The many faces of MDR 3 deficiency

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1 The many faces of MDR 3 deficiency Relevance of canalicular membrane transporting proteins for human liver disease Peter LM Jansen and Marleen de Vree Academic Medical Center Amsterdam, The Netherlands

2 MRP3 MRP4 OSTαβ MDR3 BSEP ATP8B1 ABCG5/8 Cholestasis genes MDR1 ABCB11/BSEP ABCB4/MDR3 ATP8B1 BAAT ATP8B1 TJP-1 CFTR Bile acid synthesis genes e.g. HSD3B7 ASBT MRP2 BCRP Possible modifier genes FXR, PXR, VDR, CAR HNF4α OSTαβ SHP FGF19 MRP3 MRP3, MRP4, OSTαβ

3 Cholestatic diseases with a genetic background, low phospholipid associated cholelithiasis (intrahepatic gallstones, periportal fibrosis) ICP, intrahepatic cholestasis of pregnancy DILI, drug-induced liver injury IAD, idiopathic adult ductopenia PFIC, progressive familial intrahepatic cholestasis BRIC, benign recurrent intrahepatic cholestasis

4 Monogenetic diseases Multifactorial Affected transport function PFIC type 3 ICP, high GGT MDR3 Phosphatidylcholine PFIC type 2 BRIC type 2 DILI ICP, low GGT BSEP Bile acids Cholesterol Sitosterolemia Gallstones ABCG5/8

5 Pathophysiology of ABCB4/MDR3 deficiency MDR3 Cholangiopathy BSEP Bile acids Toxic bile ABCG5/8 Cholesterol

6 Pathophysiology of ABCB4/MDR3 deficiency Causes MDR3 BSEP ABCG5/8 Primary deficiency Genetic Secondary deficiency Cytokines/Sepsis Hepatitis C Drugs, Cyclosporin A, Sirolimus, Vinblastine, Verapamil Total parenteral nutrition

7 Pathophysiology of ABCB4/MDR3 deficiency Symptoms, Signs Pruritus MDR3 BSEP ABCG5/8 High GGT Low/absent lipoprotein X Bilirubin normal - high Therapy Urso Experimental FXR, PPARα agonists (fibrates)

8 Established PFIC type 3 ICP, high GGT type Fibrosing cholestatic liver disease ABCB4/MDR3 phenotypes Deleuze 1996; De Vree 1998 Jacquemin 1999; Dixon 2000 Rosmorduc 2001 Ziol 2008 Probable Idiopathic adult ductopenia Post liver transplant strictures Possible DILI PSC HCC and PSC Hypothetical Oriental hepatolithiasis Atherosclerosis Jansen 2004 Geuken 2004 Lang, 2006 Pauli-Magnus 2004, Rosmorduc 2004 Saitta abstract EASL 2008 Shoda 2001, 2006 Pennings 2007

9 # Age G Nucleotide Amino acid Phenotype Reports C>T Leu817Phe A>G 959 C>T Ser27Gly Ser320Phe IAD?, Urso response IAD, Cirrhosis, OLT IAD, Cirrhosis PFIC3 ICP, dupT Ser339hefsX16, Pancreatitis PSC, HCC G>A Ala934Thre C>T Ala574Val ICP, Statin-cholestasis C>T Thr438Met OAC-cholestasis A>G 1954 A>G Thr175Ala Arg652Gly ICP C>T Pro726Leu PSC G>A 523 A>G 1814 A>T Arg590Gln Thr175Ala Asp605Val, cirrhosis, TIPS ICP, PFIC3 ICP PFIC C>T 1015 dupt Ser320Phe Ser339PhefsX16 PFIC3, Urso response A>G Lys410Arg + ICP G>C 3242 T>C Gly270Arg Leu1081Pro G>T Gly959Val G>A Arg590Gln ICP, A>T Arg469Trp, cirrhosis, pancreatitis G>A 956 G>A Arg47Gln Gly319Glu ICP and C>T Pro726Leu ICP

10 # Age G Nucleotide Amino acid Phenotype Reports _2088del Val695Glu fs Cholestase First report G>T Splicing def PFIC 3 First report G>T Splicing def PFIC 3 First report _643del Arg215Ser fsx4 ICP, First report _2757delAT Tyr919Cys fsx1 PFIC 3 First report G>A Ala984Thr PFIC 3 First report C>A Ala953Asp PFIC 3 PFIC T>G 2800G>A Leu703Arg Ala934Thr PFIC 3 First report G>A 1769G>A Ser436Asn Arg590Gln PFIC 3 First report DILI, PFIC G>C Gln631His Cholestase First report G>A Ser436Asn Cholestase First report G>A Arg788Gln PFIC A>C His1154Arg ICP First report

11 PFIC3 MDR3/ABCB4 mutations ICP PSC ICP IAD Cirrhosis Cirrhosis Cirrhosis IAD PFIC3 ICP ICP Statincholestasis OAC- Cholestasis

12 Drug induced cholestasis: oral anticonceptiva Stop UDCA Restart UDCA Start UDCA Stop OAC

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14 ABCB4/MDR3 heterozygosity ICP cirrhosis pancreatitis PFIC3 IAD (VBD) DILI atorvastatin contraceptives ABCB4/MDR3 homozygosity

15 Conclusions for the clinician Patients with ICP are at risk to develop, cirrhosis and/or OAC/Statin-induced cholestasis Parents of PFIC3 patients are at risk to develop liver disease Patients with intrahepatic gallstones may be heterozygous for ABCB4/MDR 3 mutations Heterozygosity for ABCB4/MDR 3 mutations can be associated with considerable hepatic fibrosis Relative risk for HCC?

16 Case

17 Female 27 yrs old Jan caesarian section at 33 wks of pregnancy because of fetal stress, first child Patient transferred to our hospital with acute renal failure, jaundice, trombocytopenia, ascites, abnormal clotting

18 Female 27 yrs old Jan caesarian section at 33 wks of pregnancy because of fetal stress, first child Patient transferred to our hospital with acute renal failure, jaundice, trombocytopenia, ascites, abnormal clotting Diagnosis : HELLP Syndrome

19 Creatinine243 micromol/l (< 100) Bilirubin total 215 micromol/l (<17) Bilirubin direct 161 micromol/l (<10) ASAT 94 U/l (< 40) ALAT 68 U/l (<45) Alk phos 290 U/l (<120) GGT 20 U/l (<60) Haptoglobin < 0.20 g/l Hb 5.2 mmol/l (>8.0) Trombocytes 95 x10 9 /l (>150) Fragmentocytes + INR 2.5 D-dimers elevated Ultrasound liver: no steatosis

20 Female 27 yrs old Pruritus in last trimester of pregnancy Family: mother and aunt pruritus during OAC and pregnancies

21 Female 27 yrs old Pruritus in last trimester of pregnancy Family: mother and aunt pruritus during OAC and pregnancies Diagnosis : HELLP + ICP Jaundice only very slowly improving, 4 months after delivery bilirubin still elevated

22 Female 27 yrs old Mutation analysis: No ABCB4/MDR3 mutation found

23 Female 27 yrs old Mutation analysis: No ABCB4/MDR3 mutation found ABCB11 gene mutation 1723 C>T

24 Strautnieks ea Gastroenterology :

25 Diagnosis HELLP syndrome Low GGT ICP Associated with/ Due to (?): ABCB11 gene mutation

26 Marleen de Vree, AMC Liver Center Henny Bikker, department of Clinical Genetics Academic Medical Center Amsterdam