Advanced Alcoholic Liver Disease Research Articles

Alcoholism and Socioeconomic Status among Patients with Hepatic Encephalopathy in Association with Increased Mortality.

Hepatic encephalopathy (HE) is a complex neuropsychiatric disorder indicated by a deterioration in the functioning of hepatocytes. Impaired brain function is observed in advanced alcoholic liver disease particularly manifesting as HE. The pathophysiology of alcohol-related HE remains unclear. Accordingly, this study aimed to assess alcoholism and socioeconomic status of patients with liver disease compared with stages of HE. This cross-sectional study was conducted on 62 alcoholic patients who have been consuming alcohol for more than 14 years. Patients were recruited based on the assessment of clinical symptoms and diagnosed according to the MELD and Child-Pugh scoring systems. Descriptive statistics including demographic details and clinical features of patients were classified based on alcoholism and socioeconomic status. Patients belonging to the lower- and middle-income classes were more in number with a mean age of 46.66±10.21 and 47.14±6.36 years, respectively compared to upper-middle- and upper-income classes. The amount of alcohol intake was 116.59±45.60 in the middle class and 110.0±62.45 in the upper class. Increased progression of HE leads to a rise in the mortality rate due to higher consumption of alcohol. HE is a severe complication in alcohol-related liver cirrhosis that contributes to impaired cognitive function in patients.

Aeromonas sobria cellulitis with septic shock: rare but potentially lethal in chronic liver disease

Aeromonas, a common bacterial resident of freshwater is known to cause gastrointestinal illness in humans. Contaminated water and aquatic foods are the usual sources. Gastrointestinal disease is usually mild in normal individuals and responds to common antibiotics. However, extra-intestinal infections by Aeromonas species have been increasingly reported. Severe skin and soft tissue infection followed by septic shock may be seen in immunocompromised individuals. Bacteremia can also occur secondary to invasive gastroenteritis in persons with impaired immunity. Patients with decompensated chronic liver disease have been noted to be at especially high risk for fatal infection due to this pathogen. It can cause early bacteremia and rapid death without surgical debridement. We report a case of fatal Aeromonas cellulitis with septic shock in a patient with known advanced alcoholic liver disease. It started following minor skin injury and subsequent exposure to pond water. The patient presented late with septic shock and succumbed to his illness.

Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients.

Hepatocellular carcinoma (HCC) is a severe complication of advanced alcoholic liver disease, which is modulated by genetic predisposition. Identifying new genetic loci might improve screening. Genetic variation of SAMM50 was linked to HCC. We aimed to validate this finding in a large cohort of patients with advanced alcoholic liver disease (ALD). A large, well-characterised cohort of patients with alcoholic cirrhosis without (n = 674) and with (n = 386) HCC, as well as controls with HCC due to viral hepatitis (n = 134), controls with heavy alcohol abuse without liver disease (n = 266) and healthy subjects (n = 237), were genotyped for SAMM50 rs3827385 and rs3761472 and for PNPLA3 rs738409. Genotype frequencies were compared between patients with alcohol-associated cirrhosis with and without HCC by uni- and multivariate analysis. Minor variants in both SAMM50 rs3827385 and rs3761472 were significantly more frequent in patients with alcoholic HCC versus alcoholic cirrhosis and versus the control cohorts. An even stronger association was noted for PNPLA3 rs738409. The univariate analysis resulted in an odds ratio (OR) of 1.8 for carriers of at least one minor variant of SAMM50 rs3827385 and rs3761472 (each p < 0.001), but this association was lost in multivariate analysis with age (OR 1.1/year), male sex (OR 3.2), diabetes (OR 1.9) and carriage of PNPLA3 148M (OR 2.1) remaining in the final model. Although minor variants of both SAMM50 loci are strongly associated with alcoholic HCC, this association is not independent of carriage of the well-known risk variant PNPLA3 148M.

Transcriptional and Epigenetic Regulation of Monocyte and Macrophage Dysfunction by Chronic Alcohol Consumption.

