Abstract
Familial cholestatic diseases exhibit familial patterns of occurrence and result from known or presumed gene defects. Until recently, these diseases were all considered syndromes, with recognizable patterns of clinical characteristics. Moreover, little was know about the molecular pathophysiology of cholestasis in general, and nothing was known about any of these diseases. The recent discovery and characterization of the genes involved in five of these diseases has led to improved understanding of the diseases and of the physiologic function and importance of the gene products. Furthermore, as has happened many times in the past, these patients with genetic disease have served as human models of disease pathophysiology. Study of the course of the disease in these patients has rapidly increased our understanding of the molecular mechanisms of bile formation, cholestasis, and liver injury caused by cholestasis.
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References and Recommended Reading
Whitington PF: Chronic cholestasis of infancy. Pediatr Clin North Am 1996, 43:1–26.
Trauner M, Meier PJ, Boyer JL: Molecular pathogenesis of cholestasis. New Engl J Med 1998, 339:1217–1227. Outstanding review of the mechanisms of bile formation and the pathophysiology of cholestasis, incorporating most of the new information about gene defects and how the products of these genes play roles in bile formation.
Whitington PF, Freese DK, Sharp HL, et al.: Clinical and biochemical findings in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 1994, 18:134–141.
Alonso EM, Snover DC, Montag A, et al.: Histologic pathology of the liver in progressive familial intrahepatic cholestasis. J Pediatr Gastroenterol Nutr 1994, 18:128–133.
Emond JC, Whitington PF: Selective surgical management of progressive familial intrahepatic cholestasis (Byler’s disease). J Pediatr Surg 1995; 30:1635–1641.
Bull LN, van Eijk MJ, Pawlikowska L, et al.: A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nature Genet 1998; 18:219–224. This article reports on identification of the gene involved in BRIC and PFIC-1.
Bull LN, Carlton VE, Stricker NL, et al.: Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity. Hepatology 1997, 26:155–164.
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, 61:630–633. This article reports on identification of the gene involved in PFIC-2.
Strautnieks SS, Bull LN, Knisely AS, et al.: A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nature Genetics 1998, 20:233–238. This article provides characterization of the gene involved in PFIC-1.
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, 95:282–287. This article identifies and characterizes the molecular defect in MDR-3(-) disease.
Crawford AR, Smith AJ, Hatch VC, et al.: Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. J Clin Invest 1997, 100:2562–2567.
Ornvold K, Nielsen I-M, Poulsen H: Fatal familial cholestatic syndrome in Greenland Eskimo children. A histomorphological analysis of 16 cases. Virchows Archiv Pathol Anat 1989, 415:275–281.
Weber AM, Tuchweber B, Yousef I, et al.: Severe familial cholestasis in North American Indian children: a clinical model of microfilament dysfunction? Gastroenterology 1981; 81:653–662.
Aagenaes O, Sigstad H, Bjorn-Hansen R: Lymphoedema in hereditary recurrent cholestasis from birth. Arch Dis Child 1970, 45:690–695.
Summerskill WHJWJ: Benign recurrent intrahepatic ‘obstructive’ jaundice. Lancet 1959, 2:686–690.
Watson GM, Miller V: Arteriohepatic dysplasia: Familial pulmonary artery stenosis with neonatal liver disease. Arch Dis Child 1993, 49:459–467.
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, 110:195–200.
Emerick KMRE, Goldmuntz E, Krantz ID, et al.: Features of Alagille Syndrome in 92 patients: Frequency and relation to prognosis. Hepatology 1999, 29:822–829. Report on a follow-up study of a very large series of patients with Alagille syndrome which presents new features and factors related to prognosis.
Kahn E: Paucity of Interlobular bile ducts. Arteriohepatic dysplasia and nonsyndromic bile duct paucity. Perspect Pediatr Path 1991, 14:168–215.
Krantz ID, Colliton RP, Genin A, et al.: Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet 1998, 62:1361–1369. Description of the gene defect in Alagille syndrome, which points out poor genotype-to-phenotype relationship. Description of the gene defect in Alagille syndrome, which points out poor genotype-to-phenotype relationship.
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Emerick, K.M., Whitington, P.F. Clinical aspects of familial cholestasis (with molecular explanations). Curr Gastroenterol Rep 1, 223–230 (1999). https://doi.org/10.1007/s11894-999-0039-x
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DOI: https://doi.org/10.1007/s11894-999-0039-x