Gut non-bacterial microbiota contributing to alcohol-associated liver disease.

Intestinal microbiota, dominated by bacteria, plays an important role in the occurrence and the development of alcohol-associated liver disease (ALD), which is one of the most common liver diseases around the world. With sufficient studies focusing on the gut bacterial community, chronic alcohol consumption is now known as a key factor that alters the composition of gut bacterial community, increases intestinal permeability, causes intestinal dysfunction, induces bacterial translocation, and exacerbates the process of ALD via gut-liver axis. However, gut non-bacterial communities including fungi, viruses, and archaea, which may also participate in the disease, has received little attention relative to the gut bacterial community. This paper will systematically collect the latest literatures reporting non-bacterial communities in mammalian health and disease, and review their mechanisms in promoting the development of ALD including CLEC7A pathway, Candidalysin (a peptide toxin secreted by Candida albicans), metabolites, and other chemical substances secreted or regulated by gut commensal mycobiome, virome, and archaeome, hoping to bring novel insights on our current knowledge of ALD.

Increased Sensitivity to Binge Alcohol-Induced Gut Leakiness and Inflammatory Liver Disease in HIV Transgenic Rats.

The mechanisms of alcohol-mediated advanced liver injury in HIV-infected individuals are poorly understood. Thus, this study was aimed to investigate the effect of binge alcohol on the inflammatory liver disease in HIV transgenic rats as a model for simulating human conditions. Female wild-type (WT) or HIV transgenic rats were treated with three consecutive doses of binge ethanol (EtOH) (3.5 g/kg/dose oral gavages at 12-h intervals) or dextrose (Control). Blood and liver tissues were collected at 1 or 6-h following the last dose of ethanol or dextrose for the measurements of serum endotoxin and liver pathology, respectively. Compared to the WT, the HIV rats showed increased sensitivity to alcohol-mediated gut leakiness, hepatic steatosis and inflammation, as evidenced with the significantly elevated levels of serum endotoxin, hepatic triglycerides, histological fat accumulation and F4/80 staining. Real-time PCR analysis revealed that hepatic levels of toll-like receptor-4 (TLR4), leptin and the downstream target monocyte chemoattractant protein-1 (MCP-1) were significantly up-regulated in the HIV-EtOH rats, compared to all other groups. Subsequent experiments with primary cultured cells showed that both hepatocytes and hepatic Kupffer cells were the sources of the elevated MCP-1 in HIV-EtOH rats. Further, TLR4 and MCP-1 were found to be upregulated by leptin. Collectively, these results show that HIV rats, similar to HIV-infected people being treated with the highly active anti-retroviral therapy (HAART), are more susceptible to binge alcohol-induced gut leakiness and inflammatory liver disease than the corresponding WT, possibly due to additive or synergistic interaction between binge alcohol exposure and HIV infection. Based on these results, HIV transgenic rats can be used as a surrogate model to study the molecular mechanisms of many disease states caused by heavy alcohol intake in HIV-infected people on HAART.

An annual topic highlight: alcohol and liver, 2011.

AN ANNUAL TOPIC HIGHLIGHT: Alcohol and Liver, 2011, covers the important and new aspects of pathogenesis of alcoholic liver diseases (ALD). It includes broad topics ranging from the exacerbation of ALD by infectious (viral) agents (hepatitis C virus and human immunodeficiency virus) to the influence of alcohol on liver fibrogenesis, lipid rafts, autophagy and other aspects. This issue is recommended for both basic scientists and clinicians who are involved in alcoholic liver research.

Liver transplantation for alcoholic liver disease.

