How do you differentiate between acute on chronic liver failure (ACLF) and liver cirrhosis in a patient presenting with signs of liver dysfunction?

Differentiating Acute-on-Chronic Liver Failure from Liver Cirrhosis

ACLF is fundamentally distinguished from stable cirrhosis by the presence of organ system failures (≥1 organ failure using CLIF-SOFA criteria) combined with acute decompensation and a 28-day mortality risk of ≥20%, whereas cirrhosis without ACLF has a 28-day mortality of ≤5%. 1, 2

Core Diagnostic Framework

Defining Characteristics of ACLF vs. Cirrhosis

ACLF represents an acute deterioration requiring hospitalization with organ failure(s), while cirrhosis alone may be compensated or decompensated without meeting organ failure thresholds. 1

The critical distinction centers on three elements:

• Organ failure presence: ACLF requires ≥1 organ system failure by CLIF-SOFA criteria, whereas cirrhosis patients may have complications (ascites, encephalopathy) without meeting organ failure definitions 1, 2
• Acute precipitating event: ACLF typically involves an identifiable trigger (infection with sepsis, severe alcohol-related hepatitis, drug toxicity, viral reactivation) in 60% of cases, though 40% have no apparent precipitant 3, 4
• Mortality trajectory: ACLF carries 30-50% 28-day mortality versus <5% in decompensated cirrhosis without ACLF 1, 2

CLIF-SOFA Organ Failure Criteria (The Diagnostic Backbone)

Use the CLIF-SOFA score to objectively identify organ failures—this is the gold standard for ACLF diagnosis. 1, 2

The six organ systems evaluated are:

• Liver failure: Bilirubin ≥12 mg/dL 2, 5
• Kidney failure: Creatinine ≥2.0 mg/dL 2
• Cerebral failure: Hepatic encephalopathy Grade III-IV (West Haven criteria) 1, 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

Once organ failures are identified, grade the severity:

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

Clinical Trajectory Classification

Patients with acutely decompensated cirrhosis can be retrospectively classified into distinct groups based on their 3-month trajectory, which helps differentiate stable cirrhosis from pre-ACLF states. 1

The EASL framework identifies six distinct patient groups:

• Stable decompensated cirrhosis (SDC): Discharged without readmission during 3-month follow-up 1, 6
• Unstable decompensated cirrhosis (UDC): Liver-related complications requiring readmission but not developing ACLF 1, 6
• Pre-ACLF: Patients who subsequently develop ACLF during 3-month follow-up 1, 6
• ACLF Grades 1-3: Present with organ failures at admission 1

Inflammatory Markers as Differentiating Tools

Elevated CRP and WBC counts identify patients at higher risk of progressing from decompensated cirrhosis to ACLF, though they lack sufficient accuracy as standalone predictors. 2

Key inflammatory distinctions:

• ACLF patients: Progressive increases in CRP and WBC during follow-up, reflecting systemic inflammatory response syndrome 2, 3
• Stable cirrhosis: Lower baseline inflammatory markers without progressive elevation 2
• Clinical caveat: The PREDICT study definitively demonstrated that no individual biomarker accurately predicts ACLF development, emphasizing the need for composite clinical assessment 2

Prognostic Scoring Systems

Scores accounting for hepatic and extrahepatic organ failures (NACSELD, CLIF-C ACLF, or AARC scores) are superior to conventional cirrhosis scores (MELD, MELD-Na) for assessing prognosis in ACLF. 1, 2

CLIF-C ACLF Score (Preferred for ACLF)

• Incorporates CLIF-C Organ Failure score, age, and WBC count 2
• Provides better prognostic accuracy than MELD or MELD-Na in ACLF patients 2
• Serial calculation at Days 3-7 improves prognostic accuracy: 90-day mortality in ACLF-3 patients who improve by Day 3 is 40% versus 79% in those who don't improve 1

MELD-Lactate Model

• Combines MELD score with lactate levels 2
• Demonstrates excellent predictive accuracy for in-hospital mortality, outperforming MELD, MELD-Na, or lactate alone 2

Critical Pitfalls to Avoid

Not All Altered Mental Status is Hepatic Encephalopathy

In ACLF patients with altered mental status, systematically exclude non-HE causes (alcohol-related conditions, septic encephalopathy, metabolic derangements) before attributing changes solely to hepatic encephalopathy. 1

The four concurrent management principles are:

• Airway protection to prevent aspiration 1
• Investigation of alternative causes of altered mental status 1
• Identification and treatment of HE precipitating factors 1
• Empiric HE therapy 1

Misclassifying Decompensated Cirrhosis as ACLF

Patients with ascites, variceal bleeding, or Grade I-II encephalopathy without meeting organ failure thresholds have decompensated cirrhosis, not ACLF. 1, 2

Common errors include:

• Labeling any acute decompensation as ACLF without verifying organ failure criteria 1
• Using MELD score alone for prognostication in suspected ACLF (MELD underestimates mortality as it doesn't capture extrahepatic organ failures) 2, 5
• Failing to recognize that bilirubin <12 mg/dL excludes liver failure by CLIF-SOFA criteria, even if other parameters are abnormal 2, 5

Geographic Definition Variations

Be aware that APASL and NACSELD definitions differ from EASL-CLIF criteria, which may cause confusion in literature interpretation. 1

Key differences:

• APASL definition: Restricted to acute intrahepatic precipitants; excludes bacterial infection, GI bleeding, or surgery as ACLF triggers 1
• NACSELD definition: Only captures most severe patients receiving organ support; doesn't consider liver dysfunction severity or coagulopathy 1
• EASL-CLIF definition (used in these guidelines): Includes both intrahepatic and extrahepatic precipitants; applies to all cirrhosis stages 1

Practical Clinical Algorithm

Step 1: Identify Acute Decompensation

• Hospitalization required for acute liver-related complication (ascites, encephalopathy, GI hemorrhage) 1, 6

Step 2: Calculate CLIF-SOFA Score

• Assess all six organ systems using objective criteria 1, 2
• Document specific values (bilirubin, creatinine, INR, encephalopathy grade, vasopressor use, PaO₂/FiO₂) 2

Step 3: Determine Organ Failure Presence

• ≥1 organ failure present → Diagnose ACLF and grade severity 1, 2
• No organ failures → Classify as decompensated cirrhosis (SDC, UDC, or pre-ACLF based on trajectory) 1, 6

Step 4: Identify Precipitating Factors

• Screen for infection (blood cultures, ascitic fluid analysis, chest X-ray, urinalysis) 1, 2
• Assess for active alcohol use, drug toxicity, viral reactivation 1, 2
• Document if no precipitant identified (occurs in 40% of cases) 3

Step 5: Risk Stratification

• Calculate CLIF-C ACLF score for mortality prediction 1, 2
• Consider MELD-Lactate if available 2
• Plan serial reassessment at Days 3-7 1

Step 6: Triage and Management

• ACLF patients: Admit to ICU or intermediate care unit 2
• Decompensated cirrhosis without ACLF: Standard hepatology ward care may be appropriate 1
• ACLF Grade 2-3: Early liver transplant evaluation 2, 5