Clinical determinants of hospital mortality in liver failure: a comprehensive analysis of 62,717 patients

Abstract

Background Liver failure (LF) is characterised by a loss of the synthetic and metabolic liver function and is associated with a high mortality. Large-scale data on recent developments and hospital mortality of LF in Germany are missing. A systematic analysis and careful interpretation of these datasets could help to optimise outcomes of LF.

Methods We used standardised hospital discharge data of the Federal Statistical Office to evaluate current trends, hospital mortality and factors associated with an unfavourable course of LF in Germany between 2010 and 2019.

Results A total of 62,717 hospitalised LF cases were identified. Annual LF frequency decreased from 6716 (2010) to 5855 (2019) cases and was higher among males (60.51%). Hospital mortality was 38.08% and significantly declined over the observation period. Mortality significantly correlated with patients’ age and was highest among individuals with (sub)acute LF (47.5%). Multivariate regression analyses revealed pulmonary (OR_ARDS: 2.76, OR_{mechanical ventilation}: 6.46) and renal complications (OR_{acute kidney failure}: 2.04, OR_{hepatorenal syndrome}: 2.92) and sepsis (OR: 1.92) as factors for increased mortality. Liver transplantation reduced mortality in patients with (sub)acute LF. Hospital mortality significantly decreased with the annual LF case volume and ranged from 47.46% to 29.87% in low- or high-case-volume hospitals, respectively.

Conclusions Although incidence rates and hospital mortality of LF in Germany have constantly decreased, hospital mortality has remained at a very high level. We identified a number of variables associated with increased mortality that could help to improve framework conditions for the treatment of LF in the future.

Graphical Abstract

Zusammenfassung

Hintergrund Das Leberversagen (LV) ist durch einen Verlust der synthetischen und metabolischen Leberfunktion gekennzeichnet und mit einer hohen Mortalität verbunden. Zentrumsübergreifende Daten zu aktuellen Entwicklungen und Krankenhaussterblichkeit des LV in Deutschland fehlen. Eine systematische Analyse und sorgfältige Interpretation dieser Daten könnte dabei helfen, das Outcome des LV zu verbessern.

Methoden Standardisierte Krankenhausentlassungsdaten des Statistischen Bundesamtes wurden verwendet, um aktuelle Trends, die Krankenhausmortalität sowie Faktoren, die mit einem ungünstigen klinischen Verlauf des LV in Deutschland zwischen 2010 und 2019 assoziiert sind, zu analysieren.

Ergebnisse Insgesamt wurden 62.717 hospitalisierte LV-Fälle identifiziert. Die jährliche Inzidenz des LV sank von 6.716 (2010) auf 5.855 (2019) Fälle und war bei Männern höher (60,51%). Die Krankenhausmortalität betrug 38,08% und reduzierte sich im Beobachtungszeitraum deutlich (2010: 39,5%, 2019: 34,9%). Die Krankenhaussterblichkeit korrelierte signifikant mit dem Patientenalter und war bei Patienten mit (sub)akutem LV am höchsten (47,5%). Multivariate Regressionsanalysen identifizierten pulmonale (OR_ARDS: 2,76, OR_{mechanische Beatmung}: 6,46) und renale Komplikationen (OR_{akutes Nierenversagen}: 2,04, OR_{hepatorenales Syndrom}: 2,92) sowie die Sepsis (OR: 1,92) als Schlüsselfaktoren einer erhöhten Mortalität. Eine Lebertransplantation senkte die Krankenhaussterblichkeit insbesondere bei Patienten mit (sub)akutem LV. Die Krankenhaussterblichkeit nahm signifikant mit dem jährlichen LV-Fallvolumen einzelner Krankenhäuser ab und reichte von 47,46% bis 29,87% in Krankenhäusern mit niedrigem bzw. hohem Fallvolumen.

Schlussfolgerungen Obwohl die Inzidenz und Krankenhausmortalität des LV in Deutschland kontinuierlich sank, verblieb die Krankenhaussterblichkeit auf einem sehr hohen Niveau. Wir identifizierten verschiedene Variablen, die mit einer erhöhten Sterblichkeit assoziiert sind und die zukünftig dazu beitragen könnten, die Rahmenbedingungen für die Behandlung des LV zu verbessern.