Drinking alcohol, even in moderation, can affect the immune system. Studies have shown disproportionate effects of alcohol on circulating and tissue-resident myeloid cells (granulocytes, monocytes, macrophages, dendritic cells). These cells orchestrate the body’s first line of defense against microbial challenges as well as maintain tissue homeostasis and repair. Alcohol’s effects on these cells are dependent on exposure pattern, with acute drinking dampening but chronic drinking enhancing production of inflammatory mediators. Although chronic drinking is associated with heightened systemic inflammation, studies on tissue resident macrophage populations in several organs including the spleen, liver, brain, and lung have also shown compromised functional and metabolic capacities of these cells. Many of these effects are thought to be mediated by oxidative stress caused by alcohol and its metabolites which can directly impact the cellular epigenetic landscapes. In addition, since myeloid cells are relatively short-lived in circulation and are under constant repopulation from the bone marrow compartment, alcohol’s effects on bone marrow progenitors and hematopoiesis are important for understanding the impact of alcohol systemically on these myeloid populations. Alcohol-induced disruption of progenitor, circulating, and tissue resident myeloid populations contribute to the increased susceptibility of patients with alcohol use disorders to viral and bacterial infections. In this review, we provide an overview of the impact of chronic alcohol consumption on the function of monocytes and macrophages in host defense, tissue repair and inflammation. We then summarize our current understanding of the mechanisms underlying alcohol-induced disruption and examine changes in transcriptome and epigenome of monocytes and mcrophages. Overall, chronic alcohol consumption leads to hyper-inflammation concomitant with decreased microbial and wound healing responses by monocytes/macrophages due to a rewiring of the epigentic and transcriptional landscape. However, in advanced alcoholic liver disease, myeloid cells become immunosuppressed as a response to the surrounding hyper-inflammatory milieu. Therefore, the effect of chronic alcohol on the inflammatory response depends on disease state and the immune cell population.

A mini-review of the rodent models for alcoholic liver disease: shortcomings, application, and future prospects.

Rodents are the most common models in studies of alcoholic liver disease (ALD). Although several rodents ALD models have been established and multiple mechanisms have been elucidated based on them, these models have some non-negligible shortcomings, specifically only inducing early stage (mainly steatosis, slight to moderate steatohepatitis) but not the whole spectrum of human ALD. The resistance of rodents to advanced ALD has been suggested to be due to the physiological differences between rodents and human beings. Previous studies have reported significant interstrain differences in the susceptibility to ethanol-induced liver injury and in the manifestation of ALD (such as different alteration of lipid profiles). Therefore, it would be interesting to characterize the manifestation of ethanol-induced liver damage in various rodents, which may provide a recommendation to investigators of ALD. Furthermore, more severe ALD models need to be established for the study of serious ALD forms, which may be achieved by using genetic modified rodents.

ABL2 promotes alcohol‐induced steatosis through regulation of PPARg expression

Alcoholic liver disease (ALD) represents a spectrum of alcohol use-related diseases, ranging from steatosis to cirrhosis, and is one of the primary causes of chronic liver disease worldwide. Outside of alcohol abstinence, there are currently no FDA-approved treatments for advanced ALD, necessitating a greater understanding of ALD pathogenesis and potential molecular targets for therapeutic intervention. The ABL-family proteins, including ABL1 and ABL2, are non-receptor tyrosine kinases that participate in a diverse set of cellular functions including mitosis, adhesion, differentiation, and stress response. We demonstrate that the ABL kinases are highly activated in ALD patient liver samples as well liver tissues from mice subjected to an alcohol feeding regimen. To further our understanding of the role of the ABL kinases in ALD, we established strains of liver-specific ABL1 and ABL2 knockout mice. When subjected to alcohol feeding, we found that knockout of ABL2, but not ABL1, abrogated alcohol-induced steatosis. Subsequent RNA-sequencing and gene set enrichment analyses of mouse liver tissues revealed that, relative to wild-type alcohol-fed mice, ABL2 knockout alcohol-fed mice exhibited numerous pathway changes including significantly decreased PPAR signaling. Further examination revealed that PPARg, a previously identified regulator of ALD pathogenesis, was induced upon alcohol feeding in wild-type mice, but not in ABL2 knockout mice, suggesting a potential novel role for ABL2 in the regulation of PPARg. In vitro analyses conducted in HepG2, an immortalized liver cell line, revealed that PPARg protein levels increase in response to alcohol treatment leading to marked increases in lipid accumulation as determined by Oil Red O staining. shRNA-mediated knockdown of ABL2, however, abolished the alcohol-induced accumulation of PPARg as well as subsequent lipid-accumulation. Conversely, forced overexpression of ABL2 resulted in increased PPARg protein expression. Furthermore, treatment with GMB475, a recently developed, highly specific proteolysis-targeting chimera (PROTAC) directed against the ABL kinases, attenuated alcohol-induced PPARg protein accumulation as well as subsequent lipid droplet formation. Based on our current evidence, we propose that alcohol-induced ABL2 activation promotes ALD through increasing PPARg expression and ABL2 inhibition may serve as a promising target for the treatment of ALD.

