1Digestive Disease Department, Hospital Clínico Universitario de Valencia, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain. Electronic address: email@example.com.
2Institute of Liver Studies, Department of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King´s College London, London, United Kingdom.
3Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
4INCLIVA Biomedical Research Institute, Valencia, Spain.
5Digestive Diseases Department, Ciberehd, Virgen del Rocío University Hospital, Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), University of Seville, Sevilla, Spain.
6Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.
7Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
8Digestive Disease Department, Hospital Clínico Universitario de Valencia, Spain; Department of Medicine, Faculty of Medicine, University of Valencia, Spain.
9INCLIVA Biomedical Research Institute, Valencia, Spain; Department of Pathology, Faculty of Medicine, University of Valencia, Spain.
10Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; European Foundation for the Study of Chronic Liver Failure (EF Clif), Spain. Electronic address: firstname.lastname@example.org.
Background & aims: Neuropsychological and psychophysical tests are recommended to assess the risk of overt hepatic encephalopathy (OHE), but their accuracy is limited. Hyperammonaemia is central in the pathogenesis of OHE, but its predictive utility is unknown. In this study, we aimed to determine the role of neuropsychological or psychophysical tests and ammonia, and to develop a model (AMMON-OHE) to stratify the risk of subsequent OHE development in outpatients with cirrhosis.
Methods: This observational, prospective study included 426 outpatients without previous OHE from three liver units followed for a median of 2.5 years. Psychometric hepatic encephalopathy score (PHES) <-4 or critical flicker frequency (CFF) <39 was considered abnormal. Ammonia was normalized to upper limit of normal (AMM-ULN) at the respective reference laboratory. Multivariable frailty competing risk and random survival forest analyses were performed to predict future OHE and to develop the AMMON-OHE model. External validation was carried out using 267 and 381 patients from two independent units.
Results: Significant differences were found in time-to-OHE (log-rank p <0.001) according to PHES or CFF and ammonia, with the highest risk in patients with abnormal PHES plus high AMM-ULN (hazard ratio 4.4; 95% CI 2.4-8.1; p <0.001 compared with normal PHES and AMM-ULN). On multivariable analysis, AMM-ULN but not PHES or CFF was an independent predictor of the development of OHE (hazard ratio 1.4; 95% CI 1.1-1.9; p = 0.015). The AMMON-OHE model (sex, diabetes, albumin, creatinine and AMM-ULN) showed a C-index of 0.844 and 0.728 for the prediction of a first episode of OHE in two external validation cohorts.
Conclusions: In this study, we developed and validated the AMMON-OHE model, comprising readily available clinical and biochemical variables that can be used to identify outpatients at the highest risk of developing a first episode of OHE.
Impact and implications: In this study, we aimed to develop a model to predict which patients with cirrhosis are at risk of developing overt hepatic encephalopathy (OHE). Using data from three units and including 426 outpatients with cirrhosis, we developed the AMMON-OHE model - comprising sex, diabetes, albumin, creatinine and ammonia levels - which demonstrated good predictive ability. The AMMON-OHE model performs better than PHES and CFF to predict the first episode of OHE in outpatients with cirrhosis. This model was validated in 267 and 381 patients from two independent liver units. The AMMON-OHE model is available online for clinical use.