Hepatic Encephalopathy Is Associated With Mortality in Patients With Cirrhosis Independent of Other Extrahepatic Organ Failures

Published:October 05, 2016DOI:

      Background & Aims

      Although survival times have increased for patients with cirrhosis, hepatic encephalopathy (HE) remains a major complication and its relative contribution toward mortality in North America is unclear. We investigated whether HE is associated with mortality independent of extrahepatic organ failures (EHOFs).


      We collected data from the North American Consortium for Study of End-stage Liver Disease database of hospitalized patients with cirrhosis at tertiary-care centers. EHOFs were defined as need for ventilation (respiratory failure), dialysis (renal failure), or shock (circulatory failure). We analyzed in-hospital and 30-day mortality for patients with varying HE grades and EHOF using adjusted models.


      We analyzed data from 1560 patients, 516 with HE (371 grade 1–2 and 145 grade 3–4). Patients with maximum HE grade 3–4 HE during hospitalization had a higher median model for end-stage liver disease (MELD) score (22) than patients with HE grade 1–2 (MELD score, 19) or no HE (MELD score, 18) (P < .0001). Thirty-day mortality for patients with HE grade 3–4 was significantly higher (38%) than for patients with HE grade 1–2 (8%) or no HE (7%). A total of 107 patients had 2 or more EHOFs, with or without HE; 151 had 1 EHOF and 1302 had no organ failure. Unadjusted mortality was highest for patients with HE of grade 3–4 with 2 EHOFs (n = 44). On regression analysis, HE severity was significantly associated with in-hospital and 30-day mortality, independent of any EHOF, white blood cell count, systemic inflammatory response syndrome, or MELD score (odds ratio, 3.3; P < .0001).


      In an analysis of more than 1500 patients hospitalized for cirrhosis, HE of grade 3 or 4 was associated with higher in-hospital and 30-day mortality, independently of failure of other organs.


      Abbreviations used in this paper:

