SUMMARY A new antigen-antibody system associated with the hepatitis B virus and immunologically distinct from the HB surface, core, and e systems is reported. The new antigen, termed 3, was detected by direct immunofluorescence only in the liver cell nuclei of patients with HBsAg positive chronic liver disease. At present, the intrahepatic expression of HBcAg and 6 antigen appears to be mutually exclusive. No ultrastructural aspect corresponding to the antigen could be identified under the electron microscope. 8 antibody was found in the serum of chronic HBsAg carriers, with a higher prevalence in patients with liver damage. The nuclear fluorescence patterns of HBcAg and antigen were similar; it is only possible to discriminate between the two antigens by using the respective specific antisera.While studying liver biopsies from patients who were seropositive for the hepatitis B surface antigen (HBsAg) in direct immunofluorescence, it was noted that an antiserum against the hepatitis B core antigen (HBcAg), as well as staining specimens in which core particles could be demonstrated by the electron microscope (EM), also reacted with additional biopsies which did not contain core particles (at electron microscopy) and were negative with other reference antisera against HBcAg.When the EM core positive and core negative specimens were tested with several HBsAg positive sera, it soon became apparent that some sera reacted with either one or the other liver substrate; this suggested that there were two distinct nuclear antigenic specificities.The identification of this new antigen and of its antibody as an immunological system independent of other known reactions associated with the HB virus is reported in this communication. Provisionally, we propose that it should be called 6.

The small number of sufficiently reliable studies, the strong indications of heterogeneity across them and the suspicion of publication bias suggest that there is a great need for well-conducted epidemiological studies performed in several countries, to examine the dose-response relationship between alcohol intake and the risk of several alcohol-related conditions, as well as the role of drinking pattern in determining the risk.

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. 3 Evidence in this respect has been given by ecological, 3-5 prevalence, 6-9 case-control, 10-15 and cohort 16,17 studies. However, several observations suggest that other factors should interact with alcohol consumption in causing liver damage. [18][19][20] In alcoholics, liver histology is normal in 5% to 25% of biopsies and 18% of autopsy findings, 21 and cirrhosis develops at a low yearly incidence rate of around 2%. 16 Thus, only 10% to 25% of alcoholics will suffer from cirrhosis during their life. 22 Among these interacting factors, the role of chronic infection with hepatitis B virus is still debated. [23][24][25][26] 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. 28 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...

To assess the characteristics of chronic hepatitis in hepatitis B surface antigen (HBsAg) carriers with intrahepatic delta antigen, the hepatic histologic findings of 137 patients were reviewed; 101 patients were followed for 2 to 6 years. The predominant liver disease was chronic active hepatitis in 93 patients or cirrhosis in 32; minor forms of chronic persistent or lobular hepatitis were seen in 12 patients. Eight of the 26 patients with an initial diagnosis of cirrhosis died during the follow-up period. Cirrhosis developed in 31 of 75 patients (41%) without nodular regeneration seen in the first biopsy specimen; 5 of these patients died. Treatment with prednisone or azathioprine did not induce histologic amelioration of delta hepatitis or prevent cirrhosis. Chronic HBsAg hepatitis with intrahepatic expression of the delta antigen is an active, progressive disease unresponsive to conventional immunosuppressive treatment.

Acetaldehyde and malonildialdehyde can form hybrid protein adducts, named MAA adducts that have strong immunogenic properties. The formation of MAA adducts in the liver of chronic alcohol-fed rats is associated with the development of circulating antibodies that specifically recognized these adducts. The aim of this study was to examine whether MAA adducts might participate in the immune response associated with human alcohol-induced liver disease. Circulating antibodies against MAA adducts were evaluated in 50 patients with alcohol-induced hepatitis or cirrhosis, in 40 patients with non-alcohol-induced liver disease, in 15 heavy drinkers without liver damage and in 40 healthy controls by enzyme-linked immunosorbent assays (ELISA). Immunoglobulin G (IgG) reacting with MAA-modified proteins were significantly increased in the patients with alcohol-induced cirrhosis or hepatitis. The individual levels of anti-MAA IgG in those patients were associated with the severity of liver damage. Anti-MAA antibodies were also positively correlated with the levels of IgG recognizing epitopes generated by acetaldehyde and malonildialdehyde. However, competitive inhibition experiments indicated that the anti-MAA antibodies were unrelated to those against acetaldehyde-or malonildialdehydederived antigens and mainly recognized a specific, cyclic MAA epitope. Some degree of immune reactivity towards MAA adducts was also observed in patients with nonalcohol-induced liver injury. However, competitive ELISA showed that the antigens recognized by these sera were not the cyclic MAA adducts. Altogether, these results showed the formation of MAA antigens during alcohol-induced liver disease and suggest their possible contribution to the development of immunologic reactions associated with alcohol-related liver damage. (HEPATOLOGY 2000;31:878-884.)

