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Jiao J, Morotti R, Shafizadeh N, Jain D. Expanding the spectrum of progressive familial intrahepatic cholestasis: A report of 3 cases. Am J Clin Pathol 2025; 163:332-339. [PMID: 39333837 DOI: 10.1093/ajcp/aqae123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
OBJECTIVES Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders caused by defects in bile secretion or transport usually presenting as cholestasis in pediatric age. Herewith, we describe 3 PFIC cases with diagnostic challenges and highlight the role of genetic analysis. METHODS The clinical history, laboratory data, liver biopsy, and molecular analysis for each case were reviewed. RESULTS Case 1, a Hispanic male from Puerto Rico with hepatomegaly since age 2 months, was eventually diagnosed with PFIC3 following identification of a homozygous splice site variant in ATP binding cassette subfamily B member 4 (ABCB4) (c.2784-12T>C) at age 17 years by whole-exome sequencing (WES). Case 2 was a 37-year-old man with a history of alcoholism, abnormal liver function tests, and ductopenia on biopsy. Molecular testing revealed a pathogenic heterozygous ABCB4 mutation (c.1633C>T) variant leading to a diagnosis of PFIC3. Case 3 was a 2-year-old female initially presenting as a drug-induced liver injury but was diagnosed with PFIC10 following identification of a heterozygous frameshift mutation (p.Asp300Trpfs*19) and a heterozygous missense mutation (c.1357T>C) in myosin VB (MYO5B) by WES. CONCLUSIONS These PFIC cases highlight the heterogenous presentation and diagnostic challenges, and they emphasize the role of next-generation sequencing, particularly the utility of WES.
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Affiliation(s)
- Jingjing Jiao
- Department of Pathology, Yale School of Medicine, New Haven, CT, US
| | | | - Nafis Shafizadeh
- Department of Pathology, Southern California Permanente Medical Group, Woodland Hills Medical Center, Los Angeles, CA, US
| | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, CT, US
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2
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Verkade HJ, Felzen A, Keitel V, Thompson R, Gonzales E, Strnad P, Kamath B, van Mil S. EASL Clinical Practice Guidelines on genetic cholestatic liver diseases. J Hepatol 2024; 81:303-325. [PMID: 38851996 DOI: 10.1016/j.jhep.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 04/05/2024] [Indexed: 06/10/2024]
Abstract
Genetic cholestatic liver diseases are caused by (often rare) mutations in a multitude of different genes. While these diseases differ in pathobiology, clinical presentation and prognosis, they do have several commonalities due to their cholestatic nature. These Clinical Practice Guidelines (CPGs) offer a general approach to genetic testing and management of cholestatic pruritus, while exploring diagnostic and treatment approaches for a subset of genetic cholestatic liver diseases in depth. An expert panel appointed by the European Association for the Study of the Liver has created recommendations regarding diagnosis and treatment, based on the best evidence currently available in the fields of paediatric and adult hepatology, as well as genetics. The management of these diseases generally takes place in a tertiary referral centre, in order to provide up-to-date approaches and expertise. These CPGs are intended to support hepatologists (for paediatric and adult patients), residents and other healthcare professionals involved in the management of these patients with concrete recommendations based on currently available evidence or, if not available, on expert opinion.
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Hegarty R, Gurra O, Tarawally J, Allouni S, Rahman O, Strautnieks S, Kyrana E, Hadzic N, Thompson RJ, Grammatikopoulos T. Clinical outcomes of ABCB4 heterozygosity in infants and children with cholestatic liver disease. J Pediatr Gastroenterol Nutr 2024; 78:339-349. [PMID: 38374565 DOI: 10.1002/jpn3.12080] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 09/24/2023] [Accepted: 09/29/2023] [Indexed: 02/21/2024]
Abstract
OBJECTIVES Biallelic variants in the adenosine triphosphate binding cassette subfamily B member 4 (ABCB4) gene which encodes the multidrug resistance 3 protein (MDR3) leads to progressive familiar intrahepatic cholestasis type 3. However, monoallelic variants are increasingly recognized as contributing to liver disease in adults. Our aim was to describe the clinical characteristics of MDR3 heterozygous variants in a large cohort of infants and children with cholestatic liver disease. METHODS The clinical and genotypic data on pediatric patients seen at King's College Hospital, London, between 2004 and 2022 and found to harbour heterozygous variants in ABCB4 were reviewed. RESULTS Ninety-two patients amongst 1568 tested were identified with a monoallelic variant (5.9%). The most common presenting problem was conjugated hyperbilirubinemia (n = 46; 50%) followed by cholelithiasis (n = 12; 13%) and cholestatic hepatitis (n = 10; 11%). The median values of liver biochemistry at presentation were: GGT 105 IU/L and total bilirubin 86 µmol/L. Thirty-two genetic variants were identified including 22 missense (69%), 4 deletions (13%), 5 splice site (16%) and 1 termination (3%). At a median follow up of 1 year there was resolution of liver disease. CONCLUSIONS Rare variants in ABCB4 were found amongst infants and children with cholestatic liver disease. The presenting problems were variable and abnormalities tended to normalize over time. Those with severe mutations could develop liver disease later in life when exposed to further insult and should be counseled appropriately.
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Affiliation(s)
- Robert Hegarty
- Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | | | | | - Sammi Allouni
- Liver Molecular Genetics Lab, Institute of Liver Studies, King's College Hospital, London, UK
| | - Obydur Rahman
- Liver Molecular Genetics Lab, Institute of Liver Studies, King's College Hospital, London, UK
| | - Sandra Strautnieks
- Liver Molecular Genetics Lab, Institute of Liver Studies, King's College Hospital, London, UK
| | - Eirini Kyrana
- Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Nedim Hadzic
- Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
| | - Richard J Thompson
- Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
- Liver Molecular Genetics Lab, Institute of Liver Studies, King's College Hospital, London, UK
| | - Tassos Grammatikopoulos
- Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK
- King's College London, London, UK
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Zöllner J, Finer S, Linton KJ, van Heel DA, Williamson C, Dixon PH. Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom. Sci Rep 2023; 13:8120. [PMID: 37208429 PMCID: PMC10199085 DOI: 10.1038/s41598-023-33391-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 04/12/2023] [Indexed: 05/21/2023] Open
Abstract
This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency < 5%. Variants were filtered, and annotated to perform rare variant burden analysis, protein structure, and modelling analysis in-silico. Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic and 9 pathogenic. We identified variants in volunteers with gallstone disease (n = 31), intrahepatic cholestasis of pregnancy (ICP, n = 16), cholangiocarcinoma and cirrhosis (n = 2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11. Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.
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Affiliation(s)
| | - Sarah Finer
- Institute for Population Health Sciences, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kenneth J Linton
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - David A van Heel
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Catherine Williamson
- Department of Women and Children's Health, School of Life Course Sciences, FOLSM, King's College London, 2.30W Hodgkin Building, Guy's Campus, London, SE1 1UL, UK.
| | - Peter H Dixon
- Department of Women and Children's Health, School of Life Course Sciences, FOLSM, King's College London, 2.30W Hodgkin Building, Guy's Campus, London, SE1 1UL, UK
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5
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Bozward A, Ce M, Dell'oro L, Oo YH, Ronca V. Breakdown in hepatic tolerance and its relation to autoimmune liver diseases. Minerva Gastroenterol (Torino) 2023; 69:10-22. [PMID: 33793157 DOI: 10.23736/s2724-5985.21.02853-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The liver is a complex immunological organ. It has both immunogenic and tolerogenic capacity. Tolerogenic potential of human liver with its protective firewalls is required to guard the body against the continuous influx of microbial product from the gut via the sinusoids and biliary tree. Immunotolerance and anergic state is maintained by a combined effort of both immune cells, parenchyma cells, epithelial and endothelial cells. Despite this, an unknown trigger can ignite the pathway towards breakdown in hepatic tolerance leading to autoimmune liver diseases. Understanding the initial stimulus which causes the hepatic immune system to switch from the regulatory arm towards self-reactive effector arm remains challenging. Dissecting this pathology using the current technological advances is crucial to develop curative immune based therapy in autoimmune liver diseases. We discuss the hepatic immune cells and non-immune cells which maintain liver tolerance and the evidence of immune system barrier breach which leads to autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis.
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Affiliation(s)
- Amber Bozward
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK
| | - Maurizio Ce
- Department of Health Sciences, University of Milan, Milan, Italy
| | | | - Ye H Oo
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
| | - Vincenzo Ronca
- Center for Liver and Gastro Research and NIHR Biomedical Research Center, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK - .,Center for Rare Diseases, European Reference Network Centre - Rare Liver, Birmingham, UK.,Liver Transplant and Hepatobiliary Unit, University Hospital of Birmingham NHS Foundation Trust, Birmingham, UK
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Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases. Int J Mol Sci 2023; 24:ijms24021236. [PMID: 36674751 PMCID: PMC9867378 DOI: 10.3390/ijms24021236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/15/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
ABCB4 (ATP-binding cassette subfamily B member 4) is a hepatocanalicular floppase involved in biliary phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. Our results provide evidence that functional ABCB4 mutations are rescued by ivacaftor, paving the way for the repositioning of this potentiator for the treatment of selected patients with PFIC3 caused by mutations in the ATP-binding sites of ABCB4.
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7
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Stieger B, Boyer JL. In Memoriam: Peter J. Meier (1947-2021). J Hepatol 2021; 75:S0168-8278(21)01889-4. [PMID: 34332756 DOI: 10.1016/j.jhep.2021.06.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 06/28/2021] [Indexed: 12/04/2022]
Affiliation(s)
- Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich and University of Zurich, 8091 Zurich, Switzerland.
| | - James L Boyer
- Department of Medicine and Liver Center, Yale University School of Medicine, New Haven, CT 06520, USA.
