Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Acute-on-chronic liver failure in cirrhosis

Nature Reviews Disease Primers volume 2, Article number: 16041 (2016) Cite this article

Subjects

Abstract

The definition of acute-on-chronic liver failure (ACLF) remains contested. In Europe and North America, the term is generally applied according to the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium guidelines, which defines this condition as a syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure and high short-term mortality. One-third of patients who are hospitalized for acute decompensation present with ACLF at admission or develop the syndrome during hospitalization. ACLF frequently occurs in a closed temporal relationship to a precipitating event, such as bacterial infection or acute alcoholic, drug-induced or viral hepatitis. However, no precipitating event can be identified in approximately 40% of patients. The mechanisms of ACLF involve systemic inflammation due to infections, acute liver damage and, in cases without precipitating events, probably intestinal translocation of bacteria or bacterial products. ACLF is graded into three stages (ACLF grades 1–3) on the basis of the number of organ failures, with higher grades associated with increased mortality. Liver and renal failures are the most common organ failures, followed by coagulation, brain, circulatory and respiratory failure. The 28-day mortality rate associated with ACLF is 30%. Depending on the grade, ACLF can be reversed using standard therapy in only 16–51% of patients, leaving a considerable proportion of patients with ACLF that remains steady or progresses. Liver transplantation in selected patients with ACLF grade 2 and ACLF grade 3 increases the 6-month survival from 10% to 80%.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The clinical course of cirrhosis.
Figure 2: Different ACLF definitions capture different patient populations.
Figure 3: Structural feature recognition of bacteria and induction of the inflammatory response.
Figure 4: Intestinal dysbiosis and bacterial translocation.
Figure 5: Relationship between organ failure and mortality in ACLF.
Figure 6: Liver transplantation increases survival of patients with ACLF.
Figure 7: Proposed algorithm for the management of patients with ACLF or decompensated cirrhosis.

Similar content being viewed by others

References

  1. Ginés, P. et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology 7, 122–128 (1987).

    Article  PubMed  Google Scholar 

  2. Schrier, R. W. et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 8, 1151–1157 (1998).

    Article  Google Scholar 

  3. Fraser, C. L. & Arieff, A. I. Hepatic encephalopathy. N. Engl. J. Med. 313, 865–873 (1985).

    Article  CAS  PubMed  Google Scholar 

  4. Polio, J. & Groszmann, R. J. Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin. Liver Dis. 6, 318–331 (1986).

    Article  CAS  PubMed  Google Scholar 

  5. Ramachandran, P., Iredale, J. P. & Fallowfield, J. A. Resolution of liver fibrosis: basic mechanisms and clinical relevance. Semin. Liver Dis. 35, 119–131 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Bernardi, M., Moreau, R., Angeli, P., Schnabl, B. & Arroyo, V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J. Hepatol. 63, 1272–1284 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Moreau, R. et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 144, 1426–1437.e9 (2013). This article describes the first prospective investigation assessing the diagnostic criteria (EASL-CLIF Consortium definition of ACLF), prevalence, precipitating events, grading of severity and prognosis of ACLF in a large series of European patients hospitalized with decompensated cirrhosis using a pragmatic approach.

    Article  PubMed  Google Scholar 

  9. Wlodzimirow, K. A., Eslami, S., Abu-Hanna, A., Nieuwoudt, M. & Chamuleau, R. A. F. M. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. Liver Int. 33, 40–52 (2013).

    Article  PubMed  Google Scholar 

  10. Jalan, R. & Williams, R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif. 20, 252–261 (2002).

    Article  PubMed  Google Scholar 

  11. Sarin, S. K. et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL). Hepatol. Int. 3, 269–282 (2009). This article describes the results of a consensus conference promoted by the APASL aiming to assess the diagnostic definition of ACLF.

    Article  PubMed  Google Scholar 

  12. Sarin, S. K. et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014. Hepatol. Int. 8, 453–471 (2014).

    Article  PubMed  Google Scholar 

  13. Bajaj, J. S. et al. Survival in infection-related acute-on-chronic liver failure is defined by extra-hepatic organ failures. Hepatology 60, 250–256(2014). This study shows the prevalence of ACLF and associated mortality in a large series of patients with cirrhosis and bacterial infection from the United States.

    Article  PubMed  Google Scholar 

  14. Jalan, R. et al. Acute-on chronic liver failure. J. Hepatol. 57, 1336–1348 (2012).

    Article  PubMed  Google Scholar 

  15. Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Diseases and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. [Diagnostic and treatment guidelines for liver failure (2012 version)]. Zhonghua Gan Zang Bing Za Zhi 21, 177–183 (in Chinese) (2013).

