Pattern recognition receptor CD14 gene polymorphisms in alcohol use disorder patients and its Influence on liver disease susceptibility.

Background: Alcohol use disorders (AUDs) leading to liver disease is major concern over other spectrum of disorder. Excessive alcohol consumption resulting in leaky gut syndrome is attributed to alcohol-induced liver injury through portal translocation of bacterial endotoxin. Susceptibility to alcoholic liver disease (ALD) in AUD patients could be dependent upon genes responsible for inflammation and alcohol metabolism. The pattern recognition receptor CD14 gene is a major player in endotoxin-mediated inflammation and susceptibility to ALD. This study investigated the genetic association of CD14 polymorphisms and other mechanisms relevant to altered inflammatory responses leading to ALD. Methods: Patients with alcohol use disorder with ALD (n = 128) and without liver disease (ALC, n = 184) and controls without alcohol use disorder (NALC, n = 152) from North India were enrolled. The CD4 gene polymorphisms in the North Indian population were evaluated by RFLP and sequencing. Secretory CD14 (sCD14), LBP, TLR4, MD2, TNFα, IL1b, IFNγ, IL6, IL10, and IL4 levels in serum were measured by ELISA among groups. The influence of polymorphisms on CD14 gene promoter activity and circulatory bacterial DNA level was determined. Results: The CD14 gene promoter and exonic region SNPs were found to be monomorphic, except for SNP rs2569190 for the North Indian population. The genetic association of SNP rs2569190(C/T) with the risk of developing ALD was found significant for TT genotype [ORTT, 95% CI = 2.19, 1.16-4.13 for ALD vs. ALC and OR, 2.09, 1.18-3.72 for ALD vs. NALC]. An increased sCD14 level was observed in AUD patients compared to NALC control. Increased levels of LBP, TLR4, TNFα, IL1ß, IFNγ, and IL6 and reduced levels of MD2, IL10, and IL4 were observed among the ALD patients compared to the other two control groups. Elevated levels of pro-inflammatory and reduced levels of anti-inflammatory cytokines were observed in the risk genotype TT groups of ALD patients and the ALC group compared to NALC. Promoter activity was observed in the intronic region flanking SNPs and risk genotype can influence reporter activity, indicating CD14 gene expression. Conclusion: Enhanced CD14 expression associated with inflammatory responses increases susceptibility to ALD in the TT genotype of AUD patients.

Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death.

BACKGROUND/AIMS: India is hyper-endemic for hepatitis E virus (HEV). HEV infection in cirrhosis may cause high mortality. Prospective study evaluating HEV infection in cirrhotics is scarce. METHODS: Consecutive patients with cirrhosis and healthy controls were included. Cirrhotics were categorized to 3 groups, (Group I - rapid decompensation, Group II - chronically decompensated, Group III - cirrhotics without decompensation). Sera from cirrhotics and controls were tested for HEV-RNA (RT-PCR). HEV-RNA positivity among cirrhotics and controls was compared. Natural course and mortality rate between HEV infected and non-infected cirrhotics were assessed during a 12-month follow-up. RESULTS: 107 cirrhotics and 200 controls were included. 30 (28%) cirrhotics and 9 (4.5%) controls had detectable HEV-RNA (p<0.001). HEV- RNA positivity among Group I (n=42), II (n=32) and III (n=33) cirrhotics was 21 (50%), 6 (19%) and 3 (10%), respectively (p=0.002). 70% (21/30) with HEV infection and 27% (21/77) without it had rapid decompensation (p=0.001). Mortality between HEV infected and non-infected cirrhotics at 4 weeks (43% vs. 22%, p=0.001) and 12 month (70% vs. 30%, p=0.001) was different. Multivariate analysis identified HEV infection, Child-Pugh's score, renal failure, and sepsis as independent factors for mortality. CONCLUSIONS: In India, cirrhotics were prone to HEV infection, which was associated with rapid decompensation and death.