Intestinal Virome in Patients With Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.

Optimal control of HCV transmission under liquoring.

Chronic hepatitis C virus (HCV) and alcohol are common causes of chronic liver diseases and both are recognized as major causes of liver disease worldwide. Each poses a major public and economic burden to society, and when the two co-exist they appear to have a synergistic effect in the progression of chronic liver disease. In this research, we developed a SIRS model of transmission of the hepatitis C virus (HCV) under effect of liquoring in six compartments: Susceptible, Low liquoring, High liquoring, Acute, Chronic and Recovered Individuals. The system of non-linear ordinary differential equations is formulated. Basic reproduction number R0 is computed using the next generation matrix approach. The stability of the model is worked out at the equilibrium point. Model analysis shows that the disease-free equilibrium point is both locally and globally asymptotically stable. Sensitivity analysis with respect to key parameters of R0 indicates that control strategies should target reduction of the amount of alcohol use amongst people with HCV as it prevents or delays HCV disease progression. The control in our model is in terms of rehabilitation center which helps people to divert from high liquoring to low liquoring. Numerical simulation has been carried out to show the impact of control on different compartment. This research shows the positive impact of rehabilitation on liquoring habits and subsequently on HCV transmission.

Spontaneous clearance of hepatitis C virus during alcoholic hepatitis: the alcohol killed the virus?

Spontaneous clearance of hepatitis C virus during chronic infection is uncommon. We report the case of a patient who cleared hepatitis C virus during an episode of presumed alcoholic hepatitis. A brief discussion on the immunological aspects of chronic hepatitis C and the impact of alcohol consumption on it is presented as well.

Hepatitis C as a prognostic indicator among noncirrhotic patients hospitalized with alcoholic hepatitis.

OBJECTIVE: A nationwide analysis of alcoholic hepatitis (AH) admissions was conducted to determine the impact of hepatitis C virus (HCV) infection on short-term survival and hospital resource utilization. METHODS: Using the Nationwide Inpatient Sample, noncirrhotic patients admitted with AH throughout the United States between 1998 and 2006 were identified with diagnostic codes from the International Classification of Diseases, Ninth Revision. The in-hospital mortality rate (primary end point) of AH patients with and without co-existent HCV infection was determined. Hospital resource utilization was assessed as a secondary end point through linear regression analysis. RESULTS: From 1998 to 2006, there were 112,351 admissions for AH. In-hospital mortality was higher among patients with coexistent HCV infection (41.1% versus 3.2%; P=0.07). The adjusted odds of in-hospital mortality in the presence of HCV was 1.48 (95% CI 1.10 to 1.98). Noncirrhotic patients with AH and HCV also had longer length of stay (5.8 days versus 5.3 days; P<0.007) as well as greater hospital charges (US$25,990 versus US$21,030; P=0.0002). CONCLUSIONS: Among noncirrhotic patients admitted with AH, HCV infection was associated with higher in-hospital mortality and resource utilization.

Human herpesvirus-6 has no apparent influence on course of HCV hepatitis, but may complicate HBV hepatitis and alcoholic liver disease. A pilot study.

Human herpesvirus-6 (HHV-6) is a widespread virus with occasional reactivation and a potential hepatotropism. The present study was undertaken to investigate the frequency of HHV-6 reactivation in viral (HCV, HBV) and alcoholic liver diseases and its implication for the course of the primary disease. Serological and immunohistochemical tests were done to document viral activity, hepatocellular apoptosis or proliferation, and autoantibody formation. While the course of HCV remains apparently uninfluenced by HHV-6, HBV hepatitis and alcoholic liver disease show a higher incidence of autoantibody formation if HHV-6 is present. The data of this pilot study warrant more extensive investigations of the clinical pathology of HHV-6 in liver diseases.

Interaction of alcohol and hepatitis viral proteins: implication in synergistic effect of alcohol drinking and viral hepatitis on liver injury.

