Prognosis and Biomarkers in Acute-on-Chronic Liver Failure

 

 Buy Article Permissions and Reprints

Abstract

As formal definitions of acute-on-chronic liver failure (ACLF) have now been established, and given an increased recognition of the dynamic nature of this condition, there is a growing clinical need to assess prognosis and response to interventions. Conventional scoring systems such as Model for End-Stage Liver Disease (MELD) fail to capture the two key prognostic elements in ACLF—namely, extrahepatic organ failure and measures of systemic inflammation—and as such are limited in their prognostic accuracy. Even the best available scoring systems such as the recently described CLIF (Chronic Liver Failure) Consortium ACLF (CLIF-C ACLF) score, are at best 75% accurate and need to be applicable to all etiologies of liver disease. Thus, in the absence of “gold standard” markers of prognosis that render one scoring system superior to another, there is a need to explore other markers of pathophysiology that may better define outcome. This review addresses the evidence for markers of oxidative stress, including those reflecting the inflammasome; elements of cell death such as cytokeratins M30 and M65; and indicators of immune dysfunction, innate immune failure and gut dysbiosis. Finally, evidence for relevance of markers of organ dysfunction, including hemodynamic response, are explored along with associated mediators such as copeptin, dimethylarginines, and renin. It is anticipated that further critique and validation of emerging and relevant biomarkers will facilitate a composite score which, either alone or in combination with existing scoring systems such as CLIF-C, will enable improved prognostication and targeting of therapy in ACLF.

