Euroasian journal of hepato-gastroenterology

Register      Login

VOLUME 8 , ISSUE 2 ( July-December, 2018 ) > List of Articles

REVIEW ARTICLE

Alagille Syndrome and the Liver: Current Insights

Shivaram P Singh, Girish K Pati

Keywords : Alagille syndrome, Bile duct paucity, Butter fly vertebra cholestasis, Posterior embryotoxon

Citation Information : Singh SP, Pati GK. Alagille Syndrome and the Liver: Current Insights. Euroasian J Hepatogastroenterol 2018; 8 (2):140-147.

DOI: 10.5005/jp-journals-10018-1280

License: CC BY-NC 4.0

Published Online: 01-01-2019

Copyright Statement:  Copyright © 2018; The Author(s).


Abstract

Alagille syndrome (ALGS) is an autosomal dominant disorder, with multisystem involvement, which usually occurs due to Notch signaling pathway defects, mostly due to JAG1 mutation (ALGS type 1), but rarely due to neurogenic locus notch homolog protein (NOTCH2) mutation (ALGS type 2). It was suspected in cases having at least three out of five major clinical criteria: cholestasis with a paucity of the bile duct, congenital cardiac defects, ocular posterior embryotoxon, typical facial features, and skeletal malformation. Till date, no early predictive marker for hepatic outcome in ALGS has found. No genotypic or, phenotype features or correlation could predict the development of endstage liver disease, which poses a unique management challenge. Cases with progressive liver damage, unremitting cholestasis and intractable pruritus often depend on liver transplantation as last resort. The cardiac, and renal status should be well accessed before liver transplant for the better post-transplantation outcome. Most of the clinical manifestations usually improve the following transplant, except any change in stature. The post liver transplantation outcome was usually comparable with other conditions which require liver transplantation as a last resort, but in this disease the effect of long term immunosuppression on other affected systems not evaluated well till date. Therefore long term post transplant prospective study is required to address these issues.


