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