To provide an overview of published literature on the interaction of alcohol and hepatitis C virus (HCV) in the accelerated progression of liver disease to cirrhosis as relates to decision-making for the management of the liver transplant candidate and recipient.

General PubMed search was employed along with expert input to identify the relevant articles on the topic. The authors also utilized both backward and forward citation review of the relevant articles and reviews to identify articles on identified topic.

In HCV cases, heavy alcohol use has been associated with more severe fibrosis, but even low rates of use may have deleterious effects. Patients with chronic hepatitis C and alcoholic liver disease can be cured of the HCV-theoretically positively impacting outcome and reducing the need for liver transplantation. Current antiviral therapy achieves virologic cure or sustained viral response (SVR) in over 90% of cases. Antiviral therapy is so effective that most liver transplant candidates or recipients can be cured of HCV either prior to or after transplantation. However, despite successful antiviral therapy, liver disease may progress after SVR due to the effects of ongoing alcohol use.

Antiviral therapy in patients with HCV plus alcohol should improve pre- and post-transplant outcomes, but providers must remain firm in limiting use of alcohol to avoid progression of liver disease post HCV cure.

Abusive alcohol use and chronic hepatitis C virus (HCV) commonly co-exist and both need to be addressed in liver disease. With high rates of HCV cure with new therapies, attention needs to turn toward ongoing abusive alcohol patterns that may determinately impact liver health both before and after liver transplant.

Hepatitis C virus (HCV) is a blood-borne pathogen that was identified as an etiologic agent of non-A, non-B hepatitis in 1989. HCV is estimated to have infected at least 170 million people worldwide. The majority of patients infected with HCV do not clear the virus and become chronically infected, and chronic HCV infection increases the risk for hepatic steatosis, cirrhosis, and hepatocellular carcinoma. HCV induces oxidative/nitrosative stress from multiple sources, including inducible nitric oxide synthase, the mitochondrial electron transport chain, hepatocyte NAD(P)H oxidases, and inflammation, while decreasing glutathione. The cumulative oxidative burden is likely to promote both hepatic and extrahepatic conditions precipitated by HCV through a combination of local and more distal effects of reactive species, and clinical, animal, and in vitro studies strongly point to a role of oxidative/nitrosative stress in HCV-induced pathogenesis. Oxidative stress and hepatopathogenesis induced by HCV are exacerbated by even low doses of alcohol. Alcohol and reactive species may have other effects on hepatitis C patients such as modulation of the host immune system, viral replication, and positive selection of HCV sequence variants that contribute to antiviral resistance. This review summarizes the current understanding of redox interactions of HCV, outlining key experimental findings, directions for future research, and potential applications to therapy.

Prolonged alcohol consumption is a significant co-factor in the progression of chronic viral infections including hepatitis C and HIV, which are both single-stranded RNA viruses. Toll like receptor 8 (TLR8), a pattern recognition receptor expressed in monocytes, senses viral single stranded RNA as a danger signal and leads to the induction of Type I interferon (IFN) as well as the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha). Lipopolysaccharide (LPS), a Toll like receptor 4 (TLR4) ligand, was shown to affect inflammatory cell activation after alcohol consumption and in HIV and HCV infections. Here we hypothesized that alcohol exposure modulates TLR8- and TLR4-ligand-induced monocyte activation and affects both type I IFN and inflammatory cytokine induction.

The TLR8 ligand, CL075, as well as the TLR4 ligand, LPS, resulted in a significant induction of TNF alpha both at the mRNA and protein levels in human monocytes. We found that both acute and prolonged alcohol treatment resulted in inhibition of type I IFN induction by either TLR8 or TLR4 ligands in human monocytes at the protein and mRNA levels. In contrast to Type I IFN production, the effects of acute and prolonged alcohol were different on inflammatory cytokine activation after TLR8 or TLR4 ligand stimulation. Acute alcohol inhibited TLR8- or TLR4-induced TNF alpha protein and mRNA induction while it augmented IL-10 production in monocytes. In contrast, prolonged alcohol treatment augmented TNF alpha without affecting IL-10 production significantly in response to either TLR8 or TLR4 ligand stimulation.

These novel results suggest first, that alcohol has a profound inhibitory effect on Type I IFN induction regardless of intracellular (TLR8) or cell surface-derived (TLR4) danger signals. Second, both acute and prolonged alcohol exposure can inhibit antiviral Type I IFN pathway activation. Third, the opposite effects of acute (inhibitory) and prolonged alcohol (augmentation) treatment on pro-inflammatory cytokine activation extend to TLR8-induced signals beyond the previously shown TLR4/LPS pathway.

