Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Inherited disorders associated with conjugated hyperbilirubinemia

Jayanta Roy-Chowdhury, MD, MRCP
Namita Roy-Chowdhury, PhD
Section Editor
Keith D Lindor, MD
Deputy Editor
Anne C Travis, MD, MSc, FACG, AGAF


Conditions that cause hyperbilirubinemia can be classified into those that result in a predominantly unconjugated hyperbilirubinemia and those that are associated with an elevation of both conjugated and unconjugated forms of bilirubin. (See "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

Excretion of conjugated bilirubin is impaired in a number of acquired conditions (such as alcoholic and viral hepatitis, biliary obstruction, cholestasis of pregnancy) and in inherited disorders (such as Dubin-Johnson syndrome, Rotor syndrome, benign recurrent intrahepatic cholestasis). This topic review will discuss the inherited disorders associated with conjugated hyperbilirubinemia. The other conditions are presented separately. (See appropriate topic reviews).


Elimination of conjugated bilirubin in bile is affected in several inherited disorders that work through different mechanisms. In all these situations, the abnormality of biliary excretion of bilirubin is shared with excretory defect of all or some other organic anions. Inherited syndromes of intrahepatic cholestasis commonly result from mutations in the following genes: SERPINAI (alpha 1- antitrypsin), JAG1 (causing Alagille syndrome), ATP8B1 (also known as FIC1), ABCB11 (bile salt export pump [BSEP]), MDR3 (ABCB4), and MRP2 (causing Dubin-Johnson syndrome). The genetic basis of Rotor syndrome has not been identified [1].

Although Dubin-Johnson syndrome and Rotor syndrome have similar phenotypes (mild, fluctuating elevation of both unconjugated and conjugated bilirubin in plasma), in Dubin-Johnson syndrome biliary excretion of organic anions, except bile acids, is impaired, while Rotor syndrome is a disorder of hepatic storage. Other inherited conditions, like progressive familial intrahepatic cholestasis and benign recurrent intrahepatic cholestasis, cause conjugated hyperbilirubinemia as a consequence of reduced bile flow [2].


In 1954, Dubin and Johnson [3] and Sprinz and Nelson [4] described patients with predominantly conjugated chronic hyperbilirubinemia that was not associated with hemolysis. The disorder occurs in all races and nationalities and both sexes [4-7]. It is rare except in Sephardic Jews in whom the incidence is approximately 1:3000 [7].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Dec 10, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Liu C, Aronow BJ, Jegga AG, et al. Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. Gastroenterology 2007; 132:119.
  2. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998; 339:1217.
  3. DUBIN IN, JOHNSON FB. Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine (Baltimore) 1954; 33:155.
  4. SPRINZ H, NELSON RS. Persistent non-hemolytic hyperbilirubinemia associated with lipochrome-like pigment in liver cells: report of four cases. Ann Intern Med 1954; 41:952.
  5. DUBIN IN. Chronic idiopathic jaundice; a review of fifty cases. Am J Med 1958; 24:268.
  6. Cohen L, Lewis C, Arias IM. Pregnancy, oral contraceptives, and chronic familial jaundice with predominantly conjugated hyperbilirubinemia (Dubin-Johnson syndrome). Gastroenterology 1972; 62:1182.
  7. Shani M, Seligsohn U, Gilon E, et al. Dubin-Johnson syndrome in Israel. I. Clinical, laboratory, and genetic aspects of 101 cases. Q J Med 1970; 39:549.
  8. DITTRICH H, SEIFERT E. [On the behavior of pigment and biligraffin excretion in a patient with Dubin-Johnson syndrome]. Acta Hepatosplenol 1962; 9:45.
  9. Morita M, Kihara T. Intravenous cholecystography and metabolism of meglumine iodipamide (Biligrafin) in Dubin-Johnson syndrome. Radiology 1971; 99:57.
  10. ESSNER E, NOVIKOFF AB. Human hepatocellular pigments and lysosomes. J Ultrastruct Res 1960; 3:374.
  11. Swartz HM, Sarna T, Varma RR. On the natural and excretion of the hepatic pigment in the Dubin-Johnson syndrome. Gastroenterology 1979; 76:958.
  12. Rubinstein ZJ, Seligsohn U, Modan M, Shani M. Hepatic computerized tomography in the Dubin-Johnson syndrome: increased liver density as a diagnostic aid. Comput Radiol 1985; 9:315.
