Serum testosterone levels and androgen receptor CAG polymorphism correlate with hepatitis B virus (HBV)-related acute liver failure in male HBV carriers.

BACKGROUND: Augmentation of androgen/androgen receptor (AR) pathway may influence chronic hepatitis B (CHB) more likely in males. AR activity is modulated by a polymorphic CAG repeat sequence in AR exon 1. This study aimed to investigate the relationship between serum testosterone levels, CAG repeat numbers and hepatitis B virus (HBV)-related acute liver failure (ALF). METHODS: Three hundred and seventy eight male CHB patients with ALF and 441 asymptomatic HBV carriers (AsCs) were recruited. AR CAG repeats numbers were analyzed. The serum testosterone levels of AsCs, ALFs and patients with hepatitis B flare groups, and sequential serum samples, were assessed quantitatively. RESULTS: The median CAG repeat (M-CAG) frequency was significantly higher in ALF patients than AsCs (P<0.001). Patients with M-CAG alleles (P<0.001, OR 3.0, 95% CI 2.1-4.2) had the highest risk for ALF. Serum testosterone levels were significantly higher (P<0.001) at hepatitis flare point (8.2 ± 3.0 ng/mL) than inactive phase (6.4 ± 2.0 ng/mL). CHB (8.30 ± 2.71 ng/mL, P = 7.6 × 10(-6)) and ALF group (2.61 ± 1.83 ng/mL, P = 1.7 × 10(-17)) had significantly different levels of testosterone in comparison with AsCs group (6.56 ± 2.36 ng/mL). The serum testosterone levels sharply decreased from hepatitis flare phase to liver failure phase, and tended to be normal at the recovery phase. Male AsCs with M-CAG alleles had significantly lower serum testosterone levels (P<0.05). CONCLUSIONS: There was a serum testosterone fluctuation during hepatitis B flare and HBV-related ALF, and the median CAG repeats in AR gene exon 1 were associated with lower serum testosterone levels in asymptomatic HBV carriers and an increased susceptibility to HBV-related ALF.

SLCO1B1 *15 haplotype is associated with rifampin-induced liver injury.

The organic anion transporting polypeptide 1B1 (OATP1B1, encoded by SLCO1B1) plays an important role in the transport of endogenous and xenobiotic compounds, such as bile acids and rifampin. In this study, the association between OATP1B1 polymorphisms and rifampin hepatotoxicity was investigated using integrated population genetic analysis and functional studies. A total of 273 unrelated patients treated with rifampin were recruited. The allele frequencies were examined in patients with drug (rifampin)-induced liver injury (DILI) (n = 118) and without (non-DILI) (n = 155). Functional analyses were conducted to determine whether the inhibition of bile acids by rifampin was associated with OATP1B1 variants. In the present study, 24 single nucleotide polymorphisms (SNPs) in OATP1B1 were detected in a Chinese population, with two of them causing an amino acid change (rs2306283 and rs4149056). The haplotypes constructed by these two SNPs were OATP1B1 *1a, *1b, *5 and *15, with their respective frequencies being 23.44, 66.30, 0.73 and 9.52% in a total of 273 individuals. The logistic regression analysis indicated that the *15 haplotype was associated with susceptibility to DILI (p = 0.03, OR = 2.04, 95% CI 1.05-3.96). The frequency of the *15 haplotype in DILI patients was significantly higher than that in non-DILI patients (p = 0.03). In the subgroup analysis, the *15 haplotype was associated with susceptibility to cholestatic/mixed injury (p = 0.03, OR = 2.31, 95% CI 1.06-5.02). Functional assessment of the OATP1B1 *15 haplotype revealed that the activity of bile acid uptake was markedly reduced compared to the three other haplotypes. In the inhibition study, the inhibition by rifampin in the *15 haplotype was greater compared to that in the other haplotypes. These results suggest that the OATP1B1 *15 haplotype is an important predisposing factor for rifampin-induced liver injury.

[Analysis of the correlation between the pre-S1 antigen, pre-S2 antigen and DNA of hepatitis B virus in the serum of chronic hepatitis B patients undergoing nucleoside analogue therapy.].

OBJECTIVE: To investigate the dynamic correlation between pre-S1 antigen, pre-S2 antigen and HBV DNA in the serum of chronic hepatitis B (CHB) patients undergoing nucleoside analogue therapy. METHODS: 12 CHB patients with transient virological response after lamivudine treatment, and 20 patients treated with adefovir for 5 years were recruited in this study. Serum samples were collected at four time points when HBV DNA fluctuated sharply during lamivudine treatment, and at 0, 8, 12, 28, 52, 104, 156, 208, 260 weeks following adefovir treatment. HBV DNA was quantified by real-time PCR, pre-S1 and pre-S2 antigens were detected by ELISA. RESULTS: The titers of pre-S1 and pre-S2 antigens were not correlated with the HBV DNA level in the serum of lamivudine treated patients. Only in one case of the adfovir treated patients, the decrease of pre-S1 and pre-S2 antigens was in parallel with the decrease of HBV DNA. Linear regression analysis indicated that neither pre-S1 antigen nor pre-S2 antigen was correlated with HBV DNA in the serum of lamivudine or adfovir treated patients (P more than 0.05). CONCLUSION: Our results indicate that the titers of pre-S1 and pre-S2 antigens are not correlated with the serum HBV DNA in CHB patients undergoing nucleoside analogue therapy. Neither pre-S1 nor pre-S2 is a good predictor for the outcome of nucleoside analogue treatment.