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ABCB4 variants in adult patients with cholestatic disease are frequent and underdiagnosed. Dig Liver Dis 2021; 53:329-344. [PMID: 33390354 DOI: 10.1016/j.dld.2020.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/01/2020] [Accepted: 12/05/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Heterozygous ABCB4 variants are not routinely tested in adults with cholestasis because of their supposed rarity and high costs. METHODS Nineteen adult patients presenting with unexplained cholestasis, and/or recurrent gallstones were included; genotyping was not done in five due to lack of health insurance approval. RESULTS heterozygous ABCB4 variants were identified in seven patients, followed by cascade testing of 12 family members: one patient underwent liver transplantation at age 40 for end-stage liver disease; one had compensated cirrhosis; all symptomatic adults had gallstones, including four with low phospholipid-associated cholelithiasis; four had intrahepatic cholestasis of pregnancy; all children and one 54-year old female were asymptomatic. Genotype: Families A and C: c.2211G>A (p.Ala737=) combined with c.959C>T (p.Ser320Phe) in one subject; Family B: c.1130T>C (p.Ile377Thr); Family D: large deletion removing ABCB4 exons 1-4 plus ABCB1, RUNDC3B, SLC25A40, DBF4, ADAM22 exons 1-3; Family E: c.1565T>C (p.Phe522Ser) ; Family F: c.1356+2T>C combined with c.217C>G (p.Leu73Val). All patients responded to ursodeoxycholic acid. CONCLUSIONS We found ABCB4 variants in half of the adults with unexplained cholestasis and/or recurrent gallstones presenting at our center, suggesting that this condition is underdiagnosed and undertreated, with serious consequences not only for the patients and their families, but also in terms of healthcare costs.
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9
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Gao RY, Shearn CT, Orlicky DJ, Battista KD, Alexeev EE, Cartwright IM, Lanis JM, Kostelecky RE, Ju C, Colgan SP, Fennimore BP. Bile acids modulate colonic MAdCAM-1 expression in a murine model of combined cholestasis and colitis. Mucosal Immunol 2021; 14:479-490. [PMID: 33004979 PMCID: PMC7954872 DOI: 10.1038/s41385-020-00347-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone. Multidrug resistance protein 2 knockout (Mdr2-/-) mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC. As a novel model of PSC-IBD, we treated Mdr2-/- mice with dextran sulfate sodium (DSS) to chemically induce colitis (Mdr2-/-/DSS). Mdr2-/- mice demonstrate alterations in fecal bile acid composition and enhanced colitis susceptibility with increased colonic adhesion molecule expression, particularly mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). In vitro, ursodeoxycholic acid (UDCA) co-treatment resulted in a dose dependent attenuation of TNF-α-induced endothelial MAdCAM-1 expression. In the combined Mdr2-/-/DSS model, UDCA supplementation attenuated colitis severity and downregulated intestinal MAdCAM-1 expression. These findings suggest a potential mechanistic role for alterations in bile acid signaling in modulating MAdCAM-1 expression and colitis susceptibility in cholestasis-associated colitis. Together, our findings provide a novel model and new insight into the pathogenesis and potential treatment of PSC-IBD.
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Affiliation(s)
- Rachel Y Gao
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Colin T Shearn
- Department of Pediatrics Division of Pediatric Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - David J Orlicky
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kayla D Battista
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Erica E Alexeev
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ian M Cartwright
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Jordi M Lanis
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rachael E Kostelecky
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sean P Colgan
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Blair P Fennimore
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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10
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Sticova E, Jirsa M. ABCB4 disease: Many faces of one gene deficiency. Ann Hepatol 2021; 19:126-133. [PMID: 31759867 DOI: 10.1016/j.aohep.2019.09.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Revised: 09/04/2019] [Accepted: 09/06/2019] [Indexed: 02/07/2023]
Abstract
ATP-binding cassette (ABC) subfamily B member 4 (ABCB4), also known as multidrug resistance protein 3 (MDR3), encoded by ABCB4, is involved in biliary phospholipid secretion, protecting hepatobiliary system from deleterious detergent and lithogenic properties of the bile. ABCB4 mutations altering canalicular ABCB4 protein function and expression may have variable clinical presentation and predispose to several human liver diseases. Well-established phenotypes of ABCB4 deficit are: progressive familial intrahepatic cholestasis type 3, gallbladder disease 1 (syn. low phospholipid associated cholelithiasis syndrome), high ɣ-glutamyl transferase intrahepatic cholestasis of pregnancy, chronic cholangiopathy, and adult biliary fibrosis/cirrhosis. Moreover, ABCB4 aberrations may be involved in some cases of drug induced cholestasis, transient neonatal cholestasis, and parenteral nutrition-associated liver disease. Recently, genome-wide association studies have documented occurrence of malignant tumours, predominantly hepatobiliary malignancies, in patients with ABCB4/MDR3 deficit. The patient's age at the time of the first presentation of cholestatic disease, as well as the severity of liver disorder and response to treatment are related to the ABCB4 allelic status. Mutational analysis of ABCB4 in patients and their families should be considered in all individuals with cholestasis of unknown aetiology, regardless of age and/or time of onset of the first symptoms.
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Affiliation(s)
- Eva Sticova
- Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic; Pathology Department, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Srobarova, Prague, Czech Republic.
| | - Milan Jirsa
- Institute for Clinical and Experimental Medicine, Videnska, Prague, Czech Republic; Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and Faculty General Hospital, U Nemocnice, Prague, Czech Republic
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Liu J, Cui JY, Lu YF, Corton JC, Klaassen CD. Sex-, Age-, and Race/Ethnicity-Dependent Variations in Drug-Processing and NRF2-Regulated Genes in Human Livers. Drug Metab Dispos 2021; 49:111-119. [PMID: 33162398 PMCID: PMC7804821 DOI: 10.1124/dmd.120.000181] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 10/20/2020] [Indexed: 12/14/2022] Open
Abstract
Individual variations in xenobiotic metabolism affect the sensitivity to diseases. In this study, the impacts of sex, age, and race/ethnicity on drug-processing genes and nuclear factor erythroid 2-related factor 2 (NRF2) genes in human livers were examined via QuantiGene multiplex suspension array (226 samples) and quantitative polymerase chain reaction (qPCR) (247 samples) to profile the expression of nuclear receptors, cytochrome P450s, conjugation enzymes, transporters, bile acid metabolism, and NRF2-regulated genes. Sex differences were found in expression of about half of the genes, but in general the differences were not large. For example, females had higher transcript levels of catalase, glutamate-cysteine ligase catalytic subunit (GCLC), heme oxygenase 1 (HO-1), Kelch-like ECH-associated protein 1 (KEAP1), superoxide dismutase 1, and thioredoxin reductase-1 compared with males via qPCR. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit (GCLM) and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor (FXR) but higher expression of HO-1, Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of FXR, SULT2A1, small heterodimer partner, and bile salt export pump. An examination of 34 diseased and control human liver samples showed that compared with disease-free livers, fibrotic livers had higher NAD(P)H-quinone oxidoreductase 1 (NQO1), GCLC, GCLM, and NRF2; hepatocellular carcinoma had higher transcript levels of NQO1 and KEAP1; and steatotic livers had lower GCLC, GCLM, and HO-1 expression. In summary, in drug-processing gene and NRF2 genes, sex differences were the major findings, and there were no apparent age differences, and race/ethnicity differences occurred for a few genes. These descriptive findings could add to our understanding of the sex-, age-, and race/ethnicity-dependent differences in drug-processing genes as well as NRF2 genes in normal and diseased human livers. SIGNIFICANCE STATEMENT: In human liver drug-processing and nuclear factor erythroid 2-related factor 2 genes, sex differences were the main finding. There were no apparent differences due to age, except children had higher glutamate-cysteine ligase modifier subunit, and elderly had higher multidrug resistance protein 3. African Americans had lower expression of farnesoid X receptor (FXR) but higher expression of heme oxygenase 1, Caucasians had higher expression of organic anion transporter 2, and Hispanics had higher expression of FXR, small heterodimer partner, SULT2A1, and bile salt export pump.
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Affiliation(s)
- Jie Liu
- University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
| | - Julia Yue Cui
- University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
| | - Yuan-Fu Lu
- University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
| | - J Christopher Corton
- University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
| | - Curtis D Klaassen
- University of Kansas Medical Center, Kansas City, Kansas (J.L., J.Y.C., Y.-F.L., C.D.K.); Zunyi Medical University, Zunyi, China (J.L.,Y.-F.L.); University of Washington, Seattle, Washington (J.Y.C); and Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, North Carolina (J.L., J.C.C.)
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12
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Kroll T, Prescher M, Smits SHJ, Schmitt L. Structure and Function of Hepatobiliary ATP Binding Cassette Transporters. Chem Rev 2020; 121:5240-5288. [PMID: 33201677 DOI: 10.1021/acs.chemrev.0c00659] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research.