Alcohol drinking and hepatitis C virus (HCV) infection frequently coexist in patients with chronic liver disease. There is limited information, however, about the impact of alcohol on host cell innate immunity and full cycle replication of HCV. This study investigated whether alcohol impairs the intracellular innate immunity in human hepatocytes, promoting HCV infection and replication. Alcohol treatment of human hepatocytes before, during and after viral infection significantly enhanced full cycle HCV replication. Alcohol suppressed intracellular expression of type I interferons (IFN-α/β) in human hepatocytes. Investigation of the mechanisms responsible for the alcohol action revealed that alcohol inhibited the expression of the IFN regulatory factors (IRF-5 and IRF-7), and signal transducer and activator of transcription (STAT-1 and STAT-2), the key positive regulators in type I IFN signaling pathway. In addition, alcohol induced the expression of suppressors of cytokine signaling (SOCS-2 and SOCS-3), the key negative regulators of IFN-α/β expression. These in vitro findings suggest that alcohol, through modulating the expression of key regulators in IFN signaling pathway, inhibits type I IFN-based intracellular innate immunity in hepatocytes, which may contribute to the chronicity of HCV infection and the poor efficacy of IFN-α-based therapy.

Multiple line of clinical and experimental evidence demonstrates that both acute, moderate, and chronic, excessive alcohol use result in various abnormalities in the functions of the immune system.

Medline and PubMed databases were used to identify published reports with particular interest in the period of 2000-2008 in the subject of alcohol use, infection, inflammation, innate, and adaptive immunity.

This review article summarizes recent findings relevant to acute or chronic alcohol use-induced immunomodulation and its consequences on host defense against microbial pathogens and tissue injury. Studies with in vivo and in vitro alcohol administration are both discussed. The effects of alcohol on lung infections, trauma and burn injury, liver, pancreas, and cardiovascular diseases are evaluated with respect to the role of immune cells. Specific changes in innate immune response and abnormalities in adaptive immunity caused by alcohol intake are detailed.

Altered inflammatory cell and adaptive immune responses after alcohol consumption result in increased incidence and poor outcome of infections and other organ-specific immune-mediated effects.

Niuchangchih (Antrodia camphorata (M. Zang & C.H. Su) Sheng H. Wu, Ryvarden & T.T. Chang) is a basidiomycete endemic to Taiwan. It is well known as a Traditional Chinese Medicine (TCM), and Taiwanese aborigines used this species to treat liver diseases and food and drug intoxication. The compounds identified in Niuchangchih are predominantly polysaccharides, triterpenoids, steroids, benzenoids and maleic/succinic acid derivatives. Recent research has revealed that Niuchangchih possesses extensive biological activity, such as hepatoprotective, antihypertensive, anti-hyperlipidemic, immuno-modulatory, anticancer, anti-inflammatory and antioxidant activities. The fruiting bodies and fermented products of Niuchangchih have been reported to exhibit activity when treating liver diseases, such as preventing ethanol-, CCl(4)- and cytokine-induced liver injury, inhibiting the hepatitis B virus, ameliorating fatty liver and liver fibrosis, and inhibiting liver cancer cells. This review will address the protective effects of Niuchangchih on the pathological development of liver diseases, and the underlying mechanisms of action are also discussed.

Liver iron accumulation in patients with chronic hepatitis C (CHC) has received increasing attention in recent years. The aim of this study was to determine the prevalence and severity of liver iron deposition in CHC, to assess its relationship with clinical, biochemical and histological characteristics, and to study its influence on the response to interferon (IFN) plus ribavirin combination therapy.

We studied liver biopsy specimens from 103 hepatitis C virus (HCV) and 34 hepatitis B virus (HBV) infected patients and total iron score (TIS) was measured. Seventy patients infected with HCV genotype 1b were treated with IFN/ribavirin for 24 weeks.

CHC patients had a significantly higher TIS than chronic hepatitis B (CHB) patients (7.03 +/- 5.34 vs 4.41 +/- 4.49, P = 0.0056). TIS was significantly correlated with alcohol intake (P = 0.0213, r = 0.290), transaminase level (P = 0.0126, r = 0.247), platelet count (P = 0.0002, r = -0.369), histological grading (P = 0.0121, r = 0.248) and staging (P = 0.0003, r = 0.356) in CHC patients. Pretreatment TIS was significantly higher in non-sustained virological responders (SVR) than in SVR to IFN/ribavirin treatment (TIS = 7.69 +/- 5.76 vs 4.39 +/- 3.27, P = 0.0310). Multiple regression analysis showed that TIS was the only independent variable associated with resistance to IFN/ribavirin (P = 0.0277).