Modeling Alcoholic Liver Disease in a Human Liver-Chip

Fatty liver disease (FLD) is a major public health burden that affects up to 30% of people in Western countries and leads to progressive liver injury, comorbidities, and increased mortality. One risk factor for developing FLD is alcohol consumption, which is growing in prevalence worldwide. There is an urgent need for human-relevant preclinical models to improve our understanding of FLD progression to steatohepatitis in alcoholic liver disease (ALD) and to develop sensitive noninvasive diagnostics and therapies of FLD in general. Here, by leveraging a tri-culture human Liver-Chip with biomimetic hepatic sinusoids and bile canaliculi, we achieve the first in vitro modeling of ALD that uses human relevant blood alcohol concentrations (BAC) and affords multimodal profiling of clinically relevant endpoints. Our ALD Liver-Chip recapitulates established FLD markers in response to ethanol in a concentration-dependent manner, including lipid accumulation and oxidative stress. The ALD Liver-Chip also supports the study of secondary insults common in patients with advanced ALD, such as high blood endotoxin levels due to alcohol-associated increased intestinal permeability and barrier dysfunction. Moreover, the ALD Liver-Chip enables the measurement of structural changes of the hepatic bile canaliculi network as a novel in vitro quantitative readout of alcoholic liver toxicity, and the co-culture of human stellate cells to study their role in FLD progression and liver fibrosis. In summary, we report the development of a human ALD Liver-Chip as a new platform for modeling the progression of alcohol-induced liver injury and fatty liver disease with direct translation to clinical research.

Combined alcoholic and non-alcoholic steatohepatitis.

SummaryWhile metabolic syndrome and alcohol consumption are the two main causes of chronic liver disease, one of the two conditions is often predominant, with the other acting as a cofactor of morbimortality. It has been shown that obesity and alcohol act synergistically to increase the risk of fibrosis progression, hepatic carcinogenesis and mortality, while genetic polymorphisms can strongly influence disease progression. Based on common pathogenic pathways, there are several potential targets that could be used to treat both diseases; based on the prevalence and incidence of these diseases, new therapies and clinical trials are needed urgently.

A study of alanine aminotransferase - aspartate aminotransferase as a marker of advanced alcoholic liver disease

Background: Alcohol is one of the most common etiology for chronic liver disease. There are several enzymes which remain elevated in both excessive Alcohol consumption and Alcohol induced liver cirrhosis1. But none is sensitive or specific. The ratio of Aspartate transaminase (AST) with Alanine transaminase (ALT) is one of the best marker for alcohol liver disease. Current study mainly compares the ratio of AST/ALT with both Alcoholic liver disease and excessive Alcohol consumption patients.Methods: Observational, cross sectional study conducted on 50 patients diagnosed with alcoholic liver disease and 50 patients of alcohol withdrawal syndrome. Either admitted or seen on outpatient basis at Bangalore medical college and research institute and data was compared among the groups and appropriate statistical methods are applied.Results: The mean ratio of AST/ALT ratio in 50 patients of alcoholic liver disease group was 3.45, whereas the mean ratio in 50 patient of alcohol withdrawal was about 99. When compared statistically this ratio was significant in chronic liver disease group.Conclusions: Most of the patients with heavy alcohol drinking had high AST and alt levels. But ratio of AST/ALT levels was significant high and suggest chronic liver disease secondary to alcohol.

