S11.1 IMPACT OF ALCOHOL DRINKING ON THE PROGRESSION AND TREATMENT OF CHRONIC HEPATITIS C AND B {#article-title-2} In chronic hepatitis C, male gender, older age, excessive alcohol consumption, immunosuppressive regimen, and HIV infection are independent risk factors of hospitalization. It is important to outline that alcohol abuse and HCV (and to a lesser extent HBV) frequently coexist in the same patient. Several studies have shown increased rate of fibrosis progression and development of cirrhosis in drinking HCV subjects compared with nondrinking HCV subjects. The structure of the interaction between lifetime daily alcohol intake and HCV is additive for consumption between 50 g to 125g /day and multiplicative for consumption above 125 g/day. It seems that alcohol increases apoptosis, lipid peroxidation and oxidant stress. Chronic alcohol intake is linked to a decreased therapeutic response to interferon, which may be corrected by alcohol withdrawal. Nevertheless, large data are still needed to assess HCV treatment efficacy in heavy drinkers. Although less data are available as compared to HCV infection, alcohol consumption also impacts fibrosis progression in chronic hepatitis B and blunts the risk of hepatocellular carcinoma. In terms of treatment, the potential negative impact of chronic alcohol consumption seems more likely to be related to a poor compliance rather than to a decrease in antiviral activity of oral drugs. Thus, patients with chronic hepatitis B and C should be advised to stop or at least to reduce alcohol consumption. # S11.2 DRUGS IN ALCOHOL ABUSERS: A POTENTIAL THERAPEUTIC MISADVENTURE {#article-title-3} It is generally accepted that drugs should be used with extreme caution in patients with chronic liver disease, due to alterations in xenobiotic metabolism, or interference with hemodynamic compensatory mechanisms (NSAIDs and renal failure for example). In addition to the commonly reported adverse events associated with drugs, patients with alcohol misuse should be considered at increased risk of drug-induced liver injury. The reasons for this include, 1) an overinduction of the cytochrome P-450 2E1 (involved in alcohol metabolism as well as other xenobiotics), with the risk of increased production of toxic metabolites and consecutive decreased glutathion reserve, 2) a decreased antioxidants stores (glutathion, vitamins), favoured by chronic alcohol and a poor nutritional status, and 3) the presence of a compensated or decompensated underlying alcoholic liver disease. Accordingly, hepatic steatosis (macro- or microvesicular), almost always associated with excessive alcohol consumption, increases the sensitivity of the liver to additional injury. Alcoholic steatohepatitis that frequently arises in a patient with underlying cirrhosis may not be clinically evident in mild to moderate presentations. Thus, a number of commonly prescribed drugs may either potentiate liver injury and therefore influence the natural history of alcoholic liver disease, or precipitate an acute episode in these patients with alcohol abuse. NSAIDs may induce microvesicular steatosis, and double the risk of gastrointestinal bleeding in the alcoholic patient. The risk of paracetamol hepatotoxicity, probably overestimated in the past, is increased by starvation and poor nutritional status. In the absence of such conditions, a daily dose of 2 grams can be given. Drugs that mimic alcoholic lesions (amiodarone, tamoxifen, diltiazem, nifedipine) should not be administered. The risk of fibrosis progression and cirrhosis described with the antirheumatic agent methotrexate is associated with the regular use of alcohol, as well as the cumulative dose. However, in the absence of liver fibrosis, methotrexate can be prescribed to patients with regular alcohol consumption using provided that non-invasive markers are used for monitoring. Overall, drug prescription in patients with alcohol abuse should be carefully evaluated with regards to indication, absolute contraindication, and risks. Liver function tests, non-invasive markers of fibrosis and liver biopsy should be used to detect drug-induced liver injury. # S11.3 THE OBESE ALCOHOLIC: NASH/ASH INTERACTIONS {#article-title-4} The strict separation between alcoholic and non-alcoholic liver fatty liver disease (NAFLD) is increasingly recognized as deceitful. In fact, a large number of individuals presenting with excessive alcohol consumption, have significant metabolic risk factors, such as obesity, diabetes, dyslipidemia, and hypertension. On the other hand, patients with metabolic risk factors often have concomitant alcohol consumption, that although modest may be a significant co-factor in progression of the disease. In fact, according to a population-based study of Health in Pomerania, it was found a broad overlap between obesity and excessive alcohol consumption (Volzke, WJG, 2012). Furthermore, both entities have similar histopathological patterns. Several years ago, we showed that the clinical and biochemical presentation of a group of ambulatory (stable) alcoholic hepatitis patients was very similar to that of non-alcoholic steatohepatitis patients (Pinto, DDS, 1996), and also found that survival was similar in that particular subset of patients (Cortez-Pinto, DDS, 2003). The interaction of metabolic risk factors and alcohol consumption was demonstrated in several studies. Ecksted et al. have shown in a group of 71 NAFLD patients, that heavy episodic drinking associated with a marked increase on the probability of fibrosis progression after a median follow-up of 12.3 years (Ecksted et al, Scand J Gastro, 2009). Also, in a population –based study, of about 10000 individuals, with a mean follow-up of about 30 years, that the interaction of raised BMI and alcohol consumption had a supra-additive effect, demonstrating clearly the synergistic effect of alcohol and increased BMI on causing liver disease (Hart, BMJ, 2010). It was also shown in a group of NASH patients, that any alcohol consumption markedly increased the risk of hepatocellular carcinoma (Ascha et al, Hepatology, 2010). In summary, fatty-liver disease is a disease of multiple causes, where management has to be individualized, based on the specific risk factors of each patient. # S11.4 HEPATOCELLULAR CARCINOMA IN ALCOHOLIC CIRRHOSIS: ROLE OF HOST-ENVIRONMENT INTERACTIONS {#article-title-5} The incidence of hepatocellular carcinoma (HCC) is rising with alcoholic cirrhosis as a major risk factor. While the causal role of alcohol in the development of liver cirrhosis is undisputed, its modulating impact in hepatocarcinogenesis is just emerging. HCC develops in 1-2% of cirrhotics per year whereas only a small fraction of HCC cases develop in non-cirrhotic alcoholic patients emphasizing cirrhosis as a priming condition. Among the mechanisms leading to HCC are interactions between dietary or environmental carcinogens ingested along with alcohol. Alcohol induces cytochrome P450 2E1 (CYP2E1) leading to activation of several procarcinogens, including nitrosamines. Induced CYP2E1 produces toxic and mutagenic acetaldehyde and results in increased oxidative stress with subsequent lipid peroxidation. The second enzyme system by which alcohol is metabolized is alcohol dehydrogenase (ADH), and genetic variation of ADH1B and ADH1C genes code for enzymes with altered activities. An association between the more active ADH1C*1-allele and alcohol-associated malignancies, including HCC, was demonstrated. Furthermore, alcohol interacts with methyl group transfer and thus causes impaired hepatic detoxification capacity by reducing glutathione, and altered methylation of oncogenes and tumor suppressor genes. Heavy alcohol consumption reduces hepatic retinoic acid levels causing enhanced cell proliferation and malignant transformation. Genetic studies identified a variation within the gene coding for PNPLA3 as a significant risk factor for developing alcoholic cirrhosis. Carriage of PNPLA3 variant rs738409 is particularly frequent in alcoholic cirrhotics with HCC. Functionally, variant PNPLA3 rs738409 codes for an enzyme leading to increased lipogenesis supporting the lipotoxicity hypothesis underlying HCC evolution.