Ammonia-lowering treatment aided patients with hepatic encephalopathy

BOSTON — In a cohort of cirrhotic patients with episodic hepatic encephalopathy, glycerol phenylbutyrate safely reduced the number and severity of episodes compared with placebo, according to data presented at The Liver Meeting 2012.

In a randomized, double blind trial, researchers administered 6 mL glycerol phenylbutyrate (GPB) (n=90) or placebo (n=88) twice a day to cirrhotic patients with hepatic encephalopathy (HE). All participants had experienced two or more episodes of West Haven (WH) Grade 2 or higher within 6 months, while treated with lactulose and/or rifaximin.

“Ammonia is suspected, but not established as important in [HE] pathogenesis,” researcher Don C. Rockey, MD, chairman of the department of medicine at Medical University of South Carolina in Charleston, said. “GPB is an ammonia-lowering investigational drug … shown to lower ammonia in HE patients. Our aim was to test the hypothesis that ammonia lowering with GPB benefits HE patients.”

The number of patients experiencing HE events was smaller in the treated group (21% compared with 36% in the placebo group; P=.021), along with the number of events (35 compared with 57; P=.035). Patients experienced fewer symptomatic days as measured by the Clinical Hepatic Encephalopathy Staging Scale (CHESS) (13 days vs. 27; P=.015), and fewer hospitalizations occurred in the treated group, with the difference nearing statistical significance (13 vs. 25; P=.064)

Venous ammonia levels were significantly reduced in the treated group (45 umol/L vs. 58 umol/L; P=.037). Researchers also noted that patients who experienced HE events onsite had higher ammonia levels at baseline than those who did not, and they observed a significant correlation between ammonia levels and the likelihood of an onsite HE event.

Among rifaximin-naive patients (n=60, treated group; n=59, placebo), the differences in HE event incidence (10% vs. 32%; P=.003) and total events (6 vs. 19; P=.0002 were more pronounced, and significantly fewer patients experienced HE events of WH grade 2 or higher (5% vs. 28%; P=.001). Among patients taking rifaximin at baseline (n=30, treated patients; n=29, placebo), no significant differences were observed in the number of patients experiencing events (13 for both groups; P=.909) or number of hospitalizations (11 vs. 20; P=.095).

Adverse events were reported by 78.9% of treated patients and 76.1% of those receiving placebo; they included nausea, diarrhea, abdominal pain and increased AST. Serious events occurred in 20 treated patients, with one considered related to treatment, and in 12 patients in the placebo group, with four related to treatment. Common serious events included GI bleeding and urinary tract infections.

“We conclude that ammonia is important in the pathogenesis of HE, and that based on its safety and efficacy profile, GPB shows promise as a novel therapeutic agent for HE,” Rockey said. “Ammonia correlated with risk of HE events, there was a highly significant treatment effect on patients not on rifaximin at baseline, and there is potential for incremental benefit among rifaximin patients.”

Disclosure: The researchers report numerous financial disclosures.

For more information:

Rockey DC. #112: Randomized, controlled, double blind study of glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy. Presented at: The Liver Meeting 2012; Nov. 9-13, Boston.