How do you differentiate between alcoholic hepatitis and Acute-on-Chronic Liver Failure (ACLF) in a patient with a history of chronic liver disease and alcohol use disorder?

Differentiating Alcoholic Hepatitis from ACLF

Alcoholic hepatitis can exist as a distinct clinical entity OR serve as the precipitating event that triggers ACLF—the key distinction is whether extrahepatic organ failures are present. 1

Understanding the Relationship

These are not mutually exclusive diagnoses but rather overlapping clinical syndromes:

• Severe alcoholic hepatitis (sAH) is defined by rapid onset jaundice (bilirubin >3 mg/dL), AST >50 IU/mL (rarely >400), AST/ALT ratio >1.5, recent heavy alcohol use within 60 days, and Maddrey Discriminant Function ≥32 or MELD >20 1, 2

• ACLF requires three minimum components: (1) acute deterioration in clinical condition, (2) liver failure (elevated bilirubin AND elevated INR), and (3) at least one extrahepatic organ failure (neurologic, circulatory, respiratory, or renal) 1

• Severe alcoholic hepatitis is the precipitating event for ACLF in approximately 30-57% of Western ACLF cases 1

The Critical Differentiating Factor: Organ Failures

The presence and number of extrahepatic organ failures determines whether a patient has isolated alcoholic hepatitis versus ACLF:

Isolated Severe Alcoholic Hepatitis (No ACLF)

• Jaundice, coagulopathy (INR elevated), and hepatic dysfunction present 1
• May have ascites, mild encephalopathy (Grade I-II), or tender hepatomegaly 2
• No extrahepatic organ failures by CLIF-SOFA criteria 1
• 28-day mortality approximately 30-50% without treatment 2

Alcoholic Hepatitis WITH ACLF

• All features of severe alcoholic hepatitis PLUS 1
• One or more extrahepatic organ failures defined by CLIF-SOFA score:
  • Kidney: Creatinine ≥2.0 mg/dL (or ≥1.5 mg/dL with another organ failure) 1
  • Brain: Grade III-IV hepatic encephalopathy (or Grade I-II with another organ failure) 1
  • Circulation: Mean arterial pressure <70 mmHg or vasopressor requirement 1
  • Respiration: PaO2/FiO2 ratio ≤200 or SpO2/FiO2 ratio ≤214 1
  • Coagulation: INR >2.5 (in context of other organ failures) 1
• 28-day mortality ranges from 30% (ACLF-1) to 72% (ACLF-3) 3

Practical Clinical Algorithm

Step 1: Confirm Severe Alcoholic Hepatitis

• Recent heavy alcohol use (<60 days) 1, 2
• Rapid onset jaundice with bilirubin >3 mg/dL 1, 2
• AST 50-400 IU/mL with AST/ALT ratio >1.5 1, 2
• Calculate mDF ≥32 or MELD >20 2
• Exclude biliary obstruction, viral hepatitis, drug-induced liver injury 2

Step 2: Assess for Extrahepatic Organ Failures Using CLIF-SOFA

Systematically evaluate all six organ systems 1:

Liver: Bilirubin level (already elevated in AH)

Coagulation: INR >2.5 indicates failure 1

Kidney:

• Creatinine ≥2.0 mg/dL = kidney failure 1
• Creatinine 1.5-1.9 mg/dL = kidney dysfunction (counts as ACLF-1b if another organ fails) 1

Brain:

• Grade III-IV encephalopathy = brain failure 1
• Grade I-II encephalopathy = brain dysfunction (counts as ACLF-1b if another organ fails) 1

Circulation: MAP <70 mmHg or vasopressor use = circulatory failure 1

Respiration: PaO2/FiO2 ≤200 or mechanical ventilation = respiratory failure 1

Step 3: Grade the ACLF (if present)

• No ACLF: Isolated severe alcoholic hepatitis only 1
• ACLF-1: Single kidney failure OR single non-kidney/non-brain failure + kidney/brain dysfunction 1
• ACLF-2: Two organ failures 1
• ACLF-3: Three or more organ failures 1

Critical Prognostic Implications

Patients with severe alcoholic hepatitis who develop ACLF have dramatically worse outcomes:

• Severe alcoholic hepatitis WITHOUT ACLF: 28-day mortality 10-31% 3
• Severe alcoholic hepatitis WITH ACLF-1: 28-day mortality 31% 3
• Severe alcoholic hepatitis WITH ACLF-2: 28-day mortality 58% 3
• Severe alcoholic hepatitis WITH ACLF-3: 28-day mortality 72% 3

In critically ill ICU patients, those with severe alcoholic hepatitis-precipitated ACLF have significantly higher mortality than non-alcoholic hepatitis ACLF (adjusted sHR 1.57, p=0.001) 4

Management Divergence Based on Classification

For Severe Alcoholic Hepatitis WITHOUT ACLF:

• Prednisolone 40 mg daily (if no contraindications) 2
• Enteral nutrition 30-40 kcal/kg/day with 1.0-1.5 g protein/kg/day 2
• Assess Lille score at day 7 (≥0.45 indicates non-response, stop steroids) 2
• Standard ward-level care typically sufficient 1

For Severe Alcoholic Hepatitis WITH ACLF:

• ICU admission required for close monitoring and organ support 1
• Prednisolone effectiveness diminishes with ACLF 5, 3
• Full organ support (mechanical ventilation, vasopressors, renal replacement therapy as needed) 1
• Early liver transplantation evaluation is critical—this is potentially the most effective therapy 5, 6
• Prognosis reassessment after 3-7 days of full organ support 1
• Consider withdrawal of care if >4 organ failures or CLIF-C ACLF score >70 after 3-7 days in non-transplant candidates 1

Common Pitfalls to Avoid

Do not assume all jaundiced alcoholic patients have "just" alcoholic hepatitis—systematically assess for organ failures, as 47.9% of severe alcoholic hepatitis patients have prevalent ACLF at presentation 3

Do not overlook infection as a trigger—bacterial infection is the strongest independent predictor of developing incident ACLF during hospitalization (relative risk 41.87) 3

Do not delay ICU transfer in ACLF patients—outcomes are similar to non-cirrhotic ICU patients when baseline characteristics are matched, and early organ support improves survival 1

Do not use traditional alcoholic hepatitis scores alone in ACLF—mDF and MELD underestimate mortality when ACLF is present; use CLIF-C ACLF score (incorporates age, white cell count, and CLIF-C organ failure score) 1, 3

Recognize that 17.5% of patients with initially isolated severe alcoholic hepatitis will develop incident ACLF during follow-up, almost always preceded by infection 3