation is an important event that simultaneously triggers rejection and tolerogenic immune responses.35–37 Pretransplant immunodepletion with anti-leukocyte antibodies is used to rein in the expected early alloresponse into a manageable range. This is combined with minimal posttransplantation monotherapy immunosuppression in an attempt to facilitate activation-induced apoptosis of donor-reactive lymphocytes.36 A final goal of this study was to determine whether histopathologic observations in this unique patient population shed any insight into our conceptual understanding of HCV pathogenesis in the allografted liver.