• References

• 1 Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002; 20 (3) 252-261
  CrossrefPubMedGoogle Scholar
• 2 Moreau R, Jalan R, Gines P , et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (7) 1426-1437 , 1437.e1–1437.e9
  CrossrefPubMedGoogle Scholar
• 3 Gustot T, Fernandez J, Garcia E , et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis. Hepatology 2015; 62 (1) 243-252
  PubMedGoogle Scholar
• 4 Jalan R, Saliba F, Pavesi M , et al; CANONIC study investigators of the EASL-CLIF Consortium. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 2014; 61 (5) 1038-1047
  CrossrefPubMedGoogle Scholar
• 5 Jalan R, Pavesi M, Saliba F , et al; CANONIC Study Investigators; EASL-CLIF Consortium. The CLIF Consortium Acute Decompensation score (CLIF-C ADs) for prognosis of hospitalised cirrhotic patients without acute-on-chronic liver failure. J Hepatol 2015; 62 (4) 831-840
  CrossrefPubMedGoogle Scholar
• 6 Garg H, Kumar A, Garg V, Sharma P, Sharma BC, Sarin SK. Clinical profile and predictors of mortality in patients of acute-on-chronic liver failure. Dig Liver Dis 2012; 44 (2) 166-171
  CrossrefPubMedGoogle Scholar
• 7 Olson JC, Kamath PS. Acute-on-chronic liver failure: concept, natural history, and prognosis. Curr Opin Crit Care 2011; 17 (2) 165-169
  CrossrefPubMedGoogle Scholar
• 8 Jalan R. Acute-on-chronic liver failure: from concept to a new syndrome. Curr Opin Crit Care 2011; 17 (2) 152
  CrossrefPubMedGoogle Scholar
• 9 Di Martino V, Coutris C, Cervoni JP , et al. Prognostic value of C-reactive protein levels in patients with cirrhosis. Liver Transpl 2015; 21 (6) 753-760
  CrossrefPubMedGoogle Scholar
• 10 Cai J, Han T, Nie C , et al. Biomarkers of oxidation stress, inflammation, necrosis and apoptosis are associated with hepatitis B-related acute-on-chronic liver failure. Clin Res Hepatol Gastroenterol 2016; 40 (1) 41-50
  CrossrefPubMedGoogle Scholar
• 11 Sha Y, Zmijewski J, Xu Z, Abraham E. HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol 2008; 180 (4) 2531-2537
  CrossrefPubMedGoogle Scholar
• 12 Oettl K, Birner-Gruenberger R, Spindelboeck W , et al. Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival. J Hepatol 2013; 59 (5) 978-983
  CrossrefPubMedGoogle Scholar
• 13 Jalan R, Schnurr K, Mookerjee RP , et al. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Hepatology 2009; 50 (2) 555-564
  PubMedGoogle Scholar
• 14 Cao Z, Li F, Xiang X , et al. Circulating cell death biomarker: good candidates of prognostic indicator for patients with hepatitis B virus related acute-on-chronic liver failure. Sci Rep 2015; 5: 14240
  CrossrefPubMedGoogle Scholar
• 15 Adebayo D, Morabito V, Andreola F , et al. Mechanism of cell death in acute-on-chronic liver failure: a clinico-pathologic-biomarker study. Liver Int 2015; 35 (12) 2564-2574
  CrossrefPubMedGoogle Scholar
• 16 Ben Moshe T, Barash H, Kang TB , et al. Role of caspase-8 in hepatocyte response to infection and injury in mice. Hepatology 2007; 45 (4) 1014-1024
  CrossrefPubMedGoogle Scholar
• 17 Mencin A, Kluwe J, Schwabe RF. Toll-like receptors as targets in chronic liver diseases. Gut 2009; 58 (5) 704-720
  CrossrefPubMedGoogle Scholar
• 18 Bernsmeier C, Pop OT, Singanayagam A , et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology 2015; 148 (3) 603-615.e14
  CrossrefPubMedGoogle Scholar
• 19 Wasmuth HE, Kunz D, Yagmur E , et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol 2005; 42 (2) 195-201
  PubMedGoogle Scholar
• 20 Mookerjee RP, Stadlbauer V, Lidder S , et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007; 46 (3) 831-840
  CrossrefPubMedGoogle Scholar
• 21 Ariza X, Graupera I, Coll M , et al. Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis. J Hepatol 2016; ; Mar 14 [Epub head of print]
  PubMedGoogle Scholar
• 22 Chen Y, Guo J, Qian G , et al. Gut dysbiosis in acute-on-chronic liver failure and its predictive value for mortality. J Gastroenterol Hepatol 2015; 30 (9) 1429-1437
  CrossrefPubMedGoogle Scholar
• 23 Mookerjee RP, Lackner C, Stauber R , et al. The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol 2011; 55 (5) 1103-1111
  CrossrefPubMedGoogle Scholar
• 24 Garg H, Kumar A, Garg V , et al. Hepatic and systemic hemodynamic derangements predict early mortality and recovery in patients with acute-on-chronic liver failure. J Gastroenterol Hepatol 2013; 28 (8) 1361-1367
  CrossrefPubMedGoogle Scholar
• 25 Cárdenas A, Solà E, Rodríguez E , et al; CANONIC study investigators of the EASL-CLIF Consortium. Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study. Crit Care 2014; 18 (6) 700
  CrossrefPubMedGoogle Scholar
• 26 Solà Verges E, Kerbert AJC, Verspaget HW , et al. Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis. J Hepatol 2016; ; In press
  PubMedGoogle Scholar
• 27 Matsuyama T, Uemura M, Ishikawa M , et al. Increased von Willebrand factor over decreased ADAMTS13 activity may contribute to the development of liver disturbance and multiorgan failure in patients with alcoholic hepatitis. Alcohol Clin Exp Res 2007; 31 (1, Suppl): S27-S35
  CrossrefPubMedGoogle Scholar
• 28 Reuken PA, Kussmann A, Kiehntopf M , et al. Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis. Liver Int 2015; 35 (1) 37-45
  CrossrefPubMedGoogle Scholar
• 29 Mookerjee RP, Dalton RN, Davies NA , et al. Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure. Liver Transpl 2007; 13 (3) 400-405
  CrossrefPubMedGoogle Scholar
• 30 Mookerjee RP, Malaki M, Davies NA , et al. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology 2007; 45 (1) 62-71
  CrossrefPubMedGoogle Scholar
• 31 Mookerjee RP, Davies NA, Dalton RN, Jalan R. Evaluation of the biomarker, dimethylarginine score- ischemia modified albumin ratio (DASIMAR) to identify risk of progression to acute on chronic liver failure and mortality (ACLF) in patients with decompensated cirrhosis. Hepatology 2007; 46 (4) 615A
  CrossrefPubMedGoogle Scholar
• 32 Wan ZH, Wang JJ, You SL , et al. Cystatin C is a biomarker for predicting acute kidney injury in patients with acute-on-chronic liver failure. World J Gastroenterol 2013; 19 (48) 9432-9438
  CrossrefPubMedGoogle Scholar
• 33 Ariza X, Solà E, Elia C , et al. Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis. PLoS ONE 2015; 10 (6) e0128145
  CrossrefPubMedGoogle Scholar