Restricted immunological and cellular pathways are shared by murine models of chronic alcohol consumption

Murine models of chronic alcohol consumption are frequently used to investigate alcoholic liver injury and define new therapeutic targets. Lieber-DeCarli diet (LD) and Meadows-Cook diet (MC) are the most accepted models of chronic alcohol consumption. It is unclear how similar these models are at the cellular, immunologic, and transcriptome levels. We investigated the common and specific pathways of LD and MC models. Livers from LD and MC mice were subjected to histologic changes, hepatic leukocyte population, hepatic transcripts level related to leukocyte recruitment, and hepatic RNA-seq analysis. Cross-species comparison was performed using the alcoholic liver disease (ALD) transcriptomic public dataset. Despite LD mice have increased liver injury and steatosis by alcohol exposure, the number of CD45+ cells were reduced. Opposite, MC mice have an increased number of monocytes/liver by alcohol. The pattern of chemokine gradient, adhesion molecules, and cytokine transcripts is highly specific for each model, not shared with advanced human alcoholic liver disease. Moreover, hepatic RNA-seq revealed a limited and restricted number of shared genes differentially changed by alcohol exposure in these 2 models. Thus, mechanisms involved in alcohol tissue injury are model-dependent at multiple levels and raise the consideration of significant pathophysiological diversity of human alcoholic liver injury.

Increased Prevalence of Obesity and Metabolic Syndrome in Patients with Alcoholic Fatty Liver Disease.

Obesity and diabetes are risk factors for advanced alcoholic liver disease, and both are components of the metabolic syndrome. We aimed to assess the prevalence of metabolic syndrome and its components in a contemporary US cohort of adults with alcoholic liver disease and compare it to a historic cohort to assess changes over time. Individuals 18years or older who participated in the National Health and Nutrition Examination Survey during 2009-2014 and 1999-2001 were used as the contemporary and historic cohort, respectively. Alcoholic liver disease was defined as excessive alcohol consumption (men: ≥ 3drinks/day; women: ≥ 2drinks/day) and elevated alanine aminotransferase. Metabolic syndrome definition was based on the updated International Diabetes Federation criteria. Data are presented as mean ± standard error or unweighted frequency. A logistic regression analysis was performed to assess differences in metabolic syndrome components between the two period cohorts while adjusting for central obesity. The mean age for our contemporary cohort was 41.9, 66.1% being male. Central obesity was present in 66.3%, type 2 diabetes in 18.7%, low high-density lipoprotein in 28.3%, hypertriglyceridemia in 44.8%, and hypertension in 54.7%. 36.9% met the criteria for metabolic syndrome. Compared to the historic cohort, patients in the contemporary cohort were more likely to have central obesity (50% vs. 66%, p = 0.002), metabolic syndrome (26% vs. 37%, p = 0.044), and type 2 diabetes (12% vs. 19%, p = 0.099). Prevalence of both obesity and metabolic syndrome is increasing in alcoholic liver disease patients. Further studies are required to investigate effective interventions to avoid disease progression in these high-risk patients.

Recent Insights Into the Role of Immune Cells in Alcoholic Liver Disease.

Accumulating clinical and experimental evidences have demonstrated that both innate and adaptive immunity are involved in the pathogenesis of alcoholic liver disease (ALD), in which the role of immunity is to fuel the inflammation and to drive the progression of ALD. Various immune cells are implicated in the pathogenesis of ALD. The activation of innate immune cells induced by alcohol and adaptive immune response triggered by oxidative modification of hepatic constituents facilitate the persistent hepatic inflammation. Meanwhile, the suppressed antigen-presenting capability of various innate immune cells and impaired function of T cells may consequently lead to an increased risk of infection in the patients with advanced ALD. In this review, we summarized the significant recent findings of immune cells participating in ALD. The pathways and molecules involved in the regulation of specific immune cells, and novel mediators protecting the liver from alcoholic injury via affecting these cells are particularly highlighted. This review aims to update the knowledge about immunity in the pathogenesis of ALD, which may facilitate to enhancement of currently available interventions for ALD treatment.

SAT-271-Genetic risk factors for advanced alcoholic and non-alcoholic liver disease in the general population

SAT-271-Genetic risk factors for advanced alcoholic and non-alcoholic liver disease in the general population

THU-429-Serial testing with the enhanced liver fibrosis test and liver stiffness is cost-effective for detection of advanced alcoholic liver disease in primary care

THU-429-Serial testing with the enhanced liver fibrosis test and liver stiffness is cost-effective for detection of advanced alcoholic liver disease in primary care

Inhibition of Hepatotoxicity by a LXR Inverse Agonist in a Model of Alcoholic Liver Disease.