  14. SCHOENFIELD LJ, McGILL DB, HUNTON DB, et al. Studies of chronic idiopathic jaundice (Dubin-Johnson syndrome). I. Demonstration of hepatic excretory defect. Gastroenterology 1963; 44:101.
  15. Erlinger S, Dhumeaux D, Desjeux JF, Benhamou JP. Hepatic handling of unconjugated dyes in the Dubin-Johnson syndrome. Gastroenterology 1973; 64:106.
  16. Nakata F, Oyanagi K, Fujiwara M, et al. Dubin-Johnson syndrome in a neonate. Eur J Pediatr 1979; 132:299.
  17. Koskelo P, Toivonen I, Adlercreutz H. Urinary coproporphyrin isomer distribution in the Dubin-Johnson syndrome. Clin Chem 1967; 13:1006.
  18. Kondo T, Kuchiba K, Shimizu Y. Coproporphyrin isomers in Dubin-Johnson syndrome. Gastroenterology 1976; 70:1117.
  19. Seligsohn U, Shani M, Ramot B, et al. Hereditary deficiency of blood clotting factor VII and Dubin-Johnson syndrome in an Israeli family. Isr J Med Sci 1969; 5:1060.
  20. Seligsohn U, Shani M, Ramot B, et al. Dubin-Johnson syndrome in Israel. II. Association with factor-VII deficiency. Q J Med 1970; 39:569.
  21. Levanon M, Rimon S, Shani M, et al. Active and inactive factor VII in Dubin-Johnson syndrome with factor-VII deficiency, hereditary factor-VII deficiency and on coumadin administration. Br J Haematol 1972; 23:669.
  22. Cornelius CE. Organic anion transport in mutant sheep with congenital hyperbilirubinemia. Arch Environ Health 1969; 19:852.
  23. Alpert S, Mosher M, Shanske A, Arias IM. Multiplicity of hepatic excretory mechanisms for organic anions. J Gen Physiol 1969; 53:238.
  24. Arias IM, Bernstein L, Roffler R, et al. Black liver diseases in Corriedale sheep: Metabolism of tritiated epinephrine and incorporation of isotope into the hepatic pigment in vivo. J Clin Invest 1965; 44:1026.
  25. Kitamura T, Alroy J, Gatmaitan Z, et al. Defective biliary excretion of epinephrine metabolites in mutant (TR-) rats: relation to the pathogenesis of black liver in the Dubin-Johnson syndrome and Corriedale sheep with an analogous excretory defect. Hepatology 1992; 15:1154.
  26. Jansen PL, van Klinken JW, van Gelder M, et al. Preserved organic anion transport in mutant TR- rats with a hepatobiliary secretion defect. Am J Physiol 1993; 265:G445.
  27. Kitamura T, Jansen P, Hardenbrook C, et al. Defective ATP-dependent bile canalicular transport of organic anions in mutant (TR-) rats with conjugated hyperbilirubinemia. Proc Natl Acad Sci U S A 1990; 87:3557.
  28. Jansen PL, Peters WH, Lamers WH. Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology 1985; 5:573.
  29. Oude Elferink RP, Meijer DK, Kuipers F, et al. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochim Biophys Acta 1995; 1241:215.
  30. Schulman FY, Montali RJ, Bush M, et al. Dubin-Johnson-like syndrome in golden lion tamarins (Leontopithecus rosalia rosalia). Vet Pathol 1993; 30:491.
  31. Nishida T, Hardenbrook C, Gatmaitan Z, Arias IM. ATP-dependent organic anion transport system in normal and TR- rat liver canalicular membranes. Am J Physiol 1992; 262:G629.
  32. Ishikawa T, Müller M, Klünemann C, et al. ATP-dependent primary active transport of cysteinyl leukotrienes across liver canalicular membrane. Role of the ATP-dependent transport system for glutathione S-conjugates. J Biol Chem 1990; 265:19279.
  33. Kobayashi K, Sogame Y, Hara H, Hayashi K. Mechanism of glutathione S-conjugate transport in canalicular and basolateral rat liver plasma membranes. J Biol Chem 1990; 265:7737.
