Glutamine and hyperammonemic crises in patients with urea cycle disorders

Abstract

Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients. Methods The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate. Results The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8–29%) as compared with 56% (28%–154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 µmol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2] µmol/L) than patients with baseline glutamine ≤900 µmol/L (26.6 [18.0] µmol/L). Glutamine values >900 µmol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR]=1.98; p=0.173). However, glutamine lost predictive significance (OR=1.47; p=0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia ≥ 1.0 upper limit of normal (ULN) was highly statistically significant (OR=4.96; p=0.013). There was no significant effect of glutamine >900 µmol/L on time to first HAC crisis (hazard ratio [HR]=1.14; p=0.813), but there was a significant effect of baseline ammonia ≥ 1.0 ULN (HR=4.62; p=0.0011). Conclusions The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels.

Hyperammonemic crises in patients with urea cycle disorders on chronic nitrogen scavenger therapy with either sodium phenylbutyrate or glycerol phenylbutyrate

“…Previous findings from this data indicate that fasting ammonia levels, and glutamine to a much weaker extent, correlate with daily ammonia exposure and that these values are also predictive of a future HAC [6,10,11]. Modeling data in this analysis indicate that fasting ammonia of ≥1.0 ULN was found to increase the probability of high daily ammonia exposure and 37% of these patients experienced ≥1 HAC over 12 months.…”

“…Research Robert J Holt and three 12-month safety extension studies in 100 adult and pediatric UCD patients were used in this analysis [6,10,11]. The trials compared 24hour ammonia levels during short-term steadystate dosing with GPB or sodium phenylbutyrate (NaPBA) and studied longer-term outcomes, including HACs, among 100 UCD patients, including 49 pediatric patients, treated with GPB for up to 1 year.…”

Biochemical markers and neuropsychological functioning in distal urea cycle disorders

“…For ASA, ammonia clearly related to aspects of cognitive outcome, but so did glutamine. Others have suggested that elevated glutamine serves as a harbinger for sudden hyperammonemia (Lee et al, 2016). Our study suggests that glutamine can also be used as a marker for neuropsychological functioning.…”

Urea Cycle Related Amino Acids Measured in Dried Bloodspots Enable Long-Term In Vivo Monitoring and Therapeutic Adjustment

“…Monitoring of leucine and valine, which have been recently associated with faltering growth in urea cycle defects [32], could help to optimise supplementation to achieve physiological levels. Careful monitoring of glutamate and glutamine could identify patients with higher risk of decompensations [33].…”