Acute-on-Chronic Liver Failure (ACLF) Definition
ACLF is defined by three minimum critical components: (1) acute onset with rapid clinical deterioration, (2) liver failure with elevated bilirubin and INR in patients with chronic liver disease (with or without cirrhosis), and (3) at least one extrahepatic organ failure (neurologic, circulatory, respiratory, or renal). 1
Core Diagnostic Components
The 2024 AASLD Practice Guidance establishes that all three elements must be present simultaneously for ACLF diagnosis 1:
- Acute deterioration: Rapid worsening of clinical status, though the exact timeframe remains somewhat undefined in the literature 1
- Hepatic failure: Demonstrated by elevated bilirubin (cutoffs of 5-12 mg/dL have been examined) and elevated INR (typically 1.5-2.5 or above) 1
- Extrahepatic organ failure: At least one organ system must fail beyond the liver itself 1
Specific Organ Failure Criteria
The EASL-CLIF criteria use the CLIF-SOFA scoring system to define organ failures 2:
- Liver failure: Bilirubin ≥12 mg/dL 2
- Kidney failure: Creatinine ≥2 mg/dL 2
- Cerebral failure: Hepatic encephalopathy grade III-IV 2
- Coagulation failure: INR ≥2.5 or platelet count ≤20,000/mm³ 2
- Circulatory failure: Requirement for vasopressor support 2
- Respiratory failure: PaO₂/FiO₂ ≤200 or SpO₂/FiO₂ ≤214 2
ACLF Grading System
ACLF severity is classified based on the number and type of organ failures 2:
- Grade 1a: Single kidney failure 2
- Grade 1b: Single non-kidney organ failure with creatinine 1.5-1.9 mg/dL and/or hepatic encephalopathy grade 1-2 2
- Grade 2: Two organ failures 2
- Grade 3: Three or more organ failures 2
The 28-day mortality escalates dramatically with grade: approximately 30-50% overall, reaching 78% for Grade 3 ACLF 2, 3.
Key Distinguishing Features
ACLF differs fundamentally from both acute liver failure and stable cirrhosis progression 4, 3:
- Occurs in patients with pre-existing chronic liver disease or cirrhosis 1
- Characterized by systemic inflammation and immune dysfunction 3, 5
- Has potential for reversibility, unlike acute liver failure which often progresses irreversibly 1
- Associated with specific precipitating events in 60% of cases (infections, active alcoholism, GI bleeding, drug toxicity, viral hepatitis reactivation) 1, 6, 7
Regional Definition Variations
Important caveat: Different geographic regions use varying criteria 8:
- APASL (Asian): More sensitive, identifies earlier-stage disease, focuses primarily on liver failure parameters, includes non-cirrhotic chronic liver disease 8
- EASL (European): More specific, identifies intermediate-to-late stage disease with higher mortality, requires cirrhosis as underlying condition 8
- NACSELD (North American): Most restrictive, requires two or more extrahepatic organ failures, identifies patients at often preterminal stage 1
The AASLD guidance acknowledges these differences but emphasizes that any definition must include both hepatic dysfunction and extrahepatic organ failure 1, 8.
Clinical Context and Prognosis
ACLF develops in the setting of intense systemic inflammation, with severity correlating directly with the number of organ failures and mortality risk 3, 5. The syndrome can develop at any stage of chronic liver disease, from compensated cirrhosis to long-standing decompensation 3. The CLIF-C ACLF score provides superior prognostic accuracy compared to traditional MELD or MELD-Na scores 2.