Acute-on-chronic liver failure: Definitions, pathophysiology and principles of treatment

Abstract

The term acute-on-chronic liver failure (ACLF) defines an abrupt and life-threatening worsening of clinical conditions in patients with cirrhosis or chronic liver disease. In recent years, different definitions and diagnostic criteria for the syndrome have been proposed by the major international scientific societies. The main controversies relate to the type of acute insult (specifically hepatic or also extrahepatic), the stage of underlying liver disease (cirrhosis or chronic hepatitis) and the concomitant extrahepatic organ failure(s) that should be considered in the definition of ACLF. Therefore, different severity criteria and prognostic scores have been proposed and validated. Current evidence shows that the pathophysiology of ACLF is closely associated with an intense systemic inflammation sustained by circulating pathogen-associated molecular patterns and damage-associated molecular patterns. The development of organ failures may be a result of a combination of tissue hypoperfusion, direct immune-mediated damage and mitochondrial dysfunction. Management of ACLF is currently based on the supportive treatment of organ failures, mainly in an intensive care setting. For selected patients, liver transplantation is an effective treatment that offers a good long-term prognosis. Future studies on potential mechanistic treatments that improve patient survival are eagerly awaited.

Keywords: AARC, APASL ACLF Research Consortium; ACLF, acute-on-chronic liver failure; AKI, acute kidney injury; APASL, Asian Pacific Association for the Study of the Liver; Acute decompensation; Bacterial infections; Bacterial translocation; CLIF, Chronic Liver Failure-Consortium; COSSH, Chinese Group on the Study of Severe Hepatitis; DAMPs, damage-associated molecular patterns; EASL, European Association for the Study of the Liver - Chronic Liver; ER, endoplasmic reticulum; HMGB1, high mobility group box 1; ICU, intensive care unit; INR, international normalised ratio; Immunopathology; Inflammatory response; MELD, model for end-stage liver disease; Metabolism; Multiorgan failure; NACSELD, North American Consortium for the Study of End-stage Liver Disease; NO, nitric oxide; OF, organ failure; PAMPs, pathogen-associated molecular patterns; PRR, pattern-recognition receptors; Sterile inflammation; TLR, Toll-like receptor; UNOS, United Network for Organ Sharing.

Fig. 1

Definitions of organ system failures used by European and Chinese investigators and North American investigators for defining ACLF. (A) Chronic Liver Failure-Consortium Organ Failure (known as CLIF-C OF) scale used by investigators from Europe (European Association for the Study of the Liver – Chronic Liver Failure Consortium)) and China (Chinese Group on the Study of Severe Hepatitis B).^, The red and yellow boxes indicate the thresholds for organ system failure and organ dysfunction, respectively. (B) Definitions of organ system failures used by the investigators of the North American Consortium for the Study of End-stage Liver Disease (known as NACSELD). E, epinephrine; FiO₂, fraction of inspired oxygen; HE, hepatic encephalopathy; INR, international normalised ratio; MAP, mean arterial pressure; NE, norepinephrine; PaO₂, partial pressure of arterial oxygen; RRT, renal replacement therapy; SpO₂, oxygen saturation as measured by pulse oximetry.

Fig. 2

Scores developed by different consortia to assess the prognosis of ACLF. (A) Scores developed by European (CLIF-C ACLF score) and Chinese (COSSH-ACLF score) groups.^, (B) The organ system assessment with the HBV-SOFA scale enables calculation of the HBV-SOFA score. (C) Components of the AARC scoring system. (D) Grading of ACLF according to AARC scores. AARC, Asian Pacific Association for the Study of the Liver ACLF Research Consortium; ACLF, acute-on-chronic liver failure; CLIF-C, Chronic Liver Failure-Consortium; COSSH, Chinese Group on the Study of Severe Hepatitis B; FiO₂, fraction of inspired oxygen; HE, hepatic encephalopathy; INR, international normalised ratio; MAP, mean arterial pressure; PaO₂, partial pressure of arterial oxygen; RRT, renal replacement therapy; SOFA, sequential organ failure assessment; SpO₂, oxygen saturation as measured by pulse oximetry.

Fig. 3

Pathophysiology of ACLF. Schematic of induction of systemic inflammation and its role in the development of organ failures. ACLF, acute-on-chronic liver failure; AKI, acute kidney injury; DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns; PRRs, pattern-recognition receptors; iNOS, inducible nitric oxide synthase; OxPhos, oxidative phosphorylation; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

Fig. 4

Principles of treatment of organ failure in ACLF. What should be done is shown in green boxes. What should be avoided is shown in red boxes. ACLF, acute-on-chronic liver failure; AKI, acute kidney injury; KDIGO, Kidney Disease Improving Global Outcomes; LT, liver transplantation; NSAID, non-steroidal anti-inflammatory drugs; PPI, proton pump inhibitors; RRT, renal replacement therapy.