    Google Scholar 

  16. Vincent, J. L. et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 22, 707–710 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Wehler, M., Kokoska, J., Reulbach, U., Hahn, E. G. & Strauss, R. Short-term prognosis in critically ill patients with cirrhosis assessed by prognostic scoring systems. Hepatology 34, 255–261 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Das, V. et al. Cirrhotic patients in the medical intensive care unit: early prognosis and long-term survival. Crit. Care Med. 38, 2108–2116 (2010).

    Article  PubMed  Google Scholar 

  19. Levesque, E. et al. Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit. J. Hepatol. 56, 95–102 (2012).

    Article  PubMed  Google Scholar 

  20. Jalan, R. et al. Development and validation of a prognostic score to predict mortality in patients with acute on chronic liver failure. J. Hepatol. 61, 1038–1047 (2014). This study describes a prognostic score specifically designed for patients with ACLF. The accuracy of this score (CLIF-C ACLF score) is significantly higher than that of all scores currently used in clinical practice.

    Article  PubMed  Google Scholar 

  21. Bernal, W. et al. Acute-on-chronic liver failure. Lancet 386, 1576–1587 (2015).

    Article  PubMed  Google Scholar 

  22. Bernsmeier, C. et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology 148, 603–615.e14 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, Q. et al. Comparison of current diagnostic criteria for acute-on-chronic liver failure. PLoS ONE 10, e0122158 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Li, H. et al. Characteristics, diagnosis and prognosis of acute-on-chronic liver failure in cirrhosis associated to hepatitis B. Sci. Rep. 6, 25487 (2016). This study indicates that the EASL-CLIF Consortium definition of ACLF designed for European patients can also be used in Chinese patients with cirrhosis due to HBV infection with no major differences in prevalence, severity and prognosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dirchwolf, M. et al. Immune dysfunction in cirrhosis: distinct cytokines phenotypes according to cirrhosis severity. Cytokine 77, 14–25 (2015).

    Article  PubMed  CAS  Google Scholar 

  26. Amarapurkar, D. et al. Acute-on-chronic liver failure: a prospective study to determine the clinical profile, outcome, and factors predicting mortality. Indian J. Gastroenterol. 34, 216–224 (2015).

    Article  PubMed  Google Scholar 

  27. Li, H. et al. Submassive hepatic necrosis distinguishes HBV-associated acute on chronic liver failure from cirrhotic patients with acute decompensation. J. Hepatol. 63, 50–59 (2015).

    Article  PubMed  Google Scholar 

  28. Singh, H. & Pai, C. G. Defining acute-on-chronic liver failure: east, west or middle ground? World J. Hepatol. 7, 2571–2577 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Agrawal, S., Duseja, A., Gupta, T., Dhiman, R. K. & Chawla, Y. Simple organ failure count versus CANONIC grading system for predicting mortality in acute-on-chronic liver failure. J. Gastroenterol. Hepatol. 30, 575–581 (2015).

    Article  PubMed  Google Scholar 

  30. Lee, M. et al. CLIF-SOFA scoring system accurately predicts short-term mortality in acutely decompensated patients with alcoholic cirrhosis: a retrospective analysis. Liver Int. 35, 46–57 (2015).

    Article  PubMed  Google Scholar 

  31. Dhiman, R. K., Agrawal, S., Gupta, T., Duseja, A. & Chawla, Y. Chronic Liver Failure-Sequential Organ Failure Assessment is better than the Asia-Pacific Association for the Study of Liver criteria for defining acute-on-chronic liver failure and predicting outcome. World J. Gastroenterol. 20, 14934–14941 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kim, H. Y. et al. Characterization of acute-on-chronic liver failure and prediction of mortality in Asian patients with active alcoholism. J. Gastroenterol. Hepatol. 31, 427–433 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Kim, T. Y. & Kim, D. J. Acute-on-chronic liver failure. Clin. Mol. Hepatol. 19, 349–359 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Jalan, R. et al. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology 147, 4–10 (2014).

    Article  PubMed  Google Scholar 

  35. Kim, T. Y. et al. Characteristics and discrepancies in acute-on-chronic liver failure: need for a unified definition. PLoS ONE 11, e0146745 (2016). This study is the first to show that the EASL-CLIF Consortium definition and the APASL definition of ACLF include different populations of patients.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Sarin, S. K. & Choudhury, A. Acute-on-chronic liver failure: terminology, mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 13, 131–149 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Olson, J. C. & Kamath, P. S. Acute-on-chronic liver failure: concept, natural history, and prognosis. Curr. Opin. Crit. Care 17, 165–169 (2011).

