Novel Agents in the Management of Hepatic Encephalopathy: A Review

Abstract

RAVICTI is indicated for use as a nitrogen-binding agent for chronic management of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) that cannot be managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential amino acids, arginine, citrulline, protein-free calorie supplements). ( 1) Limitations of Use:  RAVICTI is not indicated for treatment of acute hyperammonemia in patients with UCDs. (1)  Safety and efficacy for treatment of N-acetylglutamate synthase (NAGS) deficiency has not been established. (1)  The use of RAVICTI in patients <2 months of age is contraindicated (4) DOSAGE AND ADMINISTRATION RAVICTI should be prescribed by a physician experienced in management of UCDs. (2.1)  Instruct patients to take with food and to administer directly into mouth via oral syringe or dosing cup. (2.1)  Total daily dosage is given in 3 equally divided dosages, rounded up to nearest 0.5 mL. (2.1)  Maximum daily dosage is 17.5 mL (19 g). (2.1)  Must be used with dietary protein restriction. (2.1) Switching From Sodium Phenylbutyrate to RAVICTI:  Daily dosage of RAVICTI (mL) = daily dosage of sodium phenylbutyrate (g) x 0.86. (2.2) Initial Dosage in Phenylbutyrate-Naïve Patients:  Recommended dosage range is 4.5 to 11.2 mL/m 2 /day (5 to 12.4 g/m 2 /day). (2.3)  For patients with some residual enzyme activity who are not adequately controlled with dietary restriction, recommended starting dose is 4.5 mL/m 2 /day. (2.3)  Take into account patient's estimated urea synthetic capacity, dietary protein intake, and diet adherence. (2.3) Dosage Modifications in Patients With Hepatic Impairment:  Start dosage at lower end of range. (2.5, 8.6) DOSAGE FORMS AND STRENGTHS Oral liquid: 1.1 g/mL of glycerol phenylbutyrate. (3) ___________________ CONTRAINDICATIONS ____________________  Patients <2 months of age. (4)  Known hypersensitivity to phenylbutyrate. (4)

Hepatic Encephalopathy: Current and Emerging Treatment Modalities

“…37 LOLA can also increase urea production by activating the rate limiting enzyme of urea cycle, carbamoyl phosphate synthetase. 38,39 By activation of glutamine synthetase, LOLA also augments glutamine production in perivenous hepatocytes and skeletal muscles. 37,38 Multiple trials confirmed the potential beneficial role of LOLA in HE treatment.…”

“…38,39 By activation of glutamine synthetase, LOLA also augments glutamine production in perivenous hepatocytes and skeletal muscles. 37,38 Multiple trials confirmed the potential beneficial role of LOLA in HE treatment. 40 A metaanalysis including 36 trials with 2377 patients showed that LOLA had beneficial effect on mortality (RR, 0.42; 95% CI, 0.24-0.72) and HE (RR, 0.47; 95% CI, 0.06-3.58) as compared with placebo or no intervention.…”

“…Therefore, LOLA is not considered a first-line treatment in HE and is only recommended as an alternative/additional agent in patients with HE that does not respond to conventional treatment modalities. 38 Acetyl-L-carnitine*. Carnitine plays a role in transferring fatty acid across the inner mitochondrial membrane, and ester of this nutrient, acetyl-L-carnitine, has been hypothesized to induce ureagenesis leading to decreased ammonia levels in blood and brain and HE improvement.…”

“…44 Overall, larger trials with improved design are required to evaluate the safety and potential role of this ester in HE treatment. 38 Branched-chain amino acids. The 3 essential branched-chain amino acids (BCAAs) are valine, leucine, and isoleucine.…”

“…Albumin has been shown to act as a scavenger of reactive oxygen species and inhibitor of inflammatory mediators that can potentially contribute to HE improvement. 38,56 A recent meta-analysis including 12 studies with 2087 patients with cirrhosis revealed that albumin administration was associated with decreased risk of HE in patients with and without baseline overt HE (odds ratio, 0.43; 95% CI, 0.27-0.68 and odds ratio, 0.54; 95% CI, 0.32-0.86, respectively). It also showed the association of albumin administration with a lower risk of inpatient mortality (odds ratio, 0.36; 95% CI, 0.21-0.60).…”