Effects of Sapropterin on Portal and Systemic Hemodynamics... : Official journal of the American College of Gastroenterology | ACG (original) (raw)

ORIGINAL CONTRIBUTIONS: LIVER

Reverter, Enric MD1,2; Mesonero, Francisco MD2,3; Seijo, Susana MD, PhD1,2; Martínez, Javier MD2,3; Abraldes, Juan G MD, PhD1,2; Peñas, Beatriz MD2,3; Berzigotti, Annalisa MD, PhD1,2; Deulofeu, Ramon PhD2,4; Bosch, Jaume MD, PhD1,2; Albillos, Agustín MD, PhD2,3; García-Pagán, Joan Carles MD, PhD1,2

1Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain

2Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain

3Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, Madrid, Spain

4Department of Biochemistry and Molecular Genetics, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain

Correspondence: Joan Carles García-Pagán, Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. E-mail: [email protected]

Received 01 December 2014; accepted 03 March 2015

Guarantor of the article: Joan Carles García-Pagán, MD, PhD.

Specific authors contributions: Study concept and design: Enric Reverter, Joan Carles García-Pagán, Agustín Albillos, Juan G. Abraldes, and Jaume Bosch; screening, inclusion and follow-up of patients, performance of hemodynamic studies and acquisition of data: Enric Reverter, Francisco Mesonero, Susana Seijo, Javier Martínez, Beatriz Peñas, Annalisa Berzigotti, Agustín Albillos, and Joan Carles García-Pagán; biochemical analysis: Ramon Deulofeu; analysis and interpretation of data: Enric Reverter, Joan Carles García-Pagán, Agustín Albillos, and Jaume Bosch; drafting of the manuscript: Enric Reverter and Joan Carles García-Pagán; critical revision of the manuscript for important intellectual content: Jaume Bosch, Agustín Albillos, Juan G. Abraldes, Annalisa Berzigotti, Ramon Deulofeu, and Joan Carles García-Pagán. All the authors read and approved the final version of the paper.

Financial support: This study was supported by the Ministry of Health and Social Policy (Proyectos de Investigación Clínica Independiente, Orden SAS/2377/2010, EC10-069), Ministry of Education and Science (SAF-2013-44723-R), and Instituto de Salud Carlos III (PI13/00341). The Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) is funded by the Instituto de Salud Carlos III. ER was recipient of a Río Hortega award, Instituto de Salud Carlos III.

Potential competing interests: None.

Abstract

OBJECTIVES:

Tetrahydrobiopterin (BH4), a cofactor of nitric oxide synthase, might have a role in the treatment of portal hypertension (PHT) as its administration improves endothelial nitric oxide generation and hepatic endothelial dysfunction, and reduces portal pressure in experimental models of cirrhosis. Sapropterin is an oral synthetic analogue of BH4 recently approved for the treatment of phenylketonuria. This study evaluated the safety and effects of sapropterin on hepatic and systemic hemodynamics in patients with cirrhosis and PHT.

METHODS:

Forty patients with cirrhosis and PHT (hepatic venous pressure gradient (HVPG) ≥10 mm Hg) were randomly allocated to receive sapropterin ( n =19) for 2 weeks (5 mg/kg/day increased to 10 at day 8) or placebo ( n =21) in a double-blind multicenter clinical trial. Randomization was stratified according to concomitant treatment with β-adrenergic blockers. We studied at baseline and post-treatment splanchnic (HVPG and hepatic blood flow (HBF)) and systemic hemodynamics, endothelial dysfunction and oxidative stress markers (von Willebrand factor and malondialdehyde), liver function tests, and safety variables.

RESULTS:

HVPG was not modified by either sapropterin (16.0±4.4 vs. 15.8±4.7 mm Hg) or placebo (16.0±4.6 vs. 15.5±4.9 mm Hg). HBF, systemic hemodynamics, endothelial dysfunction markers, and liver function tests remained unchanged. Sapropterin was well tolerated (no patient required dose adjustment or withdrawal), and adverse events were mild and similar between groups.

CONCLUSIONS: