Randomized, double‐blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy

Abstract

Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P = 0.02), time to first event (hazard ratio [HR] = 0.56; P < 0.05), as well as total events (35 versus 57; P = 0.04), and was associated with fewer HE hospitalizations (13 versus 25; P = 0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P < 0.01), time to first event (HR = 0.29; P < 0.01), and total events (7 versus 31; P < 0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. Conclusion: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167). (Hepatology 2014;59:1073-1083)

Diagnosis and Treatment of Low-Grade Hepatic Encephalopathy

“…A randomised control trial, though not conducted in patients with mHE, has suggested that there is a reduction in blood ammonia levels and that this is accompanied by a decrease in the proportion of patients with an HE event and an increase in the time to first HE event [34]. …”

Is it time to target gut dysbiosis and immune dysfunction in the therapy of hepatic encephalopathy?

“…Antibiotics such as neomycin, metronidazole and vancomycin have been used with the aim of reducing the production of ammonia by gut microbiota, but their long-term use has been associated with adverse side effects of nephrotoxicity, ototoxicity and peripheral neuropathy. Selective gut decontamination may therefore have utility, but this does not, however, explain why germ-free animals whose guts have been totally irradiated still develop HE and why therapies such as glyceryl phenylbutyrate [23], L-ornithine L-aspartate [24] and L-ornithine phenylacetate [25], which increase ammonia removal, are efficacious. This indicates that other pathophysiological factors may also have importance, including the presence of phosphate-activating glutaminase in enterocytes resulting in net ammonia production and the impact that systemic inflammation alone has on neurocognitive function in those without evidence of liver disease, such as those with septic encephalopathy or delirium [20].…”

Glycine and hyperammonemia: potential target for the treatment of hepatic encephalopathy

“…Studies have also shown a beneficial effect on lowering blood ammonia and HE events by administering the glutamine scavenger phenylacetate (as glycerol phenylbutyrate, pro-drug for phenylacetate) (McGuire et al 2010;Rockey et al 2014).…”