title: Selected Cytokines Serve as Potential Biomarkers for Predicting Liver Inflammation and Fibrosis in Chronic Hepatitis B Patients With Normal to Mildly Elevated Aminotransferases.
abstract: Previous studies of small cohorts have implicated several circulating cytokines with progression of chronic hepatitis B (CHB). However, to date there have been no reliable biomarkers for assessing histological liver damage in CHB patients with normal or mildly elevated alanine aminotransferase (ALT). The aim of the present study was to investigate the association between circulating cytokines and histological liver damage in a large cohort. Also, this study was designed to assess the utility of circulating cytokines in diagnosing liver inflammation and fibrosis in CHB patients with ALT less than 2 times the upper limit of normal range (ULN). A total of 227 CHB patients were prospectively enrolled. All patients underwent liver biopsy and staging by Ishak system. Patients with at least moderate inflammation showed significantly higher levels of CXCL-11, CXCL-10, and interleukin (IL)-2 receptor (R) than patients with less than moderate inflammation (P < 0.001). Patients with significant fibrosis had higher levels of IL-8 (P = 0.027), transforming growth factor alpha (TGF-α) (P = 0.011), IL-2R (P = 0.002), and CXCL-11 (P = 0.032) than the group without significant fibrosis. In addition, 31.8% and 29.1% of 151 patients with ALT < 2 × ULN had at least moderate inflammation and significant fibrosis, respectively. Multivariate analysis demonstrated that CXCL-11 was independently associated with at least moderate inflammation, and TGF-α and IL-2R independently correlated with significant fibrosis in patients with ALT < 2 × ULN. Based on certain cytokines and clinical parameters, an inflammation-index and fib-index were developed, which showed areas under the receiver operating characteristics curve (AUROC) of 0.75 (95% CI 0.66-0.84) for at least moderate inflammation and 0.82 (95% CI 0.75-0.90) for significant fibrosis, correspondingly. Compared to existing scores, fib-index was significantly superior to aspartate aminotransferase (AST) to platelet ratio index (APRI) and FIB-4 score for significant fibrosis. In conclusion, CXCL-11 was independently associated with at least moderate inflammation, whereas IL-2R and TGF-α were independent indicators of significant fibrosis in both, total CHB patients and patients with normal or mildly elevated ALT. An IL-2R and TGF-α based score (fib-index) was superior to APRI and FIB-4 for the diagnosis of significant fibrosis in patients with normal or mildly elevated ALT.
authors.affiliation: From the Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital (Y-QD, HZ, J-YZ, G-QW); Department of Infectious Disease, China-Japan Friendship Hospital, Beijing (A-LM); Department of Infectious Disease, The Third Affiliated Hospital Sun Yat-Sen University, Guangzhou, Guangdong (S-BX); Department of Infectious Diseases, South West Hospital affiliated to Third Military Medical University (X-QZ); Department of Infectious Diseases, Second Affiliated Hospital of Chongqing Medical University, Chongqing (D-ZZ); Department of Infectious Diseases, Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai (QX); Department of Infectious Diseases, The People's Hospital of Guang Xi Zhuang Autonomous Region, Nanning, Guangxi (GZ); Department of Infectious Diseases, The People's Hospital Of He Nan province, Zhengzhou, Henan (J-S); Department of Infectious Diseases, Di Tan Hospital affiliated to Capital Medical University, Beijing (JC); Department of Infectious Diseases, Xinxiang Medical University Third Hospital, Xinxiang, Henan (W-FZ); Department of Infectious Diseases, Yantai City Hospital for Infectious Disease, Yantai, Shandong (Z-QZ); Department of Infectious Diseases, Shenyang Sixth People's Hospital, Shenyang (M-XZ); and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang; Liaoning, China (G-QW).
authors.forename: Yong-Qiong
authors.initials: YQ
authors.lastname: Deng
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: An-Lin
authors.initials: AL
authors.lastname: Ma
authors.forename: Ji-Yuan
authors.initials: JY
authors.lastname: Zhou
authors.forename: Shi-Bin
authors.initials: SB
authors.lastname: Xie
authors.forename: Xu-Qing
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang
authors.forename: Jia
authors.initials: J
authors.lastname: Shang
authors.forename: Jun
authors.initials: J
authors.lastname: Cheng
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Zhao
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Zou
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Zhang
authors.forename: Gui-Qiang
authors.initials: GQ
authors.lastname: Wang
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D015415:Biomarkers; D016207:Cytokines / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D019694:Hepatitis B, Chronic / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000473:pathology; D008103:Liver Cirrhosis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D016207:Cytokines; D000410:Alanine Transaminase