Alcoholic liver disease (ALD) is the second commonest indication for liver transplantation after viral hepatitis in the United States and Europe. Controversies surround the indications and allocation of scarce and expensive resource for this so called self inflicted disease. Controversies stem from the apprehension that alcoholic recipients are likely to relapse and cause damage to the graft. There is a need to select those candidates with lower risk for relapse with the available predictive factors and scores. Substance abuse specialist and psychiatrists are mandatory in the pre-transplant evaluation and in the post-transplant follow-up. There is conflicting evidence to support a fixed period of pretransplant abstinence, although most units do follow this. Alcoholic hepatitis (AH) continues to be a contraindication for transplantation, however there is a need for further research in this field as a subset of patients with AH who do not respond to medical treatment, have high early mortality and could benefit from transplantation. One year, 3-year, and 5-year survival post-transplant is similar for both ALD and non-ALD recipients. The incidence of post-transplant rejection and retransplantation is also similar to other recipients. ALD with viral hepatitis especially hepatitis C virus leads to a more aggressive liver disease with early presentation for transplantation. ALD patients are more prone to develop de-novo malignancy; this is attributed to the long term effect of alcohol, tobacco combined with immunosuppression. Post-transplant surveillance is important to detect early relapse to alcoholism, presence of de-novo malignancy and treat the same adequately.

Immunohistochemical comparative study of fibrosis and biliary ductular reaction in alcoholic and viral chronic hepatitis.

Our study includes 102 cases of liver biopsy previously diagnosed with chronic alcoholic hepatitis and also B and C viral hepatitis. In these cases, we analyzed the extension of fibrosis with two different methods. First, we evaluated fibrosis with the subjective Knodell score; secondly, we used digital image analysis to achieve this. We also used immunohistochemical methods to mark those cells positive at Smooth Muscle Actin (SMA) and Glial Fibrillary Acidic Protein (GFAP). We have observed that the extension of fibrosis was most predominant in cases with B viral chronic hepatitis, while the number of cells responsible of fibrosis (stellate cells, myofibroblasts) was highest in C viral chronic hepatitis. These differences help clinician to divide patients into those who may be treated with interferon and those treatable with antiviral therapy. We observed ductular reaction (as shown by cytokeratin 7 immunostaining) within the lobular structure more frequently in alcohol related chronic hepatitis, whilst in C viral chronic hepatitis this reaction was more readily seen in portal spaces. We have concluded that patients with C viral hepatitis can benefit most from a correctly indicated hepatic biopsy since in these cases the lesions might be observed in an early and potentially curable phase.

Alcohol consumption among patients with hepatitis B infection in northern Portugal considering gender and hepatitis B virus genotype differences.

Alcohol abuse is an important public health problem. In Portugal with a population of 10 millions of inhabitants, there are around 10% of alcoholics or excessive alcohol drinkers and 1% of chronically infected patients with hepatitis B virus (HBV). To examine the characteristics of patients with higher levels of alcohol consumption and to investigate the association between alcohol consumption and liver damage a total of 298 chronically infected individuals, with HBV genotyped and submitted to liver biopsy, were classified with Child's grading and separated by habits of alcohol intake, less and greater than 20g/day. No significant differences were observed about genotype but genotypes A and D were predominant in both of them. A higher percentage of males (P<.001) were observed in the group with alcohol intake above 20g/day, as well a lower proportion of patients with HBeAg negativity (P< or =.035). In this group, biochemistry parameters, such as alanine aminotransferase (P=.006), aspartate aminotransferase (P=.001), gamma-glutamyl transferase (P<.001) were elevated in a significantly higher proportion than in the other group. The analysis of hematological parameters showed significantly lower values of platelets (P=.042) and mean corpuscular volume (P<.001) and significantly higher values of prothrombin time (P<.001) in the group with higher levels of alcohol consumption. The characteristics of biopsy (P<.001) and Child-Phug's classification (P=.002) revealed more severe results in this group. Logistic regression showed a positive association between liver damage and alcohol intake, increasing with age. In female patients, a strong positive association between alcohol intake and liver damage was also found (odds ratio: 9.379; 95% confidence interval: 0.859-468.422; P = .037); however, the most severe cases were only observed in women older than 45 years. In patients with HBV infection, alcohol is associated with a more severe liver disease. No evidence was found concerning association with HBV genotype.

Hepatitis C virus and alcohol.

