What is the evidence supporting plasma exchange (PE) as an adjunctive therapy in adult acute liver failure (ALF)?

Plasma Exchange in Acute Liver Failure

Direct Recommendation

Plasma exchange should be used in adult acute liver failure patients with hyperammonemia (ammonia >150 μmol/L) as adjunctive therapy to bridge to transplantation or support spontaneous recovery, with the strongest evidence supporting its use in Wilson disease-related ALF where it should be initiated immediately. 1

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Evidence-Based Framework

Primary Indication: Hyperammonemia in ALF

• The American College of Critical Care Medicine recommends plasma exchange for ALF patients with ammonia levels >150 μmol/L, though this is a conditional recommendation based on low-quality evidence. 1

• Hyperammonemia independently predicts intracranial hypertension and hepatic encephalopathy in ALF, with 55% of patients developing intracranial hypertension when ammonia exceeds 200 μmol/L. 1

• ALF patients are particularly vulnerable to cerebral edema and intracranial hypertension due to hyperammonemia, unlike those with acute-on-chronic liver failure. 1

Specific Etiologies Requiring Immediate Plasma Exchange

• Wilson disease-related ALF requires immediate plasma exchange initiation as a bridge to transplantation, as this presentation is uniformly fatal without transplant. 1

• Plasma exchange should be considered in acute fatty liver of pregnancy, though expeditious delivery remains the primary treatment. 1

Survival Benefit Evidence

• A 2024 meta-analysis of 343 ALF patients demonstrated that plasma exchange significantly improved 30-day survival (RR 1.41,95% CI 1.06-1.87, p=0.02) and overall survival (RR 1.35,95% CI 1.12-1.63, p=0.002) compared to standard medical therapy. 2

• A 2025 real-world Mexican study showed 92% survival at 30 days in the plasma exchange group versus 50% in standard medical treatment alone (p=0.02), with the greatest benefit in Grade 4 encephalopathy patients. 3

• High-volume plasma exchange (8-12 L per procedure) improved transplant-free survival in a 2016 multicenter RCT of 182 ALF patients (HR 0.56, p=0.0083). 1

Contradictory Evidence

However, a 2025 UK multicentre study of 378 ALF patients found no survival benefit from plasma exchange in real-world practice (overall survival 51.4% vs 62.6% for standard therapy, p=0.12), despite improvements in hemodynamic parameters. 4 This represents the most recent high-quality evidence but conflicts with earlier trials, possibly reflecting selection bias or differences in patient populations and timing of intervention.

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Clinical Algorithm for ALF

Step 1: Confirm ALF Diagnosis

• Absence of known chronic liver disease with liver-based coagulopathy (INR ≥1.5) and hepatic encephalopathy. 5

Step 2: Measure Ammonia Level

• If ammonia >150 μmol/L: Initiate plasma exchange as adjunctive therapy. 1
• If Wilson disease suspected or confirmed: Initiate plasma exchange immediately regardless of ammonia level. 1

Step 3: Simultaneous Actions

• List for liver transplantation in appropriate candidates, as plasma exchange is a bridge therapy, not definitive treatment. 1
• Provide standard supportive care including management of coagulopathy, hemodynamic support, and treatment of precipitating factors. 1

Step 4: Consider High-Volume Plasma Exchange

• For patients with high severity scores (CLIF-C ACLF ≥13) or Grade 4 encephalopathy, high-volume plasma exchange (8-12 L per procedure) may provide additional benefit. 6, 3

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Important Caveats

Resource and Expertise Requirements

• The conditional nature of guideline recommendations means clinical circumstances and resource availability should influence decisions. 1
• Plasma exchange requires access to experienced operators at centers with expertise. 7

What NOT to Use

• Traditional therapies for chronic liver failure, such as lactulose and rifaximin, have not demonstrated benefit in acute liver failure and should not be relied upon. 1

Mechanism of Benefit

• Plasma exchange removes inflammatory cytokines, damage-associated molecular patterns, and endotoxin while improving coagulopathy, total bilirubin, transaminases, and ammonia levels. 8, 6

Distinction from ACLF

This recommendation applies specifically to acute liver failure, NOT acute-on-chronic liver failure. The European Association for the Study of the Liver explicitly recommends against routine plasma exchange for ACLF outside research trials. 7, 9 The American Association for the Study of Liver Diseases suggests plasma exchange only for ALF with hyperammonemia, not for ACLF. 7, 9