Alcohol drinking and viral hepatitis are both recognized as major causes of liver disease worldwide, and they frequently coexist and synergistically cause liver injury in patients with chronic liver disease. Several mechanisms have been implicated in exacerbation of liver injury in patients with alcohol drinking and viral hepatitis. These include impairment of host defense and liver regeneration by alcohol consumption. The findings obtained from my laboratory have demonstrated that alcohol potentiates cooperatively several signals activated by hepatitis B virus X protein (HBX) or hepatitis C virus core protein, and HBX sensitizes hepatocytes to tumor necrosis factor-alpha (TNF-alpha)- and ethanol-induced apoptosis by a caspase-3-dependent mechanism, which may also contribute to the synergistic effect of alcohol drinking and viral hepatitis on liver injury.

A clinicopathological study of acute hepatitis in heavy drinkers, unrelated to hepatitis A, B, or C viruses.

BACKGROUND: There are six histological classifications of alcoholic liver disease (ALD) in Japan. However, it is unclear whether all cases of the disease conform to these criteria. This study investigated the clinicopathological features of eight histologically unusual cases of ALD. METHODS: The characteristic features of alcohol drinking behavior, subjective and objective symptoms, laboratory data on admission, and progress after admission were analyzed for eight patients with acute-onset hepatitis. RESULT: The eight patients showed histologically acute hepatitis, with much spotty necrosis that contained granular ceroid pigment by Kupffer cells, which indicated acute parenchymal damage of the liver, but with no Mallory bodies and unremarkable intrasinusoidal neutrophilic infiltration. The only etiological factor for all the cases was habitual alcohol consumption, with increased consumption just before the onset of symptoms. In five cases that were tested, the patients were negative for hepatic viral markers, which included hepatitis G virus RNA and TT virus DNA. CONCLUSION: Some cases of ALD may not conform to the current histological classifications in either Japan or Western countries. It seems natural to consider that these cases are developed by other, unknown causes that overlap with ALD rather than as a result of damage from alcoholic overload.

Clinicopathological study of chronic hepatitis induced by alcohol with or without hepatitis G virus.

The concept of chronic hepatitis induced by alcohol (AL-CH) has not been widely accepted, because AL-CH may be due to non-A-E hepatitis virus in heavy drinkers. Recently, hepatitis G virus (HGV) was identified as a positive-strand RNA virus related to members of the Flaviviridae family. In this study, we determined serum HGV in patients with AL-CH and analyzed the clinicopathological changes after abstinence to evaluate whether AL-CH is caused by alcohol or not. Serum samples were obtained from 16 patients with AL-CH who had neither hepatitis B nor C virus. The diagnosis was confirmed histologically. In eight patients, liver biopsy was performed twice, within 3 days and 4 to 8 weeks after abstinence. The NS3 region of the HGV genome was detected using an reverse transcriptase-polymerase chain reaction method. Serum levels of AST, ALT and gamma-glutamyltranspeptidase were measured once a week sequentially after admission. Serum HGV-RNA was detected in only one patient with AL-CH (6.3%). In all patients, including one patient with HGV, serum levels of AST, ALT and gamma-glutamyltranspeptidase clearly decreased to normal levels after abstinence. Inflammatory activity in the periportal area of patients with actively drinking decreased or disappeared after abstinence for 4 to 8 weeks. These results suggest that HGV may not play an important role for development of AL-CH, and that AL-CH may be caused by alcohol itself, although a more larger number of patients with AL-CH are needed to obtain definitive conclusions.

Hepatitis C virus infection in patients with clinically diagnosed alcoholic liver diseases.

To determine the incidence of hepatitis C virus (HCV) infection in patients with alcoholic liver disease (ALD), serum samples from 252 patients with ALD were tested for anti-HCV and HCV RNA. Serial sera of these patients were collected and stored under optimal conditions to allow exact quantification of HCV RNA. Fifteen patients who visited our hospital during the same period of time with chronic HCV infections served as controls. In those with ALD, anti-HCV and HCV RNA were positive in 55.5% and 41.2%, respectively. Patients with histologically diagnosed chronic hepatitis and hepatocellular carcinoma had much higher prevalence rates of HCV RNA (84% and 100%, respectively) compared to those with fatty liver (4.3%), hepatic fibrosis (10.1%) and alcoholic hepatitis (22.2%) (P < 0.01). Although no difference in serum HCV RNA levels was observed between the patients with both ALD and chronic HCV infection and those with chronic HCV infection alone, HCV RNA levels significantly (10-fold) dropped after abstinence in nearly half of the patients (P < 0.01). These data indicate that HCV infection in patients with ALD promotes progression of liver disease, and abstinence from alcohol is associated with a reduction in serum HCV RNA levels.

