To elucidate the risk factors for liver carcinogenesis and to examine the incidence of hepatocellular carcinoma (HCC) after interferon therapy, 1,022 chronic hepatitis C patients treated with interferon were followed by ultrasonography for 13 to 97 months (median 36 months). Sustained response with prolonged alanine aminotransferase normalization was found in 313 patients, transient response with alanine aminotransferase relapse after therapy in 304, and no response in 405. Forty-six developed HCC, of whom 5 were sustained responders, 9 were transient responders, and 32 were nonresponders. The cumulative incidence of HCC in transient responders was almost equal to that in sustained responders, and it was significantly higher in nonresponders than in sustained and transient responders (P ‫؍‬ .0009). The seventh-year cumulative incidence rates of HCC in sustained responders, transient responders, and nonresponders were estimated to be 4.3%, 4.7%, and 26.1%, respectively. However, there was no significant difference in the cumulative incidence of HCC between patients with HCV subtype 1 and 2 (P ‫؍‬ .14). Cox regression analysis showed that the risk of HCC development was not elevated in transient responders compared with sustained responders, but that the risk was 7.90-fold higher in nonresponders than in sustained responders (P ‫؍‬ .008). Patients H55 years of age had a significantly higher risk ratio (4.65) than did those under 55 years of age (P ‫؍‬ .006). The risk of HCC development in men was 4.35 times higher than the risk in women (P ‫؍‬ .02). However, the degree of fibrosis was not a significant risk factor for the development of HCC (risk ratio, 3.16; P ‫؍‬ .052). These results suggest that patients in the high-risk group of HCC after interferon therapy were those who showed no response, those who were older, and those who were male, and that such patients should be carefully followed using ultrasonography.(HEPATOLOGY 1998;27:1394-1402.) Hepatocellular carcinoma (HCC) is one of the most common malignancies, especially in Southeast Asia. In Japan, its incidence has been increasing over the last 30 years, and epidemiological surveys have shown that as a causative agent, hepatitis C virus (HCV) is more common than hepatitis B virus. Chronic hepatitis C has been demonstrated to evolve to cirrhosis and HCC. 1,2 When blood transfusion is the cause, the intervals from its administration to the diagnosis of cirrhosis and HCC have been reported to be 20 to 25 years and 30 years, respectively. 2 The incidence of HCC has been shown to be higher in patients with chronic hepatitis C than in those with chronic hepatitis B. 3 Moreover, the HCC occurrence rate in cirrhotic patients with antibodies to HCV has been reported to increase steadily, with a yearly incidence of 1.4% to 7%. [4][5][6] Thus, a majority of cases with chronic HCV infection progress slowly to liver cirrhosis and HCC.In Japan, more than two hundred thousand patients with chronic hepatitis C have been treated with interferon. Many investigators have repo...

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The long-term impact of acute self-limited hepatitis B on the liver is unknown. Fourteen patients were recalled at a median of 4.2 years (range, 1.8-9.5 years) after the onset of acute hepatitis B. All showed clinical and serologic recovery with circulating hepatitis B surface antigen (HBsAg) clearance. Antibody to HBsAg (anti-HBs) had developed in 12 patients. Nine underwent liver biopsies at a median of 7.2 years, and histologic findings were evaluated using Ishak scores. Serum samples and frozen liver tissue were subjected to real-time detection polymerase chain reaction (PCR) to quantify the surface and X regions of the hepatitis B virus (HBV) genome and qualitative PCR to detect the covalently closed circular (ccc) HBV DNA replicative intermediate. Three patients had low levels of circulating HBV DNA up to 8.9 years after the onset, whereas both HBV DNA surface and X regions were found in the liver of all 9 patients examined, including 7 negative for serum HBV DNA. Liver viral loads assessed by the 2 regions showed a significant correlation (r ‫؍‬ 0.946; P ‫؍‬ .008), and all patients tested positive for ccc HBV DNA. Liver fibrosis and mild inflammation persisted in 8 patients. The fibrosis stage had relation to peak serum HBV DNA in the acute phase (P ‫؍‬ .046) but not to liver viral loads in the late convalescent phase. T he clearance of circulating hepatitis B surface antigen (HBsAg) and appearance of antibody to HBsAg (anti-HBs) with normalization of liver function have been generally accepted as evidence of clinical and serologic recovery from acute hepatitis B. However, in chronic HBsAg carriers, there is growing evidence that hepatitis B virus (HBV) DNA sequences persist in the liver for years after seroclearance of HBsAg and seroconversion to anti-HBs. 1-3 Although the clinical and pathologic implications of occult HBV infection in the liver are unknown, viral eradication is unlikely to be achieved once chronic HBV infection has been established. The cytotoxic T-lymphocyte (CTL) response is weak or undetectable in chronic HBV infection. In contrast, a vigorous, polyclonal, and HBV-specific CTL response against multiple HBV epitopes is readily detectable during acute self-limited HBV infection. 4-7 HBV-specific CTLs further persist in the blood for several decades after recovery from acute hepatitis B. 7,8 In the face of an enhanced immune response leading to disease resolution, the virologic outcomes of acute self-limited hepatitis B may differ from those of HBsAg seroclearance and anti-HBs seroconversion in the course of chronic HBV infection.At present, the long-term histologic and virologic impact of acute self-limited hepatitis B on the liver is unexplored. Studies using polymerase chain reaction (PCR) to detect HBV DNA sequences have shown that low levels of circulating HBV DNA can persist after clinical and serologic recovery from acute hepatitis B but tend to disappear after long-term follow-up. 9,10 Peripheral blood mononuclear cells are known as the site of persistent HBV infection long afte...

The human leukocyte antigen is a crucial genetic factor that initiates or regulates immune response by presenting foreign or self antigens to T lymphocytes. The aim of this study was to investigate whether HLA polymorphism is associated with the onset or progression of liver injury in

Apoptosis is a type of cell death that occurs in acute or chronic hepatitis. It has been suggested to be mediated through Fas antigen. To evaluate the role of apoptosis on liver injury of chronic hepatitis C, we studied the expressions of Fas antigen and hepatitis C virus antigen (core antigen) immunohistochemically. Forty liver biopsy samples from patients with type C chronic liver disease were immunostained for Fas antigen and hepatitis C virus antigen. Expression of Fas antigen was found mainly in the cytoplasm of hepatocytes, and these positive cells were found particularly among infiltrating lymphocytes at the advancing edges of "piecemeal necrosis." The histological activity index showed inflammation of both portal and periportal areas to be more severe in the Fas antigen-positive samples than in the Fas antigen-negative ones (p < 0.05 and p < 0.001, respectively). Furthermore, semiquantitative analysis revealed more expression of Fas antigen in the liver tissues with active inflammation than in those without it (p < 0.01). The prevalence of Fas antigen expression in the hepatitis C virus antigen-positive group was higher than that in the hepatitis C virus antigen-negative group (p < 0.05). Our findings suggest that Fas antigen expression (apoptosis) plays an important role in inflammation in the hepatitis C virus-infected liver, particularly in the active inflammation of chronic hepatitis C.