Seronegative occult hepatitis C virus infection: what is its clinical relevance?

Occult hepatitis C virus infection (OCI) is defined by the presence of detectable HCV-RNA in liver tissue but not in serum without detectable anti-HCV antibodies (seronegative or primary OCI) or with detectable anti-HCV antibodies (seropositive or secondary OCI). The latter is considered a persistence of virus activity after appropriate antiviral therapy, whilst the former may be related to a mutation which prevents virus encapsidation, and the immune system from mounting an appropriate response. Seronegative OCI has been widely investigated as a possible cause of liver damage in patients with hepatitis, cirrhosis and in liver transplant recipients. OCI has been searched for in cryptogenic liver disease, alcoholic and non-alcoholic fatty liver disease, hepatitis B virus infection and hepatocellular carcinoma, as concomitant cause of liver damage. Liver biopsy is currently the gold standard for diagnosis of OCI. Non-invasive tests, such as search for HCV-RNA in peripheral blood mononuclear cells, can also reach acceptable diagnostic accuracy. Response to antiviral therapy has been reported. However, more studies are needed to determine whether treatment can modify morbidity and/or mortality associated to liver disease. OCI has also been investigated in special populations, like kidney transplant recipients or human immunodeficiency virus-infected patients, as worsening factor of the underlying disease. Lastly, some studies have been conducted on healthy populations, such as blood donors, with consequent concern arising from possible asymptomatic OCI infectivity. Few observational studies with a long-term follow-up have been conducted, with discordant results. Additional and larger studies are needed to clarify the natural course of OCI and to assess its clinical implications. In this review we discuss these aspects of OCI.