Advertisement

Hyperammonemias and Related Disorders

  • Johannes HäberleEmail author
  • Vicente Rubio
Chapter

Abstract

The term hyperammonemia describes a clinical situation marked by increased plasma ammonia concentration. It is generally due to decreased ammonia detoxification as urea. Patients can be of any age. Since ammonia is neurotoxic, life and mental status can be threatened within few hours of breaking the balance between ammonia production and detoxification, as in neonatal urea cycle defects patients when they stop relying on maternal ammonia detoxification upon birth. The urea cycle, fully expressed exclusively in periportal hepatocytes, is the main pathway to detoxify ammonia; it can be primarily affected by an inherited enzyme or transporter defect (primary hyperammonemia) or secondarily by toxic metabolites or substrate depletion (secondary hyperammonemia). Hyperammonemia in infants and children is mainly due to inborn metabolic errors causing primary or secondary hyperammonemia. In adults, hyperammonemia is more often due to acquired hepatic disease. The clinical manifestations of hyperammonemia are generally unspecific and are mainly neurological, gastrointestinal, or psychiatric. The hallmark of hyperammonemia is an unexplained change in consciousness; thus, in any unexplained encephalopathy hyperammonemia must be excluded without delay to avoid severe neurological sequelae. Treatment of acute hyperammonemia most urgently requires the establishment of anabolism and the avoidance of protein catabolism, with rapid initiation of parenteral glucose infusion and protein restriction. Additional urgent measures include the use of dialysis to remove ammonia and of medications that can improve residual urea cycle function (carbamylglutamate and either L-arginine or L-citrulline) and that allow circumventing the urea cycle (the nitrogen scavengers sodium benzoate and/or sodium phenylbutyrate). Liver transplantation is curative. Prognosis of acute hyperammonemia remains poor but can be improved by increasing awareness of healthcare professionals. This chapter focuses on hyperammonemia due to urea cycle defects but also deals with the very rare deficiencies of pyrroline-5-carboxylate synthetase and glutamine synthetase and with the transient hyperammonemia of the newborn.

Keywords

Glutamine Synthetase Urea Cycle Plasma Ammonia Urea Cycle Disorder Argininosuccinate Lyase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Bachmann C (2002) Mechanisms of hyperammonemia. Clin Chem Lab Med 40:653–662PubMedCrossRefGoogle Scholar
  2. Batshaw ML, MacArthur RB, Tuchman M (2001) Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 138:S46–S54; discussion S54–S55PubMedCrossRefGoogle Scholar
  3. Brusilow SW (1984) Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis. J Clin Invest 74:2144–2148PubMedCentralPubMedCrossRefGoogle Scholar
  4. Brusilow S, Horwich A (2001) Urea cycle enzymes. In: Scriver C, Beaudet A, Sly W, Valle D (eds) The metabolic & molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 1909–1963Google Scholar
  5. Colombo JP, Peheim E, Kretschmer R, Dauwalder H, Sidiropoulos D (1984) Plasma ammonia concentrations in newborns and children. Clin Chim Acta 138:283–291PubMedCrossRefGoogle Scholar
  6. Enns GM (2010) Nitrogen sparing therapy revisited 2009. Mol Genet Metab 100(Suppl 1):S65–S71PubMedCrossRefGoogle Scholar
  7. Grisolia S, Báguena R, Mayor F (eds) (1976) The urea cycle. Wiley, New York. ISBN 0-471-32791-3Google Scholar
  8. Gropman AL, Batshaw ML (2004) Cognitive outcome in urea cycle disorders. Mol Genet Metab 81(Suppl 1):S58–S62PubMedCrossRefGoogle Scholar
  9. Gropman AL, Summar M, Leonard JV (2007) Neurological implications of urea cycle disorders. J Inherit Metab Dis 30:865–879PubMedCentralPubMedCrossRefGoogle Scholar
  10. Häberle J (2011) Clinical practice: the management of hyperammonemia. Eur J Pediatr 170:21–34PubMedCrossRefGoogle Scholar
  11. Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Sanjurjo Crespo P, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C (2012) Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 7:32PubMedCentralPubMedCrossRefGoogle Scholar
  12. Häussinger D (1990a) Liver glutamine metabolism. J Parenter Enteral Nutr 14:56S–62SCrossRefGoogle Scholar
  13. Häussinger D (1990b) Nitrogen metabolism in liver: structural and functional organization and physiological relevance. Biochem J 267:281–290PubMedCentralPubMedGoogle Scholar
  14. Häussinger D, Görg B (2010) Interaction of oxidative stress, astrocyte swelling and cerebral ammonia toxicity. Curr Opin Clin Nutr Metab Care 13:87–92PubMedCrossRefGoogle Scholar
  15. Imamura Y, Kobayashi K, Shibatou T, Aburada S, Tahara K, Kubozono O, Saheki T (2003) Effectiveness of carbohydrate-restricted diet and arginine granules therapy for adult-onset type II citrullinemia: a case report of siblings showing homozygous SLC25A13 mutation with and without the disease. Hepatol Res 26:68–72PubMedCrossRefGoogle Scholar
  16. Leonard JV (2001) The nutritional management of urea cycle disorders. J Pediatr 138:S40–S44; discussion S44–S45PubMedCrossRefGoogle Scholar
  17. Leonard JV, McKiernan PJ (2004) The role of liver transplantation in urea cycle disorders. Mol Genet Metab 81(Suppl 1):S74–S78PubMedCrossRefGoogle Scholar
  18. Leonard JV, Morris AA (2002) Urea cycle disorders. Semin Neonatol 7:27–35PubMedCrossRefGoogle Scholar
  19. Mori M, Gotoh T, Nagasaki A, Takiguchi M, Sonoki T (1998) Regulation of the urea cycle enzyme genes in nitric oxide synthesis. J Inherit Metab Dis 21(Suppl 1):59–71PubMedCrossRefGoogle Scholar
  20. Mutoh K, Kurokawa K, Kobayashi K, Saheki T (2008) Treatment of a citrin-deficient patient at the early stage of adult-onset type II citrullinaemia with arginine and sodium pyruvate. J Inherit Metab Dis 31(Suppl 2):S343–S347PubMedCrossRefGoogle Scholar
  21. Nassogne MC, Heron B, Touati G, Rabier D, Saudubray JM (2005) Urea cycle defects: management and outcome. J Inherit Metab Dis 28:407–414PubMedCrossRefGoogle Scholar
  22. Palladino AA, Stanley CA (2010) The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord 11:171–178PubMedCrossRefGoogle Scholar
  23. Picca S, Dionisi-Vici C, Abeni D, Pastore A, Rizzo C, Orzalesi M, Sabetta G, Rizzoni G, Bartuli A (2001) Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol 16:862–867PubMedCrossRefGoogle Scholar
  24. Rubio V, Grisolia S (1981) Treating urea cycle defects. Nature 292:496PubMedCrossRefGoogle Scholar
  25. Singh RH (2007) Nutritional management of patients with urea cycle disorders. J Inherit Metab Dis 30:880–887PubMedCrossRefGoogle Scholar
  26. Summar ML, Dobbelaere D, Brusilow S, Lee B (2008) Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr 97:1420–1425PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Division of Metabolism and Children’s Research CenterUniversity Children’s HospitalZürichSwitzerland
  2. 2.Structural Enzymopathology Unit, Department of Genomics and ProteomicsInstituto de Biomedicina de Valencia of the Spanish National Research Council (CSIC) and Centre for Biomedical Network Research on Rare Diseases (CIBERER)ValenciaSpain

Personalised recommendations