    Article  PubMed  Google Scholar 

  38. Singh, K. K., Panda, S. K., & Shalimar Acharya, S. K. Patients with diabetes mellitus are prone to develop severe hepatitis and liver failure due to hepatitis virus infection. J. Clin. Exp. Hepatol. 3, 275–280 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Verbeke, L., Nevens, F. & Laleman, W. Bench-to-beside review: acute-on-chronic liver failure — linking the gut, liver and systemic circulation. Crit. Care 15, 233 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Suntharalingam, G. et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 355, 1018–1028 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Medzhitov, R., Schneider, D. S. & Soares, M. P. Disease tolerance as a defense strategy. Science 335, 936–941 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Iwasaki, A. & Medzhitov, R. Control of adaptive immunity by the innate immune system. Nat. Immunol. 16, 343–353 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wu, J. & Chen, Z. J. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 32, 461–488 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Xu, H. et al. Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome. Nature 513, 237–241 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Zhao, Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596–600 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Martinon, F., Mayor, A. & Tschopp, J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 27, 229–265 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8, 279–289 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rickard, J. A. et al. RIPK1 regulates RIPK3–MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157, 1175–1188 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Angus, D. C. & van der Poll, T. Severe sepsis and septic shock. N. Engl. J. Med. 369, 840–851 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Medzhitov, R. Inflammation 2010: new adventures of an old flame. Cell 140, 771–776 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chovatiya, R. & Medzhitov, R. Stress, inflammation, and defense of homeostasis. Mol. Cell 54, 281–288 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Jalan, R. et al. Bacterial Infections in cirrhosis. A position statement based on the EASL Special Conference 2013. J. Hepatol. 60, 1310–1324(2014).

    Article  PubMed  Google Scholar 

  56. Wiest, R., Lawson, M. & Geuking, M. Pathological bacterial translocation in liver cirrhosis. J. Hepatol. 60, 197–209 (2014).

    Article  PubMed  Google Scholar 

  57. Byl, B., Roucloux, I., Crusiaux, A., Dupont, E. & Devière, J. Tumor necrosis factor alpha and interleukin 6 plasma levels in infected cirrhotic patients. Gastroenterology 104, 1492–1497 (1993).

    Article  CAS  PubMed  Google Scholar 

  58. Navasa, M. et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality. Hepatology 27, 1227–1232 (1998). References 57 and 58 show for the first time an in vivo overproduction of pro-inflammatory cytokines in patients with cirrhosis.

    Article  CAS  PubMed  Google Scholar 

  59. Gustot, T., Durand, F., Lebrec, D., Vincent, J.-L. & Moreau, R. Severe sepsis in cirrhosis. Hepatology 50, 2022–2033 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Devière, J. et al. Excessive in vitro bacterial lipopolysaccharide-induced production of monokines in cirrhosis. Hepatology 11, 628–634 (1990). This paper shows for the first time that the ex vivo innate immune response to LPS is deregulated in monocytes from patients with alcoholic cirrhosis.

    Article  PubMed  Google Scholar 

  61. Le Moine, O. et al. Role of defective monocyte interleukin-10 release in tumor necrosis factor-alpha overproduction in alcoholics cirrhosis. Hepatology 22, 1436–1439 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Tazi, K. A. et al. Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M. J. Hepatol. 45, 280–289 (2006). This paper describes the intracellular mechanisms involved in the excessive innate immune response to LPS in monocytes from patients with decompensated cirrhosis.

    Article  CAS  PubMed  Google Scholar 

  63. Tazi, K. A. et al. Protein array technology to investigate cytokine production by monocytes from patients with advanced alcoholic cirrhosis: an ex vivo pilot study. Hepatol. Res. 39, 706–715 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Galbois, A. et al. Ex vivo effects of high-density lipoprotein exposure on the lipopolysaccharide-induced inflammatory response in patients with severe cirrhosis. Hepatology 49, 175–184 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Coant, N. et al. Glycogen synthase kinase 3 involvement in the excessive proinflammatory response to LPS in patients with decompensated cirrhosis. J. Hepatol. 55, 784–793 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Gandoura, S. et al. Gene- and exon-expression profiling reveals an extensive LPS-induced response in immune cells in patients with cirrhosis. J. Hepatol. 58, 936–948 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Heller, J. et al. Effects of lipopolysaccharide on TNFα production, hepatic NOS2 activity, and hepatic toxicity in rats with cirrhosis. J. Hepatol. 33, 376–381 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Moreau, R. et al. Terlipressin inhibits in vivo aortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis. Hepatology 36, 1070–1078 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Urbanowicz, W. et al. Tezosentan, an endothelin receptor antagonist, limits liver injury in endotoxin challenged cirrhotic rats. Gut 53, 1844–1849 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tazi, K. A. et al. In vivo altered unfolded protein response and apoptosis in livers from lipopolysaccharide-challenged cirrhotic rats. J. Hepatol. 46, 1075–1088 (2007). This paper shows for the first time that LPS-induced hepatic endoplasmic reticulum stress inhibits the accumulation of NF-κB-dependent anti-apoptotic proteins in livers from rats with cirrhosis.