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Affiliation(s)
- Tim Kroll
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Martin Prescher
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Sander H J Smits
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.,Center for Structural Studies, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany
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13
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Mitra S, Das A, Thapa B, Kumar Vasishta R. Phenotype-Genotype Correlation of North Indian Progressive Familial Intrahepatic Cholestasis type2 Children Shows p.Val444Ala and p.Asn591Ser Variants and Retained BSEP Expression. Fetal Pediatr Pathol 2020; 39:107-123. [PMID: 31335238 DOI: 10.1080/15513815.2019.1641860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Backgrounds and Aims: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by a defect or deficiency of bile salt export protein (BSEP) due to mutation in the ABCB11 gene. We intend to evaluate the phenotype-genotype correlation in 10 diagnosed cases of PFIC2 in a single tertiary care center in North India. Methods: The clinical, biochemical, histopathological, immunohistochemical, ultrastructural and genetic data of the 10 diagnosed cases of PFIC2 were recorded. Results: Icterus, pruritus and bleeding manifestations were the commonest clinical symptoms. Giant cell transformation was seen in 50% of the patients. Two predominant genetic variants were ABCB11 missense p.Val444Ala (c. 1331 T > C) and ABCB11 missense p.Asn591Ser (c. 1772 A > G) in their homozygous or compound heterozygous states and were associated with retained BSEP immunopositivity and reduced but retained BSEP immunopositivity respectively. Conclusion: Retention of BSEP is common in North Indian children of PFIC2 with no phenotype-genotype correlation.
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Affiliation(s)
| | - Ashim Das
- PGIMER, Histopathology, Chandigarh, India
| | - Baburam Thapa
- Post Graduate Institute of Medical Education and Research, Pediatric Gastroenterology, Nehru Hospital, Chandigarh, India
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14
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Jetter A, Kullak-Ublick GA. Drugs and hepatic transporters: A review. Pharmacol Res 2020; 154:104234. [DOI: 10.1016/j.phrs.2019.04.018] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/25/2019] [Accepted: 04/16/2019] [Indexed: 12/22/2022]
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15
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Adult onset of genetic disorders in bile acid transport in the liver. Hum Pathol 2020; 96:2-7. [DOI: 10.1016/j.humpath.2019.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 12/27/2022]
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16
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Structure of the human lipid exporter ABCB4 in a lipid environment. Nat Struct Mol Biol 2019; 27:62-70. [PMID: 31873305 DOI: 10.1038/s41594-019-0354-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 11/22/2019] [Indexed: 02/08/2023]
Abstract
ABCB4 is an ATP-binding cassette transporter that extrudes phosphatidylcholine into the bile canaliculi of the liver. Its dysfunction or inhibition by drugs can cause severe, chronic liver disease or drug-induced liver injury. We determined the cryo-EM structure of nanodisc-reconstituted human ABCB4 trapped in an ATP-bound state at a resolution of 3.2 Å. The nucleotide binding domains form a closed conformation containing two bound ATP molecules, but only one of the ATPase sites contains bound Mg2+. The transmembrane domains adopt a collapsed conformation at the level of the lipid bilayer, but we observed a large, hydrophilic and fully occluded cavity at the level of the cytoplasmic membrane boundary, with no ligand bound. This indicates a state following substrate release but prior to ATP hydrolysis. Our results rationalize disease-causing mutations in human ABCB4 and suggest an 'alternating access' mechanism of lipid extrusion, distinct from the 'credit card swipe' model of other lipid transporters.
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17
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Expression Analysis of ATP-Binding Cassette Transporters ABCB11 and ABCB4 in Primary Sclerosing Cholangitis and Variety of Pediatric and Adult Cholestatic and Noncholestatic Liver Diseases. Can J Gastroenterol Hepatol 2019; 2019:1085717. [PMID: 31886153 PMCID: PMC6925824 DOI: 10.1155/2019/1085717] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 10/11/2019] [Accepted: 11/06/2019] [Indexed: 12/16/2022] Open
Abstract
ATP-binding cassette (ABC) transporters are the members of the efflux pumps that are responsible for the removal of cytotoxic substances by active transport. ABCB11, the bile salt efflux pump of hepatocytes, coordinates cellular excretion of numerous conjugated bile salts into the bile canaliculi, whereas ABCB4 acts as an ATP-dependent floppase translocating phosphatidylcholine from the inner to the outer leaflet of the bile canalicular membrane. Loss of functional ABCB11 and ABCB4 proteins causes early-onset refractory cholestasis or cholangiopathy. In this study, we investigated the expression and localization pattern of ABCB11 and ABCB4 using immunohistochemistry and RNA profiling in liver samples from patients with different types and stages of chronic cholestatic liver disease, with emphasis on primary sclerosing cholangitis (PSC), compared to a variety of cholestatic and noncholestatic hepatopathies. Therefore, ABCB11 and ABCB4 expressions were investigated on formalin-fixed and paraffin-embedded (FFPE) material in a patient cohort of total 43 patients with or without cholestatic liver diseases, on protein level using immunohistochemistry and on RNA level using nanoString technology. Intriguingly, our results demonstrated increased expression of ABCB11 and ABCB4 on protein as well as RNA level in PSC, and the expression pattern correlated with disease progression. We concluded from our study that patients with PSC demonstrate altered expression levels and pattern of ABCB11 and ABCB4 which correlated with disease progression; thereby, ABCB11 and ABCB4 analysis may be a useful tool for assessment of disease stages in PSC.
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18
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Prenatal dexamethasone exposure-induced a gender-difference and sustainable multi-organ damage in offspring rats via serum metabolic profile analysis. Toxicol Lett 2019; 316:136-146. [DOI: 10.1016/j.toxlet.2019.09.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 08/01/2019] [Accepted: 09/08/2019] [Indexed: 11/19/2022]
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19
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Ruperti-Repilado FJ, Haefliger S, Rehm S, Zweier M, Rentsch KM, Blum J, Jetter A, Heim M, Leuppi-Taegtmeyer A, Terracciano L, Bernsmeier C. Danger of Herbal Tea: A Case of Acute Cholestatic Hepatitis Due to Artemisia annua Tea. Front Med (Lausanne) 2019; 6:221. [PMID: 31681778 PMCID: PMC6798169 DOI: 10.3389/fmed.2019.00221] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 09/26/2019] [Indexed: 01/16/2023] Open
Abstract
Background:Artemisia annua is a Chinese medicinal herb. Artemisinin-derivatives are recommended as part of a combination treatment for uncomplicated malaria. Herbal and dietary supplements (HDS) are increasingly used worldwide and HDS-induced liver injury is becoming a growing concern. Case Report: We present the first case of severe acute cholestatic hepatitis due to the intake of Artemisia annua tea as chemoprophylaxis for malaria in a patient returning from Ethiopia. The patients presented with jaundice, elevated transaminases, and parameters of cholestasis (total bilirubin 186.6 μmol/L, conjugated bilirubin 168.5 μmol/L). A liver biopsy showed a portal hepatitis with lymphocytic infiltration of the bile ducts and diffuse intra-canalicular and intra-cytoplasmic bilirubinostasis. The toxicologic analysis of the Artemisia tea revealed the ingredients arteannuin b, deoxyartemisin, campher, and scopoletin. There were no other identifiable etiologies of liver disease. The Roussel Uclaf Causality Assessment Method (RUCAM) score assessed a “probably” causal relationship. Sequencing of genes encoding for hepatic transporters for bile acid homeostasis (BSEP, MDR3, and FIC1) found no genetic variants typically associated with hereditary cholestasis syndromes. Normalization of bilirubin occurred 3 months after the onset of disease. Conclusion: The use of artemisinin-derivatives for malaria prevention is ineffective and potentially harmful and should thus be discouraged. Moreover, the case demonstrates our as yet inadequate understanding of the pathophysiology and susceptibility to HDS induced liver injury.
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Affiliation(s)
| | - Simon Haefliger
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
| | - Sophia Rehm
- Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Markus Zweier
- Institute of Medical Genetics, University of Zurich, Zurich, Switzerland
| | - Katharina M Rentsch
- Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Johannes Blum
- Swiss Tropical and Public Health Institute, Basel, Switzerland
| | - Alexander Jetter
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Markus Heim
- University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Anne Leuppi-Taegtmeyer
- Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital Basel, Basel, Switzerland
| | - Luigi Terracciano
- Institute of Pathology, University Hospital Basel, Basel, Switzerland
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20
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M Z, S M D, F E, M R F, M M, S M B T. Molecular Modelling and Evaluation of Hidden Information in ABCB11 Gene Mutations. J Biomed Phys Eng 2019; 9:303-316. [PMID: 31341876 PMCID: PMC6613151 DOI: 10.31661/jbpe.v9i3jun.680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 12/20/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Cholestatic disorders are divided in the extra and intra-hepatic that created due to the severe liver diseases. ABCB11 encodes the bile salt export pump and this gene is mutated in several forms of intrahepatic cholestasis. So far, some molecular features of this gene was studies. OBJECTIVE Using a developed web server, we identified high number of rare codons in this gene, and four cases were related to BSEP-deficient patients which can be used for drug design. MATERIAL AND METHODS By in-silico modelling of ABCB11, some of rare codons in different locations of ATP8b1 gene were identified and evaluated. Using several web servers a number of mutations that converted non-rare codons to rare codon in these patients were identified. RESULTS Some of these rare Codons were located at special positions by mutation of which, the new side chains do not seem suitable for protein structure and function. Furthermore, this mutation changed the protein folding rate that may have a critical role in proper folding. Thus, primary change of these codons contributes to BSEP deficiency. CONCLUSION This work is a comprehensive analysis of rare codons of ABCB11 and assessment of a number of these rare codon in protein levels. Rare codons evaluation can enhance our understanding of ABCB11 structural protein of ABCB11, and help us to develop mutation-specific therapies in design of new drugs.
