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Defining Acute-on-Chronic Liver Failure: Will East and West Ever Meet?

  • Jasmohan S. Bajaj
    Correspondence
    Reprint requests Address requests for reprints to: Jasmohan S Bajaj, MD, MS, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia 23249. fax: (804) 675-5816
    Affiliations
    Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and, McGuire VA Medical Center, Richmond, Virginia
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      See “Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis,” by Moreau R, Jalan R, Gines P, et al, on page 1426.
      The increasing burden of cirrhosis and chronic liver disease worldwide should raise concerns regarding the prevention of morbidity and mortality in these patients.
      • Kim W.R.
      • Brown Jr., R.S.
      • Terrault N.A.
      • et al.
      Burden of liver disease in the United States: summary of a workshop.
      World Health Organization
      Projections of mortality and burden of disease in 2030.
      There is ample evidence that, when patients with cirrhosis develop infections or organ failure, their prognosis is significantly worse than comparable patients without cirrhosis.
      • Arabi Y.M.
      • Dara S.I.
      • Memish Z.
      • et al.
      Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis.
      However, research into acute-on-chronic liver failure (ACLF) has been hampered by single-center studies and incongruent definitions. This confusion has led many physicians to believe that ACLF is similar to acute decompensation of cirrhosis. The study by Moreau et al
      • 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.
      published in this issue of Gastroenterology provided convincing evidence that ACLF is a clinical entity distinct from acute decompensation of cirrhosis. This study also demonstrated the value of investing in setting up clinical consortia to study complicated diseases or controversial topics that would help to generate results that can be generalized across centers and allow consensus regarding diagnosis or treatment to be built.
      As in many other aspects of life and medicine, there is a sharp East–West divide with respect to the definition of ACLF (Table 1). The definition of ACLF by the Asia-Pacific Association for the Study of Liver (APASL) is: “Acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease.”
      • Sarin S.K.
      • Kumar A.
      • Almeida J.A.
      • et al.
      Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL).
      The American Association for the Study of Liver Disease/European Association for the Study of the Liver (EASL) consensus defines it as: “Acute deterioration of pre-existing, chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 months due to multi-system organ failure.”
      • Olson J.C.
      • Wendon J.A.
      • Kramer D.J.
      • et al.
      Intensive care of the patient with cirrhosis.
      • Jalan R.
      • Gines P.
      • Olson J.C.
      • et al.
      Acute-on chronic liver failure.
      The latter definition was then refined by the same authors to: “A syndrome that defines a subgroup of cirrhotic patients who develop organ failure following hospital admission with or without an identifiable precipitating event and have increased mortality rates.”
      • Jalan R.
      • Gines P.
      • Olson J.C.
      • et al.
      Acute-on chronic liver failure.
      Pondering these definitions is not just a matter of semantics because they determine the incidence and outcomes of ACLF, as well as how data are interpreted to formulate policies and foster future research in this growing field. The differences in definition largely reflect the differences in underlying etiologies of acute deterioration of liver disease between the East and the West. In the Asia-Pacific region, the majority of ACLF is precipitated by hepatitis B flares and acute hepatitis A or E, superimposed on chronic liver disease, which is not necessarily cirrhosis.
      • Hamid S.S.
      • Atiq M.
      • Shehzad F.
      • et al.
      Hepatitis E virus superinfection in patients with chronic liver disease.
      • Keeffe E.B.
      Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases?.
      • Garg V.
      • Garg H.
      • Khan A.
      • et al.
      Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure.
      In sharp contrast, in Western societies, these viral etiologies are largely supplanted by nonviral insults, especially bacterial infections, in patients who are either known or are discovered to have cirrhosis upon admission.
      • Olson J.C.
      • Wendon J.A.
      • Kramer D.J.
      • et al.
      Intensive care of the patient with cirrhosis.
      • 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.
      Given global human proclivities, alcohol-related ACLF is equally represented worldwide.
      Table 1Differences in Current Definitions of ACLF
      APASL DefinitionAASLD/EASL Consensus
      Duration between insult and ACLFFour weeksNot defined
      Duration in which there is higher mortalityNot defined3 months
      What qualifies as “chronic liver disease”Chronic liver disease with/without only compensated cirrhosisOnly cirrhosis, including those with prior decompensation
      What qualifies as precipitants?
       Alcohol, drugs, hepatotropic viruses, surgery, traumaYesYes
       SepsisNoYes
       Variceal bleedingNo consensusYes
      APASL, Asia-Pacific Association for the Study of Liver; EASL, European Association for the Study of the Liver.
      There is an urgent need to join forces to first define ACLF within a region and then hopefully, expand the definitions worldwide. The EASL Chronic Liver Failure (EASL-CLIF) consortium is a laudable effort of 81 investigators.
      • 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.
      These investigators enrolled 1343 patients with cirrhosis hospitalized for an acute decompensation in 29 liver centers in 8 countries in a prospective, observational study. Standardized definition of clinical events and management of cirrhosis complications were followed. Diagnostic criteria of ACLF were obtained after identifying subgroups of patients with organ failure and high 28-day mortality (>15%). The authors adapted the existing Sequential Organ Failure Assessment (SOFA) to liver disease by creating the CLIF-SOFA score that a priori defined ACLF in their expert opinion.
