Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders

Roland Posset; Sven F Garbade; Florian Gleich; Sandesh C S Nagamani; Andrea L Gropman; Friederike Epp; Nesrine Ramdhouni; Ann-Catrin Druck; Georg F Hoffmann; Stefan Kölker; Matthias Zielonka; Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group

doi:10.1016/j.ymgme.2023.108112

Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders

Mol Genet Metab. 2024 Mar;141(3):108112. doi: 10.1016/j.ymgme.2023.108112. Epub 2023 Dec 10.

Collaborators

Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) consortia study group:
Andreas Schulze⁶, Angeles García-Cazorla⁷, Can Ficicioglu⁸, Cary O Harding⁹, Christina Lam¹⁰, Curtis R Coughlin 2nd¹¹, Cynthia Le Mons¹², Derek Wong¹³, Dries Dobbelaere¹⁴, George A Diaz¹⁵, Gerard T Berry¹⁶, Gregory M Enns¹⁷, Greta Wilkening¹⁸, J Lawrence Merritt 2nd¹⁹, Jennifer Seminara²⁰, Laura Konczal²¹, Lindsay C Burrage³, Margo Breilyn²², Martin Lindner²³, Matthias R Baumgartner²⁴, Nicholas Ah Mew²⁵, Renata C Gallagher²⁶, Shawn E McCandless²⁷, Susan A Berry²⁸, Tamar Stricker²⁴

Affiliations

¹ Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. Electronic address: [email protected].
² Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany.
³ Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
⁴ Children's National Health System and The George Washington School of Medicine, Washington, DC, USA.
⁵ Heidelberg University, Medical Faculty Heidelberg, and Center for Pediatric and Adolescent Medicine, Department I, Division of Pediatric Neurology and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. Electronic address: [email protected].
⁶ The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.
⁷ Neurometabolic Unit, Department of Neurology, Hospital Sant Joan de Déu, CIBERER, Barcelona, Spain.
⁸ Children' Hospital of Philadelphia, Philadelphia, USA.
⁹ Oregon Health and Science University, Portland, OR, USA.
¹⁰ Department of Biochemical Genetics, Seattle Children's Hospital, Washington, USA.
¹¹ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹² National Urea Cycle Disorders Foundation, Pasadena, CA, USA.
¹³ David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹⁴ Centre de Référence Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte, Jeanne de Flandre Hospital, CHRU Lille, and RADEME EA 7364, Faculty of Medicine, University Lille 2, Lille, France.
¹⁵ Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Harvard Medical School and Boston Children's Hospital, Boston, MA, USA.
¹⁷ Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
¹⁸ Department of Neurology, Children's Hospital of Colorado, Aurora, CO, USA.
¹⁹ Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
²⁰ Children's National Health System, Washington, DC, USA.
²¹ University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
²² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²³ Department of Pediatrics, Division of Neuropaediatrics, Goethe University Frankfurt, Frankfurt (Main), Germany.
²⁴ Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Switzerland.
²⁵ Children's National Health System, The George Washington School of Medicine, Washington, DC, USA.
²⁶ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
²⁷ Children's Hospital Colorado, Aurora, CO, USA.
²⁸ University of Minnesota, Minneapolis, MN, USA.

PMID: 38301530
DOI: 10.1016/j.ymgme.2023.108112

Abstract

Objective: Liver transplantation (LTx) is an intervention when medical management is not sufficiently preventing individuals with urea cycle disorders (UCDs) from the occurrence of hyperammonemic events. Supplementation with L-citrulline/arginine is regularly performed prior to LTx to support ureagenesis and is often continued after the intervention. However, systematic studies assessing the impact of long-term L-citrulline/arginine supplementation in individuals who have undergone LTx is lacking to date.

Methods: Using longitudinal data collected systematically, a comparative analysis was carried out by studying the effects of long-term L-citrulline/arginine supplementation vs. no supplementation on health-related outcome parameters (i.e., anthropometric, neurological, and cognitive outcomes) in individuals with UCDs who have undergone LTx. Altogether, 52 individuals with male ornithine transcarbamylase deficiency, citrullinemia type 1 and argininosuccinic aciduria and a pre-transplant "severe" disease course who have undergone LTx were investigated by using recently established and validated genotype-specific in vitro enzyme activities.

Results: Long-term supplementation of individuals with L-citrulline/arginine who have undergone LTx (n = 16) does neither appear to alter anthropometric nor neurocognitive endpoints when compared to their severity-adjusted counterparts that were not supplemented (n = 36) after LTx with mean observation periods between four to five years. Moreover, supplementation with L-citrulline/arginine was not associated with an increase of disease-specific plasma arithmetic mean values for the respective amino acids when compared to the non-supplemented control cohort.

Conclusion: Although supplementation with L-citrulline/arginine is often continued after LTx, this pilot study does neither identify altered long-term anthropometric or neurocognitive health-related outcomes nor does it find an adequate biochemical response as reflected by the unaltered plasma arithmetic mean values for L-citrulline or L-arginine. Further prospective analyses in larger samples and even longer observation periods will provide more insight into the usefulness of long-term supplementation with L-citrulline/arginine for individuals with UCDs who have undergone LTx.

Keywords: E-IMD; L-citrulline/arginine supplementation; Liver transplantation; UCDC; Urea cycle disorders.

MeSH terms

Arginine / metabolism
Citrulline / therapeutic use
Dietary Supplements
Humans
Liver Transplantation*
Male
Pilot Projects
Urea / metabolism
Urea Cycle Disorders, Inborn* / drug therapy
Urea Cycle Disorders, Inborn* / surgery

Substances

Citrulline
Arginine
Urea

Grants and funding

U54 HD061221/HD/NICHD NIH HHS/United States