Role of viral replication in extrahepatic syndromes related to hepatitis B virus infection

Approximately 20% of patients with hepatitis B virus (HBV) infection may experience extrahepatic disease. These manifestations include a viral prodrome with a serum sickness-like syndrome, polyarteritis nodosa, glomerulonephritis, as well as various neurological and dermatologic diseases amongst other manifestations. The viral pathogenesis is not well understood and has been difficult to study due to the lack of an animal model of HBV-related extrahepatic disease. Deposition of immune complexes and activation of the complement cascade has been most widely studied. However, circulating immune complexes are physiologic and occur more frequently than extrahepatic disease. Also, HBV-related extrahepatic syndromes occur in the absence of immune complex formation. Several studies support the notion that HBV replication in extrahepatic tissues may also precipitate disease but extrahepatic replication has commonly been observed without any apparent cytopathic or immune related tissue damage. It is clear that suppression of viral replication with antiviral therapy or spontaneous viral clearance positively correlates with resolution of extrahepatic disease. The use of continuous immunosuppressive therapy has largely been abandoned with the advent of robust antiviral strategies to manage disease. These data support the notion that a combination of factors including inadequate clearance immune complexes and viral replication in extrahepatic tissues play an important role in the pathogenesis. This conceptual framework is potentially significant as it emphasizes the importance of antiviral treatment in the management of extrahepatic disease.