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During a 4-year period from January 1995 to December 1998, blood samples and questionnaire data were obtained from 333 incident cases of hepatocellular carcinoma (HCC), as well as from 360 controls who were hospitalized for eye, ear, nose, throat or orthopedic conditions in Athens, Greece. Coded sera were tested for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) by third-generation enzyme immunoassays, and information on smoking habits and beverage consumption was obtained. We found a significant dose-response, positive association between smoking and HCC risk [>/= 2 packs per day, odds ratio (OR)=2.5]. This association was stronger in individuals without chronic infection with either HBV or HCV (>/= 2 packs per day, OR=2.8). Consumption of alcoholic beverages above a threshold of 40 glasses per week increased the risk of HCC (OR=1.9). We also found evidence of a strong, statistically significant and apparently super-multiplicative effect of heavy smoking and heavy drinking in the development of HCC (OR for both exposures=9.6). This interaction was particularly evident among individuals without either HBsAg or anti-HCV (OR for both exposures=10.9). Coffee intake was not positively associated with HCC risk, but the reverse could not be excluded for the subgroup of chronically infected individuals. In conclusion, tobacco smoking and heavy alcohol consumption are associated with increased risk of HCC, especially when these 2 exposures occur together., (Copyright 2000 Wiley-Liss, Inc.)

Objectives: The purpose of this study was to describe the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) in the etiology of hepatocellular carcinoma (HCC)., Methods: During a 4-year period from January 1995 to December 1998, blood samples and questionnaire data were obtained from 333 incident cases of HCC from Athens, Greece, as well as from patients in two control groups, also from Athens. Controls were 272 metastatic liver cancer (MLC) patients and 360 patients hospitalized for injuries or eye, ear, nose or throat conditions. Coded sera were tested for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) by third-generation enzyme immunoassays., Results: The odds ratios (with 95% confidence intervals) in logistic regression modeling comparing the HCC cases to the combined control series were 48.8 (30.5-78.3) for the presence of HBsAg and 23.2 (11.4-47.3) for the presence of anti-HCV. The odds ratio for concurrent infection with HBV and HCV was 46.2 (9.9-216.6) compared to infection with neither virus., Conclusions: Although HBV and HCV are both important causes of HCC in this study population the data do not suggest, neither do they conclusively refute, a super-additive interaction between the two infections in the development of this malignancy. In this population, 58% of HCC cases can be attributed to HBV, 12% to HCV, and 3% to dual infection with these viruses.

In an ongoing case-control study in Athens on the etiology of hepatocellular carcinoma (HCC), an analysis was made in order to assess whether HCV genotype 1b is associated with hepatocellular carcinoma (HCC). The HCV genotype was determined in 17 HCC patients, 87 patients with chronic hepatitis C (CHC) without cirrhosis (NC-CHC) and 23 patients with CHC and cirrhosis (C-CHC). HCV genotype 1b was detected in 14/17, 16/23 and 23/87 of HCC, C-CHC and NC-CHC respectively. The age- and gender-adjusted odds ratios contrasting HCC with NC-CHC and C-CHC with NC-CHC were 8.3 and 3.8 respectively. These data strongly support the hypothesis that HCV 1b is a stronger liver carcinogen than other HCV genotypes, probably through increased HCV replication and enhanced liver cytopathicity.

During a 16-month period in 1991-1992, blood samples and questionnaire data were obtained from 65 incident cases of hepatocellular carcinoma (HCC) as well as from 2 control groups of hospitalized patients matched on gender and age, which included 65 metastatic liver cancer (MLC) patients and 65 patients hospitalized for eye, ear, nose or throat conditions. Coded sera were tested for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen, antibody to HBsAg and antibody to hepatitis C virus (anti-HCV) by enzyme immunoassay. The odds ratios (with 95% confidence intervals) in logistic regression modeling comparing the HCC cases to the combined control series were 18.8 (8.2-43.2) for the presence of HBsAg and 7.7 (1.7-35.1) for anti-HCV. In the present hospital-based case-control study anti-HCV testing was conducted on recently collected sera, using a second-generation enzyme immunoassay with confirmation by immunoblot assay. Comparisons with previous work in a similar population demonstrated that, when second-generation anti-HCV assays are applied to sera stored for 7-15 years, confirmatory assays or a higher diagnostic cut-off point may be necessary to ensure that the testing is specific.