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Affiliation(s)
- Zarenezhad M
- MD, PhD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- MD, PhD, legal medicine research center, legal medicine organization, Tehran , iran
| | - Dehghani S M
- MD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ejtehadi F
- MD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fattahi M R
- MD, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mortazavi M
- PhD, Department of Biotechnology, Institute of Science and High Technology and Environmental Science, Graduate University of Advanced Technology, Kerman, Iran
| | - Tabei S M B
- MD, Genetic Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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21
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Dröge C, Bonus M, Baumann U, Klindt C, Lainka E, Kathemann S, Brinkert F, Grabhorn E, Pfister ED, Wenning D, Fichtner A, Gotthardt DN, Weiss KH, McKiernan P, Puri RD, Verma IC, Kluge S, Gohlke H, Schmitt L, Kubitz R, Häussinger D, Keitel V. Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. J Hepatol 2017; 67:1253-1264. [PMID: 28733223 DOI: 10.1016/j.jhep.2017.07.004] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 06/16/2017] [Accepted: 07/07/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.
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Affiliation(s)
- Carola Dröge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Michele Bonus
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Germany
| | - Ulrich Baumann
- Pediatric Gastroenterology and Hepatology, Department for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Germany
| | - Caroline Klindt
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Elke Lainka
- Department for Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Clinic for Pediatrics II, University Children's Hospital Essen, University Duisburg-Essen, Germany
| | - Simone Kathemann
- Department for Pediatric Nephrology, Gastroenterology, Endocrinology and Transplant Medicine, Clinic for Pediatrics II, University Children's Hospital Essen, University Duisburg-Essen, Germany
| | - Florian Brinkert
- Pediatric Gastroenterology and Hepatology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Germany
| | - Enke Grabhorn
- Pediatric Gastroenterology and Hepatology, University Children's Hospital, University Medical Center Hamburg-Eppendorf, Germany
| | - Eva-Doreen Pfister
- Pediatric Gastroenterology and Hepatology, Department for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Germany
| | - Daniel Wenning
- Department of General Pediatrics, Heidelberg University Hospital, Germany
| | - Alexander Fichtner
- Department of General Pediatrics, Heidelberg University Hospital, Germany
| | - Daniel N Gotthardt
- Department of Internal Medicine IV, University Hospital Heidelberg, Germany
| | - Karl Heinz Weiss
- Department of Internal Medicine IV, University Hospital Heidelberg, Germany
| | - Patrick McKiernan
- Pittsburgh Liver Research Center, University of Pittsburgh and Children's Hospital of Pittsburgh of UPMC, Pittsburgh, USA
| | - Ratna Dua Puri
- Institute of Medical Genetics & Genomics, Sir Ganga Ram Hospital, New Delhi, India
| | - I C Verma
- Institute of Medical Genetics & Genomics, Sir Ganga Ram Hospital, New Delhi, India
| | - Stefanie Kluge
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Holger Gohlke
- Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Germany
| | - Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany.
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany.
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22
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Andress EJ, Nicolaou M, McGeoghan F, Linton KJ. ABCB4 missense mutations D243A, K435T, G535D, I490T, R545C, and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population. Cell Mol Life Sci 2017; 74:2513-2524. [PMID: 28220208 PMCID: PMC5487885 DOI: 10.1007/s00018-017-2472-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 12/30/2016] [Accepted: 01/19/2017] [Indexed: 12/15/2022]
Abstract
Bile salts are natural detergents required to solubilise dietary fat and lipid soluble vitamins. They are synthesised in hepatocytes and secreted into the luminal space of the biliary tree by the bile salt export pump (BSEP), an ATP-binding cassette (ABC) transporter in the canalicular membrane. BSEP deficiency causes cytotoxic accumulation of bile salts in the hepatocyte that results in mild-to-severe forms of cholestasis. The resulting inflammation can also progress to hepatocellular cancer via a novel mechanism involving upregulation of proliferative signalling pathways. A second ABC transporter of the canalicular membrane is also critical for bile formation. ABCB4 flops phosphatidylcholine into the outer leaflet of the membrane to be extracted by bile salts in the canalicular space. These mixed micelles reduce the detergent action of the bile salts and protect the biliary tree from their cytotoxic activity. ABCB4 deficiency also causes cholestasis, and might be expected to cause cholangitis and predispose to liver cancer. Non-synonymous SNPs in ABCB4 have now been described in patients with liver cancer or with inflammatory liver diseases that are known to predispose to cancer, but data showing that the SNPs are sufficiently deleterious to be an etiological factor are lacking. Here, we report the first characterisation at the protein level of six ABCB4 variants (D243A, K435T, G535D, I490T, R545C, and S978P) previously found in patients with inflammatory liver diseases or liver cancer. All significantly impair the transporter with a range of phenotypes exhibited, including low abundance, intracellular retention, and reduced floppase activity, suggesting that ABCB4 deficiency is the root cause of the pathology in these cases.
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Affiliation(s)
- Edward J Andress
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, E1 2AT, London, UK
| | - Michael Nicolaou
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, E1 2AT, London, UK
| | - Farrell McGeoghan
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, E1 2AT, London, UK
| | - Kenneth J Linton
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, E1 2AT, London, UK.
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Lee SJ, Kim JE, Choe BH, Seo AN, Bae HI, Hwang SK. Early Diagnosis of ABCB11 Spectrum Liver Disorders by Next Generation Sequencing. Pediatr Gastroenterol Hepatol Nutr 2017; 20:114-123. [PMID: 28730136 PMCID: PMC5517378 DOI: 10.5223/pghn.2017.20.2.114] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 10/21/2016] [Indexed: 01/27/2023] Open
Abstract
PURPOSE The goal of this study was the early diagnosis of ABCB11 spectrum liver disorders, especially those focused on benign recurrent intrahepatic cholestasis and progressive familial intrahepatic cholestasis. METHODS Fifty patients presenting neonatal cholestasis were evaluated to identify underlying etiologies. Genetic analysis was performed on patients suspected to have syndromic diseases or ABCB11 spectrum liver disorders. Two families with proven ABCB11 spectrum liver disorders were subjected to genetic analyses to confirm the diagnosis and were provided genetic counseling. Whole exome sequencing and Sanger sequencing were performed on the patients and the family members. RESULTS Idiopathic or viral hepatitis was diagnosed in 34%, metabolic disease in 20%, total parenteral nutrition induced cholestasis in 16%, extrahepatic biliary atresia in 14%, genetic disease in 10%, neonatal lupus in 2%, congenital syphilis in 2%, and choledochal cyst in 2% of the patients. The patient with progressive familial intrahepatic cholestasis had novel heterozygous mutations of ABCB11 c.11C>G (p.Ser4*) and c.1543A>G (p.Asn515Asp). The patient with benign recurrent intrahepatic cholestasis had homozygous mutations of ABCB11 c.1331T>C (p.Val444Ala) and heterozygous, c.3084A>G (p.Ala1028Ala). Genetic confirmation of ABCB11 spectrum liver disorder led to early liver transplantation in the progressive familial intrahepatic cholestasis patient. In addition, the atypically severe benign recurrent intrahepatic cholestasis patient was able to avoid unnecessary liver transplantation after genetic analysis. CONCLUSION ABCB11 spectrum liver disorders can be clinically indistinguishable as they share similar characteristics related to acute episodes. A comprehensive genetic analysis will facilitate optimal diagnosis and treatment.
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Affiliation(s)
- Su Jeong Lee
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jung Eun Kim
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
| | - An Na Seo
- Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Han-Ik Bae
- Department of Pathology, Kyungpook National University School of Medicine, Daegu, Korea
| | - Su-Kyeong Hwang
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
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24
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Delaunay JL, Durand-Schneider AM, Dossier C, Falguières T, Gautherot J, Davit-Spraul A, Aït-Slimane T, Housset C, Jacquemin E, Maurice M. A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3. Hepatology 2016; 63:1620-31. [PMID: 26474921 DOI: 10.1002/hep.28300] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 09/24/2015] [Accepted: 10/15/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED Progressive familial intrahepatic cholestasis type 3 is caused by biallelic variations of ABCB4, most often (≥70%) missense. In this study, we examined the effects of 12 missense variations identified in progressive familial intrahepatic cholestasis type 3 patients. We classified these variations on the basis of the defects thus identified and explored potential rescue of trafficking-defective mutants by pharmacological means. Variations were reproduced in the ABCB4 complementary DNA and the mutants, thus obtained, expressed in HepG2 and HEK293 cells. Three mutants were either fully (I541F and L556R) or largely (Q855L) retained in the endoplasmic reticulum, in an immature form. Rescue of the defect, i.e., increase in the mature form at the bile canaliculi, was obtained by cell treatments with cyclosporin A or C and, to a lesser extent, B, D, or H. Five mutations with little or no effect on ABCB4 expression at the bile canaliculi caused a decrease (F357L, T775M, and G954S) or almost absence (S346I and P726L) of phosphatidylcholine secretion. Two mutants (T424A and N510S) were normally processed and expressed at the bile canaliculi, but their stability was reduced. We found no defect of the T175A mutant or of R652G, previously described as a polymorphism. In patients, the most severe phenotypes appreciated by the duration of transplant-free survival were caused by ABCB4 variants that were markedly retained in the endoplasmic reticulum and expressed in a homozygous status. CONCLUSION ABCB4 variations can be classified as follows: nonsense variations (I) and, on the basis of current findings, missense variations that primarily affect the maturation (II), activity (III), or stability (IV) of the protein or have no detectable effect (V); this classification provides a strong basis for the development of genotype-based therapies.
