A possible causative role for the recently discovered hepatitis C virus (HCV) in the development of hepatocellular carcinoma (HCC) was investigated by assay of sera from HCC patients in Japan for antibodies to a recombinant HCV antigen and to hepatitis B virus (HBV) antigens. Among the 253 HCC patients examined, 156 (61.7%) had no serum markers of either a previous or a current HBV infection (group I), 46 (18.2%) were negative for HBV surface antigen but positive for anti-HBV surface and/or anti-HBV core antibody, indicating the occurrence of a previous, transient HBV infection (group II), and 51 (20.2%) were chronically infected HBV carriers as evidenced by positivity for HBV surface antigen (group Ill). The prevalence of HCV antibody in group I (68.6%) and II (58.7%) patients was significantly higher than for group m1 (3.9%) or in 148 additional patients with other (non-HCC) cancers (10.1%) (P < 0.01). Thus, there appears to be a strong association between HCV infection and the development of HCC, particularly in patients for which HBV infection cannot be implicated as a causative factor. The data also suggest an additional mode of transmission for HCV other than blood transfusion, since a history of blood transfusion was shown in only about 30% of the HCV antibodypositive HCC patients in groups I and 11. A high prevalence of HCV antibody was also shown among patients with HCC whose disease was originally thought to be due to very high ethanol consumption.The development of specific serological tests for infection by hepatitis A virus (HAV) and hepatitis B virus (HBV) has revealed that a large proportion of hepatitis cases are not caused by either ofthese agents (1-3). The resultant diagnosis of exclusion, non-A, non-B hepatitis (NANBH), now accounts for 95% of all posttransfusion hepatitis and over one-third of sporadic, acute hepatitis cases in Japan. Although symptoms in the acute phase of this disease are generally less severe than with HAV or HBV infection, NANBH is much more likely to develop into a persistent, chronic state. Over 50% of posttransfusion NANBH cases become chronically infected versus less than 10% in the case of HBV infections; typically, no chronicity results from infection by HAV. It is also clearly established that chronic NANBH can develop into hepatic cirrhosis (4-6). Accumulated serological, pathological, epidemiological, and clinical evidence suggests a significant association ofthe HBV carrier state with hepatocellular carcinoma (HCC) (7,8). In Japan, however, less than one-third ofHCC patients are also chronic HBV carriers, and the number of surgically treated HCC cases with no serological markers of prior or current HBV infection has increased steadily in Japan during the last 10 years (9). This suggests another causative factor(s). It has been hypothesized that NANBH virus(es) might be the missing causative agent in HCC development (10)(11)(12)(13)(14).The etiological agent(s) of NANBH has long been sought by many research groups (15,16), and recently a NANBH agent, ter...

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A cDNA clone has been derived from the plasma of a chimpanzee with chronic non-A, non-B viral hepatitis (NANBH). We have assayed for antibodies reacting with the encoded antigen in sera from posttrnnsfusion hepatitis patients (643 samples from 23 patients) and their corresponding donors collected during the past 10 years in Japan. The antibody was detected in 15 out of 17 (88.2%) posttransfusion NANBH (PT-NANBH) patients whose sera over time displayed multiple alanine aminotransferase (ALT) peaks. In general, the antibody was detected after several peaks of serum ALT elevations and, once detected, it persisted for years. In contrast to the patients of chronic hepatitis, the antibody was barely detected in patients with a single episode of ALT elevation (1 out of 6). Of the 15 well-dermed cases of PT-NANBH that showed multiple ALT peaks and hepatitis C virus seroconversions, 11(73.3%) were shown to be transfused with at least one unit of blood positive for the antibody. The retrospective analysis showed that all tested donor blood found to be positive for the antibody had been transfused to recipients who afterwards developed NANBH. These data strongly suggest that the cloned cDNA originated from an etiological agent of NANBH termed the hepatitis C virus. Furthermore, the present study demonstrates that had the screening been done with the anti-hepatitis C virus assay, 11 out of 17 (64.7%) cases of chronic PT-NANBH and 1 out of 6 (16.6%) acute PT-NANBH would have been prevented. The antibody assay thus can be used for diagnosis and blood screening for PT-NANBH.Even though donor blood is routinely screened for the hepatitis B virus (HBV) with sensitive assays, about 10% of blood transfusion recipients still develop viral hepatitis (refs. 1 and 2; T.K., unpublished data). Non-A, non-B hepatitis (NANBH) virus(es) is responsible for over 90%o of the posttransfusion hepatitis (PTH) cases and causes a serious health problem throughout the world. NANBH is much more likely to become chronic than HBV-induced hepatitis and often progresses to chronic liver disease, including liver cirrhosis (3, 4). A role for NANBH in the development of hepatocellular carcinoma has also been suggested (5, 6).The genome of a NANBH virus, termed hepatitis C virus (HCV), was cloned recently and shown to contain a positivestranded RNA molecule (7). An assay for circulating viral antibodies was developed by using an HCV antigen purified from recombinant yeast clones to capture reactive antibodies. Results obtained using this assay indicated that HCV is a major cause of transfusion-associated NANBH throughout the world as well as community-acquired NANBH in which no previous parenteral exposure to the virus could be identified (8).In this study, we assayed for HCV antibody in wellpedigreed transfusion-associated NANBH patients in Japan. The serum samples were from patients diagnosed on the basis of clinical presentation in the absence of markers indicating infection with HBV and hepatitis A virus (HAV).-The recipient sera were a series ...

Recently, a cDNA from the hepatitis C virus (HCV) RNA genome has been isolated in the USA from a chronically infected chimpanzee. In order to isolate HCV cDNA derived from human material, RNA was extracted from plasma of a Japanese blood donor implicated in post-transfusion non-A, non-B hepatitis and HCV cDNA was synthesized and amplified by the PCR method using HCV-specific oligonucleotide primers. The cDNA fragment, 583 nucleotides long, showed 79.8% homology at the nucleotide level and 92.2% homology at the amino acid level compared with the prototype HCV cDNA. These results provides further evidence to show that HCV is closely associated with the development of post transfusion non-A, non-B hepatitis.

Most cases of hepatitis C virus (HCV) infection result inHepatitis C virus (HCV) is the most important causative agent of blood-borne non-A non-B hepatitis, infecting a million people a year worldwide.