María Pilar Ballester, Rocío Gallego-Durán, Shalimar, Karen Louise Thomsen, Constantine J. Karvellas, Srinivasan Dasarathy, Debbie L. Shawcross, Dominique Thabut, Jinjun Chen, Christopher F. Rose, Rajiv Jalan, A.J. Montano-Loza, Aldo Torre, Analissa Berzigotti, Annarein Kerbert, Atoosa Rabiee, Banwari Agarwal, Beatriz Mínguez, Christian Labenz, Christophe Bureau, Cornelius Engelmann, Cristina Ripoll, Elizabeth Lee, Felicity Williams, Hendrik Vilstrup, Jennifer Towey, Juan Antonio Carbonell‐Asins, Kohilan Gananandan, Karin Weissenborn, Kristoffer Kjaergaard, Lorenzo Ridola, Manuel Romero, Manuela Merli, Marika Rudler, Marina Berenguer, Mark Swain, Mattias Mandorfer, Mette Munk Lauridsen, Minneke Coenraad, Nicolas Weiss, Paola Andrenacci, Patricia Bloom, Peter Ott, Rakhi Maiwall, Rubén Hernáez, Sara Montagnese, Sumeet Asrani, Thomas Reiberger, R. Todd Frederick, William Bernal
BACKGROUND & AIMS: Ammonia is a neurotoxin implicated in the pathogenesis of hepatic encephalopathy (HE). Yet, the clinical utility of blood ammonia measurement in patients with cirrhosis remains controversial due to methodological variability, inconsistent interpretation, and lack of standardised guidance. The aim of this consensus document, developed by the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN), is to provide evidence-based recommendations on the role of ammonia measurement in the diagnosis, monitoring, and treatment of patients with cirrhosis. METHODS: A modified Delphi process was conducted involving a multidisciplinary and international panel of experts in cirrhosis and ammonia metabolism. The writing committee comprised 11 experts, and the panel included 39 members selected by ISHEN based on expertise, global representation, and gender balance. Twenty-five PICO questions were generated. Following literature review and based on the level of evidence, recommendations and statements were formulated. The questions, recommendations, and statements underwent approval across four Delphi rounds. RESULTS: The panel reached ≥90% consensus on all the questions, including the clinical significance of ammonia as a biomarker in both inpatient and outpatient settings, best practices for sample collection and analysis, and the role of ammonia in risk stratification, therapeutic monitoring, and prognostication. Specific research gaps were identified, including the need for point-of-care ammonia testing, validation of ammonia-based risk models and better characterisation of non-hyperammonemic encephalopathy. CONCLUSIONS: This ISHEN consensus is the first structured international effort to define the role of ammonia measurement in the care of patients with cirrhosis. It offers practical recommendations for clinicians, outlines priorities for future research, and provides a foundation for harmonizing clinical practice and trial design related to ammonia and HE. IMPACT AND IMPLICATIONS: This is the first international, evidence-based consensus describing the role of ammonia measurement in patients with cirrhosis. The consensus details guidance on how to measure ammonia, the role of ammonia measurement in predicting development of overt hepatic encephalopathy and other liver-related complications, and its role in the diagnosis and prognosis of patients with overt hepatic encephalopathy. This document will help harmonise practices across the world in the way ammonia should be measured and reported, impacting significantly on patient outcomes, research and drug development efforts.