Acute-on-Chronic Liver Failure in the ICU: A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath , claude.ai

Abstract

Background: Acute-on-chronic liver failure (ACLF) represents a distinct clinical syndrome characterized by acute deterioration of liver function in patients with pre-existing chronic liver disease, leading to multi-organ failure and high short-term mortality. The management of ACLF in the intensive care unit (ICU) requires a multidisciplinary approach addressing complex pathophysiology involving sepsis, coagulopathy, acute kidney injury, and potential transplant considerations.

Objective: To provide a comprehensive review of ACLF management in the ICU, focusing on sepsis control, coagulopathy management, renal replacement therapy, and transplant bridging strategies.

Methods: Literature review of current evidence-based practices, international guidelines, and expert consensus statements on ACLF management.

Conclusions: Early recognition, aggressive supportive care, infection prevention and treatment, careful fluid and hemodynamic management, and timely transplant evaluation are crucial for improving outcomes in ACLF patients.

Keywords: Acute-on-chronic liver failure, critical care, sepsis, coagulopathy, renal replacement therapy, liver transplantation

Introduction

Acute-on-chronic liver failure (ACLF) represents one of the most challenging scenarios in hepatology and critical care medicine. Unlike acute liver failure in previously healthy individuals or stable chronic liver disease, ACLF presents as a unique syndrome with distinct pathophysiology, clinical course, and management requirements.¹ The syndrome is characterized by acute deterioration of liver function in patients with pre-existing chronic liver disease, resulting in liver failure and extrahepatic organ failures within a short timeframe, typically associated with high 28-day mortality rates ranging from 30-90% depending on the number of organ failures.²

The Asian Pacific Association for the Study of the Liver (APASL) defines ACLF as "an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease."³ The European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) consortium provides a more organ-failure centered definition, emphasizing the presence of acute decompensation with organ failures.⁴

Pathophysiology and Clinical Pearls

The Inflammatory Storm

ACLF is fundamentally driven by an excessive systemic inflammatory response, often termed "cytokine storm," which leads to organ dysfunction beyond the liver.⁵ This inflammatory cascade involves:

Bacterial translocation from compromised gut barrier
Damage-associated molecular patterns (DAMPs) release
Complement activation and neutrophil dysfunction
Endothelial dysfunction leading to capillary leak

Clinical Pearl 🔍: The degree of systemic inflammation, measured by C-reactive protein, procalcitonin, and white cell count, often correlates better with prognosis than traditional liver function tests alone.

Precipitating Factors

Common precipitants include:

Bacterial infections (40-60% of cases)
Alcohol consumption in chronic alcoholic liver disease
Viral hepatitis reactivation (HBV, HCV, HEV)
Drug-induced liver injury
Portal vein thrombosis
Surgical procedures

Oyster Alert ⚠️: Up to 40% of ACLF cases have no identifiable precipitant, making prevention challenging but not impossible through optimal management of underlying chronic liver disease.

Sepsis Management in ACLF

Early Recognition and Source Control

Sepsis in ACLF patients presents unique challenges due to altered immune responses and atypical presentations. The compromised reticuloendothelial system and portal hypertension create a perfect storm for bacterial translocation and systemic infection.

Clinical Hack 💡: Use a modified sepsis screening approach:

Lower the threshold for blood culture collection (every 48-72 hours if clinically indicated)
Bronchial lavage early in ventilated patients
Ascitic fluid analysis with absolute neutrophil count >250 cells/μL indicating spontaneous bacterial peritonitis (SBP)

Antibiotic Stewardship

First-line empirical therapy:

Community-acquired infections: Third-generation cephalosporins (ceftriaxone 2g daily) or fluoroquinolones
Healthcare-associated infections: Piperacillin-tazobactam 4.5g TDS or meropenem 1g TDS
SBP treatment: Ceftriaxone 2g daily for 5-7 days

Pearl for Educators 📚: The concept of "antibiotic resistance in liver disease" - These patients have higher rates of extended-spectrum beta-lactamase (ESBL) producing organisms due to frequent healthcare contact and antibiotic exposure.

Hemodynamic Management

ACLF patients exhibit a hyperdynamic circulation with:

High cardiac output, low systemic vascular resistance
Relative adrenal insufficiency (consider hydrocortisone 200mg daily)
Vasopressor requirements: Norepinephrine remains first-line, but terlipressin may be considered for hepatorenal syndrome

Advanced Hack 🎯: Use transpulmonary thermodilution (PiCCO) or pulmonary artery catheter for hemodynamic monitoring in complex cases - these patients often have high cardiac output with low afterload, making clinical assessment unreliable.