Liver iron deposition was common in CHC compared to CHB and was associated with liver disease progression. Increased hepatic iron stores in CHC were related to resistance to IFN/ribavirin treatment.

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family that is estimated to have infected 170 million people worldwide. HCV can cause serious liver disease in humans, such as cirrhosis, steatosis, and hepatocellular carcinoma. HCV induces a state of oxidative/nitrosative stress in patients through multiple mechanisms, and this redox perturbation has been recognized as a key player in HCV-induced pathogenesis. Studies have shown that alcohol synergizes with HCV in the pathogenesis of liver disease, and part of these effects may be mediated by reactive species that are generated during hepatic metabolism of alcohol. Furthermore, reactive species and alcohol may influence HCV replication and the outcome of interferon therapy. Alcohol consumption has also been associated with increased sequence heterogeneity of the HCV RNA sequences, suggesting multiple modes of interaction between alcohol and HCV. This review summarizes the current understanding of oxidative and nitrosative stress during HCV infection and possible combined effects of HCV, alcohol, and reactive species in the pathogenesis of liver disease.

Alcoholic liver disease has a known aetiology but a complex and incompletely known pathogenesis. It is an extremely common disease with significant morbidity and mortality, but the reason why only a relatively small proportion of heavy drinkers progress to advanced disease remains elusive.

To recognize the factors responsible for the development and progression of alcoholic liver disease, in the light of current knowledge on this matter.

We performed a structured literature review identifying studies focusing on the complex pathogenetic pathway and risk factors of alcoholic liver disease. Results In addition to the cumulative amount of alcohol intake and alcohol consumption patterns, factors such as gender and ethnicity, genetic background, nutritional factors, energy metabolism abnormalities, oxidative stress, immunological mechanisms and hepatic co-morbid conditions play a key role in the genesis and progression of alcoholic liver injury.

Understanding the pathogenesis and risk factors of alcoholic liver disease should provide insight into the development of therapeutic strategies.

This article presents the proceedings of a symposium presented at the meeting of the Research Society on Alcoholism, held in Santa Barbara, California, in June 2005. The organizers and chairs were Sam Zakhari and Gyongyi Szabo. The presentations included (1) Mitochondrial Abnormalities Induced by Hepatitis C -Alcohol Interaction by Steven Weinman; (2) Effects of Acute and Chronic Ethanol on Innate Antiviral Signaling Pathways, Hepatitis C Replication, and Human Liver Cell Transcription by Stephen Polyak; (3) Ethanol Alters Dendritic Cell Function In Vivo and Impairs the Subsequent Cellular Immune Responses to Hepatitis C Proteins by Costica Aloman; and (4) Pathogenic Interactions Between Hepatitis C Virus and Alcohol Use in Humans: Dendritic Cells as Common Targets by Gyongyi Szabo. This symposium summarizes the state of knowledge of cellular and molecular pathways by which alcohol and HCV have pathogenic interactions resulting in depression of the immune response and liver damage in chronic HCV infection.

This article summarizes the proceedings of the RSA 2004 Combined Basic Research Satellite Meeting convened at the Westin Bayshore Resort and Marina, Vancouver, CA. The session "Hepatitis virus and alcohol interactions in immunity and liver disease" featured four speakers and was chaired by Drs. Diane Lucas and Samuel French. The presentations were 1) Mitochondrial effects of HCV proteins and alcohol by Steve Weinman, 2) Chronic alcohol consumption accelerates viral hepatitis and T-cell hepatitis via dysregulation of cytokine signaling by Bin Gao 3) Interactions between alcohol, hepatitis C virus and innate defense pathways by Steve Polyak and 4) Scavenger Receptor-mediated modulation of the innate and adaptive immune responses following chronic ethanol consumption by Geoffrey Thiele.

Chronic hepatitis C induces a state of hepatic oxidative stress that is more pronounced than that present in many other inflammatory liver diseases. This review summarizes recent information that the hepatitis C virus (HCV) core protein plays an important role in this phenomenon. Core protein localizes to mitochondria, particularly at the points of contact between mitochondrial outer membrane and endoplasmic reticulum. Its expression causes inhibition of electron transport at complex I, increased complex I reactive oxygen species (ROS) production, decreased mitochondrial glutathione, and increased mitochondrial permeability transition in response to exogenous oxidants and tumor necrosis factor-alpha. Possible mechanisms of the core protein effects include direct interaction with electron carriers and indirect effects mediated by changes in mitochondrial calcium. These results suggest that antioxidant approaches may prove beneficial for patients with chronic hepatitis C.

