glycerol-phenylbutyrate and Hepatic-Encephalopathy

Pharmacologic management of hepatic encephalopathy includes a broad range of therapies. This article covers the specific mainstays of therapies, such as antimicrobials and laxatives, with an established evidence base. This article also covers newer modalities of therapies, such as fecal microbiota transplant, probiotics, bioartificial support systems, small molecular therapies such as l-ornithine l-aspartate, branched chain amino acids, l-carnitine, zinc, and other forms of therapy currently under review.

Topics: Acarbose; Amino Acids, Branched-Chain; Anti-Bacterial Agents; Dipeptides; Fecal Microbiota Transplantation; Flumazenil; GABA Modulators; Glycerol; Glycoside Hydrolase Inhibitors; Hepatic Encephalopathy; Humans; Lactulose; Laxatives; Phenylbutyrates; Probiotics; Rifaximin

Despite widespread use of lactulose and rifaximin for the treatment of hepatic encephalopathy, this complication of advanced liver disease remains a major burden on the health care system in the United States and continues to predispose to high morbidity and mortality. Several agents have surfaced over recent years with promise to treat hepatic encephalopathy and mitigate the cognitive impairment associated with this disease process. The purpose of this article is to highlight the leading emerging therapies in hepatic encephalopathy as well as their therapeutic targets.

Topics: Acetylcarnitine; Albumins; Ammonia; Dipeptides; Fecal Microbiota Transplantation; Flumazenil; GABA Modulators; Glycerol; Hepatic Encephalopathy; Humans; Nootropic Agents; Ornithine; Phenylbutyrates; Polyethylene Glycols; Probiotics; Surface-Active Agents

Hepatic encephalopathy is one of the most debilitating clinical manifestations of cirrhosis and associated with increased morbidity and mortality. Treatment modalities available include the nonabsorbable disaccharides (lactulose) and the nonabsorbable antibiotics (rifaximin).. Newer therapeutic targets under evaluation include ammonia scavengers (ornithine phenylacetate) and modulation of gut microbiota (fecal microbiota transplantation).. This review will focus on the pathophysiology of hepatic encephalopathy along with an update on therapeutic targets under investigation.

Topics: Amino Acids, Aromatic; Amino Acids, Branched-Chain; Ammonia; Dipeptides; Fecal Microbiota Transplantation; Frailty; Gastrointestinal Agents; Gastrointestinal Microbiome; Glycerol; Hepatic Encephalopathy; Humans; Hypertension, Portal; Lactulose; Liver Cirrhosis; Ornithine; Phenylbutyrates; Polyethylene Glycols; Probiotics; Rifaximin; Trace Elements; Zinc

Hepatic encephalopathy (HE) is a common complication of cirrhosis, leading to frequent hospitalizations. Because ammonia is thought to play an important role in the pathogenesis of HE, therapies specifically aimed at reducing ammonia levels have been developed for conditions causing hyperammonemia, including HE. Ammonia scavengers have been used in HE patients, leading to improvements in symptoms. Bowel cleansing with polyethylene glycol has also been studied recently, resulting in more rapid improvement in acute HE compared with lactulose. Extracorporeal devices have been used in cases of refractory HE but currently are used primarily in research settings and not approved for clinical management for HE.

Topics: Ammonia; Carbon; Gastrointestinal Agents; Glycerol; Hepatic Encephalopathy; Humans; Ornithine; Oxides; Phenylbutyrates; Polyethylene Glycols; Urea

Hepatic encephalopathy (HE) is defined by an altered mental status in the setting of portosystemic shunting, with or without cirrhosis. The basis of HE is probably multi-factorial, but increased ammonia delivery to the brain is thought to play a pivotal role. Medical therapies have typically focused on reducing blood ammonia concentrations. These measures are moderately effective, but further improvements will require identification of new therapeutic targets. Two medications, lactulose and rifaximin, are currently approved for the treatment of HE in the USA - new compounds are available off-label, and are in clinical trials. The presence of HE is associated with a higher risk of death in cirrhotic patients. Liver transplantation typically cures HE, but HE does not increase the MELD score, and therefore does not contribute to the likelihood of liver transplantation.

Topics: Amino Acids, Branched-Chain; Ammonia; Arteriovenous Fistula; Dipeptides; Gastrointestinal Agents; Glycerol; Hepatic Encephalopathy; Humans; Lactulose; Liver Failure; Malnutrition; Ornithine; Phenylbutyrates; Probiotics; Rifamycins; Rifaximin

Topics: Albumins; Amino Acids; Diagnosis, Differential; Diet; Disaccharides; Drug Resistance; Electroencephalography; Glycerol; Hepatic Encephalopathy; Humans; Liver Cirrhosis; Magnetic Resonance Imaging; Neomycin; Neurologic Examination; Nucleic Acid Synthesis Inhibitors; Ornithine; Phenylbutyrates; Probiotics; Protein Synthesis Inhibitors; Rifamycins; Rifaximin; Terminal Care; Tomography, X-Ray Computed

Hyperammonemia is thought to be central in the pathophysiology of hepatic encephalopathy in patients suffering from liver failure. The purpose of this article is to explore existing treatment options that help lower ammonia levels in patients and alleviate symptoms of hepatic encephalopathy.. There are two ways to approach modulating ammonia levels and its effect on the brain. The first targets ammonia levels itself and the second targets inflammation, which makes the brain susceptible to the deleterious effect of ammonia. Recent studies provide new evidence for the use of lactulose, probiotics and rifaximin, as well as closure of large portosystemic shunts in the treatment of hepatic encephalopathy.. Over the past 20 years or so, many new approaches to treat hepatic encephalopathy have been developed based upon better understanding of interorgan ammonia metabolism. Reduction in ammonia can be achieved by targeting its production, absorption or elimination. This review will primarily focus on these strategies that reduce ammonia levels in liver failure patients.

Topics: Ammonia; Brain; Glycerol; Hepatic Encephalopathy; Humans; Hyperammonemia; Lactulose; Phenylbutyrates; Probiotics; Randomized Controlled Trials as Topic; Rifamycins; Rifaximin

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.. 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).

Topics: Adult; Aged; Ammonia; Double-Blind Method; Female; Glutamine; Glycerol; Hepatic Encephalopathy; Humans; Hyperammonemia; Male; Middle Aged; Phenylbutyrates; Treatment Outcome; Urea; Young Adult

Topics: Ammonia; Female; Glycerol; Hepatic Encephalopathy; Humans; Hyperammonemia; Male; Phenylbutyrates

Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels.. The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values.. Only 0.2% (11) of 4683 samples exceeded 500 μg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels>500 μg/ml.. The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Topics: Biomarkers; Drug-Related Side Effects and Adverse Reactions; Glutamine; Glycerol; Hepatic Encephalopathy; Humans; Liver; Neoplasms; Phenylacetates; Phenylbutyrates; Randomized Controlled Trials as Topic; Urea Cycle Disorders, Inborn