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Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder.

ABSTRACT: PURPOSE:The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders. METHODS:The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders. RESULTS:Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), 0.5 to <1.0 ULN, and ?1.0 ULN, the probability of a normal average daily ammonia value was 87, 60, and 39%, respectively, and 10.3, 14.1, and 37.0% of these patients, respectively, experienced ?1 hyperammonemic crisis over 12 months. Time to first hyperammonemic crisis was shorter (P = 0.008) and relative risk (4.5×; P = 0.011) and rate (~5×, P = 0.006) of hyperammonemic crises were higher in patients with fasting ammonia ?1.0 ULN vs. <0.5ULN; relative risk was even greater (20×; P = 0.009) in patients ?6 years old. A 10- or 25-µmol/l increase in ammonia exposure increased the relative risk of a hyperammonemic crisis by 50 and >200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24-hour area under the curve and was not a significant predictor of hyperammonemic crisis. CONCLUSION:Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control.

SUBMITTER: Lee B

PROVIDER: S-EPMC4465427 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder.

Lee Brendan B Diaz George A GA Rhead William W Lichter-Konecki Uta U Feigenbaum Annette A Berry Susan A SA Le Mons Cindy C Bartley James A JA Longo Nicola N Nagamani Sandesh C SC Berquist William W Gallagher Renata R Bartholomew Dennis D Harding Cary O CO Korson Mark S MS McCandless Shawn E SE Smith Wendy W Cederbaum Stephen S Wong Derek D Merritt J Lawrence JL Schulze Andreas A Vockley Jerry J Kronn David D Zori Roberto R Summar Marshall M Milikien Douglas A DA Marino Miguel M Coakley Dion F DF Mokhtarani Masoud M Scharschmidt Bruce F BF

Genetics in medicine : official journal of the American College of Medical Genetics 20141211 7

<h4>Purpose</h4>The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders.<h4>Methods</h4>The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders.<h4>Results</h4>Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), ...[more]

PMID: 25503497

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Project description:UnlabelledGlycerol phenylbutyrate (glyceryl tri (4-phenylbutyrate)) (GPB) is being studied as an alternative to sodium phenylbutyrate (NaPBA) for the treatment of urea cycle disorders (UCDs). This phase 2 study explored the hypothesis that GPB offers similar safety and ammonia control as NaPBA, which is currently approved as adjunctive therapy in the chronic management of UCDs, and examined correlates of 24-h blood ammonia.MethodsAn open-label, fixed sequence switch-over study was conducted in adult UCD patients taking maintenance NaPBA. Blood ammonia and blood and urine metabolites were compared after 7 days (steady state) of TID dosing on either drug, both dosed to deliver the same amount of phenylbutyric acid (PBA).ResultsTen subjects completed the study. Adverse events were comparable for the two drugs; 2 subjects experienced hyperammonemic events on NaPBA while none occurred on GPB. Ammonia values on GPB were approximately 30% lower than on NaPBA (time-normalized AUC=26.2 vs. 38.4 micromol/L; Cmax=56.3 vs. 79.1 micromol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time-normalized AUC) by post hoc analysis. Systemic exposure (AUC(0-24)) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 microgh/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 microg h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 microg h/mL) were similar. Urinary PAGN excretion accounted for approximately 54% of PBA administered for both NaPBA and GPB; other metabolites accounted for <1%. Intact GPB was generally undetectable in blood and urine. Blood ammonia correlated strongly and inversely with urinary PAGN (r=-0.82; p<0.0001) but weakly or not at all with blood metabolite levels.ConclusionsSafety and ammonia control with GPB appear at least equal to NaPBA. Urinary PAGN, which is stoichiometrically related to nitrogen scavenging, may be a useful biomarker for both dose selection and adjustment for optimal control of venous ammonia.

Dataset Information

Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder.

Publications

Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder.

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