  34. Jedlitschky G, Leier I, Buchholz U, et al. ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 1994; 54:4833.
  35. Nishida T, Gatmaitan Z, Roy-Chowdhry J, Arias IM. Two distinct mechanisms for bilirubin glucuronide transport by rat bile canalicular membrane vesicles. Demonstration of defective ATP-dependent transport in rats (TR-) with inherited conjugated hyperbilirubinemia. J Clin Invest 1992; 90:2130.
  36. Higgins CF. ABC transporters: from microorganisms to man. Annu Rev Cell Biol 1992; 8:67.
  37. Paulusma CC, Bosma PJ, Zaman GJ, et al. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 1996; 271:1126.
  38. Allikmets R, Gerrard B, Hutchinson A, Dean M. Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum Mol Genet 1996; 5:1649.
  39. Tsujii H, König J, Rost D, et al. Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome. Gastroenterology 1999; 117:653.
  40. Toh S, Wada M, Uchiumi T, et al. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am J Hum Genet 1999; 64:739.
  41. Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology 1997; 25:1539.
  42. Wada M, Toh S, Taniguchi K, et al. Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome. Hum Mol Genet 1998; 7:203.
  43. Kajihara S, Hisatomi A, Mizuta T, et al. A splice mutation in the human canalicular multispecific organic anion transporter gene causes Dubin-Johnson syndrome. Biochem Biophys Res Commun 1998; 253:454.
  44. Mor-Cohen R, Zivelin A, Rosenberg N, et al. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J Biol Chem 2001; 276:36923.
  45. Keitel V, Kartenbeck J, Nies AT, et al. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology 2000; 32:1317.
  46. Kaplowitz N, Javitt N, Kappas A. Coproporphyrin I and 3 excretion in bile and urine. J Clin Invest 1972; 51:2895.
  47. Wolkoff AW, Cohen LE, Arias IM. Inheritance of the Dubin-Johnson syndrome. N Engl J Med 1973; 288:113.
  48. Rotor AB, Manahan L, Florentin A. Familial nonhemolytic jaundice with direct van den Bergh reaction. Acta Med Phil 1948; 5:37.
  49. Pereira-Lima JE, Utz E, Rosenberg I. Hereditary nonhemolytic conjugated hyperbilirubinemia without abnormal liver cell pigmentation: A family study. Am J Med 1966; 40:628.
  50. Wolkoff AW, Wolpert E, Pascasio FN, Arias IM. Rotor's syndrome. A distinct inheritable pathophysiologic entity. Am J Med 1976; 60:173.
  51. Wolpert E, Pascasio FM, Wolkoff AW, Arias IM. Abnormal sulfobromophthalein metabolism in Rotor's syndrome and obligate heterozygotes. N Engl J Med 1977; 296:1099.
  52. Kawasaki H, Kimura N, Irisa T, Hirayama C. Dye clearance studies in Rotor's syndrome. Am J Gastroenterol 1979; 71:380.
  53. Shimizu Y, Naruto H, Ida S, Kohakura M. Urinary coproporphyrin isomers in Rotor's syndrome: a study in eight families. Hepatology 1981; 1:173.
  54. Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology 2014; 146:1625.
  55. van de Steeg E, Stránecký V, Hartmannová H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest 2012; 122:519.
  56. SEARCH Collaborative Group, Link E, Parish S, et al. SLCO1B1 variants and statin-induced myopathy--a genomewide study. N Engl J Med 2008; 359:789.
  57. Kenyon AP, Girling JC. Liver disease in pregnancy. Women's Health Medicine 2005; 2:26.
  58. Clayton RJ, Iber FL, Ruebner BH, McKusick VA. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred. Am J Dis Child 1969; 117:112.
  59. Klomp LW, Bull LN, Knisely AS, et al. A missense mutation in FIC1 is associated with greenland familial cholestasis. Hepatology 2000; 32:1337.
  60. Bull LN, van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 1998; 18:219.
  61. Eppens EF, van Mil SW, de Vree JM, et al. FIC1, the protein affected in two forms of hereditary cholestasis, is localized in the cholangiocyte and the canalicular membrane of the hepatocyte. J Hepatol 2001; 35:436.
  62. Strautnieks SS, Kagalwalla AF, Tanner MS, et al. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24. Am J Hum Genet 1997; 61:630.
  63. Strautnieks SS, Byrne JA, Pawlikowska L, et al. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 2008; 134:1203.
  64. Wang L, Soroka CJ, Boyer JL. The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II. J Clin Invest 2002; 110:965.