      • Vincent J.L.
      • Moreno R.
      • Takala J.
      • 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.
      They found that 28-day mortality in the patients with ACLF at enrollment, ACLF after enrollment, and no ACLF were 34%, 30%, and 2%, respectively. Although there was considerable regional variation in outcomes, the results showed it is indeed “organ failure,” especially kidney failure, which accounted for the high mortality and differentiated acute decompensation from ACLF. Patients with ACLF had higher leukocyte counts and plasma C-reactive protein levels, and were more likely to be actively drinking, and higher CLIF-SOFA score and leukocyte counts were independent predictors of mortality in patients with ACLF.
      As with most landmark studies, the results of this study raise several interesting questions. First, the precise contribution of alcohol and alcoholic hepatitis to ACLF needs to be studied further. Alcoholic liver disease, especially alcoholic hepatitis, is associated with immune dysfunction predisposing to a higher prevalence of sepsis, which was among the most common precipitants of ACLF in this study.
      • Rosa H.
      • Silverio A.O.
      • Perini R.F.
      • et al.
      Bacterial infection in cirrhotic patients and its relationship with alcohol.
      • Mookerjee R.P.
      • Stadlbauer V.
      • Lidder S.
      • et al.
      Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome.
      High leukocyte count is a common feature of alcoholic hepatitis and infection. In this study, alcohol was the cause of cirrhosis in 51% of patients, of whom 29% had active alcoholism within 3 months of admission. The authors attempted to address this issue by comparing the incidence and predictors of ACLF between the patients with alcoholic versus nonalcoholic cirrhosis, but given the large proportion of patients with alcoholic cirrhosis and presumed alcoholic hepatitis, further studies are needed to validate the role of leukocyte count and C-reactive protein in predicting mortality in patients with ACLF. Second, the finding that patients without prior acute decompensation were at greater risk for ACLF development, possibly owing to a lack of tolerance is novel and should spur further research into the balance between the systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome in this population.
      • Wasmuth H.E.
      • Kunz D.
      • Yagmur E.
      • et al.
      Patients with acute on chronic liver failure display “sepsis-like” immune paralysis.
      • Cazzaniga M.
      • Dionigi E.
      • Gobbo G.
      • et al.
      The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome.
      Third, the lack of a specific precipitating factor in 43% of patients with ACLF is intriguing; the depth of investigation into precipitating factors determines the yield and it may be possible that variations in the intensity of the search for precipitating factors existed within this large consortium. This finding places an impetus into the discovery of novel biomarkers that could predict ACLF development that occurs without “classic” precipitating factors.” Finally, the CLIF-SOFA score was created based on expert opinion of European hepatologists. The accuracy of CLIF-SOFA score in predicting mortality in other patient populations with ALF need to be validated. Furthermore, although the SOFA and CLIF-SOFA scores are important for patients managed in intensive care units, their practical application could be difficult in the hands of internists, gastroenterologists, or hepatologists who will be managing many of these patients. This study found similar survival prediction with the Model for End-Stage Liver Disease score, which hepatologists are more familiar with.
      • Kamath P.S.
      • Wiesner R.H.
      • Malinchoc M.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      Simpler methods of defining organ failures may therefore be needed to translate these concepts of organ failure in ACLF into daily practice. It may follow that scores like CLIF-SOFA would be used to define organ failures in trials while Model for End-Stage Liver Disease or simpler definitions of organ failure would be used in clinical practice.
      • Bahirwani R.
      • Shaked O.
      • Bewtra M.
      • et al.
      Acute-on-chronic liver failure before liver transplantation: impact on posttransplant outcomes.
      It may also be helpful to keep in mind the “PIRO” (predisposition, injury/insult, response and outcome) concept developed from sepsis, while understanding organ failures associated with ACLF.
      • Moreno R.P.
      • Metnitz B.
      • Adler L.
      • et al.
      Sepsis mortality prediction based on predisposition, infection and response.
      The results of this large multinational effort clearly demonstrate that ACLF is a separate entity from acute decompensation in patients with cirrhosis. As expected from a study in the West, the precipitants of ACLF were mostly bacterial infections and alcohol, and all patients had cirrhosis. Similar results relating organ failures with survival were found in the infected cirrhotic patients in another Western consortium, the North American Consortium for the Study of End-Stage Liver Disease (NACSELD), in which ≥2 extrahepatic organ failures were associated with a significant increase in mortality compared with patients with 1 or 0 organ failures.
      • Bajaj J.S.
      • Kamath P.S.
      • O'Leary J.G.
      • et al.
      Multiple organ dysfunction defines acute-on-chronic liver failure (ACLF): the NACSELD study.
      However, the results from either of these studies are not directly applicable in the Asia-Pacific region, where the majority of the world resides.
      Therefore, although this study by the EASL-CLIF consortium is a major step forward in defining ACLF, it also underscores the need to form consortia across geographical regions and ultimately worldwide. A multiregion effort by the World Gastroenterology Organization has been initiated to encompass patients with disparate etiologies, precipitants and definitions and to develop a unifying definition of ACLF that would encourage therapeutic trials leading to improved outcomes. Until then we may have to live with Rudyard Kipling's assessment that “East is East and West is West and never the twain shall meet.”

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