2025/10/29 by Xinjie Li, Meijie Shi, Xiaozhong Wang +13
Medicine · #Hepatitis B Virus Studies #Liver Disease Diagnosis and Treatment #Liver Diseases and Immunity
paper · doi:10.1093/infdis/jiaf554
BACKGROUND: Individuals with chronic hepatitis B (CHB) may harbor occult yet significant liver pathology despite normal alanine aminotransferase (ALT) levels, representing a major diagnostic challenge. We aimed to identify and validate noninvasive biomarkers for detecting significant liver pathology among this population. METHODS: This multicenter study screened 3258 CHB cases from 2013 to 2023, enrolling 137 treatment-naive hepatitis B e antigen (HBeAg)-positive (HBeAg+) and 253 HBeAg-negative patients with CHB with normal ALT levels (≤40 U/L). All participants underwent liver biopsy (reference standard) and measurement of liver function and novel biomarkers (including cytokeratin 18 [CK18]-M30, CK18-M65, Golgi protein (GP73), interleukin 10, and interleukin 2 receptor). Significant liver pathology was defined as inflammation grade and/or fibrosis stage ≥2. Sixteen CK18-M65-centered biomarker combinations were evaluated using 8 machine learning algorithms with multicenter stratified validation. RESULTS: Significant liver pathology was observed in 45.2% of patients with HBeAg+ infection. CK18-M65, CK18-M30, and GP73 were strongly correlated with the severity of pathology (correlation with inflammation grade, r = 0.757, r = 0.688, and r = 0.453, respectively; P < .001), independent of ALT levels. CK18-M65 demonstrated optimal diagnostic performance (area under the curve, 0.934 [95% confidence interval, .896-.973]) with 85.5% sensitivity and 88% specificity, especially in those with low-normal ALT. High CK18-M65 levels conferred >40-fold increased risk of severe liver injury (adjusted odds ratio, 40.64). The optimal biomarker combination (CK18-M65 + CK18-M30 + GP73) achieved an area under the receiver operating characteristic curve of 0.942, significantly outperforming liver stiffness measurement (0.824), aspartate aminotransferase-to-platelet ratio index (0.783), and Fibrosis-4 score (0.745) (all P < .01), with enhanced clinical utility. HBeAg-negative patients with CHB showed significant pathology in 46%, but exhibited weaker diagnostic performance. CONCLUSIONS: CK18-M65-centered biomarker models suggest promising noninvasive tools for detecting occult liver pathology and risk stratification of ALT-normal HBeAg+ CHB infection, potentially avoiding unnecessary biopsies while identifying candidates for early intervention, nonetheless requiring validation in larger cohorts.