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Liver Disease in Alagille Syndrome

  • Alyssa Kriegermeier
  • Andrew Wehrman
  • Binita M. KamathEmail author
  • Kathleen M. LoomesEmail author
Chapter

Abstract

Hepatic disease in Alagille syndrome manifests with a wide range of clinical severity, even in patients with the same genetic mutation. Liver disease commonly presents in the neonatal period during evaluation for cholestasis with elevated bilirubin and GGT. The classic finding on liver biopsy is bile duct paucity; however, this is not diagnostic and not all children with Alagille syndrome have paucity on liver biopsy. There are specific clinical criteria for diagnosis of Alagille syndrome, including bile duct paucity on liver biopsy; however with the availability of genetic testing, not all criteria have to be met for the diagnosis in a patient with known genetic mutation or positive family history. In contrast to some other pediatric liver disorders, ALGS liver disease can improve over the first several years of life. Despite this, in some children cholestasis can progress to end-stage liver disease, cirrhosis, portal hypertension, and eventual need for liver transplantation. There is no specific treatment for hepatic disease in Alagille syndrome, and management focuses on treatment of symptoms of chronic cholestasis, including pruritus, xanthomata, malnutrition, and fat-soluble vitamin deficiencies. Surgical therapies, such as external biliary diversion, are used in children when medical management of cholestasis fails, although these procedures are not effective in all children. Ultimately if liver disease progresses to cirrhosis and complications of portal hypertension, liver transplant may be indicated.

