Although alcohol intake and hepatitis C virus (HCV) infection are the major determinants of liver cirrhosis (LC) in Western countries, the joint effect of these two factors on LC risk has not yet been adequately studied. We used data from two hospital-based case-control studies performed in Italy. Cases were 285 cirrhotic patients admitted for the first time to district hospitals for liver decompensation. Controls were 417 patients admitted during the same period, and in the same hospitals as the cases, for acute diseases unrelated to alcohol. Alcohol consumption was expressed as lifetime daily alcohol intake (LDAI). Serum HCV antibodies (anti-HCV) were detected using a secondgeneration test and recombinant immunoblotting assay. We found a dose-effect relationship between LDAI and the risk of LC in both anti-HCV-negative and -positive subjects. Considering the extreme LDAI categories (LDAI ؍ 0 g, lifetime teetotalers, and LDAI ؍ 175 g), the LC odds ratios increased from 1.0 (reference category) to 15.0 (95% CI, 7.1-31.7) and from 9.2 (95% CI, 2.0-43.2) to 147.2 (95% CI, 42.1-514.3) in anti-HCV-negative and -positive patients respectively. The interaction between LDAI and HCV showed an additive structure for LDAI F50 g/day and a multiplicative structure for consumption G125 g/day. Alcohol intake and HCV infection are independent risk factors for symptomatic liver cirrhosis, each being sufficient to induce the disease. In subjects with high alcohol intake, the coexistence of HCV infection multiplies the alcohol-associated risk of cirrhosis. In subjects with low alcohol intake, other factors could be involved. (HEPATOLOGY 1998;27:914-919.) Alcohol intake represents the main determinant of liver cirrhosis in Italy 1,2 and other Western countries. Evidence in this respect has been given by ecological, 3-5 prevalence, 6-9 case-control, 10-15 and cohort studies. However, several observations suggest that other factors should interact with alcohol consumption in causing liver damage. In alcoholics, liver histology is normal in 5% to 25% of biopsies and 18% of autopsy findings, and cirrhosis develops at a low yearly incidence rate of around 2%. Thus, only 10% to 25% of alcoholics will suffer from cirrhosis during their life. Among these interacting factors, the role of chronic infection with hepatitis B virus is still debated. Similarly, despite the initial suggestion that chronic infection with hepatitis C virus (HCV) may multiplicatively interact with alcohol intake in determining cirrhosis, 27 recent evidence suggests that these two factors act independently. The aim of the present study was to assess, using a case-control design, the risk of developing liver cirrhosis associated with alcohol intake, HCV infection, and the combined action of these factors.
PATIENTS AND METHODS
Selection of Cases and Controls.
We used the data from two hospitalbased case-control studies performed with the same design in two different periods and in two different Italian areas.
The design of the studies considered as cases the patients admitted to the medical departments of the six district hospitals of the province of L'Aquila (central Italy: first study) or to the gastroenterology unit of a district hospital of Turin (northern Italy: second study), for signs of liver decompensation (ascites, jaundice, edema) or bleeding from ruptured esophageal varices, in whom the diagnosis of cirrhosis was made for the first time by percutaneous liver biopsy. Exclusion criteria were invalidating hepatic encephalopathy, coexisting hepatocellular carcinoma, or a final diagnosis of primary biliary cirrhosis. Thus, we enrolled 115 cases during the period from November 1989 to May 1990 (first study) and 170 cases during the period from February to November 1993 (second study).
The control patients were enrolled during the same period as the cases, after admission to the same hospitals for acute diseases unrelated to alcohol consumption. Exclusion criteria were actual admission to orthopedic, infectious disease, psychiatry, gynecology or obstetric departments; and actual presence of gastroenterological, metabolic, neoplastic, or cardiovascular diseases. Thus, we enrolled 417 patients (167 and 250 in the first and second study respectively) admitted for minor surgical operations (48.7% and 48.2%), acute urinary tract diseases (20.9% and 22.9%), and nontraumatic dental/ ocular or ear/nose/throat diseases (30.4% and 28.8%).
Data Collection. All 702 patients were interviewed a few days after admission by a trained interviewer blinded with respect to the aim of the study. The interview was presented as part of routine recording of the medical history in the hospitals involved in the study. Thus, no specific patient consent was required by the local ethical authority and the participation rate was 100%. A structured questionnaire was used to collect social, demographic, and life-style information, including alcohol consumption.
Alcohol consumption was assessed retrospectively, dividing the Abbreviations: HCV, hepatitis C virus; LDAI, average lifetime daily alcohol intake; HBsAg, hepatitis B virus surface antigen; anti-HCV, antibodies against HCV; RIBA, recombinant immunoblot assay; OR, odds ratio; CI, confidence interval; D-statistics, D ϭ Ϫ2 ln of the likelihood ratio; df, degrees of freedom; LC, liver cirrhosis.