Alcohol abuse is a major cause of liver disease and mortality worldwide and is a significant public health issue. Patients with alcoholic liver disease (ALD) have severe hepatic lipid accumulation, inflammation, and fibrosis. Therapies for ALD are very limited and even abstinence from alcohol consumption does not necessarily protect patients from progression of the disease. We sought to evaluate the efficacy of a liver X receptor (LXR) inverse agonist, SR9238, in an animal model of ALD. SR9238 suppresses hepatic lipogenesis, a pathological hallmark of ALD, and we hypothesized that targeting suppression of hepatic metabolic pathways that are activated in ALD may be an effective treatment for the disease. A chronic ethanol diet with or without a final ethanol binge treatment was used to induce ALD in mice. Mice were administered the liver specific LXR inverse agonist SR9238 for 4 weeks after the mice had been maintained on the ethanol diet for 14 days. Mice developed all the hallmarks of advanced ALD demonstrating significant pathophysiology and hepatotoxicity. SR9238 significantly attenuated liver injury and hepatic steatosis and fibrosis was nearly eliminated in SR9238 treated mice. SR9238 treatment reversed the damage associated with chronic ethanol use returning the liver to near normal morphology. These results indicate that inhibiting LXR activity using the inverse agonist has a hepatoprotective effect in rodent models of ALD; thus, this pharmacological approach may be efficacious for treatment of ALD in humans.

Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease

Few data exist on predictors of long-term prognosis in patients with alcoholic liver disease (ALD). Most studies have only assessed short-term prognosis in patients with advanced ALD. We aimed to assess the prognostic impact of clinical, biochemical and histological parameters on long-term prognosis in patients with early/compensated and decompensated ALD. Consecutive patients (n=192) with biopsy-proven liver disease due to alcohol abuse were analyzed retrospectively. Prognostic factors were evaluated in patients with early/compensated ALD (n=60) and in patients with decompensated ALD (clinical decompensation and/or bilirubin >3mg/dl at entry) (n=132). Factors that predict long-term survival were identified using Cox regression models. Liver-related mortality at 5years was 13% in early/compensated and 43% in decompensated ALD. In early/compensated ALD patients, long-term prognosis was determined by fibrosis stage, but not by clinical or biochemical variables. Severe fibrosis (F3/4) was present in 52% and had a major impact on 10-year mortality (F3/4: 45% vs. F0-2: 0%, p<0.001). In contrast, in decompensated patients, a combination of clinical features (sex), biochemical markers of liver failure (bilirubin, international normalized ratio [INR]), and histological features (pericellular fibrosis) predicted long-term survival. During follow-up, abstinence from alcohol was an important predictor of survival in both early/compensated and decompensated ALD. Fibrosis stage is the main predictor of long-term survival in patients with early/compensated ALD, while clinical, biochemical and histological parameters predict survival in patients with decompensated disease. Promoting abstinence may improve survival in patients with both early and advanced ALD. In this study, we evaluated long-term outcome in 192 patients with alcoholic liver disease who underwent liver biopsy: 60 patients with early disease (no symptoms) and 132 patients with advanced disease (jaundice, complications of cirrhosis). Importantly, half of the patients with 'early' disease already had severe fibrosis or cirrhosis on liver histology and dismal outcome (45% mortality at 10years). Abstinence from alcohol improved the prognosis in both early and advanced stages of the disease.

Fecal microbiota manipulation prevents dysbiosis and alcohol-induced liver injury in mice