PDF Share
  1. Spinner NB, Leonard LD, Krantz ID. Alagille syndrome.
  2. Alagille D, Habib EC, Thomassin N. L'atresie des voiesbiliaires intrahepatiques avec voiesbiliaires extrahepatiques permeables chez l'enfant. J Par Pediatr. 1969;301.
  3. Watson GH, Miller V. Arteriohepatic dysplasia. Archives of disease in childhood. 1973 Jun 1;48(6):459-466.
  4. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. The Journal of pediatrics. 1975 Jan 1;86(1):63-71.
  5. Danks DM, Campbell PE, Jack I, Rogers J, Smith AL. Studies of the aetiology of neonatal hepatitis and biliary atresia. Archives of disease in childhood. 1977 May 1;52(5):360-367.
  6. Krantz ID, Colliton RP, Genin A, Rand EB, Li L, Piccoli DA, Spinner NB. Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. The American Journal of Human Genetics. 1998 Jun 30;62(6):1361- 1369.
  7. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nature genetics. 1997 Jul 1;16(3):243-251.
  8. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, et al. Mutations in the human Jagged1 gene is responsible for Alagille syndrome. Nature genetics. 1997 Jul 1;16(3):235- 242.
  9. McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, et al. Spinner NB. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. The American Journal of Human Genetics. 2006 Jul 1;79(1):169-73.
  10. Crosnier C, Driancourt C, Raynaud N, Dhorne. Pollet S, Pollet N, Bernard O, et al. Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999 May 31;116(5):1141-1148.
  11. Spinner NB, Colliton RP, Crosnier C, Krantz ID, Hadchouel M, Meunier-Rotival M. Jagged1 mutations in Alagille syndrome. Human mutation. 2001 Jan 1;17(1):18.
  12. Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. Journal of medical genetics. 2003 Dec 1;40(12):891-895.
  13. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut. 2001 Sep 1;49(3):431-435.
  14. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. The Journal of pediatrics. 1975 Jan 1;86(1):63-71.
  15. Bhatia V, Kumar P. Alagille syndrome with a previously undescribed mutation. Indian Pediatr. 2014;51:314-316.
  16. Pati GK, Singh A, Nath P, Narayan J, Padhi PK, Parida PK. A 10-year-old child presenting with syndromic paucity of bile ducts (Alagille syndrome): a case report. Journal of medical case reports. 2016 Nov 30; 10(1):342.
  17. Kamath BM, Podkameni G, Hutchinson AL, Leonard LD, Gerfen J, Krantz ID, et al. Renal anomalies in Alagille syndrome: A disease-defining feature. American Journal of Medical Genetics Part A. 2012 Jan 1; 158(1):85-89.
  18. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. European Journal of Human Genetics. 2012 Mar;20(3):251.
  19. Guegan K, Stals K, Day M, Turnpenny P, Ellard S. JAG1 mutations are found in approximately one third of patients presenting with only one or two clinical features of Alagille syndrome. Clinical genetics. 2012 Jul 1;82(1):33-40.
  20. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999 Mar 1;29(3):822-829.
  21. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, et al. Vascular anomalies in Alagille syndrome. Circulation. 2004 Mar 23;109(11):1354-1358.
  22. Ghidini A, Incerti M, Andreani M. Alagille syndrome: prenatal sonographic findings. Journal of Clinical Ultrasound. 2007 Mar 1; 35(3):156-158.
  23. Subramaniam P, Knisely A, Portmann B, Qureshi SA, Aclimandos WA, Karani JB, et al. Diagnosis of Alagille syndrome. 25 years of experience at King's College Hospital. Journal of pediatric gastroenterology and nutrition. 2011 Jan 1;52(1):84- 89.
  24. Kaye AJ, Rand EB, Munoz PS, Spinner NB, Flake AW, Kamath BM. Effect of Kasai procedure on hepatic outcome in Alagille syndrome. Journal of pediatric gastroenterology and nutrition. 2010 Sep 1;51(3):319-321.
  25. Kamath BM, Munoz PS, Bab N, Baker A, Chen Z, Spinner NB, et al. A longitudinal study to identify laboratory predictors of liver disease outcome in Alagille syndrome. Journal of pediatric gastroenterology and nutrition. 2010 May; 50(5): 526.
  26. Krantz ID, Smith R, Colliton RP, Tinkel H, Zackai EH, Piccoli DA, et al. Jagged 1 mutation in patients ascertained with isolated congenital heart defects. American journal of medical genetics. 1999 May 7; 84(1):56-60.
