Case Control Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2019; 25(23): 2935-2946
Published online Jun 21, 2019. doi: 10.3748/wjg.v25.i23.2935
Plasma Nogo-A and placental growth factor levels are associated with portal hypertension in patients with liver cirrhosis
Sigita Gelman, Violeta Salteniene, Andrius Pranculis, Jurgita Skieceviciene, Romanas Zykus, Dalius Petrauskas, Limas Kupcinskas, Ali Canbay, Alexander Link, Juozas Kupcinskas
Sigita Gelman, Romanas Zykus, Dalius Petrauskas, Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
Violeta Salteniene, Jurgita Skieceviciene, Institute for Digestive Research, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
Andrius Pranculis, Department of Radiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
Limas Kupcinskas, Juozas Kupcinskas, Institute for Digestive Research and Department of Gastroenterology, Medical Academy, Lithuanian University of Health Sciences, Kaunas 44307, Lithuania
Ali Canbay, Alexander Link, Department of Gastroenterology, Hepatology and Infectious Diseases Otto-von-Guericke University, Magdeburg 39106, Germany
Author contributions: Kupcinskas L and Kupcinskas J designed the research; Gelman S, Zykus R and Petrauskas D treated patients, collected material and clinical data from the patients; Salteniene V and Skieceviciene J performed the assays, Pranculis A performed hepatic vein catheterization and HVPG measurement, Gelman S analyzed the data and drafted the manuscript, Canbay A, Link A and Kupcinskas J approved the final version of the manuscript .
Supported by the Research Fund of Lithuanian University of Health Sciences (SV5-074/BN17-99), No. LSMU-21.
Institutional review board statement: This study was approved by the institutional review board of Lithuanian University of Health Sciences.
Informed consent statement: Informed consent was obtained from each patient.
Conflict-of-interest statement: The authors have declared no conflicts of interest.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
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/
Corresponding author: Juozas Kupcinskas, MD, PhD, Doctor, Professor, Research Fellow, Senior Researcher, Senior Scientist, Institute for Digestive Research, Lithuanian University of Health Sciences, A. Mickeviciaus Str. 9, Kaunas 44307, Lithuania. juozas.kupcinskas@lsmuni.lt
Telephone: +370-37-326898
Received: March 23, 2019
Peer-review started: March 25, 2019
First decision: April 11, 2019
Revised: April 18, 2019
Accepted: April 29, 2019
Article in press: April 29, 2019
Published online: June 21, 2019
Processing time: 90 Days and 8.2 Hours
Abstract
BACKGROUND

Clinically significant portal hypertension (CSPH) and severe portal hypertension (SPH) increase the risk for decompensation and life-threatening complications in liver cirrhosis. Pathologic angiogenesis might contribute to the formation of these conditions. Placental growth factor (PlGF) and Nogo-A protein are biomarkers of pathological angiogenesis, but data on their role in liver cirrhosis and portal hypertension is scarce.

AIM

To determine plasma levels of PlGF and Nogo-A in patients with liver cirrhosis, CSPH, SPH and potential to predict portal hypertension.

METHODS

A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized hepatic venous pressure gradient (HVPG) were included in the study. Demographic data, medical history, Child-Turcotte-Pugh and Model of End Stage liver disease score, clinical chemistry, liver stiffness values were recorded on the day of the procedure prior HVPG measurement. The degree of portal hypertension was determined by the invasive HVPG measurement. Nogo-A and PlGF plasma levels were evaluated using enzyme linked immunosorbent assay. The control group consisted of 30 healthy age- and sex- matched individuals.

RESULTS

Peripheral PlGF levels were higher and Nogo-A levels were lower in patients with liver cirrhosis (23.20 vs 9.85; P < 0.0001 and 2.19 vs 3.12; P = 0.004 respectively). There was a positive linear correlation between peripheral levels of PlGF and HVPG (r = 0.338, P = 0.001) and negative linear correlation between the peripheral Nogo-A levels and HVPG (r = -0.267, P = 0.007). PlGF levels were higher in CSPH and SPH (P = 0.006; P < 0.0001) whereas Nogo-A levels were lower (P = 0.01; P < 0.033). Area under the curve for the diagnosis of CSPH for PlGF was 0.68 (P = 0.003) and for Nogo-A - 0.67 (P = 0.01); for SPH 0.714 (P < 0.0001) and 0.65 (P = 0.014) respectively. PlGF levels were higher and Nogo-A levels were lower in patients with esophageal varices (P < 0.05). PlGF cut-off value of 25 pg/mL distinguished patients with CSPH at 55.7% sensitivity and 76.7% specificity; whereas Nogo-A cut-off value of 1.12 ng/mL was highly specific (93.1%) for the diagnosis of CSPH.

CONCLUSION

Plasma PlGF levels were higher while Nogo-A levels were lower in patients with liver cirrhosis and portal hypertension. Biomarkers showed moderate predictive value in determining CSPH and SPH.

Keywords: Liver cirrhosis; Portal hypertension; Angiogenesis; Placental growth factor; Nogo-A; Hepatic venous pressure gradient

Core tip: In this study, we aimed to evaluate plasma levels of angiogenesis mediators placental growth factor and Nogo-A protein in patients with liver cirrhosis, clinically significant portal hypertension, severe portal hypertension as well as biomarker potential to predict clinically significant and severe portal hypertension. Higher levels of placental growth factor have previously been associated with portal hypertension in animal models; however, data in patients with liver cirrhosis are scarce. To date this is the first study to evaluate Nogo-A protein levels in patients with liver cirrhosis and portal hypertension. Furthermore, to our best knowledge this is the first study to evaluate prognostic potential of these biomarkers to detect clinically significant and severe portal hypertension. We believe that this study adds additional knowledge on the complex pathogenesis of portal hypertension and might provide new insights for future research of new diagnostic approaches and treatment targets in the field.