A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria

Sandesh C.S. Nagamani, Oleg A. Shchelochkov, Mary A. Mullins, Susan Carter, Brendan Lanpher, Qin Sun, Soledad Kleppe, Ayelet Erez, E. O'Brian Smith, Juan C. Marini, Brendan Lee

Research output: Contribution to journalArticle

23 Scopus citations


Objective: To compare the effects of combinatorial therapy with low-dose arginine and a nitrogen scavenging agent (sodium phenylbutyrate) vs. monotherapy with high-dose arginine on liver function tests in patients with argininosuccinic aciduria (ASA). Study design: Twelve patients with ASA were enrolled in a double-blind, placebo-controlled, cross-over study design. Subjects were randomized to receive either a low-dose of arginine therapy (100mg·kg-1·d-1) combined with sodium phenylbutyrate (500mg·kg-1·d-1) (LDA arm) or a high-dose of arginine alone (500mg·kg-1·d-1) (HDA arm) for one week. At the end of one week of therapy, liver function tests were assessed and metabolite fluxes were measured using a multi-tracer stable isotope protocol. Results: Plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and measures of synthetic functions of the liver were the primary outcomes. Subjects had significantly increased levels of argininosuccinate (P<0.03) and AST levels (P<0.01) after treatment with high-dose arginine. In the subset of subjects with elevated AST or ALT, treatment with high-dose of arginine was associated with further increases in plasma levels of both aminotransferases. Whereas subjects had increased arginine and citrulline flux with high-dose arginine therapy, the glutamine flux was not different between the two treatment arms. The synthetic liver functions as assessed by prothrombin time, INR, and coagulation factor levels were not different between the HDA and LDA arms. Conclusions: Administering higher doses of arginine in subjects with ASA results in increases in AST and ALT levels, especially in the subset of patients with elevated baseline aminotransferases. Hence, low-dose arginine sufficient to normalize arginine levels in plasma combined with nitrogen scavenging therapy should be considered as a therapeutic option for treatment of ASA in patients with elevations of hepatic aminotransferases.

Original languageEnglish (US)
Pages (from-to)315-321
Number of pages7
JournalMolecular Genetics and Metabolism
Issue number3
StatePublished - Nov 1 2012
Externally publishedYes



  • Arginine therapy
  • Argininosuccinate lyase
  • Argininosuccinic aciduria
  • Hepatic disease
  • Rare disease clinical research

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Nagamani, S. C. S., Shchelochkov, O. A., Mullins, M. A., Carter, S., Lanpher, B., Sun, Q., Kleppe, S., Erez, A., O'Brian Smith, E., Marini, J. C., & Lee, B. (2012). A randomized controlled trial to evaluate the effects of high-dose versus low-dose of arginine therapy on hepatic function tests in argininosuccinic aciduria. Molecular Genetics and Metabolism, 107(3), 315-321. https://doi.org/10.1016/j.ymgme.2012.09.016