  27. Mouzaki M, Bass LM, Sokol RJ, Piccoli DA, Quammie C, Loomes KM, et al. Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome. Liver International. 2016 May 1;36(5):755-60.
  28. Makino S, Ohkubo Y, Tampo H. Optical coherence tomography and fundus autofluorescence imaging study of chorioretinal atrophy involving the macula in Alagille syndrome. Clinical Ophthalmology (Auckland, NZ). 2012;6:1445.
  29. McDonald-McGinn DM, Kirschner R, Goldmuntz E, Sullivan K, Eicher P, Gerdes M, et al. The Philadelphia story: the 22q11.2 deletion: report on 250 patients. Genetic counseling (Geneva, Switzerland). 1999; 10(1):11-24.
  30. Nischal KK, Hingorani M, Bentley CR, Vivian AJ, Bird AC, Baker AJ, et al. Ocular ultrasound in Alagille syndrome: a new sign. Ophthalmology. 1997 Jan 1;104(1):79-85.
  31. Sanderson E, Newman V, Haigh SF, Baker A, Sidhu PS. Vertebral anomalies in children with Alagille syndrome: an analysis of 50 consecutive patients. Pediatric radiology. 2002 Feb 1;32(2):114.
  32. Zanotti S, Canalis E. Notch signaling and the skeleton. Endocrine reviews. 2016 Apr 13;37(3):223-53.
  33. Kamath BM, Loomes KM, Oakey RJ, Krantz ID. Supernumerary digital flexion creases: an additional clinical manifestation of Alagille syndrome. American Journal of Medical Genetics Part A. 2002 Oct 1;112(2):171-5.
  34. Bales CB, Kamath BM, Munoz PS, Nguyen A, Piccoli DA, Spinner NB, et al. Pathologic lower extremity fractures in children with Alagille syndrome. Journal of pediatric gastroenterology and nutrition. 2010 Jul;51(1):66.
  35. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. Journal of medical genetics. 1997 Feb 1;34(2):152-7.
  36. Lin HC, Le Hoang P, Hutchinson A, Chao G, Gerfen J, Loomes KM, et al. Alagille syndrome in a Vietnamese cohort: mutation analysis and assessment of facial features. American Journal of Medical Genetics Part A. 2012 May 1;158(5):1005- 1013.
  37. Salem JE, Bruguiere E, Iserin L, Guiochon-Mantel A, Plouin PF. Hypertension and aortorenal disease in Alagille syndrome. J Hypertens. 2012 Jul;30(7):1300-1306.
  38. Emerick KM, Krantz ID, Kamath BM, Darling C, Burrowes DM, Spinner NB, et al. Intracranial vascular abnormalities in patients with Alagille syndrome. J Pediatr Gastroenterol- Nutr. 2005 Jul;41(1):99-107.
  39. Arvay JL, Zemel BS, Gallagher PR, Rovner AJ, Mulberg AE, Stallings VA, et al. Body composition of children aged 1 to 12 years with biliary atresia or Alagille syndrome. J Pediatr Gastroenterol Nutr. 2005 Feb;40(2):146-150.
  40. Olsen IE, Ittenbach RF, Rovner AJ, Leonard MB, Mulberg AE, Stallings VA, et al. Deficits in size-adjusted bone mass in children with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2005 Jan;40(1):76-82.
  41. Bucuvalas JC, Horn JA, Carlsson LE, Balistreri WF, Chernausek SD. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature. The Journal of Clinical Endocrinology & Metabolism. 1993 Jun; 76(6):1477-1482.
  42. Shamoun ST, Le Friec G, Spinner N, Kemper C, Baker AJ. Immune dysregulation in Alagille syndrome: A new feature of the evolving phenotype. Clinics and research in hepatology and gastroenterology. 2015 Oct 31;39(5):566-569.
  43. Chong SK, Lindridge J, Moniz C, Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts. Journal of pediatric gastroenterology and nutrition. 1989 Nov 1;9(4):445-449.
  44. Alagille D, Estrada A, Hadchouel M, Gautler M, Odievre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. The Journal of pediatrics. 1987 Feb 1;110(2): 195-200.
  45. Ferrarese A, Senzolo M, Burra P. Successful pregnancy in Alagille Syndrome. Dig Liver Dis. 2015 Jan;47(1):86-87.
  46. Deprettere A, Portmann B, Mowat AP. Syndromic paucity of the intrahepatic bile ducts: diagnostic difficulty; severe morbidity throughout early childhood. Journal of pediatric gastroenterology and nutrition. 1986 Dec;6(6):865-871.
  47. Hashida Y, Yunis EJ. Syndromatic paucity of interlobular bile ducts: hepatic histopathology of the early and endstage liver. Pediatric Pathology. 1988 Jan 1;8(1):1-5.
