The treatment of ASA involves two different scenarios – 1) rapid control of hyperammonemia during metabolic decompensations and 2) chronic long term management to help prevent episodes of hyperammonemia and the long term complications
During acute hyperammonemic episodes, the management of ASA is not much different than other UCD excepting that a higher dose of intravenous arginine is used for the priming and maintenance infusion. In short the management of hyperammonemia includes discontinuing the oral protein intake, caloric supplementation with intravenous glucose and/or lipids along with initiation of intravenous drugs to scavenge ammonia (2001; Enns et al., 2007
). Chronic management of ASA includes dietary restriction of protein and arginine supplementation. Patients who have had frequent metabolic decompensations or elevated ammonia are candidates for additional oral nitrogen scavenging therapy with either sodium benzoate or sodium phenyl butyrate. Diet constitutes a key component of the treatment. The Recommended Daily Allowance (RDA) for dietary protein is often higher than the minimum needed for normal growth. Most patients with a UCD can receive less than the RDA of protein and still maintain adequate growth patterns. There are some contradicting evidences regarding the correlation between compliance with the prescribed diet and outcome. Dietary therapy along with arginine supplementation has been shown to reverse the abnormalities of hair and to improve cognitive outcome including reversal of abnormalities on EEG (Ficicioglu et al., 2009
; Kvedar et al., 1986; Coryell et al., 1964
). However, dietary therapy has not been shown to influence the outcome of liver disease (Mori et al., 2002
, Mercimek-Mahmutoglu et al, 2010). In addition, the efficacy of arginine supplementation in either preventing the hyperammonemic episodes or the chronic complications is not known. While evidence suggests that arginine supplementation may prevent metabolic decompensations in patients with severe early onset disease, long term follow up of patients detected through NBS did not show any discernible difference in outcomes between those on supplementation as compared to those who were not on arginine (Donn et al., 1985; Batshaw et al., 2001; Ficicioglu et al., 2009
; Mercimek-Mahmutoglu et al., 2010). While this observation is counterintuitive to the notion of decrease in arginine as a cause for these complications, it may support a unique role for ASL in the subcellular compartmentalization for arginine utilization and the basis for the “arginine paradox” (B. Lee unpublished data).
A theoretical concern with arginine supplementation is that while it compensates for the decreased synthesis, it also generates increased amounts of argininosuccinic acid that is hypothesized to be toxic together with increase in guanidino acetate (Schulze et al., 2001
). Magnetic resonance spectroscopy of brain in ASA patients on arginine supplementation has revealed elevations of guanidino acetate with either normal decreased or elevated levels of creatine (Sijens et al., 2006
; van Spronsen et al., 2006
). Hence, the ideal dosing of arginine and its utility in treatment of ASA is still unclear.
The alternative pathway therapy includes the use of sodium benzoate and sodium phenyl butyrate to stimulate the excretion of nitrogen in the form of hippuric acid and phenylacetylglutamine, respectively (Batshaw et al., 2001). Though there have been no controlled studies, and it is unlikely that there ever will be due to ethical reasons, treatment with alternative pathway therapy appears to have improved survival, biochemical control and neurologic outcome in patients with urea cycle disorders (Batshaw et al., 1982; Maestri et al., 1991; Maestri et al., 1995). However for reasons mentioned above that point to metabolites other than ammonia that are also involved in long term complications in ASA, the efficacy of nitrogen scavenging therapy in prevention of the same is not known. As many patients with ASA are metabolically well controlled with diet and arginine supplementation, it would seem reasonable to use the phenyl butyrate and benzoate in patients who have had hyperammonemia and have not been controlled with arginine, and at the same time to minimize the effective chronic dosing of arginine.
Long term correction of the defect in urea cycle can be accomplished by orthotopic liver transplantation (OLT) (Lee and Goss, 2001). OLT has resulted in biochemical cure in patients with ASA (Newnham et al., 2008; Robberecht et al., 2006; Marble et al., 2008). However OLT does not correct the biochemical abnormalities including arginine deficiency at the tissue levels or elevation of argininosuccinic acid, two abnormalities that have been hypothesized to account for the long term complications. This being the case, it is our policy to recommend OLT only in patients with recurrent hyperammonemia, metabolic decompensations that are resistant to conventional therapy or in cases with cirrhosis with decompensation.