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

Abstract

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.

Figure 1. Distribution of AR CAG repeat alleles in male patients with HBV-related acute liver failure (ALFs) and asymptomatic HBV carriers (AsCs).

Figure 2. Relationship between the onset age of HBV-related acute liver failure (ALFs) and AR CAG repeat categories.

Kaplan–Meier survival curves demonstrating age of ALF occurrence based on AR CAG repeat alleles: S-CAG (CAG repeat number <19, red line), M-CAG (CAG repeat number 19–20, blue line) and L-CAG (CAG repeat number >20, green line). P value based on Log Rank test is given.

Figure 3. Fluctuations of serum testosterone levels at different phases of chronic hepatitis B.

(A) The serum testosterone levels in three male HBV carriers groups. AsC, asymptomatic HBV carriers. HB, patients with mild to moderate hepatitis B flare. ALF, patients with HBV-related acute liver failure. P value based on one-way ANOVA was given. (B) Serum testosterone levels in 26 male chronic hepatitis B patients with sequential serum samples both at inactive phase and hepatitis B flare. ALT, alanine aminotransferase. TBil, total bilirubin. T, testosterone. (C–F) Serum testosterone levels in four patients with sequential serum samples both at inactive phase (with normal serum liver enzymes and bilirubin levels) and severe hepatitis phase (TBil >10× ULN). ALT, alanine aminotransferase. TBil, total bilirubin. T, testosterone. ALF, patients with HBV-related acute liver failure. Phase 1, inactive phase. Phase 2, hepatitis flare phase. Phase 3, liver failure phase (TBil >10× ULN, coagulation abnormality with INR ≥1.5). Phase 4, recovery phase.

Figure 4. Correlation between serum testosterone levels and AR CAG repeat length.

A total of 251 male asymptomatic HBV carriers (AsCs) with normal liver enzyme levels were detected for serum testosterone levels. AR gene alleles were categorized by exon 1 CAG repeat numbers: S-CAG (CAG repeat number <19), M-CAG (CAG repeat number 19–20) and L-CAG (CAG repeat number >20). P value based on one-way ANOVA was given.