NTBC and Correction of Renal Dysfunction

  • Arianna MaioranaEmail author
  • Carlo Dionisi-Vici
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 959)


Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. Kidney involvement is characterized by hypophosphatemic rickets and Fanconi syndrome. Different animal models were useful to investigate the pathophysiology of the disease and the effects of NTBC therapy on liver and kidney function. NTBC has revolutionized the prognosis of HT1 and its acute and chronic effects on renal tubular function have been proved, with normalization of tubular function within a few weeks, particularly hypophosphatemia and proteinuria. NTBC therapy is highly effective in improving renal function both at short and long-term. However, its efficacy critically depends on the age at start of treatment with normal outcome in patients diagnosed at birth by newborn screening.


Renal tubular dysfunction Rickets Fanconi syndrome NTBC therapy 



Calculated glomerular filtration rate




Fumarylacetoacetate hydrolase


Hepatocellular carcinoma


Homogentisic acid


Hydroxyphenylpyruvate dioxygenase


Hereditary tyrosinemia type 1




Orthotopic liver transplantation




Succinyl acetoacetate


Tubular reabsorption of phosphate


  1. Arnon R, Annunziato R, Miloh T, Wasserstein M, Sogawa H, Wilson M, Suchy F, Kerkar N (2011) Liver transplantation for hereditary tyrosinemia type I: analysis of the UNOS database. Pediatr Transplant 15:400–405CrossRefPubMedGoogle Scholar
  2. Bartlett DC, Preece MA, Holme E, Lloyd C, Newsome PN, McKiernan PJ (2013) Plasma succinylacetone is persistently raised after liver transplantation in tyrosinaemia type 1. J Inherit Metab Dis 36:15–20CrossRefPubMedGoogle Scholar
  3. Bartlett DC, Lloyd C, McKiernan PJ, Newsome PN (2014) Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post-transplant renal function. J Inherit Metab Dis 37:745–752CrossRefPubMedGoogle Scholar
  4. Chakrapani A, Gissen P, McKiernan P (2012) Disorders of tyrosine metabolism. In: Saudubray J-M, van den Berghe G, Walter JH (eds) Inborn metabolic diseases, 5th edn. Springer, Heidelberg, pp 275–276. Chapter 18Google Scholar
  5. Couce ML, Dalmau J, del Toro M, Pintos-Morell G, Aldámiz-Echevarría L, Spanish Working Group on Tyrosinemia type 1 (2011) Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome. Ped Intern 53:985–989CrossRefGoogle Scholar
  6. de Laet C, Dionisi-Vici C, Leonard J, McKiernan P, Mitchell G, Monti L, de Baulny H, Pintos-Morell G, Spiekerkötter U (2013) Recommendations for the management of tyrosinaemia type 1. Orphanet J Rare Dis 8:8CrossRefPubMedPubMedCentralGoogle Scholar
  7. El-Karaksy H, Rashed M, El-Sayed R, El-Raziky M, El-Koofy N, El-Hawary M, Al-Dirbashi O (2010) Clinical practice. NTBC therapy for tyrosinemia type 1: how much is enough? Eur J Pediatr 169(6):689–693CrossRefPubMedGoogle Scholar
  8. Endo F, Kubo S, Awata H, Kiwaki K, Katoh H, Kanegae Y, Saito I, Miyazaki J, Yamamoto T, Jakobs C, Hattori S, Matsuda I (1997) Complete rescue of lethal albino c14CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygense and induction of apoptosis of hepatocytes in these mice by an in vivo retrieval of the tyrosine catabolic pathway. J Biol Chem 272:24426–24432CrossRefPubMedGoogle Scholar
  9. Forget S, Patriquin HB, Dubois J, Lafortune M, Merouani A, Paradis K, Russo P (1999) The kidney in children with tyrosniemia: sonographic, CT and biochemical findings. Pediatr Radiol 29:104–108CrossRefPubMedGoogle Scholar
  10. Gluecksohn-Waelsch S (1979) Genetic control of morphogenetic and biochemical differentiation: lethal albino deletion in the mouse. Cell 16:225–237CrossRefPubMedGoogle Scholar