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Affiliation(s)
- Jean-Louis Delaunay
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Anne-Marie Durand-Schneider
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Claire Dossier
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Thomas Falguières
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Julien Gautherot
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Anne Davit-Spraul
- Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Laboratoire de biochimie, Le Kremlin Bicêtre, France
| | - Tounsia Aït-Slimane
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
| | - Chantal Housset
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Référence Maladies Rares Maladies Inflammatoires des Voies Biliaires & Service d'Hépatologie, Paris, France
| | - Emmanuel Jacquemin
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Hépatologie Pédiatrique & Unité de Transplantation Hépatique, Centre de Référence Maladies Rares Atrésies des Voies Biliaires de l'Enfant, Le Kremlin Bicêtre, France.,Université Paris-Sud 11, INSERM, UMR_S 1174, Hepatinov, Orsay, France
| | - Michèle Maurice
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, Paris, France
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25
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Degiorgio D, Crosignani A, Colombo C, Bordo D, Zuin M, Vassallo E, Syrén ML, Coviello DA, Battezzati PM. ABCB4 mutations in adult patients with cholestatic liver disease: impact and phenotypic expression. J Gastroenterol 2016; 51:271-80. [PMID: 26324191 DOI: 10.1007/s00535-015-1110-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 07/26/2015] [Indexed: 02/04/2023]
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.
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Affiliation(s)
- Dario Degiorgio
- E.O. Ospedali Galliera, Laboratory of Human Genetics and Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Andrea Crosignani
- Division of Internal Medicine and Liver Unit, School of Medicine Ospedale San Paolo, Department of Health Sciences, Università degli Studi di Milano, 20143, Milan, Italy
| | - Carla Colombo
- Department of Pathophysiology and Transplantation, Fondazione Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Domenico Bordo
- IRCCS Azienda Ospedaliera-Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
| | - Massimo Zuin
- Division of Internal Medicine and Liver Unit, School of Medicine Ospedale San Paolo, Department of Health Sciences, Università degli Studi di Milano, 20143, Milan, Italy
| | - Emanuela Vassallo
- Division of Internal Medicine, Ospedale Civile di Castel San Giovanni, Piacenza, Italy
| | - Marie-Louise Syrén
- Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Clinical and Community Sciences, Division of Pediatrics, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Domenico A Coviello
- E.O. Ospedali Galliera, Laboratory of Human Genetics and Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Pier Maria Battezzati
- Division of Internal Medicine and Liver Unit, School of Medicine Ospedale San Paolo, Department of Health Sciences, Università degli Studi di Milano, 20143, Milan, Italy.
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26
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Kohjima M, Enjoji M, Yada R, Yoshimoto T, Nakamura T, Fukuizumi K, Fukushima N, Murata Y, Nakashima M, Kato M, Kotoh K, Shirabe K, Maehara Y, Nakajima A, Nozaki Y, Honda A, Matsuzaki Y, Nakamuta M. Pathophysiological analysis of primary biliary cirrhosis focusing on choline/phospholipid metabolism. Liver Int 2015; 35:1095-102. [PMID: 24620780 DOI: 10.1111/liv.12526] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 03/05/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Injury to biliary epithelial cells caused by disorders in bile composition may be the initial step in the pathogenesis of primary biliary cirrhosis (PBC). We therefore examined choline/phospholipid metabolism in livers of patients with PBC. METHODS Hepatic levels of mRNA encoded by choline metabolism-related genes in early stage PBC patients were quantified by real-time RT-PCR. Serum cholesterol and triglyceride concentrations in each lipoprotein compartment and serum/tissue choline levels were also measured. OCT1 expression was quantified by genotype (rs683369 and rs622342). RESULTS Serum choline concentrations were significantly higher in PBC patients than in normal individuals, with the concentrations in the former lowered by treatment with fibrates. Hepatic choline levels were markedly lower in PBC patients than in controls. The levels of expression of genes associated with choline uptake (OCT1 and CTL1), phosphatidylcholine synthesis (PEMT and BHMT), and phosphatidylcholine transport (MDR3) were significantly upregulated in PBC compared with control livers. Serum cholesterol concentrations and the cholesterol/triglyceride ratio in serum very low density lipoprotein were markedly higher in PBC patients than in controls. In PBC liver, OCT1 protein levels were lower in patients with minor (CG/GG at rs683369 and/or CC at rs622342) than major (CC at rs683369 and AA at rs622342) genotypes of the OCT1 gene. CONCLUSION During early stage PBC, hepatocellular choline uptake and PC synthesis become dysregulated. OCT1 genotypes may influence the pathogenesis of PBC.
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Affiliation(s)
- Motoyuki Kohjima
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
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The association between bile salt export pump single-nucleotide polymorphisms and primary biliary cirrhosis susceptibility and ursodeoxycholic acid response. DISEASE MARKERS 2014; 2014:350690. [PMID: 25392597 PMCID: PMC4216684 DOI: 10.1155/2014/350690] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 09/15/2014] [Indexed: 12/24/2022]
Abstract
Background. Primary biliary cirrhosis (PBC) is a chronic and progressive cholestasis liver disease. Bile salt export pump (BSEP) is the predominant bile salt efflux system of hepatocytes. BSEP gene has been attached great importance in the susceptibility of PBC and the response rate of ursodeoxycholic acid (UDCA) treatment of PBC patients. Methods. In this study, TaqMan assay was used to genotype four variants of BSEP, and the Barcelona criteria were used for evaluating the response rate of UDCA treatment. Results. Variant A allele of BSEP rs473351 (dominant model, OR = 2.063; 95% CI, 1.254–3.393; P = 0.004) was highly associated with PBC susceptibility. On the contrary, variant A allele of BSEP rs2287618 (dominant model, OR = 0.617; 95% CI, 0.411–0.928; P = 0.020) provided a protective role and Barcelona evaluation criterion indicated that the frequency of variant allele at BSEP rs2287618 was significantly decreased in UDCA-responsive PBC patients (P = 0.021). Conclusion. These results suggested that BSEP rs473351 was closely associated with the susceptibility of PBC and if people with BSEP rs2287618 were diagnosed as PBC, the UDCA treatment was not satisfactory. Larger studies with mixed ethnicity subjects and stratified by clinical and subclinical characteristics are needed to validate our findings.
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28
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Pan S, Li X, Jiang P, Jiang Y, Shuai L, He Y, Li Z. Variations of ABCB4 and ABCB11 genes are associated with primary intrahepatic stones. Mol Med Rep 2014; 11:434-46. [PMID: 25323205 DOI: 10.3892/mmr.2014.2645] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 08/11/2014] [Indexed: 01/21/2023] Open
Abstract
Variations of the ABCB4 and ABCB11 genes affect the composition of bile and are associated with cholestasis and cholelithiasis. However, their roles in the formation of primary intrahepatic stones (PIS) remains to be elucidated. The aim of the present study was to determine whether there is an association between PIS and variations in these genes. Exon sequencing was performed in order to analyze the ABCB4 and ABCB11 genes of 176 patients with PIS and 178 healthy subjects. One mutation in ABCB4 (no. 69233, G>A) and two other mutations in ABCB11, reference single nucleotide polymorphism (rs)118109635 and rs497692, were identified in association with PIS (P<0.001, P=0.04 and P=0.02, respectively). A synonymous mutation at no. 69233 G>A was detected in exon 26 of ABCB4 in 23 heterozygous patients with PIS. This mutation was not detected in healthy individuals or in the Single Nucleotide Polymorphism Database. No. 69233 G>A in ABCB4 was not associated with altered protein expression but with a reduced rate of PIS recurrence (P=0.01). The missense mutation rs118109635 was located on exon 21 of ABCB11 and was associated with the increased expression of ABCB11 protein (P=0.032) as well as altered bile salt export pump function. Another synonymous mutation, rs497692 in exon 24 was reported to decrease ABCB11 protein expression (P=0.001). In addition, the mutations of ABCB11 were associated with preoperative jaundice (P<0.001 and P=0.03, respectively). Consistently decreased levels of ABCB11 protein were associated with recurrent episodes of cholangitis (P=0.006) and preoperative jaundice (P=0.015). By contrast, ABCB4 expression was not found to be associated with clinical manifestations of PIS.
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Affiliation(s)
- Shuguang Pan
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Xiaowu Li
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Peng Jiang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Yan Jiang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Ling Shuai
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Yu He
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
| | - Zhihua Li
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Shapingba, Chongqing 400038, P.R. China
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Hu G, He P, Liu Z, Chen Q, Zheng B, Zhang Q. Diagnosis of ABCB11 gene mutations in children with intrahepatic cholestasis using high resolution melting analysis and direct sequencing. Mol Med Rep 2014; 10:1264-74. [PMID: 24969679 PMCID: PMC4121405 DOI: 10.3892/mmr.2014.2349] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 04/28/2014] [Indexed: 12/17/2022] Open
Abstract
Intrahepatic cholestasis represents a heterogeneous group of disorders that begin during childhood, most commonly manifesting as neonatal cholestasis, and lead to ongoing liver dysfunction in children and adults. For children, inherited pathogenic factors of cholestasis have gained increasing attention owing to the rapid development of molecular biology technology. However, these methods have their advantages and disadvantages in terms of simplicity, sensitivity, specificity, time required and expense. In the present study, an effective, sensitive and economical method is recommended, termed high-resolution melting (HRM) analysis and direct sequencing, based on general polymerase chain reaction, to detect mutations in disease-causing genes. As one type of inherited intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by pathogenic mutations in the ABCB11 gene, HRM was used to detect mutations in the ABCB11 gene in the present study, and the diagnosis for PFIC2 was made by comprehensive analysis of genetic findings and clinical features. Furthermore, the characteristics of mutations and single nucleotide polymorphisms (SNPs) in the ABCB11 gene were elucidated. A total of 14 types of mutations/polymorphisms were identified in 20 patients from mainland China, including six missense mutations (p.Y337H, p.Y472C, p.R696W, p.Q931P, p.D1131V and p.H1198R), one nonsense mutation (p.R928X) and seven SNPs (p.D36D/rs3815675, p.F90F/rs4148777, p.Y269Y/rs2287616, p.I416I/rs183390670, p.V444A/rs2287622, p.A865V/rs118109635 and p.A1028A/rs497692). Five mutations were novel. The majority of the mutations were different from those detected in other population groups. A total of 4/20 patients (1/5) were diagnosed to be PFIC2 by combining genetic findings with the clinical features. Polymorphisms V444A and A1028A, with an allele frequency of 74.5 and 67.2%, respectively, were highly prevalent in the mainland Chinese subjects. No differences were found between the patients with cholestasis and the control subjects. Efficient genetic screening facilitates the clinical diagnosis of genetic disorders. The present study demonstrated that HRM analysis was efficient and effective in detecting mutations and expanded the known spectrum of ABCB11 gene mutations.