Keywords

ACLF - ALF - liver transplantation - DRG - ICD-10

Schlüsselwörter

ACLF - ALF - Lebertransplantation - DRG - ICD-10

Publication History

Received: 29 July 2022

Accepted after revision: 16 January 2023

Article published online:
27 March 2023

• References

• 1 Jalan R, Gines P, Olson JC. et al. Acute-on chronic liver failure. J Hepatol 2012; 57: 1336-1348
• 2 Williams R, Schalm SW, O’Grady JG. Acute liver failure: redefining the syndromes. Lancet 1993; 342: 273-275
• 3 Bernal W, Auzinger G, Dhawan A. et al. Acute liver failure. Lancet 2010; 376: 190-201
• 4 Mahmud N, Kaplan DE, Taddei TH. et al. Incidence and Mortality of Acute-on-Chronic Liver Failure Using Two Definitions in Patients with Compensated Cirrhosis. Hepatology 2019; 69: 2150-2163
• 5 Donnelly MC, Davidson JS, Martin K. et al. Acute liver failure in Scotland: changes in aetiology and outcomes over time (the Scottish Look-Back Study). Aliment Pharmacol Ther 2017; 45: 833-843
• 6 Weiler N, Schlotmann A, Schnitzbauer AA. et al. The epidemiology of acute liver failure: Results of a population-based study including 25 million state-insured individuals. Dtsch Arztebl Int 2020; 117: 43-50
• 7 Wlodzimirow KA, Eslami S, Abu-Hanna A. et al. Systematic review: Acute liver failure – One disease, more than 40 definitions. Aliment Pharmacol Ther 2012; 35: 1245-1256
• 8 Sarin SK, Choudhury A, Sharma MK. et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update. 2019
• 9 Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F. Progress in Liver Diseases. 1970: 282-298
• 10 Lee WM, Stravitz RT, Larson AM. AASLD Position Paper: The Management of Acute Liver Failure: Update 2011. Hepatology 2011; 55: 1-22
• 11 Hadem J, Stiefel P, Bahr MJ. et al. Prognostic Implications of Lactate, Bilirubin, and Etiology in German Patients With Acute Liver Failure. Clin Gastroenterol Hepatol 2008; 6: 339-345
• 12 Allen AM, Kim WR, Moriarty JP. et al. Time trends in the health care burden and mortality of acute on chronic liver failure in the United States. Hepatology 2016; 64: 2165-2172
• 13 Sarin SK, Kedarisetty CK, Abbas Z. et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014. Hepatol Int 2014; 8: 453-471
• 14 Axley P, Ahmed Z, Arora S. et al. NASH Is the Most Rapidly Growing Etiology for Acute-on-Chronic Liver Failure-Related Hospitalization and Disease Burden in the United States: A Population-Based Study. Liver Transplant 2019; 25: 695-705
• 15 Moreau R, Jalan R, Gines P. et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144: 1426-1437.e9
• 16 Sars C, Tranäng M, Ericzon BG. et al. Liver transplantation for acute liver failure–a 30-year single center experience. Scand J Gastroenterol 2018; 53: 876-882
• 17 Silva PES e., Fayad L, Lazzarotto C. et al. Single-centre validation of the EASL-CLIF Consortium definition of acute-on-chronic liver failure and CLIF-SOFA for prediction of mortality in cirrhosis. Liver Int 2015; 35: 1516-1523
• 18 Fernández J, Acevedo J, Wiest R. et al. Bacterial and fungal infections in acute-on-chronic liver failure: Prevalence, characteristics and impact on prognosis. Gut 2017; 67: 1870-1880
• 19 Cordoba J, Ventura-Cots M, Simón-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
• 20 Bernal W, Hyyrylainen A, Gera A. et al. Lessons from look-back in acute liver failure? A single centre experience of 3300 patients. J Hepatol 2013; 59: 74-80
• 21 Scott RA, Austin AS, Kolhe N V. et al. Acute kidney injury is independently associated with death in patients with cirrhosis. Frontline Gastroenterol 2013; 4: 191-197
• 22 Martnllah M, Guevara M, Torre A. et al. Prognostic importance of the cause of renal failure in patients with cirrhosis. Gastroenterology 2011; 140: 488-496.e4
• 23 Levesque E, Saliba F, Ichaï P. et al. Outcome of patients with cirrhosis requiring mechanical ventilation in ICU. J Hepatol 2014; 60: 570-578
• 24 Murata A, Matsuda S, Mayumi T. et al. Effect of hospital volume on clinical outcome in patients with acute pancreatitis, based on a national administrative database. Pancreas 2011; 40: 1018-1023
• 25 Loosen SH, Essing T, Jördens M. et al. Current epidemiological trends and in-hospital mortality of acute pancreatitis in Germany: a systematic analysis of standardized hospital discharge data between 2008 and 2017. Z Gastroenterol 2022; 60: 310-319
• 26 Jalan R, Saliba F, Pavesi M. et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014; 61: 1038-1047
• 27 Asrani SK, Devarbhavi H, Eaton J. et al. Burden of liver diseases in the world. J Hepatol 2019; 70: 151-171
