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Vullierme MP, Desterke C, Hillaire S, Parfait B, Vilgrain V, Rebours V, Lewin M. Primary intrahepatic lithiasis in western countries: role of ultrasound and comparison with MRI with MRCP. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00521. [PMID: 40359291 DOI: 10.1097/meg.0000000000002984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
OBJECTIVES To study hepatobiliary expert ultrasound (US) in a cohort of suspected primary intrahepatic lithiasis (IHL) and to compare these findings with MRI/MRCP data. METHODS All patients with a diagnosis of primary-IHL based upon biological and, or, clinical symptoms who underwent US between 2008 and 2023 were retrospectively enrolled in two tertiary hepatobiliary centers. Clinical characteristics, available genetic and radiological features (expert US and MRCP) were recorded. Data were compared for the presence of comet-tail images or stones on US, between US and MRCP features and between imaging and patients' genetic status. Statistical analyses were performed with R software environment version 4.2.1, by univariate and multivariate analysis. RESULTS A total of 112 primary-IHL patients were included (mean age 43 years old ±14 and 55% women). US identified primary-IHL in 92/112 (82%) patients including intrahepatic biliary comet-tail in 82/112 (73%) and stones in 51/112 (46%). Among these, 66/112 (68%) had both US and MRCP. Lithiasis was identified in 60/76 US (79%) and 44/76 MRCP (58%). MRCP showed only stones in 22/76, 29%. Genetic testing was performed in 66/112 (58%) patients. Thirty-two (49%) of these patients had pathogenic ABCB4/MDR3 gene variants, 14/66 (21%) other pathogenic variants and 5/66 (5%) had unknown significant variants. No genetic abnormalities were found in 19/66 (29%). A multivariate logistic model with the comet-tail sign as an outcome showed that there was a significant negative correlation between other pathogenic genetic variants and the comet-tail phenotype (P-value = 0.049). CONCLUSION US, and not MRCP, should be the primary diagnostic tool in suspected primary-IHL patients.
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Affiliation(s)
- Marie-Pierre Vullierme
- Department of Radiology, Paul Brousse University Hospital, Paris-Cité University, Villejuif, France
| | - Christophe Desterke
- INSERM U1310, Paris-Saclay University, Medicine Faculty, Paul Brousse University Hospital, Villejuif, France
| | - Sophie Hillaire
- Department of Hepatology, Beaujon University Hospital, Clichy, AP-HP, Paris-Cité University, Clichy, France
| | - Béatrice Parfait
- Department of Genomic Medicine, Cochin University Hospital, Paris, AP-HP Paris-Cité University, Paris, France
| | - Valérie Vilgrain
- Department of Radiology, Beaujon University Hospital, Clichy, AP-HP, Paris-Cité University, Clichy, France
| | - Vinciane Rebours
- Department of Pancreatology and digestive oncology, Beaujon University Hospital, Clichy, AP-HP, Paris-Cité University, Clichy, France
| | - Maïté Lewin
- Department of Radiology, Paul Brousse University Hospital, Villejuif, AP-HP, Paris-Saclay University, Villejuif, France
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Ciricillo JA, Rahim F, Sharma Y. Unveiling the Genetic Culprit: A Diagnostic Dilemma of Recurrent Cholestasis With Intrahepatic Stones. ACG Case Rep J 2025; 12:e01624. [PMID: 40018694 PMCID: PMC11864301 DOI: 10.14309/crj.0000000000001624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 01/17/2025] [Indexed: 03/01/2025] Open
Abstract
Recurrent cholestasis poses diagnostic challenges and necessitates repeated testing. The ABCB4 (adenosine triphosphate-binding cassette, subfamily B, member 4) gene encodes a protein that removes phospholipids from the hepatic canalicular membrane through bile salts. Mutations lead to a spectrum of clinical syndromes that cause recurrent cholestasis, pruritus, and jaundice. This case follows a young female with recurrent cholestasis postcholecystectomy, intrahepatic stones on endoscopic retrograde cholangiopancreatography, and repeated intrahepatic cholestasis of pregnancy. Phenotypes of ABCB4 mutations should be considered when facing cholestasis of unclear etiology. Early genetic testing and ursodeoxycholic acid treatment may prevent progression toward hepatic fibrosis and end-stage liver disease.
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Affiliation(s)
- Jacob A. Ciricillo
- Division of Digestive Diseases, University of Cincinnati Medical Center, Cincinnati, OH
| | - Farrah Rahim
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Yeshika Sharma
- Division of Digestive Diseases, University of Cincinnati Medical Center, Cincinnati, OH
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Di Ciaula A, Portincasa P. Let us maximize the clinical utility of genetic testing while unraveling the pathogenesis of gallstone disease. Intern Emerg Med 2025; 20:343-344. [PMID: 39885041 DOI: 10.1007/s11739-025-03878-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 01/18/2025] [Indexed: 02/01/2025]
Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Aldo Moro, 70124, Bari, Italy.
| | - Piero Portincasa
- Clinica Medica "A. Murri", Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Aldo Moro, 70124, Bari, Italy.
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4
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Lim JJ, Klaassen CD, Cui JY. Deciphering the cell type-specific and zonal distribution of drug-metabolizing enzymes, transporters, and transcription factors in livers of mice using single-cell transcriptomics. Drug Metab Dispos 2025; 53:100029. [PMID: 39919554 DOI: 10.1016/j.dmd.2024.100029] [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: 08/12/2024] [Accepted: 11/08/2024] [Indexed: 02/09/2025] Open
Abstract
The liver contains multiple cell types, including resident cell types and immune cells. The liver is also categorized into 3 zones: periportal (zone 1), midzonal (zone 2), and centrilobular (zone 3). The goal of this study was to characterize the distribution of drug-processing genes (DPGs) in mouse liver using published single-cell and nuclei transcriptomic datasets, which were subjected to zonal deconvolution. Filtering, normalization, clustering, and differential expression analyses were performed using Seurat V5 in R. Hepatocytes were assigned to 3 zones based on known zonal markers and validated with published spatial transcriptomics data. Among the 195 DPGs profiled, most were expressed highest in hepatocytes (61.3%). Interestingly, certain DPGs were expressed most highly in nonparenchymal cells, such as in cholangiocytes (11.2%, eg, carboxylesterase [Ces] 2e, Ces2g), endothelial cells (7.2%, eg, aldo-keto reductase [Akr] 1c19, Akr1e1), Kupffer cells (5.3%, eg, Akr1a1, Akr1b10), stellate cells (5.1%, eg, retinoic acid receptor [Rar] α, Rarβ), myofibroblasts (2.9%, RAR-related orphan receptor [Rar] α), and a few were expressed in immune cell types. In hepatocytes, 72.4% of phase-I enzymes were enriched in zone 3. Phase-II conjugation enzymes such as UDP-glucuronosyltransferases (75%) were enriched in zone 3, whereas sulfotransferases (40%) were enriched in zone 1. Hepatic xenobiotic transporters were enriched in zone 3. The xenobiotic biotransformation-regulating transcription factors were enriched in zone 3 hepatocytes. The enrichment of DPGs in liver cell types, including non-parenchymal cells and zone 1 hepatocytes, may serve as an additional repertoire for xenobiotic biotransformation. SIGNIFICANCE STATEMENT: Our study is among the first to systematically characterize the baseline mRNA enrichment of important drug-processing genes in different cell types and zones in the liver. This finding will aid in further understanding the mechanisms of chemical-induced liver injury with improved resolution and precision.
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Affiliation(s)
- Joe Jongpyo Lim
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington; Environmental Health and Microbiome Research Center (EHMBRACE), Seattle, Washington
| | - Curtis Dean Klaassen
- Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kanas.
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington; Environmental Health and Microbiome Research Center (EHMBRACE), Seattle, Washington.
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Elbahnsi A, Dudas B, Callebaut I, Hinzpeter A, Miteva MA. ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches. Pharmaceuticals (Basel) 2024; 17:1602. [PMID: 39770445 PMCID: PMC11676857 DOI: 10.3390/ph17121602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 01/11/2025] Open
Abstract
The ATP-binding cassette (ABC) and solute carrier (SLC) transporters play pivotal roles in cellular transport mechanisms, influencing a wide range of physiological processes and impacting various medical conditions. Recent advancements in structural biology and computational modeling have provided significant insights into their function and regulation. This review provides an overview of the current knowledge of human ABC and SLC transporters, emphasizing their structural and functional relationships, transport mechanisms, and the contribution of computational approaches to their understanding. Current challenges and promising future research and methodological directions are also discussed.
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Affiliation(s)
- Ahmad Elbahnsi
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
| | - Balint Dudas
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
| | - Isabelle Callebaut
- Muséum National d’Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie—IMPMC, Sorbonne Université, 75005 Paris, France
| | - Alexandre Hinzpeter
- CNRS, INSERM, Institut Necker Enfants Malades—INEM, Université Paris Cité, 75015 Paris, France
| | - Maria A. Miteva
- Inserm U1268 MCTR, CiTCoM UMR 8038 CNRS, Université Paris Cité, 75006 Paris, France
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Nishi Y, Funamizu N, Ito C, Shine M, Nagaoka T, Honjo M, Tamura K, Sakamoto K, Ogawa K, Takada Y. A Case of a Young Adult with Multiple Intrahepatic Stones Diagnosed as Low Phospholipid-Associated Cholelithiasis Showing <i>ABCB4</i> Gene Mutation. KANZO 2024; 65:566-571. [DOI: 10.2957/kanzo.65.566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/19/2025]
Affiliation(s)
- Yusuke Nishi
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Naotake Funamizu
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Chihiro Ito
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Mikiya Shine
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Tomoyuki Nagaoka
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Masahiko Honjo
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Kei Tamura
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Katsunori Sakamoto
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Kohei Ogawa
- Department of HBP and Transplantation Surgery, Ehime University Hospital
| | - Yasutsugu Takada
- Department of HBP and Transplantation Surgery, Ehime University Hospital
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Cozma MA, Găman MA, Srichawla BS, Dhali A, Manan MR, Nahian A, Marsool MDM, Suteja RC, Kutikuppala LVS, Kipkorir V, Găman AM, Diaconu CC. Acute cholangitis: a state-of-the-art review. Ann Med Surg (Lond) 2024; 86:4560-4574. [PMID: 39118745 PMCID: PMC11305776 DOI: 10.1097/ms9.0000000000002169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 05/05/2024] [Indexed: 08/10/2024] Open
Abstract
Acute cholangitis is a potentially life-threatening bacterial infection of the intra and/or extrahepatic bile ducts. It remains the second and third cause of community-acquired and hospital-acquired bacteremia, respectively, and is associated with mortality rates of up to 15%, despite advances in broad-spectrum antimicrobial therapy and improved access to emergency biliary tract decompression procedures. Even though not much has changed in recent years in terms of diagnosis or treatment, new data have emerged regarding multidrug-resistant bacteria that serve as etiologic agents of cholangitis. Moreover, different approaches in antibiotic regimes depending on severity grading and bile sample cultures as well as novel minimally invasive endoscopic procedures that can help when consecrated treatments such as endoscopic retrograde cholangiopancreatography (ERCP) fail, cannot be performed, or are unavailable have been proposed. This state-of-the-art review aims to offer a complete and updated assessment of the epidemiology, novel diagnostic and therapeutic methods, complications, and prognostic variables of acute cholangitis. The authors will review the prognostic implications of unusual complications, the relevance of regular bile samples and antibiograms, and their new role in guiding antibiotic therapy and limiting antibiotic resistance to present an organized and comprehensive approach to the care of acute cholangitis.