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Affiliation(s)
- Guorui Hu
- Medical College of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Ping He
- Medical College of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Zhifeng Liu
- Medical College of Nanjing University, Nanjing, Jiangsu 210093, P.R. China
| | - Qian Chen
- Department of Digestive Disease, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Bixia Zheng
- Department of Digestive Disease, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Qihua Zhang
- Department of Digestive Disease, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
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30
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Guyot C, Hofstetter L, Stieger B. Differential effects of membrane cholesterol content on the transport activity of multidrug resistance-associated protein 2 (ABCC2) and of the bile salt export pump (ABCB11). Mol Pharmacol 2014; 85:909-20. [PMID: 24711118 DOI: 10.1124/mol.114.092262] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Rat canalicular membranes contain microdomains enriched in cholesterol and ATP-binding cassette transporters. Cholesterol is known to regulate the activity of transporters. Here, we investigated the effect of membrane cholesterol on the transport kinetics of multidrug resistance-associated protein 2 (MRP2) and of bile salt export pump (BSEP) variants and mutants. MRP2 and BSEP were expressed with baculoviruses in insect cells, followed by vesicle isolation from control and cholesterol-loaded cells (1 mM cholesterol@randomly methylated-β-cyclodextrin) for transport assays. We found that cholesterol stimulates MRP2 transport activity for substrates of different molecular weights: estradiol-17-β-glucuronide (E17βG), prostaglandin E2 (PGE2), cholecystokinin 8 (CCK8), and vasopressin displayed an increase of Vmax and a variable decrease of Km. Kinetics of E17βG showed a sigmoidal shape and a mild cooperativity in Hanes-Woolf plots in control membranes. High cholesterol content shifted E17βG to Michaelis-Menten kinetics. PGE2/glutathione transport followed Michaelis-Menten kinetics irrespective of cholesterol. The MRP2 substrates CCK8 and vasopressin exhibited Michaelis-Menten kinetics independent of membrane cholesterol content. Transport of ochratoxin A was ATP-dependent but was neither mediated by MRP2 nor stimulated by cholesterol. Transport of the two most common BSEP variants p.444V/A showed Michaelis-Menten kinetics irrespective of membrane cholesterol, whereby cholesterol leads to an increased Vmax while Km remains unchanged. The transport activity of the BSEP mutants p.E297G and p.R432T increased at high cholesterol content but did not reach the capacity of normal BSEP. Hence, changing membrane cholesterol content modulates BSEP and MRP2 transport kinetics differently. Cholesterol increases the transport rates of BSEP and MRP2, but with the latter, may also modify the binding site as for E17βG.
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Affiliation(s)
- Christelle Guyot
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland
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31
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Jirsa M, Bronský J, Dvořáková L, Šperl J, Šmajstrla V, Horák J, Nevoral J, Hřebíček M. ABCB4 mutations underlie hormonal cholestasis but not pediatric idiopathic gallstones. World J Gastroenterol 2014; 20:5867-5874. [PMID: 24914347 PMCID: PMC4024796 DOI: 10.3748/wjg.v20.i19.5867] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 07/25/2013] [Accepted: 08/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the contribution of ABCB4 mutations to pediatric idiopathic gallstone disease and the potential of hormonal contraceptives to prompt clinical manifestations of multidrug resistance protein 3 deficiency.
METHODS: Mutational analysis of ABCB4, screening for copy number variations by multiplex ligation-dependent probe amplification, genotyping for low expression allele c.1331T>C of ABCB11 and genotyping for variation c.55G>C in ABCG8 previously associated with cholesterol gallstones in adults was performed in 35 pediatric subjects with idiopathic gallstones who fulfilled the clinical criteria for low phospholipid-associated cholelithiasis syndrome (LPAC, OMIM #600803) and in 5 young females with suspected LPAC and their families (5 probands, 15 additional family members). The probands came to medical attention for contraceptive-associated intrahepatic cholestasis.
RESULTS: A possibly pathogenic variant of ABCB4 was found only in one of the 35 pediatric subjects with idiopathic cholesterol gallstones whereas 15 members of the studied 5 LPAC kindreds were confirmed and another one was highly suspected to carry predictably pathogenic mutations in ABCB4. Among these 16, however, none developed gallstones in childhood. In 5 index patients, all young females carrying at least one pathogenic mutation in one allele of ABCB4, manifestation of LPAC as intrahepatic cholestasis with elevated serum activity of gamma-glutamyltransferase was induced by hormonal contraceptives. Variants ABCB11 c.1331T>C and ABCG8 c.55G>C were not significantly overrepresented in the 35 examined patients with suspect LPAC.
CONCLUSION: Clinical criteria for LPAC syndrome caused by mutations in ABCB4 cannot be applied to pediatric patients with idiopathic gallstones. Sexual immaturity even prevents manifestation of LPAC.
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Abstract
Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (∼1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions.
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Affiliation(s)
- James L Boyer
- Department of Medicine and Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
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Ono C, Kikkawa H, Suzuki A, Suzuki M, Yamamoto Y, Ichikawa K, Fukae M, Ieiri I. Clinical impact of genetic variants of drug transporters in different ethnic groups within and across regions. Pharmacogenomics 2013; 14:1745-64. [DOI: 10.2217/pgs.13.171] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Drug transporters, together with drug metabolic enzymes, are major determinants of drug disposition and are known to alter the response to many commonly used drugs. Substantial frequency differences for known variants exist across geographic regions for certain drug transporters. To deliver efficacious medicine with the right dose for each patient, it is important to understand the contribution of genetic variants for drug transporters. Recently, mutual pharmacokinetic data usage among Asian regions, which are thought to be relatively similar in their own genetic background, is expected to accelerate new drug applications and reduce developmental costs. Polymorphisms of drug transporters could be key factors to be considered in implementing multiethnic global clinical trials. This review addresses the current knowledge on genetic variations of major drug transporters affecting drug disposition, efficacy and toxicity, focusing on the east Asian populations, and provides insights into future directions for precision medicine and drug development in east Asia.
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Affiliation(s)
- Chiho Ono
- Department of Clinical Pharmacology, Clinical Research, Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan
| | - Hironori Kikkawa
- Department of Clinical Pharmacology, Clinical Research, Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan
| | - Akiyuki Suzuki
- Department of Clinical Pharmacology, Clinical Research, Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan
| | - Misaki Suzuki
- Department of Clinical Pharmacology, Clinical Research, Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan
| | - Yuichi Yamamoto
- Department of Clinical Pharmacology, Clinical Research, Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan
| | - Katsuomi Ichikawa
- Department of Clinical Pharmacology, Clinical Research, Pfizer Japan Inc., 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan
| | - Masato Fukae
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
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Sticova E, Jirsa M. New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol 2013; 19:6398-6407. [PMID: 24151358 PMCID: PMC3801310 DOI: 10.3748/wjg.v19.i38.6398] [Citation(s) in RCA: 123] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Revised: 07/18/2013] [Accepted: 08/09/2013] [Indexed: 02/06/2023] Open
Abstract
Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.
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El Sherrif Y, Potts JR, Howard MR, Barnardo A, Cairns S, Knisely AS, Verma S. Hepatotoxicity from anabolic androgenic steroids marketed as dietary supplements: contribution from ATP8B1/ABCB11 mutations? Liver Int 2013; 33:1266-70. [PMID: 23750872 DOI: 10.1111/liv.12216] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 05/05/2013] [Indexed: 12/20/2022]
Abstract
BACKGROUND Though possession of androgenic anabolic steroids (AAS) is illegal, non-prescription use of AAS persists. METHODS We describe two Caucasian males (aged 25 and 45 years) with cholestatic hepatitis following ingestion of the dietary supplement Mass-Drol ('Celtic Dragon') containing the AAS 2α-17α-dimethyl-etiocholan-3-one,17β-ol. RESULTS Despite substantial hyperbilirubinaemia peak gamma-glutamyl transferase (GGT) remained normal. Besides 'bland' intralobular cholestasis, liver biopsy in both found deficiency of canalicular expression of ectoenzymes as seen in ATP8B1 disease. In the older patient, bile salt export pump marking (encoded by ABCB11) was focally diminished. We hypothesized that AAS had either induced inhibition of normal ATP8B1/ABCB11 expression or triggered initial episodes of benign recurrent intrahepatic cholestasis (BRIC) type 1/or 2. On sequencing, ATP8B1 was normal in both patients although the younger was heterozygous for the c.2093G>A mutation in ABCB11, a polymorphism previously encountered in drug-induced liver injury. CONCLUSION AAS marketed as dietary supplements continue to cause hepatotoxicity in the UK; underlying mechanisms may include unmasking of genetic cholestatic syndromes.
