Clinical and Molecular Risk Factors of Anti-tubercular Therapy Induced Hepatitis.

BACKGROUND: This is a case-control study aimed at evaluating clinical as well as molecular risk factors for occurrence of ATT induced hepatitis in Northern Indian population. METHODS: 100 patients of tuberculosis were recruited from both Outdoor patient department and wards of Lok Nayak Hospital, New Delhi. 40 out of 100 patients who developed ATT induced hepatitis were taken as test group and 60 out of 100 patients who didn't develop liver dysfunction on ATT were taken as controls and studied and compared for clinical factors such as age, gender, nutritional status, HBsAg carrier, chronic hepatitis C and HIV infection. Molecular factors i.e. NAT2 acetylator status, GSTT1 and M1 null mutations were also determined in all of the patients in each group and compared. RESULTS: Mean body weight and serum albumin were significantly lower in the ATT induced hepatitis patients as compared to the control group. No preferential association was observed between age and gender with ATT induced hepatitis. HBsAg carrier (OR-6.5; P = 0.03), HIV infection (OR-5.1; P = 0.01), slow acetylator phenotype (OR-3.85; P = 0.02), GSTM1 null mutation (OR-2.72; P = 0.02) and GSTT1 null mutation (OR-3.12; P = 0.02) were found to be positively co-related to ATT induced hepatitis according to the univariate analysis. HBsAg carrier (OR-23.18; P = 0.01), HIV infection (OR-16.92; P = 0.02), Slow acetylator phenotype (OR-70.90; P = 0.001), GSTM1 null mutation (OR-37.03; P = 0.002) and GSTT1 null mutation (OR-8.19; P = 0.014) were also found to be independently increasing the risk of ATT induced hepatitis using multivariate analysis. CONCLUSION: The present study established a positive co-relation between malnutrition, HBsAg carrier, HIV infection, NAT2 slow acetylators, GSTM1 null mutation, GSTT1 null mutation and ATT induced hepatitis.

HLA-DQA1 & DQB1 variants associated with hepatitis B virus-related chronic hepatitis, cirrhosis & hepatocellular carcinoma.

Background & objectives: Clinical outcome after hepatitis B virus (HBV) exposure varies extremely from spontaneous clearance to chronic hepatitis B and often progresses to liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Host genetic factor plays an important role in the regulation of immune response. This study was aimed to investigate whether HLA class II DQA1 and DQB1 gene polymorphism were associated with chronic hepatitis B infection and in the development of HBV-related LC and HCC. Methods: DQA1 and DQB1 allele polymorphism were studied in 187 patients with HBV-related liver diseases (which included 73 chronic hepatitis B, 84 LC and 30 HCC patients) and 109 controls who had spontaneously recovered from HBV infection using polymerase chain reaction amplification with sequence-specific primers. Results: Our data suggested that DQA1*0101/2/4 [odds ratio (OR)=2.78; Pc=0.003], DQA1*0103 (OR=2.64; Pc=0.0007) and DQB1*0302/3 (OR=2.15; Pc=0.01) were associated with the protection from chronic HBV infection, whereas DQB1*0402 (OR=0.25; Pc=0.001) showed susceptible effect on chronic HBV infection. DQB1*0601 (OR=3.73; Pc=0.006) conferred protective effect from developing LC; similarly, DQB1*0302/3 (OR=5.53; Pc=0.05) and DQB1*0402 (OR=0.00; Pc=0.001) conferred protective effect from developing HCC. However, DQA1*0601 and DQB1*0503 showed susceptible effect on chronic HBV infection; these associations were no longer significant after Bonferroni correction. Interpretation & conclusions: Our results revealed HLA-DQA1*0101/2/4 - DQA1*0103 - DQB1*0302/3 and DQB1*0601 as protective and DQB1*0402 as risk alleles. The study suggests that various subtypes of HLA-DQA1 and DQB1 are associated with both HBV clearance and development of chronic HBV infections.

A study of association between regulatory polymorphism in the IL-10 gene promoter region and acute viral hepatitis, and acute liver failure.