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Affiliation(s)
- Matei-Alexandru Cozma
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest
- Department of Gastroenterology, Colentina Clinical Hospital, Bucharest
| | - Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest
- Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest
| | - Bahadar S. Srichawla
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA
| | - Arkadeep Dhali
- NIHR Academic Clinical Fellow in Gastroenterology, University of Sheffield; Internal Medicine Trainee, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | - Ahmed Nahian
- Medical Student, LECOM at Seton Hill, Greensburg, PA, USA
| | | | | | | | - Vincent Kipkorir
- Department of Human Anatomy and Physiology, Faculty of Health Sciences, University of Nairobi, Nairobi, Kenya
| | - Amelia Maria Găman
- Department of Pathophysiology, University of Medicine and Pharmacy of Craiova
- Clinic of Hematology, Filantropia City Hospital, Craiova, Romania
| | - Camelia Cristina Diaconu
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest
- Internal Medicine Clinic, Clinical Emergency Hospital of Bucharest, Bucharest
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8
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Trinh A, Tjandra D, Park YA, Sood S, Thomson B, Speer T, Buchanan D, Boussioutas A, Metz AJ. Searching for low phospholipid associated cholelithiasis among patients with post-cholecystectomy biliary pain. ANZ J Surg 2024; 94:1102-1107. [PMID: 38361311 DOI: 10.1111/ans.18904] [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: 01/02/2024] [Accepted: 01/28/2024] [Indexed: 02/17/2024]
Abstract
INTRODUCTION Low phospholipid associated cholelithiasis (LPAC) is associated with variants of the adenosine triphosphate-binding cassette subfamily B, member 4 (ABCB4) gene and is characterized by reduced phosphatidylcholine secretion into bile, impairing the formation of micelles and thus exposing bile ducts to toxic bile acids and increasing cholesterol saturation. LPAC is present in 1% of patients with gallstones and post-cholecystectomy pain is common in this group. LPAC is an under-appreciated cause of post-cholecystectomy pain. The aim of this study is to assess a cohort of patients with post-cholecystectomy pain to identify those with clinical features suggesting that further investigations for LPAC would be beneficial. METHODS A retrospective chart review was performed of the first 2 years of post-operative follow-up for all patients under 40 years of age undergoing cholecystectomy for symptomatic gallstones at a tertiary centre between January 2016 and December 2017. RESULTS 258 patients under the age of 40 underwent a cholecystectomy. 50 patients (19.4%) reported abdominal pain post-cholecystectomy. Five patients (1.9%) fulfilled the criteria for suspected LPAC. Family history of gallstones was documented in 33 of 258 (12.8%) of cases. Obstetric history was obtained in 69 of 197 (35%) female patients. None of the five patients identified above who satisfied the criteria of LPAC had the diagnosis of LPAC considered by their treating clinicians. CONCLUSION LPAC is an under-recognized cause of post-cholecystectomy pain. Treatment can avoid long-term symptoms and complications. Clinicians should take a family history and obstetric history to alert them to the diagnosis of LPAC.
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Affiliation(s)
- Andrew Trinh
- Department of Medicine, Royal Melbourne Hospital and The University of Melbourne, Parkville, Victoria, Australia
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
| | - Doug Tjandra
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Yeung-Ae Park
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Siddharth Sood
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Benjamin Thomson
- Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia
| | - Tony Speer
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Daniel Buchanan
- Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
| | - Alex Boussioutas
- Department of Medicine, Royal Melbourne Hospital and The University of Melbourne, Parkville, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Gastroenterology, The Alfred and Monash University, Melbourne, Victoria, Australia
| | - Andrew J Metz
- Department of Medicine, Royal Melbourne Hospital and The University of Melbourne, Parkville, Victoria, Australia
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria, Australia
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9
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Salin G, Corpechot C, Ouazana S, Dong C, Becq A, Lemoinne S, Ben Belkacem K, Leenhardt R, Chaput U, Chazouillères O, Kirchgesner J, Camus M. Endoscopic features of low-phospholipid-associated cholelithiasis syndrome: A retrospective cohort study. Clin Res Hepatol Gastroenterol 2024; 48:102324. [PMID: 38527568 DOI: 10.1016/j.clinre.2024.102324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 03/17/2024] [Accepted: 03/23/2024] [Indexed: 03/27/2024]
Abstract
BACKGROUND AND OBJECTIVE LPAC (low phospholipid-associated cholelithiasis) syndrome is a rare genetic form of cholelithiasis. ERCP (endoscopic retrograde cholangiopancreatography) is often used to remove gallstones in the bile duct. No published data is available on the role of ERCP in LPAC syndrome. PATIENTS AND METHODS In this retrospective cohort study, we included patients diagnosed with LPAC syndrome in a single tertiary referral center between 2009 and 2021. Our aim was to assess the frequency, indications, modalities, results, and complications of ERCP, as well as predictive factors for ERCP, in LPAC syndrome. Independent factors associated with ERCP occurrence were identified using a multivariable Cox regression analysis. RESULTS ERCP was required in 31.2 % of the 269 patients included for analysis. Among patients who required ERCPs, 78.6 % had the procedure before diagnosis (i.e., starting UDCA). Most common indications were choledocholithiasis (53.6 %) and acute cholangitis (29.5 %). Post ERCP pancreatitis, perforation and bleeding rates were 7.2 %, 2.6 %, and 1.3 %, respectively. Age and history of cholelithiasis in first-degree relatives were associated with a higher risk of ERCP (Hazard-ratio [HR]=1.30 [95 %confidence-interval [CI] 1.04-1.62] and HR=1.88 [95 %CI 1.15-3.07] respectively). Female gender and UDCA intake ≥ 1 year were associated with a lower risk of ERCP (HR=0.49 [95 %CI 0.29-0.82] and HR=0.44 [95 %CI 0.22-0.90] respectively). Median follow-up was 10.8 years. CONCLUSION One-third of patients with LPAC syndrome undergo sphincterotomy. However, most procedures are performed before diagnosis and UDCA is associated with a lower risk of endoscopic procedure. Earlier diagnosis and treatment with UDCA may further reduce the need for ERCP in patients with LPAC syndrome.
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Affiliation(s)
- G Salin
- Sorbonne University, Hepatogastroenterology - Endoscopy unit, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France.
| | - C Corpechot
- Sorbonne University, Reference center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France; French National Cohort of Patients with LPAC syndrome RaDiCo-COLPAC, RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - S Ouazana
- Sorbonne University, Hepatogastroenterology - Endoscopy unit, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France
| | - C Dong
- Sorbonne University, Reference center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France; French National Cohort of Patients with LPAC syndrome RaDiCo-COLPAC, RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - A Becq
- Paris-Est Creteil University, Department of Gastroenterology, Henri Mondor Hospital, Assistance Publique - Hopitaux de Paris, Paris, France
| | - S Lemoinne
- Sorbonne University, Reference center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France; French National Cohort of Patients with LPAC syndrome RaDiCo-COLPAC, RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - K Ben Belkacem
- Sorbonne University, Reference center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France; French National Cohort of Patients with LPAC syndrome RaDiCo-COLPAC, RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - R Leenhardt
- Sorbonne University, Hepatogastroenterology - Endoscopy unit, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France
| | - U Chaput
- Sorbonne University, Hepatogastroenterology - Endoscopy unit, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France
| | - O Chazouillères
- Sorbonne University, Reference center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France; French National Cohort of Patients with LPAC syndrome RaDiCo-COLPAC, RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - J Kirchgesner
- Sorbonne University, Department of Gastroenterology, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France
| | - M Camus
- Sorbonne University, Hepatogastroenterology - Endoscopy unit, Saint-Antoine Hospital and Research Center, Assistance Publique - Hopitaux de Paris, Paris, France
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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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11
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Soret PA, Lemoinne S, Mallet M, Belkacem KB, Chazouillères O, Corpechot C. Obeticholic acid as a second-line treatment for low phospholipid-associated cholelithiasis syndrome. Aliment Pharmacol Ther 2024; 59:113-117. [PMID: 37818704 DOI: 10.1111/apt.17761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/29/2023] [Accepted: 10/01/2023] [Indexed: 10/12/2023]
Abstract
BACKGROUND Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare genetic cause of hepatolithiasis. A pathogenic variant of the ABCB4 gene is reported in half of all patients. Ursodeoxycholic acid (UDCA) is the only drug approved. However, in some patients, UDCA fails to prevent recurrence of symptoms and complications. Experimental evidence suggests that agonists of the farnesoid-X receptor (FXR), the main transcription factor regulating ABCB4, may be beneficial in this context. AIM To study the efficacy of obeticholic acid (OCA) in patients with LPAC syndrome with an inadequate response or intolerance to UDCA. METHODS This was a retrospective study of patients with LPAC syndrome treated with OCA, a selective FXR agonist. RESULTS We reviewed the records of five OCA-treated patients (4 women; median age 29; ABCB4 variant in 4; no hepatic fibrosis). All patients received OCA at an initial dose of 5 mg daily and then 10 mg daily for a median period of 36 months in combination with UDCA (4 patients) or as a monotherapy (one patient). There were no adverse effects reported. Four patients had improvement in their symptoms - three completely and one partially. One patient had no clinical benefit. Abnormalities of blood liver tests persisted in one patient despite resolution of symptoms. Radiological signs of hepatolithiasis persisted in three of the four patients who responded clinically to OCA. CONCLUSIONS These preliminary observations suggest that OCA may have the potential to effectively treat LPAC syndrome in patients with inadequate response or intolerance to UDCA. Larger studies are needed to confirm these data.
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Affiliation(s)
- Pierre-Antoine Soret
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
- Saint-Antoine Research Center (CRSA), INSERM, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), Paris, France
- RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - Sara Lemoinne
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
- Saint-Antoine Research Center (CRSA), INSERM, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), Paris, France
- RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - Maxime Mallet
- Hepatology and Gastroenterology Department, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Karima Ben Belkacem
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
- Saint-Antoine Research Center (CRSA), INSERM, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), Paris, France
- RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
- Saint-Antoine Research Center (CRSA), INSERM, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), Paris, France
- RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
- Saint-Antoine Research Center (CRSA), INSERM, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), Paris, France
- RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
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El Moutaoukil N, Zouaoui M, Hnach Y, Azouaoui M, Aqodad N. Considerations for Low Phospholipid-Associated Cholelithiasis (LPAC) Syndrome: Report of Three Cases. Cureus 2023; 15:e48082. [PMID: 38046505 PMCID: PMC10689977 DOI: 10.7759/cureus.48082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2023] [Indexed: 12/05/2023] Open
Abstract
Low phospholipid-associated cholelithiasis (LPAC) syndrome is a rare underdiagnosed genetic feature presenting less than 1% of symptomatic cholelithiasis, with variable clinical forms ranging from simple to complications. Diagnosis criteria are recurrent biliary symptomatology occurring in young patients (<40 years old) and/or recurrence after cholecystectomy and/or having a history of biliary gallstones in first-degree relatives and characteristic ultrasound findings. Early detection of this entity, due to the awareness of gastroenterologists, radiologists, and visceral surgeons, will allow an improvement in the quality of life of patients and the prevention of complications. We report three cases of the LPAC syndrome and discuss its different aspects.