Coagulopathy Management: Beyond INR

Understanding the "Rebalanced Hemostasis"

ACLF patients exhibit a complex coagulopathy that differs from classic bleeding disorders:

Decreased procoagulant factors (II, V, VII, IX, X, XI)
Decreased anticoagulant factors (protein C, S, antithrombin III)
Increased factor VIII and von Willebrand factor
Thrombocytopenia with enhanced platelet function

Oyster Moment ⚠️: INR in liver disease doesn't predict bleeding risk as accurately as in anticoagulated patients. Many ACLF patients maintain hemostatic balance despite prolonged INR.

Evidence-Based Coagulopathy Management

Bleeding Prevention Strategy:

Platelet transfusion: Only if count <50,000/μL AND active bleeding or before procedures
Fresh frozen plasma (FFP): Limited benefit; consider only for massive bleeding (>15ml/kg may cause volume overload)
Cryoprecipitate: If fibrinogen <100mg/dL with active bleeding
Prothrombin complex concentrate (PCC): Emerging evidence for urgent reversal before high-risk procedures

Clinical Pearl 🔍: Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) provide better assessment of global hemostatic function than conventional coagulation tests.

Thromboprophylaxis Paradox

The Teaching Point: Despite prolonged INR, ACLF patients remain at risk for thrombosis due to:

Portal vein thrombosis (up to 25% of cases)
Pulmonary embolism from prolonged immobilization
Central line-associated thrombosis

Evidence-based approach:

Use mechanical prophylaxis universally
Consider pharmacological prophylaxis (enoxaparin 40mg daily) if platelet count >50,000/μL and no active bleeding
Monitor with anti-Xa levels in renal impairment

Renal Support in ACLF

Hepatorenal Syndrome (HRS) vs. Acute Tubular Necrosis (ATN)

Distinguishing HRS from ATN is crucial but challenging:

**HRS Criteria (ICA-AKI):**⁶

Serum creatinine >1.5mg/dL or 50% increase from baseline
No improvement after volume expansion
Absence of shock, nephrotoxins, or structural kidney disease
Urine sodium <20mEq/L, FENa <1%

Clinical Hack 💡: The "volume challenge test" - Give 1g/kg albumin (max 100g) over 2 days. Lack of response suggests HRS rather than prerenal azotemia.

Medical Management of HRS

First-line therapy:

Terlipressin: 1-2mg IV every 4-6 hours (increase by 1-2mg every 3 days if no response)
Albumin: 1g/kg on day 1, then 20-40g daily
Target: 25% reduction in creatinine by day 3

Alternative regimens:

Octreotide 100μg TDS + midodrine 7.5mg TDS + albumin (if terlipressin unavailable)
Norepinephrine infusion + albumin (in ICU setting)

Renal Replacement Therapy (RRT) Considerations

Indications for RRT in ACLF:

Volume overload unresponsive to diuretics
Severe metabolic acidosis (pH <7.25)
Hyperkalemia >6.5mEq/L
Uremic complications
Bridge to transplant evaluation

Technical Pearls:

Continuous RRT preferred due to hemodynamic instability
Citrate anticoagulation when possible (monitor for citrate accumulation in liver failure)
Phosphate replacement essential (increased losses with CRRT)

Educator's Insight 📚: The "futility question" - RRT in ACLF should be viewed as organ support rather than cure. Clear goals of care discussions are essential.

Transplant Evaluation and Bridging

Timing of Transplant Evaluation

Early evaluation criteria:

MELD score >20 with acute decompensation
ACLF Grade 2 or 3 (EASL-CLIF criteria)
Persistent organ failures despite 48-72 hours of optimal medical therapy

Absolute contraindications:

Active uncontrolled sepsis
Severe cardiopulmonary disease
Active malignancy (except hepatocellular carcinoma within criteria)
Severe psychiatric illness
Active substance use

Bridging Strategies

Artificial Liver Support:

Molecular Adsorbent Recirculating System (MARS)
- Removes protein-bound toxins
- Limited evidence for survival benefit
- May bridge patients to recovery or transplant
Plasmapheresis
- Removes inflammatory mediators
- Temporary improvement in coagulopathy
- Consider in fulminant presentations

Clinical Reality Check 🎯: Most artificial liver support systems show biochemical improvement but limited survival benefit. Use judiciously in transplant candidates.