This review will focus on the prevalence of hepatitis c virus (HCV) infection in alcoholics with and without liver disease. Evidence will be presented to demonstrate that ethanol and chronic HCV infection synergistically accelerate liver injury. Some of the major postulated mechanisms responsible for disease progression include high rates of apoptosis, lipid peroxidation, and generation of free radicals and reactive oxygen species with reduced antioxidant capacity of the liver. Acquisition and persistence of HCV infection may be due to the adverse effects of ethanol on humoral and cellular immune responses to HCV. Dendritic cells (DC) appear to be one of the major targets for ethanol's action and DC dysfunction impairs the ability of the host to generate viral specific cluster of differentiation 4 (CD4+) and cluster of differentiation 8 (CD8+) immune responses. There is a relationship between increased alcohol intake and decreased response to interferon (IFN) therapy, which may be reversed by abstinence. Clinical studies are needed to optimize treatment responses in alcoholic patients with chronic HCV infection.

Comparison of deaths related to Hepatitis C and AIDS in Scotland.

In resource-rich countries, the incidence of and mortality from AIDS has fallen dramatically since the introduction of combination antiretroviral therapy. In contrast, developed countries have observed increases in the public health burden associated with the hepatitis C virus (HCV). We compared past and current trends in mortality related to HCV sequelae and HIV/AIDS in Scotland by linking death records with national databases of persons diagnosed with HCV and HIV/AIDS. AIDS-related deaths increased rapidly during the late-1980s to mid-1990s and declined dramatically after 1996. Deaths related to HCV (i.e., viral hepatitis, liver cancer, alcoholic liver disease, or non-alcoholic liver disease) surpassed the number of AIDS-related deaths in 1998 and increased at an average annual rate of 10.5% (95% confidence interval = 7-14%) during 1996-2005. The leading underlying cause of HCV-related deaths was alcoholic liver disease (50% of deaths during 2001-2005). This study highlights the increasing public health burden, vis-à-vis mortality, of HCV, when compared with HIV/AIDS in developed countries. Increased diagnosis and treatment of eligible HCV-infected individuals will be required if we wish to mitigate the future impact of HCV morbidity and mortality.

Redox regulation of hepatitis C in nonalcoholic and alcoholic liver.

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.

[Liver damage caused by hepatitis C viral infection and ethyl alcohol consumption].

BACKGROUND/AIM: Hepatitis C virus infection (HCV) is a complex disease, most commonly chronicle (80-85%). The aim of this research was to determinate the level of the liver damage in the patients cansed by HCV in conjunction with consuming ethyl alcohol. METHODS: The research included 15 patients with chronic HCV infection supported by the misuse of ethyl alcohol, as well. The diagnosis of C infection hepatitis was proved using the ELISA test and PCR method. RESULTS: The results of the study showed the liver damage by both HCV infection and ethyl alcohol, which was verified by the presence of biochemical changes and patohystological processing of the patients (liver biopsy and prosection). Patohystological changes were at the level of liver cirrhosis and carcinoma (2 patients). There was a signficant difference between the two subgroups (p < 0.001) regarding the examined values gamma-GT, PLT and PTV. The basic therapeutic procedure was to introduce this category of patients into alcohol abstinence, and, in a few patients, to apply the antivirus therapy, as well. CONCLUSION: Based on the number of the examined patients (n = 15), we could conclude that a prolonged ethyl alcohol misuse with the presence of HCV infection was in a correlation with the liver disease progression.

Alcohol and hepatitis C.

Alcohol abuse and hepatitis C virus (HCV) infection coexist with chronic liver disease in many patients. The mechanism of injury in these patients is probably multifactorial and involves, but is not limited to, a combination of diminished immune clearance of HCV, oxidative stress, emergence of HCV quasi-species, hepatic steatosis, increased iron stores, and increased rate of hepatocyte apoptosis. In patients with HCV infection, alcohol consumption is known to cause accelerated progression of liver fibrosis, higher frequency of cirrhosis, and increased incidence of hepatocellular carcinoma (HCC). These patients also have decreased survival as compared with patients with either alcohol abuse or HCV liver injury alone. Alcohol abuse causes decreased response to interferon treatment in HCV patients. It is therefore necessary for patients with HCV infection to abstain from alcohol consumption.