Keywords

Cholestasis Bile duct paucity Cholestasis management Pediatric liver disease 

References

  1. 1.
    Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. 1973;48:459–66.CrossRefGoogle Scholar
  2. 2.
    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. J Pediatr. 1975;86:63–71.CrossRefGoogle Scholar
  3. 3.
    Alagille D, Habib E, Thomassin N. L’atresie des voies biliaires intrahepatiques avec voies biliaires extrahepatiques permeables chez l’enfant. J Par Pediatr. 1969:301–8.Google Scholar
  4. 4.
    Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr. 1995;127:220–4.CrossRefGoogle Scholar
  5. 5.
    Emerick K, Rand E, Goldmuntz E, Krantz I, Spinner N, Piccoli D. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29:822–9.CrossRefGoogle Scholar
  6. 6.
    Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Hall TR, McDiarmid SV, et al. Variable morbidity in alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr. 1999;29:431–7.CrossRefGoogle Scholar
  7. 7.
    Subramaniam P, Knisely A, Portmann B, Qureshi SA, Aclimandos WA, Karani JB, Baker AJ. Diagnosis of Alagille syndrome-25 years of experience at King’s College Hospital. J Pediatr Gastroenterol Nutr. 2011;52:84–9.CrossRefGoogle Scholar
  8. 8.
    Kamath BM, Spinner NB, Piccoli DA. Alagille syndrome. In: Suchy FJ, Sokol RJ, Balistreri WF, editors. Liver disease in children. 4th ed. Cambridge, MA: Cambridge University Press; 2014. p. 216–33.CrossRefGoogle Scholar
  9. 9.
    Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr. 1987;110:195–200.CrossRefGoogle Scholar
  10. 10.
    Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut. 2001;49:431–5.CrossRefGoogle Scholar
  11. 11.
    Garcia MA, Ramonet M, Ciocca M, Cabrera H, Lapunzina P, Alvarez E, de Davila MT. Alagille syndrome: cutaneous manifestations in 38 children. Pediatr Dermatol. 2005;22:11–4.CrossRefGoogle Scholar
  12. 12.
    Russo P, Magee JC, Anders RA, Bove KE, Chung C, Cummings OW, Finegold MJ, et al. Key histopathologic features of liver biopsies that distinguish biliary atresia from other causes of infantile cholestasis and their correlation with outcome: a multicenter study. Am J Surg Pathol. 2016;40:1601–15.CrossRefGoogle Scholar
  13. 13.
    Treem WR, Krzymowski GA, Cartun RW, Pedersen CA, Hyams JS, Berman M. Cytokeratin immunohistochemical examination of liver biopsies in infants with Alagille syndrome and biliary atresia. J Pediatr Gastroenterol Nutr. 1992;15:73–80.CrossRefGoogle Scholar
  14. 14.
    Deprettere A, Portmann B, Mowat AP. Syndromic paucity of the intrahepatic bile ducts: diagnostic difficulty; severe morbidity throughout early childhood. J Pediatr Gastroenterol Nutr. 1987;6:865–71.CrossRefGoogle Scholar
  15. 15.
    Russo P, Rand EB, Loomes K. Diseases of the Biliary Tree. In: Russo P, Ruchelli ED, Piccoli DA, editors. Pathology of pediatric gastrointestinal and liver disease. Berlin Heidelberg: Springer; 2014.CrossRefGoogle Scholar
  16. 16.
    Kaye AJ, Rand EB, Munoz PS, Spinner NB, Flake AW, Kamath BM. Effect of Kasai procedure on hepatic outcome in Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;51:319–21.PubMedGoogle Scholar
  17. 17.
    Rapp JB, Bellah RD, Maya C, Pawel BR, Anupindi SA. Giant hepatic regenerative nodules in Alagille syndrome. Pediatr Radiol. 2017;47:197–204.CrossRefGoogle Scholar
  18. 18.
    Alhammad A, Kamath BM, Chami R, Ng VL, Chavhan GB. Solitary hepatic nodule adjacent to the right portal vein: a common finding of Alagille syndrome? J Pediatr Gastroenterol Nutr. 2016;62:226–32.CrossRefGoogle Scholar
  19. 19.
    Kamath BM, Yin W, Miller H, Anand R, Rand EB, Alonso E, Bucuvalas J, et al. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl. 2012;18:940–8.CrossRefGoogle Scholar
  20. 20.
    Kamath BM, Ye W, Goodrich NP, Loomes KM, Romero R, Heubi JE, Leung DH, et al. Characteristics and outcomes of pediatric cholestasis in alagille syndrome in the Modern Era: results of a ,multi-centre prospective observational study. In: Hepatology. Hoboken: Wiley; 2017. p. 60A.Google Scholar
  21. 21.