Psychosocial Considerations

The 6-month rule controversy: Many centers require 6 months of sobriety for alcohol-related ACLF, but emerging evidence suggests:

Early transplant may be appropriate in carefully selected patients
Psychosocial evaluation more important than arbitrary time periods
Multidisciplinary team approach essential

ICU-Specific Management Pearls

Mechanical Ventilation Considerations

Lung-protective strategies with modifications:

Tidal volume: 6ml/kg ideal body weight (account for ascites affecting chest wall compliance)
PEEP strategy: Higher PEEP may be needed due to increased intra-abdominal pressure
Prone positioning: Consider early in ARDS, but monitor for increased intracranial pressure

Nutrition and Metabolic Support

Protein requirements: 1.2-1.5g/kg/day (contrary to old belief of protein restriction)

Branched-chain amino acids may improve encephalopathy
Enteral nutrition preferred when possible
Monitor ammonia levels but don't restrict protein based solely on elevated levels

Encephalopathy Management

Grading and monitoring:

Use West Haven criteria for grading
Consider continuous EEG monitoring for subclinical seizures
Lactulose: 15-30ml QID, titrate to 2-3 soft stools/day
Rifaximin: 550mg BID as adjunctive therapy

Advanced Pearl 🔍: L-ornithine L-aspartate (LOLA) 20g daily IV may be superior to lactulose in acute settings, though availability varies by region.

Monitoring and Prognostication

Dynamic Scoring Systems

CLIF-C ACLF Score: More accurate than static scores

Incorporates age, white cell count, creatinine, INR, bilirubin, sodium
Provides 28-day, 90-day, and 1-year mortality predictions
Should be calculated serially, not just on admission

The Delta-MELD Concept: Rate of MELD score change over first 48-72 hours may be more predictive than absolute values.

Biomarkers for Prognosis

Emerging biomarkers:

Procalcitonin: Better than traditional inflammatory markers
Lactate clearance: Predictor of organ recovery
Ammonia: Correlates with encephalopathy grade
Alpha-fetoprotein: Marker of hepatocyte regeneration

Quality Improvement and System-Based Practice

ICU Bundles for ACLF

The ACLF Bundle:

Infection surveillance within 6 hours
Fluid resuscitation with albumin when appropriate
Early nutrition within 24 hours
Transplant evaluation within 48 hours if appropriate
Daily assessment of extrahepatic organ function

Multidisciplinary Team Approach

Essential team members:

Hepatologist/Gastroenterologist
Critical care physician
Transplant surgeon (when appropriate)
Clinical pharmacist
Dietitian
Social worker
Palliative care (for end-stage cases)

Future Directions and Research

Emerging Therapies

Regenerative medicine:

Mesenchymal stem cell therapy (clinical trials ongoing)
Hepatocyte transplantation
Tissue engineering approaches

Targeted anti-inflammatory therapy:

Anti-TNF agents (limited evidence)
Complement inhibitors
Granulocyte colony-stimulating factor (G-CSF)

Artificial Intelligence and Precision Medicine

Machine learning applications:

Predictive models for transplant urgency
Personalized treatment protocols
Real-time risk stratification

Conclusion

ACLF represents a complex syndrome requiring sophisticated critical care management. Success depends on early recognition, aggressive treatment of precipitating factors (especially sepsis), careful fluid and hemodynamic management, appropriate use of renal replacement therapy, and timely transplant evaluation when appropriate. The key to improving outcomes lies in understanding the unique pathophysiology of ACLF, which differs significantly from both acute liver failure and stable chronic liver disease.

Critical care physicians must maintain a high index of suspicion for sepsis, use coagulation management strategies specific to liver disease, and recognize that standard ICU mortality prediction scores may not apply to this population. The decision-making process should involve multidisciplinary teams and clear communication with patients and families about prognosis and goals of care.

As our understanding of ACLF pathophysiology evolves, novel therapeutic targets continue to emerge. However, the foundation of care remains excellent supportive therapy, infection prevention and treatment, and timely consideration of liver transplantation.

Key Teaching Points for Trainees

The Five Pillars of ACLF Management:

Identify and treat precipitants (especially infections)
Support failing organs (renal, respiratory, circulatory)
Prevent complications (bleeding, encephalopathy, further infections)
Consider transplant candidacy early
Communicate prognosis honestly with patients and families

The ACLF Mantra: "Time is hepatocyte" - Early recognition and aggressive management in the first 48-72 hours can dramatically alter outcomes.

References

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Conflict of Interest Statement: The authors declare no conflicts of interest related to this work.

Funding: This review received no specific funding from any commercial, public, or not-for-profit organization.

Wednesday, September 17, 2025