Hyperammonaemia and IEM

  • Roshni Vara
  • Andrew Durward


Hyperammonaemia is a metabolic emergency and prompt treatment is paramount to optimize neurological outcome. Ammonia is extremely neurotoxic and increased levels can arise from an inherited or acquired defect in hepatic detoxification. Inborn errors of metabolism leading to hyperammonaemia mainly affect the hepatic urea cycle due to single enzyme deficiencies, transporter defects or mitochondrial dysfunction. Primary hyperammonaemia is a consequence of direct urea cycle dysfunction whereas secondary hyperammonaemia can result from disturbance of the urea cycle by toxic metabolites or substrate deficiencies. Immediate recognition and early initiation of specific treatment are of utmost importance. Prognostic factors include duration of hyperammonaemic coma and the extent of ammonia accumulation (Häberle et al. Orphanet J Rare Dis 7:32, 2012). The principles of management in the acute situation aim to rapidly remove ammonia, decrease production and replace rate limiting amino acids.


Inherited metabolic disease Ammonia Renal replacement therapy Dialysis Mitochondrial Liver 


  1. 1.
    Adeva MM, Souto G, Blanco N, Donapetry C. Ammonium metabolism in humans. Metabolism. 2012;61(11):1495–511.CrossRefPubMedGoogle Scholar
  2. 2.
    Jackson MJ, Beaudet AL, O’Brien WE. Mammalian urea cycle enzymes. Annu Rev Genet. 1986;20:431–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bowker R, Green A, Bonham JR. Guidelines for the investigation and management of a reduced level of consciousness in children: implications for clinical biochemistry laboratories. Ann Clin Biochem. 2007;44:506–11.CrossRefPubMedGoogle Scholar
  5. 5.
    Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, Sniderman King L, Smith M, Summar M. Urea cycle disorders: clinical presentation outside the newborn period. Crit Care Clin. 2005;21(4 Suppl):S9–17.CrossRefPubMedGoogle Scholar
  6. 6.
    Saudubray JM, Nassogne MC, de Lonlay P, Touati G. Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol. 2002;7(1):3–15.CrossRefPubMedGoogle Scholar
  7. 7.
    Barsotti RJ. Measurement of ammonia in blood. J Pediatr. 2001;138(1 Suppl):S11–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Wertheim-Tysarowska K, Gos M, Sykut-Cegielska J. Bal J; genetic analysis in inherited metabolic disorders--from diagnosis to treatment. Own experience, current state of knowledge and perspectives. Dev Period Med. 2015;19(4):413–31.PubMedGoogle Scholar
  9. 9.
    Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat. 2006;27(7):626–32.CrossRefPubMedGoogle Scholar
  10. 10.
    Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B. The incidence of urea cycle disorders. European registry and network for intoxication type metabolic diseases (E-IMD). Mol Genet Metab. 2013;110(1–2):179–80.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Legido-Quigley C, Cloarec O, Parker DA, Murphy GM, Holmes E, Lindon JC, Nicholson JK, Mitry RR, Vilca-Melendez H, Rela M, Dhawan A, Heaton N. First example of hepatocyte transplantation to alleviate ornithine transcarbamylase deficiency, monitored by NMR-based metabonomics. Bioanalysis. 2009;1(9):1527–35.CrossRefPubMedGoogle Scholar
  12. 12.
    Kido J, Matsumoto S, Momosaki K, Sakamoto R, Mitsubuchi H, Endo F, Nakamura K. Liver transplantation may prevent neurodevelopmental deterioration in high-risk patients with urea cycle disorders. Pediatr Transplant. 2017;21(6)Google Scholar
  13. 13.
    Yu L, Rayhill SC, Hsu EK, Landis CS. Liver transplantation for urea cycle disorders: analysis of the united network for organ sharing database. Transplant Proc. 2015;47(8):2413–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003;162(6):410–6.PubMedGoogle Scholar
  15. 15.
