Systemic Viral Infections and Collateral Damage in the Liver

Abstract

The liver is involved in infections by hepatotropic viruses that replicate in the liver and for which the liver is the main target. These include hepatitis A, hepatitis B, hepatitis C, and hepatitis E viruses. In all of these infections, hepatitis and liver damage arise as a consequence of the immune response to virus within the liver.1 In addition, the liver can be affected as part of a generalized host infection with viruses that primarily target other tissues, particularly the upper respiratory tract. Examples of this phenomenon include the herpes viruses (Epstein-Barr virus, cytomegalovirus [CMV], and herpes simplex virus), parvovirus, adenovirus,2 and severe acute respiratory syndrome (SARS)-associated coronavirus.3 Liver involvement in nonhepatotropic viral infections can range from mildly deranged liver biochemistry to fulminant liver failure. In most of these infections, hepatitis is thought to be a consequence of an immune response to viral antigens with a close topographic association between the presence of viral antigens and the associated inflammatory infiltrates in the liver. Loss of immune control may be responsible for the development of hepatitis in CMV hepatitis4 and other opportunistic viral infections such as adenovirus.4 Similar activities may also be involved in SARS-associated hepatitis, which is characterized by focal lobular lymphocytic infiltrates.5 The paper by Polakos et al6 in this issue of The American Journal of Pathology broadens the mechanism by which viruses can cause hepatitis by demonstrating that viral-specific CD8+ T cells, generated in response to a viral infection restricted to sites outside the liver, can trigger T-cell-mediated hepatitis in the absence of viral antigens in the liver. They describe the involvement of the liver during pulmonary infection with influenza virus and demonstrate that hepatitis can occur even in the absence of detectable virus in the liver. The authors describe the hepatitis in influenza infection as “collateral damage” and suggest that it occurs as a consequence of the recruitment to the liver of CD8+ effector T cells that expand systemically in response to the viral infection. These observations are of great importance for understanding the involvement of the liver in systemic infections and elucidate some of the clinical syndromes of liver inflammation that cannot be easily explained by invoking antigen-specific T-cell responses in the liver.