[Serologic signs of Epstein Barr virus activity in acute viral hepatitis, symptomless HbsAg carriers as well as in alcoholic liver diseases]. / Az Epstein-Barr-vírus aktivitásának szerológiai jelei akut virushepatitisekben, tünetmentes HbsAg hordozókban és alkoholos eredetü májbetegségekben.

The authors, based on their previous observations, analysed the serological incidence of the EBV infection in patients with viral hepatitis, HBsAg carriers and alcoholic liver diseases compared to control group. For the better statistical comparison they have selected the patients of 20-60 years of age and by using Khi-square probe, compared the incidence of IgM and IgG type antibodies against EBV in the samples. Significantly higher incidence (P < 0.05) of IgM antibodies were found in the samples of patients with alcoholic liver disease and of HBsAg carriers compared to the patients of viral hepatitis and control group. No similar distribution was observed related to the IgG type antibodies. Certain degree of "immunocompromised" condition is suspected in the cases of patients with HBsAg carrier state and with alcoholic liver disease known from the literature as the main reason behind the relatively more frequent Epstein-Barr virus infection.

Hepatitis B virus with X gene mutation is associated with the majority of serologically "silent" non-b, non-c chronic hepatitis.

Hepatitis B virus (HBV) with X gene mutations has been a putative pathogen of chronic hepatitis without serological markers of known hepatitis viruses. The aim of this study was to reconfirm whether the HBV with the X gene mutation is associated with these serologically "silent" non-B, non-C (NBNC) chronic hepatitis, alcoholic liver disease (ALD) and autoimmune hepatitis (AIH). HBV DNA was amplified from serum and sequenced in 30 patients with NBNC chronic hepatitis in comparison with 20 patients with ALD and 5 patients with AIH. HBV DNA was identified in 21 patients (70%) in NBNC chronic hepatitis by nested polymerase chain reaction while only one patient (5%) in ALD and none in AIH showed HBV DNA. Eighteen (85.7%) of the 21 identified HBV DNAs had an identical 8-nucleotide deletion mutation at the distal part of the X region. This mutation affected the core promoter and the enhancer II sequence of HBV DNA and created a translational stop codon which truncated the X protein by 20 amino acids from the C-terminal end. All the HBV DNAs had a precore mutation at the 83rd nucleotide resulting in disruption of HBe antigen synthesis. These results indicate that HBV mutants are closely associated with the majority of serologically "silent" NBNC chronic hepatitis cases and the population of such mutant HBV DNAs is not uniform.

[Study of hepatocellular carcinoma type C by quantitation of serum HCV-RNA using branched DNA probe assay].

Serum HCV-RNA levels were determined by newly developed branched DNA probe (bDNA) assay in 87 patients with hepatocellular carcinoma (HCC), compared with 73 patients with chronic hepatitis active and 30 patients with liver cirrhosis. Patients with decompensated liver cirrhosis (LC-d) had a significant lower viremia (mean 3.2Meg.eq./ml, bDNA positive rate; 40%) than chronic hepatitis active (18.0; 64%) and compensated LC (LC-c, 17.9; 80%) (p < 0.05). Those data indicates that HCV replication may decrease as progression of LC. In contrast, there was no difference between the levels of HCC with LC-c (8.2; 85%) and LC-d (6.1; 89%), and their positive rate of bDNA assay were significantly higher than LC-d without HCC (p < 0.01). Therefore, patients undergoing LC in whom serum HCV-RNA sustained high level may correspond to the high risk group of HCC. In HCC of heavy drinker, serum HCV-RNA levels (11.3; 91%) were significantly higher than the levels (4.6; 79%) of HCC without heavy drink (p < 0.05). The result indicates that heavy drink may induced an increase in HCV replication.