Two distinct subtypes of hepatitis B virus-related acute liver failure are separable by quantitative serum immunoglobulin M anti-hepatitis B core antibody and hepatitis B virus DNA levels

Abstract

Hepatitis B virus (HBV)-related acute liver failure (HBV-ALF) may occur after acute HBV infection (AHBV-ALF) or during an exacerbation of chronic HBV infection (CHBV-ALF). Clinical differentiation of the two is often difficult if a previous history of HBV is not available. Quantitative measurements of immunoglobulin M (IgM) anti-hepatitis B core antibody (anti-HBc) titers and of HBV viral loads (VLs) might allow the separation of AHBV-ALF from CHBV-ALF. Of 1,602 patients with ALF, 60 met clinical criteria for AHBV-ALF and 27 for CHBV-ALF. Sera were available on 47 and 23 patients, respectively. A quantitative immunoassay was used to determine IgM anti-HBc levels, and real-time polymerase chain reaction (rtPCR) was used to determine HBV VLs. AHBV-ALFs had much higher IgM anti-HBc titers than CHBV-ALFs (signal-to-noise [S/N] ratio median: 88.5; range, 0-1,120 versus 1.3, 0-750; P < 0.001); a cut point for a S/N ratio of 5.0 correctly identified 44 of 46 (96%) AHBV-ALFs and 16 of 23 (70%) CHBV-ALFs; the area under the receiver operator characteristic curve was 0.86 (P < 0.001). AHBV-ALF median admission VL was 3.9 (0-8.1) log10 IU/mL versus 5.2 (2.0-8.7) log10 IU/mL for CHBV-ALF (P < 0.025). Twenty percent (12 of 60) of the AHBV-ALF group had no hepatitis B surface antigen (HBsAg) detectable on admission to study, wheras no CHBV-ALF patients experienced HBsAg clearance. Rates of transplant-free survival were 33% (20 of 60) for AHBV-ALF versus 11% (3 of 27) for CHBV-ALF (P = 0.030).

Conclusions: AHBV-ALF and CHBV-ALF differ markedly in IgM anti-HBc titers, in HBV VLs, and in prognosis, suggesting that the two forms are, indeed, different entities that might each have a unique pathogenesis.

Figure 1. Study schema

Of the 1,602 acute liver failure (ALF) patients in the US ALF Study Group, there were 105 hepatitis B virus-related ALF (HBV-ALF) patients identified. Eighteen were excluded: 2 co-infected with hepatitis C virus, one determined to have hepatocellular carcinoma and 15 whom we were unable to define as either acute or chronic. Sixty were identified as AHBV-ALF of whom 47 had sera collected on admission and 14 had sera collected serially up to the 4^th day. Twenty-seven patients were identified as CHBV-ALF; 9 appeared to show spontaneous exacerbation (non-immunosuppressed CHBV-ALF) and 18 were considered immunosuppressed; admission and serial sera over 4 days in these groups are also listed.

Figure 2. IgM anti-HBc levels for the various groups

Admission IgM anti-HBc levels were much higher in AHBV-ALFs than in the overall CHBV-ALF group. Median IgM anti-HBc index value (signal/noise), on admission to hospital in the 46 AHBV-ALFs was 88.5 (0–1,120), significantly higher than that of the 23 overall CHBV-ALFs [1.30 (0–750), p<0.001], or the 8 non-immunosuppressed CHBV-ALFs [**], 1.9 (0–28.9), p<0.001]. The median (range) value for the 15 immunosuppressed CHBV-ALFs [*] was 1.27 (0–750). There was no difference observed between the two CHBV-ALF sub-groups.

Figure 3. Hepatitis B viral loads for the various groups

Median admission viral load (VL) in 51 patients with AHBV-ALF was 3.9 (0–8.1) log10 IU/mL, significantly lower than observed for the 24 patients in the overall CHBV-ALF group [5.2 (2.0–8.7) log10 IU/mL, p=0.025], but not for the 8 non-immunosuppressed CHBV-ALF patients [3.8 (2.5–8.7) log10 IU/mL, p=0.982]. The median (range) for the 16 in the immunosuppressed subgroup was 6.28 (1.97–8.28) log10 IU/mL. There were no significant differences in admission VLs between the two CHBV-ALF subgroups; horizontal line in each bar graph represents median VL.

Figure 4. ANCOVA for VLs measured over time for AHBV-ALF and the overall CHBV-ALF groups adjusting for baseline IgM anti-HBc levels

The decrease in VLs was significant for each of the two groups (p<0.001). VLs in AHBV-ALFs were consistently lower than in CHBV-ALFs at all time points (p<0.001). Admission IgM anti-HBc level was the only covariate that remained significant in the ANCOVA model (p=0.137). Error bars are 95% confidence intervals.