Survival after Treatment with Phenylacetate and Benzoate for Urea-Cycle Disorders

Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, United States
New England Journal of Medicine (Impact Factor: 55.87). 05/2007; 356(22):2282-92. DOI: 10.1056/NEJMoa066596
Source: PubMed


The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects.
We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia.
Overall survival was 84% (250 of 299 patients). Ninety-six percent of the patients survived episodes of hyperammonemia (1132 of 1181 episodes). Patients over 30 days of age were more likely than neonates to survive an episode (98% vs. 73%, P<0.001). Patients 12 or more years of age (93 patients), who had 437 episodes, were more likely than all younger patients to survive (99%, P<0.001). Eighty-one percent of patients who were comatose at admission survived. Patients less than 30 days of age with a peak ammonium level above 1000 micromol per liter (1804 microg per deciliter) were least likely to survive a hyperammonemic episode (38%, P<0.001). Dialysis was also used in 56 neonates during 60% of episodes and in 80 patients 30 days of age or older during 7% of episodes.
Prompt recognition of a urea-cycle disorder and treatment with both sodium phenylacetate and sodium benzoate, in conjunction with other therapies, such as intravenous arginine hydrochloride and the provision of adequate calories to prevent catabolism, effectively lower plasma ammonium levels and result in survival in the majority of patients. Hemodialysis may also be needed to control hyperammonemia, especially in neonates and older patients who do not have a response to intravenous sodium phenylacetate and sodium benzoate.

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    • "Conversely, benzoate combines with glycine to form hippurate, which is also excreted in urine[13,15]. Both compounds reduce the total body nitrogen content; however, this therapy has also failed in a fraction of patients with hyperammonemic crisis who became refractory most probably due to the accumulation of nitrogen waste[9]. This led to the concept that only blood ammonia concentrations below 500 lM should be treated pharmacologically; whereas, more severe hyperammonemia requires aggressive interventions with renal replacement therapies, such as hemodialysis[12,16]. "
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    ABSTRACT: & aims: Recently, spatial-temporal/metabolic mathematical models have been established that allow the simulation of metabolic processes in tissues. We applied these models to decipher ammonia detoxification mechanisms in the liver.Methods: An integrated metabolic-spatial-temporal model was used to generate hypotheses of ammonia metabolism. Predicted mechanisms were validated using time resolved analyses of nitrogen metabolism, activity analyses, immunostaining and gene expression after induction of liver damage in mice. Moreover, blood from the portal vein, liver vein and mixed venous blood was analyzed in a time dependent manner.Results: Modeling revealed an underestimation of ammonia consumption after liver damage when only the currently established mechanisms of ammonia detoxification were simulated. By iterative cycles of modeling and experiments the reductive amidation of alpha-ketoglutarate (α-KG) via glutamate dehydrogenase (GDH) was identified as the lacking component. GDH is released from damaged hepatocytes into the blood where it consumes ammonia to generate glutamate, thereby providing systemic protection against hyperammonemia. This mechanism was exploited therapeutically in a mouse model of hyperammonemia by injecting GDH together with optimized doses of co-factors. Intravenous injection of GDH (720 U/kg), α-KG (280 mg/kg) and NADPH (180 mg/kg) reduced the elevated blood ammonia concentrations (>200 μM) to levels close to normal within only 15 min.Conclusion: If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia.
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    • "This concentration is considerably higher than those seen in hepatic encephalopathy of <300 lM (Lockwood et al., 1979), with brain concentrations of ammonia ranging between 1.0 and 2.0 mM (Schenker et al., 1967; Hindfelt, 1975; Ehrlich et al., 1980). However, plasma ammonia concentrations well above 300 lM are seen in valproate poisoning (Commandeur et al., 2010), and in urea cycle disorders plasma ammonia concentrations of 600 lM are far from the maximum concentrations encountered (Enns et al., 2007). Although cerebral ammonia toxicity is undoubtedly multifactorial , the restricted brain extracellular space and the encagement of the brain within the skull may be the main reason for rapid ammonia-induced death due to cerebral swelling. "
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    • "BCAA levels in patients with acute injury are normal or even increased , and their enhanced intake should be avoided. Favorable effects of ammonia-lowering strategies have been reported in urea cycle disorders (Brusilow 1991; Enns et al. 2007) and in liver cirrhosis (Walshe 1953; McGuire et al. 2010). However, the use of ammonia-lowering strategies has not been found to be effective enough in patients with acute liver failure (Acharya et al. 2009; Bémeur and Butterworth 2013). "
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