    Batshaw ML, Tuchman M, Summar M, Seminara J, Members of the Urea Cycle Disorders Consortium. A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014;113(1–2):127–3.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Burgard P, Kölker S, Haege G, Lindner M, Hoffmann GF. Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders—review and meta-analysis of observational studies published over more than 35 years. J Inherit Metab Dis. 2016;39(2):219–2.CrossRefPubMedGoogle Scholar
  17. 17.
    Posset R, Garcia-Cazorla A, Valayannopoulos V, Teles EL, Dionisi-Vici C, Brassier A, Burlina AB, Burgard P, Cortès-Saladelafont E, Dobbelaere D, Couce ML, Sykut-Cegielska J, Häberle J, Lund AM, Chakrapani A, Schiff M, Walter JH, Zeman J, Vara R, Kölker S. Additional individual contributors of the E-IMD consortium; age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis. 2016;39(5):661–72.CrossRefPubMedGoogle Scholar
  18. 18.
    Fraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical management update. Curr Opin Pediatr. 2016;28(6):682–93.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Oplin SE. Pathophysiology of fatty acid oxidation disorders and resultant phenotypic variability. J Inherit Metab Dis. 2013;36(4):645–58.CrossRefGoogle Scholar
  20. 20.
    Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab. 2012;106(1):12–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Martinelli D, Diodato D, Ponzi E, Monné M, Boenzi S, Bertini E, Fiermonte G, Dionisi-Vici C. The hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Orphanet J Rare Dis. 2015;10:29.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Palladino AA, Stanley CA. The hyperinsulinism/hyperammonemia syndrome. Rev Endocr Metab Disord. 2010;11(3):171–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Häberle J. Clinical and biochemical aspects of primary and secondary hyperammonemic disorders. Arch Biochem Biophys. 2013;536(2):101–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Magner M, Dvorakova V, Tesarova M, Mazurova S, Hansikova H, Zahorec M, Brennerova K, Bzduch V, Spiegel R, Horovitz Y, Mandel H, Eminoğlu FT, Mayr JA, Koch J, Martinelli D, Bertini E, Konstantopoulou V, Smet J, Rahman S, Broomfield A, Stojanović V, Dionisi-Vici C, van Coster R, Morava E, Sperl W, Zeman J, Honzik T. TMEM70 deficiency: long-term outcome of 48 patients. J Inherit Metab Dis. 2015;38(3):417–26.CrossRefPubMedGoogle Scholar
  25. 25.
    Diez-Fernandez C, Rüfenacht V, Santra S, Lund AM, Santer R, Lindner M, Tangeraas T, Unsinn C, de Lonlay P, Burlina A, van Karnebeek CD, Häberle J. Defective hepatic bicarbonate production due to carbonic anhydrase VA deficiency leads to early-onset life-threatening metabolic crisis. Genet Med. 2016;18(10):991–1000.CrossRefPubMedGoogle Scholar
  26. 26.
    Auron A, Brophy PD. Hyperammonemia in review: pathophysiology, diagnosis, and treatment. Pediatr Nephrol. 2012;27(2):207–22.CrossRefPubMedGoogle Scholar
  27. 27.
    Häberle J. Clinical practice: the management of hyperammonemia. Eur J Pediatr. 2011;170(1):21–34.CrossRefPubMedGoogle Scholar
  28. 28.
    Lang W, Blöck TM, Zander R. Solubility of NH3 and apparent pK of NH4+ in human plasma, isotonic salt solutions and water at 37 degrees C. Clin Chim Acta. 1998;273(1):43–58.CrossRefPubMedGoogle Scholar
  29. 29.
    da Fonseca-Wollheim F, Heinze KG. Solubility of NH3 and apparent pK of NH4+ in human plasma, isotonic salt solutions and water at 37 degrees C. Eur J Clin Chem Clin Biochem. 1992;30(12):867–9.PubMedGoogle Scholar
  30. 30.
    Thrane V, Thrane A, Wang W, et al. Solubility of NH3 and apparent pK of NH4+ in human plasma, isotonic salt solutions and water at 37 degrees C. Nat Med. 2013;19(12):1643–8.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Berry E, Rhead S, Brusilow W, Hamosh S. Survival after treatment with phenyl acetate and benzoate for urea cycle disorders. NEJM. 2007;356:2282–92.CrossRefPubMedGoogle Scholar