    Mouzaki M, Bass LM, Sokol RJ, Piccoli DA, Quammie C, Loomes KM, Heubi JE, et al. Early life predictive markers of liver disease outcome in an international, multicentre cohort of children with Alagille syndrome. Liver Int. 2016;36:755–60.CrossRefGoogle Scholar
  22. 22.
    Kamath BM, Loomes KM, Piccoli DA. Medical Management of Alagille Syndrome. J Pediatr Gastroenterol Nutr. 2010;50:580–6.CrossRefGoogle Scholar
  23. 23.
    Wasserman D, Zemel BS, Mulberg AE, John HA, Emerick KM, Barden EM, Piccoli DA, et al. Growth, nutritional status, body composition, and energy expenditure in prepubertal children with Alagille syndrome. J Pediatr. 1999;134:172–7.CrossRefGoogle Scholar
  24. 24.
    Rovner AJ, Schall JI, Jawad AF, Piccoli DA, Stallings VA, Mulberg AE, Zemel BS. Rethinking growth failure in Alagille syndrome: the role of dietary intake and steatorrhea. J Pediatr Gastroenterol Nutr. 2002;35:495–502.CrossRefGoogle Scholar
  25. 25.
    da Silva FV, Ferri PM, Nascentes Queiroz TC, de Souza Haueisen Barbosa P, Cassiano de Oliveira MC, de Melo Pereira LJ, Simoes ESAC, et al. Nutritional evaluation of children with chronic cholestatic disease. J Pediatr. 2016;92:197–205.CrossRefGoogle Scholar
  26. 26.
    Feranchak AP, Sokol RJ. Medical and nutritional management of cholestasis in infants and children. In: Suchy F, Sokol R, Balistreri W, editors. Liver disease in children. Cambridge`, MA: Cambridge University Press; 2007. p. 190–231.CrossRefGoogle Scholar
  27. 27.
    Shen Y-M, Wu J-F, Hsu H-Y, Ni Y-H, Chang M-H, Liu Y-W, Lai H-S, et al. Oral ABsorbable fat-soluble vitamin formulation in pediatric patients with cholestasis. J Pediatr Gastroenterol Nutr. 2012;55:587–91.CrossRefGoogle Scholar
  28. 28.
    Argao EA, Heubi JE. Fat-soluble vitamin deficiency in infants and children. Curr Opin Pediatr. 1993;5:562–6.CrossRefGoogle Scholar
  29. 29.
    de Albuquerque Taveira AT, Fernandes MI, Galvao LC, Sawamura R, de Mello VE, de Paula FJ. Impairment of bone mass development in children with chronic cholestatic liver disease. Clin Endocrinol. 2007;66:518–23.Google Scholar
  30. 30.
    Argao EA. Bone mineral content in infants and children with chronic cholestatic liver disease. Pediatrics. 1993;91:1151–4.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Sokol RJ. A new old treatment for vitamin E deficiency in cholestasis. J Pediatr Gastroenterol Nutr. 2016;63:577–8.CrossRefGoogle Scholar
  32. 32.
    Thebaut A, Nemeth A, Le Mouhaer J, Scheenstra R, Baumann U, Koot B, Gottrand F, et al. Oral Tocofersolan corrects or prevents vitamin E deficiency in children with chronic cholestasis. J Pediatr Gastroenterol Nutr. 2016;63:610–5.CrossRefGoogle Scholar
  33. 33.
    Sathe MN, Patel AS. Update in pediatrics: focus on fat-soluble vitamins. Nutr Clin Pract. 2010;25:340–6.CrossRefGoogle Scholar
  34. 34.
    Sokol R. Fat-soluble vitamins and their importance in patients with cholestatic liver diseases. Gastroenterol Clin N Am. 1994;23:673–705.Google Scholar
  35. 35.
    Feranchak AP, Gralla J, King R, Ramirez RO, Corkill M, Narkewicz MR, Sokol RJ. Comparison of indices of vitamin A status in children with chronic liver disease. Hepatology. 2005;42:782–92.CrossRefGoogle Scholar
  36. 36.
    Moisseiev E, Cohen S, Dotan G. Alagille syndrome associated with xerophthalmia. Case Rep Ophthalmol. 2013;4:311–5.CrossRefGoogle Scholar
  37. 37.
    Dituri F, Buonocore G, Pietravalle A, Naddeo F, Cortesi M, Pasqualetti P, Tataranno ML, et al. PIVKA-II plasma levels as markers of subclinical vitamin K deficiency in term infants. J Matern Fetal Neonatal Med. 2012;25:1660–3.CrossRefGoogle Scholar
  38. 38.
    Kamath BM, Abetz-Webb L, Kennedy C, Hepburn B, Gauthier M, Johnson N, Medendorp S, et al. Development of a novel tool to assess the impact of itching in pediatric cholestasis. Patient. 2018;11:69–82.CrossRefGoogle Scholar
  39. 39.
    Elman S, Hynan LS, Gabriel V, Mayo MJ. The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010;162:587–93.CrossRefGoogle Scholar
  40. 40.
    Morris V, Murphy LM, Rosenberg M, Rosenberg L, Holzer CE 3rd, Meyer WJ 3rd. Itch assessment scale for the pediatric burn survivor. J Burn Care Res. 2012;33:419–24.CrossRefGoogle Scholar
  41. 41.