      CI (confidence interval), EHOF (extrahepatic organ failures), HE (hepatic encephalopathy), MELD (model for end-stage liver disease), NACSELD (North American Consortium for the Study of End-Stage Liver Disease), OR (odds ratio), SIRS (systemic inflammatory response syndrome), WBC (white blood cell)
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        • Bajaj J.S.
        • Reddy K.R.
        • Tandon P.
        • et al.
        The three-month readmission rate remains unacceptably high in a large North American cohort of cirrhotic patients.
        Hepatology. 2015; 64: 200-208
        • Cordoba J.
        • Ventura-Cots M.
        • Simon-Talero M.
        • et al.
        Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
        J Hepatol. 2014; 60: 275-281
        • Tapper E.B.
        Challenge accepted: confronting readmissions for our patients with cirrhosis.
        Hepatology. 2016; 64: 26-28
        • Bajaj J.S.
        • Wade J.B.
        • Gibson D.P.
        • et al.
        The multi-dimensional burden of cirrhosis and hepatic encephalopathy on patients and caregivers.
        Am J Gastroenterol. 2011; 106: 1646-1653
        • Vilstrup H.
        • Amodio P.
        • Bajaj J.
        • et al.
        Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver.
        Hepatology. 2014; 60: 715-735
        • Jalan R.
        • Yurdaydin C.
        • Bajaj J.S.
        • et al.
        Toward an improved definition of acute-on-chronic liver failure.
        Gastroenterology. 2014; 147: 4-10
        • Bajaj J.S.
        Defining acute-on-chronic liver failure: will east and west ever meet?.
        Gastroenterology. 2013; 144: 1337-1339
        • Bajaj J.S.
        • O'Leary J.G.
        • Reddy K.R.
        • et al.
        Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience.
        Hepatology. 2012; 56: 2328-2335
        • Bajaj J.S.
        • O'Leary J.G.
        • Reddy K.R.
        • et al.
        Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures.
        Hepatology. 2014; 60: 250-256
        • O’Leary J.
        • Reddy K.
        • Garcia-Tsao G.
        • et al.
        P0119: Validation of the NACSELD Infection-Related Acute-on-Chronic Liver Failure (I-ACLF) score in an independent multicenter cohort.
        J Hepatol. 2015; 62: S345
        • Volk M.L.
        • Tocco R.S.
        • Bazick J.
        • et al.
        Hospital readmissions among patients with decompensated cirrhosis.
        Am J Gastroenterol. 2012; 107: 247-252
        • Tapper E.B.
        • Halbert B.
        • Mellinger J.
        Rates of and reasons for hospital readmissions in patients with cirrhosis: a multistate population-based cohort study.
        Clin Gastroenterol Hepatol. 2016; 14: 1181-1188
        • Bajaj J.S.
        • Cordoba J.
        • Mullen K.D.
        • et al.
        Review article: the design of clinical trials in hepatic encephalopathy. An International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement.
        Aliment Pharmacol Ther. 2011; 33: 739-747
        • Salam M.
        • Matherly S.
        • Farooq I.S.
        • et al.
        Modified-orientation log to assess hepatic encephalopathy.
        Aliment Pharmacol Ther. 2012; 35: 913-920
        • Olde Damink S.W.
        • Jalan R.
        • Dejong C.H.
        Interorgan ammonia trafficking in liver disease.
        Metab Brain Dis. 2009; 24: 169-181
        • Wong R.J.
        • Aguilar M.
        • Gish R.G.
        • et al.
        The impact of pretransplant hepatic encephalopathy on survival following liver transplantation.
        Liver Transpl. 2015; 21: 873-880
        • Wong R.J.
        • Gish R.G.
        • Ahmed A.
        Hepatic encephalopathy is associated with significantly increased mortality among patients awaiting liver transplantation.
        Liver Transpl. 2014; 20: 1454-1461
        • Stewart C.A.
        • Malinchoc M.
        • Kim W.R.
        • et al.
        Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease.
        Liver Transpl. 2007; 13: 1366-1371
        • Nadim M.K.
        • Durand F.
        • Kellum J.A.
        • et al.
        Management of the critically ill patient with cirrhosis: a multidisciplinary perspective.
        J Hepatol. 2016; 64: 717-735
        • Landis C.S.
        • Ghabril M.
        • Rustgi V.
        • et al.
        Prospective multicenter observational study of overt hepatic encephalopathy.
        Dig Dis Sci. 2016; 61: 1728-1734
        • Sharma B.C.
        • Sharma P.
        • Agrawal A.
        • et al.
        Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo.
        Gastroenterology. 2009; 137 (891 e1): 885-891
        • Bass N.M.
        • Mullen K.D.
        • Sanyal A.
        • et al.
        Rifaximin treatment in hepatic encephalopathy.
        N Engl J Med. 2010; 362: 1071-1081
        • Patidar K.R.
        • Bajaj J.S.
        Covert and overt hepatic encephalopathy: diagnosis and management.
        Clin Gastroenterol Hepatol. 2015; 13: 2048-2061
        • Bajaj J.S.
        • Sanyal A.J.
        • Bell D.
        • et al.
        Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients.
        Aliment Pharmacol Ther. 2010; 31: 1012-1017
        • Tapper E.B.
        • Finkelstein D.
        • Mittleman M.A.
        • et al.
        A quality improvement initiative reduces 30-day rate of readmission for patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2016; 14: 753-759
        • Kanwal F.
        • Asch S.M.
        • Kramer J.R.
        • et al.
        Early outpatient follow-up and 30-day outcomes in patients hospitalized with cirrhosis.
        Hepatology. 2016; 64: 569-581
        • Bajaj J.S.
        • Schubert C.M.
        • Heuman D.M.
        • et al.
        Persistence of cognitive impairment after resolution of overt hepatic encephalopathy.
        Gastroenterology. 2010; 138: 2332-2340
        • Riggio O.
        • Ridola L.
        • Pasquale C.
        • et al.
        Evidence of persistent cognitive impairment after resolution of overt hepatic encephalopathy.
        Clin Gastroenterol Hepatol. 2011; 9: 181-183
        • Shalimar
        • Saraswat V.
        • Singh S.
        • et al.
        Acute on chronic liver failure in India: the INASL Consortium experience.
        J Gastroenterol Hepatol. 2016; 31: 1742-1749
        • Shi Y.
        • Yang Y.
        • Hu Y.
        • et al.
        Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.
        Hepatology. 2015; 62: 232-242
        • Hassanein T.I.
        • Tofteng F.
        • Brown Jr., R.S.
        • et al.
        Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.
        Hepatology. 2007; 46: 1853-1862