    Article  CAS  PubMed  Google Scholar 

  71. Thabut, D. et al. High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats. Hepatology 46, 1893–1906 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Malhi, H. & Kaufman, R. J. Endoplasmic reticulum stress in liver disease. J. Hepatol. 54, 795–809 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Chaisson, M. L., Brooling, J. T., Ladiges, W., Tsai, S. & Fausto, N. Hepatocyte-specific inhibition of NF-κB leads to apoptosis after TNF treatment, but not after partial hepatectomy. J. Clin. Invest. 110, 193–202 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Louvet, A. et al. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology 137, 541–548 (2009).

    Article  CAS  PubMed  Google Scholar 

  75. Lucey, M. R., Mathurin, P. & Morgan, T. R. Alcoholic hepatitis. N. Engl. J. Med. 360, 2758–2769 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Úbeda, M. et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J. Hepatol. 64, 1049–1057 (2015).

    Article  PubMed  CAS  Google Scholar 

  77. Du Plessis, J. et al. Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function. J. Hepatol. 58, 1125–1132 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Francés, R. et al. Bacterial translocation is downregulated by anti-TNFα monoclonal antibody administration in rats with cirrhosis and ascites. J. Hepatol. 46, 797–803 (2007).

    Article  PubMed  CAS  Google Scholar 

  79. Dominguez, M. et al. Hepatic expression of CXC chemokines predicts portal hypertension and survival in patients with alcoholic hepatitis. Gastroenterology 136, 1639–1650 (2009). This paper shows that neutrophil-attracting chemokines are overexpressed in livers from patients with severe alcoholic cirrhosis.

    Article  PubMed  Google Scholar 

  80. Charo, I. F. & Ransohoff, R. M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Kubes, P. & Mehal, W. Z. Sterile inflammation in the liver. Gastroenterology 143, 1158–1172 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Larosche, I. et al. Prolonged ethanol administration depletes mitochondrial DNA in MnSOD-overexpressing transgenic mice, but not in their wild type littermates. Toxicol. Appl. Pharmacol. 234, 326–338 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Choumar, A. et al. Lipopolysaccharide-induced mitochondrial DNA depletion. Antioxid. Redox Signal. 15, 2837–2854 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Dubuquoy, L. et al. Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis. Gut 64, 1949–1960 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Brenner, D. A., Paik, Y.-H. & Schnabl, B. Role of gut microbiota in liver disease. J. Clin. Gastroenterol. 49, S25–S27 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bajaj, J. S. et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J. Hepatol. 60, 940–947 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Bajaj, J. S. et al. Linkage of gut microbiome with cognition in hepatic encephalopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G168–G175 (2012).

    Article  CAS  PubMed  Google Scholar 

  89. Chen, Y. et al. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562–572 (2011).

    Article  PubMed  Google Scholar 

  90. Chen, Y. et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. J. Gastroenterol. Hepatol. 30, 1429–1437 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Pan, C. et al. Dynamic changes of lipopolysaccharide levels in different phases of acute on chronic hepatitis B liver failure. PLoS ONE 7, e49460 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bauer, T. M. et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am. J. Gastroenterol. 97, 2364–2370 (2002). This paper shows an association between microbiota alterations and systemic endotoxaemia in patients with cirrhosis.

    Article  PubMed  Google Scholar 

  93. Zapater, P. et al. Serum and ascitic fluid bacterial DNA: a new independent prognostic factor in noninfected patients with cirrhosis. Hepatology 48, 1924–1931 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. McPhail, M. J. W. et al. Increased survival for patients with cirrhosis and organ failure in liver intensive care and validation of the Chronic Liver Failure-Sequential Organ Failure Scoring System. Clin. Gastroenterol. Hepatol. 13, 1353–1360.e8 (2015).

    Article  PubMed  Google Scholar 

  95. Silva, P. E. S. E. 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. 35, 1516–1523 (2015).

    Article  PubMed  Google Scholar 

  96. Gustot, T. et al. Clinical course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 62, 243–252 (2015). This study is the first investigation defining the clinical course of ACLF within 28 days following diagnosis. It shows that ACLF is an extremely dynamic syndrome that may improve, worsen or follow a steady course. Prognosis is highly dependent on the clinical course within the first week after diagnosis.

    Article  PubMed  Google Scholar 

  97. Shi, Y. et al. Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults. Hepatology 62, 232–242 (2015). This study confirms the results of the CANONIC study in European patients, showing that short-term (28-day and 90-day) mortality in Asian patients with ACLF depends on the number of organ failures and not on the aetiology (the type of precipitating events) of the syndrome.