  32. 32.
    Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. J Inherit Metab Dis. 1998;21(Suppl 1):151–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Msall M, Batshaw ML, Suus R, Brusilow SW, Mellitis ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med. 1984;310(23):1500–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Westrope C, Morris K, Burford D, Morrison G. Continuous hemofiltration in the control of neonatal hyperammonemia: a 10-year experience. Pediatr Nephrol. 2010;25(9):1725–30.CrossRefPubMedGoogle Scholar
  35. 35.
    Picca S, Dionisi-Vici C, Bartuli A, De Palo T, Papadia F, Montini G, Materassi M, Donati MA, Verrina E, Schiaffino MC, Pecoraro C, Iaccarino E, Vidal E, Burlina A, Emma F. Short-term survival of hyperammonemic neonates treated with dialysis. Pediatr Nephrol. 2015;30:839–47.CrossRefPubMedGoogle Scholar
  36. 36.
    Schaefer F, Straube E, Oh J, Mayatepeck E. Dialysis in neonates with inborn errors of metabolism. Nephrol Dial Transplant. 1999;14:910–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Arbeiter AK, Kranz B, Wingen AM, Bonzel KE, Dohna-Schwake C, Hanssler L, Neudorf U, Hoyer PF, Büscher R. Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism. Nephrol Dial Transplant. 2010;25(4):1257–65.CrossRefPubMedGoogle Scholar
  38. 38.
    McBryde KD, Kershaw DB, Bunchman TE, Maxvold NJ, Mottes TA, Kudelka TL, Brophy PD. Renal replacement therapy in the treatment of confirmed or suspected inborn errors of metabolism. J Pediatr. 2006;148:770–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Spinale JM, Laskin BL, Sondheimer N, Swartz SJ, Goldstein SL. High-dose continuous renal replacement therapy for neonatal hyperammonemia. Pediatr Nephrol. 2013;28:983–6.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Hackbarth R, Bunchman TE, Chua AN, et al. The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry. Int J Artif Organs. 2007;30:1116–21.CrossRefPubMedGoogle Scholar
  41. 41.
    Picca S, Dionisi-Vici C, Abeni D, Pastore A, Rizzo C, Orzalesi M, Sabetta G, Rizzoni G, Bartuli A. Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators. Pediatr Nephrol. 2001;16(11):862–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Lai Y-C, Huang H-P, Tsai I-J, Tsau Y-K. High-volume continuous venovenous hemofiltration as an effective therapy for acute management of inborn errors of metabolism in young children. Blood Purif. 2007;25:303–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Clark WR, Turk JE, Kraus MA, Gao D. Dose determinants in continuous renal replacement therapy. Int J Artif Organs. 2003;27:815–20.CrossRefGoogle Scholar
  44. 44.
    Huang Z, Letteri J, Clark WJ, Ronco C, Gao D. Operational characteristics of continuous renal replacement modalities used for critically ill patients with acute kidney injury. Int J Artif Organs. 2008;31(6):525–34.CrossRefPubMedGoogle Scholar
  45. 45.
    Troyanov S, Cardinal J, Geadah D, Parent D, Courteau S, et al. Solute clearances during continuous venovenous haemofiltration at various ultrafiltration flow rates using Multiflow-100 and HF1000 filters. Nephrol Dial Transplant. 2003;18:961–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Little MA, Conlon PJ, Walshe JJ. Access recirculation in temporary hemodialysis catheters as measured by the saline dilution technique. Am J Kidney Dis. 2000;6:1135–9.CrossRefGoogle Scholar
  47. 47.
    Bunchman TE, Barletta GM, Winters JW, Gardner JJ, Crumb TL, McBryde KD. Phenylacetate and benzoate clearance in a hyperammonemic infant on sequential hemodialysis and haemofiltration. Pediatr Nephrol. 2007;22(7):1062–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Paediatric Inherited Metabolic DiseaseEvelina London Children’s HospitalLondonUK
  2. 2.Paediatric Intensive Care UnitEvelina London Children’s HospitalLondonUK

Personalised recommendations