What is the treatment for hyperammonemia in patients with cirrhosis?

From the Guidelines

The treatment for hyperammonemia in patients with cirrhosis should primarily focus on lactulose administration, aiming to reduce ammonia levels and improve symptoms. The first-line treatment is lactulose, typically started at 30–45 mL orally every 1–2 hours until the patient is having at least 2 bowel movements a day, as recommended by the kasl clinical practice guidelines for liver cirrhosis 1. This approach is supported by the high efficacy of lactulose in improving symptoms, with a response rate of 82.5% and a significant reduction in symptoms compared to placebo, with a relative risk (RR) of 0.62 (95% CI, 0.46–0.84) 1. Key aspects of lactulose treatment include:

• Initial dosing: 30–45 mL every 1–2 hours orally until 2 bowel movements occur
• Maintenance dosing: titrated to achieve 2–3 soft stools per day, with an equivalent daily dose of lactitol being 67–100 g if used instead
• Administration route: oral, with nasogastric tube or enema (300 mL lactulose and 700 mL water, 3–4 times per day) considered for severe cases or inability to take orally Addressing precipitating factors such as gastrointestinal bleeding, infection, electrolyte disturbances, or medication side effects is also crucial in managing hyperammonemia in cirrhosis patients. Additionally, considering the use of intravenous albumin, which has shown to improve recovery rates when combined with lactulose in patients with West-Haven criteria grade ≥2 HE, with a better recovery rate within 10 days (75% vs. 53.3%, P=0.03) 1. However, the primary focus should remain on lactulose due to its established efficacy and the recommendation as the initial therapeutic option for hyperammonemia in cirrhosis patients 1.

From the FDA Drug Label

For the prevention and treatment of portal-systemic encephalopathy, including the stages of hepatic pre-coma and coma. 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.

The treatment for hyperammonemia in patients with cirrhosis is lactulose. It has been shown to reduce blood ammonia levels by 25 to 50% and improve mental state and EEG patterns in patients with portal-systemic encephalopathy, including those with hepatic pre-coma and coma 2.

• Key benefits of lactulose include:
  • Reduction of blood ammonia levels
  • Improvement in mental state
  • Improvement in EEG patterns
  • Increase in patients' protein tolerance Another option is rifaximin, which has been shown to reduce the risk of hepatic encephalopathy breakthrough by 58% during a 6-month treatment period, and reduce the risk of HE-related hospitalizations by 50% during the same period 3.
• Key benefits of rifaximin include:
  • Reduction of risk of hepatic encephalopathy breakthrough
  • Reduction of risk of HE-related hospitalizations

From the Research

Treatment Options for Hyperammonemia in Cirrhosis

• The treatment of hyperammonemia in patients with cirrhosis involves the use of ammonia-targeting drugs, such as glycerol phenylbutyrate and lactulose + rifaximin, which have been shown to increase ammonia clearance and reduce ammonia production 4.
• L-ornithine L-aspartate has also been found to have a beneficial effect on mortality, hepatic encephalopathy, and serious adverse events in patients with cirrhosis, although the quality of the evidence is very low 5.
• A network meta-analysis found that rifaximin and lactulose were the most effective treatments for reversing minimal hepatic encephalopathy, while L-ornithine L-aspartate and lactulose were the most effective for preventing overt hepatic encephalopathy 6.
• However, another study found that ammonia levels do not guide clinical management of patients with hepatic encephalopathy caused by cirrhosis, and that lactulose therapy is not influenced by ammonia levels 7.
• A meta-analysis of randomized controlled trials found that L-ornithine L-aspartate appears to be comparable or superior in efficacy to non-absorbable disaccharides or probiotics for the treatment of hepatic encephalopathy 8.

Ammonia-Targeting Treatments

• Glycerol phenylbutyrate has been shown to increase ammonia clearance by 11% in patients with cirrhosis 4.
• Lactulose + rifaximin has been found to reduce ammonia production by 20% in patients with cirrhosis 4.
• L-ornithine L-aspartate has been found to have a beneficial effect on ammonia levels, with a concomitant lowering of fasting blood ammonia reported in all randomized controlled trials using this endpoint 5, 8.

Clinical Management

• The management of hepatic encephalopathy in patients with cirrhosis is not influenced by ammonia levels, and lactulose therapy is not adjusted based on ammonia levels 7.
• The use of ammonia-targeting treatments, such as glycerol phenylbutyrate and lactulose + rifaximin, may be effective in reducing ammonia levels and improving clinical outcomes in patients with cirrhosis 4, 6.