What is the mechanism of action of lactulose in treating hepatic encephalopathy?

Mechanism of Action of Lactulose in Hepatic Encephalopathy

Lactulose works primarily by acidifying the colonic contents, which traps ammonia as ammonium ions in the colon and prevents its absorption, while also promoting the growth of beneficial bacteria that incorporate nitrogen, ultimately reducing blood ammonia levels and improving hepatic encephalopathy. 1

Primary Mechanisms

• Lactulose is a non-absorbable disaccharide that reaches the colon essentially unchanged, where it is metabolized by colonic bacteria 1
• Bacterial degradation of lactulose produces organic acids (primarily short-chain fatty acids) that acidify the colonic contents 1, 2
• This acidification creates an environment where ammonia (NH₃) is converted to the non-absorbable ammonium ion (NH₄⁺), effectively trapping it in the colon 1
• The trapped ammonium ions are then expelled through the laxative action of lactulose metabolites 1
• The acidic environment also promotes the growth of beneficial bacteria that incorporate nitrogen into bacterial proteins, further reducing ammonia production 2, 3

Secondary Effects

• Lactulose increases fecal nitrogen excretion by approximately fourfold, primarily through increased bacterial mass and soluble nitrogen compounds 3
• The carbohydrate-rich environment created by lactulose reduces the breakdown of other nitrogen-containing compounds to ammonia and other potential cerebral toxins 2
• Lactulose shifts the colonic bacterial fermentation pattern toward production of non-toxic acetate (increased from 65% to 89%) and away from potentially neurotoxic 3-6 carbon fatty acids (decreased from 35% to 11%) 3
• Lactulose reduces urea production rate, consistent with reduced entry of ammonia into portal blood 2

Clinical Efficacy

• Lactulose therapy typically reduces blood ammonia levels by 25-50%, which generally parallels improvement in mental state and EEG patterns 1
• Clinical response is observed in approximately 75% of patients with hepatic encephalopathy 1
• Lactulose is the first choice for treatment of episodic overt hepatic encephalopathy (Grade II-1, B, 1 recommendation) 4, 5
• It is also recommended for prevention of recurrent episodes of hepatic encephalopathy after the initial episode (Grade II-1, A, 1) 4, 5

Pharmacokinetics

• Lactulose is poorly absorbed from the gastrointestinal tract, with only small amounts reaching the bloodstream 1
• Urinary excretion is 3% or less and is essentially complete within 24 hours 1
• Lactulose is not hydrolyzed by human small intestinal mucosa enzymes 1

Clinical Considerations

• Lactulose significantly improves cognitive function and health-related quality of life in patients with minimal hepatic encephalopathy 6
• In a multicenter randomized controlled trial, lactulose achieved a 64.18% minimal hepatic encephalopathy reversal rate compared to 22.58% in the control group 6
• Gut microbiota changes in hepatic encephalopathy patients can modulate the effectiveness of lactulose therapy 6

Potential Pitfalls

• Simple laxatives alone do not have the prebiotic properties of disaccharides like lactulose and are not recommended for hepatic encephalopathy 5, 4
• For patients who cannot tolerate lactulose, rifaximin may be considered, though evidence supports lactulose as first-line therapy 4
• In specific situations like post-TIPS hepatic encephalopathy, neither lactulose nor rifaximin has been shown to be better than placebo for prevention 4, 5