• 28 Pimpin L, Cortez-Pinto H, Negro F. et al. Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies. J Hepatol 2018; 69: 718-735
• 29 Bernal W, Lee WM, Wendon J. et al. Acute liver failure: A curable disease by 2024?. J Hepatol 2015; 62: S112-S120
• 30 Gu W, Hortlik H, Erasmus HP. et al. Trends and the course of liver cirrhosis and its complications in Germany: Nationwide population-based study (2005 to 2018). Lancet Reg Heal – Eur 2022; 12: 100240
• 31 Loosen SH, Bock HH, Hellmich M. et al. Krankenhausmortalität und aktuelle Entwicklungen der Lebertransplantation in Deutschland. Dtsch Arztebl Int 2021; 118: 497-502
• 32 Trebicka J, Fernandez J, Papp M. et al. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol 2020; 73: 842-854
• 33 Sundaram V, Jalan R, Wu T. et al. Factors Associated with Survival of Patients With Severe Acute-On-Chronic Liver Failure Before and After Liver Transplantation. Gastroenterology 2019; 156: 1381-1391.e3
• 34 Cardoso FS, Fidalgo P, Bagshaw SM. et al. Persistent But Not Transient Acute Kidney Injury Was Associated With Lower Transplant-Free Survival in Patients With Acute Liver Failure: A Multicenter Cohort Study. Crit Care Med 2022; 50 (09) 1329-1338
• 35 Jiang W, Hu Y, Sun Y. et al. Prevalence and short-term outcome of acute kidney injury in patients with acute-on-chronic liver failure: A meta-analysis. J Viral Hepat 2020; 27: 810-817
• 36 Boente RD, Sheikh A, Bosslet GT. et al. Outcomes of Acute Respiratory Distress Syndrome in Mechanically Ventilated Patients With Cirrhosis. Crit Care Explor 2019; 1: e0040
• 37 Xu J, Du F, Yang N. et al. Risk factors and prognostic model for HBV-related subacute liver failure. Ann Transl Med 2022; 10: 406-406
• 38 Wu W, Sun S, Wang Y. et al. Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure. Front Immunol 2021; 12: 1-12
• 39 Trovato FM, Zia R, Napoli S. et al. Dysregulation of the Lysophosphatidylcholine/Autotaxin/Lysophosphatidic Acid Axis in Acute-on-Chronic Liver Failure Is Associated With Mortality and Systemic Inflammation by Lysophosphatidic Acid–Dependent Monocyte Activation. Hepatology 2021; 74: 907-925
• 40 Cardoso CC, Matiollo C, Pereira CHJ. et al. B-cell compartment abnormalities are associated with ACLF and mortality in patients with liver cirrhosis. Clin Res Hepatol Gastroenterol 2021; 45
• 41 Wirtz TH, Reuken PA, Jansen C. et al. Balance between macrophage migration inhibitory factor and sCD74 predicts outcome in patients with acute decompensation of cirrhosis. JHEP Reports 2021; 3: 100221
• 42 Wang Y, Wu F, Chen C. et al. Soluble urokinase plasminogen activator receptor is associated with short-term mortality and enhanced reactive oxygen species production in acute-on-chronic liver failure. BMC Gastroenterol 2021; 21: 1-12
• 43 Anand AC, Nightingale P, Neuberger JM. Early indicators of prognosis in fulminant hepatic failure: An assessment of the King’s criteria. J Hepatol 1997; 26: 62-68
• 44 Verma N, Dhiman RK, Choudhury A. et al. Dynamic assessments of hepatic encephalopathy and ammonia levels predict mortality in acute-on-chronic liver failure. Hepatol Int 2021; 15: 970-982
• 45 Wang L, Zhu S, Liu Y. et al. Prognostic value of decline in model for end-stage liver disease score and hepatic encephalopathy in hepatitis B-related acute-on-chronic liver failure patients treated with plasma exchange. Scand J Gastroenterol 2022;
• 46 Schulz MS, Gu W, Schnitzbauer AA. et al. Liver Transplantation as a Cornerstone Treatment for Acute-On-Chronic Liver Failure. Transpl Int 2022; 35: 1-12
• 47 Toshima T, Harada N, Itoh S. et al. Outcomes of living-donor liver transplantation for acute-on-chronic liver failure based on newly proposed criteria in Japan. Clin Transplant 2022; 1-9
• 48 Otto G. Donor shortage in Germany: Impact on short- and long-term results in liver transplantation. Visc Med 2018; 34: 449-452
• 49 de Ville de Goyet J, Baumann U, Karam V. et al. European Liver Transplant Registry: Donor and transplant surgery aspects of 16,641 liver transplantations in children. Hepatology 2022; 75: 634-645
• 50 Ananthakrishnan AN, McGinley EL, Saeian K. Higher hospital volume is associated with lower mortality in acute nonvariceal upper-GI hemorrhage. Gastrointest Endosc 2009; 70: 422-432
• 51 KassenärztlicheBundesvereinigung. Wesentliche Änderungen im Überblick-Informationsmaterial zur Anpassung an die Jahresversion 2022. 2022 https://www.kbv.de/media/sp/Wesentliche_Kode-Aenderungen_ICD-10-GM_2022.pdf
• 52 Mezzano G, Juanola A, Cardenas A. et al. Global burden of disease: Acute-on-chronic liver failure, a systematic review and meta-analysis. Gut 2022; 71