NIH Consensus Development Conference on
Management of Hepatitis C
It has become apparent that hepatitis C virus (HCV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. Evidence linking HCV with HCC includes the following: (l) A high proportion of patients with HCC have anti-HCV or HCV RNA detectable in serum. This is particularly apparent in southern Europe and Japan where 50-75 percent of patients with HCC have evidence of HCV infection. (1-3) (2) In patients with chronic HCV infection, progression can be noted from milder forms of hepatitis to cirrhosis and eventually, to HCC. This progression may take decades to occur.
The precise mechanism by which HCV causes HCC is not known. Unlike the hepatitis B virus (HBV), HCV is not a DNA virus and does not become integrated within the genome of hepatocytes. It is more likely that HCC occurs against a background of inflammation and regeneration, associated with liver injury due to chronic hepatitis. Most, but not all, cases of HCV-related HCC occur in the presence of cirrhosis, suggesting that it is the underlying liver disease per se that is the risk factor for HCC rather than HCV infection. (4) The prevailing hypothesis has been that some cirrhotic nodules which grow larger than others (referred to as adenomatous hyperplasia) were the precursor for HCC. Recently, however, it has been suggested that foci of transformed hepatocytes may arise in between cirrhotic nodules and grow to become adenomatous hyperplasia and, eventually, HCC. (5)
Host factors which have been implicated in increasing the risk for development of HCC include age, male gender, and severity of underlying liver disease. Viral genotype may be important, although early suggestions that infection with genotype lb is more likely to result in the development of HCC have not been confirmed in larger studies. (6) Although viral load has been related to the severity of liver disease, no clear link has been established between serum levels of HCV RNA and progression to HCC. Some external factors that might add to the risk for HCC in patients with HCV infection include alcohol consumption, coexistent HBV infection, and porphyria cutanea tarda, although this latter condition is found only in some geographic areas.
The risk for a patient with HCV infection developing HCC cannot be calculated with any precision. It is known that approximately 20 percent of patients with chronic HCV infection develop histologic evidence of cirrhosis over a 10-year period. Furthermore, among patients with established cirrhosis due to HCV infection in screening programs, it has been found that 31 percent per year develop HCC, at least for the first 4-5 years of screening. (7,8) By extrapolation, after 20 years of infection, 6-8 percent of patients with chronic hepatitis C can be expected to have developed HCC, although these calculations need to be validated by more prospective studies. Studies from Japan have found that the mean interval from HCV infection to the development of HCC is approximately 25 years, but these periods have a very wide range of variation. (9) In the United States, HCC has been described as soon as 5 years from the onset of HCV infection. (4)
Typically, HCC carries a poor prognosis, with survival times from diagnosis measured in months. Screening studies have shown that small amounts of HCC can be detected at an early stage when it may be more amenable to curative therapy. (7) At present surgical resection offers the best hope for prolonged disease-free survival. This may take the form of partial or total hepatectomy. Unfortunately, partial hepatectomy for HCC is associated with a very high recurrence rate (approximating 25 percent per year) while total hepatectomy implies liver transplantation. Thus, the true cost-effectiveness of screening for HCC remains uncertain.
It has been suggested that progression to HCC can be halted or slowed down by treatment of the underlying hepatitis C. Recent studies from Japan, for example, have suggested that patients with cirrhosis due to chronic HCV infection have a significantly lower risk of HCC if treated with alpha interferon than patients who were not treated. (8) This improvement in risk was noted both in patients who had a good response to interferon as well those who did not. Data from these studies await confirrnation in Europe or the United States.
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