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Affiliation(s)
- Najoua El Moutaoukil
- Gastroenterology and Hepatology, University Hospital Souss Massa, University Ibn Zohr, Faculty of Medicine and Pharmacy, Agadir, MAR
| | - Mehdi Zouaoui
- Gastroenterology and Hepatology, University Hospital Souss Massa, University Ibn Zohr, Faculty of Medicine and Pharmacy, Agadir, MAR
| | - Youssef Hnach
- Gastroenterology and Hepatology, University Hospital Souss Massa, University Ibn Zohr, Faculty of Medicine and Pharmacy, Agadir, MAR
| | - Mbarek Azouaoui
- Gastroenterology and Hepatology, University Hospital Souss Massa, University Ibn Zohr, Faculty of Medicine and Pharmacy, Agadir, MAR
| | - Nourdin Aqodad
- Gastroenterology and Hepatology, University Hospital Souss Massa, University Ibn Zohr, Faculty of Medicine and Pharmacy, Agadir, MAR
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13
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Zheng M, Hakim A, Konkwo C, Deaton AM, Ward LD, Silveira MG, Assis DN, Liapakis A, Jaffe A, Jiang ZG, Curry MP, Lai M, Cho MH, Dykas D, Bale A, Mistry PK, Vilarinho S. Advancing diagnosis and management of liver disease in adults through exome sequencing. EBioMedicine 2023; 95:104747. [PMID: 37566928 PMCID: PMC10433007 DOI: 10.1016/j.ebiom.2023.104747] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 07/24/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND Whole-exome sequencing (WES) is an effective tool for diagnosis in patients who remain undiagnosed despite a comprehensive clinical work-up. While WES is being used increasingly in pediatrics and oncology, it remains underutilized in non-oncological adult medicine, including in patients with liver disease, in part based on the faulty premise that adults are unlikely to harbor rare genetic variants with large effect size. Here, we aim to assess the burden of rare genetic variants underlying liver disease in adults at two major tertiary referral academic medical centers. METHODS WES analysis paired with comprehensive clinical evaluation was performed in fifty-two adult patients with liver disease of unknown etiology evaluated at two US tertiary academic health care centers. FINDINGS Exome analysis uncovered a definitive or presumed diagnosis in 33% of patients (17/52) providing insight into their disease pathogenesis, with most of these patients (12/17) not having a known family history of liver disease. Our data shows that over two-thirds of undiagnosed liver disease patients attaining a genetic diagnosis were being evaluated for cholestasis or hepatic steatosis of unknown etiology. INTERPRETATION This study reveals an underappreciated incidence and spectrum of genetic diseases presenting in adulthood and underscores the clinical value of incorporating exome sequencing in the evaluation and management of adults with liver disease of unknown etiology. FUNDING S.V. is supported by the NIH/NIDDK (K08 DK113109 and R01 DK131033-01A1) and the Doris Duke Charitable Foundation Grant #2019081. This work was supported in part by NIH-funded Yale Liver Center, P30 DK34989.
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Affiliation(s)
- Melanie Zheng
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Aaron Hakim
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Chigoziri Konkwo
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | | | | | - Marina G Silveira
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - David N Assis
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - AnnMarie Liapakis
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Ariel Jaffe
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Z Gordon Jiang
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Michael P Curry
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Michelle Lai
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Michael H Cho
- Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Daniel Dykas
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
| | - Allen Bale
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
| | - Pramod K Mistry
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Silvia Vilarinho
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
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Ceci L, Han Y, Krutsinger K, Baiocchi L, Wu N, Kundu D, Kyritsi K, Zhou T, Gaudio E, Francis H, Alpini G, Kennedy L. Gallstone and Gallbladder Disease: Biliary Tract and Cholangiopathies. Compr Physiol 2023; 13:4909-4943. [PMID: 37358507 DOI: 10.1002/cphy.c220028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Cholestatic liver diseases are named primarily due to the blockage of bile flow and buildup of bile acids in the liver. Cholestasis can occur in cholangiopathies, fatty liver diseases, and during COVID-19 infection. Most literature evaluates damage occurring to the intrahepatic biliary tree during cholestasis; however, there may be associations between liver damage and gallbladder damage. Gallbladder damage can manifest as acute or chronic inflammation, perforation, polyps, cancer, and most commonly gallstones. Considering the gallbladder is an extension of the intrahepatic biliary network, and both tissues are lined by biliary epithelial cells that share common mechanisms and properties, it is worth further evaluation to understand the association between bile duct and gallbladder damage. In this comprehensive article, we discuss background information of the biliary tree and gallbladder, from function, damage, and therapeutic approaches. We then discuss published findings that identify gallbladder disorders in various liver diseases. Lastly, we provide the clinical aspect of gallbladder disorders in liver diseases and ways to enhance diagnostic and therapeutic approaches for congruent diagnosis. © 2023 American Physiological Society. Compr Physiol 13:4909-4943, 2023.
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Affiliation(s)
- Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Yuyan Han
- School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, USA
| | - Kelsey Krutsinger
- School of Biological Sciences, University of Northern Colorado, Greeley, Colorado, USA
| | | | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, USA
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15
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Wang HH, Portincasa P, Liu M, Wang DQH. Effects of Biliary Phospholipids on Cholesterol Crystallization and Growth in Gallstone Formation. Adv Ther 2023; 40:743-768. [PMID: 36602656 DOI: 10.1007/s12325-022-02407-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/08/2022] [Indexed: 01/06/2023]
Abstract
The prevalence of cholesterol gallstone disease is increasing, primarily due to the global epidemic of obesity associated with insulin resistance, and this trend leads to a considerable healthcare, financial, and social burden worldwide. Although phospholipids play an essential role in maintaining cholesterol solubility in bile through both mixed micelles and vesicles, little attention has been paid to the impact of biliary phospholipids on the pathogenesis of cholesterol gallstone formation. A reduction or deficiency of biliary phospholipids results in a distinctly abnormal metastable physical-chemical state of bile predisposing to supersaturation with cholesterol. Changes in biliary phospholipid concentrations influence cholesterol crystallization by yielding both liquid crystalline and "anhydrous" crystalline metastable intermediates, evolving into classical parallelogram-shaped cholesterol monohydrate crystals in supersaturated bile. As a result, five distinct crystallization pathways, A-E, have been defined, mainly based on the prime habits of liquid and solid crystals in the physiological or pathophysiological cholesterol saturation of gallbladder and hepatic bile. This review concisely summarizes the chemical structures and physical-chemical properties of biliary phospholipids and their physiological functions in bile formation and cholesterol solubility in bile, as well as comprehensively discusses the latest advances in the role of biliary phospholipids in cholesterol crystallization and growth in gallstone formation, largely based on the findings from clinical and animal studies and in vitro experiments. The insights gleaned from uncovering the cholelithogenic mechanisms are expected to form a fundamental framework for investigating the hitherto elusive events in the earliest stage of cholesterol nucleation and crystallization. This may help to identify better measures for early diagnosis and prevention in susceptible subjects and effective treatment of patients with gallstones.
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Affiliation(s)
- Helen H Wang
- Division of Gastroenterology and Liver Diseases, Department of Medicine and Genetics, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri", University of Bari Medical School, Bari, Italy
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45237, USA
| | - David Q-H Wang
- Division of Gastroenterology and Liver Diseases, Department of Medicine and Genetics, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
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16
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Targeted liver ultrasound performed by an expert is the pivotal imaging examination for low phospholipid-associated cholelithiasis. Eur J Gastroenterol Hepatol 2023; 35:327-332. [PMID: 36708304 DOI: 10.1097/meg.0000000000002492] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVES Low phospholipid-associatedcholelithiasis (LPAC) is a clinical syndrome that can be associated with variants in the adenosinetriphosphate-binding cassette subfamily B, member 4 (ABCB4) transporter gene, in a proportion of patients. The diagnosis of LPAC is defined by clinical as well as imaging criteria of intrahepatic hyperechoic foci or microlithiasis and biliary sludge on ultrasound. The aim of the study was to assess the role of imaging in investigating patients presenting with clinical features suggesting a diagnosis of LPAC. METHODS Imaging findings in 51 patients with clinical LPAC were retrospectively reviewed. Most patients had been referred with difficult-to-manage biliary pain postcholecystectomy and some with intrahepatic dilated ducts and stones. The diagnosis of LPAC was made on clinical features. RESULTS The patients were young with symptom onset at median age 24 years and were mainly female (75%). Ultrasound was performed by an expert in 48/51 and magnetic resonance cholangiopancreatography (MRCP) in 47/51 patients. Targeted liver ultrasound found small hyperechoic foci with comet tail artifacts or posterior acoustic shadowing typical of LPAC in 30/48 (63%) of examinations. However, ultrasound examinations performed before referral for investigation did not report these findings. Intrahepatic duct dilatation was seen in 26/51 (51%) of cases. MRCP did not reliably detect microlithiasis. CONCLUSIONS Targeted liver ultrasound performed by an expert aware of the possible diagnosis is the pivotal investigation for patients with clinical features suggesting LPAC. The findings in ultrasound performed before referral suggest LPAC is under-recognized and under-diagnosed.
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17
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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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18
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Mansour S, Kluger Y, Khuri S. Primary Recurrent Common Bile Duct Stones: Timing of Surgical Intervention. J Clin Med Res 2022; 14:441-447. [PMID: 36578366 PMCID: PMC9765319 DOI: 10.14740/jocmr4826] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 10/24/2022] [Indexed: 11/30/2022] Open
Abstract
Cholelithiasis (gallstones) is a very common medical problem worldwide, with 5-30% of patients demonstrating a combined condition of cholelithiasis and choledocholithiasis (common bile duct stones (CBDS)). CBDS are usually classified as primary or secondary stones. Primary CBDS are defined as stones detected 2 years or more following cholecystectomy, while secondary stones, the most common type, usually migrate from the gallbladder to the bile ducts. Recurrent CBDS are defined as stones detected 6 months or more following endoscopic retrograde cholangiopancreatography (ERCP) with complete duct clearance. Although ERCP with endoscopic sphincterotomy has emerged as the main therapeutic option for CBDS, with up to 95% bile duct clearance rate, up to 25% of said patients develop recurrent bile duct stones. Thus far, several issues related to recurrent CBDS are still unclear and questions regarding this specific pathology have no precise answers: how many trials of ERCP and endoscopic sphincterotomy should be attempted before referring the patient for surgical management? Is there an association between risk factors and early surgical intervention? Thus, currently, there is no worldwide scientific-based consensus regarding the best management of this specific group of patients. The main issue for this article is to review the relevant English literature and find out the main high risk factors for recurrent CBDS, and form a diagnostic and treatment plan, hence, identifying the subgroup of patients that will benefit from early surgical management, preventing further ERCP-associated complications.
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Affiliation(s)
- Subhi Mansour
- Department of General Surgery, Rambam Health Care Campus, Haifa, Israel
| | - Yoram Kluger
- Department of General Surgery, Rambam Health Care Campus, Haifa, Israel
- HPB and Surgical Oncology Unit, Rambam Health Care Campus, Haifa, Israel
| | - Safi Khuri
- Department of General Surgery, Rambam Health Care Campus, Haifa, Israel
- HPB and Surgical Oncology Unit, Rambam Health Care Campus, Haifa, Israel
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Cherraqi A, Imrani K, Andour H, Messaoud O, Benelhosni K, Billah NM, Nassar I. Low phospholipids associated cholelithiasis syndrome in a young women: A rare case report. Radiol Case Rep 2022; 18:11-16. [PMID: 36324844 PMCID: PMC9619147 DOI: 10.1016/j.radcr.2022.09.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 09/18/2022] [Accepted: 09/21/2022] [Indexed: 11/07/2022] Open
Abstract
Low phospholipid-associated cholelithiasis (LPAC) is a rare, still poorly understood genetic disorder characterized by the association of an ABCB4 mutation and low biliary phospholipid concentration with recurrent cholelithiasis, responsible for the development of intrahepatic lithiasis in adults. The mutation of the ABCB4 gene, which codes for the ABCB4/MDR3 ductal protein, a biliary transporter, leads to precipitation of cholesterol crystals in the bile ducts leading to the formation of intrahepatic stones. The diagnosis should be suspected when at least 2 of the following criteria are present: onset of symptoms before age 40; recurrence of biliary symptoms (biliary colic, jaundice, cholangitis, acute pancreatitis) after cholecystectomy; presence of echogenic foci in the liver indicative of intrahepatic stones or biliary sludge; previous episode(s) of intrahepatic cholestasis during pregnancy; and a family history of gallstones in first degree relatives. Imaging techniques, especially ultrasound, play an important role in the detection of intrahepatic stones. The majority of clinical situations are simple and not serious, often managed by medical treatment with ursodeoxycholic acid, but certain complicated forms may require more invasive endoscopic or surgical treatment. We report a case of a 43-year-old woman, cholecystectomized 5 years ago, who presented with liver colic-like pain with cytolysis and biological cholestasis. Ultrasound and MRI showed the presence of intrahepatic calculi disseminated along the bile duct pathway creating a comet tail appearance and generating a posterior shadow cone. The interrogation of the patient showed that her sister was being followed for LPAC syndrome. The diagnosis of LPAC syndrome was retained and the patient was put under medical treatment with ursodeoxycholic acid with regular clinical, biological and radiological follow-up.