The aim of this study was to evaluate the prevalence of hepatitis C virus infection (HCV) in Greece, to estimate its frequency in chronic liver disease and to explore the role of HCV infection in the aetiology of hepatocellular carcinoma. A series of 1034 patients with chronic liver disease of various aetioloigies and 299 patients with hepatocellular carcinoma allocated to two case-control studies was tested for anti-HCV. Twelve recent reports on HCV infection in Greece were reviewed and analyzed. The results of the present study indicate the existence of a large pool of HCV infection in Greece and an impressive spread of the virus in high-risk groups. Chronic HCV infection was found to account for 83.6% of patients with chronic non-A, non-B hepatitis parenterally transmitted, 56.5% of cases of sporadic community-acquired disease and for almost 1/4 of all patients with chronic liver disease. The relative risks for development of hepatocellular carcinoma of patients with chronic HCV infection was 6.3 in the first and 13.7 in the second case-control study, increasing to 20.0 and 18.7, respectively, when hepatitis B surface antigen (HBsAg) was positive. Serum HBV-DNA was positive and/or anti-HBc IgM levels were high in 12 of 15 (80%) patients with hepatocellular carcinoma positive only for HBsAg, and in 7 of 15 (47%) positive both for HBsAg and antibodies to HCV. The present data support the view that hepatitis B and C virus have an interacting role in the origin of hepatocellular carcinoma.

It is frequently assumed that the risk of hepatocellular carcinoma related to hepatitis B virus is higher when chronic hepatitis B virus infection is acquired early in life. This hypothesis has never been directly evaluated. However, firstborn and secondborn children are exposed to common infections after their school enrollment, whereas laterborn children are exposed much earlier, through their older siblings. The authors analyzed sibship size and birth order data from a large case-control study of patients admitted to Athens, Greece, hospitals between April 1976 and October 1984. The analyses included 185 patients with hepatocellular carcinoma, 35 patients with metastatic liver cancer, and 432 other hospital controls. There was a tendency for cases of hepatocellular carcinoma to concentrate at higher birth orders. When the analysis was restricted to cases and controls who were positive for hepatitis B surface antigen, this tendency was even more notable. These results are compatible with the hypothesis that establishment of chronic hepatitis B virus infection at an early age increases the risk of hepatocellular carcinoma substantially more than does chronic infection with this virus established at a later age.

Stored sera from 181 Greek patients with hepatocellular carcinoma (HCC), 35 patients with metastatic liver cancer, and 416 hospital controls with diagnoses other than malignant neoplasm or liver disease were examined with first and second generation hepatitis C virus (HCV) enzyme immunoassays as well as with five HCV supplemental assays based on structural and nonstructural HCV peptides. Second generation HCV enzyme immunoassays were more sensitive than first generation assays. However, both assays had suboptimal specificity using the standard reactivity criterion (absorbance of sample to cutoff greater than or equal to 1.0). Specificity was improved by centrifugation and by using a sample's optical density to cutoff ratio greater than or equal to 3.0 or supplemental assays; in this instance the prevalence of antibodies to HCV was 13.3% (24 of 181), 0 (0 of 35), and 1.4% (6 of 416) in HCC, metastatic liver cancer, and hospital controls, respectively. A similar estimation of prevalence of antibody to HCV in HCC (12.5% or 4 of 32) was obtained when the recombinant immunoblot assay, second generation, was used to screen a random sample of HCC patients. The relative risk linking HCV to HCC was estimated as 10.4 (95% confidence interval, 4.2-26.0; P less than 0.0001). These data suggest that the prevalence of antibodies to HCV in HCC using stored sera has been previously overestimated even though the evidence of a causal association of HCV with HCC persists.

A recently introduced enzyme immunoassay procedure for antibodies against the hepatitis-C virus (HCV) was used to test samples from 185 cases with hepatocellular carcinoma (HCC) and 432 hospital controls. The anti-HCV results were examined in conjunction with previously reported data from this study concerning hepatitis-B virus (HBV) serology, hepatitis-D virus (HDV) antibodies, presence of cirrhosis and tobacco smoking. There was evidence for interaction between HBV and HCV in the causation of HCC: as previously reported, the rate ratio (RR) linking the presence of anti-HCV to HCC among subjects positive for hepatitis-B surface antigen (HBsAg) was substantially higher than the corresponding RR among those negative for this marker; furthermore, among HCC patients positive for HBsAg, a high proportion (33/61) of those who were positive for hepatitis-Be antigen (HBeAg) or its antibody were positive for anti-HCV, whereas among HBsAg-positive controls who were also positive for HBeAg or its antibody, none was positive for anti-HCV (0/18; p less than 10(-4)). The anti-HCV-related RR for HCC was also higher among HCC patients with cirrhosis than among those without evidence of co-existing cirrhosis (RR 11.4 vs. 4.4; p = 0.06). In addition, there was some evidence of interaction between tobacco smoking and HCV in the origin of HCC; after controlling for age, sex and HBsAg status, the RR for subjects positive for anti-HCV was 6.8 among smokers but only 3.2 among non-smokers (p = 0.26). By contrast, there was no suggestion of an interaction between anti-HCV and anti-HDV, in agreement with the presumed minimal role, if any, of HDV in HCC etiology. These results support the notion that HCV is involved in the etiology of HCC by advancing, through a chronic liver disease process, carcinogenesis initiated by other factors.

