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

Recent Advances in Management of Hepatic Encephalopathy

Rifaximin added to lactulose represents the most significant recent advance in hepatic encephalopathy management, reducing recurrence risk by 58% and improving both hospitalization rates and mortality outcomes. 1, 2, 3

Core Treatment Algorithm

First-Line Therapy: Lactulose

• Lactulose remains the first-choice treatment for episodic overt hepatic encephalopathy (OHE), achieving clinical response in approximately 75% of patients and reducing blood ammonia levels by 25-50%. 1, 4
• Initiate at 25-30 mL (20-30g) every 1-2 hours until achieving at least 2 soft bowel movements daily, then titrate to maintain 2-3 bowel movements per day 2, 3
• For severe HE (West-Haven grade 3 or higher), administer lactulose enema (300 mL lactulose + 700 mL water) 3-4 times daily until clinical improvement 2
• In patients unable to take oral medications, administer via nasogastric tube 2, 3

Critical Pitfall: Overuse of lactulose can cause aspiration, dehydration, hypernatremia, and severe perianal skin irritation—avoid excessive dosing beyond achieving target bowel movements 2, 3

Second-Line/Add-On Therapy: Rifaximin

• Rifaximin should be added to lactulose (not used as monotherapy) after the second episode of HE or when lactulose alone fails to prevent recurrence. 1, 2, 5
• Standard dosing: 550 mg twice daily 1, 2, 5
• The combination of rifaximin plus lactulose improves recovery from HE within 10 days (76% vs 44% with lactulose alone) and shortens hospital stays (5.8 vs 8.2 days) 2
• In the pivotal trials, 91% of patients were using lactulose concomitantly—there are no solid data supporting rifaximin monotherapy. 1, 5

Prevention Strategy

• After the first episode of OHE, maintain lactulose for secondary prophylaxis to prevent recurrence. 1, 3
• After the second episode of OHE, add rifaximin 550 mg twice daily to ongoing lactulose therapy. 1, 2, 3
• This dual therapy approach reduces HE recurrence, hospitalizations, and mortality rates 2, 3, 6

Alternative and Emerging Therapies

For Lactulose-Refractory Cases

• IV L-ornithine L-aspartate (LOLA) can be used as an alternative or additional agent for patients nonresponsive to conventional therapy (oral LOLA is ineffective) 1
• Oral branched-chain amino acids (BCAAs) improve manifestations of episodic HE and can be used as alternative or additional therapy (IV BCAAs are ineffective for acute episodes) 1

Less Preferred Alternatives

• Neomycin is an alternative choice for OHE but carries risks of ototoxicity, nephrotoxicity, and neurotoxicity with long-term use 1, 7
• Metronidazole can be used short-term but is unattractive for continuous therapy due to ototoxicity, nephrotoxicity, and neurotoxicity 1

Investigational Agents Showing Promise

• Glyceryl phenylbutyrate (GPB), a metabolic ammonia scavenger, demonstrated fewer HE episodes, fewer hospitalizations, and longer time to first event in patients with recurrent HE on standard therapy (lactulose ± rifaximin). 1
• Ornithine phenylacetate is under investigation but awaits further clinical reports 1, 6

Probiotics

• Probiotics showed similar efficacy to lactulose in reducing HE episodes in one open-label study, but no difference in readmission rates—insufficient evidence for routine recommendation 1

Special Clinical Scenarios

Post-TIPS Hepatic Encephalopathy

• Neither rifaximin nor lactulose prevents post-TIPS HE better than placebo—routine prophylactic therapy is not recommended. 1, 2
• If severe HE develops post-TIPS, shunt diameter reduction can reverse HE 1
• Careful case selection and avoiding portal pressure reduction below 12 mmHg reduces post-TIPS HE incidence 1

Spontaneous Portosystemic Shunts

• In patients with recurrent OHE and preserved liver function, search for large spontaneous portosystemic shunts (especially splenorenal shunts) that may be amenable to embolization 1, 3

Albumin Therapy

• Daily IV albumin in OHE patients on rifaximin showed no effect on HE resolution but was associated with better postdischarge survival 1

Essential Management Principles

Four-Pronged Approach

1. Initiate appropriate supportive care with intensive monitoring for higher-grade HE patients who cannot protect their airway 3
2. Identify and treat alternative causes of altered mental status that may coexist with HE 3
3. Identify and correct precipitating factors (infection, GI bleeding, medications, electrolyte disturbances)—this resolves HE in nearly 90% of patients 1, 3
4. Commence empirical HE treatment without delay 3

Nutritional Considerations

• Avoid protein restriction—it worsens malnutrition and sarcopenia, which are risk factors for HE 3
• Encourage small meals distributed throughout the day with a late-night snack 3
• Avoid prolonged fasting periods which can worsen HE 3

Transplant Evaluation

• Consider liver transplantation in patients with recurrent intractable HE and liver failure 3
• Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of trial patients had MELD scores over 19—there is increased systemic exposure in more severe hepatic dysfunction 5