Abstract
Background
The ABCB4 gene encodes the MDR3 protein. Mutations of this gene cause progressive familial intrahepatic cholestasis type 3 (PFIC3) in children, but their clinical relevance in adults remains ill defined. The study of a well-characterized adult patient series may contribute to refining the genetic data regarding cholangiopathies of unknown origin. Our aim was to evaluate the impact of ABCB4 mutations on clinical expression of cholestasis in adult patients.
Methods
We consecutively evaluated 2602 subjects with hepatobiliary disease. Biochemical evidence of a chronic cholestatic profile (CCP) with elevated serum gamma-glutamyltransferase activity or diagnosis of intrahepatic cholestasis of pregnancy (ICP) and juvenile cholelithiasis (JC) were inclusion criteria. The personal/family history of additional cholestatic liver disease (PFH-CLD), which includes ICP, JC, or hormone-induced cholestasis, was investigated. Mutation screening of ABCB4 was carried out in 90 patients with idiopathic chronic cholestasis (ICC), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), ICP, and JC.
Results
Eighty patients had CCP. PSC and ICC patients with PFH-CLD had earlier onset of disease than those without it (p = 0.003 and p = 0.023, respectively). The mutation frequency ranged from 50 % (ICP, JC) to 17.6 % (PBC). Among CCP patients, presence or absence of PFH-CLD was associated with ABCB4 mutations in 26.8 vs 5.1 % (p = 0.013), respectively; in the subset of ICC and PSC patients, the corresponding figures were 44.4 vs 0 % (p = 0.012) and 28.6 vs 8.7 % (p = 0.173).
Conclusions
Cholangiopathies attributable to highly penetrant ABCB4 mutant alleles are identifiable in a substantial proportion of adults that generally have PFH-CLD. In PSC and ICC phenotypes, patients with MDR3 deficiency have early onset of disease.
Similar content being viewed by others
References
Wagner M, Zollner G, Trauner M. New molecular insights into the mechanisms of cholestasis. J Hepatol. 2009;51:565–80.
Hirschfield GM, Heathcote EJ. Cholestasis and cholestatic syndromes. Curr Opin Gastroenterol. 2009;25:175–9.
Davit-Spraul A, Gonzales E, Baussan C, et al. The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Semin Liver Dis. 2010;30:134–46.
Hirschfield GM, Chapman RW, Karlsen TH, et al. The genetics of complex cholestatic disorders. Gastroenterology. 2013;144:1357–74.
Fletcher RW, Fletcher SW. Clinical epidemiology: the essentials. 4th ed. Baltimore: Lippincott Williams and Wilkins; 2005
de Vree JML, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad USA. 1998;95:282–7.
Colombo C, Vajro P, Degiorgio D, et al. Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type-3 related to ABCB4 mutations. J Pediatr Gastroenterol Nutr. 2011;52:73–83.
Degiorgio D, Colombo C, Seia M, et al. Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3). Eur J Hum Genet. 2007;15:1230–8.
Klein I, Sarkadi B, Varadi A. An inventory of the human ABC proteins. Biochim Biophys Acta. 1999;1461:237–62.
Smit JJM, Shinkel AH, Oude Elferink RPJ, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell. 1993;75:451–62.
Degiorgio D, Corsetto PA, Rizzo AM, et al. Two ABCB4 point mutations of strategic NBD-motifs do not prevent protein targeting to the plasma membrane but promote MDR3 dysfunction. Eur J Hum Genet. 2014;22:633–9.
Bacq Y, Gendrot C, Perrotin F, et al. ABCB4 gene mutations and single-nucleotide polymorphisms in women with intrahepatic cholestasis of pregnancy. J Med Genet. 2009;46:711–5.
Tavian D, Degiorgio D, Roncaglia N, et al. A new splicing site mutation of ABCB4 gene in intrahepatic cholestasis of pregnancy with raised serum gamma-GT. Dig Liver Dis. 2009;41:671–5.
Poupon R, Rosmorduc O, Boëlle PY, et al. Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients. Hepatology. 2013;58:1105–10.
Gotthardt D, Runz H, Keitel V, et al. A mutation in the canalicular phospholid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Hepatology. 2008;48:1157–66.
Lucena JF, Herrero JI, Quiroga J, et al. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis. Gastroenterology. 2003;124:1037–42.
Denk GU, Bikker H, Lekanne dit Deprez RH, et al. ABCB4 deficiency: a family saga of early onset cholelithiasis, sclerosing cholangitis and cirrhosis and a novel mutation in the ABCB4 gene. Hepatol Res. 2010;40:937–41.
Rosmorduc O, Hermelin B, Boelle PY, et al. ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterology. 2003;125:452–9.
Tougeron D, Fotsing G, Barbu V, et al. ABCB4/MDR3 gene mutations and cholangiocarcinomas. J Hepatol. 2012;57:467–8.
Ohishi Y, Nakamura M, Iio N, et al. Single-nucleotide polymorphism analysis of the multidrug resistance protein 3 gene for the detection of clinical progression in Japanese patients with primary biliary cirrhosis. Hepatology. 2008;48:853–62.
Pauli-Magnus C, Kerb R, Fattinger K, et al. BSEP and MDR3 haplotype structure in healthy caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology. 2004;39:779–91.
Rosmorduc O, Hermelin B, Boelle PY, et al. ABCB4 gene mutations and primary sclerosing cholangitis. Gastroenterology. 2004;126:1220–2.
Fickert P, Fuchsbichler A, Wagner M, et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2004;127:261–74.
Trauner M, Fickert P, Wagner M. MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis. 2007;27:77–98.
Ziol M, Barbu V, Rosmorduc O, et al. ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults. Gastroenterology. 2008;135:131–41.
Gordo-Gilart R, Andueza S, Hierro L, et al. Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity. Gut. 2015;64:147–55.
Andress EJ, Nicolaou M, Romero MR, et al. Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. Hepatology. 2014;59:1921–31.
Czaja AJ. The overlap syndromes of autoimmune hepatitis. Dig Dis Sci. 2013;58:326–43.
Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PE. Improving sequence variant descriptions in mutation databases and literature using the mutalyzer sequence variation nomenclature checker. Hum Mutat. 2008;29:6–13.
Williamson KD, Chapman W. Primary sclerosing cholangitis. Dig Dis. 2014;32:438–45.
Fickert P, Pollheimer MJ, Beuers U, et al. Characterization of animal models for primary sclerosing cholangitis (PSC). J Hepatol. 2014;60:1290–303.
Crosignani A, Battezzati PM, Invernizzi P, et al. Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008;14:3313–27.
Momah N, Lindor KD. Primary biliary cirrhosis in adults. Expert Rev Gastroenterol Hepatol. 2014;8:427–33.
Haas J, Roth S, Arnold K, et al. The protein model portal—a comprehensive resource for protein structure and model information. Database (Oxford). 2013;bat031. doi:10.1093/database/bat031.
Acknowledgments
We thank Drs. M. Castagni and L. Paganini for their valuable technical assistance.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
This study was supported by a grant (PRIN contract #2005068307_005) of the Italian Ministry of Education, University and Research (MIUR), Italy (MIUR).
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
D. Degiorgio and A. Crosignani contributed equally to this work and should be considered as first authors.
Rights and permissions
About this article
Cite this article
Degiorgio, D., Crosignani, A., Colombo, C. et al. ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression. J Gastroenterol 51, 271–280 (2016). https://doi.org/10.1007/s00535-015-1110-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00535-015-1110-z