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Biyoukar M, Corpechot C, El Mouhadi S, Chambenois E, Vanderbecq Q, Barbu V, Dong C, Lemoinne S, Tordjman M, Jomaah R, Chazouilleres O, Arrivé L. ABCB4 variant is associated with hepatobiliary MR abnormalities in people with low phospholipid associated cholelithiasis syndrome. JHEP Rep 2022; 4:100590. [PMID: 36277956 PMCID: PMC9582794 DOI: 10.1016/j.jhepr.2022.100590] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/09/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Affiliation(s)
- Moustafa Biyoukar
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Sanaâ El Mouhadi
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Edouard Chambenois
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Quentin Vanderbecq
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
| | - Véronique Barbu
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Catherine Dong
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Sara Lemoinne
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Mickael Tordjman
- Department of Radiology, Raymond Poincaré Hospital, Assistance Publique – Hôpitaux de Paris (APHP), Garches, France
| | - Raphel Jomaah
- Faculty of Arts and Science, University of Toronto, Toronto, ON, Canada
| | - Olivier Chazouilleres
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare-Liver, Department of Hepatology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP), and INSERM, UMRS 938 Sorbonne University, Paris, France
| | - Lionel Arrivé
- Department of Radiology, Saint-Antoine Hospital, Assistance Publique – Hôpitaux de Paris (APHP) and Sorbonne University, Paris, France
- Corresponding author. Address: Department of Radiology, Saint-Antoine Hospital, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France. Tel.: +33-149282257.
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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22
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Halleb Y, Ben Jazia E, Akkari I, Zaghouani H, Hmila F, Ghrissi R, Saad A, Gribaa M. Clinical, biological, radiological, and genetic study of LPAC syndrome in Tunisian patients. Arab J Gastroenterol 2022; 23:210-217. [PMID: 35922258 DOI: 10.1016/j.ajg.2022.06.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 05/12/2022] [Accepted: 06/07/2022] [Indexed: 10/16/2022]
Abstract
BACKGROUND AND STUDY AIMS Low phospholipid-associated cholelithiasis (LPAC) syndrome is a form of cholelithiasis associated with the ABCB4 gene mutation. The defects of the protein ABCB4 encoded by this gene promote the formation of biliary cholesterol microcalculations. ABCB4 screening is negative in a significant proportion of patients. PATIENTS AND METHODS An analytical study of the epidemiological, clinical, biological, and radiological characteristics of 19 patients was conducted, followed by Sanger-type sequencing of the 27 exons encoding the ABCB4 gene. RESULTS Our results showed a female predominance, symptomatic vesicular lithiasis predominance, and a high frequency of biliary complications in patients carrying an ABCB4 mutation. Normal liver enzyme values were found in 84.2% of the cases. Intrahepatic hyperechoic foci were present in 68.4%. Molecular analysis detected a pathogenic mutation of the ABCB4 gene in 31.57% of patients. The mutations found were a nonsense mutation and three missense mutations, including two new mutations. CONCLUSION Our epidemiological, clinical, and genetic results concord with previous studies of LPAC syndrome. Two of the mutations we found have never been detected in patients with LPAC. The low percentage of ABCB4 gene mutations can be explained by the absence of studies of other genes involved in bile acid homeostasis besides the ABCB4 gene and by the inclusion criteria used in this study.
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Affiliation(s)
- Yosra Halleb
- Laboratory of Cytogenetics, Molecular Genetics and Biology of Human Reproduction, University Hospital Farhat Hached, Sousse, Tunisia; Faculty of Medicine of Sousse, University of Sousse.
| | - Elhem Ben Jazia
- Faculty of Medicine of Sousse, University of Sousse; Gastroenterology Department, University Hospital Farhat Hached, Sousse, Tunisia
| | - Imen Akkari
- Faculty of Medicine of Sousse, University of Sousse; Gastroenterology Department, University Hospital Farhat Hached, Sousse, Tunisia
| | - Houneida Zaghouani
- Faculty of Medicine of Sousse, University of Sousse; Medical Imaging Department, University Hospital Farhat Hached , Sousse, Tunisia
| | - Fahmi Hmila
- Faculty of Medicine of Sousse, University of Sousse; Department of General Surgery, University Hospital Farhat Hached, Sousse, Tunisia
| | - Rafik Ghrissi
- Faculty of Medicine of Sousse, University of Sousse; Department of General Surgery, University Hospital Farhat Hached, Sousse, Tunisia
| | - Ali Saad
- Laboratory of Cytogenetics, Molecular Genetics and Biology of Human Reproduction, University Hospital Farhat Hached, Sousse, Tunisia; Faculty of Medicine of Sousse, University of Sousse
| | - Moez Gribaa
- Laboratory of Cytogenetics, Molecular Genetics and Biology of Human Reproduction, University Hospital Farhat Hached, Sousse, Tunisia; Faculty of Medicine of Sousse, University of Sousse
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23
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Wang HH, Portincasa P, Liu M, Wang DQH. Genetic Analysis of ABCB4 Mutations and Variants Related to the Pathogenesis and Pathophysiology of Low Phospholipid-Associated Cholelithiasis. Genes (Basel) 2022; 13:1047. [PMID: 35741809 PMCID: PMC9222727 DOI: 10.3390/genes13061047] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 06/08/2022] [Indexed: 12/28/2022] Open
Abstract
Clinical studies have revealed that the ABCB4 gene encodes the phospholipid transporter on the canalicular membrane of hepatocytes, and its mutations and variants are the genetic basis of low phospholipid-associated cholelithiasis (LPAC), a rare type of gallstone disease caused by a single-gene mutation or variation. The main features of LPAC include a reduction or deficiency of phospholipids in bile, symptomatic cholelithiasis at <40 years of age, intrahepatic sludge and microlithiasis, mild chronic cholestasis, a high cholesterol/phospholipid ratio in bile, and recurrence of biliary symptoms after cholecystectomy. Needle-like cholesterol crystals, putatively “anhydrous” cholesterol crystallization at low phospholipid concentrations in model and native bile, are characterized in ABCB4 knockout mice, a unique animal model for LPAC. Gallbladder bile with only trace amounts of phospholipids in these mice is supersaturated with cholesterol, with lipid composition plotting in the left two-phase zone of the ternary phase diagram, consistent with “anhydrous” cholesterol crystallization. In this review, we summarize the molecular biology and physiological functions of ABCB4 and comprehensively discuss the latest advances in the genetic analysis of ABCB4 mutations and variations and their roles in the pathogenesis and pathophysiology of LPAC in humans, based on the results from clinical studies and mouse experiments. To date, approximately 158 distinct LPAC-causing ABCB4 mutations and variants in humans have been reported in the literature, indicating that it is a monogenic risk factor for LPAC. The elucidation of the ABCB4 function in the liver, the identification of ABCB4 mutations and variants in LPAC patients, and the exploration of gene therapy for ABCB4 deficiency in animal models can help us to better understand the cellular, molecular, and genetic mechanisms underlying the onset of the disease, and will pave the way for early diagnosis and prevention of susceptible subjects and effective intervention for LPAC in patients.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, 70124 Bari, Italy;
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA;
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
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24
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Fairfield CJ, Drake TM, Pius R, Bretherick AD, Campbell A, Clark DW, Fallowfield JA, Hayward C, Henderson NC, Iakovliev A, Joshi PK, Mills NL, Porteous DJ, Ramachandran P, Semple RK, Shaw CA, Sudlow CLW, Timmers PRHJ, Wilson JF, Wigmore SJ, Spiliopoulou A, Harrison EM. Genome-wide analysis identifies gallstone-susceptibility loci including genes regulating gastrointestinal motility. Hepatology 2022; 75:1081-1094. [PMID: 34651315 DOI: 10.1002/hep.32199] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment. APPROACH AND RESULTS We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (p < 5 × 10-8 ), of which 46 were new. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism, and gastrointestinal motility. Anoctamin 1 (ANO1) and transmembrane Protein 147 (TMEM147), both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression, suggesting that the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared with the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes, and C-reactive protein concentrations, and decreased lipoprotein cholesterol concentrations. CONCLUSIONS This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.
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Affiliation(s)
- Cameron J Fairfield
- Center for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Thomas M Drake
- Center for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Riinu Pius
- Center for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Andrew D Bretherick
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Archie Campbell
- Center for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
- Center for Genomic and Experimental MedicineInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Health Data Research UKUniversity of EdinburghEdinburghScotland
| | - David W Clark
- Center for Global Health ResearchUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Jonathan A Fallowfield
- Centre for Inflammation ResearchQueen's Medical Research InstituteUniversity of EdinburghEdinburghScotland
| | - Caroline Hayward
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Neil C Henderson
- Centre for Inflammation ResearchQueen's Medical Research InstituteUniversity of EdinburghEdinburghScotland
| | - Andrii Iakovliev
- Center for Population Health SciencesUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Peter K Joshi
- Center for Global Health ResearchUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Nicholas L Mills
- Center for Cardiovascular ScienceQueen's Medical Research InstituteUniversity of EdinburghEdinburghScotland
| | - David J Porteous
- Center for Genomic and Experimental MedicineInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Prakash Ramachandran
- Centre for Inflammation ResearchQueen's Medical Research InstituteUniversity of EdinburghEdinburghScotland
| | - Robert K Semple
- Center for Cardiovascular ScienceQueen's Medical Research InstituteUniversity of EdinburghEdinburghScotland
| | - Catherine A Shaw
- Center for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Cathie L W Sudlow
- Center for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Paul R H J Timmers
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Center for Global Health ResearchUsher InstituteUniversity of EdinburghEdinburghScotland
| | - James F Wilson
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Center for Global Health ResearchUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Stephen J Wigmore
- Department of Clinical SurgeryDivision of Health SciencesUniversity of EdinburghEdinburghScotland
| | - Athina Spiliopoulou
- Center for Population Health SciencesUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Ewen M Harrison
- Center for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
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25
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Association Study of SLCO1B3 and ABCC3 Genetic Variants in Gallstone Disease. Genes (Basel) 2022; 13:genes13030512. [PMID: 35328066 PMCID: PMC8951115 DOI: 10.3390/genes13030512] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 12/10/2022] Open
Abstract
There is growing evidence that gallstone formation may be genetically determined. Recent studies have shown that polymorphism of genes encoding proteins involved in bile acid transport may be associated with the risk of gallstone disease. The aim of this study was to investigate the association between SLCO1B3 (rs4149117:G>T, rs7311358:A>G) and ABCC3 (rs4793665:T>C, rs11568591:G>A) genetic variants and susceptibility to cholesterol gallstone disease, as well as gallstone composition. The study included 317 patients suffering from cholelithiasis who underwent cholecystostomy and 249 controls with no evidence of stones, confirmed by ultrasound examination. There were no statistically significant differences in the distribution of studied gene polymorphisms between patients with gallstone disease and healthy controls. No significant associations were observed between studied genotypes and the content of analyzed gallstone components: total cholesterol, bilirubin, CaCO3, nor the total bile acids. There was also no association between bile acid content in gallstones and the polymorphisms studied. The results of this study suggest that polymorphisms of SLCO1B3 and ABCC3 genes are not a valuable marker of gallstone disease susceptibility and do not influence gallstone composition.
