What is the role of lactulose in treating hyperammonemia?

From the Guidelines

Lactulose is the first-line treatment for elevated ammonia levels, particularly in hepatic encephalopathy, with a recommended dose of 20-30 g orally 3-4 times per day, as stated in the 2020 guidelines by the Clinical and Molecular Hepatology 1. The goal of lactulose treatment is to achieve 2-3 soft bowel movements per day, and the dose should be titrated accordingly.

• Lactulose works by creating an acidic environment in the colon that converts ammonia (NH3) to ammonium (NH4+), which cannot be absorbed back into the bloodstream.
• It also has an osmotic laxative effect that accelerates intestinal transit time, reducing bacterial ammonia production and facilitating ammonia excretion.
• For severe cases, an enema with lactulose 200 g and 700 mL water may be performed 3-4 times per day, as recommended by the guidelines 1.
• Common side effects of lactulose include bloating, flatulence, abdominal cramping, and diarrhea.
• Treatment should continue as long as the risk of hyperammonemia persists, which for many patients with liver disease means indefinite therapy, as supported by the 2014 practice guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases 1.
• Blood ammonia levels should be monitored periodically, but clinical improvement in mental status is a more important marker of treatment success than laboratory values alone.
• The use of lactulose is also supported by other studies, including a systematic review and meta-analysis that found lactulose or lactitol to be more effective in improving symptoms than placebo, with a relative risk of 0.62 (95% CI, 0.46-0.84) 1.

From the FDA Drug Label

Controlled studies have shown that lactulose solution therapy reduces the blood ammonia levels by 25 to 50%; this is generally paralleled by the improvement in the patients’ mental state and by an improvement in EEG patterns. Lactulose causes a decrease in blood ammonia concentration and reduces the degree of portal-systemic encephalopathy. The acid colonic contents converts NH3 to the ammonium ion (NH4)+, trapping it and preventing its absorption.

Lactulose is used to treat elevated ammonia levels, specifically in the context of portal-systemic encephalopathy. It has been shown to reduce blood ammonia levels by 25 to 50% in controlled studies 2. The mechanism of action involves the acidification of colonic contents, which traps ammonia and prevents its absorption into the bloodstream 2.

• Key benefits of lactulose therapy include:
  • Reduction in blood ammonia levels
  • Improvement in mental state
  • Improvement in EEG patterns
  • Increased protein tolerance in patients
• Clinical response has been observed in about 75% of patients, making it a satisfactory treatment option for elevated ammonia levels 2.

From the Research

Lactulose for Elevated Ammonia

• Lactulose is considered the first-line therapeutic agent for treating hepatic encephalopathy, which is often associated with elevated ammonia levels 3.
• The drug works by acidifying the gastrointestinal tract, thereby inhibiting the production of ammonia by coliform bacteria 3.
• However, a study found that ammonia levels do not guide clinical management of patients with hepatic encephalopathy caused by cirrhosis, and lactulose dose is not correlated with ammonia level 4.

Comparison with Other Treatments

• Rifaximin, a semisynthetic antibiotic, has been shown to be effective in improving behavioral, laboratory, mental, and intellectual abnormalities in patients with hepatic encephalopathy, and is often used in combination with lactulose 3, 5.
• A randomized controlled trial found that the combination of lactulose and rifaximin is more effective than lactulose alone in the treatment of overt hepatic encephalopathy 5.
• Another study found that the addition of rifaximin to lactulose significantly reduces the risk of overt hepatic encephalopathy recurrence and hepatic encephalopathy-related hospitalization, compared with lactulose therapy alone 6.

Special Considerations

• In cases of dehydration-associated pseudo-hyperammonemia, intravascular resuscitation may be beneficial, and lactulose or rifaximin may not be required 7.
• Long-term management of hepatic encephalopathy with lactulose and/or rifaximin has been shown to be effective and safe, with the addition of rifaximin to lactulose resulting in substantial reductions in healthcare resource utilization 6.