Association of alcohol consumption and exaggerated immunopathologic effects in the liver induced by infectious organism.

The cause of alcoholic liver disease (ALD) is multifactorial and poorly understood. It is clear that alcohol alone is not responsible for most of the changes associated with ALD and that cofactors are involved in initiation and production of ALD. One cofactor that has received a great deal of attention recently is the concomitant infection with hepatitis C virus (HCV) and alcohol abuse. The interactive effects of HCV and alcohol abuse are still unclear, but apparently they are the result of an inability of the immune system to control the viral infection and exaggerated hepatocyte damage mediated by either the cells of the inflammatory response or factors produced by the inflammatory cells. A major effort in my laboratory has been focused on defining the effects of alcohol consumption on immunity to various infectious agents. Efforts have also been directed to elucidating the pathologic effects in the liver of inflammatory and immune responses to microorganisms that either specifically or ultimately infect the liver from an initial site of infection other than the liver. This review will focus on one aspect of the possible pathogenic effects associated with alcohol abuse and hepatic infections: the possible role of the immune system, notably the cytotoxic T lymphocyte (CTL) response. It is clear that the development of a CTL response is critical for the control of HCV and other infections, and it is also likely that this response is involved in liver damage. In this review, the evidence that shows the importance of the CD8+ CTL in bacterial and viral clearance and the role for pathogenesis will be presented. Findings obtained from animal studies that support the suggestion that activated CD8+ CTLs can induce liver damage will be presented, as will results of recent studies from my laboratory that provide evidence for an effect of alcohol to enhance the liver damage mediated by activated CD8+ T cells.

[Diagnosis and histologic surveillance of hepatitis C]. / Diagnostic et surveillance histologiques de l'hépatite C.

The role of liver biopsy in hepatitis C viral infection is diagnostic and prognostic. It states diagnoses of chronic hepatitis, cirrhosis and hepatocellular carcinoma. The association of portal lymphoid nodules, inflammatory bile duct lesions and steatosis suggests an hepatitis C viral etiology. Liver biopsy allows grading (extent of necro-inflammatory lesions) and staging (amount of fibrosis) of the disease using scoring systems proposed by Knodell et al. and (or) by METAVIR group. It can be helpful in confirming (or refuting) the presence of secondary diagnoses such as alcohol-induce liver disease or haemochromatosis and in assessing the efficacy of antiviral treatments.

[Chronic viral hepatitis and alcoholic liver: clinico-morphological correlations]. / Khronicheskii virusnyi gepatit i alkogol'naia pechen': kliniko- morfologicheskaia korreliatsiia.

69 patients with alcohol addiction infected with hepatitis viruses underwent clinical, laboratory and morphological examinations using light and electron microscopic studies of liver biopsies. Light microscopy revealed three variants of liver damage: viral, alcoholic and mixed. Both etiological factors affect manifestations and course of the disease as shown by electron microscopy in spite of morphological signs of only viral or mixed lesion. The lowest index of histological activity is found in combination alcohol + HCV, the highest index being in patients with HBV + HCV and HBV + HDV. Alcohol abuse in combination with HCV infection increases histological activity of liver damage.

Contribution of hepatitis C virus to the progression of alcoholic liver disease.