In order to assess the interaction between alcohol intake, tobacco smoking and coffee consumption in determining the risk of liver cirrhosis we carried out a hospital-based case-control study involving 115 patients at their first diagnosis of cirrhosis and 167 control patients consecutively enrolled in the General Hospitals of the Province of L'Aquila (Central Italy). The mean life-time daily alcohol intake (as g ethanol consumed daily) was measured by direct patient interviews, whose reproducibility was > 0.80 and similar for cases and controls, as checked by interviewing the relatives of a sample of 50 cases and 73 controls. During the same patient's interview we also measured the mean consumption of coffee (daily number of cups of filtered coffee) and tobacco (life-time daily number of cigarettes smoked). A dose-effect relationship on the risk of cirrhosis was present both for alcohol intake--for which the risk was significantly increased above 100 g of daily intake--and for cigarette consumption. The latter did not however improve the goodness-of-fit of a logistic regression model including alcohol intake as covariate. By contrast, coffee consumption had a protective effect on the risk of cirrhosis and significantly improved the goodness-of-fit of such a model. Abstaining from coffee consumption determined both a significantly increased risk of cirrhosis, even for daily alcohol intake below 100 g, and a multiplicative effect with alcohol intake on this risk. In patients drinking > or = 101 g ethanol daily the relative risk increased from 5.5 (95% confidence interval: 1.4-22.0) for coffee consumers to 10.8 (95% confidence interval: 1.3-58.1) for coffee abstainers.(ABSTRACT TRUNCATED AT 250 WORDS)

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. 3 Evidence in this respect has been given by ecological, 3-5 prevalence, 6-9 case-control, 10-15 and cohort 16,17 studies. However, several observations suggest that other factors should interact with alcohol consumption in causing liver damage. [18][19][20] In alcoholics, liver histology is normal in 5% to 25% of biopsies and 18% of autopsy findings, 21 and cirrhosis develops at a low yearly incidence rate of around 2%. 16 Thus, only 10% to 25% of alcoholics will suffer from cirrhosis during their life. 22 Among these interacting factors, the role of chronic infection with hepatitis B virus is still debated. [23][24][25][26] 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. 28 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 desi...

The chronic use of alcohol can lead to the onset of an alcohol use disorder (AUD). About 50% of subjects with an AUD may develop alcohol withdrawal syndrome (AWS) when they reduce or discontinue their alcohol consumption and, in 3-5% of them, convulsions and delirium tremens (DTs), representing life-threatening complications, may occur. Unfortunately, few physicians are adequately trained in identifying and treating AWS. The Italian Society on Alcohol has, therefore, implemented a task force of specialists to draw up recommendations for the treatment of AWS with the following main results: (1) while mild AWS may not require treatment, moderate and severe AWS need to be pharmacologically treated; (2) out-patient treatment is appropriate in patients with mild or moderate AWS, while patients with severe AWS need to be treated as in-patients; (3) benzodiazepines, BDZs are the "gold standard" for the treatment of AWS and DTs; (4) alpha-2-agonists, beta-blockers, and neuroleptics may be used in association when BDZs do not completely resolve specific persisting symptoms of AWS; (5) in the case of a refractory form of DTs, the use of anaesthetic drugs (propofol and phenobarbital) in an intensive care unit is appropriate; (6) alternatively to BDZs, sodium oxybate, clomethiazole, and tiapride approved in some European Countries for the treatment of AWS may be employed for the treatment of moderate AWS; (7) anti-convulsants are not sufficient to suppress AWS, and they may be used only in association with BDZs for the treatment of refractory forms of convulsions in the course of AWS.