What is the definition of Acute-on-Chronic Liver Failure (ACLF) in a patient with pre-existing chronic liver disease?

Definition of Acute-on-Chronic Liver Failure (ACLF)

ACLF is defined as an acute deterioration of liver function in patients with pre-existing chronic liver disease (with or without cirrhosis) that results in hepatic and extrahepatic organ failures, associated with high short-term mortality of 30-50% at 28 days. 1, 2

Core Diagnostic Components

The minimum critical components required for ACLF diagnosis include: 1

• Acute onset with rapid deterioration
• Liver failure (elevated bilirubin and INR)
• At least one extrahepatic organ failure
• Pre-existing chronic liver disease (cirrhosis not mandatory)

Key Definitional Differences Across Societies

EASL-CLIF Definition (European - Most Widely Referenced)

The EASL definition applies only to patients with established cirrhosis (including those with previous decompensation) and identifies patients in intermediate to late disease stages. 3, 4 This is the definition used in the 2023 EASL Clinical Practice Guidelines unless otherwise specified. 3

Organ failure criteria using CLIF-SOFA scoring system: 2

• Liver failure: Bilirubin ≥12 mg/dL
• Kidney failure: Creatinine ≥2 mg/dL
• Cerebral failure: Hepatic encephalopathy grade III-IV
• Coagulation failure: INR ≥2.5 or platelets ≤20,000/mm³
• Circulatory failure: Requirement for vasopressors
• Respiratory failure: PaO₂/FiO₂ ≤200 or SpO₂/FiO₂ ≤214

ACLF grading by organ failures: 2

• Grade 1a: Single kidney failure
• Grade 1b: Single non-kidney organ failure with creatinine 1.5-1.9 mg/dL and/or hepatic encephalopathy grade 1-2
• Grade 2: Two organ failures
• Grade 3: Three or more organ failures (28-day mortality ~78%)

AASLD Definition (North American - Most Inclusive)

The AASLD defines ACLF as occurring in patients with chronic liver disease with or without cirrhosis, making it the most inclusive definition. 1 The AASLD emphasizes that cirrhosis is not required at any diagnostic step and that patients with advanced fibrosis (F3) can develop ACLF. 1

APASL Definition (Asia-Pacific - Early Stage Focus)

The APASL definition is restricted to acute liver dysfunction triggered by acute intrahepatic precipitants and applies to both cirrhotic patients without prior decompensation and those with non-cirrhotic chronic liver disease. 3, 4 Notably, APASL does not consider bacterial infection, gastrointestinal bleeding, or surgery as potential precipitating events. 3 This definition is more sensitive but less specific, identifying patients at earlier stages with lower mortality. 4

NACSELD Definition (North American - Most Restrictive)

The NACSELD definition captures only the most severe patients requiring organ support with two or more extrahepatic organ failures, representing a preterminal stage. 3, 1 This definition does not consider severity of liver dysfunction or coagulopathy. 3

Pathophysiologic Framework

ACLF is characterized by: 5, 6, 7

• Dysregulated systemic inflammatory response with altered host response to injury
• Immune dysfunction leading to pro-inflammatory status
• Circulating pathogen-associated and damage-associated molecular patterns
• Combination of tissue hypoperfusion, direct immune-mediated damage, and mitochondrial dysfunction leading to organ failures

Clinical Implications

Common precipitating factors include: 5, 8, 9

• Bacterial infections
• Active alcoholism/acute alcoholic hepatitis
• Viral hepatitis reactivation
• Gastrointestinal hemorrhage
• Drug-induced liver injury
• Frequently no identifiable cause

Critical practice points: 1, 2

• Presence or absence of cirrhosis should be documented as it affects transplant evaluation and prognosis
• ACLF without cirrhosis may have different patterns of organ failure and precipitants compared to ACLF with cirrhosis
• The condition is potentially reversible in many cases with appropriate management