Top

Published in:

01-03-2012 | Original Article

Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations

Authors: Dominique Wendum, Véronique Barbu, Olivier Rosmorduc, Lionel Arrivé, Jean-François Fléjou, Raoul Poupon

Published in: Virchows Archiv | Issue 3/2012

Abstract

The aims of this study were to describe the histological liver lesions in adult patients with MDR3/ ABCB4 mutation and to study the usefulness of MDR3 immunostaining as a diagnostic tool. All adult patients from our institution with an MDR3/ABCB4 mutation and a liver histology were included (n = 13). Eleven patients had a single heterozygous gene mutation and two patients had two heterozygous mutations. Two patients had no liver lesions. Eight patients had a mild ductular reaction and portal fibrosis. One patient had a few fibrous septa and two patients had biliary cirrhosis. In three cases intraductal lipid crystals were identified. Two patients had biliary fibroobliterative lesions with no sclerosing cholangitis on cholangiography. Biliary dysplasia was identified in hepatectomy specimens from two patients, one of whom developed an intrahepatic cholangiocarcinoma. One patient with biliary cirrhosis developed a hepatocellular carcinoma. MDR3 immunostainings performed on formalin-fixed paraffin-embedded sections showed a strong canalicular staining in all patients except in one. To conclude, the predominant histological features were ductular reaction with no or mild fibrosis without cholangitis. Liver lesions previously unreported in association with MDR3/ABCB4 gene mutations (biliary dysplasia, cholangiocarcinoma, small duct sclerosing cholangitis) were also found. Lipid crystals in bile ducts may be suggestive of MDR3/ABCB4 mutation. MDR3 immunostaining on formalin-fixed paraffin-embedded sections does not seem to be sensitive for the diagnosis of heterozygous MDR3/ABCB4 mutations.

Oude Elferink RP, Paulusma CC (2007) Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Arch 453:601–610PubMedCrossRef

Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E (2009) Progressive familial intrahepatic cholestasis. Orphanet J Rare Dis 4:1PubMedCrossRef

Rosmorduc O, Hermelin B, Poupon R (2001) MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology 120:1459–1467PubMedCrossRef

Jacquemin E, De Vree JM, Cresteil D, Sokal EM, Sturm E, Dumont M, Scheffer GL, Paul M, Burdelski M, Bosma PJ, Bernard O, Hadchouel M, Elferink RP (2001) The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 120:1448–1458PubMedCrossRef

Gotthardt D, Runz H, Keitel V, Fischer C, Flechtenmacher C, Wirtenberger M, Weiss KH, Imparato S, Braun A, Hemminki K, Stremmel W, Ruschendorf F, Stiehl A, Kubitz R, Burwinkel B, Schirmacher P, Knisely AS, Zschocke J, Sauer P (2008) A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Hepatology 48:1157–1166PubMedCrossRef

Ziol M, Barbu V, Rosmorduc O, Frassati-Biaggi A, Barget N, Hermelin B, Scheffer GL, Bennouna S, Trinchet JC, Beaugrand M, Ganne-Carrie N (2008) ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults. Gastroenterology 135:131–141PubMedCrossRef

Poupon R, Barbu V, Chamouard P, Wendum D, Rosmorduc O, Housset C (2010) Combined features of low phospholipid-associated cholelithiasis and progressive familial intrahepatic cholestasis 3. Liver Int 30:327–331PubMedCrossRef

Mauad TH, van Nieuwkerk CM, Dingemans KP, Smit JJ, Schinkel AH, Notenboom RG, van den Bergh Weerman MA, Verkruisen RP, Groen AK, Oude Elferink RP et al (1994) Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol 145:1237–1245PubMed

Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, Krause R, Lammert F, Langner C, Zatloukal K, Marschall HU, Denk H, Trauner M (2004) Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 127:261–274PubMedCrossRef

10.

Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ (2004) BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 39:779–791PubMedCrossRef

11.

