Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients

Abstract

Urea cycle disorders (UCDs) are a group of inborn errors of hepatic metabolism caused by the loss of enzymatic activities that mediate the transfer of nitrogen from ammonia to urea. These disorders often result in life-threatening hyperammonemia and hyperglutaminemia. A combination of sodium phenylbutyrate and sodium phenylacetate/benzoate is used in the clinical management of children with urea cycle defects as a glutamine trap, diverting nitrogen from urea synthesis to alternatives routes of excretion. We have observed that patients treated with these compounds have selective branched chain amino acid (BCAA) deficiency despite adequate dietary protein intake. However, the direct effect of alternative therapy on the steady state levels of plasma branched chain amino acids has not been well characterized. We have measured steady state plasma branched chain and other essential non-branched chain amino acids in control subjects, untreated ornithine transcarbamylase deficiency females and treated null activity urea cycle disorder patients in the fed steady state during the course of stable isotope studies. Steady-state leucine levels were noted to be significantly lower in treated urea cycle disorder patients when compared to either untreated ornithine transcarbamylase deficiency females or control subjects (P<0.0001). This effect was reproduced in control subjects who had depressed leucine levels when treated with sodium phenylacetate/benzoate (P<0.0001). Our studies suggest that this therapeutic modality has a substantial impact on the metabolism of branched chain amino acids in urea cycle disorder patients. These findings suggest that better titration of protein restriction could be achieved with branched chain amino acid supplementation in patients with UCDs who are on alternative route therapy.

Introduction

Urea cycle disorders (UCDs) are a group of inborn errors of hepatic metabolism that result in often life-threatening hyperammonemia and hyperglutaminemia [1]. The management of hyperammonemic episodes in these disorders is achieved by dietary protein restriction, supportive management of catabolic stress, and the use of compounds that remove nitrogen by alternative pathways. Alternative pathway therapy includes the use of sodium phenylacetate/benzoate (Ucephan) or sodium phenylbutyrate (Buphenyl) to stimulate the excretion of nitrogen as phenylacetylglutamine and hippuric acid (in the case of Ucephan) [2], [3]. Phenylbutyrate does not accumulate in plasma, and within minutes, it is first activated to its CoA ester, and then converted to phenylacetylCoA via β-oxidation [2]. This ultimately is conjugated with glutamine in the liver and kidney to yield phenylacetylglutamine, which is excreted in the urine. Hence, it replaces urea as a means of eliminating excess nitrogen compounds. We have previously shown that the treatment with Ucephan in both control and UCD subjects will increase glutamine flux and decrease total body urea flux directly proportional to the molar conversion of phenylacetate to phenylacetylglutamine [4].

We have observed in our UCD patient population that this therapy leads to a marked fall in serum branched chain amino acids (BCAA) concentrations in spite of apparently adequate levels of total protein intake. This observed fall has often preceded a metabolic decompensation. One predicted effect of these compounds might be the dysregulation of global protein synthesis. Phenylbutyrate-induced glutamine depletion in healthy subjects has been shown to exert a profound effect on leucine metabolism including the lowering of plasma leucine concentrations and increasing leucine oxidation [5]. In addition, several conditions leading to hyperammonemia, including liver cirrhosis and idiopathic portal hypertension, a condition characterized by extensive portal-systemic shunting, are invariably associated with a decline in the plasma levels of BCAA [6], [7]. This suggests that hyperammonemia and intracellular glutamate depletion may contribute to BCAA deficiency through the stimulation of BCAA transamination. The present study was designed to achieve a deeper understanding of the effect of alternative pathway therapy on branched chain amino acid metabolism in fed UCD patients, asymptomatic untreated ornithine transcarbamylase (OTC)-deficient females, and normal controls.