    Article  PubMed  Google Scholar 

  98. Jalan, R. et al. The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure. J. Hepatol. 62, 831–840 (2015).

    Article  PubMed  Google Scholar 

  99. Kamath, P. S. & Kim, W. R. The model for end-stage liver disease (MELD). Hepatology 45, 797–805 (2007).

    Article  PubMed  Google Scholar 

  100. Durand, F. & Valla, D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J. Hepatol. 42, S100–S107 (2005).

    Article  PubMed  Google Scholar 

  101. Biggins, S. W. Use of serum sodium for liver transplant graft allocation: a decade in the making, now is it ready for primetime? Liver Transpl. 21, 279–281 (2015).

    Article  PubMed  Google Scholar 

  102. Fernandez, J. & Arroyo, V. Bacterial infections in cirrhosis: a growing problem with significant implications. Clin. Liver Dis. 2, 102–105 (2013).

    Article  Google Scholar 

  103. Sarin, S. K. et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol. Int. 10, 1–98 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. Sort, P. et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N. Engl. J. Med. 341, 403–409 (1999). This randomized controlled trial was the first to show that intravenous albumin administration (1.5 g per kg of body weight at infection diagnosis and 1 g per kg of body weight at the third day) is highly effective in preventing type 1 HRS and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.

    Article  CAS  PubMed  Google Scholar 

  105. Arroyo, V., García-Martinez, R. & Salvatella, X. Human serum albumin, systemic inflammation, and cirrhosis. J. Hepatol. 61, 396–407 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Guevara, M. et al. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. J. Hepatol. 57, 759–765 (2012).

    Article  CAS  PubMed  Google Scholar 

  107. Thévenot, T. et al. Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. J. Hepatol. 62, 822–830 (2015).

    Article  PubMed  CAS  Google Scholar 

  108. Ginés, P. et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 12, 716–724 (1990).

    Article  PubMed  Google Scholar 

  109. Soriano, G. et al. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 103, 1267–1272 (1992).

    Article  CAS  PubMed  Google Scholar 

  110. Fernández, J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133, 818–824 (2007). This randomized controlled trial was the first to show that long-term oral administration of norfloxacin prevents the development of spontaneous bacterial peritonitis and type 1 HRS and improves survival in patients with cirrhosis and severe liver and renal dysfunction.

    Article  PubMed  CAS  Google Scholar 

  111. Zapater, P. et al. Norfloxacin modulates the inflammatory response and directly affects neutrophils in patients with decompensated cirrhosis. Gastroenterology 137, 1669–1679.e1 (2009).

    Article  CAS  PubMed  Google Scholar 

  112. Gómez-Hurtado, I. et al. Interleukin-10-mediated heme oxygenase 1-induced underlying mechanism in inflammatory down-regulation by norfloxacin in cirrhosis. Hepatology 53, 935–944 (2011).

    Article  PubMed  CAS  Google Scholar 

  113. Gómez-Hurtado, I. et al. Role of interleukin 10 in norfloxacin prevention of luminal free endotoxin translocation in mice with cirrhosis. J. Hepatol. 61, 799–808 (2014).

    Article  PubMed  CAS  Google Scholar 

  114. Akriviadis, E. et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology 119, 1637–1648 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Nguyen-Khac, E. et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N. Engl. J. Med. 365, 1781–1789 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Thursz, M. R. et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N. Engl. J. Med. 372, 1619–1628 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Kedarisetty, C. K. et al. Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis. Gastroenterology 148, 1362–1370.e7 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Arroyo, V., Moreau, R., Jalan, R. & Ginès, P. Acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis. J. Hepatol. 62, S131–S143 (2015).

    Article  PubMed  Google Scholar 

  119. Seto, W.-K., Lai, C.-L. & Yuen, M.-F. Acute-on-chronic liver failure in chronic hepatitis B. J. Gastroenterol. Hepatol. 27, 662–669 (2012).

    Article  PubMed  Google Scholar 

  120. Garg, H. et al. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. Hepatology 53, 774–780 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Philips, C. A. & Sarin, S. K. Potent antiviral therapy improves survival in acute on chronic liver failure due to hepatitis B virus reactivation. World J. Gastroenterol. 20, 16037–16052 (2014). The results of this study are a clear indication that potent antiviral therapy significantly improves the clinical course and survival of patients with ACLF due to reactivation of HBV.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Arabi, Y. M. et al. Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis. Hepatology 56, 2305–2315 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Tandon, P. & Garcia-Tsao, G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin. Liver Dis. 28, 26–42 (2008).