Rosmorduc O, Hermelin B, Boelle PY, Poupon RE, Poupon R, Chazouilleres O (2004) ABCB4 gene mutations and primary sclerosing cholangitis. Gastroenterology 126:1220–1222, author reply 1222-1223PubMedCrossRef

12.

Davit-Spraul A, Gonzales E, Baussan C, Jacquemin E (2010) The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Semin Liver Dis 30:134–146PubMedCrossRef

13.

Colombo C, Vajro P, Degiorgio D, Coviello DA, Costantino L, Tornillo L, Motta V, Consonni D, Maggiore G (2011) Clinical features and genotype-phenotype correlations in children with progressive familial intrahepatic cholestasis type 3 related to ABCB4 mutations. J Pediatr Gastroenterol Nutr 52:73–83PubMedCrossRef

14.

Rosmorduc O, Hermelin B, Boelle PY, Parc R, Taboury J, Poupon R (2003) ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterology 125:452–459PubMedCrossRef

15.

Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, Hong SM, Hytiroglou P, Kloppel G, Lauwers GY, van Leeuwen DJ, Notohara K, Oshima K, Quaglia A, Sasaki M, Sessa F, Suriawinata A, Tsui W, Atomi Y, Nakanuma Y (2007) Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 20:701–709PubMedCrossRef

16.

Poupon R, Arrive L, Rosmorduc O (2010) The cholangiographic features of severe forms of ABCB4/MDR3 deficiency-associated cholangiopathy in adults. Gastroenterol Clin Biol 34:380–387PubMedCrossRef

17.

Carey MC (1978) Critical tables for calculating the cholesterol saturation of native bile. J Lipid Res 19:945–955PubMed

18.

Shoda J, Oda K, Suzuki H, Sugiyama Y, Ito K, Cohen DE, Feng L, Kamiya J, Nimura Y, Miyazaki H, Kano M, Matsuzaki Y, Tanaka N (2001) Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi. Hepatology 33:1194–1205PubMedCrossRef

19.

Trauner M, Fickert P, Wagner M (2007) MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin Liver Dis 27:77–98PubMedCrossRef

20.

Kawakami H, Kuwatani M, Onodera M, Hirano S, Kondo S, Nakanishi Y, Itoh T, Asaka M (2007) Primary cholesterol hepatolithiasis associated with cholangiocellular carcinoma: a case report and literature review. Intern Med 46:1191–1196PubMedCrossRef

21.

Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Semin Liver Dis 24:115–125PubMedCrossRef

22.

Shoda J, Tanaka N, Osuga T (2003) Hepatolithiasis—epidemiology and pathogenesis update. Front Biosci 8:e398–e409PubMedCrossRef

23.

Keitel V, Burdelski M, Warskulat U, Kuhlkamp T, Keppler D, Haussinger D, Kubitz R (2005) Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology 41:1160–1172PubMedCrossRef

24.

Delaunay JL, Durand-Schneider AM, Delautier D, Rada A, Gautherot J, Jacquemin E, Ait-Slimane T, Maurice M (2009) A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature. Hepatology 49:1218–1227PubMedCrossRef

25.

Degiorgio D, Colombo C, Seia M, Porcaro L, Costantino L, Zazzeron L, Bordo D, Coviello DA (2007) Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3). Eur J Hum Genet 15:1230–1238PubMedCrossRef

Title: Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations
Authors: Dominique Wendum
Véronique Barbu
Olivier Rosmorduc
Lionel Arrivé
Jean-François Fléjou
Raoul Poupon
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 3/2012
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-012-1202-6

At a glance: The STEP trials

Springer Medicine

Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2012

Decentral gene expression analysis for ER+/Her2− breast cancer: results of a proficiency testing program for the EndoPredict assay

Diagnostic value of neutrophil gelatinase-associated lipocalin (NGAL) immunoexpression in follicular-patterned lesions of the thyroid gland

Phenotyping of pulmonary carcinoids and a Ki-67-based grading approach

Dedifferentiated peripheral chondrosarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of four cases

Urothelial carcinoma of the renal pelvis with simultaneous trophoblastic and malignant clear cell endodermal-type differentiation

Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features