  65. Jansen PL, Müller MM. Progressive familial intrahepatic cholestasis types 1, 2, and 3. Gut 1998; 42:766.
  66. Knisely AS, Strautnieks SS, Meier Y, et al. Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 2006; 44:478.
  67. Jara P, Hierro L, Martínez-Fernández P, et al. Recurrence of bile salt export pump deficiency after liver transplantation. N Engl J Med 2009; 361:1359.
  68. Keitel V, Burdelski M, Vojnisek Z, et al. De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. Hepatology 2009; 50:510.
  69. Lam P, Pearson CL, Soroka CJ, et al. Levels of plasma membrane expression in progressive and benign mutations of the bile salt export pump (Bsep/Abcb11) correlate with severity of cholestatic diseases. Am J Physiol Cell Physiol 2007; 293:C1709.
  70. Hayashi H, Sugiyama Y. 4-phenylbutyrate enhances the cell surface expression and the transport capacity of wild-type and mutated bile salt export pumps. Hepatology 2007; 45:1506.
  71. Gonzales E, Grosse B, Schuller B, et al. Targeted pharmacotherapy in progressive familial intrahepatic cholestasis type 2: Evidence for improvement of cholestasis with 4-phenylbutyrate. Hepatology 2015; 62:558.
  72. Jacquemin E, De Vree JM, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001; 120:1448.
  73. Nies AT, Gatmaitan Z, Arias IM. ATP-dependent phosphatidylcholine translocation in rat liver canalicular plasma membrane vesicles. J Lipid Res 1996; 37:1125.
  74. de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 1998; 95:282.
  75. Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology 2001; 120:1459.
  76. Rosmorduc O, Poupon R. Low phospholipid associated cholelithiasis: association with mutation in the MDR3/ABCB4 gene. Orphanet J Rare Dis 2007; 2:29.
  77. Ziol M, Barbu V, Rosmorduc O, et al. ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults. Gastroenterology 2008; 135:131.
  78. Fein F, Hermelin B, Becker MC, et al. Acute recurrent biliary pancreatitis associated with the ABCB4 gene mutation. Gastroenterol Clin Biol 2007; 31:106.
  79. Jacquemin E, Hermans D, Myara A, et al. Ursodeoxycholic acid therapy in pediatric patients with progressive familial intrahepatic cholestasis. Hepatology 1997; 25:519.
  80. Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E. Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 2009; 4:1.
  81. Squires RH, Ng V, Romero R, et al. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology 2014; 60:362.
  82. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988; 95:130.
  83. Arnell H, Bergdahl S, Papadogiannakis N, et al. Preoperative observations and short-term outcome after partial external biliary diversion in 13 patients with progressive familial intrahepatic cholestasis. J Pediatr Surg 2008; 43:1312.
  84. van der Woerd WL, Kokke FT, van der Zee DC, Houwen RH. Total biliary diversion as a treatment option for patients with progressive familial intrahepatic cholestasis and Alagille syndrome. J Pediatr Surg 2015; 50:1846.
  85. Kurbegov AC, Setchell KD, Haas JE, et al. Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile. Gastroenterology 2003; 125:1227.
  86. Schukfeh N, Metzelder ML, Petersen C, et al. Normalization of serum bile acids after partial external biliary diversion indicates an excellent long-term outcome in children with progressive familial intrahepatic cholestasis. J Pediatr Surg 2012; 47:501.
  87. Hollands CM, Rivera-Pedrogo FJ, Gonzalez-Vallina R, et al. Ileal exclusion for Byler's disease: an alternative surgical approach with promising early results for pruritus. J Pediatr Surg 1998; 33:220.
  88. Kaliciński PJ, Ismail H, Jankowska I, et al. Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal bypass. Eur J Pediatr Surg 2003; 13:307.
  89. Englert C, Grabhorn E, Richter A, et al. Liver transplantation in children with progressive familial intrahepatic cholestasis. Transplantation 2007; 84:1361.
  90. Lykavieris P, van Mil S, Cresteil D, et al. Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. J Hepatol 2003; 39:447.
  91. de Vree JM, Ottenhoff R, Smith AJ, et al. Long term effects of hepatocyte transplantation in an animal model of progressive familial intrahepatic cholestasis (abstract). Hepatology 1999; 30(4 pt.2):409A.
  92. De Vree JM, Ottenhoff R, Bosma PJ, et al. Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. Gastroenterology 2000; 119:1720.