    Article  CAS  PubMed  Google Scholar 

  124. Fernández, J., Tandon, P., Mensa, J. & Garcia-Tsao, G. Antibiotic prophylaxis in cirrhosis: good and bad. Hepatology 63, 2019–2031(2016).

    Article  PubMed  Google Scholar 

  125. Chen, T. et al. Nucleoside analogues improve the short-term and long-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure. Clin. Exp. Med. 12, 159–164 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Xie, F. et al. Effects of nucleoside analogue on patients with chronic hepatitis B-associated liver failure: meta-analysis. PLoS ONE 8, e54773 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Yang, J. et al. Initial combination anti-viral therapy with lamivudine and adefovir dipivoxil decreases short-term fatality rate of hepatitis-B-virus-related acute-on-chronic liver failure. Virol. J. 12, 97 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Garg, V. et al. Granulocyte colony-stimulating factor mobilizes CD34+ cells and improves survival of patients with acute-on-chronic liver failure. Gastroenterology 142, 505–512.e1 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Angeli, P. et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J. Hepatol. 62, 968–974 (2015). This article provides the most modern clinical guidelines on the diagnosis and treatment of AKI in cirrhosis.

    Article  PubMed  Google Scholar 

  130. Belcher, J. M. et al. Urinary biomarkers and progression of AKI in patients with cirrhosis. Clin. J. Am. Soc. Nephrol. 9, 1857–1867 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Rivers, E. et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N. Engl. J. Med. 345, 1368–1377 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Fede, G. et al. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology 55, 1282–1291 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Vilstrup, H. 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 60, 715–735 (2014).

    Article  PubMed  Google Scholar 

  134. Bianchini, M., De Pietri, L. & Villa, E. Coagulopathy in liver diseases: complication or therapy? Dig. Dis. 32, 609–614 (2014).

    Article  PubMed  Google Scholar 

  135. de Franchis, R. & Baveno VI Faculty. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J. Hepatol. 63, 743–752 (2015). This article provides the most modern clinical guidelines on the diagnosis management of portal hypertension and gastrointestinal haemorrhage in cirrhosis. There is a detailed description on the management of coagulopathy in patients with portal vein thrombosis.

    Article  PubMed  Google Scholar 

  136. Lee, S. Y., Kim, H. J. & Choi, D. Cell sources, liver support systems and liver tissue engineering: alternatives to liver transplantation. Int. J. Stem Cells 8, 36–47 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Struecker, B., Raschzok, N. & Sauer, I. M. Liver support strategies: cutting-edge technologies. Nat. Rev. Gastroenterol. Hepatol. 11, 166–176 (2014). This article contains a comprehensive review of the artificial liver support strategies in patients with acute liver failure and ACLF.

    Article  CAS  PubMed  Google Scholar 

  138. Bañares, R. et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 57, 1153–1162 (2013).

    Article  PubMed  CAS  Google Scholar 

  139. Kribben, A. et al. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 142, 782–789.e3 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Lee, K. C. L. et al. Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: results of a pivotal pre-clinical study. J. Hepatol. 63, 634–642 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Larsen, F. S. et al. High-volume plasma exchange in patients with acute liver failure: an open randomised controlled trial. J. Hepatol. 64, 69–78 (2016).

    Article  PubMed  Google Scholar 

  142. Bahirwani, R., Shaked, O., Bewtra, M., Forde, K. & Reddy, K. R. Acute-on-chronic liver failure before liver transplantation: impact on posttransplant outcomes. Transplantation 92, 952–957 (2011).

    Article  PubMed  Google Scholar 

  143. Duan, B.-W. et al. Liver transplantation in acute-on-chronic liver failure patients with high model for end-stage liver disease (MELD) scores: a single center experience of 100 consecutive cases. J. Surg. Res. 183, 936–943 (2013).

    Article  PubMed  Google Scholar 

  144. Finkenstedt, A. et al. Acute-on-chronic liver failure: excellent outcomes after liver transplantation but high mortality on the wait list. Liver Transpl. 19, 879–886 (2013).

    Article  PubMed  Google Scholar 

  145. Sharma, P., Schaubel, D. E., Gong, Q., Guidinger, M. & Merion, R. M. End-stage liver disease candidates at the highest model for end-stage liver disease scores have higher wait-list mortality than status-1A candidates. Hepatology 55, 192–198 (2012).

    Article  PubMed  Google Scholar 

  146. Chan, A. C. et al. Liver transplantation for acute-on-chronic liver failure. Hepatol. Int. 3, 571–581 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Chan, A. C. Y. & Fan, S. T. Criteria for liver transplantation in ACLF and outcome. Hepatol. Int. 9, 355–359 (2015).

