Soluble Axl is an accurate biomarker of cirrhosis and hepatocellular carcinoma development: results from a large scale multicenter analysis
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Mirko Dengler1,*, Katharina Staufer2,12,*, Heidemarie Huber1, Rudolf Stauber3, Heike Bantel4, Karl Heinz Weiss5, Patrick Starlinger6, Hannelore Pock3, Petra Klöters-Plachky5, Daniel N. Gotthardt5, Peter Rauch7, Carolin Lackner8, Judith Stift9, Christine Brostjan6, Thomas Gruenberger6, Takashi Kumada10, Hidenori Toyoda10, Toshifumi Tada10, Thomas S. Weiss11, Michael Trauner12 and Wolfgang Mikulits1
1Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
2Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria
3Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
4Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
5University Hospital Heidelberg, Heidelberg, Germany
6Department of Surgery, Division of General Surgery, Medical University of Vienna, Vienna, Austria
7Candor Bioscience GmbH, Wangen im Allgäu, Germany
8Institute of Pathology, Medical University of Graz, Graz, Austria
9Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
10Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
11Center for Liver Cell Research, Children’s University Hospital (KUNO), University of Regensburg Hospital, Regensburg, Germany
12Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
*These authors have contributed equally to this work
Wolfgang Mikulits, email: [email protected]
Keywords: soluble Axl, biomarker, fibrosis, cirrhosis, hepatocellular carcinoma
Received: September 01, 2016 Accepted: April 06, 2017 Published: May 03, 2017
Patients with chronic liver disease (CLD) and cirrhosis are at high risk for hepatocellular carcinoma (HCC). Current diagnostic tools for HCC detection include imaging techniques and serum biomarkers such as α-fetoprotein (AFP). Yet, these methods are limited in sensitivity and specificity to accurately detect early HCC. Here we focused on the potential of soluble Axl (sAxl) as a biomarker in CLD patients by analyzing serum samples of 1067 patients and healthy controls from centers in Europe and Asia. We show that serum concentrations of sAxl were significantly increased at early (82.57 ng/mL) and later stages of HCC (114.50 ng/mL) as compared to healthy controls (40.15 ng/mL). Notably, no elevated sAxl levels were detected in patients with CLD including chronic viral hepatitis, autoimmune hepatitis, cholestatic liver disease, or non-alcoholic fatty liver disease versus healthy controls. Furthermore, sAxl did not rise in liver adenomas or cholangiocarcinoma (CCA). Yet, patients with advanced fibrosis (F3) or cirrhosis (F4) showed enhanced sAxl concentrations (F3: 54.67 ng/mL; F4: 94.74 ng/mL). Hepatic myofibroblasts exhibited an increased release of sAxl, suggesting that elevated sAxl levels arise from these cells during fibrosis. Receiver operating characteristic curve analysis of sAxl displayed a strongly increased sensitivity and specificity to detect both cirrhosis (80.8%/92.0%) and HCC (83.3%/86.7%) with an area under the curve of 0.935/0.903 as compared to AFP. In conclusion, sAxl shows high diagnostic accuracy at early stage HCC as well as cirrhosis, thereby outperforming AFP. Importantly, sAxl remains normal in most common CLDs, liver adenomas and CCA.
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