BACKGROUND: The level of inflammatory cytokine Interleukin (IL)-10 is increased in patients infected with hepatitis-related acute liver failure (ALF), and this was thought to be because of the regulatory polymorphism in the IL-10 gene promoter region. The present study was designed to analyze the possible association between IL-10 gene promoter polymorphism and acute viral hepatitis (AVH), and ALF. An attempt was made to quantify IL-10 levels at admission, during the hospital stay, and at the final outcome to study its relationship with liver injury among patients with AVH, ALF, and controls. METHODS: The study included 40 patients each with ALF and AVH. IL-10 gene promoter polymorphism was detected by the PCR-RFLP method. Quantification of IL-10 was done using commercially available ELISA kits. RESULTS: The individuals with -592 AC, -819 TC, -1082 AA genotypes were found to have a significantly higher risk of ALF whereas those with -592 AA and - 819 CC polymorphism were found to be less susceptible. Individuals with - 819 CC were found to be more susceptible to AVH while those with -592 AA and -819 TT were less susceptible as compared to controls. Mean serum IL-10 at admission was significantly elevated in patients with ALF (38.4±11.3 pg/mL) as compared to patients with AVH (16.7±5.4 pg/mL) and control population (8.3±3.6 pg/mL, p < 0.05). CONCLUSION: Regulatory polymorphism in the IL-10 gene promoter has a possible and significant association with severity and outcome in patients with AVH and ALF. Raised levels of IL-10 could be predictive of prognosis in patients with ALF.

Clinical Significance of Quantitative HBsAg Titres and its Correlation With HBV DNA Levels in the Natural History of Hepatitis B Virus Infection.

BACKGROUND/OBJECTIVE: Quantification of serum hepatitis B antigen (HBsAg) is an important test that marks active infection with hepatitis B and helps in the prediction of the clinical outcome and management of hepatitis B virus (HBV) infection. Correlation with HBV DNA quantitative levels may help in developing strategies for antiviral treatment. This study is aimed to evaluate HBsAg titres in various phase of HBV infection in HBsAg positive patients, and its correlation with HBV DNA viral load levels. METHODS: 976 HBV related patients were analysed in this retrospective cross-sectional study. Patients were categorised on the basis of the phase of HBV infection: immune tolerant phase (IT, n = 123), immune clearance phase (IC, n = 192), low-replicative phase (LR, n = 476), and HBeAg-negative hepatitis (ENH, n = 185). HBsAg titres were quantified and correlated with HBV-DNA levels and clinical parameters. RESULTS: Median HBsAg titres were different between each phases of HBV infection (P < 0.001): (4.62 log10 IU/ml), IC (3.88 log10 IU/ml), LR (2.76 log10 IU/ml) and ENH (2.94 log10 IU/ml). HBsAg and HBV DNA levels showed significant correlation in the whole group (r = 0.694, P < 0.001), and this was also observed in different phases of HBV infection. Strong correlation in IT phase (r = 0.603, P < 0.001) and IC phase (r = 0.523, P < 0.001), moderate in LR phase (r = 0.362, P < 0.001) and weak in ENH (r = 0.110, P = 0.04). No correlation was observed between serum HBsAg levels and biochemical parameters. CONCLUSION: The study demonstrated significant difference in the median baseline values of serum HBsAg titres in different phases of HBV infection and provides additional information in understanding the natural history of HBV-infection.

IL-18 polymorphisms in hepatitis B virus related liver disease.

Interleukine-18 (IL-18) was originally called interferon (INF-γ) inducing factor and plays a critical dual role in Th1 polarization and viral clearance. We aimed to explore whether single-nucleotide promoter polymorphisms (SNPs) are associated with the outcome of hepatitis B virus (HBV) infection. 271 HBV infected patients were recruited in this study out of these 109 were spontaneously recovered and 162 were diagnosed to be having persistent HBV infection which includes 48 chronic hepatitis, 84 liver cirrhosis, 30 HCC cases and were compared with 280 healthy controls. IL-18 promoter genotyping was performed with sequence-specific primers. The results demonstrated the significant involvement of genotype AA at position -607 in healthy controls (38.6%) when compared to cases (26.0%) (OR=0.54 (0.385-0.797)) and also associated with spontaneous clearance (37.6%) compared to persistent HBV infections (17.9%) (OR=2.76 (1.582-4.832)). Whereas, genotype CC at position -607 in cases (18.0%) when compared to healthy controls (6.7%) (OR=3.03 (1.734-5.303)) also associated with persistent HBV infections (24.1%) compared to spontaneous clearance (9.2%) (OR=0.31 (0.151-0.67)). And genotype GC at position -137 in cases (49.5%) compared to healthy controls (38.5%) (OR=1.55 (1.11-2.18)). Whereas, genotype GG at position -137 in healthy controls (56.8%) compared to cases (45.4%) (OR=0.63 (0.451-0.885)). No significant difference at position -137 was observed between spontaneous clearance and persistent HBV infections. These polymorphisms of the IL-18 gene promoter region at position -607 and -137 could be associated with different outcomes of HBV infection. The people with allele A at position -607 may be protected against HBV infection; moreover AA genotype is associated with spontaneous clearance.