  11. Grompe M (2001) The pathophysiology and treatment of hereditary Tyrosinemia type 1. Semin Liver Dis 21:563–571CrossRefPubMedGoogle Scholar
  12. Grompe M, Al Dhalimy M, Finegold M, Ou CN, Burlingame T, Kennaway NG, Soriano P (1993) Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes Dev 7:2298–2307CrossRefPubMedGoogle Scholar
  13. Grompe M, Lindstedt S, Al Dhalimy M, Kennaway NG, Papaconstantinou J, Torres-Ramos CA, Ou CA, Finegold M (1995) Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinemia type I. Nat Genet 10:453–460CrossRefPubMedGoogle Scholar
  14. Grompe M, Overturf K, Al-Dhalimy M, Finegold M (1998) Therapeutic trials in the murine model of hereditary tyrosinemia type I: a progress report. J Inherit Metab Dis 21:518–531CrossRefPubMedGoogle Scholar
  15. Haber BA, Chuang E, Lee V, Taub R (1996) Variable gene expression with human tyrosinemia type 1 liver may reflect region-specific dysplasia. Hepatology 24:65–71CrossRefPubMedGoogle Scholar
  16. Herzog D, Martin S, Turpin S, Alvarez F (2006) Normal glomerular filtration rate in long-term follow-up of children after orthotopic liver transplantation. Transplantation 8:672–677CrossRefGoogle Scholar
  17. Jorquera R, Tanguay RM (1997) The mutagenicity of the tyrosine metabolite, fumarylacetoacetate, is enhanced by glutathione depletion. Biochem Biophys Res Commun 232:42–48CrossRefPubMedGoogle Scholar
  18. Jorquera R, Tanguay RM (2001) Fumarylacetoacetate, the metabolite accumulating in hereditary tyrosinemia, activates the ERK pathway and induces mitotic abnormalities and genomic instability. Hum Mol Genet 10:1741–1752CrossRefPubMedGoogle Scholar
  19. Kubo S, Kiwaki K, Awata H, Katoh H, Kanegae Y, Saito I, Yamamoto T, Miyazaki J, Matsuda I, Endo F (1997) In vivo correction with recominant adenovirus of 4-hydroxyphenylpyruvate acid dioxygenase deficiencies in train III mice. Hum Gene Ther 8:65–71CrossRefPubMedGoogle Scholar
  20. Kvittingen EA, Jellum E, Stokke O, Flatmark A, Bergan A, Sødal G, Halvorsen S, Schrumpf E, Gjone E (1986) Liver transplantation in a 23-year-old tyrosinaemia patient: effects on the renal tubular dysfunction. J Inherit Metab Dis 9:216–224CrossRefPubMedGoogle Scholar
  21. Larochelle J, Alvarez F, Bussières JF, Chevalier I, Dallaire L, Dubois J, Faucher F, Fenyves D, Goodyer P, Grenier A, Holme E, Laframboise R, Lambert M, Lindstedt S, Maranda B, Melançon S, Merouani A, Mitchell J, Parizeault G, Pelletier L, Phan V, Rinaldo P, Scott CR, Scriver C, Mitchell GA (2012) Effect of nitisinone (NITISINONE) treatment on the clinical course of hepatorenal tyrosinemia in Québec. Mol Genet Metab 107:49–54CrossRefPubMedGoogle Scholar
  22. Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B (1992) Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. Lancet 340:813–817CrossRefPubMedGoogle Scholar
  23. Maiorana A, Malamisura M, Emma F, Boenzi S, Di Ciommo VM, Dionisi-Vici C (2014) Early effect of NTBC on renal tubular dysfunction in hereditar tyrosinemia type 1. Mol Genet Metab 113:188–193CrossRefPubMedGoogle Scholar
  24. Manabe S, Sassa S, Kappas A (1985) Hereditary tyrosinemia. Formation of succinylacetone-amino acid adducts. J Exp Med 162:1060–1074CrossRefPubMedGoogle Scholar
  25. Masurel-Paulet A, Poggi-Bach J, Rolland MO, Bernard O, Guffon N, Dobbelaere D, Sarles J, de Baulny HO, Touati G (2008) NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. J Inherit Metab Dis 31:81–87CrossRefPubMedGoogle Scholar
