A new glutamine synthetase index to evaluate hepatic lobular restoration in advanced fibrosis during anti‐HBV therapy

Abstract Hepatic lobular architecture distortion is a deleterious turning point and a crucial histological feature of advanced liver fibrosis in chronic liver diseases. Regression of fibrosis has been documented in chronic hepatitis B (CHB) patients. However, whether lobular architecture could be restored following fibrosis regression after antiviral therapy is still unclear. Glutamine synthetase (GS) is generally expressed by perivenular hepatocytes around hepatic veins (HV). In this study, we defined abnormal lobular architecture (GS PT ) as GS expressing in the vicinity of portal tracts (PT), which denotes parenchymal extinction and lobular collapse. We defined normal lobular architecture (GS HV ) as GS positivity area not approximating PTs. Therefore, we propose a new GS‐index, defined as the percentage of GS HV /(GS HV + GS PT ), to evaluate the extent of architectural disruption and restoration. We evaluated 43 CHB patients with advanced fibrosis (Ishak stage ≥4). Posttreatment liver biopsy was performed after 78 weeks of anti‐HBV therapy. The median GS‐index improved from 7% (interquartile range [IQR]: 0%–23%) at baseline to 36% (IQR: 20%–57%) at Week 78 ( p < 0.001). Totals of 22 patients (51%) had significant GS‐index improvement from 0% (IQR: 0%–13%) to 55% (IQR: 44%–81%), while the other half had almost no change between 17% (IQR: 0%–33%) to 20% (IQR: 12%–31%). When GS‐index 78w ≥ 50% was used to define hepatic lobular restoration, 37% of patients (16/43) achieved lobular restoration, with much improvement in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (median value of ∆/Baseline in ALT: restored vs. nonrestored was 79.1% vs. 48.8%, p = 0.018; median value of ∆/Baseline in AST: restored vs. nonrestored was 69.1% vs. 32.5%, p = 0.005). More importantly, lobular restoration correlated with fibrosis regression (median value of ∆/Baseline in Ishak stage: restored vs. nonrestored was 25.0% vs. 0%, p = 0.008). Therefore, in the era of antiviral therapy for CHB, restoration of hepatic lobular architecture is achievable in patients with advanced fibrosis. GS‐index provides additional insight into fibrosis regression that goes beyond collagen degradation.