Noninvasive Detection of Occult yet Significant Liver Pathology in Alanine Aminotransferase-Normal Chronic Hepatitis B: A Multicenter Study.

Abstract

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. 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. 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. 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.