Published online Jun 21, 2019. doi: 10.3748/wjg.v25.i23.2935
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
Portal hypertension (PH) is a consequence of liver cirrhosis and can cause serious life-threatening complications. The degree of portal hypertension is one of the most important prognostic factors and is defined by the hepatic venous pressure gradient (HVPG). In order to optimize the care of patients with liver cirrhosis, it is essential to detect early PH and prevent the development of clinically significant PH (CSPH) to avoid decompensation. As current options for prevention and treatment of CSPH are limited to attenuating splanchnic vasodilatation, new insights and deeper knowledge about pathogenetic mechanisms of PH and molecules involved, would aid in search for newer and more effective treatment strategies.
With growing burden on chronic liver diseases worldwide, the optimization of care provided to the patients with liver cirrhosis has become a priority. According to the Baveno VI consensus meeting the detection and treatment of early PH as well as the prevention and timely treatment of CSPH, in order to avoid complications and decompensation, are of utmost importance. The consensus has encouraged the search for new treatment strategies to target different patho-genetic components of PH. Recent studies suggest that one of these alternative pathogenetic components is pathologic angiogenesis. Pathologic angiogenesis has been reported to result from the upregulation of proangiogenic factors and simultaneous downregulation of angiogenesis inhibitors, thus both stimuli might be important and contribute to the pa-thophysiological mechanisms. This prospective study was aimed to gain deeper knowledge on the molecules involved in abnormal angiogenesis-one of the pa-thogenetic components of PH. PlGF has previously been associated with portal hypertension in animal models; however, data in patients with liver cirrhosis are scarce. Nogo-A protein has not been previously evaluated in patients with liver cirrhosis and PH.
In this study we aimed to evaluate plasma levels of PlGF and Nogo-A in liver cirrhosis patients with normal portal pressure and portal hypertension as well as in controls. We also aimed to evaluate the potential of plasma PlGF and Nogo-A levels as biomarkers to predict CSPH and SPH as well as complications of portal hypertension.
A cohort of 122 patients with hepatitis C virus and/or alcohol-induced liver cirrhosis with characterized 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 placental growth factor levels in plasma were evaluated using enzyme liked im40munosorbent assay. The control group consisted of 30 healthy age- and sex- matched individuals
We have demonstrated differences of proangiogenic mediator PlGF and angiogenesis inhibitor Nogo-A plasma levels in patients with liver cirrhosis, when compared to controls. We have also determined a clear correlation of these mediators to PH and complications of PH. Furthermore, we have for the first time demonstrated that plasma concentration of Nogo-A is lower in liver cirrhosis and PH, as well as the predictive values of plasma PlGF and Nogo-A levels in diagnosing CSPH, SPH and PH complications. Futher research will be addressed to evaluate Nogo-A expression in healthy and cirrhotic liver.
We have for the first time demonstrated that plasma concentration of Nogo-A is lower in liver cirrhosis and PH, as well as the predictive values of plasma PlGF and Nogo-A levels in diagnosing CSPH, SPH and PH complications. We believe that our study expands the knowledge on pathologic angiogenesis and its role in the pathogenesis of PH as well as molecules involved. We have demonstrated that indeed PH is a complicated pathology with multiple pathogenetic pathways, which are important in optimizing the care of patients with portal hypertension. This information provides further insights in the pathogenesis of PH in liver cirrhosis and might be useful in creating new noninvasive diagnostic models for CSPH, as it is one of the most important prognostic factors for patients with liver cirrhosis. We have proposed the new hypothesis that Nogo-A protein is associated with portal hypertension and pathologic angiogenesis. This study examined two novel non-invasive markers of portal hypertension, which could be useful in creatinf noninvasive diagnostic models for PH, or new treatment targets. We have demonstrated that two biomarkers of pathologic angiogenesis have moderate predictive value in diagnosing CSPH and SPH as well as high risk esophageal varices. Our study demonstrated that biomarkers of pathologic angiogenesis are associated with liver cirrhosis and PH and have moderate ability to predict CSPH and SPH. These findings might be useful in creating new noninvasive diagnostic models for PH as well as new treatment targets of PH.
Future research will be directed towards gaining more detailed information about Nogo-A protein expression in healthy and cirrhotic liver as well as further understanding of Nogo-A protein roles outside the central nervous system. We plan to conduct mechanistic studies, using liver cell models as well as liver tissue biopsy specimens.