What is the preferred treatment for hepatic encephalopathy, lacrulose (lactulose) or rifampin (rifampicin)?

Lactulose is the Preferred First-Line Treatment for Hepatic Encephalopathy

Lactulose is the recommended first-line treatment for hepatic encephalopathy, with rifaximin added only after a second recurrence of overt hepatic encephalopathy (OHE) or when lactulose alone is insufficient. 1, 2

Treatment Algorithm for Hepatic Encephalopathy

First-Line Treatment

• Identify and treat precipitating factors of hepatic encephalopathy as the cornerstone of management 1
• Initiate lactulose therapy at 25 mL every 12 hours, titrating to achieve 2-3 soft bowel movements daily 1, 2
• Lactulose reduces blood ammonia levels by 25-50%, which typically correlates with improved mental status 3
• Lactulose is FDA-approved specifically for the prevention and treatment of portal-systemic encephalopathy 3

Second-Line/Add-on Treatment

• Add rifaximin only after lactulose failure or for prevention of recurrence after a second episode of OHE 1, 2
• Rifaximin should not be used alone as first-line therapy as no solid data support this approach 1, 2
• The typical rifaximin dosage is 400 mg three times daily or 550 mg twice daily 4

Evidence Comparison Between Treatments

Lactulose Efficacy

• Lactulose significantly improves cognitive function and health-related quality of life in patients with minimal hepatic encephalopathy 5
• Recent meta-analyses of 16 RCTs showed non-absorbable disaccharides (lactulose/lactitol) are associated with more frequent resolution of acute or chronic overt HE and reduced mortality 1
• Lactulose has been shown effective as both primary and secondary prophylaxis of HE 5

Rifaximin Efficacy

• Rifaximin has shown beneficial effects on complete resolution of HE and mortality in meta-analyses 1
• A multinational study demonstrated rifaximin's superiority versus placebo for maintaining remission, but 91% of patients were also on lactulose 1
• Rifaximin has been found to be equal or superior to lactulose in some studies, but is typically used as add-on therapy 4

Common Pitfalls to Avoid

• Overuse of lactulose can lead to serious complications including aspiration, dehydration, hypernatremia, severe perianal skin irritation, and can even precipitate HE 1, 2
• Failing to identify and treat precipitating factors (present in up to 90% of cases) can lead to poor outcomes 1
• Using rifaximin alone without lactulose is not supported by solid evidence 1, 2
• Not considering rifaximin add-on therapy after multiple recurrences despite lactulose treatment 2

Special Considerations

• Lactitol (another non-absorbable disaccharide) is comparable to lactulose with potentially fewer side effects and better palatability 6, 5
• For patients not responsive to conventional therapy, consider oral branched-chain amino acids (BCAAs) or IV L-ornithine L-aspartate (LOLA) 2
• Combination therapy with lactulose and rifaximin may provide additive benefits in patients who have not responded adequately to lactulose alone 7
• Lactulose can be administered via nasogastric tube in patients who are unable to swallow or have aspiration risk 1

In summary, lactulose remains the preferred first-line treatment for hepatic encephalopathy based on efficacy, safety, and cost considerations, with rifaximin reserved as an add-on therapy for recurrent episodes or when lactulose alone is insufficient.