Reply to: “Ammonia and prognosis of cirrhosis: A new perspective for identifying high risk patients”

Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosisJournal of HepatologyVol. 77Issue 6PreviewHyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. Full-Text PDF Open AccessAmmonia and prognosis of cirrhosis: A new perspective for identifying high-risk patientsJournal of HepatologyPreviewWe read with interest the paper by Tranah et al.1 The authors carried out a prospective study evaluating the association between ammonia and adverse outcomes in individuals with stable cirrhosis across 3 independent liver units and conclude that ammonia is a key determinant that helps to predict which patients will be hospitalized, develop liver-related complications and die; this was confirmed in an independent cohort.1 Full-Text PDF We would like to thank Ridola et al. for their interest in our recently published article.[1]Tranah T.H. Ballester M.P. Carbonell-Asins J.A. Ampuero J. Alexandrino G. Caracostea A. et al.Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.J Hepatol. 2022; (online ahead of print)Abstract Full Text Full Text PDF Scopus (3) Google Scholar,[2]Ridola L. Riggio O. Ammonia and prognosis of cirrhosis: a new perspective for identifying high risk patients.J Hepatol. 2022; (online ahead of print)Abstract Full Text Full Text PDF Google Scholar Our study of 754 outpatients with cirrhosis, demonstrated that ammonia was an independent predictor of mortality and when expressed as a ratio of the local laboratory upper limit of normal (AMM-ULN), >1.4 defines a high-risk group for the development of liver-related complications. This was confirmed in an independent validation cohort of 130 stable outpatients with cirrhosis. Ridola et al. raised 5 points for further clarification in their letter:1.Potential role of sarcopenia: We did not quantify severity of sarcopenia but we did perform a single-centre sub-analysis of clinically validated metrics of sarcopenia and malnutrition that included estimated dry BMI, handgrip strength, median arm circumference and triceps skinfold thickness in addition to the global nutrition score and saw no association between sarcopenia and either AMM-ULN levels or the development of liver-related complications.2.Degree of spontaneous portosystemic shunts (SPSS): This was not measured in this study. Most patients included in our study (94%) had indirect evidence of clinically significant portal hypertension as measured by either a history of oesophago-gastric varices, use of non-selective beta blockers or splenomegaly. We would agree that SPSS are pathophysiologically relevant and that the mechanism of occurrence of hepatic encephalopathy (HE) in this setting is driven by hyperammonaemia. Thus, AMM-ULN measurement here may act as a biochemical surrogate of the severity of portal hypertension and portosystemic shunting. This association between ammonia levels and the degree of shunting has been explored in previous modelling studies of ammonia metabolism.[3]Noiret L. Baigent S. Jalan R. Arterial ammonia levels in cirrhosis are determined by systemic and hepatic hemodynamics, and by organ function: a quantitative modelling study.Liver Int. 2014 Jul; 34: e45-e55Crossref Scopus (12) Google Scholar3.The presence or absence of previous episodes and role of psychometric tests: Although previous decompensation was a risk factor for the prediction of liver-related complications in a univariable analysis, and it was included in the best model in multivariable competing risk analyses, it did not reach statistical significance when incorporating other variables such as AMM-ULN. The role of psychometric tests in the occurrence of HE and mortality is an important question and is the subject of an ongoing study of the AMMON Consortium.4.Reporting crude ammonia values: Both absolute values of ammonia and AMM-ULN values were reported in our paper. AMM-ULN performed better than crude ammonia levels in predicting both complications and mortality. Therefore, we propose that using AMM-ULN may harmonise the different absolute ammonia levels being reported in the literature.5.Predictive ability of AMM-ULN compared to traditional severity scores: Despite no significant differences in mortality, AMM-ULN demonstrated improved predictive performance for the development of liver-related complications when compared against the MELD score both at 6 months and 1 year and showed a tendency to be higher than the Child-Pugh score. These data are described in the paper.[1]Tranah T.H. Ballester M.P. Carbonell-Asins J.A. Ampuero J. Alexandrino G. Caracostea A. et al.Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.J Hepatol. 2022; (online ahead of print)Abstract Full Text Full Text PDF Scopus (3) Google Scholar This research was funded by the Medical Research Council (MR/V006757/1) and Instituto de Salud Carlos III (FIS PI18/00150); Fundación Ramón Areces, Consellería de Educación Generalitat Valenciana (PROMETEOII/2018/051), co-funded with European Regional Development Funds (ERDF). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Rajiv Jalan is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Discovery, a spin out company from University College London, Hepyx Limited and Cyberliver. He had research collaborations with Yaqrit Discovery. The other authors have no conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details. Statistical analyses were performed by JA C-A. The manuscript was prepared and written by THT and MPB and revised by RJ and DLS. All authors have reviewed and approved the final submitted manuscript. The following are the supplementary data to this article: Download .pdf (.61 MB) Help with pdf files Multimedia component 1