What is Acute-on-Chronic Liver Failure (ACLF) and how is it managed?

Acute-on-Chronic Liver Failure (ACLF): Definition and Management

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by acute decompensation of liver cirrhosis, organ dysfunction, and high short-term mortality (30-40% at 28 days) that requires intensive care management focused on organ support, treating precipitating factors, and early consideration for liver transplantation in eligible patients. 1

Definition of ACLF

ACLF is defined by three critical components:

1. Acute onset with rapid clinical deterioration
2. Liver failure (elevated bilirubin and INR) in patients with chronic liver disease with or without cirrhosis
3. At least one extrahepatic organ failure (neurologic, circulatory, respiratory, or renal) 1

Different regional definitions exist:

• APASL (Asian Pacific): Focuses on early disease stage with acute hepatic insult in chronic liver disease
• EASL-CLIF (European): Grades ACLF from 1-3 based on number of organ failures
• NACSELD (North American): Includes patients with ≥2 extrahepatic organ failures 1, 2

Pathophysiology

ACLF is characterized by:

• Uncontrolled systemic inflammation with elevated inflammatory markers (C-reactive protein, white blood cells)
• Paradoxical immunoparesis leading to increased susceptibility to infections
• Organ failures resulting from tissue hypoperfusion, immune-mediated damage, and mitochondrial dysfunction 3, 4

Common Precipitating Factors

• Alcohol consumption (alcoholic hepatitis)
• Bacterial infections
• Gastrointestinal bleeding
• Viral hepatitis (especially HBV reactivation)
• Surgery
• No identifiable precipitant in approximately 40% of cases 5, 2

Diagnosis and Assessment

1. Identify organ failures:

   • Liver: Elevated bilirubin, INR
   • Kidney: Rising creatinine, oliguria
   • Brain: Hepatic encephalopathy
   • Respiratory: Hypoxemia
   • Circulatory: Hypotension requiring vasopressors
   • Coagulation: Thrombocytopenia, elevated INR 1, 2

2. Prognostic scoring systems:

   • CLIF-C ACLF score: Includes organ failures, age, and WBC count
   • NACSELD ACLF score: Includes advanced extrahepatic organ failures, age, MELD, WBC, and albumin
   • AARC score: Includes bilirubin, INR, lactate, creatinine, and HE grade 1

Management Approach

1. Initial Assessment and Monitoring

• Admit to ICU or intermediate care setting
• Implement continuous pulse oximetry monitoring
• Assess oxygen saturation (SpO2) - do not use vasopressors like terlipressin in patients with hypoxia (SpO2 <90%) 6
• Assess ACLF grade and volume status 1, 2

2. Identify and Treat Precipitating Factors

• Infections: Start broad-spectrum antibiotics within 1 hour of shock onset
• HBV reactivation: Initiate nucleoside analogues (tenofovir, entecavir) immediately
• Alcoholic hepatitis: Consider steroids if appropriate
• Gastrointestinal bleeding: Endoscopic intervention, octreotide/somatostatin, antibiotics 2

3. Organ Support

Neurological (Hepatic Encephalopathy)

• Lactulose (nonabsorbable disaccharide) for overt hepatic encephalopathy
• Rifaximin as adjunctive therapy
• Consider L-ornithine L-aspartate (LOLA) 2

Circulatory Support

• Volume expansion with crystalloids as first option
• Norepinephrine for refractory hypotension
• Avoid terlipressin in patients with hypoxia or ACLF Grade 3 due to risk of serious or fatal respiratory failure 6

Renal Support

• For hepatorenal syndrome:
  • Terlipressin 0.85 mg IV every 6 hours (with albumin) may improve kidney function
  • CAUTION: Monitor for respiratory failure, especially in patients with volume overload or ACLF Grade 3 6
  • Renal replacement therapy for severe acute kidney injury

Respiratory Support

• Continuous pulse oximetry monitoring
• Supplemental oxygen as needed
• Mechanical ventilation for respiratory failure
• CAUTION: Patients with fluid overload are at increased risk of respiratory failure 6

Coagulation Management

• Vitamin K administration
• Fresh frozen plasma only for active bleeding or invasive procedures
• Platelet transfusion for counts <10,000/mm³ or before invasive procedures 2

4. Liver Transplantation Evaluation

• Early referral to transplant centers is critical
• Even patients with multiple organ failures may achieve >80% 1-year survival with transplantation
• CAUTION: Terlipressin-related adverse reactions (respiratory failure, ischemia) may make a patient ineligible for liver transplantation 2, 6

5. Palliative Care Considerations

• Consider withdrawal of intensive care support in patients who:
  • Are not transplant candidates
  • Have ≥4 organ failures after one week of adequate intensive treatment
  • Show 90-100% mortality at 28-90 days 2
• Palliative care consultation should be obtained for all patients with cirrhosis admitted to ICU or diagnosed with ACLF, regardless of transplant listing status 2

Pitfalls and Caveats

1. Respiratory failure risk: Terlipressin may cause serious or fatal respiratory failure, especially in patients with volume overload or ACLF Grade 3. Monitor oxygen saturation continuously and discontinue if SpO2 drops below 90% 6

2. Transplant eligibility: Treatment-related complications may make patients ineligible for liver transplantation. For patients with high MELD scores (≥35), carefully weigh risks and benefits of vasopressor therapy 6

3. Diagnostic confusion: Different regional definitions of ACLF may lead to inconsistent diagnosis and management approaches. Focus on identifying organ failures and providing appropriate support 1

4. Delayed recognition: Early recognition and prompt management of ACLF and its complications improve outcomes. Implement continuous monitoring for early detection of organ dysfunction 1

5. Infection risk: ACLF patients have increased susceptibility to infections due to immunoparesis. Maintain high vigilance for infections and initiate early antimicrobial therapy when indicated 7