In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis

Mol Genet Metab. 2016 Jan;117(1):19-26. doi: 10.1016/j.ymgme.2015.11.007. Epub 2015 Nov 14.

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.

Conclusion: 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.

Keywords: (13)C-stable isotope; Sodium [1,2-13C]-acetate; UCD; Urea cycle defect; Ureagenesis.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Carbon Isotopes / metabolism
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Hyperammonemia / diagnosis
  • Hyperammonemia / metabolism
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Monitoring, Physiologic
  • Ornithine Carbamoyltransferase Deficiency Disease / diagnosis
  • Radioactive Tracers
  • Sodium Acetate / administration & dosage
  • Sodium Acetate / pharmacokinetics*
  • Urea / metabolism*
  • Urea Cycle Disorders, Inborn / diagnosis*
  • Young Adult

Substances

  • Carbon Isotopes
  • Radioactive Tracers
  • Sodium Acetate
  • Urea