What is the role of plasma exchange in the management of Acute-on-Chronic Liver Failure (ACLF)?

Plasma Exchange in Acute-on-Chronic Liver Failure

Primary Recommendation

Plasma exchange should NOT be used routinely in ACLF outside of research protocols, but may be considered in highly selected critically ill patients as a bridge to transplantation when standard therapies fail. 1

Guideline-Based Framework

Current Guideline Positions

The major hepatology societies have divergent positions on plasma exchange for ACLF:

• EASL (European) explicitly recommends against routine use of plasma exchange for ACLF outside research trials, except in highly selected critically ill patients as a bridge to transplantation when standard therapies fail 1

• AASLD (American) suggests plasma exchange only for acute liver failure (ALF) with hyperammonemia (ammonia >150 μmol/L), NOT for ACLF, with a conditional recommendation based on low-quality evidence 2, 1

• APASL and Chinese guidelines support plasma exchange as a promising treatment for ACLF patients awaiting liver transplants or experiencing spontaneous regeneration 1

• American College of Critical Care Medicine provides a conditional recommendation (low quality evidence) for plasma exchange in critically ill ALF patients with hyperammonemia, but this does not extend to ACLF 3

Critical Distinction: ALF vs ACLF

The key distinction is that plasma exchange has stronger evidence and guideline support for acute liver failure (ALF), not acute-on-chronic liver failure (ACLF). 2, 1 This is because:

• ALF patients with hyperammonemia (>150 μmol/L) are more vulnerable to cerebral edema and intracranial hypertension, where plasma exchange may provide benefit 2
• ACLF patients have different pathophysiology with chronic liver disease as the substrate 1

Evidence Base Analysis

Research Evidence Shows Potential Benefit

Despite guideline caution, emerging research suggests survival benefit:

• A 2025 meta-analysis of 23 studies (5,336 ACLF patients) showed plasma exchange associated with significant mortality reduction at 30 days (RR 0.70; 95% CI 0.60-0.81), 90 days (RR 0.81; 95% CI 0.77-0.86), and 1 year (RR 0.85; 95% CI 0.79-0.92) 4

• A 2024 systematic review of 20 studies (5,705 ACLF patients) demonstrated plasma exchange associated with higher 30-day survival (RR 1.36; 95% CI 1.22-1.52) and 90-day survival (RR 1.21; 95% CI 1.10-1.34) 5

• A 2021 propensity-matched study from the AARC database (208 patients) showed plasma exchange associated with higher resolution of SIRS (OR 9.23; 95% CI 3.42-24.8), lower development of multiorgan failure (HR 7.1; 95% CI 4.5-11.1), and lower liver-failure-related deaths 6

Critical Limitation of Research Evidence

However, when analyzing only randomized controlled trials in the subgroup analysis, no survival differences were found between plasma exchange and standard medical therapy in ACLF. 5 This explains why guidelines remain cautious despite observational data showing benefit.

Mechanism of Action in ACLF

Plasma exchange appears to work by:

• Clearing inflammatory cytokines, damage-associated molecular patterns, and endotoxin 6
• Improving monocyte phagocytic function and mitochondrial respiration in responders 6
• Increasing anti-inflammatory cytokine IL-1RA 6
• Attenuating systemic inflammatory response syndrome (SIRS) and reducing SOFA scores 6

Clinical Algorithm for Decision-Making

When to Consider Plasma Exchange in ACLF

Consider plasma exchange ONLY if ALL of the following criteria are met:

1. Patient is listed for liver transplantation and awaiting organ availability 1
2. Deteriorating despite standard medical therapy (treatment of precipitating factors, organ support) 1
3. Center has plasma exchange expertise and resources available 3, 1
4. Ideally enrolled in a research protocol given the conditional nature of evidence 1

When NOT to Use Plasma Exchange

Do NOT use plasma exchange routinely for:

• ACLF patients not being considered for transplantation 1
• ACLF patients responding to standard medical therapy 1
• Centers without plasma exchange expertise 3
• As first-line therapy before optimizing standard management 1

Etiology-Specific Considerations

HBV-Related ACLF

• Meta-analysis showed significant mortality reduction at 90 days (RR 0.79; 95% CI 0.74-0.85) with plasma exchange 4

Alcohol-Related ACLF

• Meta-analysis showed significant mortality reduction at 90 days (RR 0.69; 95% CI 0.52-0.92) with plasma exchange 4

Priority Management Before Considering Plasma Exchange

Standard ACLF management must be optimized first: 1

• Early identification and treatment of precipitating factors (especially bacterial infections) 1
• Organ support (renal replacement therapy, mechanical ventilation, vasopressors as needed) 1
• Evaluation for liver transplantation eligibility 1

Safety Profile

• Most common adverse effects are skin rash and allergic reactions (14% incidence) 4
• Plasma exchange had fewer adverse effects compared to Fractional Plasma Separation and Adsorption (FPSA) 6

Common Pitfalls

• Confusing ALF with ACLF: Plasma exchange has stronger evidence for ALF with hyperammonemia, not ACLF 2, 1
• Using plasma exchange as first-line therapy: Standard management must be optimized first 1
• Ignoring resource limitations: The conditional recommendation means clinical circumstances and resource availability should heavily influence decisions 2
• Relying on observational data: RCT subgroup analysis showed no benefit, explaining guideline caution 5