Alcoholic liver disease (ALD) is a leading cause of liver failure and mortality. In humans, severe alcoholic hepatitis is associated with key changes to intestinal microbiota (IM), which influences individual sensitivity to develop advanced ALD. We used the different susceptibility to ALD observed in two distinct animal facilities to test the efficiency of two complementary strategies (fecal microbiota transplantation and prebiotic treatment) to reverse dysbiosis and prevent ALD. Mice were fed alcohol in two distinct animal facilities with a Lieber DeCarli diet. Fecal microbiota transplantation was performed with fresh feces from alcohol-resistant donor mice to alcohol-sensitive receiver mice three times a week. Another group of mice received pectin during the entire alcohol consumption period. Ethanol induced steatosis and liver inflammation, which were associated with disruption of gut homeostasis, in alcohol-sensitive, but not alcohol resistant mice. IM analysis showed that the proportion of Bacteroides was specifically lower in alcohol-sensitive mice (p<0.05). Principal coordinate analysis showed that the IM of sensitive and resistant mice clustered differently. We targeted IM using two different strategies to prevent alcohol-induced liver lesions: (1) pectin treatment which induced major modifications of the IM, (2) fecal microbiota transplantation which resulted in an IM very close to that of resistant donor mice in the sensitive recipient mice. Both methods prevented steatosis, liver inflammation, and restored gut homeostasis. Manipulation of IM can prevent alcohol-induced liver injury. The IM should be considered as a new therapeutic target in ALD. Sensitivity to alcoholic liver disease (ALD) is driven by intestinal microbiota in alcohol fed mice. Treatment of mice with alcohol-induced liver lesions by fecal transplant from alcohol fed mice resistant to ALD or with prebiotic (pectin) prevents ALD. These findings open new possibilities for treatment of human ALD through intestinal microbiota manipulation.

Decreased hepatic iron in response to alcohol may contribute to alcohol-induced suppression of hepcidin.

Hepatic Fe overload has often been reported in patients with advanced alcoholic liver disease. However, it is not known clearly whether it is the effect of alcohol that is responsible for such overload. To address this lacuna, a time-course study was carried out in mice in order to determine the effect of alcohol on Fe homoeostasis. Male Swiss albino mice were pair-fed Lieber-DeCarli alcohol diet (20 % of total energy provided as alcohol) for 2, 4, 8 or 12 weeks. Expression levels of duodenal and hepatic Fe-related proteins were determined by quantitative PCR and Western blotting, as were Fe levels and parameters of oxidative stress in the liver. Alcohol induced cytochrome P4502E1 and oxidative stress in the liver. Hepatic Fe levels and ferritin protein expression dropped to significantly lower levels after 12 weeks of alcohol feeding, with no significant effects at earlier time points. This was associated, at 12 weeks, with significantly decreased liver hepcidin expression and serum hepcidin levels. Protein expressions of duodenal ferroportin (at 8 and 12 weeks) and divalent metal transporter 1 (at 8 weeks) were increased. Serum Fe levels rose progressively to significantly higher levels at 12 weeks. Histopathological examination of the liver showed mild steatosis, but no stainable Fe in mice fed alcohol for up to 12 weeks. In summary, alcohol ingestion by mice in this study affected several Fe-related parameters, but produced no hepatic Fe accumulation. On the contrary, alcohol-induced decreases in hepatic Fe levels were seen and may contribute to alcohol-induced suppression of hepcidin.

Alcoholic hepatitis accelerates early hepatobiliary cancer by increasing stemness and miR-122-mediated HIF-1α activation

Alcohol-related hepatocellular carcinoma (HCC) develops with advanced alcoholic liver disease and liver fibrosis. Using adult mice, we evaluate the effect of alcoholic steatohepatitis on early hepatobiliary carcinoma after initiation by diethyl-nitrosamine (DEN). Here we show that alcohol-fed DEN-injected mice have higher ALT and liver-to-body weight ratio compared to pair-fed DEN-injected mice. Alcohol feeding results in steatohepatitis indicated by increased pro-inflammatory cytokines and fibrotic genes. MRI and liver histology of alcohol+DEN mice shows hepatobiliary cysts, early hepatic neoplasia and increase in serum alpha-fetoprotein. Proliferation makers (BrdU, cyclin D1, p53) and cancer stem cell markers (CD133 and nanog) are significantly up-regulated in livers of alcohol-fed DEN-injected mice compared to controls. In livers with tumors, loss of miR-122 expression with a significant up-regulation of miR-122 target HIF-1α is seen. We conclude that alcoholic steatohepatitis accelerates hepatobiliary tumors with characteristic molecular features of HCC by up-regulating inflammation, cell proliferation, stemness, and miR-122 loss.

Alcoholic liver disease and hepatitis C virus infection.

Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.