    Article  PubMed  Google Scholar 

  148. Reddy, M. S., Rajalingam, R. & Rela, M. Liver transplantation in acute-on-chronic liver failure: lessons learnt from acute liver failure setting. Hepatol. Int. 9, 508–513 (2015).

    Article  PubMed  Google Scholar 

  149. Khanam, A. et al. Altered frequencies of dendritic cells and IFN-γ-secreting T cells with granulocyte colony-stimulating factor (G-CSF) therapy in acute-on- chronic liver failure. Liver Int. 34, 505–513 (2014).

    Article  CAS  PubMed  Google Scholar 

  150. Duan, X.-Z. et al. Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acute-on-chronic liver failure. World J. Gastroenterol. 19, 1104–1110 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ma, X.-R. et al. Transplantation of autologous mesenchymal stem cells for end-stage liver cirrhosis: a meta-analysis based on seven controlled trials. Gastroenterol. Res. Pract. 2015, 908275 (2015).

    PubMed  PubMed Central  Google Scholar 

  152. Volk, M. L., Tocco, R. S., Bazick, J., Rakoski, M. O. & Lok, A. S. Hospital readmissions among patients with decompensated cirrhosis. Am. J. Gastroenterol. 107, 247–252 (2012).

    Article  PubMed  Google Scholar 

  153. Reddy, K. R. et al. High risk of delisting or death in liver transplant candidates following infections: results from the North American Consortium for the Study of End-Stage Liver Disease. Liver Transpl. 21, 881–888 (2015).

    Article  PubMed  Google Scholar 

  154. O'Leary, J. G. et al. Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis. Clin. Gastroenterol. Hepatol. 13, 753–759.e2 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Battle, C. E., Davies, G. & Evans, P. A. Long term health-related quality of life in survivors of sepsis in south west Wales: an epidemiological study. PLoS ONE 9, e116304 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Vanwijngaerden, Y.-M. et al. Critical illness evokes elevated circulating bile acids related to altered hepatic transporter and nuclear receptor expression. Hepatology 54, 1741–1752 (2011).

    Article  CAS  PubMed  Google Scholar 

  157. Katoonizadeh, A. et al. Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study. Gut 59, 1561–1569 (2010).

    Article  PubMed  Google Scholar 

  158. Hotchkiss, R. S., Monneret, G. & Payen, D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 13, 862–874 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Gomez, H. et al. A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock 41, 3–11 (2014). This article contains a comprehensive review of the mechanisms of AKI associated with systemic inflammation in sepsis. Concepts might be extended to AKI and other types of organ failure in ACLF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Jiménez, W., Clária, J., Arroyo, V. & Rodés, J. Carbon tetrachloride induced cirrhosis in rats: a useful tool for investigating the pathogenesis of ascites in chronic liver disease. J. Gastroenterol. Hepatol. 7, 90–97 (1992).

    Article  PubMed  Google Scholar 

  161. Harry, D. et al. Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic rat. Hepatology 30, 1198–1205 (1999).

    Article  CAS  PubMed  Google Scholar 

  162. Bass, N. M. et al. Rifaximin treatment in hepatic encephalopathy. N. Engl. J. Med. 362, 1071–1081 (2010). This article reports a randomized controlled trial showing that oral rifaximin is highly effective in preventing the recurrence of hepatic encephalopathy in cirrhosis.

    Article  CAS  PubMed  Google Scholar 

  163. Bernardi, M. et al. Long-term use of human albumin for the treatment of ascites in patients with hepatic cirrhosis: the interim analysis of the ANSWER study. Dig. Liv. Dis. 47 (Suppl. 1), e6 (2015).

    Article  Google Scholar 

  164. Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).

    Article  CAS  PubMed  Google Scholar 

  165. Verbeke, L. et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 59, 2286–2298 (2014).

    Article  CAS  PubMed  Google Scholar 

  166. Verbeke, L. et al. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am. J. Pathol. 185, 409–419 (2015). This article reports a study in experimental cirrhosis showing that oral obeticholic acid improves gut permeability, intestinal inflammation and bacterial translocation.

    Article  CAS  PubMed  Google Scholar 

  167. Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 1246–1249 (2013).

    Article  CAS  PubMed  Google Scholar 

  168. Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).

    Article  CAS  PubMed  Google Scholar 

  169. Broz, P. Immunology: caspase target drives pyroptosis. Nature 526, 642–643 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Sargenti, K., Prytz, H., Nilsson, E. & Kalaitzakis, E. Predictors of mortality among patients with compensated and decompensated liver cirrhosis: the role of bacterial infections and infection-related acute-on-chronic liver failure. Scand. J. Gastroenterol. 50, 875–883 (2015).