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Affiliation(s)
- Yasser El Sherrif
- Department of Gastroenterology and Hepatology, Brighton and Sussex University Hospitals, Brighton, UK
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Liu LY, Wang XH, Lu Y, Zhu QR, Wang JS. Association of variants of ABCB11 with transient neonatal cholestasis. Pediatr Int 2013; 55:138-44. [PMID: 23279303 DOI: 10.1111/ped.12049] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 08/30/2012] [Accepted: 12/06/2012] [Indexed: 01/29/2023]
Abstract
BACKGROUND The significance of ABCB11 variants have been studied in some cholestatic diseases, but this is not clear in transient neonatal cholestasis (TNC). The aim of the present study was to explore the association between ABCB11 variants and TNC. METHODS This was a case-control study. A total of 192 children with TNC referred to a tertiary referral hospital in eastern China were enrolled as subjects, and 196 healthy children were selected as controls. Part of the promoter and exons of the ABCB11 gene were sequenced directly. The single nucleotide polymorphism (SNP) site of V444A was tested using fluorescent quantitative polymerase chain reaction. Potential consequences of variants were predicted using bioinformatics software. The biochemistry indices were compared between the patients with or without possibly pathogenic variants/mutations. RESULTS Twenty-eight variants, including 14 novel ones, were detected. Four novel, possibly pathogenic mutations (I416I, K436N, R928Q and IVS7+5G>A) were detected in six subjects. The γ-glutamyltransferase level of these six was lower than in the others (P = 0.054). The genotype distribution of the four common SNP sites, V444A, A535A, A865V and A1082A, was not significantly different between TNC patients and controls. CONCLUSIONS Approximately 3% of TNC cases can be attributed to ABCB11 mutations.
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Affiliation(s)
- Li-Yan Liu
- Department of Pediatrics, Center for Pediatric Liver Disease, Children's Hospital of Fudan University, Shanghai Medical College of Fudan University, Shanghai, China
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Anzivino C, Odoardi MR, Meschiari E, Baldelli E, Facchinetti F, Neri I, Ruggiero G, Zampino R, Bertolotti M, Loria P, Carulli L. ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population. Dig Liver Dis 2013; 45:226-232. [PMID: 23022423 DOI: 10.1016/j.dld.2012.08.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2012] [Revised: 07/30/2012] [Accepted: 08/15/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Genetic alterations in the ATP-binding cassette subfamily B member 4 (ABCB4) and ATP-binding cassette subfamily B member 11 (ABCB11) have been associated to the onset of intrahepatic cholestasis of pregnancy (ICP) in predisposed women. AIMS To identify new and/or frequent ABCB4 and ABCB11 genes variants in a cohort of Italian patients with ICP and to evaluate the possible pathogenetic role for the novel mutations identified. METHODS DNA of 33 unrelated Italian women with obstetric cholestasis were screened for mutations in the entire coding sequence of ABCB4 and ABCB11 genes. Polymerase chain reaction and automated sequencing was performed on the 27 coding exons of both genes. RESULTS Genotyping revealed 11 mutations, 5 of whom were novel variants: 2 localized on ABCB4 (p.I587DfsX603, p.I738LfsX744) and 3 on ABCB11 (p.V284D, p.Q558H, p.P731S). The most severe phenotypes were associated with the variants p.I587DfsX603, p.I738LfsX744 and p.V284D. Moreover, the already described mutation p.N510S found in ABCB4 seems to be strictly involved in the onset of ICP in that particular patient. CONCLUSIONS Our data support the hypothesis of a significant involvement of ABCB4 mutations in the onset of ICP, but also confirm an important role for ABCB11 mutations in increasing the susceptibility to cholestasis of pregnancy.
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Affiliation(s)
- Claudia Anzivino
- Department of Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Italy
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Jang GH, Kim TH, Choe Y, Ham A, Choi JH. Functional characterization of genetic variations in the MDR3 promoter. Biochem Biophys Res Commun 2012; 430:1312-8. [PMID: 23261441 DOI: 10.1016/j.bbrc.2012.12.041] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Accepted: 12/07/2012] [Indexed: 01/28/2023]
Abstract
Multidrug resistance 3 (MDR3) is present on the canalicular membrane of the hepatocyte and plays an important role in protecting the liver from bile acids. In this study, we characterized the transcriptional effects of four common haplotypes and four polymorphic variants in the promoter region of MDR3 that were identified in 126 DNA samples from Koreans. We measured the luciferase activities of the four MDR3 promoter haplotypes using in vitro reporter assays. Among them, two haplotypes showed a significant decrease in reporter activity compared to the reference. One of the mechanisms by which these haplotypes might decrease MDR3 transcriptional activity was determined: one of the polymorphisms that are present in haplotype 3, was associated with a significant reduction in the promoter activity of MDR3, and the transcription factor NF-Y was predicted to bind to the promoter in the region of g.-1584C>T. Electrophoretic mobility shift assays showed that the g.-1584C allele exhibited greater binding to NF-Y than did the g.-1584T allele. Through the measurement of promoter activity after the overexpression of NF-Y, we found that NF-Y can act as a transcriptional activator of MDR3. These data suggest that the reduced transcriptional activity of g.-1584C>T results from a reduction in the binding affinity of the activator NF-Y to the MDR3 promoter region. Our study suggests that two common haplotypes of MDR3 can regulate the transcriptional rate of MDR3 and that NF-Y may be one of the transcriptional factors involved in this regulation.
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Affiliation(s)
- Geun Hye Jang
- Department of Pharmacology, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
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39
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The bile salt export pump (BSEP) in health and disease. Clin Res Hepatol Gastroenterol 2012; 36:536-53. [PMID: 22795478 DOI: 10.1016/j.clinre.2012.06.006] [Citation(s) in RCA: 134] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 05/29/2012] [Accepted: 06/06/2012] [Indexed: 02/04/2023]
Abstract
The bile salt export pump (BSEP) is the major transporter for the secretion of bile acids from hepatocytes into bile in humans. Mutations of BSEP are associated with cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 2 (PFIC-2), benign recurrent intrahepatic cholestasis type 2 (BRIC-2) and genetic polymorphisms are linked to intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). Detailed analysis of these diseases has considerably increased our knowledge about physiology and pathophysiology of bile secretion in humans. This review focuses on expression, localization, and function, short- and long-term regulation of BSEP as well as diseases association and treatment options for BSEP-associated diseases.
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40
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Trivedi PJ, Chapman RW. PSC, AIH and overlap syndrome in inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2012; 36:420-36. [PMID: 22306055 DOI: 10.1016/j.clinre.2011.10.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 10/08/2011] [Accepted: 10/14/2011] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disorder characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include pruritus, fatigue and in advanced cases ascending cholangitis, cirrhosis and end-stage hepatic failure. Patients are at an increased risk of malignancy arising from the bile ducts, gallbladder, liver and colon. The majority (>80%) of Northern European patients with PSC also have inflammatory bowel disease (IBD), usually ulcerative colitis (UC). IBD commonly presents before the onset of PSC, although the opposite can occur and the onset of both conditions can be separated by many years. The colitis associated with PSC is characteristically mild although frequently involves the whole colon. Despite the majority of patients having relatively inactive colonic disease, paradoxically the risk of colorectal malignancy is substantially increased. Patients may also develop dominant, stenotic lesions of the biliary tree which may be difficult to differentiate from cholangiocarcinoma and the coexistence of IBD may influence the development of this complication. Ursodeoxycholic acid may offer a chemoprotective effect against colorectal malignancy and improve liver biochemical indices. Evidence of any beneficial effect on histological progression of hepatobiliary disease is less clear. High doses (∼25-30 mg/kg/d) may be harmful and should be avoided. Autoimmune hepatitis (AIH) is less common in patients with IBD than PSC, however, an association has been observed. A small subgroup may have an overlap syndrome between AIH and PSC and management should be individualised dependant on liver histology, serum immunoglobulin levels, autoantibodies, degree of biochemical cholestasis and cholangiography.
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Affiliation(s)
- P J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Wolfson Drive, Edgbaston, Birmingham, B15 2TT United Kingdom.
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41
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Næss S, Shiryaev A, Hov JR, Franke A, Karlsen TH. Genetics in primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol 2012; 36:325-33. [PMID: 22554879 DOI: 10.1016/j.clinre.2012.02.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Accepted: 02/24/2012] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder with a progressive course. PSC is strongly associated with inflammatory bowel disease and is often complicated by cholangiocarcinoma development. Etiology and pathogenesis remain obscure, but the diverse clinical manifestation of the disease might, to some extent, indicate different genetic susceptibility in subgroups of patients. In recent years, genome-wide association studies performed in PSC have identified a number of genetic susceptibility loci. In this mini-review, we suggest that the genetic associations established can be grouped according to four pathogenic aspects relating to inflammation, cholangiocyte function, fibrosis and carcinogenesis. Subclassification of PSC patients according to their genetic predisposition could be a valuable tool in future functional and clinical studies.
