{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:10:12Z","timestamp":1785161412961,"version":"3.55.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["824B2063"],"award-info":[{"award-number":["824B2063"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Innovation Fund for Outstanding Doctoral Candidates of Peking University Health Science Center","award":["BMU2024BSS001"],"award-info":[{"award-number":["BMU2024BSS001"]}]},{"DOI":"10.13039\/501100005198","name":"Chinese Foundation for Hepatitis Prevention and Control","doi-asserted-by":"publisher","award":["GRG202301"],"award-info":[{"award-number":["GRG202301"]}],"id":[{"id":"10.13039\/501100005198","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This multicenter study screened 3258 CHB cases from 2013 to 2023, enrolling 137 treatment-naive hepatitis B e antigen (HBeAg)\u2013positive (HBeAg+) and 253 HBeAg-negative patients with CHB with normal ALT levels (\u226440\u2005U\/L). All participants underwent liver biopsy (reference standard) and measurement of liver function and novel biomarkers (including cytokeratin 18 [CK18]\u2013M30, CK18-M65, Golgi protein (GP73), interleukin 10, and interleukin 2 receptor). Significant liver pathology was defined as inflammation grade and\/or fibrosis stage \u22652. Sixteen CK18-M65\u2013centered biomarker combinations were evaluated using 8 machine learning algorithms with multicenter stratified validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 &amp;lt; .001), independent of ALT levels. CK18-M65 demonstrated optimal diagnostic performance (area under the curve, 0.934 [95% confidence interval, .896\u2013.973]) with 85.5% sensitivity and 88% specificity, especially in those with low-normal ALT. High CK18-M65 levels conferred &amp;gt;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\u2013to-platelet ratio index (0.783), and Fibrosis-4 score (0.745) (all P &amp;lt; .01), with enhanced clinical utility. HBeAg-negative patients with CHB showed significant pathology in 46%, but exhibited weaker diagnostic performance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CK18-M65\u2013centered 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiaf554","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T13:06:11Z","timestamp":1761743171000},"page":"528-540","source":"Crossref","is-referenced-by-count":1,"title":["Noninvasive Detection of Occult yet Significant Liver Pathology in Alanine Aminotransferase\u2013Normal Chronic Hepatitis B: A Multicenter Study"],"prefix":"10.1093","volume":"233","author":[{"given":"Xinjie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijie","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine , Guangzhou, Guangdong Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaozhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Liver Disease, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University , Urumqi, Xinjiang Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Liver Disease, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University , Urumqi, Xinjiang Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Infection Hospital Area of the First Affiliated Hospital of University of Science and Technology of China (Hefei Infectious Disease Hospital) , Hefei, Anhui Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xihong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The People's Hospital of Chizhou , Chizhou, Anhui Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine , Guangzhou, Guangdong Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, The People's Hospital of Chizhou , Chizhou, Anhui Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyuan","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The People's Hospital of Chizhou , Chizhou, Anhui Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The People's Hospital of Chizhou , Chizhou, Anhui Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinbao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The People's Hospital of Chizhou , Chizhou, Anhui Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Chi","sequence":"additional","affiliation":[{"name":"Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine , Guangzhou, Guangdong Province ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1365-9862","authenticated-orcid":false,"given":"Tao","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University , Beijing ,","place":["China"]},{"name":"Peking University\u2014YHLO Joint Laboratory for Molecular Diagnostics of Infectious Diseases, Peking University , Beijing 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