Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2016; 22(44): 9744-9751
Published online Nov 28, 2016. doi: 10.3748/wjg.v22.i44.9744
Angiopoietin-2/angiopoietin-1 as non-invasive biomarker of cirrhosis in chronic hepatitis C
Angel Hernández-Bartolomé, Rosario López-Rodríguez, María Jesús Borque, Leticia González-Moreno, Yolanda Real-Martínez, Luisa García-Buey, Ricardo Moreno-Otero, Paloma Sanz-Cameno
Rosario López-Rodríguez, Leticia González-Moreno, Yolanda Real-Martínez, Luisa García-Buey, Ricardo Moreno-Otero, Paloma Sanz-Cameno, Ángel Hernández-Bartolomé, Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, 28006 Madrid, Spain
María Jesús Borque, Molecular Biology Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, 28006 Madrid, Spain
Luisa García-Buey, Ricardo Moreno-Otero, Paloma Sanz-Cameno, CIBERehd, 28006 Madrid, Spain
Author contributions: Hernández-Bartolomé A contributed to acquisition, analysis and interpretation of data, final approval given; López-Rodríguez R contributed to acquisition, analysis and interpretation of data, critical revision of the manuscript, final approval given; Borque MJ contributed to acquisition of data; González-Moreno L, Real-Martínez Y, García-Buey L and Moreno-Otero R contributed to clinical management of patients, critical revision of the manuscript, final approval given; Sanz-Cameno P contributed to conception and design of the study, analysis and interpretation of data, drafting of the manuscript and final approval given.
Supported by the Ministerio de Ciencia e Innovación (SAF: 2010/21805, partially); CIBERehd (Instituto de Salud Carlos III, Madrid); Fundación Mutua Madrileña (to Moreno-Otero R); and a grant from Asociación Española Contra el Cáncer (AIO 2010, AECC, to Sanz-Cameno P).
Institutional review board statement: This study was reviewed and approved by the clinical research ethics committee of Hospital Universitario de la Princesa.
Informed consent statement: Written informed consent was obtained from all subjects at the time of enrollment or blood sampling.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Paloma Sanz-Cameno, PhD, Liver Unit, Gastroenterology Service, Instituto Investigación Sanitaria Princesa, IIS-IP, 28006 Madrid, Spain. paloma_march@hotmail.com
Telephone: +34-91-5202334 Fax: +34-91-4022299
Received: May 28, 2016
Peer-review started: May 30, 2016
First decision: August 8, 2016
Revised: September 9, 2016
Accepted: October 10, 2016
Article in press: October 10, 2016
Published online: November 28, 2016
Abstract
AIM

To evaluate the efficacy of peripheral blood concentrations of angiopoietins (Ang) as cirrhosis biomarkers of chronic hepatitis C (CHC).

METHODS

Ang1 and Ang2 serum levels were measured by enzyme-linked immunosorbent assays (ELISA) in samples from 179 cirrhotic and non-cirrhotic CHC patients, classified according to the METAVIR system. Groups were compared by non-parametric Mann-Whitney U test. Subsequently, the association of peripheral concentrations of angiopoietins with the stage of fibrosis was analyzed using Spearman correlation test. Finally, the accuracy, sensitivity and specificity of circulating angiopoietins for cirrhosis diagnosis were determined by the study of the respective area under the curve of receiver operator characteristics (AUC-ROC).

RESULTS

Peripheral blood concentrations of Ang1 and Ang2 in CHC patients were significantly related to fibrosis. While Ang1 was decreased in cirrhotic subjects compared to non-cirrhotic (P < 0.0001), Ang2 was significantly increased as CHC progressed to the end stage of liver disease (P < 0.0001). Consequently, Ang2/Ang1 ratio was notably amplified and significantly correlated with fibrosis (P < 0.0001). Interestingly, the individual performance of each angiopoietin for the diagnosis of cirrhosis reached notable AUC-ROC values (above 0.7, both), but the Ang2/Ang1 ratio was much better (AUC-ROC = 0.810) and displayed outstanding values of sensitivity (71%), specificity (84%) and accuracy (82.1%) at the optimal cut-off (10.33). Furthermore, Ang2/Ang1 ratio improved the performance of many other previously described biomarkers or scores of liver cirrhosis in CHC.

CONCLUSION

Ang2/Ang1 ratio might constitute a useful tool for monitoring the progression of chronic liver disease towards cirrhosis and play an important role as therapeutic target.

Keywords: Chronic hepatitis C, Area under the curve of receiver operator characteristics, Liver fibrosis, Cirrhosis, Angiopoietin-2, Angiopoietin-1, Biomarker, Angiogenesis

Core tip: Chronic hepatitis C (CHC) is the leading cause of cirrhosis and hepatocellular carcinoma and monitoring of liver fibrosis is essential for the prognosis and treatment of these patients. Liver biopsy, the gold standard for fibrosis determination, is invasive and costly. Therefore, novel reliable non-invasive biomarkers are crucial for CHC management. Angiogenesis is closely related to the pathogenesis of the disease and angiopoietins play a relevant role in this process. Interestingly, this study confirms the valuable association of circulating angiopoitein-1 (Ang1) and angiopoitein-2 (Ang2) levels with CHC progression and reveals the outstanding role of Ang2/Ang1 ratio as potential non-invasive biomarker of cirrhosis.