What is the role of glycerol phenylbutyrate in the treatment of hepatic encephalopathy?

Glycerol Phenylbutyrate in Hepatic Encephalopathy

Glycerol phenylbutyrate should NOT be routinely used for hepatic encephalopathy in critically ill patients, but may be considered as an investigational add-on therapy in select patients with recurrent hepatic encephalopathy despite optimal standard treatment with lactulose and rifaximin. 1

Guideline Recommendations

Critical Care Setting (ACLF Patients)

• The 2023 Critical Care Medicine guidelines explicitly recommend AGAINST routine use of glycerol phenylbutyrate (GPB) in critically ill acute-on-chronic liver failure (ACLF) patients with overt hepatic encephalopathy (conditional recommendation, very low quality of evidence). 1
• This negative recommendation applies to IV flumazenil, probiotics, zinc supplementation, and acarbose as well. 1
• There is insufficient evidence to issue any recommendation for GPB in acute liver failure (ALF) patients with hyperammonemia. 1

Chronic Liver Disease Setting

• The 2014 AASLD/EASL guidelines describe GPB as a "promising investigational agent" but do not provide a formal recommendation for its routine clinical use. 1
• GPB was tested in patients who had experienced two or more episodes of hepatic encephalopathy in the last 6 months while maintained on standard therapy (lactulose ± rifaximin). 1
• The guidelines state that "more clinical studies on the same principle are under way and, if confirmed, may lead to clinical recommendations." 1

Mechanism and Clinical Evidence

How GPB Works

• GPB functions as a metabolic ammonia scavenger that provides an alternate pathway to urea for waste nitrogen excretion. 2, 3
• Upon oral administration, pancreatic lipases hydrolyze GPB to release phenylbutyric acid (PBA), which undergoes β-oxidation to phenylacetic acid (PAA). 4, 3
• PAA conjugates with glutamine to form phenylacetylglutamine (PAGN), which is excreted in urine, effectively removing nitrogen without requiring a functional urea cycle. 2, 4, 3

Clinical Trial Data

• The pivotal 2014 randomized controlled trial (n=178) showed that GPB 6 mL orally twice daily significantly reduced hepatic encephalopathy events (21% vs 36%; P=0.02) compared to placebo. 3
• GPB reduced time to first event (HR=0.56; P<0.05), total events (35 vs 57; P=0.04), and hepatic encephalopathy hospitalizations (13 vs 25; P=0.06). 3
• Among patients NOT on rifaximin at enrollment, the benefit was even more pronounced: 10% vs 32% event rate (P<0.01), with HR=0.29 for time to first event. 3
• Plasma ammonia was significantly lower in GPB-treated patients and correlated with hepatic encephalopathy events. 3
• The safety profile was similar to placebo (79% vs 76% adverse events). 3

Current Treatment Algorithm

First-Line Therapy

1. Lactulose remains the first choice for treatment of overt hepatic encephalopathy (GRADE II-1, B, 1). 1, 2
   • Dose: 25 mL every 12 hours initially, titrated to 2-3 soft bowel movements per day. 1

Second-Line Therapy

1. Rifaximin 550 mg twice daily is the only FDA-approved add-on therapy for prevention of hepatic encephalopathy recurrence, used in combination with lactulose (GRADE I, A, 1). 1, 2
   • No solid data support the use of rifaximin alone. 1

Third-Line Considerations

1. Intravenous L-ornithine L-aspartate (LOLA) can be considered as an alternative or additional agent for patients nonresponsive to lactulose and rifaximin (GRADE I, B, 2). 1, 5
   • Dose: 30 g/day intravenously. 5
   • Oral LOLA is ineffective. 1, 5

Investigational Status of GPB

1. GPB occupies an investigational position for patients with recurrent hepatic encephalopathy (≥2 episodes in 6 months) despite optimal standard therapy. 1, 2
   • This is NOT a guideline-endorsed routine therapy but may be considered in research settings or compassionate use scenarios. 1

Critical Caveats and Pitfalls

Dosing Considerations

• The studied dose is 6 mL (6.6 g) orally twice daily; higher doses (9 mL twice daily) were associated with more adverse events and higher PAA plasma concentrations without additional benefit. 6
• GPB exhibits delayed-release characteristics with peak metabolite levels occurring later than immediate-release formulations. 4, 7

Population-Specific Concerns

• In critically ill ACLF patients, the evidence quality is very low, and the 2023 guidelines recommend against routine use. 1
• The pivotal trial enrolled patients with cirrhosis who had experienced recurrent events, not acutely decompensated or critically ill patients. 3
• 59 of 178 patients in the trial were already taking rifaximin, suggesting GPB was tested as a third-line agent. 3

Metabolic Monitoring

• Saturation of PAA conjugation with glutamine can occur, particularly with increasing doses and in patients with severe hepatic impairment. 4
• The ratio of plasma PAA to PAGN increases with dose escalation and hepatic dysfunction severity. 4
• Approximately 69% of administered PBA is excreted as PAGN in adults with urea cycle disorders; similar conversion occurs in cirrhotic patients. 4, 7

Safety Profile

• GPB has not been studied in patients with impaired renal function, end-stage renal disease, or those on hemodialysis. 4
• The drug is generally well-tolerated with adverse event rates similar to placebo in clinical trials. 3, 7
• No QTc prolongation concerns (upper bound of 95% CI <10 ms). 4

Divergent Evidence

There is a notable discrepancy between the 2014 AASLD/EASL guidelines and the 2023 Critical Care Medicine guidelines:

• The 2014 guidelines describe GPB as "promising" with potential for future recommendations pending additional studies. 1
• The 2023 guidelines explicitly recommend AGAINST routine use in critically ill ACLF patients due to very low quality evidence. 1

This divergence reflects the difference between chronic outpatient management of recurrent hepatic encephalopathy versus acute critical care management, as well as the lack of high-quality evidence in critically ill populations. 1