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26
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Belabbes FZ, Benfaida A, Nawal B, El Idrissi Lamghari A, Rouibaa F. Low Phospholipid-Associated Cholelithiasis: Contribution of Imaging in Two Cases. Cureus 2022; 14:e22383. [PMID: 35371833 PMCID: PMC8935970 DOI: 10.7759/cureus.22383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2022] [Indexed: 11/14/2022] Open
Abstract
Low phospholipid-associated cholelithiasis (LPAC) is a genetic disease responsible for the development of intrahepatic lithiasis. It is retained in the presence of two of the following three criteria: age of onset of biliary symptoms less than 40 years; echogenic intrahepatic images or microlithiasis; and the recurrence of biliary clinical signs after cholecystectomy. The majority of clinical situations are simple and not serious, but some complicated forms may require more invasive endoscopic or surgical treatments. By presenting two case studies, we illustrated and summarized the different aspects of this entity.
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27
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Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer. J Pers Med 2022; 12:jpm12020234. [PMID: 35207722 PMCID: PMC8877116 DOI: 10.3390/jpm12020234] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 11/08/2021] [Accepted: 12/23/2021] [Indexed: 02/01/2023] Open
Abstract
Gallbladder cancer (GBC) is an aggressive neoplasm that in an early stage is generally asymptomatic and, in most cases, is diagnosed in advanced stages with a very low life expectancy because there is no curative treatment. Therefore, understanding the early carcinogenic mechanisms of this pathology is crucial to proposing preventive strategies for this cancer. The main risk factor is the presence of gallstones, which are associated with some environmental factors such as a sedentary lifestyle and a high-fat diet. Other risk factors such as autoimmune disorders and bacterial, parasitic and fungal infections have also been described. All these factors can generate a long-term inflammatory state characterized by the persistent activation of the immune system, the frequent release of pro-inflammatory cytokines, and the constant production of reactive oxygen species that result in a chronic damage/repair cycle, subsequently inducing the loss of the normal architecture of the gallbladder mucosa that leads to the development of GBC. This review addresses how the different risk factors could promote a chronic inflammatory state essential to the development of gallbladder carcinogenesis, which will make it possible to define some strategies such as anti-inflammatory drugs or public health proposals in the prevention of GBC.
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28
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Falcão D, Pedroto I, Moreira T. The wide phenotypic and genetic spectrum of ABCB4 gene deficiency: A case series. Dig Liver Dis 2022; 54:221-227. [PMID: 34376370 DOI: 10.1016/j.dld.2021.07.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND ABCB4-gene mutations are responsible for several cholestatic diseases with a heterogeneous clinical spectrum. AIMS To analyse phenotype/genotype relationships in ABCB4-mutations. METHODS Retrospective characterization of adult patients with ABCB4-variations diagnosed between 2015 and 2020. Genotype-phenotype correlations were analysed and compared with previously reported data. RESULTS Twenty patients from 12 families were included. Thirteen patients presented recurrent elevated liver tests, eight fulfilled Low-Phospholipid-Associated-Cholelithiasis syndrome criteria, five had Intrahepatic Cholestasis of Pregnancy and three patients developed Drug-Induced-Liver-Injury. ABCB4 screening identified eight different mutations. Five patients were homozygotes to the variant c.504T > C. Ten patients had one mutation in heterozygote-state and five patients had two mutations in compound-heterozygosity. Portal fibrosis occurred in two patients. One of these patients presented progressive fibrosis and progression of cholestasis despite ursodeoxycholic-acid treatment, this patient also harbours a ABCB11 polymorphism. CONCLUSION Although, phenotype-genotype relationships have not been clearly defined, an early diagnosis of ABCB4-variants may have an important role in management decisions and patient outcomes. To our knowledge, we describe a not previously reported deletion (c.1181delT) in ABCB4. The c.504T > C polymorphism, although a silent mutation at the protein level, seems to be associated to different cholestatic diseases. The role of other genes variants, namely ABCB11, as co-factor for progression, needs to be clarified.
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Affiliation(s)
- Daniela Falcão
- Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal.
| | - Isabel Pedroto
- Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal
| | - Teresa Moreira
- Largo do Prof. Abel Salazar, Centro Hospitalar Universitário do Porto, Praça D. Filipa de Lencastre n° 189, 2° frente, Porto 4050-189, Portugal
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29
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Han SJ, Chang JH, Gweon TG, Kim TH, Kim HK, Kim CW. Analysis of symptomatic recurrences of common bile ducts stones after endoscopic removal: Factors related to early or multiple recurrences. Medicine (Baltimore) 2022; 101:e28671. [PMID: 35060565 PMCID: PMC8772677 DOI: 10.1097/md.0000000000028671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 01/06/2022] [Indexed: 01/05/2023] Open
Abstract
Early or multiple recurrences of symptomatic common bile duct (CBD) stones are troublesome late complications after endoscopic stone removal. We aimed to determine the factors related to early or multiple recurrences of CBD stones.We retrospectively analyzed patients who underwent endoscopic CBD stone extraction in a single institute between January 2006 and December 2015. Patients were divided into 2 groups according to the number and interval of CBD stone recurrences: single versus multiple (≥2) and early (<1.5 years) versus late (≥1.5 years) recurrence.After exclusion, 78 patients were enrolled and followed up for a median of 1974 (IQR: 938-3239) days. Twenty-seven (34.6%) patients experienced multiple recurrences (≥2 times), and 26 (33.3%) patients experienced early first recurrence (<1.5 years). In the multivariate analysis, CBD angulation was independently related to multiple CBD stone recurrence (OR: 4.689, P = .016), and endoscopic papillary large balloon dilation was independently related to late first CBD stone recurrence (OR: 3.783, P = .025). The mean CBD angles were more angulated with increasing instances of recurrence (0, 1, 2, 3, and ≥4 times) with corresponding values of 150.3°, 148.2°, 143.6°, 142.2°, and 126.7°, respectively (P = .011). The period between the initial treatment and first recurrence was significantly longer than the period between the first and second recurrence (P = .048).In conclusion, greater CBD angulation is associated with the increased number of CBD stone recurrence, and EPLBD delays the recurrence of CBD stones after endoscopic CBD stone removal.
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30
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Jüngst C, Justinger C, Fischer J, Berg T, Lammert F. Common ABCB4 and ABCB11 Genotypes Are Associated with Idiopathic Chronic Cholestasis in Adults. Dig Dis 2021; 40:489-496. [PMID: 34348275 DOI: 10.1159/000518203] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 06/14/2021] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Pathogenic mutations in genes encoding the hepatocanalicular transporters ATP8B1, ABCB11 and ABCB4 are causative for progressive cholestatic liver disease in children. In adults, less severe variants such as the common ABCB4 c.711A>T polymorphism have been associated with intrahepatic cholestasis in pregnancy and elevated liver enzymes. Hence, our aim was to study the role of common polymorphisms in adult patients with chronic unexplained cholestasis. METHODS Screening of outpatients of two university hospitals identified a cohort of 94 patients with chronic cholestasis of unknown origin after thorough exclusion of other causes. Genotyping was performed using TaqMan assays, and frequencies for the ABCB4 rs2109505 (c.711A>T), rs1202283 (c.504T>C), ABCB11 rs2287622 (p.A444V) and rs497692 (c.3084A>G) variants of the study cohort were compared to a cohort of 254 healthy controls. RESULTS The dominating symptoms of the patients were pruritus and jaundice, though the majority of them did not report symptoms at inclusion. Advanced fibrosis or cirrhosis was present in 11 patients (11.7%) only. Genotyping revealed the presence of the ABCB4 c.711A>T risk variant in 79 patients (84%), a frequency that is significantly (p = 0.037) higher than that in controls (71%). The ABCB11 p.A444V variant was also more frequent in cholestatic patients (p = 0.042). CONCLUSION The common ABCB4 c.711A>T and ABCB11 p.A444V polymorphisms are more prevalent in adult patients with idiopathic cholestasis than in healthy controls and may therefore represent risk factors for the development of chronic cholestatic liver disease.
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Affiliation(s)
- Christoph Jüngst
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.,Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Christina Justinger
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Janett Fischer
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.,Hannover Medical School (MHH), Hannover, Germany
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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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32
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Wu Y, Xu CJ, Xu SF. Advances in Risk Factors for Recurrence of Common Bile Duct Stones. Int J Med Sci 2021; 18:1067-1074. [PMID: 33456365 PMCID: PMC7807200 DOI: 10.7150/ijms.52974] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 12/22/2020] [Indexed: 12/13/2022] Open
Abstract
Choledocholithiasis is a chronic common disease. The incidence of cholelithiasis is 5%-15%, of which 5%-30% are combined with Choledocholithiasis. Although endoscopic cholangiopancreatography (ERCP) + endoscopic sphincterotomy (EST) is the most common treatment procedure, which clearance rate is up to 95%, the incidence of recurrent choledocholithiasis was 4%-25%. The risk factors of recurrence after choledocholithiasis clearance are the focuses of current researches, which are caused by multiple factors. We first systematically summarize the risk factors of common bile duct stones (CBDS) recurrence into five aspects: first-episode stone related factors, congenital factors, biological factors, behavioral intervention factors, and the numbers of stone recurrence.
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Affiliation(s)
- Yao Wu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, China
| | - Chen Jing Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, China
| | - Shun Fu Xu
- Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211100, China.,Jiangsu Province Hospital, Nanjing Medical University, Nanjing, 210029, China
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33
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Dong C, Condat B, Picon-Coste M, Chrétien Y, Potier P, Noblinski B, Arrivé L, Hauuy MP, Barbu V, Maftouh A, Gaouar F, Ben Belkacem K, Housset C, Poupon R, Zanditenas D, Chazouillères O, Corpechot C. Low-phospholipid-associated cholelithiasis syndrome: Prevalence, clinical features, and comorbidities. JHEP Rep 2020; 3:100201. [PMID: 33554096 PMCID: PMC7848766 DOI: 10.1016/j.jhepr.2020.100201] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 10/18/2020] [Accepted: 10/26/2020] [Indexed: 01/02/2023] Open
Abstract
Background & Aims Low-phospholipid-associated cholelithiasis (LPAC) syndrome, a rare genetic form of intrahepatic cholelithiasis in adults, is still poorly understood. We report the results of the largest-ever case-control study of patients with LPAC syndrome aiming to assess the prevalence, clinical features, and comorbidities of the disease. Methods We included all LPAC cases diagnosed between 2001 and 2016 in 11 French centres. Controls consisted of all patients who underwent a cholecystectomy for common gallstone disease in a single non-academic centre over 1 year. A logistic regression analysis was used to identify the clinical features associated with LPAC syndrome across several patient strata with increasing levels of diagnostic confidence. The ratio between the incident cases of LPAC syndrome and the total number of cholecystectomies for gallstones was used to assess the relative prevalence of the disease. Results In this study, 308 cases and 206 controls were included. LPAC syndrome accounted for 0.5–1.9% of all patients admitted with symptomatic gallstone disease. Age at first symptoms <40 years, absence of overweight, persistence of symptoms after cholecystectomy, intrahepatic micro- or macrolithiasis, common bile duct (CBD) lithiasis, and no history of cholecystitis were independently associated with LPAC diagnosis. ATP-binding cassette subfamily B member 4 (ABCB4) variants, present in 46% of cases, were associated with CBD lithiasis, chronic elevation of gamma-glutamyltransferase (GGT), and personal or family history of hepato-biliary cancer. Conclusions In this case-control study, LPAC syndrome accounted for approximately 1% of symptomatic cholelithiasis in adults. In addition to pre-established diagnostic criteria, normal weight, CBD lithiasis, and no history of cholecystitis were significantly associated with the syndrome. ABCB4 gene variations in patients with LPAC were associated with CBD lithiasis, chronic cholestasis, and a personal or family history of hepato-biliary cancer. Lay summary In the largest case-control study ever conducted in patients with LPAC syndrome, a rare genetic form of intrahepatic cholelithiasis in young adults, LPAC syndrome was found in approximately 1% of all patients admitted to the hospital for symptomatic gallstones and, in addition to the pre-established characteristics of the syndrome (age at first symptoms <40 years, recurrence of symptoms after cholecystectomy, and/or imaging evidence of intrahepatic microlithiasis), was associated with lower BMI, higher prevalence of common bile duct stones, and lower incidence of acute cholecystitis. ABCB4 gene variants, which were detected in about half of cases, were associated with common bile duct stones and a personal or family history of hepato-biliary cancer.
