Related Experiment Video
Updated: Jan 6, 2026
Author Spotlight: Advancements and Challenges in Hepatitis B Virus Detection
Published on: December 15, 2023
Noninvasive Detection of Occult yet Significant Liver Pathology in Alanine Aminotransferase-Normal Chronic Hepatitis
Xinjie Li1, Meijie Shi2, Xiaozhong Wang3
1Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University, Beijing, China.
Insights
New biomarkers like CK18-M65 can detect significant liver disease in chronic hepatitis B patients with normal ALT levels. These non-invasive tools aid in risk stratification and may reduce the need for liver biopsies.
Area of Science:
- Hepatology
- Biomarker Discovery
- Diagnostic Technologies
Background:
- Chronic hepatitis B (CHB) poses diagnostic challenges due to potential occult liver pathology despite normal alanine aminotransferase (ALT) levels.
- Accurate detection of significant liver pathology in these patients is crucial for timely intervention.
Purpose of the Study:
- To identify and validate non-invasive biomarkers for detecting significant liver pathology in CHB patients with normal ALT.
- To evaluate the diagnostic performance of novel biomarkers and their combinations.
Main Methods:
- A multicenter study enrolled 390 treatment-naïve CHB patients (137 HBeAg+, 253 HBeAg-) with normal ALT (≤40 U/L).
- Liver biopsy was performed as the gold standard; novel biomarkers (CK18-M30, CK18-M65, GP73, IL-10, IL-2R) were measured.
- Machine learning algorithms evaluated 16 biomarker combinations for detecting significant liver pathology (inflammation/fibrosis grade/stage ≥2).
Main Results:
- Significant liver pathology was found in 45.2% of HBeAg+ and 46% of HBeAg- CHB cases.
- CK18-M65, CK18-M30, and GP73 strongly correlated with liver pathology severity, independent of ALT.
- The optimal biomarker combination (CK18-M65+CK18-M30+GP73) achieved superior diagnostic accuracy (AUROC=0.942) compared to existing non-invasive scores.
Conclusions:
- CK18-M65-centered biomarker models show promise as non-invasive tools for detecting occult liver pathology in ALT-normal CHB patients.
- These models can aid in risk stratification and potentially reduce unnecessary liver biopsies.
- Further validation in larger cohorts is warranted to confirm clinical utility.
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.
Related Concept Videos
01:22Effect of Hepatic Disease on Pharmacokinetics: Pathophysiologic Assessment and Liver Function Test
01:25Ultrasound II: Endoscopic Ultrasound and FibroScan
Endoscopic Ultrasound (EUS):