    Kronsten V, Fitzpatrick E, Baker A. Management of cholestatic pruritus in paediatric patients with alagille syndrome: the King’s college hospital experience. J Pediatr Gastroenterol Nutr. 2013;57:149–54.CrossRefGoogle Scholar
  42. 42.
    Shneider BL, Spino C, Kamath BM, Magee JC, Whitington PF, Setchell KD, Miethke AG, et al. Results of ITCH, A Multi-center Randomized Double-blind Placebo-controlled Trial of Maralixibat, an Ileal Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTi), for Pruritus in Alagille Syndrome (ALGS). In: Hepatology. Hoboken: Wiley; 2017. p. 84A.Google Scholar
  43. 43.
    Narkewicz M, Smith D, Gregory C, Lear J, Osberg I, Sokol R. Effect of ursodeoxycholic acid therapy on hepatic function in children with intrahepatic cholestatic liver disease. J Pediatr Gastroenterol Nutr. 1998;26:49–55.CrossRefGoogle Scholar
  44. 44.
    Hofmann A. Rifampicin and treatment of cholestatic pruritis. Gut. 2002;51:756–7.CrossRefGoogle Scholar
  45. 45.
    Cynamon H, Andrew J, Iafrate R. Rifampin relieves pruritus in children with cholestatic liver disease. Gastroenterology. 1990;98:1013–6.CrossRefGoogle Scholar
  46. 46.
    El-Karaksy H, Mansour S, El-Sayed R, El-Raziky M, El-Koofy N, Taha G. Safety and efficacy of rifampicin in children with cholestatic pruritus. Indian J Pediatr. 2007;74:279–81.CrossRefGoogle Scholar
  47. 47.
    Chang SH, Nahid P, Eitzman SR. Hepatotoxicity in children receiving isoniazid therapy for latent tuberculosis infection. J Pediatric Infect Dis Soc. 2014;3:221–7.CrossRefGoogle Scholar
  48. 48.
    Khurana S, Singh P. Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver Int. 2006;26:943–8.CrossRefGoogle Scholar
  49. 49.
    Zellos A, Roy A, Schwarz KB. Use of oral naltrexone for severe pruritus due to cholestatic liver disease in children. J Pediatr Gastroenterol Nutr. 2010;51:787–9.CrossRefGoogle Scholar
  50. 50.
    Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology. 2007;45:666–74.CrossRefGoogle Scholar
  51. 51.
    Thebaut A, Habes D, Gottrand F, Rivet C, Cohen J, Debray D, Jacquemin E, et al. Sertraline as an additional treatment for Cholestatic pruritus in children. J Pediatr Gastroenterol Nutr. 2017;64:431–5.CrossRefGoogle Scholar
  52. 52.
    Whitington P, Whitington G. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. 1988;95:130–6.CrossRefGoogle Scholar
  53. 53.
    Wang KS, Tiao G, Bass LM, et al. Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology. 2017;65:1645–54.CrossRefGoogle Scholar
  54. 54.
    Davit-Spraul A, Pourci M, Atger V, Cambillau M, Hadchouel M, Moatti N, Legrand A. Abnormal lipoprotein pattern in patients with Alagille syndrome depends on Icterus severity. Gastroenterology. 1996;111:1023–32.CrossRefGoogle Scholar
  55. 55.
    Nagasaka H, Yorifuji T, Egawa H, Yanai H, Fujisawa T, Kosugiyama K, Matsui A, et al. Evaluation of risk for atherosclerosis in Alagille syndrome and progressive familial intrahepatic cholestasis: two congenital cholestatic diseases with different lipoprotein metabolisms. J Pediatr. 2005;146:329–35.CrossRefGoogle Scholar
  56. 56.
    Tsai S, Gurakar A, Anders R, Lam-Himlin D, Boitnott J, Pawlik TM. Management of large hepatocellular carcinoma in adult patients with Alagille syndrome: a case report and review of literature. Dig Dis Sci. 2010;55:3052–8.CrossRefGoogle Scholar
  57. 57.
    Kim B, Park SH, Yang HR, Seo JK, Kim WS, Chi JG. Hepatocellular carcinoma occurring in alagille syndrome. Pathol Res Pract. 2005;201:55–60.CrossRefGoogle Scholar
  58. 58.
    Bhadri VA, Stormon MO, Arbuckle S, Lam AH, Gaskin KJ, Shun A. Hepatocellular carcinoma in children with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2005;41:676–8.CrossRefGoogle Scholar
  59. 59.
    Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–80.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of Gastroenterology, Hepatology and NutritionThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Division of Gastroenterology, Hepatology and NutritionThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of PediatricsUniversity of TorontoTorontoCanada
  4. 4.Department of PediatricsChildren’s Hospital of Philadelphia and Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUSA

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