Low-phospholipid-associated cholelithiasis (LPAC) syndrome affects approximately 1% of adults with symptomatic cholelithiasis. Normal weight, common bile duct stones, and lack of cholecystitis are clinical features significantly associated with this syndrome. ABCB4 variants in patients with LPAC may be associated with an increased personal or family risk of hepato-biliary cancer.
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Affiliation(s)
- Catherine Dong
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
| | - Bertrand Condat
- Division of Gastroenterology and Hepatology, French Polynesia Hospital, Pirae, French Polynesia
- Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - Magalie Picon-Coste
- Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Division of Gastroenterology and Hepatology, Aix-en-Provence Hospital, Aix-en-Provence, France
| | - Yves Chrétien
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
| | - Pascal Potier
- Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Division of Gastroenterology and Hepatology, Orléans Hospital, Orléans, France
| | - Béatrice Noblinski
- Radiology Department, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
| | - Lionel Arrivé
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Radiology Department, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
| | | | - Véronique Barbu
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Molecular Biology and Genetics Laboratory, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
| | - Anware Maftouh
- Visceral Surgery Department, Saint-Camille Hospital, Bry-sur-Marne, France
| | - Farid Gaouar
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
| | - Karima Ben Belkacem
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
| | - Chantal Housset
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
| | - Raoul Poupon
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
| | - David Zanditenas
- Association Nationale des Hépato-Gastroentérologues des Hôpitaux Généraux de France (ANGH), Montfermeil, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Division of Gastroenterology and Hepatology, Saint-Camille Hospital, Bry-sur-Marne, France
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
| | - Christophe Corpechot
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne University, Paris, France
- French National Cohort of Patients with LPAC syndrome (RaDiCo-COLPAC), RaDiCo, Inserm U933, Armand Trousseau Hospital, Paris, France
- Sorbonne University, INSERM, Centre de Recherche Saint-Antoine, Paris, France
- Corresponding author. Address: Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN RARE-LIVER, Saint-Antoine Hospital, Assistance Publique–Hôpitaux de Paris, 184 Rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France. Tel.: +33149282836, Fax: +33149282107.
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Huynh MT, Nguyen TT, Grison S, Lascols O, Fernandez E, Barbu V. Clinical characteristics and genetic profiles of young and adult patients with cholestatic liver disease. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 111:775-788. [PMID: 31538484 DOI: 10.17235/reed.2019.6168/2019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS heterozygous ABCB4, ABCB11 and ATP8B1 sequence variants were previously reported to be associated with low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis and biliary lithiasis. The present study aimed to identify the presence of sequence variations in genes responsible for Mendelian liver disorders in patients with cholestatic liver disease. METHODS targeted massive parallel sequencing of a panel of genes involved in bile acid homeostasis was performed in 105 young and adult patients with cholestatic liver disease in our laboratory for molecular diagnosis. The effects of novel variants were evaluated using bioinformatics prediction tools and the Protter and Phyre2 software programs were used to create 2D, 3D topology protein modeling. Genotype-phenotype correlation was established according to molecular analysis and clinical records. RESULTS twenty novel heterozygous ABCB4 sequence variations, one heterozygous ABCB4 large intragenic deletion and only one novel missense variant in ABCB11 and ATP8B1 were identified. Interestingly, heterozygous and homozygous SLC4A2 missense variants were detected in patients with low phospholipid-associated cholelithiasis. Two patients harbored heterozygous GPBAR1 variants. Common variants such as homozygous ABCB11 p.Val444Ala and heterozygous ABCG8 p.Asp19His were also identified in 12 cases. CONCLUSIONS forty-eight variants were identified in five genes including ABCB4, ABCB11, ATP8B1, SLC4A2 and GPBAR1, twenty-five of which were novel. This study expands the phenotypic and mutational spectrum in genes involved in bile acid homeostasis and highlights the genetic and phenotypic heterogeneity in patients with inherited liver disorders.
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Affiliation(s)
| | - Truong-Tam Nguyen
- Service de Médecine Interne, Université de Médecine Pham Ngoc Thach, Viet Nam
| | - Sophie Grison
- Hôpitaux universitaires Est Parisien, hôpital Sain, Laboratoire commun de Biologie et Génétique Moléculaires, France
| | - Olivier Lascols
- Hôpitaux universitaires Est Parisien, hôpital Sain, Laboratoire commun de Biologie et Génétique Moléculaires, France
| | - Eric Fernandez
- Hôpitaux universitaires Est Parisien, hôpital Sain, Laboratoire commun de Biologie et Génétique Moléculaires, France
| | - Véronique Barbu
- Genetics Service, Laboratoire commun de Biologie et Génétique Moléculaires, Hôpitaux universitaires Est Parisien, hôpi, France
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Stättermayer AF, Halilbasic E, Wrba F, Ferenci P, Trauner M. Variants in ABCB4 (MDR3) across the spectrum of cholestatic liver diseases in adults. J Hepatol 2020; 73:651-663. [PMID: 32376413 DOI: 10.1016/j.jhep.2020.04.036] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/18/2020] [Accepted: 04/22/2020] [Indexed: 12/14/2022]
Abstract
The ATP binding cassette subfamily B member 4 (ABCB4) gene on chromosome 7 encodes the ABCB4 protein (alias multidrug resistance protein 3 [MDR3]), a P-glycoprotein in the canalicular membrane of the hepatocytes that acts as a translocator of phospholipids into bile. Several variants in ABCB4 have been shown to cause ABCB4 deficiency, accounting for a disease spectrum ranging from progressive familial cholestasis type 3 to less severe conditions like low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy or drug-induced liver injury. Furthermore, whole genome sequencing has shown that ABCB4 variants are associated with an increased incidence of gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis or elevated liver function tests. Diagnosis of ABCB4 deficiency-related diseases is based on clinical presentation, serum biomarkers, imaging techniques, liver histology and genetic testing. Nevertheless, the clinical presentation can vary widely and clear genotype-phenotype correlations are currently lacking. Ursodeoxycholic acid is the most commonly used medical treatment, but its efficacy has yet to be proven in large controlled clinical studies. Future pharmacological options may include stimulation/restoration of residual function by chaperones (e.g. 4-phenyl butyric acid, curcumin) or induction of ABCB4 transcription by FXR (farnesoid X receptor) agonists or PPARα (peroxisome proliferator-activated receptor-α)-ligands/fibrates. Orthotopic liver transplantation remains the last and often only therapeutic option in cirrhotic patients with end-stage liver disease or patients with intractable pruritus.
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Affiliation(s)
- Albert Friedrich Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Fritz Wrba
- Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria
| | - Peter Ferenci
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Gouveia C, Flor de Lima M, Pereira F, Rosa B, Cotter J, Banhudo A, Duarte M, Ferreira A, Cravo M, Nunes J. Should patients with symptomatic cholelithiasis before 30 years of age be tested for ABCB4 gene mutations? Scand J Gastroenterol 2020; 55:958-962. [PMID: 32650689 DOI: 10.1080/00365521.2020.1790648] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/26/2020] [Accepted: 06/27/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Low phospholipid-associated cholelithiasis syndrome (LPAC) is characterized by recurrent symptomatic cholelithiasis in young adults associated with ABCB4 gene mutations. Current diagnosing criteria are complex and heterogeneous, making this a largely underdiagnosed entity. Also, although recommended, genetic testing is not necessary for the diagnosis and its real advantages are not clear. The aim of our study was to explore the prevalence of ABCB4 mutations in symptomatic patients with cholelithiasis before the age of 30. METHODS We conducted a multicentric prospective cohort study including patients with symptomatic cholelithiasis presenting before 30 years of age in 4 Portuguese centres between January 2017 and December 2019. ABCB4 gene was analyzed by next generation sequencing (NGS) including all exons and flanking regions. In 17/32 patients ABCB11 and ATP8B1 variants were also analyzed by NGS. RESULTS Thirty-two patients were included (75% females, median age of symptom onset was 23 ± 5 years). We found that 8/32 (25%) patients had mutations in ABCB4 gene, 3/17 (18%) in ATP8B1 gene and 1/17 (6%) in ABCB11 gene. 44% (8/18) of patients with LPAC syndrome criteria had identified variants, while the prevalence of mutations in patients with symptoms onset before 30 as sole criteria was 29%. CONCLUSION Our results suggest that LPAC should be systematically suspected and investigated in patients with symptomatic cholelithiasis before age of thirty, but genetic testing should only be attempted in patients complying with the more stringent LPAC criteria.
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Affiliation(s)
| | | | - Flávio Pereira
- Gastroenterology Department, Hospital Amato Lusitano, Castelo Branco
| | - Bruno Rosa
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Guimarães
- ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães
| | - José Cotter
- Gastroenterology Department, Hospital da Senhora da Oliveira, Guimarães
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Guimarães
- ICVS/3B's, PT Government Associate Laboratory, Braga, Guimarães
| | - António Banhudo
- Gastroenterology Department, Hospital Amato Lusitano, Castelo Branco
| | - Maria Duarte
- Gastroenterology Department, Hospital do Divino Espírito Santo, Ponta Delgada
| | | | - Marília Cravo
- Gastroenterology Department, Hospital Beatriz Ângelo, Loures
| | - Joana Nunes
- Gastroenterology Department, Hospital Beatriz Ângelo, Loures
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Gille N, Karila-Cohen P, Goujon G, Konstantinou D, Rekik S, Bécheur H, Pelletier AL. Low phospholipid-associated cholelithiasis syndrome: A rare cause of acute pancreatitis that should not be neglected. World J Hepatol 2020; 12:312-322. [PMID: 32742573 PMCID: PMC7364325 DOI: 10.4254/wjh.v12.i6.312] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 05/10/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Low phospholipid-associated cholelithiasis (LPAC) syndrome is a very particular form of biliary lithiasis with no excess of cholesterol secretion into bile, but a decrease in phosphatidylcholine secretion, which is responsible for stones forming not only in the gallbladder, but also in the liver. LPAC syndrome may be underreported due to a lack of testing resulting from insufficient awareness among clinicians.
AIM To describe the clinical and radiological characteristics of patients with LPAC syndrome to better identify and diagnose the disease.