Obesity potentiates the severity of alcohol-induced liver damage. Ethanol influences adipose tissue production of hormones and cytokines. The mechanisms by which adiposity and ethanol interact to produce hepatic steatosis and steatohepatitis are beginning to be studied. Exacerbation of the proinflammatory state that induces tumor necrosis factor activity and hepatic insulin resistance seems to be involved. However, the precise cellular signals that culminate in hepatocyte dysfunction and death remain controversial. Both hepatocyte apoptosis and necrosis are likely, but further study is needed to develop optimal hepatoprotective strategies. It is currently unclear whether the hepatotoxic consequences of obesity and ethanol ingestion are additive or synergistic. This information has important prognostic implications and might be useful to formulate body mass index-based guidelines for "safe" alcohol consumption. Findings of studies in experimental animals also raise questions about the relation between steatohepatitis and cirrhosis. Despite overwhelming evidence that obesity promotes alcohol-induced steatosis and steatohepatitis, most obese human beings (and mice) who drink alcohol do not become cirrhotic. Moreover, at least in mice, even severe steatohepatitis leads to cirrhosis relatively infrequently. Thus, it is conceivable that, although steatohepatitis is a permissive factor for cirrhosis, it is neither necessary nor sufficient for cirrhosis to occur. The quest to identify the proximal mediators of hepatic fibrosis should probably include an investigation of how various adipokines, neurotransmitters, and cytokines interact to regulate hepatic stellate cells. Armed with such knowledge, further modifying actions of ethanol on these mechanisms can be explored by investigators.

The mechanisms of alcohol-induced immunosuppression include defects in innate and adaptive immune responses. Monocytes and dendritic cells (DCs) link innate and adaptive immune responses as they recognize viral antigens and induce antigen-specific T-cell activation. We investigated the effects of alcohol on antigen-presenting cell functions. Acute alcohol consumption by healthy volunteers (vodka, 2 ml/kg) resulted in significantly reduced antigen-presenting cell function of monocyte-derived DCs. Reduced allostimulatory capacity of DCs treated with alcohol in vitro correlated with decreased co-stimulatory molecule (B7.1 and B7.2) expression, as well as with reduced interleukin (IL)-12 and increased IL-10 concentrations, in mixed lymphocyte cultures. Dendritic cells recognize viral antigens in hepatitis C virus (HCV) infection, and HCV disease is accelerated in alcohol-dependent individuals. For patients with chronic HCV infection, we found reduced allostimulatory capacity of myeloid DCs. Furthermore, DC function was reduced by in vitro alcohol treatment of DCs obtained from HCV-infected patients, supporting the suggestion that viral factors and alcohol may interact to doubly suppress DC functions. We found that induction of maturation with lipopolysaccharide could not fully ameliorate the reduced DC allostimulatory capacity caused by alcohol treatment, HCV infection, or their combination. In addition, soluble factors in the supernatants obtained from mixed lymphocyte cultures containing alcohol-treated DCs or DCs obtained from HCV-infected patients could transfer inhibition of T-cell proliferation in cultures containing DCs obtained from healthy volunteers. Anti-IL-10 neutralizing antibody ameliorated the reduced mixed lymphocyte reaction containing DCs obtained from HCV-infected patients, whereas exogenous IL-12, but not anti-IL-10, treatment ameliorated the reduced T-cell proliferation induced by alcohol treatment of DCs obtained from healthy volunteers. Our results support the suggestion that both acute alcohol intake and in vitro alcohol treatment inhibit DC antigen-presenting cell function and support the hypothesis that viral factors interact with alcohol to reduce DC functions in HCV infection.

Deficiencies in vitamins or other factors (B6, B12, folic acid, betaine) and genetic disorders for the metabolism of the non-protein amino acid-homocysteine (Hcy) lead to hyperhomocysteinemia (HHcy). HHcy is an integral component of several disorders including cardiovascular disease, neurodegeneration, diabetes and alcoholic liver disease. HHcy unleashes mediators of inflammation such as NFkappaB, IL-1beta, IL-6, and IL-8, increases production of intracellular superoxide anion causing oxidative stress and reducing intracellular level of nitric oxide (NO), and induces endoplasmic reticulum (ER) stress which can explain many processes of Hcy-promoted cell injury such as apoptosis, fat accumulation, and inflammation. Animal models have played an important role in determining the biological effects of HHcy. ER stress may also be involved in other liver diseases such as alpha (1)-antitrypsin (alpha(1)-AT) deficiency and hepatitis C and/or B virus infection. Future research should evaluate the possible potentiative effects of alcohol and hepatic virus infection on ER stress-induced liver injury, study potentially beneficial effects of lowering Hcy and preventing ER stress in alcoholic humans, and examine polymorphism of Hcy metabolizing enzymes as potential risk-factors for the development of HHcy and liver disease.