Acute-on-chronic liver failure – Its definition remains unclear
Authors: Kama Wlodzimirow, Ameen Abu-Hanna, Robert A.F.M. Chamuleau
Journal: Journal of Hepatology (2013)

Acute-on chronic liver failureJournal of HepatologyVol. 57Issue 6PreviewAcute-on-chronic liver failure (ACLF) is an increasingly recognised entity encompassing an acute deterioration of liver function in patients with cirrhosis, which is usually associated with a precipitating event and results in the failure of one or more organs and high short term mortality. Prospective data to define this is lacking but there is a large body of circumstantial evidence suggesting that this condition is a distinct clinical entity. From the pathophysiologic perspective, altered host response to injury and infection play important roles in its development. Full-Text PDF Open AccessReply to: “Acute-on-chronic liver failure – Its definition remains unclear”Journal of HepatologyVol. 59Issue 1PreviewWe would like to thank Dr. Wlodzimirow and colleagues for their comments. We agree with them that a uniform definition of Acute on Liver Failure (ACLF) is essential [1]. It is with this aim that the CLIF Consortium initiated the CANONIC study, the results of which provide the framework for a definition of ACLF and its diagnostic criteria on the background of cirrhosis [2,3]. The issue of liver failure that occurs on the background of chronic hepatitis is more difficult and without more data that include biopsies in this group of patients, will remain very difficult to define. Full-Text PDF Open Access We have read with interest the review by Jalan et al. [[1]Jalan R. Gines P. Olson J.C. Mookerjee R.P. Moreau R. Garcia-Tsao G. et al.Acute-on chronic liver failure.J Hepatol. 2012; 57: 1336-1348Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar] in which they focus on the current understanding of acute-on-chronic liver failure (ACLF) from the clinical, prognostic and pathophysiologic perspectives. In addition, they indicate potential biomarkers and therapeutic targets for intervention. The authors confirm that the condition remains undefined, but that two consensus working definitions for this syndrome exist: one put forward by the Asia-Pacific association for the study of liver disease (APASL) and the other based on an EASL-AASLD single topic symposium. Both definitions address the essential feature of acute hepatic insult (APASL) or acute deterioration (EASL-AASLD) in patients with pre-existing chronic liver disease. The authors emphasize that ACLF is a syndrome that defines a subgroup of cirrhotic patients. The authors show also a graphical interpretation of liver function vs. time of the clinical concept of ACLF with its acute insult in contrast to the chronic decompensation of cirrhosis. The precipitating event, which can directly exacerbate liver injury, and extrahepatic insults, which lead to liver decompensation, are also comprehensively discussed. Those are very important considerations, which help distinguish both syndromes and avoid confusion. In our former review on ACLF [[2]Wlodzimirow K.A. Eslami S. Abu-Hanna A. Nieuwoudt M. Chamuleau R.A. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality.Liver Int. 2013; 33: 40-52Crossref PubMed Scopus (125) Google Scholar], we also emphasize the ambiguity and variability in the definition of ACLF and the need for a uniform definition. The definitions and, consequently, patient inclusion criteria within the included studies are not unequivocal. One observation was that studies often do not indicate whether pre-existing cirrhosis is essential for the definition or not. Several studies on ACLF reported the inclusion of patients with underlying cirrhosis [3Katoonizadeh A. Laleman W. Verslype C. Wilmer A. Maleux G. Roskams T. et al.Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study.Gut. 2010; 59: 1561-1569Crossref PubMed Scopus (221) Google Scholar, 4Karvellas C.J. Pink F. McPhail M. Austin M. Auzinger G. Bernal W. et al.Bacteremia, acute physiology and chronic health evaluation II and modified end stage liver disease are independent predictors of mortality in critically ill nontransplanted patients with acute on chronic liver failure.Crit Care Med. 2010; 38: 121-126Crossref PubMed Scopus (74) Google Scholar]. On the other hand, there is a number of studies on ACLF including patients with chronic hepatitis B (CHB) without mentioning the presence of cirrhosis [5Zhihui X. Xiaoqiang R. Yan L. Xiaodong L. Siyu B. Yanwei Z. et al.Association of hepatitis B virus mutations in basal core promoter and precore regions with severity of liver disease: an investigation of 793 Chinese patients with mild and severe chronic hepatitis B and acute-on-chronic liver failure.J Gastroenterol. 2011; 46: 391-400Crossref PubMed Scopus (63) Google Scholar, 6Shi F. Zhang J.Y. Zeng Z. Tien P. Wang F.S. Skewed ratios between CD3(+) T cells and monocytes are associated with poor prognosis in patients with HBV-related acute-on-chronic liver failure.Biochem Biophys Res Commun. 2010; 402: 30-36Crossref PubMed Scopus (27) Google Scholar] and others that mention that cirrhosis was not present in all patients [7Garg H. Kumar A. Garg V. Sharma P. Sharma B.C. Sarin S.K. Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure.Dig Liver Dis. 2012; 44: 166-171Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 8Sun Q.-F. Ding J.-G. Xu D.-Z. Chen Y.-P. Hong L. Ye Z.-Y. et al.Prediction of the prognosis of patients with acute-on-chronic hepatitis B liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model.J Viral Hepat. 2009; 16: 464-470Crossref PubMed Scopus (73) Google Scholar, 9Zheng M.H. Shi K.Q. Fan Y.C. Li H. Ye C. Chen Q.Q. et al.A model to determine 3-month mortality risk in patients with acute-on-chronic hepatitis B liver failure.Clin Gastroenterol Hepatol. 2011; 9: 351-356Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar]. Some studies on ACLF [10Sun L.-J. Yu J.-W. Zhao Y.-H. Kang P. Li S.-C. Influential factors of prognosis in lamivudine treatment for patients with acute-on-chronic hepatitis B liver failure.J Gastroenterol Hepatol. 2010; 25: 583-590Crossref PubMed Scopus (73) Google Scholar, 11Meng Q.H. Hou W. Yu H.W. Lu J. Li J. Wang J.H. et al.Resting energy expenditure and substrate metabolism in patients with acute-on-chronic hepatitis B liver failure.J Clin Gastroenterol. 2011; 45: 456-461Crossref PubMed Scopus (23) Google Scholar] include both chronic hepatitis and cirrhosis patients, and [[11]Meng Q.H. Hou W. Yu H.W. Lu J. Li J. Wang J.H. et al.Resting energy expenditure and substrate metabolism in patients with acute-on-chronic hepatitis B liver failure.J Clin Gastroenterol. 2011; 45: 456-461Crossref PubMed Scopus (23) Google Scholar] report that patients with chronic liver disease may have the outcome of liver cirrhosis. The study of Jalan et al. contributes to this ambiguity by presenting only patients with cirrhosis at the ICU in Tables 2 and 3, although the study states reliance on the EASL-AASLD definition, which is not restricted to cirrhosis alone. Since life-threatening deterioration by an acute event can occur in both chronic hepatitis patients and cirrhotics, leading to possible outcomes such as ACLF, it seems reasonable to include both patients with cirrhosis, as well as patients with chronic hepatitis into the definition of ACLF. Variability in defining and including patients in the studies brings confusion. Not all patients with CHB develop cirrhosis in the progression of disease, but they can develop ACLF. Should or should not the group of patients with pre-existing CHB, that severely deteriorates by a precipitating event, be included in the definition of ACLF or should non-cirrhotic patients be considered as a separate group? In any case, the establishment of a uniform definition of ACLF is essential for understanding the pathophysiology, prognosis, and treatment of the syndrome. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.