Evaluation and management of urea cycle disorders using stable isotope infusions

Abstract

Diagnosing partial urea cycle deficiencies based on clinical and laboratory data is difficult and there is often poor correlation between genotype, in vitro enzyme activity, and phenorypic expression. We have used stable isotope infusions to measure total body glutamine and urea flux for the evaluation of patients with urea cycle disorders. We have previously determined the rate of total body urea production by measuring blood ¹³C-urea isotopic enrichment during an infusion with the stable isotope ¹³C-urea, and the proportional contribution of peripheral nitrogen to urea synthesis by measuring the incorporation of ¹⁵N from ¹⁵N glutamine into ¹⁵N urea. The ratio of the isotopic enrichments of ¹⁵N urea/¹⁵N-glutamine (¹⁵N-U/G) allowed us to distinguish carriers for omithine transcarbamylase deficiency (OTCD) both from their affected offspring and from normal control subjects (Lee et. al., submitted). Collectively these data suggest that the flux from ¹⁵N glutamine to ¹⁵N urea is a sensitive measure of urea cycle activity and is capable of differentiating female carriers for OTCD from normal controls.

We have now applied this method to the 1) diagnosis of asymptomatic at risk partial OTCD females, 2) titration of dietary protein tolerance for managing a severe OTCD male patient, and 3) comparison of differences in the bioavailability of enteral vs. systemic sources of nitrogen for total body urea production. By determining the ¹⁵N-U/G ratio in 5 at-risk females in two OTCD sibships in whjch mutations were not found in the index case, we were able to measure normal and abnormal urea production and determine carrier status. In the second case, we determined total body glutamine flux at 1.2 gm/kg/day and at 0.8 gm/kg/day protein intake in a 7 month null activity OTCD male to titrate protein tolerance and guide dietary therapy. In the third case, we tested the hypothesis that intestinally generated ammonia and alanine are more effective immediate precursors for urea synthesis than peripherally generated glutamine and as a consequence individuals who have a compromised urea cycle activity would metabolize excessive dietary protein more effectively than peripherally generated protein. By comparing the transfer of ¹⁵N from oral and intravenous ¹⁵NH₄Cl to urea, we found that individuals who have partial urea cycle activity metabolize excessive dietary protein more efficiently, underlying the observation thai these patients are particularly susceptible to stress and fasting. In conclusion this approach may also lead to improvements in the nutritional management of patients with urea cycle defects and those who are severely catabolic during critical illness.