Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Sabine Scholl-Bürgi, Rupert Oberhuber, Silvie Kelifova, Anne Mei-Kwun Kwok, Yuval E Landau, Jerard Vockley, Areeg H El-Gharbawy, Birgit Waldner, Thomas Zöggeler, Georg F Vogel, Denise Aldrian, Daniela Karall, Yılmaz Yıldız, Karolina M Stepien, Sarah C Grünert, Allan M Lund, Thomas Müller, Carolyn Ellaway, Mari Mori, Stefan Schneeberger, Tomas Honzik, Patrick McKiernan, Fuad Al Mutairi

Journal: Journal of inherited metabolic disease 2024;47(2):220-229

PMID: 38375550

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Abstract

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

Address: Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.; Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.; Division of Medical Genetics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Department of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Metabolic Disease Unit, Schneider Children's Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.; Genetics and Precision Medicine Department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City MNG-HA, Riyadh, Saudi Arabia.; King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.; Adult Inherited Metabolic Diseases, Salford Royal Organisation, Northern Care Alliance NHS Foundation Trust, Salford, Greater Manchester, UK.; Department of Pediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Kowloon, Hong Kong.; Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.; Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University, General University Hospital in Prague, Prague, Czech Republic.; Genetic Metabolic Disorders Service, Sydney Children's Hospital Network, Sydney, New South Wales, Australia.; Disciplines of Child and Adolescent Health and Genomic Medicine, University of Sydney, Sydney, Australia.; Departments of Clinical Genetics and Pediatrics, Center for Inherited Metabolic Diseases, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA.; Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA.; Department of General Paediatrics, Adolescent Medicine and Neonatology, Medical Centre-University of Freiburg, Faculty of Medicine, Freiburg, Germany.; Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, Innsbruck, Austria.

DOI: 10.1002/jimd.12717

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https://doi.org/10.1002/jimd.12717

MeSH Terms: Humans, Ornithine Carbamoyltransferase Deficiency Disease, Hyperammonemia, Liver Transplantation, Citrulline, Carbamyl Phosphate, Ammonia, Retrospective Studies, Carbamoyl-Phosphate Synthase (Ammonia), Arginine, Ornithine Carbamoyltransferase