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Affiliation(s)
- Sigrid Næss
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, 0027 Oslo, Norway
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Krones E, Graziadei I, Trauner M, Fickert P. Evolving concepts in primary sclerosing cholangitis. Liver Int 2012; 32:352-69. [PMID: 22097926 DOI: 10.1111/j.1478-3231.2011.02607.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 06/27/2011] [Indexed: 02/13/2023]
Abstract
Patients suffering from primary sclerosing cholangitis (PSC) show considerable differences regarding clinical manifestations (i.e. large duct versus small-duct PSC, presence or absence of concomitant inflammatory bowel disease), disease progression, risk for malignancy and response to therapy, raising the question whether PSC may represent a mixed bag of diseases of different aetiologies. The growing list of secondary causes and diseases 'mimicking' or even overlapping with PSC (e.g. IgG4-associated sclerosing cholangitis), which frequently causes problems in clear-cut discrimination from classic PSC and the emerging knowledge about potential disease modifier genes (e.g. variants of CFTR, TGR5 and MDR3) support such a conceptual view. In addition, PSC in children differs significantly from PSC in adults in several aspects resulting in distinct therapeutic concepts. From a clinical perspective, appropriate categorization and careful differential diagnosis are essential for the management of concerned patients. Therefore, the aim of the current review is to summarize current and evolving pathophysiological concepts and to provide up-to-date perspectives including future treatment strategies for PSC.
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Affiliation(s)
- Elisabeth Krones
- Department of Internal Medicine, Medical University of Graz, Graz, Austria
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43
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Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations. Virchows Arch 2012; 460:291-8. [DOI: 10.1007/s00428-012-1202-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Revised: 01/18/2012] [Accepted: 01/24/2012] [Indexed: 02/06/2023]
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease characterized by the destruction of medium- to large-sized bile ducts and intense concentric fibrosis. Complications from PSC include bacterial cholangitis, cirrhosis, and cholangiocarcinoma and a therapy that might alter the natural history of the disease remains lacking. Our understanding of the pathogenesis of PSC also remains rudimentary but the strong association between PSC and inflammatory bowel disease suggest causal links between the diseases. The male predominance in PSC, lack of a defined, pathogenic auto-antigen, and the potential role of the innate immune system suggest that PSC may be due to dysregulation of immunity rather than a classic autoimmune disease. However, PSC shares several genetic susceptibility loci with other autoimmune diseases including the human leukocyte antigen DRB01*03 haplotype. The precise immune response of PSC is largely unknown but likely involves activation of the innate immune system by bacterial components delivered to the liver via the portal vein. Induction of adhesion molecules and chemokines leads to the recruitment of intestinal lymphocytes. Bile duct injury results from the sustained inflammation and production of inflammatory cytokines. Biliary strictures may cause further damage as a result of bile stasis and recurrent secondary bacterial cholangitis. Progress in our basic understanding of PSC is desperately needed in order to rationally design new therapeutic approaches to this disease.
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Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, USA.
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45
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Abstract
The secretion of bile normally depends on the function of a number of membrane transport systems in hepatocytes and cholangiocytes. The transport of solutes from the blood to the bile is driven by transport systems in the plasma membrane of the basolateral and canalicular surfaces of the hepatocytes. In cholestatic animal models, the expression of hepatobiliary transporters changes in response to functional impairment of the efflux of bile salts and various organic anions. In recent years, several studies have led to an improved understanding of the function and regulation of hepatobiliary transport systems in patients with primary biliary cirrhosis (PBC). This review focuses on the adaptations in hepatobiliary transporters in PBC patients.
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Affiliation(s)
- Yasuaki Takeyama
- Department of Gastroenterology and Medicine, Fukuoka University Faculty of Medicine, Fukuoka, Japan
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46
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Pollheimer MJ, Halilbasic E, Fickert P, Trauner M. Pathogenesis of primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2011; 25:727-39. [PMID: 22117638 PMCID: PMC3236286 DOI: 10.1016/j.bpg.2011.10.009] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 10/25/2011] [Indexed: 01/31/2023]
Abstract
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.
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Affiliation(s)
- Marion J. Pollheimer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria,Corresponding author. Tel.:+43 (0) 1 40400 4741; fax: +43 (0) 1 40400 4735.
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First description of ABCB4 gene deletions in familial low phospholipid-associated cholelithiasis and oral contraceptives-induced cholestasis. Eur J Hum Genet 2011; 20:277-82. [PMID: 21989363 DOI: 10.1038/ejhg.2011.186] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The wide clinical spectrum of the ABCB4 gene (ATP-binding cassette subfamily B member 4) deficiency syndromes in humans includes low phospholipid-associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptives-induced cholestasis (CIC), and progressive familial intrahepatic cholestasis type 3 (PFIC3). No ABCB4 mutations are found in a significant proportion of patients with these syndromes. In the present study, 102 unrelated adult patients with LPAC (43 patients) or CIC/ICP (59 patients) were screened for ABCB4 mutations using DNA sequencing. Heterozygous ABCB4 point or short insertion/deletion mutations were found in 37% (16/43) of the LPAC patients and in 27% (16/59) of the ICP/CIC patients. High-resolution gene dosage methodologies were used in the 70 negative patients. Here, we describe for the first time ABCB4 partial or complete heterozygous deletions in 7% (3/43) of the LPAC patients, and in 2% (1/59) of the ICP/CIC patients. Our observations urge to systematically test patients with LPAC, ICP/CIC, and also children with PFIC3 for the presence of ABCB4 deletions using molecular tools allowing detection of gross rearrangements. In clinical practice, a comprehensive ABCB4 alteration-screening algorithm will permit the use of ABCB4 genotyping to confirm the diagnosis of LPAC or ICP/CIC, and allow familial testing. An early diagnosis of these biliary diseases may be beneficial because of the preventive effect of ursodeoxycholic acid on biliary complications. Further comparative studies of patients with well-characterized genotypes (including deletions) and phenotypes will help determine whether ABCB4 mutation types influence clinical outcomes.
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Kubitz R, Brinkmeyer C, Sagir A, Herebian D, Häussinger D. Genetic variants of the bile salt export pump: inducers and modifiers of liver diseases. Dig Dis 2011; 29:89-92. [PMID: 21691112 DOI: 10.1159/000324140] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The bile salt export pump (BSEP, ABCB11) is the major transporter protein for the excretion of bile salts into bile. Here we describe a spectrum of BSEP-dependent effects on the course of liver diseases, and present two mutations that differentially affect total bile acid output and the biliary bile acid profile. According to the clinical course of affected children, low bile acid output but a normal profile was less harmful than higher output in combination with changes in the ratio of chenodeoxycholic acid to cholic acid. On the other hand, the common BSEP polymorphism V444A (c.1331T>C; allele frequency 65%) emerged as an independent predictor of the success rate in patients with chronic hepatitis C treated with pegylated interferon/ribavirin. This association between bile acid transport and hepatitis C may be due to interference of bile acids with viral replication, interferon signaling or antiviral proteins.
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Affiliation(s)
- Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectiology, University Hospital Düsseldorf, Düsseldorf, Germany.
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Zimmer V, Lammert F. Genetics and epigenetics in the fibrogenic evolution of chronic liver diseases. Best Pract Res Clin Gastroenterol 2011; 25:269-80. [PMID: 21497744 DOI: 10.1016/j.bpg.2011.02.007] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Accepted: 02/18/2011] [Indexed: 01/31/2023]
Abstract
Recent years have seen unprecedented progress in the identification and characterization of genetic information related to chronic liver diseases (CLDs). However, despite the conceptual benefit in early recognition of at-risk populations amenable to pre-emptive treatment and/or surveillance strategies, recent genomic research in the field has placed focus on unravelling the genetic architecture of disease susceptibility, while data on genetic markers anticipating an accelerated fibrogenesis in an individual are still limited. Likewise, sequence variation assigning rapid fibrogenic evolution common to CLDs irrespective of etiology are poorly defined aside from PNPLA3 (adiponutrin) as a prominent exception. The emerging field of epigenetics in hepatology has mostly been studied under the perspective of gene regulation, less so as a heritable alteration in gene activity. In this article we will critically discuss recent findings in genomic hepatology with special focus on the (epi)genetic contribution to the fibrogenic evolution of CLDs.
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Affiliation(s)
- Vincent Zimmer
- Department of Medicine II, Saarland University Hospital, Saarland University, Kirrberger Str., 66421 Homburg, Germany.
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Stieger B, Geier A. Genetic variations of bile salt transporters as predisposing factors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis. Expert Opin Drug Metab Toxicol 2011; 7:411-25. [PMID: 21320040 DOI: 10.1517/17425255.2011.557067] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes. AREAS COVERED This article provides an introduction into the physiology of bile formation followed by a summary of the current knowledge on the key bile salt transporters, namely, the sodium-taurocholate co-transporting polypeptide NTCP, the organic anion transporting polypeptides (OATPs), BSEP and the multi-drug resistance protein 3. The pathophysiologic consequences of altered functions of these transporters, with an emphasis on molecular and genetic aspects, are then discussed. EXPERT OPINION Knowledge of the role of hepatocellullar transporters, especially BSEP, in acquired cholestasis is continuously increasing. A common variant of BSEP (p.V444A) is now a well-established susceptibility factor for acquired cholestasis and recent evidence suggests that the same variant also influences the therapeutic response and disease progression of viral hepatitis C. Studies in large independent cohorts are now needed to confirm the relevance of p.V444A. Genome-wide association studies should lead to the identification of additional genetic factors underlying cholestatic liver disease.
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Affiliation(s)
- Bruno Stieger
- University Hospital Zurich, Division of Clinical Pharmacology and Toxicology, 8091 Zurich, Switzerland.
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