  93. SUMMERSKILL WH, WALSHE JM. Benign recurrent intrahepatic "obstructive" jaundice. Lancet 1959; 2:686.
  94. de Pagter AG, van Berge Henegouwen GP, ten Bokkel Huinink JA, Brandt KH. Familial benign recurrent intrahepatic cholestasis. Interrelation with intrahepatic cholestasis of pregnancy and from oral contraceptives? Gastroenterology 1976; 71:202.
  95. Tygstrup N, Jensen B. Intermittent intrahepatic cholestasis of unknown etiology in five young males from the Faroe Islands. Acta Med Scand 1969; 185:523.
  96. Tygstrup N, Steig BA, Juijn JA, et al. Recurrent familial intrahepatic cholestasis in the Faeroe Islands. Phenotypic heterogeneity but genetic homogeneity. Hepatology 1999; 29:506.
  97. Klomp LW, Vargas JC, van Mil SW, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004; 40:27.
  99. Summerfield JA, Scott J, Berman M, et al. Benign recurrent intrahepatic cholestasis: studies of bilirubin kinetics, bile acids, and cholangiography. Gut 1980; 21:154.
  100. Biempica L, Gutstein S, Arias IM. Morphological and biochemical studies of benign recurrent cholestasis. Gastroenterology 1967; 52:521.
  101. van Mil SW, van der Woerd WL, van der Brugge G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 2004; 127:379.
  102. Kubitz R, Keitel V, Scheuring S, et al. Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump. J Clin Gastroenterol 2006; 40:171.
  103. van der Woerd WL, van Mil SW, Stapelbroek JM, et al. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol 2010; 24:541.
  104. Stapelbroek JM, van Erpecum KJ, Klomp LW, et al. Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis. Hepatology 2006; 43:51.
  105. Saich R, Collins P, Ala A, et al. Benign recurrent intrahepatic cholestasis with secondary renal impairment treated with extracorporeal albumin dialysis. Eur J Gastroenterol Hepatol 2005; 17:585.
  106. Uegaki S, Tanaka A, Mori Y, et al. Successful treatment with colestimide for a bout of cholestasis in a Japanese patient with benign recurrent intrahepatic cholestasis caused by ATP8B1 mutation. Intern Med 2008; 47:599.
  107. Alagille D, Estrada A, Hadchouel M, et al. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr 1987; 110:195.
  108. Alagille D. Alagille syndrome today. Clin Invest Med 1996; 19:325.
  109. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 1999; 29:822.
  110. Subramaniam P, Knisely A, Portmann B, et al. Diagnosis of Alagille syndrome-25 years of experience at King's College Hospital. J Pediatr Gastroenterol Nutr 2011; 52:84.
  111. Oda T, Elkahloun AG, Meltzer PS, Chandrasekharappa SC. Identification and cloning of the human homolog (JAG1) of the rat Jagged1 gene from the Alagille syndrome critical region at 20p12. Genomics 1997; 43:376.
  112. Gottrand F, Clavey V, Fruchart JC, Farriaux JP. Lipoprotein pattern and plasma lecithin cholesterol acyl transferase activity in children with Alagille syndrome. Atherosclerosis 1995; 115:233.
  113. 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.
  114. Clerici C, Gentili G, Dozzini G, et al. [Chronic therapy with ursodeoxycholic acid in a child with Alagille syndrome]. Pediatr Med Chir 1993; 15:521.
  115. Hofbauer LC, Mrozek-Lasota A, Jelinek T, et al. [Endocrinologic and metabolic complications of Alagille syndrome]. Med Klin (Munich) 1997; 92:528.
  116. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, et al. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995; 127:220.
  117. Phillips MJ, Azuma T, Meredith SL, et al. Abnormalities in villin gene expression and canalicular microvillus structure in progressive cholestatic liver disease of childhood. Lancet 2003; 362:1112.
  118. Pringault E, Robine S, Louvard D. Structure of the human villin gene. Proc Natl Acad Sci, USA 1991; 88:10811.
  119. Bretscher A, Weber K. Villin is a major protein of the microvillus cytoskeleton which binds both G and F actin in a calcium-dependent manner. Cell 1980; 20:839.
  120. Ferrary E, Cohen-Tannoudji M, Pehau-Arnaudet G, et al. In vivo, villin is required for Ca(2+)-dependent F-actin disruption in intestinal brush borders. J Cell Biol 1999; 146:819.