Ornithine phenylacetate may reduce ammonia in hepatic encephalopathy

Hepatic encephalopathy is a potentially reversible neuropsychiatric disorder associated with acute or chronic cirrhosis. It manifests as a broad spectrum of brain function disturbances, ranging from subclinical changes to coma.

It's estimated that two-thirds of patients with cirrhosis have some degree of subtle or overt cognitive impairment; around 30 percent have overt symptoms that result in at least 150,000 hospitalizations a year. Hepatic encephalopathy has a significant negative effect on survival in patients with end-stage liver disease, and symptoms such as sleep-wake abnormalities, personality and cognitive changes, and impaired motor function greatly affect quality of life.

The pathophysiology of hepatic encephalopathy is complex and multifactorial, but is strongly associated with hyperammonemia, which develops when gut-derived toxins, particularly ammonia, bypass a failing liver, enter the circulation and cross the blood-brain barrier. Ammonia is a byproduct of the metabolism of nitrogen-containing compounds and is neurotoxic in high concentrations.

Normally, the liver clears most of the portal vein ammonia, converting it into glutamine and to urea, which is excreted in the kidneys. But patients with liver failure or cirrhosis with hypertension or portal-systemic shunts aren't able to metabolize ammonia effectively, leading to increased levels in the blood and the resulting effect on brain function. Muscle wasting, which is common in liver disease, also may be a factor — skeletal muscle is involved in removing extrahepatic ammonia.

Bashar A. Aqel, M.D., hepatologist at Mayo Clinic's campus in Arizona, says the role of ammonia-producing gut bacteria is of increasing interest, too.

"Certain colonic bacteria, mainly coliforms and anerobes, can convert ingested amino acids into ammonia. There is ongoing research into the relation between the microbiome and hepatic encephalopathy. We need to determine if people with liver disease have a different microbiome, and if so, how we can we change it to make it more favorable," he says.

Management of hepatic encephalopathy

Dr. Aqel notes that dietary protein restriction was once advocated as a strategy for reversing circulating ammonia in patients with liver disease. "Low-protein diets helped a little, but patients became malnourished," he says. "Now we know that as many as 75 percent of patients with HE suffer from protein-calorie malnutrition, which, along with loss of muscle bulk, is a risk factor for hepatic encephalopathy and other cirrhosis complications."

The current standard of care for hepatic encephalopathy focuses on reducing ammonia in the gastrointestinal tract and reversing precipitating factors, including infection, gastrointestinal bleeding, dehydration, electrolyte imbalance, dietary protein load, constipation, and the use of sedative or hypnotic drugs.

Pharmacological approaches include the use of nonabsorbable disaccharides, such as lactulose, which reduce the amount of ammonia absorbed in the colon and, because of their osmotic effects, improve gastrointestinal transit. For patients who don't improve with lactulose, the antibiotic rifaximin is often added to the regimen, although the combination isn't always effective, Dr. Aqel says.

"These strategies have been effective in preventing recurrent episodes, but in some cases, they aren't enough, especially in the acute care of patients hospitalized with severe forms of hepatic encephalitis," he explains. "We need to find effective interventions for this challenging subset of patients — those who are hospitalized with severe episodes or near coma."

Ornithine phenylacetate

To further that search, Dr. Aqel is currently enrolling patients in a multicenter, placebo-controlled trial of ornithine phenylacetate in patients with refractory and severe hepatic encephalopathy. Ornithine phenylacetate works simultaneously on stimulation of glutamine production using ammonia as a substrate and on glutamine conjugation and excretion via the phenylacetate component, thereby improving removal of circulating ammonia.

In the current manufacturer-funded trial, hospitalized participants will receive continuous intravenous infusion of ornithine phenylacetate for up to five days in addition to standard of care. A control group will receive standard of care plus five days of a placebo infusion. The primary aim is to improve clinical status from baseline.

To date, 60 or 70 patients have been enrolled worldwide; the goal is to enroll 150 to 200. Physicians interested in referring a patient or learning more can contact Dr. Aqel directly.

For your information

Ocera Therapeutics. Phase 2B Efficacy/Safety of Ornithine Phenylacetate in Hospitalized Cirrhotic Patients With Hepatic Encephaolopathy (STOP-HE). ClinicalTrials.gov.