What are the recent advances in the treatment of hepatic encephalopathy?

Recent Advances in Treatment of Hepatic Encephalopathy

Rifaximin added to lactulose is the best-documented agent to maintain remission in patients who have already experienced one or more bouts of overt hepatic encephalopathy (OHE) while on lactulose treatment. 1

First-Line Treatment Options

• Lactulose remains the first choice for treatment of episodic OHE, with initial dosing of 25 mL of lactulose syrup every 12 hours, titrated to achieve 2-3 soft bowel movements per day 1, 2
• Lactulose works through acidification of the gastrointestinal tract, which inhibits production of ammonia by coliform bacteria 3
• Clinical response to lactulose is observed in approximately 75% of patients, which is at least as satisfactory as that resulting from neomycin therapy 4
• Overuse of lactulose can lead to complications such as aspiration, dehydration, hypernatremia, severe perianal skin irritation, and paradoxically can even precipitate HE 1, 2

Add-On Therapy for Prevention of Recurrence

• Rifaximin (550 mg twice daily) is an effective add-on therapy to lactulose for prevention of OHE recurrence with Grade I, A, 1 recommendation 1
• Rifaximin decreases intestinal production and absorption of ammonia by altering gastrointestinal flora and is almost completely excreted unchanged in the feces 3
• In the trials of rifaximin for HE, 91% of the patients were using lactulose concomitantly, and differences in treatment effect for patients not using lactulose could not be assessed 5
• Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of patients in controlled trials had MELD scores over 19 5

Alternative and Emerging Therapies

• Oral Branched-Chain Amino Acids (BCAAs) can be used as an alternative or additional agent for patients not responding to conventional therapy (Grade I, B, 2) 1, 2
• IV L-Ornithine L-Aspartate (LOLA) can be used as an alternative or additional agent for patients nonresponsive to conventional therapy (Grade I, B, 2), with demonstrated improvement in psychometric testing and postprandial venous ammonia levels 1
• Metabolic ammonia scavengers like glyceryl phenylbutyrate (GPB) have shown promise in reducing episodes of HE and hospitalizations in recent clinical trials 1
• Probiotics have shown efficacy similar to lactulose in preventing episodes of HE in patients who recovered from HE, though there was no difference in rates of readmission 1

Special Considerations

• Neomycin and metronidazole are alternative choices for treatment of OHE, but long-term use is limited by ototoxicity, nephrotoxicity, and neurotoxicity 1, 2
• Neither rifaximin nor lactulose has been shown to prevent post-TIPS HE better than placebo, and careful case selection has reduced the incidence of severe HE post-TIPS 1
• For patients with recurrent bouts of overt HE and preserved liver function, evaluation for large spontaneous portosystemic shunts should be considered, as certain types can be successfully embolized 1
• Identifying and treating precipitating factors is crucial, as nearly 90% of patients can be treated by correcting the precipitating factor alone 2, 6

Management Algorithm

1. Identify and treat precipitating factors (infections, GI bleeding, electrolyte disturbances, medication non-compliance) 1, 2
2. Initiate lactulose therapy with 25 mL every 12 hours, titrated to achieve 2-3 soft bowel movements daily 1, 4
3. For patients with recurrent episodes of OHE despite lactulose therapy, add rifaximin 550 mg twice daily 1, 5
4. For patients not responding to conventional therapy, consider:
   • Oral BCAAs as an alternative or additional agent 1, 2
   • IV LOLA (note that oral supplementation is ineffective) 1
   • Neomycin or metronidazole as short-term therapy only 1
5. For patients with preserved liver function and recurrent HE, evaluate for large spontaneous portosystemic shunts that may be amenable to embolization 1

Pitfalls to Avoid

• Overusing lactulose, which can paradoxically precipitate HE and cause complications like aspiration and dehydration 1, 2
• Using neomycin or metronidazole for long-term therapy due to toxicity concerns 1
• Failing to identify and treat precipitating factors, which is essential for successful management 2, 6
• Using oral LOLA, which is ineffective, instead of the IV formulation 1