METHODS We prospectively evaluated all patients aged over 18 years old who were consulted or hospitalized in two hospitals in Paris, France (Bichat University Hospital and Croix-Saint-Simon Hospital) between January 1, 2017 and August 31, 2018. All patients whose profiles led to a clinical suspicion of LPAC syndrome underwent a liver ultrasound examination performed by an experienced radiologist to confirm the diagnosis of LPAC syndrome. Twenty-four patients were selected. Data about the patients’ general characteristics, their medical history, their symptoms, and their blood tests results were collected during both their initial hospitalization and follow-up. Cytolysis and cholestasis were expressed compared to the normal values (N) of serum aspartate and alanine transaminase activities, and to the normal value of alkaline phosphatase level, respectively. The subjects were systematically reevaluated and asked about their symptoms 6 mo after inclusion in the study through an in-person medical appointment or phone call. Genetic testing was not performed systematically, but according to the decision of each physician.
RESULTS Most patients were young (median age of 37 years), male (58%), and not overweight (median body mass index was 24). Many had a personal history of acute pancreatitis (54%) or cholecystectomy (42%), and a family history of gallstones in first-degree relatives (30%). LPAC syndrome was identified primarily in patients with recurring biliary pain (88%) or after a new episode of acute pancreatitis (38%). When present, cytolysis and cholestasis were not severe (2.8N and 1.7N, respectively) and disappeared quickly. Interestingly, four patients from the same family were diagnosed with LPAC syndrome. At ultrasound examination, the most frequent findings in intrahepatic bile ducts were comet-tail artifacts (96%), microlithiasis (83%), and acoustic shadows (71%). Computed tomography scans and magnetic resonance imaging were performed on 15 and three patients, respectively, but microlithiasis was not detected. Complications of LPAC syndrome required hospitalizing 18 patients (75%) in a conventional care unit for a mean duration of 6.8 d. None of them died. Treatment with ursodeoxycholic acid (UDCA) was effective and well-tolerated in almost all patients (94%) with a rapid onset of action (3.4 wk). Twelve patients’ (67%) adherence to UDCA treatment was considered “good.” Five patients (36%) underwent cholecystectomy (three of them were treated both by UDCA and cholecystectomy). Despite UDCA efficacy, biliary pain recurred in five patients (28%), three of whom adhered well to treatment guidelines.
CONCLUSION LPAC syndrome is easy to diagnose and treat; therefore, it should no longer be overlooked. To increase its detection rate, all patients who experience recurrent biliary symptoms following an episode of acute pancreatitis should undergo an ultrasound examination performed by a radiologist with knowledge of the disease.
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Affiliation(s)
- Nicolas Gille
- Department of Hepato-Gastroenterology and Digestive Oncology, AP-HP Bichat University Hospital, Paris 75018, France
| | | | - Gaël Goujon
- Department of Hepato-Gastroenterology and Digestive Oncology, AP-HP Bichat University Hospital, Paris 75018, France
| | - Dimitrios Konstantinou
- Department of Hepato-Gastroenterology and Digestive Oncology, AP-HP Bichat University Hospital, Paris 75018, France
| | - Samia Rekik
- Department of Hepato-Gastroenterology and Digestive Oncology, AP-HP Bichat University Hospital, Paris 75018, France
| | - Hakim Bécheur
- Department of Hepato-Gastroenterology and Digestive Oncology, AP-HP Bichat University Hospital, Paris 75018, France
| | - Anne-Laure Pelletier
- Department of Hepato-Gastroenterology and Digestive Oncology, AP-HP Bichat University Hospital, Paris 75018, France
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Wang HH, Liu M, Portincasa P, Wang DQH. Recent Advances in the Critical Role of the Sterol Efflux Transporters ABCG5/G8 in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1276:105-136. [PMID: 32705597 PMCID: PMC8118135 DOI: 10.1007/978-981-15-6082-8_8] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cardiovascular disease is characterized by lipid accumulation, inflammatory response, cell death, and fibrosis in the arterial wall and is the leading cause of morbidity and mortality worldwide. Cholesterol gallstone disease is caused by complex genetic and environmental factors and is one of the most prevalent and costly digestive diseases in the USA and Europe. Although sitosterolemia is a rare inherited lipid storage disease, its genetic studies led to identification of the sterol efflux transporters ABCG5/G8 that are located on chromosome 2p21 in humans and chromosome 17 in mice. Human and animal studies have clearly demonstrated that ABCG5/G8 play a critical role in regulating hepatic secretion and intestinal absorption of cholesterol and plant sterols. Sitosterolemia is caused by a mutation in either the ABCG5 or the ABCG8 gene alone, but not in both simultaneously. Polymorphisms in the ABCG5/G8 genes are associated with abnormal plasma cholesterol metabolism and may play a key role in the genetic determination of plasma cholesterol concentrations. Moreover, ABCG5/G8 is a new gallstone gene, LITH9. Gallstone-associated variants in ABCG5/G8 are involved in the pathogenesis of cholesterol gallstones in European, Asian, and South American populations. In this chapter, we summarize the latest advances in the critical role of the sterol efflux transporters ABCG5/G8 in regulating hepatic secretion of biliary cholesterol, intestinal absorption of cholesterol and plant sterols, the classical reverse cholesterol transport, and the newly established transintestinal cholesterol excretion, as well as in the pathogenesis and pathophysiology of ABCG5/G8-related metabolic diseases such as sitosterolemia, cardiovascular disease, and cholesterol gallstone disease.
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Affiliation(s)
- Helen H Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri", University of Bari Medical School, Bari, Italy
| | - David Q-H Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY, USA.
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Huang YH. Response. VIDEOGIE : AN OFFICIAL VIDEO JOURNAL OF THE AMERICAN SOCIETY FOR GASTROINTESTINAL ENDOSCOPY 2019; 4:494. [PMID: 31709340 PMCID: PMC6831907 DOI: 10.1016/j.vgie.2019.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Miranda-Bautista J, Suárez-González J, Andrés-Zayas C, Buño I, Bañares R. Familial low phospholipid-associated cholelithiasis resulting from an autosomal dominant ABCB4 mutation. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2019; 111:806-808. [PMID: 31538486 DOI: 10.17235/reed.2019.6334/2019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Low phospholipid-associated cholelithiasis (LPAC) syndrome is characterized by early intrahepatic and symptomatic gallstones leading to cholangitis, acute pancreatitis and biliary colic. It has been associated with loss of function variants in the ABCB4 gene. ABCB4 encodes for a phospholipid translocator at the canalicular membrane of the hepatocyte, which "flops" phosphatidylcholine into bile. The autosomal recessive form is the most common, although autosomal dominant forms have also been described. We report the first family with autosomal dominant LPAC syndrome due to heterozygosity of the loss of function mutation c.2932T>C in ABCB4, identified by targeted next generation sequencing.
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Affiliation(s)
| | | | | | - Ismael Buño
- Hematología, Hospital General Universitario Gregorio Marañón
| | - Rafael Bañares
- Aparato Digestivo, Hospital General Universitario Gregorio Marañón, España
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Khabou B, Trigui A, Boudawara TS, Keskes L, Kamoun H, Barbu V, Fakhfakh F. A homozygous ABCB4 mutation causing an LPAC syndrome evolves into cholangiocarcinoma. Clin Chim Acta 2019; 495:598-605. [PMID: 31181191 DOI: 10.1016/j.cca.2019.06.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/16/2019] [Accepted: 06/06/2019] [Indexed: 02/08/2023]
Abstract
Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. In the present study, we reported a case of a 63-year-old woman, who presented a biliary pain beginning at the age of 30, recurrent after cholecystectomy, along with "comet-tail shadows" revealed by ultrasonography thus, fulfilling the diagnosis of LPAC. This disease evolved into a cholangiocarcinoma. To understand the molecular basis of this phenotype, we performed the ABCB4 gene sequencing, followed by in silico analysis and Q-RT-PCR assay. The results displayed a homozygous missense sequence variation (c.140G > A, p.Arg47Gln), predicted as pathogenic according to MutPred. Accordingly, this gave rise to a decreased hepatic ABCB4 mRNA level and structural alterations of the mutated protein. Eventually, we reported, here, the first description of an ABCB4 missense mutation (p.Arg47Gln) at homozygous state in a Tunisian LPAC syndrome. An elucidation of its functional consequences was performed. Besides, this case suggests that the delayed diagnosis of LPAC syndrome and the lack of UDCA treatment may contribute in the development of complications, such as cholangiocarcinoma.
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Affiliation(s)
- Boudour Khabou
- Laboratory of Molecular and Functional Genetics, Faculty of Science, University of Sfax, Tunisia.
| | - Ayman Trigui
- Department of General Surgery, Habib Bourguiba Hospital, 3027 Sfax, Tunisia
| | | | - Leila Keskes
- Laboratory of Molecular and Human Genetics, Faculty of Medecine, University of Sfax, Tunisia
| | - Hassen Kamoun
- Laboratory of Molecular and Human Genetics, Faculty of Medecine, University of Sfax, Tunisia
| | - Véronique Barbu
- Sorbonne University Medical School, APHP, St Antoine Hospital, Medical Biology and Pathology Department, LCBGM, 75012 Paris, France
| | - Faiza Fakhfakh
- Laboratory of Molecular and Functional Genetics, Faculty of Science, University of Sfax, Tunisia
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Ishizawa T, Makino N, Kakizaki Y, Ando Y, Matsuda A, Kobayashi T, Ikeda C, Sugahara S, Tsunoda M, Sato H, Murakami R, Ueno Y. A novel pathogenic variant of ATP-binding cassette subfamily B member 4 causing gallstones in a young adult. Clin J Gastroenterol 2019; 12:637-641. [DOI: 10.1007/s12328-019-00991-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 04/27/2019] [Indexed: 12/12/2022]
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Braconi C, Roessler S, Kruk B, Lammert F, Krawczyk M, Andersen JB. Molecular perturbations in cholangiocarcinoma: Is it time for precision medicine? Liver Int 2019; 39 Suppl 1:32-42. [PMID: 30829432 DOI: 10.1111/liv.14085] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/26/2019] [Accepted: 02/26/2019] [Indexed: 12/11/2022]
Abstract
The complexity of cholangiocarcinoma (CCA) cellularity and the molecular perturbation mechanisms that underlie the diversity of growth patterns of this malignancy remain a clinical concern. Tumours of the biliary system display significant intrinsic chemoresistance, caused by significant stromal involvement and genome-wide tumour heterogeneity, hampering disease remission and palliation as well as promoting the metastatic behaviour. It is crucial to advance our present understanding of the risk and molecular pathogenesis of CCA. This will facilitate the delineation of patient subsets based on molecular perturbations and adjust for precision therapies.
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Affiliation(s)
- Chiara Braconi
- Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.,Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Trust, Surrey and London, UK
| | - Stephanie Roessler
- Institute of Pathology, University Hospital Heidelberg and Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Beata Kruk
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Marcin Krawczyk
- Department of General, Transplant and Liver Surgery, Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Medical University of Warsaw, Warsaw, Poland.,Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Jesper B Andersen
- Department of Health and Medical Sciences, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N, Denmark
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Goubault P, Brunel T, Rode A, Bancel B, Mohkam K, Mabrut JY. Low-Phospholipid Associated Cholelithiasis (LPAC) syndrome: A synthetic review. J Visc Surg 2019; 156:319-328. [PMID: 30922600 DOI: 10.1016/j.jviscsurg.2019.02.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Low-Phospholipid Associated Cholelithiasis (LPAC) is a genetic disease responsible for the development of intrahepatic lithiasis. It is associated with a mutation of the ABCB4 gene which codes for protein MDR3, a biliary carrier. As a nosological entity, it is defined by presence of two of the three following criteria: age less than 40 years at onset of biliary symptoms, recurrence of biliary symptoms after cholecystectomy, and intrahepatic hyperechogenic foci detected by ultrasound. While the majority of clinical forms are simple, there also exist complicated forms, involving extended intrahepatic lithiasis and its consequences: lithiasis migration, acute cholangitis, intrahepatic abscess. Chronic evolution can lead to secondary sclerosing cholangitis or secondary biliary cirrhosis. In unusual cases, degeneration into cholangiocarcinoma may occur. Treatment is built around ursodeoxycholic acid, which yields dissolution of biliary calculi. Complicated forms may call for interventional, radiological, endoscopic or surgical treatment. This synthetic review illustrates and summarizes the different aspects of this entity, from simple gallbladder lithiasis to cholangiocarcinoma, as well as secondary biliary cirrhosis requiring liver transplant, on the basis of clinical cases and the iconography of patients treated in our ward.
