Prospective Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 27, 2022; 14(2): 429-441
Published online Feb 27, 2022. doi: 10.4254/wjh.v14.i2.429
β-arrestin-2 predicts the clinical response to β-blockers in cirrhotic portal hypertension patients: A prospective study
Sameh A Lashen, Mohammed M Shamseya, Marwa A Madkour, Radwa M Abdel Salam, Sanaa S Mostafa
Sameh A Lashen, Division of Hepatology and Gastroenterology, Faculty of Medicine, Alexandria University, Alexandria 21521, Egypt
Mohammed M Shamseya, Marwa A Madkour, Department of Experimental and Clinical Internal Medicine, Medical Research Institute, Alexandria 21561, Egypt
Radwa M Abdel Salam, Sanaa S Mostafa, Department of Pathology, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt
Author contributions: Lashen SA drafted the manuscript and performed data analysis, participated in study design, was involved with data collection, and performed the endoscopic assessment; Shamseya MM drafted the manuscript, participated in study design, was involved with data collection, and performed the endoscopic assessment; Madkour MA was involved with data collection, drafted the manuscript, performed the Doppler evaluation, and assisted in the data analysis; Abdel Salam RM and Mostafa SS equally drafted the manuscript, were involved with data collection, and performed the pathological analysis; all authors read and approved the final manuscript.
Institutional review board statement: The study was reviewed approved by the institutional review boards of the Faculty of Medicine, Alexandria University [review number: 0303608]
Clinical trial registration statement: The current study design was not a randomized clinical trial, so registration on the clinical trials database was not done.
Informed consent statement: All study participants provided written consent before study enrollment.
Conflict-of-interest statement: The authors of this manuscript have no conflicts of interest to disclose.
Data sharing statement: There are no additional data available.
CONSORT 2010 statement: All the authors have read the CONSORT 2010 Statement, and the manuscript was prepared and revised according to the CONSORT 2010 Statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sameh A Lashen, MD, PhD, Associate Professor, Division of Hepatology and Gastroenterology, Faculty of Medicine, Alexandria University, Champollion Street, El-Khartoum Square, Azarita Medical Campus, Alexandria 21521, Egypt. sameh.lashen@alexmed.edu.eg
Received: November 20, 2021
Peer-review started: November 20, 2021
First decision: December 26, 2021
Revised: January 8, 2022
Accepted: February 15, 2022
Article in press: February 15, 2022
Published online: February 27, 2022
ARTICLE HIGHLIGHTS
Research background

Variceal bleeding is a life-threatening complication of portal hypertension (PHT). Nonselective β-blockers (NSBB) are used as primary or secondary prophylaxis in patients with PHT. The use of NSBB has been associated with the development of refractory ascites and spontaneous bacterial peritonitis in a subgroup of patients. β-arrestin-2 (β-Arr-2) has been shown to predict the short-term response to NSBB in a few studies.

Research motivation

There is a gap of knowledge still present. The previous research about β-Arr-2 was about the acute hemodynamic response to NSBB infusion, but no data about the long-term effects. About two-thirds of patients with PHT fail to respond to NSBB, with the exposure to undesirable side effects. Identifying this subset of patients noninvasively is of clinical importance. Again, the long-term changes in β-Arr-2 expression after NSBB therapy have not yet been investigated.

Research objectives

We aimed to investigate the role of both serum and tissue expression of β-Arr-2 as a minimally invasive to predict the long-term clinical response of PHT to NSBB therapy, as well as to investigate the long-term changes in β-Arr-2 expression after NSBB therapy.

Research methods

We prospectively enrolled 120 patients with cirrhotic PHT. Full history and clinical evaluation were done. Laboratory investigations including serum β-Arr-2 were done. Doppler ultrasound of the portal circulation to measure the portal vein congestion index (PVCI) was obtained. Esophagogastroduodenoscopy (EGD) was performed to evaluate the presence and grade of varices and to obtain mucosal biopsies to define the expression of β-Arr-2. NSBB therapy was initiated. A follow-up for 18 mo (540 d) was done. Another endoscopic biopsy was obtained at the end of the study to re-assess the tissue expression of β-Arr-2. Patients were designated as “NSBB responders” if they didn’t experience variceal bleeding until the end of follow-up; or “NSBB non-responders” if they had bled. PVCI was re-evaluated at the end of the study.

Research results

A higher serum level and antral expression of β-Arr-2 were associated with better clinical response to NSBB (longer bleeding-free intervals, and improved grade of varices). Only 17.6% of patients with low baseline β-arr-2 expression responded to NSBB, whereas, 95.1% of patients with strong β-arr-2 expression were responders (P < 0.001). A serum β-Arr-2 value ≥ 2.23 ng/mL was associated with a lower likelihood of variceal bleeding with 90% sensitivity and 71% specificity. β-arrestin-2 expression significantly decreased after nonselective β-blocker therapy. Serum β-Arr-2 level (P < 0.001), the intensity of β-Arr-2 expression in the gastric antrum (P < 0.001), and platelet count (P = 0.006), were the only independent predictors for variceal bleeding

Research conclusions

The serum level and tissue expression of β-Arr-2 in the gastric antrum are correlated to the severity of PHT. The lower β-Arr-2 expression can predict non-response to NSBB therapy. Stronger expression is linked to a better long-term clinical response to NSBB in terms of variceal bleeding-free interval. We introduce serum β-Arr-2 level as a potential, noninvasive biomarker for selecting patients with PHT who are potentially good candidates for NSBB therapy.

Research perspectives

Future studies are needed to validate the results of our study on a wider scale of patients. Prospective research is needed to explore the relation between the expression of β-Arr-2 and the development of spontaneous bacterial peritonitis and hepatorenal syndrome in cirrhotic PHT.