title: In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis.
abstract: BACKGROUND
  The hepatic urea cycle is the main metabolic pathway for detoxification of ammonia. Inborn errors of urea cycle function present with severe hyperammonemia and a high case fatality rate. Long-term prognosis depends on the residual activity of the defective enzyme. A reliable method to estimate urea cycle activity in-vivo does not exist yet. The aim of this study was to evaluate a practical method to quantify (13)C-urea production as a marker for urea cycle function in healthy subjects, patients with confirmed urea cycle defect (UCD) and asymptomatic carriers of UCD mutations.
  
  
  METHODS
  (13)C-labeled sodium acetate was applied orally in a single dose to 47 subjects (10 healthy subjects, 28 symptomatic patients, 9 asymptomatic carriers).
  
  
  RESULTS
  The oral (13)C-ureagenesis assay is a safe method. While healthy subjects and asymptomatic carriers did not differ with regards to kinetic variables for urea cycle flux, symptomatic patients had lower (13)C-plasma urea levels. Although the (13)C-ureagenesis assay revealed no significant differences between individual urea cycle enzyme defects, it reflected the heterogeneity between different clinical subgroups, including male neonatal onset ornithine carbamoyltransferase deficiency. Applying the (13)C-urea area under the curve can differentiate between severe from more mildly affected neonates. Late onset patients differ significantly from neonates, carriers and healthy subjects.
  
  
  CONCLUSIONS
  This study evaluated the oral (13)C-ureagenesis assay as a sensitive in-vivo measure for ureagenesis capacity. The assay has the potential to become a reliable tool to differentiate UCD patient subgroups, follow changes in ureagenesis capacity and could be helpful in monitoring novel therapies of UCD.
authors.affiliation: Division of Neuropediatrics and Pediatric Metabolic Medicine, University Children's Hospital Heidelberg, Germany. Electronic address: Thomas.Opladen@med.uni-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Opladen
authors.affiliation: Division of Neuropediatrics and Pediatric Metabolic Medicine, University Children's Hospital Heidelberg, Germany; Division of Neuropaediatrics, Prevention, Endocrinology and Pediatric Metabolic Diseases, University Children's Hospital Frankfurt, Germany. Electronic address: Martin.Lindner@kgu.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Division of Metabolic Disorders, Medical School Hannover, Germany. Electronic address: Das.Anibh@mh-hannover.de.
authors.forename: Anibh M
authors.initials: AM
authors.lastname: Das
authors.affiliation: Division of Metabolic Disorders, University Children's Hospital Münster, Germany. Electronic address: Thorsten.Marquardt@ukmuenster.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Department of Medical Genetics & Pediatrics, Alberta Children's Hospital, Calgary, Canada. Electronic address: khaa@ucalgary.ca.
authors.forename: Aneal
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, USA. Electronic address: sukru.emre@yale.edu.
authors.forename: Sukru H
authors.initials: SH
authors.lastname: Emre
authors.affiliation: Children's Memorial Hospital, Chicago, USA. Electronic address: BBurton@luriechildrens.org.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Burton
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA. Electronic address: bbarshop@ucsd.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Barshop
authors.affiliation: Cytonet GmbH & Co. KG, Albert-Ludwig-Grimm-Str. 20, Weinheim, Germany. Electronic address: Thea.boehm@gmx.net.
authors.forename: Thea
authors.initials: T
authors.lastname: Böhm
authors.affiliation: Division of Neuropediatrics and Pediatric Metabolic Medicine, University Children's Hospital Heidelberg, Germany. Electronic address: Jochen.Meyburg@med.uni-heidelberg.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Meyburg
authors.affiliation: Division of Neuropediatrics and Pediatric Metabolic Medicine, University Children's Hospital Heidelberg, Germany. Electronic address: kathrin.zangerl@gmail.com.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zangerl
authors.affiliation: Division of Metabolic Disorders, Medical School Hannover, Germany. Electronic address: Sebene.Mayorandan@ukmuenster.de.
authors.forename: Sebene
authors.initials: S
authors.lastname: Mayorandan
authors.affiliation: Division of Neuropediatrics and Pediatric Metabolic Medicine, University Children's Hospital Heidelberg, Germany. Electronic address: Peter.Burgard@med.uni-heidelberg.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Burgard
authors.affiliation: Cytonet GmbH & Co. KG, Albert-Ludwig-Grimm-Str. 20, Weinheim, Germany. Electronic address: Ulrich.Duerr@cytonet.de.
authors.forename: Ulrich H N
authors.initials: UH
authors.lastname: Dürr
authors.affiliation: Division of Clinical Pharmacology, Faculty of Medicine and Health Sciences, Department of Medicine, Stellenbosch University, South Africa. Electronic address: rosenkranz@sun.ac.za.
authors.forename: Bernd
authors.initials: B
authors.lastname: Rosenkranz
authors.affiliation: Cytonet GmbH & Co. KG, Albert-Ludwig-Grimm-Str. 20, Weinheim, Germany. Electronic address: Joerg.Rennecke@cytonet.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Rennecke
authors.affiliation: Cytonet GmbH & Co. KG, Albert-Ludwig-Grimm-Str. 20, Weinheim, Germany. Electronic address: Jens.Derbinski@cytonet.de.
authors.forename: Jens
authors.initials: J
authors.lastname: Derbinski
authors.affiliation: Division of Metabolic Disease, Children's Hospital of Philadelphia, USA. Electronic address: yudkoff@email.chop.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Yudkoff
authors.affiliation: Division of Neuropediatrics and Pediatric Metabolic Medicine, University Children's Hospital Heidelberg, Germany. Electronic address: Georg.Hoffmann@med.uni-heidelberg.de.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002247:Carbon Isotopes / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D022124:Hyperammonemia / Q000175:diagnosis / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D020163:Ornithine Carbamoyltransferase Deficiency Disease / Q000175:diagnosis; D011849:Radioactive Tracers; D019346:Sodium Acetate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014508:Urea / Q000378:metabolism*; D056806:Urea Cycle Disorders, Inborn / Q000175:diagnosis*; D055815:Young Adult
chemical_list: D002247:Carbon Isotopes; D011849:Radioactive Tracers; D019346:Sodium Acetate; D014508:Urea
keywords: (13)C-stable isotope; Sodium [1,2-13C]-acetate; UCD; Urea cycle defect; Ureagenesis