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Affiliation(s)
- P Goubault
- Service de chirurgie générale, digestive et transplantation hépatique et intestinale (general, digestive, liver transplant and intestinal surgery department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France.
| | - T Brunel
- Service de radiologie (radiology department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
| | - A Rode
- Service de radiologie (radiology department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
| | - B Bancel
- Service d'anatomie et de cytologie pathologiques (pathological anatomy and cytology department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
| | - K Mohkam
- Service de chirurgie générale, digestive et transplantation hépatique et intestinale (general, digestive, liver transplant and intestinal surgery department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
| | - J-Y Mabrut
- Service de chirurgie générale, digestive et transplantation hépatique et intestinale (general, digestive, liver transplant and intestinal surgery department), hôpital de la Croix Rousse, hospices civils de Lyon, 103, grande rue de la Croix-Rousse, 69317 Lyon cedex 04, France
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Abstract
PURPOSE OF REVIEW Gallstone disease is one of the most frequent diseases in gastroenterology and treatment by endoscopy and surgery causes high costs in our health-care systems. Family and twin studies have demonstrated that gallstones are, in part, genetically determined. Here we review all recent genome-wide and phenome-wide studies of gallstones in humans and provide an updated 'inventory of human lithogenic genes.' RECENT FINDINGS The largest population attributable risk is conferred by the common variant (p.D19H) of the hepatic and intestinal cholesterol transporter ABCG5/G8. A second ABC transporter, the hepatic phosphatidylcholine translocase ABCB4, increases the risk for gallstone disease, gallbladder cancer and chronic liver diseases in general, whereas the common PNPLA3 risk variant p.I148M decreases gallstone risk. SUMMARY Better understanding of the pathomechanisms of gallstone disease might help to overcome the current invasive treatment of this exceptionally prevalent and economically significant digestive disease by personalized prevention in at-risk patients.
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LPAC syndrome: An uncommon etiology of intrahepatic cholelithiasis. Presse Med 2019; 48:72-74. [DOI: 10.1016/j.lpm.2018.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 09/23/2018] [Accepted: 11/07/2018] [Indexed: 11/18/2022] Open
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47
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Wang HH, Portincasa P, Liu M, Tso P, Wang DQH. Similarities and differences between biliary sludge and microlithiasis: Their clinical and pathophysiological significances. LIVER RESEARCH (BEIJING, CHINA) 2018; 2:186-199. [PMID: 34367716 PMCID: PMC8341470 DOI: 10.1016/j.livres.2018.10.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The terms biliary sludge and cholesterol microlithiasis (hereafter referred to as microlithiasis) were originated from different diagnostic techniques and may represent different stages of cholesterol gallstone disease. Although the pathogenesis of biliary sludge and microlithiasis may be similar, microlithiasis could be preceded by biliary sludge, followed by persistent precipitation and aggregation of solid cholesterol crystals, and eventually, gallstone formation. Many clinical conditions are clearly associated with the formation of biliary sludge and microlithiasis, including total parenteral nutrition, rapid weight loss, pregnancy, organ transplantation, administration of certain medications, and a variety of acute and chronic illnesses. Numerous studies have demonstrated complete resolution of biliary sludge in approximately 40% of patients, a cyclic pattern of disappearing and reappearing in about 40%, and progression to gallstones in nearly 20%. Although only a minority of patients with ultrasonographic demonstration of biliary sludge develop gallstones, it is still a matter of controversy whether microlithiasis could eventually evolve to cholesterol gallstones. Biliary sludge and microlithiasis are asymptomatic in the vast majority of patients; however, they can cause biliary colic, acute cholecystitis, and acute pancreatitis. Biliary sludge and microlithiasis are most often diagnosed ultrasonographically and bile microscopy is considered the gold standard for their diagnosis. Specific measures to prevent the development of biliary sludge are not practical or cost-effective in the general population. Laparoscopic cholecystectomy offers the most definitive therapy on biliary sludge. Endoscopic sphincterotomy or surgical intervention is effective for microlithiasis-induced pancreatitis. Ursodeoxycholic acid can effectively prevent the recurrence of solid cholesterol crystals and significantly reduce the risk of recurrent pancreatitis.
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Affiliation(s)
- Helen H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari “Aldo Moro” Medical School, Bari, Italy
| | - Min Liu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - David Q.-H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
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Gautherot J, Claudel T, Cuperus F, Fuchs CD, Falguières T, Trauner M. Thyroid hormone receptor β1 stimulates ABCB4 to increase biliary phosphatidylcholine excretion in mice. J Lipid Res 2018; 59:1610-1619. [PMID: 29895698 PMCID: PMC6121935 DOI: 10.1194/jlr.m084145] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 06/12/2018] [Indexed: 12/15/2022] Open
Abstract
The ATP-binding cassette transporter ABCB4/MDR3 is critical for biliary phosphatidylcholine (PC) excretion at the canalicular membrane of hepatocytes. Defective ABCB4 gene expression and protein function result in various cholestatic liver and bile duct injuries. Thyroid hormone receptor (THR) is a major regulator of hepatic lipid metabolism; we explored its potential role in ABCB4 regulation. Thyroid hormone T3 stimulation to human hepatocyte models showed direct transcriptional activation of ABCB4 in a dose- and time-dependent manner. To determine whether THRβ1 (the main THR isoform of the liver) is involved in regulation, we tested THRβ1-specific agonists (e.g., GC-1, KB-141); these agonists resulted in greater stimulation than the native hormone. KB-141 activated hepatic ABCB44 expression in mice, which enhanced biliary PC secretion in vivo. We also identified THR response elements 6 kb upstream of the ABCB4 locus that were conserved in humans and mice. Thus, T3-via THRβ1 as a novel transcriptional activator regulates ABCB4 to increase ABCB4 protein levels at the canalicular membrane and promote PC secretion into bile. These findings may have important implications for understanding thyroid hormone function as a potential modifier of bile duct homeostasis and provide pharmacologic opportunities to improve liver function in hepatobiliary diseases caused by low ABCB4 expression.
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Affiliation(s)
- Julien Gautherot
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; and
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; and
| | - Frans Cuperus
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; and
| | - Claudia Daniela Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; and
| | - Thomas Falguières
- INSERM & Pierre et Marie Curie University/Paris 06, UMR_S 938, Saint-Antoine Research Center, Paris, France
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; and.
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Khabou B, Tabebi M, Siala-Sahnoun O, Mkaouar-Rebai E, Rebai A, Fakhfakh F. Potential dysfunctional effects of synonymous variants: Insights from an exhaustive in silico analysis of the ABCB4 gene. Ann Hum Genet 2018; 82:457-468. [PMID: 30079523 DOI: 10.1111/ahg.12276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/27/2018] [Accepted: 07/04/2018] [Indexed: 11/30/2022]
Abstract
The multiple drug resistance 3 (MDR3) protein is a canalicular phospholipid translocator involved in the bile secretion and encoded by the ABCB4 gene. Its deficiency is related to a large spectrum of liver diseases. Taking into account the increased evidence about the involvement of synonymous variants in inherited diseases, this study aims to explore the putative effects of silent genetic variants on the ABCB4 expression. We performed an exhaustive computational approach using ESE finder, RegRNA 2.0, MFOLD, SNPfold, and %MinMax software added to the measurement of the Relative Synonymous Codon Usage. This analysis included 216 synonymous variants distributed throughout the ABCB4 gene. Results have shown that 11 synonymous coding SNPs decrease the ESE activity, while 8 of them change the codon frequency. Besides, the c.24C>T variation, located 21 nucleotides downstream the start A (Adenine) U (Uracil) G (Glutamine) AUG causes an increase in the local stability. Moreover, the computational analysis of the 3'UTR region showed that six of the eight variants located in this region affected the Wild Type (WT) pattern of the miRNA targets sites and/or their proper display. The 26 sSNPs retained as putatively functional possessed a very low allele frequency, supporting their pathogenicity. In conclusion, the obtained results suggest that some synonymous SNPs in the ABCB4 gene, considered up to now as neutral, may be involved in the MDR3 deficiency.
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Affiliation(s)
- Boudour Khabou
- Laboratory of Molecular and Functional Genetics, Faculty of Sciences, University of Sfax, Tunisia
| | - Mouna Tabebi
- Department of clinical and experimental medicine, Faculty of health sciences, Linköping University, Sweden
| | - Olfa Siala-Sahnoun
- Laboratory of Molecular and Functional Genetics, Faculty of Sciences, University of Sfax, Tunisia
| | - Emna Mkaouar-Rebai
- Laboratory of Molecular and Functional Genetics, Faculty of Sciences, University of Sfax, Tunisia
| | - Ahmed Rebai
- Molecular and Cellular Screening Process Laboratory, Centre of Biotechnology of Sfax, Sfax, Tunisia
| | - Faiza Fakhfakh
- Laboratory of Molecular and Functional Genetics, Faculty of Sciences, University of Sfax, Tunisia
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50
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Reichert MC, Hall RA, Krawczyk M, Lammert F. Genetic determinants of cholangiopathies: Molecular and systems genetics. Biochim Biophys Acta Mol Basis Dis 2018; 1864:1484-1490. [PMID: 28757171 DOI: 10.1016/j.bbadis.2017.07.029] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 07/24/2017] [Accepted: 07/25/2017] [Indexed: 12/16/2022]
Abstract
Familial cholangiopathies are rare but potentially severe diseases. Their spectrum ranges from fairly benign conditions as, for example, benign recurrent intrahepatic cholestasis to low-phospholipid associated cholelithiasis and progressive familial intrahepatic cholestasis (PFIC). Many cholangiopathies such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) affect first the bile ducts ("ascending pathophysiology") but others, such as PFIC, start upstream in hepatocytes and cause progressive damage "descending" down the biliary tree and leading to end-stage liver disease. In recent years our understanding of cholestatic diseases has improved, since we have been able to pinpoint numerous disease-causing mutations that cause familial cholangiopathies. Accordingly, six PFIC subtypes (PFIC type 1-6) have now been defined. Given the availability of genotyping resources, these findings can be introduced in the diagnostic work-up of patients with peculiar cholestasis. In addition, functional studies have defined the pathophysiological consequences of some of the detected variants. Furthermore, ABCB4 variants do not only cause PFIC type 3 but confer an increased risk for chronic liver disease in general. In the near future these findings will serve to develop new therapeutic strategies for patients with liver diseases. Here we present the latest data on the genetic background of familial cholangiopathies and discuss their application in clinical practice for the differential diagnosis of cholestasis of unknown aetiology. As look in the future we present "system genetics" as a novel experimental tool for the study of cholangiopathies and disease-modifying genes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
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Affiliation(s)
- Matthias C Reichert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Rabea A Hall
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany; Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany; Chair of Internal Medicine II, Saarland University, Saarbrücken, Germany.
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