  26. Mayorandan S, Meyer U, Gokcay G, Segarra NG, de Baulny HO, van Spronsen F, Zeman J, de Laet C, Spiekerkoetter U, Thimm E, Maiorana A, Dionisi-Vici C, Moeslinger D, Brunner-Krainz M, Lotz-Havla AS, Cocho de Juan JA, Couce Pico ML, Santer R, Scholl-Bürgi S, Mandel H, Bliksrud YT, Freisinger P, Aldamiz-Echevarria LJ, Hochuli M, Gautschi M, Endig J, Jordan J, McKiernan P, Ernst S, Morlot S, Vogel A, Sander J, Das AM (2014) Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice. Orphanet J Rare Dis 9:107CrossRefPubMedPubMedCentralGoogle Scholar
  27. McKiernan PJ, Preece MA, Chakrapani A (2015) Outcome of children with hereditary tyrosinaemia following newborn screening. Arch Dis Child 100:738–741CrossRefPubMedGoogle Scholar
  28. Mohan N, McKiernan P, Preece MA, Green A, Buckels J, Mayer AD, Kelly DA (1999) Indications and outcome of liver transplantation in tyrosinaemia type 1. Eur J Pediatr 158(Suppl 2):S49–S54CrossRefPubMedGoogle Scholar
  29. Nakamura K, Tanaka Y, Mitsubuchi H, Endo F (2007) Animal models of Tyrosinemia. J Nutr 137:1556S–1560SPubMedGoogle Scholar
  30. Orejuela D, Jorquera R, Bergeron A, Finegold MJ, Tanguay RM (2008) Hepatic stress in hereditary tyrosinemia type 1 (HT1) activates the AKT survival pathway in the fah−/− knockout mice model. J Hepatol 48(2):308–317CrossRefPubMedGoogle Scholar
  31. Paradis K, Weber A, Seidman EG, Larochelle J, Garel L, Lenaerts C, Roy CC (1990) Liver transplantation for he reditary tyrosinemia: the Quebec experience. Am J Hum Genet 47:338–342Google Scholar
  32. Pierik LJ, van Spronsen FJ, Bijleveld CM, van Dael CM (2005) Renal function in tyrosinaemia type I after liver transplantation: a long-term follow-up. J Inherit Metab Dis 28(6):871–876CrossRefPubMedGoogle Scholar
  33. Pronicka E, Rowinska E, Bentkowski Z, Zawadzki J, Holme E, Lindstedt S (1996) Treatment of two children with hereditary tyrosinaemia type I and long-standing renal disease with a 4 hydroxyphenylpyruvate dioxygenase inhibitor (NTBC). J Inherit Metab Dis 19:234–238CrossRefPubMedGoogle Scholar
  34. Roth K, Spencer PD, Higgins ES, Spencer RF (1985) Effects of succinylacetone on methyl α-D-glucoside uptake by the rat renal tubule. Biochim Biophys Acta 820:140–146CrossRefPubMedGoogle Scholar
  35. Santra S, Preece MA, Hulton SA, McKiernan PJ (2008) Renal tubular function in children with tyrosinaemia type I treated with nitisinone. J Inherit Metab Dis 31:399–402CrossRefPubMedGoogle Scholar
  36. Shoemaker LR, Strife CF, Balistreri WF, Ryckman FC (1992) Rapid improvement in the renal tubular dysfunction associated with tyrosinemia following hepatic replacement. Pediatrics 89(2):251–255PubMedGoogle Scholar
  37. Spencer PD, Roth KS (1987) Effects of succinylacetone on amino acid uptake in the rat kidney. Biochem Med Metab Biol 37:101–109CrossRefPubMedGoogle Scholar
  38. Spencer PD, Medow MS, Moses LC, Roth KS (1988) Effects of succinylacetone on the uptake of sugars and amino acids by brush border vesicles. Kidney Int 34(5):671–677CrossRefPubMedGoogle Scholar
  39. Sun MS, Hattori S, Kubo S, Awata H, Matsuda I, Endo F (2000) A mouse model of renal tubular Injury of tyrosinemia type 1: development of de Toni Fanconi syndrome and apoptosis of renal tubular cells in Fah/Hpd double mutant mice. J Am Soc Nephrol 11:291–300PubMedGoogle Scholar
  40. Trigg MJ, Gluecksohn-Waelsch S (1973) Ultrastructural basis of biochemical effects in a series of lethal alleles in the mouse. J Cell Biol 58:549–563CrossRefPubMedPubMedCentralGoogle Scholar
  41. Tuchman M, Freese DK, Sharp HL, Ramnaraine ML, Ascher N, Bloomer JR (1987) Contribution of extrahepatic tissues to biochemical abnormalities in hereditary tyrosinemia type I: study of three patients after liver transplantation. J Pediatr 110(3):399–403CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Metabolic Unit, Department of Pediatric SpecialtiesBambino Gesù Children’s Research HospitalRomeItaly

Personalised recommendations