Pustjens J, Brouwer WP, Ayada I, Janssen HLA, van Kleef LA. Considerations and clinical utility of referral pathways for early detection of liver disease in at-risk populations. World J Gastroenterol 2025; 31(37): 107665 [DOI: 10.3748/wjg.v31.i37.107665]
Corresponding Author of This Article
Laurens A van Kleef, MD, PhD, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Room Na-606, Postbus 2040, Rotterdam 3000, Zuid-Holland, Netherlands. l.vankleef@erasmusmc.nl
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
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/
World J Gastroenterol. Oct 7, 2025; 31(37): 107665 Published online Oct 7, 2025. doi: 10.3748/wjg.v31.i37.107665
Considerations and clinical utility of referral pathways for early detection of liver disease in at-risk populations
Jesse Pustjens, Willem P Brouwer, Ibrahim Ayada, Harry L A Janssen, Laurens A van Kleef
Jesse Pustjens, Willem P Brouwer, Ibrahim Ayada, Harry L A Janssen, Laurens A van Kleef, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam 3000, Zuid-Holland, Netherlands
Harry L A Janssen, Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada
Author contributions: Van Kleef LA, Pustjens J, and Brouwer WP contributed to writing of the manuscript; van Kleef LA, Pustjens J, Ayada I, Janssen HLA, and Brouwer WP contributed to critical review of the manuscript, writing of the manuscript, approval of final version and approval of submission.
Conflict-of-interest statement: Brouwer WP received a speaker fee from Eli Lilly, partakes in the advisory board for Novo Nordisk and is involved in trials from 89BIO, Boehringer Ingelheim, Novo Nordisk and Inventiva Pharma; Janssen HLA received grants from Gilead Sciences, GlaxoSmithKline, Janssen, Roche and Vir Biotechnology Inc and is consultant for Aligos, Gilead Sciences, GlaxoSmithKline, Grifols, Roche, Vir Biotechnology Inc. and Precision Biosciences. The other authors had no conflicts of interest.
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: Laurens A van Kleef, MD, PhD, Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Room Na-606, Postbus 2040, Rotterdam 3000, Zuid-Holland, Netherlands. l.vankleef@erasmusmc.nl
Received: March 30, 2025 Revised: June 18, 2025 Accepted: August 22, 2025 Published online: October 7, 2025 Processing time: 181 Days and 22 Hours
Abstract
Metabolic dysfunction-associated steatotic liver disease is the most prevalent chronic liver condition, affecting over one-third of the global population, with cirrhosis present in up to 3.3% of cases. Early detection of advanced liver disease in at-risk populations can enable timely intervention, prevent progression, and reduce complications. This review focuses on the current recommendations for early detection of advanced liver disease, evaluates the evidence for the performance of non-invasive tests in the target population for screening, and examines the multifaceted burden of screening, including economic implications and psychological impacts. Additionally, we discuss future directions, such as integrating liver health into a multidisciplinary care framework. Current guidelines recommend case-finding, targeting individuals with type 2 diabetes, metabolically complicated obesity, or persistent elevated liver enzymes. The Fibrosis-4 index is widely endorsed as a first-line non-invasive test, yet the diagnostic performance in primary care settings seems suboptimal, particularly for pre-cirrhotic disease. Sequential strategies incorporating novel non-invasive tests may improve accuracy and cost-effectiveness. Confirmation typically involves vibration-controlled transient elastography. Key challenges include a large eligible population, uncertainties in optimal screening intervals, patient adherence to follow-up, and limited real-world cost-effectiveness data. Integrating liver health assessment into cardiometabolic care pathways, reflex testing, telehealth, and patient education may enhance uptake. While challenges remain, early detection of advanced liver disease is already likely cost-effective. Ongoing advances in screening pathways and treatment options are expected to further strengthen the case for widespread implementation.
Core Tip: Early detection of liver fibrosis in community settings is essential for timely intervention and to prevent liver related events. Although non-invasive testing strategies are likely cost-effective, their adoption by non-hepatology specialists is limited. Key challenges include the use of overly broad target populations and suboptimal selection or application of non-invasive tests (NITs). Optimizing these pathways by integrating better NITs and refining referral algorithms can improve risk stratification, minimize unnecessary specialist referrals, reduce the burden on healthcare systems, and facilitate timely, multidisciplinary care for individuals at the highest risk for liver-related adverse outcomes.