  48. Sokol RJ, Heubi JE, Balistreri WF: Intrahepatic ‘cholestasis facies’: is it specific for Alagille syndrome? J Pediatr 1983; 103:205–208.
  49. Kamath BM, Loomes KM, Oakey RJ, Emerick KE, Conversano T, Spinner NB, et al. Facial features in Alagille syndrome: specific or cholestasis facies?.American Journal of Medical Genetics Part A. 2002 Oct 1;112(2):163-170.
  50. Libbrecht L, Cassiman D, Desmet V, Roskams T. The correlation between portal myofibroblasts and development of intrahepatic bile ducts and arterial branches in human liver. Liver International. 2002 Jun 1;22(3):252-258.
  51. Colliton RP, Bason L, Feng-Min L, Piccoli DA, Krantz ID, Spinner NB. Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. Human mutation. 2001 Feb 1;17(2): 151.
  52. Röpke A, Kujat A, Gräber M, Giannakudis J, Hansmann I. Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Human mutation. 2003 Jan 1;21(1): 100
  53. Kamath BM, Bauer RC, Loomes KM, Chao G, Gerfen J, Hutchinson A, et al. NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012;49(2):138-144.
  54. Kamath BM, Thiel BD, Gai X, et al.. SNP array mapping of chromosome 20p deletions: genotypes, phenotypes, and copy number variation. Human mutation. 2009 Mar 1;30(3): 371-378.
  55. Crosnier C, Driancourt C, Raynaud N, Dhorne–Pollet S, Pollet N, Bernard O et al. Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome. Gastroenterology. 1999 May 31;116(5):1141-1148.
  56. Eldadah ZA, Hamosh A, Biery NJ, Montgomery RA, Duke M, Elkins R, et al. Familial Tetralogy of Fallot caused by mutation in the jagged1 gene. Human molecular genetics. 2001 Jan 15; 10(2):163-169.
  57. Le Caignec C, Lefevre M, Schott JJ, Chaventre A, Gayet M, Calais C, et al. Familial deafness, congenital heart defects, and posterior embryotoxon caused by cysteine substitution in the first epidermal-growth-factor–like domain of Jagged 1. The American Journal of Human Genetics. 2002 Jul 31; 71(1):180- 186.
  58. Dyack S, Cameron M, Otley A, Greer W. An autosomal recessive form of Alagille-like syndrome that is not linked to JAG1. Genetics in Medicine. 2007 Aug 1;9(8):544-550.
  59. Tsai EA. Genomic approaches to understanding variable expressivity in alagille syndrome and genetic susceptibility to biliary atresia. University of Pennsylvania; 2013.
  60. Warthen DM, Moore EC, Kamath BM, Morrissette JJ, Sanchez P, Piccoli DA, et al. Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate. Human mutation. 2006 May 1;27(5):436-443.
  61. Pilia G, Uda M, Macis D, Frau F, Crisponi L, Balli F, et al. Jagged-1 mutation analysis in Italian Alagille syndrome patients. Human mutation. 1999 Nov 1;14(5):394-400.
  62. Colliton RP, Bason L, Feng-Min L, Piccoli DA, Krantz ID, Spinner NB. Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients. Human mutation. 2001 Feb 1;17(2):151.
  63. Heritage ML, MacMillan JC, Anderson GJ. DHPLC mutation analysis of Jagged1 (JAG1) reveals six novel mutations in Australian alagille syndrome patients. Human mutation. 2002 Dec 1;20(6):481.
  64. Emerick KM, Whitington PF. Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome. Hepatology. 2002 Jun 1;35(6):1501-1506.
  65. Mattei P, von Allmen D, Piccoli D, Rand E. Relief of intractable pruritis in Alagille syndrome by partial external biliary diversion. Journal of pediatric surgery. 2006 Jan 31;41(1):104-107.
  66. Sheflin-Findling S, Arnon R, Lee S, Chu J, Henderling F, Kerkar N, et al. Partial internal biliary diversion for Alagille syndrome: case report and review of the literature. Journal of pediatric surgery. 2012 Jul 31;47(7):1453-1456.
  67. Pawlowska J, Socha P, Jankowska I. Factors affecting catch-up growth after liver transplantation in children with cholestatic liver diseases. Annals of transplantation. 2009 Dec; 15(1):72-76.
  68. Kamath BM, Yin W, Miller H, Anand R, Rand EB, Alonso E, et al. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver transplantation. 2012 Aug 1;18(8):940-948.
  69. Kamath BM, Schwarz KB, Hadžic N. Alagille syndrome and liver transplantation. Journal of pediatric gastroenterology and nutrition. 2010 Jan 1;50(1):11-15.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.