Serum taken from patients in a case-control study in Athens, Greece, was used to examine the interactive roles of hepatitis B virus (HBV) and hepatitis C virus (HCV) in the origin of hepatocellular carcinoma (HCC). An enzyme immunoassay for anti-HCV was used to test serum taken from 185 cases with HCC, 35 cases with metastatic liver cancer (MLC), and 432 hospital controls. Weakly positive anti-HCV results were more strongly related to MLC than to HCC, implying that these anti-HCV results are false positive. By contrast, strongly positive anti-HCV results were significantly related to HCC (relative risk [RR], 6.3), whereas no significant association was evident for MLC (RR, 0.6). The association of anti-HCV with HCC was substantially higher among subjects whose radioimmunoassay was positive for hepatitis B surface antigen (RR, 20.0) than among those whose radioimmunoassay was negative for this marker (RR, 4.8). These findings indicate that HCV infection has an interactive role in the origin of HCC.

Sera from 87 patients with hepatitis B surface antigen (HBsAg)-positive hepatocellular carcinoma (HCC) and from 29 HBsAg-positive hospital controls were tested for delta (delta) antigen with an immunoenzymatic procedure and for anti-delta antibody, hepatitis Be antigen (HBeAg) and antibody to HBeAg (anti-HBe) by radioimmunoassay. All the sera, from both the HCC cases and the control patients, were negative for delta-antigen. Among the HCC cases 9 were positive for serum anti-delta (10%) whereas among the controls none was positive for this antibody (p = 0.067); the anti-delta-positive cases were found only among HCC patients negative for HBeAg. The lower prevalence of anti-delta among HBsAg-positive HCC patients, as compared to the corresponding prevalence among HBsAg-positive patients with chronic active hepatitis or cirrhosis (reported in the literature) indicates that the pathogenesis of HCC is frequently independent of the pathogenesis of the other HBsAg-positive common chronic liver diseases. By contrast, the higher prevalence of anti-delta among HBsAg-positive HCC cases than among HBsAg-positive controls may reflect the longer average duration of the carrier state in HCC patients (until integration is accomplished and the induction period completed). Serum HBeAg was higher among HBsAg-positive HCC patients with cirrhosis (23%) than among HBsAg-positive HCC patients without cirrhosis (6%) or HBsAg-positive controls (3%); thus, the conflicting results in the literature concerning the association of the HBeAg/anti-HBe system with HCC may be accounted for, in part, by the variable association of HCC with an underlying cirrhosis.

Tobacco smoking and alcohol drinking histories were obtained from 194 patients with hepatocellular carcinoma (HCC) and 456 hospital controls, and the results were analysed in conjunction with the results of serological determinations of hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) in all subjects, as well as the presence or absence of cirrhosis in HCC patients. The relative risk (RR) of HCC (and 95% confidence interval) among HBsAg-positive subjects was 13.7 (8.0-23.5), whereas the excess risk among antibody-positive subjects was small and statistically non-significant. In the presence of cirrhosis the RR for HBsAg-positive subjects was considerably higher (30.7 vs. 7.1 among HBsAg-positive subjects without cirrhosis) indicating that HBV may affect the development of HCC through at least two different and potentially multiplicative mechanisms (DNA integration and liver regeneration). Moderate ethanol consumption does not affect the risk of HCC, but there is a statistically significant and dose-dependent association between tobacco smoking and HBsAg-negative HCC. In most of the developed countries of Europe and North America, where the prevalence of HBsAg carrier state is very low and tobacco smoking very common, more cases of HCC may be due to tobacco smoking than to HBV, even though the RR for HCC is much higher among HBsAg carriers than among tobacco smokers.