BACKGROUND: We determined hepatitis C virus (HCV) antibody, HCV RNA, and genotype in patients with alcoholic liver disease and studied the involvement of HCV in alcoholic liver disease. Additionally, we used the histological activity index (HAI) to study the influence of HCV on the severity of inflammation. METHODS: The subjects were 143 patients with alcoholic liver disease: 7 with fatty liver (FL), 18 with hepatic fibrosis (HF), 24 with alcoholic hepatitis (ALH), 39 with chronic hepatitis (CH), 42 with liver cirrhosis (LC), and 13 with hepatocellular carcinoma (HCC). The HCV RNA positivity rate in each type of disease was 0/7 (0%), 1/18 (6%), 2/24 (8%), 27/39 (69%), 24/42 (57%), and 7/13 (54%), respectively. It was high in the advanced hepatic lesions. RESULTS: Clinically, the serum hepatic function tests after abstinence from drinking improved significantly in the HCV RNA negative patients compared with the positive patients. The proportion of genotype II in each type of disease was 0/0, 0/1 (0%), 1/2 (50%), 18/27 (67%), 18/24 (75%), and 7/7 (100%), respectively. It became high with the advance of pathophysiology. The HCV RNA amount stood at 7.5 +/- 0.4 [log (copies/ml)] in CH, 7.9 +/- 0.4 in LC, and 8.4 +/- 0.8 in HCC, with a statistically significant difference between CH and HCC. However, we found no changes in the HCV RNA amount due to abstinence from drinking. The HAI score was high in the HCV RNA positive patients, but several cases in the HCV RNA negative group showed severe inflammatory changes. Therefore, judging the presence or absence of HCV RNA with the HAI score alone was considered difficult. CONCLUSIONS: These results suggest that HCV, particularly genotype II, plays an important role in the advance of disease to LC and HCC in heavy drinkers.

Lack of influence of hepatitis G virus infection on alcohol-related hepatic lesions.

BACKGROUND: The purposes of this study were to analyse the prevalence and histologic impact of hepatitis G virus (HGV), a newly discovered virus, in alcoholic patients, a population known to be at risk for viral hepatitis. METHODS: One hundred and thirty-nine consecutive alcoholics admitted to our liver unit (106 men and 33 women; mean age, 47.1 +/- 10.9 years) were included in the study. All patients had consumed more than 60 g of ethanol per day for at least 1 year. One hundred healthy blood donors constituted a control group. Antibodies to HGV E2 protein and HGV-RNA testing by reverse transcription-polymerase chain reaction (RT-PCR) with primers derived from the NS5 coding region were performed in all serum samples. RESULTS: A significantly higher seroprevalence of anti-E2 antibodies was observed in alcoholic patients than in healthy blood donors (41 (29.5%) versus 8 (8%); P < 0.0001). Moreover, the prevalence of HGV-RNA was significantly higher in alcoholic patients (13 (9.3%) versus 1 (1%); P = 0.01). HGV-RNA and anti-HGV antibodies were never detected simultaneously. HGV viraemia was not associated with an increased risk of cirrhosis or hepatocarcinoma in alcoholic subjects. CONCLUSIONS: Our study reports a high prevalence of HGV in alcoholic patients. HGV infection does not modify or aggravate the course of alcoholic liver disease.

Hepatitis G virus infection in Spanish patients with hepatocellular carcinoma.

AIMS/BACKGROUND: To establish the rate of infection with a newly discovered Flaviviridae family member hepatitis G virus (HGV) -- in Spanish patients with hepatocellular carcinoma (HCC), chronic alcoholic liver disease (CALD) with cirrhosis, or hepatitis C virus (HCV)-induced chronic hepatitis (CH). METHODS: The presence of HGV-RNA was assessed in sera of 117 patients divided in three groups: group 1: 40 patients with HCC (35 men, mean age 62.7 years, SD 10.9 years); group 2: 41 patients with chronic alcoholic liver disease (CALD) (36 men, mean age 52.5 years, SD 9.8 years); group 3: 36 patients with HCV-induced CH (27 men, mean age 35.8 years, SD 8.5 years). Serum samples were tested for HGV-RNA by specific reverse transcriptase-polymerase chain reaction (RT-PCR). Serological markers of hepatitis B virus (HBV) and HCV were investigated in all patients and were negative in CALD patients, as a prerequisite for their inclusion in the study. All patients in group 1 were also tested for HBV-DNA. RESULTS: Rates of HGV-RNA positivity were, respectively, 47%, 10% and 28% in groups 1, 2 and 3. Differences were significant between groups 1 and 2 (p=0.00017) and groups 2 and 3 (p= 0.042), but not between groups 1 and 3 (p=0.079). CONCLUSIONS: HGV infection is common in HCC patients, but usually in association with HCV, indicating that both agents share common routes of infection. HGV was the only hepatitis virus detected in 12% of HCC patients, but its possible role in the pathogenesis of HCC remains unclear.