    Article  CAS  PubMed  Google Scholar 

  171. Blei, A. T. & Córdoba, J. Hepatic encephalopathy. Am. J. Gastroenterol. 96, 1968–1976 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium is endorsed by the European Association for the Study of the Liver and supported by an unrestricted grant from Grifols. The authors thank D. J. Kim for the supply of the published Korean data and the Data Management Centre of the EASL-CLIF Consortium for providing the unpublished European data used in Figure 2.

Author information

Authors and Affiliations

  1. European Foundation for the Study of Chronic Liver Failure (EF-CLIF), Travessera de Gracia 11, Barcelona, 08021, Spain

    Vicente Arroyo, Richard Moreau, Rajiv Jalan, Pere Ginès, Frederik Nevens & Javier Fernández

  2. Grifols Chair for the Study of Cirrhosis, Barcelona, Spain

    Vicente Arroyo

  3. European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium, Barcelona, Spain

    Vicente Arroyo, Richard Moreau, Rajiv Jalan, Pere Ginès, Frederik Nevens & Javier Fernández

  4. Inserm, U 1149, Centre de Recherche sur l'Inflammation (CRI), Paris, France

    Richard Moreau

  5. Université Paris Diderot, Faculté de Médecine,, Paris, France

    Richard Moreau

  6. Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France

    Richard Moreau

  7. Laboratoire d'Excellence (Labex) Inflamex, ComUE Sorbonne Paris Cité, Paris, France

    Richard Moreau

  8. Division of Gastroenterology, Hepatology and Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA

    Patrick S. Kamath

  9. Institute of Hepatology, UCL Medical School, London, UK

    Rajiv Jalan

  10. Royal Free Hospital, UCL Medical School, London, UK

    Rajiv Jalan

  11. Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain

    Pere Ginès & Javier Fernández

  12. Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium

    Frederik Nevens

  13. Yale Digestive Diseases, Temple Medical Center, New Haven, Connecticut, USA

    Uyen To & Guadalupe García-Tsao

  14. Veterans Administration, Yale-New Haven Hospital, New Haven, Connecticut, USA

    Uyen To & Guadalupe García-Tsao

  15. Department of Medicine, University of California San Diego, La Jolla, San Diego, California, USA

    Bernd Schnabl

  16. Department of Medicine, VA San Diego Health Care System, San Diego, California, USA

    Bernd Schnabl

Authors
  1. Vicente Arroyo
    View author publications

    Search author on:PubMed Google Scholar

  2. Richard Moreau
    View author publications

    Search author on:PubMed Google Scholar

  3. Patrick S. Kamath
    View author publications

    Search author on:PubMed Google Scholar

  4. Rajiv Jalan
    View author publications

    Search author on:PubMed Google Scholar

  5. Pere Ginès
    View author publications

    Search author on:PubMed Google Scholar

  6. Frederik Nevens
    View author publications

    Search author on:PubMed Google Scholar

  7. Javier Fernández
    View author publications

    Search author on:PubMed Google Scholar

  8. Uyen To
    View author publications

    Search author on:PubMed Google Scholar

  9. Guadalupe García-Tsao
    View author publications

    Search author on:PubMed Google Scholar

  10. Bernd Schnabl
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Introduction (V.A.); Epidemiology (P.S.K.); Mechanisms/pathophysiology (R.M. and B.S.); Diagnosis, screening and prevention (P.G., V.A. and J.F.); Management (R.J., G.G.-T., U.T. and J.F.); Quality of life (P.S.K.); Outlook (F.N. and V.A.); Overview of Primer (V.A.). V.A. and R.M. contributed equally to this work.

Corresponding author

Correspondence to Vicente Arroyo.

Ethics declarations

Competing interests

V.A. has received research funding from Grifols and has served on the scientific advisory board for Takeda. P.G. has received research funding from Grifols, served on the scientific advisory board for Ferring and Squana Medical and received research funding from Sequana Medical. R.J. has received research funding from Vital Therapies, has served on the scientific advisory board for Conatus Pharma and Takeda, has ongoing research collaborations with Gambro and Grifiols and is the principal investigator of an industry sponsored study (Sequana Medical). F.N. has served on the scientific advisory board of Center Fract, Croix Rouge Belgium, Intercept, Gore, Bristol-Myers Squibb, AbbVie, Novartis, MSD, Janssen-Cilag, Promethera Biosciences and Gilead, and has received grants from Roche, Astellas, Ferring, Novartis, Janssen-Cilag and AbbVie. All other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Arroyo, V., Moreau, R., Kamath, P. et al. Acute-on-chronic liver failure in cirrhosis. Nat Rev Dis Primers 2, 16041 (2016). https://doi.org/10.1038/nrdp.2016.41

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/nrdp.2016.41

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing