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Verkade HJ, Felzen A, Keitel V, Thompson R, Gonzales E, Strnad P, Kamath B, van Mil S. EASL Clinical Practice Guidelines on genetic cholestatic liver diseases. J Hepatol 2024; 81:303-325. [PMID: 38851996 DOI: 10.1016/j.jhep.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 04/05/2024] [Indexed: 06/10/2024]
Abstract
Genetic cholestatic liver diseases are caused by (often rare) mutations in a multitude of different genes. While these diseases differ in pathobiology, clinical presentation and prognosis, they do have several commonalities due to their cholestatic nature. These Clinical Practice Guidelines (CPGs) offer a general approach to genetic testing and management of cholestatic pruritus, while exploring diagnostic and treatment approaches for a subset of genetic cholestatic liver diseases in depth. An expert panel appointed by the European Association for the Study of the Liver has created recommendations regarding diagnosis and treatment, based on the best evidence currently available in the fields of paediatric and adult hepatology, as well as genetics. The management of these diseases generally takes place in a tertiary referral centre, in order to provide up-to-date approaches and expertise. These CPGs are intended to support hepatologists (for paediatric and adult patients), residents and other healthcare professionals involved in the management of these patients with concrete recommendations based on currently available evidence or, if not available, on expert opinion.
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Eiamkulbutr S, Tubjareon C, Sanpavat A, Phewplung T, Srisan N, Sintusek P. Diseases of bile duct in children. World J Gastroenterol 2024; 30:1043-1072. [PMID: 38577180 PMCID: PMC10989494 DOI: 10.3748/wjg.v30.i9.1043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/26/2023] [Accepted: 02/04/2024] [Indexed: 03/06/2024] Open
Abstract
Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common disease of the bile duct in newborns is biliary atresia, whose prognosis varies according to the age of surgical correction. Other diseases such as Alagille syndrome, inspissated bile duct syndrome, and choledochal cysts are also time-sensitive because they can cause severe liver damage due to obstruction. The majority of these diseases present with cholestatic jaundice in the newborn or infant period, which is quite difficult to differentiate regarding clinical acumen and initial investigations. Intraoperative cholangiography is potentially necessary to make an accurate diagnosis, and further treatment will be performed synchronously or planned as findings suggest. This article provides a concise review of bile duct diseases, with interesting cases.
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Affiliation(s)
- Sutha Eiamkulbutr
- Department of Pediatrics, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Chomchanat Tubjareon
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Teerasak Phewplung
- Department of Radiology, Chulalongkorn University, Bangkok 10330, Thailand
| | - Nimmita Srisan
- Department of Surgery, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Palittiya Sintusek
- Center of Excellence in Thai Pediatric Gastroenterology, Hepatology and Immunology, Division of Gastroenterology, Department of Pediatrics, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand
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Hassan IE, Okudo G, Hajinicolaou C. Presentation and outcome of Alagille syndrome in paediatric patients at State Academic Hospital in South Africa. Sudan J Paediatr 2024; 24:133-140. [PMID: 39867274 PMCID: PMC11757690 DOI: 10.24911/sjp.106-1720958990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 12/23/2024] [Indexed: 01/28/2025]
Abstract
Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder in which patients may have characteristic facial features and involvement of the liver, heart, vessels, bones, eyes, kidneys and central nervous system. As there is little published data on ALGS in Africa, our aim was to describe the presentation and outcomes of ALGS in South Africa. The study constitutes a retrospective analysis of 25 patient medical records diagnosed as ALGS at Chris Hani Baragwanath Academic Hospital Pediatric Gastroenterology clinic between January 1992 and January 2020. Twenty-five patients met the diagnostic criteria for ALGS over the period investigated. Eighteen (72%) patients were less than 1 year old at first presentation. Seven patients (28%) had all five main clinical manifestations of ALGS, and the rest had an equal proportion of four and three main clinical manifestations. Cholestasis, one of the main clinical manifestations, was present in 72%; 80.0% had the typical Alagille facial features; 64% had cardiovascular disease, 36% had ocular abnormalities and 40% had skeletal abnormalities. Of the 16 patients, (64%) who presented with cardiovascular disease, seven patients presented with more than one cardiac lesion. As of January 2020, 8 (32%) patients are still being followed up at the pediatric GIT clinic, 13 (52%) patients were lost to follow-up and four patients (16%) were demised. Low- to middle-income countries, with no readily available access to genetic testing, need to rely on diagnostic criteria to make a diagnosis of Alagille syndrome in infants who present with cholestasis.
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Affiliation(s)
- Ibrahim E. Hassan
- Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital, University of Witwatersrand, Johannesburg, South Africa
| | - Grace Okudo
- Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital, University of Witwatersrand, Johannesburg, South Africa
| | - Christina Hajinicolaou
- Department of Paediatrics and Child Health, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital, University of Witwatersrand, Johannesburg, South Africa
- Divisional Head Paediatric Gastroenterology, Department of Paediatrics and Child Health, University of Witwatersrand, Johannesburg, South Africa
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Sokol RJ, Gonzales EM, Kamath BM, Baker A, Vig P, Mogul DB, Garner W, Hansen BE, Jacquemin E, Thompson RJ. Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor. Hepatology 2023; 78:1698-1710. [PMID: 37278241 PMCID: PMC10653287 DOI: 10.1097/hep.0000000000000502] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 05/14/2023] [Indexed: 06/07/2023]
Abstract
BACKGROUND AND AIMS Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor. APPROACH AND RESULTS We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids. Harrell's concordance statistic assessed goodness-of-fit, and then, Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met the criteria of receiving MRX for ≥48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival improved with a clinically meaningful >1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival. CONCLUSIONS Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.
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Affiliation(s)
- Ronald J. Sokol
- Section of Pediatric Gastroenterology, Hepatology and Nutrition and the Digestive Health Institute, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Emmanuel M. Gonzales
- Department of Pediatric Hepatology and Liver Transplantation, National reference center for biliary atresia and genetic cholestasis (AVB-CG), FSMR FILFOIE, ERN RARE-LIVER, AP-HP, Université Paris-Saclay, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- Department of Pediatric Hepatology and Liver Transplantation, Inserm UMR_S 1193, Université Paris-Saclay, FHU Hepatinov, Orsay, France
| | - Binita M. Kamath
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
| | - Alastair Baker
- Pediatric Liver Department, Pediatric Liver Centre, King’s College Hospital, London, UK
| | - Pamela Vig
- Department of Scientific and Medical Affairs, Mirum Pharmaceuticals Inc., Foster City, California, USA
| | - Douglas B. Mogul
- Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
| | - Will Garner
- Department of Scientific and Medical Affairs, Mirum Pharmaceuticals Inc., Foster City, California, USA
| | | | - Emmanuel Jacquemin
- Department of Pediatric Hepatology and Liver Transplantation, National reference center for biliary atresia and genetic cholestasis (AVB-CG), FSMR FILFOIE, ERN RARE-LIVER, AP-HP, Université Paris-Saclay, Bicêtre Hospital, Le Kremlin-Bicêtre, France
- Department of Pediatric Hepatology and Liver Transplantation, Inserm UMR_S 1193, Université Paris-Saclay, FHU Hepatinov, Orsay, France
| | - Richard J. Thompson
- Department of Inflammation Biology, Institute of Liver Studies, King’s College London, London, UK
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Arora A, George M. The Curious Case of Alagille Syndrome: A Case Report With NANDA-I Classification, NIC, and NOC Linkage to the Patient Care Plan. Gastroenterol Nurs 2023; 46:436-444. [PMID: 37581873 DOI: 10.1097/sga.0000000000000755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 05/01/2023] [Indexed: 08/16/2023] Open
Abstract
Alagille syndrome is a rare and complex pleiotropic multisystem disorder caused by an autosomal dominant genetic mutation of JAG1 (90%) and NOTCH2 (1%-2%) genes located on the short arm of chromosome 20. This case is reported as per the CA se RE ports (CARE) guidelines (2013). A 14-year-old boy who is a known case of chronic cholestatic liver disease of neonatal onset, was diagnosed with Alagille syndrome as evident from a NOTCH 2 mutation in genetic analysis and paucity of intrahepatic bile ducts on biopsy. He presented with portal hypertension, growth failure, and persistent hyperbilirubinemia. This case highlights the gamut of multisystem dysfunctions faced by this child. He is currently on conservative management and worked up for liver transplantation. The condition is often rare and challenging due to the multisystem pathogenesis. Thus, the nursing care is also multifaceted. This case study identified relevant North American Nursing Diagnosis Association (NANDA) Classification, Nursing Interventions Classification (NIC), and Nursing Outcomes Classification (NOC) concepts to describe care of children with Alagille syndrome based on actual patient data.
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Affiliation(s)
- Anjali Arora
- Anjali Arora, MSc(N), is Masters Student from College of Nursing, Institute of Liver and Biliary Sciences, New Delhi, India
- Mini George, PhD, is Principal, College of Nursing, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Mini George
- Anjali Arora, MSc(N), is Masters Student from College of Nursing, Institute of Liver and Biliary Sciences, New Delhi, India
- Mini George, PhD, is Principal, College of Nursing, Institute of Liver and Biliary Sciences, New Delhi, India
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Niknejad N, Fox D, Burwinkel JL, Zarrin-Khameh N, Cho S, Soriano A, Cast AE, Lopez MF, Huppert KA, Rigo F, Huppert SS, Jafar-Nejad P, Jafar-Nejad H. ASO silencing of a glycosyltransferase, Poglut1 , improves the liver phenotypes in mouse models of Alagille syndrome. Hepatology 2023; 78:1337-1351. [PMID: 37021797 PMCID: PMC10558624 DOI: 10.1097/hep.0000000000000380] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 03/13/2023] [Indexed: 04/07/2023]
Abstract
BACKGROUND AND AIMS Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome (ALGS), which is a genetic disease primarily caused by mutations in jagged 1 ( JAG1) , BD paucity often results in severe cholestasis and liver damage. However, no mechanism-based therapy exists to restore the biliary system in ALGS or other diseases associated with BD paucity. Based on previous genetic observations, we investigated whether postnatal knockdown of the glycosyltransferase gene protein O -glucosyltransferase 1 ( Poglut1) can improve the ALGS liver phenotypes in several mouse models generated by removing one copy of Jag1 in the germline with or without reducing the gene dosage of sex-determining region Y-box 9 in the liver. APPROACH AND RESULTS Using an ASO established in this study, we show that reducing Poglut1 levels in postnatal livers of ALGS mouse models with moderate to profound biliary abnormalities can significantly improve BD development and biliary tree formation. Importantly, ASO injections prevent liver damage in these models without adverse effects. Furthermore, ASO-mediated Poglut1 knockdown improves biliary tree formation in a different mouse model with no Jag1 mutations. Cell-based signaling assays indicate that reducing POGLUT1 levels or mutating POGLUT1 modification sites on JAG1 increases JAG1 protein level and JAG1-mediated signaling, suggesting a likely mechanism for the observed in vivo rescue. CONCLUSIONS Our preclinical studies establish ASO-mediated POGLUT1 knockdown as a potential therapeutic strategy for ALGS liver disease and possibly other diseases associated with BD paucity.
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Affiliation(s)
- Nima Niknejad
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Duncan Fox
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
- Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, TX
| | - Jennifer L. Burwinkel
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Neda Zarrin-Khameh
- Department of Pathology & Immunology, Baylor College of Medicine and Ben Taub Hospital, Houston, TX
| | - Soomin Cho
- Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX
| | | | - Ashley E. Cast
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Mario F. Lopez
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Kari A. Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | | | - Stacey S. Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | | | - Hamed Jafar-Nejad
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
- Genetics & Genomics Graduate Program, Baylor College of Medicine, Houston, TX
- Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX
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Wang MX, Han J, Liu T, Wang RX, Li LT, Li ZD, Yang JC, Liu LL, Lu Y, Xie XB, Gong JY, Li SY, Zhang L, Ling V, Wang JS. Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome. World J Pediatr 2023; 19:652-662. [PMID: 36658452 DOI: 10.1007/s12519-022-00676-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 12/14/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers. METHODS Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 μmol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≥ 85.5 μmol/L at the last follow-up. RESULTS We found that the concentrations of two poly-hydroxylated bile acids, tauro-2β,3α,7α,12α-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco- chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro-2β,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662-63.753), P = 0.002]. CONCLUSIONS We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes.
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Affiliation(s)
- Meng-Xuan Wang
- Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, 201508, China
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Jun Han
- University of Victoria-Genome BC Proteomics Centre and Division of Medical Sciences, Victoria, British Columbia, Canada
| | - Teng Liu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Ren-Xue Wang
- BC Cancer Research Centre, Vancouver, British Columbia, Canada
| | - Li-Ting Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Zhong-Die Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Jun-Cong Yang
- University of Victoria-Genome BC Proteomics Centre and Division of Medical Sciences, Victoria, British Columbia, Canada
| | - Lang-Li Liu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Yi Lu
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Xin-Bao Xie
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Jing-Yu Gong
- Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, 201508, China
| | - Shi-Yu Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China
| | - Lei Zhang
- Institutes of Biomedical Sciences, Fudan University, Shanghai, 201199, China
| | - Victor Ling
- BC Cancer Research Centre, Vancouver, British Columbia, Canada
| | - Jian-She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, 201102, China.
- Shanghai Key Laboratory of Birth Defect, Shanghai, 201102, China.
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Vandriel SM, Li L, She H, Wang J, Gilbert MA, Jankowska I, Czubkowski P, Gliwicz‐Miedzińska D, Gonzales EM, Jacquemin E, Bouligand J, Spinner NB, Loomes KM, Piccoli DA, D'Antiga L, Nicastro E, Sokal É, Demaret T, Ebel NH, Feinstein JA, Fawaz R, Nastasio S, Lacaille F, Debray D, Arnell H, Fischler B, Siew S, Stormon M, Karpen SJ, Romero R, Kim KM, Baek WY, Hardikar W, Shankar S, Roberts AJ, Evans HM, Jensen MK, Kavan M, Sundaram SS, Chaidez A, Karthikeyan P, Sanchez MC, Cavalieri ML, Verkade HJ, Lee WS, Squires JE, Hajinicolaou C, Lertudomphonwanit C, Fischer RT, Larson‐Nath C, Mozer‐Glassberg Y, Arikan C, Lin HC, Bernabeu JQ, Alam S, Kelly DA, Carvalho E, Ferreira CT, Indolfi G, Quiros‐Tejeira RE, Bulut P, Calvo PL, Önal Z, Valentino PL, Desai DM, Eshun J, Rogalidou M, Dezsőfi A, Wiecek S, Nebbia G, Pinto RB, Wolters VM, Tamara ML, Zizzo AN, Garcia J, Schwarz K, Beretta M, Sandahl TD, Jimenez‐Rivera C, Kerkar N, Brecelj J, Mujawar Q, Rock N, Busoms CM, Karnsakul W, Lurz E, Santos‐Silva E, Blondet N, Bujanda L, Shah U, Thompson RJ, Hansen BE, Kamath BM. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study. Hepatology 2023; 77:512-529. [PMID: 36036223 PMCID: PMC9869940 DOI: 10.1002/hep.32761] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND AND AIMS Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.
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Affiliation(s)
- Shannon M. Vandriel
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
| | - Li‐Ting Li
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Huiyu She
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Jian‐She Wang
- The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Melissa A. Gilbert
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Irena Jankowska
- Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Dorota Gliwicz‐Miedzińska
- Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
| | - Emmanuel M. Gonzales
- Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Bicêtre Hospital, AP‐HP and Inserm U1193, Hepatinov, Université Paris‐Saclay, Le Kremlin‐Bicêtre, France
| | - Emmanuel Jacquemin
- Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Bicêtre Hospital, AP‐HP and Inserm U1193, Hepatinov, Université Paris‐Saclay, Le Kremlin‐Bicêtre, France
| | - Jérôme Bouligand
- Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Hôpitaux Universitaires Paris‐Saclay, Assistance Publique‐Hôpitaux de Paris, Centre Hospitalier Universitaire de Bicêtre, Le Kremlin‐Bicêtre, France
| | - Nancy B. Spinner
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Kathleen M. Loomes
- Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - David A. Piccoli
- Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Lorenzo D'Antiga
- Pediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Emanuele Nicastro
- Pediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Étienne Sokal
- Service De Gastroentérologie & Hépatologie Pédiatrique, Cliniques Universitaires Saint‐Luc, Brussels, Belgium
| | - Tanguy Demaret
- Service De Gastroentérologie & Hépatologie Pédiatrique, Cliniques Universitaires Saint‐Luc, Brussels, Belgium
| | - Noelle H. Ebel
- Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA
| | - Jeffrey A. Feinstein
- Department of Pediatrics (Cardiology), Stanford University School of Medicine, Lucile Packard Children's Hospital, Palo Alto, California, USA
| | - Rima Fawaz
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Silvia Nastasio
- Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Florence Lacaille
- Department of Pediatric Gastroenterology, and Nutrition, Necker‐Enfants Malades Hospital, University of Paris, Paris, France
| | - Dominique Debray
- Pediatric Liver Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Necker‐Enfants Malades Hospital, University of Paris, Paris, France
| | - Henrik Arnell
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Björn Fischler
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
- CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Susan Siew
- Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, Australia
| | - Michael Stormon
- Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, Australia
| | - Saul J. Karpen
- Division of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Healthcare of Atlanta & Emory University School of Medicine, Atlanta, Georgia, USA
| | - Rene Romero
- Division of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Healthcare of Atlanta & Emory University School of Medicine, Atlanta, Georgia, USA
| | - Kyung Mo Kim
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Republic of Korea
| | - Woo Yim Baek
- Department of Pediatrics, University of Ulsan College of Medicine, Asan Medical Center Children's Hospital, Seoul, Republic of Korea
| | - Winita Hardikar
- Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Australia
| | - Sahana Shankar
- Mazumdar Shaw Medical Center, Narayana Health, Bangalore, India
| | - Amin J. Roberts
- Department of Paediatric Gastroenterology, Starship Child Health, Auckland, New Zealand
| | - Helen M. Evans
- Department of Paediatric Gastroenterology, Starship Child Health, Auckland, New Zealand
| | - M. Kyle Jensen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, Utah, USA
| | - Marianne Kavan
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Utah, Salt Lake City, Utah, USA
| | - Shikha S. Sundaram
- Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital of Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alexander Chaidez
- Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital of Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA
| | | | - Maria Camila Sanchez
- Pediatric Gastroenterology and Hepatology Division, Hospital Italiano Buenos Aires, Buenos Aires, Argentina
| | - Maria Lorena Cavalieri
- Pediatric Gastroenterology and Hepatology Division, Hospital Italiano Buenos Aires, Buenos Aires, Argentina
| | - Henkjan J. Verkade
- Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands
| | - Way Seah Lee
- Faculty of Medicine, Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia
| | - James E. Squires
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Christina Hajinicolaou
- Division of Paediatric Gastroenterology, Department of Paediatrics and Child Health, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa
| | - Chatmanee Lertudomphonwanit
- Division of Gastroenterology, Department of Pediatrics, Ramathibodi Hospital Mahidol University, Bangkok, Thailand
| | - Ryan T. Fischer
- Department of Gastroenterology, Section of Hepatology, Children's Mercy Kansas City, Kansas City, Missouri, USA
| | - Catherine Larson‐Nath
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | - Yael Mozer‐Glassberg
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Cigdem Arikan
- Department of Pediatric Gastroenterology and Organ Transplant, Koc University School of Medicine, Istanbul, Turkey
| | - Henry C. Lin
- Division of Pediatric Gastroenterology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA
| | - Jesus Quintero Bernabeu
- Pediatric Hepatology and Liver Transplant Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Seema Alam
- Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Deirdre A. Kelly
- Liver Unit, Birmingham Women's & Children's Hospital NHS Trust, University of Birmingham, Birmingham, UK
| | - Elisa Carvalho
- Pediatric Gastroenterology Department, Hospital da Criança de Brasília, Centro Universitário de Brasília, Brasília, Brazil
| | - Cristina Targa Ferreira
- Pediatric Gastroenterology Service, Hospital da Criança Santo Antôni, Universidade Federal de Ciências da Saúde de Porto Alegre, Complexo Hospitalar Santa Casa, Porto Alegre, RS, Brazil
| | - Giuseppe Indolfi
- Paediatric and Liver Unit, Department Neurofarba, University of Florence and Meyer Children's University Hospital, Florence, Italy
| | - Ruben E. Quiros‐Tejeira
- Department of Pediatrics, Children's Hospital & Medical Center and University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Pinar Bulut
- Division of Pediatric Gastroenterology and Hepatology, Phoenix Children's Hospital, Phoenix, USA
| | - Pier Luigi Calvo
- Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera‐Universitaria Citta' della Salute e della Scienza, Turin, Italy
| | - Zerrin Önal
- Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
| | - Pamela L. Valentino
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Dev M. Desai
- Solid Organ Transplant Department, Children's Health – Children's Medical Center, Dallas, Texas, USA
| | - John Eshun
- Department of Pediatric Gastroenterology, Le Bonheur Children's Hospital, The University of Tennessee Health Science Center, Memphis, Texas, USA
| | - Maria Rogalidou
- Division of Gastroenterology & Hepatology, First Department of Pediatrics, “Agia Sofia” Children's Hospital, University of Athens, Athens, Greece
| | - Antal Dezsőfi
- First Department of Paediatrics, Semmelweis University, Budapest, Hungary
| | - Sabina Wiecek
- Department of Pediatrics, Medical University of Silesia in Katowice, Katowice, Poland
| | - Gabriella Nebbia
- Servizio di Epatologia Pediatrica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Raquel Borges Pinto
- Division of Pediatric Gastroenterology of Hospital da Criança Conceição do Grupo Hospitalar Conceição, Porto Alegre, RS, Brazil
| | - Victorien M. Wolters
- Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Andréanne N. Zizzo
- Division of Paediatric Gastroenterology and Hepatology, London Health Sciences Centre, Children's Hospital, Western University, London, Ontario, Canada
| | - Jennifer Garcia
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Miami Transplant Institute, University of Miami, Miami, Florida, USA
| | - Kathleen Schwarz
- Division of Pediatric Gastroenterology, University of California San Diego, Rady Children's Hospital San Diego, San Diego, California, USA
| | - Marisa Beretta
- Faculty of Health Sciences, Wits Donald Gordon Medical Centre, University of the Witwatersrand, Johannesburg, South Africa
| | | | - Carolina Jimenez‐Rivera
- Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Nanda Kerkar
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA
| | - Jernej Brecelj
- Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Faculty of Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia
| | - Quais Mujawar
- Section of Pediatric Gastroenterology, Department of Pediatrics, University of Manitoba, Winnipeg, Canada
| | - Nathalie Rock
- Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals, University of Geneva, Geneva, Switzerland
| | - Cristina Molera Busoms
- Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain
| | - Wikrom Karnsakul
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Eberhard Lurz
- Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Ermelinda Santos‐Silva
- Pediatric Gastroenterology Unit, Centro Hospitalar Universitário Do Porto, Porto, Portugal
| | - Niviann Blondet
- Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, Washington, USA
| | - Luis Bujanda
- Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute, Donostia University Hospital, Universidad del País Vasco (UPV/EHU), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), San Sebastián, Spain
| | - Uzma Shah
- Harvard Medical School, Massachusetts General Hospital for Children, Boston, Massachusetts, USA
| | | | - Bettina E. Hansen
- Toronto General Hospital University Health Network, Toronto, Ontario, Canada
- Institute of Health Policy, Management and Evaluation, Toronto, Ontario, Canada
| | - Binita M. Kamath
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada
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9
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Zhao C, Matalonga J, Lancman JJ, Liu L, Xiao C, Kumar S, Gates KP, He J, Graves A, Huisken J, Azuma M, Lu Z, Chen C, Ding BS, Dong PDS. Regenerative failure of intrahepatic biliary cells in Alagille syndrome rescued by elevated Jagged/Notch/Sox9 signaling. Proc Natl Acad Sci U S A 2022; 119:e2201097119. [PMID: 36469766 PMCID: PMC9897440 DOI: 10.1073/pnas.2201097119] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 10/21/2022] [Indexed: 12/08/2022] Open
Abstract
Despite the robust healing capacity of the liver, regenerative failure underlies numerous hepatic diseases, including the JAG1 haploinsufficient disorder, Alagille syndrome (ALGS). Cholestasis due to intrahepatic duct (IHD) paucity resolves in certain ALGS cases but fails in most with no clear mechanisms or therapeutic interventions. We find that modulating jag1b and jag2b allele dosage is sufficient to stratify these distinct outcomes, which can be either exacerbated or rescued with genetic manipulation of Notch signaling, demonstrating that perturbations of Jag/Notch signaling may be causal for the spectrum of ALGS liver severities. Although regenerating IHD cells proliferate, they remain clustered in mutants that fail to recover due to a blunted elevation of Notch signaling in the distal-most IHD cells. Increased Notch signaling is required for regenerating IHD cells to branch and segregate into the peripheral region of the growing liver, where biliary paucity is commonly observed in ALGS. Mosaic loss- and-gain-of-function analysis reveals Sox9b to be a key Notch transcriptional effector required cell autonomously to regulate these cellular dynamics during IHD regeneration. Treatment with a small-molecule putative Notch agonist stimulates Sox9 expression in ALGS patient fibroblasts and enhances hepatic sox9b expression, rescues IHD paucity and cholestasis, and increases survival in zebrafish mutants, thereby providing a proof-of-concept therapeutic avenue for this disorder.
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Affiliation(s)
- Chengjian Zhao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041People’s Republic of China
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA92037
| | - Jonathan Matalonga
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA92037
| | - Joseph J. Lancman
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA92037
| | - Lu Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041People’s Republic of China
| | - Chaoxin Xiao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041People’s Republic of China
| | - Shiv Kumar
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA92037
| | - Keith P. Gates
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA92037
| | - Jiaye He
- Morgridge Institute for Research, Madison, WI53715
| | | | - Jan Huisken
- Morgridge Institute for Research, Madison, WI53715
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, WI53706
| | - Mizuki Azuma
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS66045
| | - Zhenghao Lu
- Chengdu Organoidmed Medical Laboratory Ltd., Sichuan, 610041People’s Republic of China
| | - Chong Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041People’s Republic of China
| | - Bi-Sen Ding
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, 610041People’s Republic of China
| | - P. Duc Si Dong
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA92037
- Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA92037
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10
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Chiang C, Jeng Y, Ho M, Lai M, Li H, Chen P, Lee N, Wu J, Chiu Y, Liou B, Ni Y, Hsu H, Chang M, Chen H. Different clinical and genetic features of Alagille patients with progressive disease versus a jaundice-free course. JGH Open 2022; 6:839-845. [PMID: 36514505 PMCID: PMC9730729 DOI: 10.1002/jgh3.12830] [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: 07/27/2022] [Revised: 09/30/2022] [Accepted: 10/08/2022] [Indexed: 12/14/2022]
Abstract
Background and Aim Alagille syndrome (ALGS) is a multisystem disorder with variable clinical courses. This study investigated the clinical and genetic features of ALGS patients with different outcomes and analyzed the liver pathology at liver transplantation (LT) compared with that in biliary atresia (BA). Methods We report the clinical characteristics, outcomes, and genetic mutations of 25 children with ALGS followed for a median of 7.3 years. Patients were classified into (i) jaundice-free (JF) group (resolving jaundice after 2 years of age); (ii) progressive disease (PD) group (persistent jaundice or progressive cholestasis). In addition, we analyzed the explant liver in 10 ALGS patients compared with 20 age-matched BA patients at the time of LT. Results Nine patients (36%) in the JF group had a favorable outcome, with longer native liver survival than patients with PD (n = 16, P < 0.001). Fourteen of the PD group patients received LT or died. We identified 18 different JAG1 mutations in 22 patients. Three unrelated probands in the JF group had the same de novo mutation in JAG1, c.2122-2125delCAGT. Compared with BA children, ALGS patients had lower METAVIR scores in liver pathology, higher serum albumin levels, and lower weight-for-age z-scores when receiving LT. Conclusion One-third of ALGS patients had JF and a favorable course. Children with ALGS presenting with persistent jaundice beyond 2 years of age should be cautioned for poor prognosis. ALGS patients tend to have a lesser extent of cirrhosis, and more growth problems than BA patients at the time of LT.
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Affiliation(s)
- Che‐Ming Chiang
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan,Department of Pediatrics, Tri‐Service General HospitalNational Defense Medical CenterTaipeiTaiwan
| | - Yung‐Ming Jeng
- Department of PathologyNational Taiwan University HospitalTaipeiTaiwan
| | - Ming‐Chih Ho
- Department of SurgeryNational Taiwan University Hospital Hsin‐Chu BranchHsinchuTaiwan
| | - Ming‐Wei Lai
- Division of Pediatric Gastroenterology, Department of Pediatrics, Liver Research Center, Chang Gung Memorial HospitalLinkou, Chang Gung University College of MedicineTaoyuanTaiwan
| | - Huei‐Ying Li
- Medical Microbiome CenterNational Taiwan University College of MedicineTaipeiTaiwan
| | - Pei‐Lung Chen
- Department of Medical GeneticsNational Taiwan University HospitalTaipeiTaiwan,Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan,Graduate Institute of Medical Genomics and ProteomicsNational Taiwan UniversityTaipeiTaiwan
| | - Ni‐Chung Lee
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan,Department of Medical GeneticsNational Taiwan University HospitalTaipeiTaiwan
| | - Jia‐Feng Wu
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan
| | - Yu‐Chun Chiu
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan
| | - Bang‐Yu Liou
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan
| | - Yen‐Hsuan Ni
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan
| | - Hong‐Yuan Hsu
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan
| | - Mei‐Hwei Chang
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan
| | - Huey‐Ling Chen
- Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan,Department of Medical Education and Bioethics, Graduate Institute of Medical Education and BioethicsNational Taiwan University College of MedicineTaipeiTaiwan
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11
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Ayoub MD, Kamath BM. Alagille Syndrome: Current Understanding of Pathogenesis, and Challenges in Diagnosis and Management. Clin Liver Dis 2022; 26:355-370. [PMID: 35868679 DOI: 10.1016/j.cld.2022.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alagille syndrome (ALGS) is a complex heterogenous disease with a wide array of clinical manifestations in association with cholestatic liver disease. Major clinical and genetic advancements have taken place since its first description in 1969. However, clinicians continue to face considerable challenges in the management of ALGS, particularly in the absence of targeted molecular therapies. In this article, we provide an overview of the broad ALGS phenotype, current approaches to diagnosis and with particular focus on key clinical challenges encountered in the management of these patients.
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Affiliation(s)
- Mohammed D Ayoub
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; Department of Pediatrics, Rabigh Branch, King Abdulaziz University, PO Box 80205, Jeddah 21589, Saudi Arabia
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada.
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12
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Zhao C, Lancman JJ, Yang Y, Gates KP, Cao D, Barske L, Matalonga J, Pan X, He J, Graves A, Huisken J, Chen C, Dong PDS. Intrahepatic cholangiocyte regeneration from an Fgf-dependent extrahepatic progenitor niche in a zebrafish model of Alagille Syndrome. Hepatology 2022; 75:567-583. [PMID: 34569629 PMCID: PMC8844142 DOI: 10.1002/hep.32173] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 09/20/2021] [Accepted: 09/22/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Alagille Syndrome (ALGS) is a congenital disorder caused by mutations in the Notch ligand gene JAGGED1, leading to neonatal loss of intrahepatic duct (IHD) cells and cholestasis. Cholestasis can resolve in certain patients with ALGS, suggesting regeneration of IHD cells. However, the mechanisms driving IHD cell regeneration following Jagged loss remains unclear. Here, we show that cholestasis due to developmental loss of IHD cells can be consistently phenocopied in zebrafish with compound jagged1b and jagged2b mutations or knockdown. APPROACH AND RESULTS Leveraging the transience of jagged knockdown in juvenile zebrafish, we find that resumption of Jagged expression leads to robust regeneration of IHD cells through a Notch-dependent mechanism. Combining multiple lineage tracing strategies with whole-liver three-dimensional imaging, we demonstrate that the extrahepatic duct (EHD) is the primary source of multipotent progenitors that contribute to the regeneration, but not to the development, of IHD cells. Hepatocyte-to-IHD cell transdifferentiation is possible but rarely detected. Progenitors in the EHD proliferate and migrate into the liver with Notch signaling loss and differentiate into IHD cells if Notch signaling increases. Tissue-specific mosaic analysis with an inducible dominant-negative Fgf receptor suggests that Fgf signaling from the surrounding mesenchymal cells maintains this extrahepatic niche by directly preventing premature differentiation and allocation of EHD progenitors to the liver. Indeed, transcriptional profiling and functional analysis of adult mouse EHD organoids uncover their distinct differentiation and proliferative potential relative to IHD organoids. CONCLUSIONS Our data show that IHD cells regenerate upon resumption of Jagged/Notch signaling, from multipotent progenitors originating from an Fgf-dependent extrahepatic stem cell niche. We posit that if Jagged/Notch signaling is augmented, through normal stochastic variation, gene therapy, or a Notch agonist, regeneration of IHD cells in patients with ALGS may be enhanced.
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Affiliation(s)
- Chengjian Zhao
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, People's Republic of China
| | - Joseph J Lancman
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Yi Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, People's Republic of China
| | - Keith P Gates
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Dan Cao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, People's Republic of China
| | - Lindsey Barske
- Department of Pediatrics, College of Medicine & Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Jonathan Matalonga
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Xiangyu Pan
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, People's Republic of China
| | - Jiaye He
- Morgridge Institute for Research, Madison, Wisconsin, USA
| | - Alyssa Graves
- Morgridge Institute for Research, Madison, Wisconsin, USA
| | - Jan Huisken
- Morgridge Institute for Research, Madison, Wisconsin, USA
- Department of Integrative Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Chong Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, People's Republic of China
| | - P Duc Si Dong
- Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
- Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
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13
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Gilbert MA, Loomes KM. Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts. Transl Gastroenterol Hepatol 2021; 6:22. [PMID: 33824926 DOI: 10.21037/tgh-2020-03] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 04/28/2020] [Indexed: 12/15/2022] Open
Abstract
The observation of bile duct paucity is an important diagnostic finding in children, occurring in roughly 11% of pediatric liver biopsies. Alagille syndrome (ALGS) is a well-defined syndromic form of intrahepatic bile duct paucity that is accompanied by a number of other key features, including cardiac, facial, ocular, and vertebral abnormalities. In the absence of these additional clinical characteristics, intrahepatic bile duct paucity results in a broad differential diagnosis that requires supplementary testing and characterization. Nearly 30 years after ALGS was first described, genetic studies identified a causative gene, JAGGED1, which spearheaded over two decades of research aimed to meticulously delineate the molecular underpinnings of ALGS. These advancements have characterized ALGS as a genetic disease and led to testing strategies that offer the ability to detect a pathogenic genetic variant in almost 97% of individuals with ALGS. Having a molecular understanding of ALGS has allowed for the development of numerous in vitro and in vivo disease models, which have provided hope and promise for the future generation of gene-based and protein-based therapies. Generation of these disease models has offered scientists a mechanism to study the dynamics of bile duct development and regeneration, and in doing so, produced tools that are applicable to the understanding of other congenital and acquired liver diseases.
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Affiliation(s)
- Melissa A Gilbert
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Kathleen M Loomes
- Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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14
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Hankeova S, Salplachta J, Zikmund T, Kavkova M, Van Hul N, Brinek A, Smekalova V, Laznovsky J, Dawit F, Jaros J, Bryja V, Lendahl U, Ellis E, Nemeth A, Fischler B, Hannezo E, Kaiser J, Andersson ER. DUCT reveals architectural mechanisms contributing to bile duct recovery in a mouse model for Alagille syndrome. eLife 2021; 10:60916. [PMID: 33635272 PMCID: PMC7909953 DOI: 10.7554/elife.60916] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 01/14/2021] [Indexed: 12/28/2022] Open
Abstract
Organ function depends on tissues adopting the correct architecture. However, insights into organ architecture are currently hampered by an absence of standardized quantitative 3D analysis. We aimed to develop a robust technology to visualize, digitalize, and segment the architecture of two tubular systems in 3D: double resin casting micro computed tomography (DUCT). As proof of principle, we applied DUCT to a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice), characterized by intrahepatic bile duct paucity, that can spontaneously generate a biliary system in adulthood. DUCT identified increased central biliary branching and peripheral bile duct tortuosity as two compensatory processes occurring in distinct regions of Jag1Ndr/Ndr liver, leading to full reconstitution of wild-type biliary volume and phenotypic recovery. DUCT is thus a powerful new technology for 3D analysis, which can reveal novel phenotypes and provide a standardized method of defining liver architecture in mouse models.
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Affiliation(s)
- Simona Hankeova
- Department of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden.,Department of Experimental Biology, Masaryk University, Brno, Czech Republic
| | - Jakub Salplachta
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Tomas Zikmund
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Michaela Kavkova
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Noémi Van Hul
- Department of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden
| | - Adam Brinek
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Veronika Smekalova
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Jakub Laznovsky
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Feven Dawit
- Department of Pediatrics, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital, Solna, Sweden
| | - Josef Jaros
- Department of Histology and Embryology, Masaryk University, Brno, Czech Republic
| | - Vítězslav Bryja
- Department of Experimental Biology, Masaryk University, Brno, Czech Republic
| | - Urban Lendahl
- Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden
| | - Ewa Ellis
- Department of Pediatrics, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital, Solna, Sweden
| | - Antal Nemeth
- Department of Laboratory Medicine, Karolinska Institutet, Solna, Sweden
| | - Björn Fischler
- Department of Pediatrics, Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital, Solna, Sweden
| | - Edouard Hannezo
- Institute of Science and Technology, Klosterneuburg, Austria
| | - Jozef Kaiser
- CEITEC - Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Emma Rachel Andersson
- Department of Biosciences and Nutrition, Karolinska Institutet, Solna, Sweden.,Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden
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15
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Abstract
Following injury, the liver's epithelial cells regenerate efficiently with rapid proliferation of hepatocytes and biliary cells. However, when proliferation of resident epithelial cells is impaired, alternative regeneration mechanisms can occur. Intricate lineage-tracing strategies and experimental models of regenerative stress have revealed a degree of plasticity between hepatocytes and biliary cells. New technologies such as single-cell omics, in combination with functional studies, will be instrumental to uncover the remaining unknowns in the field. In this review, we evaluate the experimental and clinical evidence for epithelial plasticity in the liver and how this influences the development of therapeutic strategies for chronic liver disease.
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Affiliation(s)
- Victoria L Gadd
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Niya Aleksieva
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK.
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16
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Shiau H, Guffey D, Loomes KM, Seidman C, Ragozzino E, Molleston JP, Schady D, Leung DH. Biopsy Validated Study of Biomarkers for Liver Fibrosis and Transplant Prediction in Inherited Cholestasis. Hepatol Commun 2020; 4:1516-1526. [PMID: 33024920 PMCID: PMC7527690 DOI: 10.1002/hep4.1569] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/29/2020] [Accepted: 06/18/2020] [Indexed: 12/12/2022] Open
Abstract
Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are inherited cholestatic disorders with risk of developing end‐stage liver disease requiring liver transplantation (LT). We investigated aspartate aminotransferase‐to‐platelet ratio index (APRI), Fibrosis‐4 score (FIB‐4), and conjugated bilirubin as biomarkers to assess fibrosis severity and risk for LT among children with ALGS and PFIC. This multicenter, cross‐sectional study included 64 children with ALGS or PFIC (per genetics or strict clinical criteria) with APRI, FIB‐4, and conjugated bilirubin levels collected within ±90 days of their most recent liver biopsy. A single, blinded pathologist staged all biopsies (metavir; F0‐F2: nonsevere, F3‐F4: severe). Logistic regression and area under the receiver operating characteristic curve analysis (AUC) were used to assess biomarker associations with fibrosis severity and risk for LT. In ALGS, only APRI distinguished F3‐F4 (AUC 0.72, P = 0.012), with a cutoff greater than 2.97 demonstrating a sensitivity of 61.5% (95% confidence interval 0.32, 0.86) and specificity of 81.5% (0.62, 0.94). In ALGS, a 50% increase of APRI increased the odds of F3‐F4 by 1.31‐fold (1.04, 1.65; P = 0.023). In ALGS, APRI (AUC 0.87; P < 0.001) and FIB‐4 (AUC 0.84; P < 0.001) were able to predict risk for LT. In PFIC, only APRI distinguished F3‐4 (AUC 0.74, P = 0.039), with a cutoff greater than 0.99 demonstrating a sensitivity of 80% (0.44, 0.98) and specificity of 64.3% (0.35, 0.87). In PFIC, only FIB‐4 was able predict risk for LT (AUC 0.80; P = 0.002). In ALGS or PFIC, conjugated bilirubin could not distinguish F3‐F4 or predict risk for LT. Conclusion: This liver biopsy–validated study suggests that APRI is able to distinguish F3‐F4 from F0‐F2 in ALGS and PFIC. APRI and FIB‐4 may also serve as predictors of risk for LT in ALGS (APRI and FIB‐4) and PFIC (FIB‐4).
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Affiliation(s)
- Henry Shiau
- Pediatric Gastroenterology, Hepatology, and Nutrition Baylor College of Medicine Houston TX.,Texas Children's Hospital Houston TX
| | - Danielle Guffey
- Institute for Clinical and Translational Research Baylor College of Medicine Houston TX
| | - Kathleen M Loomes
- Pediatric Gastroenterology, Hepatology, and Nutrition University of Pennsylvania Perelman School of Medicine Philadelphia PA.,Children's Hospital of Philadelphia Philadelphia PA
| | | | | | - Jean P Molleston
- Pediatric Gastroenterology, Hepatology, and Nutrition Indiana University-Riley Hospital for Children Indianapolis IN
| | - Deborah Schady
- Pathology and Immunology Baylor College of Medicine Houston TX
| | - Daniel H Leung
- Pediatric Gastroenterology, Hepatology, and Nutrition Baylor College of Medicine Houston TX.,Texas Children's Hospital Houston TX
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17
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Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs. LANCET REGIONAL HEALTH-WESTERN PACIFIC 2020; 1:100001. [PMID: 34327338 PMCID: PMC8315561 DOI: 10.1016/j.lanwpc.2020.100001] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/08/2020] [Accepted: 06/11/2020] [Indexed: 02/08/2023]
Abstract
Background Rapid whole-exome sequencing (rWES) offers the potential for early diagnosis-predicated precision medicine. Previous evidence focused predominantly on infants from the intensive care unit (ICU). This study sought to examine the diagnostic and clinical utility, and the economic impact on clinical management of rWES in patients beyond infancy and ICU setting. Methods rWES was performed on a prospective cohort of patients with suspected monogenic disorder referred from territory-wide paediatric ICUs and non-ICUs in Hong Kong urging for rapid genetic diagnosis. All eligible families were invited. We aimed to achieve a rapid turnaround time (TAT) of 14 days. Clinical utility and costs associated with clinical management were assessed in diagnosed cases. Actual quantitative changes in healthcare utilisation were compared with a counterfactual diagnostic trajectory and/or with matched historical control whenever possible. Findings rWES were offered to 102 families and 32/102 (31%) patients received a molecular diagnosis, with a median TAT of 11 days. Clinical management changed in 28 of 32 diagnosed patients (88%), including but not limited to modifications in treatment, avoidance of surgeries, and informing decisions on redirection of care. Cost analysis was performed in eight patients. rWES was estimated to reduce hospital length of stay by 566 days and decrease healthcare costs by HKD$8,044,250 (GBP£796,460) for these eight patients. The net cost-savings after inclusion of rWES costs were estimated to be HKD$5,325,187 (GBP£527,246). Interpretation This study replicates the diagnostic capacity and rapid TAT of rWES in predominantly Chinese patients, and demonstrates diagnosis-predicated precision medicine and net healthcare savings. Findings were corroborated by evidence from multinational cohorts, combined as part of a meta-analysis. rWES merits consideration as a first-tier diagnostic tool for patients with urgent needs in the clinical setting. Funding Health and Medical Research Fund, HKU Seed Fund for Basic Research, The Society for the Relief of Disabled Children, and Edward and Yolanda Wong Fund.
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18
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Adams JM, Huppert KA, Castro EC, Lopez MF, Niknejad N, Subramanian S, Zarrin-Khameh N, Finegold MJ, Huppert SS, Jafar-Nejad H. Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome. Hepatology 2020; 71:1331-1349. [PMID: 31469182 PMCID: PMC7048647 DOI: 10.1002/hep.30912] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 08/19/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily by haploinsufficiency of the Notch ligand jagged1. The course of the liver disease is highly variable in ALGS. However, the genetic basis for ALGS phenotypic variability is unknown. Previous studies have reported decreased expression of the transcription factor SOX9 (sex determining region Y-box 9) in late embryonic and neonatal livers of Jag1-deficient mice. Here, we investigated the effects of altering the Sox9 gene dosage on the severity of liver disease in an ALGS mouse model. APPROACH AND RESULTS Conditional removal of one copy of Sox9 in Jag1+/- livers impairs the biliary commitment of cholangiocytes and enhances the inflammatory reaction and liver fibrosis. Loss of both copies of Sox9 in Jag1+/- livers further worsens the phenotypes and results in partial lethality. Ink injection experiments reveal impaired biliary tree formation in the periphery of P30 Jag1+/- livers, which is improved by 5 months of age. Sox9 heterozygosity worsens the P30 biliary tree phenotype and impairs the partial recovery in 5-month-old animals. Notably, Sox9 overexpression improves BD paucity and liver phenotypes in Jag1+/- mice without ectopic hepatocyte-to-cholangiocyte transdifferentiation or long-term liver abnormalities. Notch2 expression in the liver is increased following Sox9 overexpression, and SOX9 binds the Notch2 regulatory region in the liver. Histological analysis shows a correlation between the level and pattern of SOX9 expression in the liver and outcome of the liver disease in patients with ALGS. CONCLUSIONS Our results establish Sox9 as a dosage-sensitive modifier of Jag1+/- liver phenotypes with a permissive role in biliary development. Our data further suggest that liver-specific increase in SOX9 levels is a potential therapeutic approach for BD paucity in ALGS.
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Affiliation(s)
- Joshua M. Adams
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX
| | - Kari A. Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Eumenia C. Castro
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
- Department of Pathology, Texas Children’s Hospital, Houston, TX
| | - Mario F. Lopez
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Nima Niknejad
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Sanjay Subramanian
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | - Neda Zarrin-Khameh
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
| | - Milton J. Finegold
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
| | - Stacey S. Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Hamed Jafar-Nejad
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
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19
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Adams JM, Jafar-Nejad H. The Roles of Notch Signaling in Liver Development and Disease. Biomolecules 2019; 9:biom9100608. [PMID: 31615106 PMCID: PMC6843177 DOI: 10.3390/biom9100608] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/07/2019] [Accepted: 10/07/2019] [Indexed: 02/07/2023] Open
Abstract
The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch activity in proper liver development and function. Specifically, we discuss the latest discoveries on how Notch, in conjunction with other signaling pathways, aids in proper liver development, regeneration and repair. In addition, we review the latest in the role of Notch signaling in the pathogenesis of liver fibrosis and chronic liver disease. Finally, recent evidence has shed light on the emerging connection between Notch signaling and glucose and lipid metabolism. We hope that highlighting the major advances in the roles of Notch signaling in the liver will stimulate further research in this exciting field and generate additional ideas for therapeutic manipulation of the Notch pathway in liver diseases.
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Affiliation(s)
- Joshua M Adams
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Hamed Jafar-Nejad
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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20
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Fischetto R, Palmieri VV, Tripaldi ME, Gaeta A, Michelucci A, Delvecchio M, Francavilla R, Giordano P. Alagille Syndrome: A Novel Mutation in JAG1 Gene. Front Pediatr 2019; 7:199. [PMID: 31157196 PMCID: PMC6529843 DOI: 10.3389/fped.2019.00199] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 04/30/2019] [Indexed: 11/18/2022] Open
Abstract
Alagille syndrome is an autosomal dominant multisystem disorder with variable phenotypic penetrance, caused by heterozygous mutations in JAG1 or NOTCH2, encoding for the components of the Notch signaling pathway. In this paper, we described a novel mutation not yet reported in literature. This 3-years old male child was referred to our Clinical Genetics Unit because of delayed psychomotor development, systolic murmur, dysmorphic facial features, and hypertransaminasemia. The novel JAG1 heterozygous c.2026delT variant in exon 16 was found. JAG1 mutations are classified as protein truncating and non-protein truncating, without any genotype-phenotype correlation. The detected mutation determines a stop codon (p.Cys676AlafsTer67) in the gene sequence, encoding a truncated protein. Our report broadens the spectrum of JAG1 gene mutations.
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Affiliation(s)
- Rita Fischetto
- Clinical Genetics Unit, Department of Paediatric Medicine, Giovanni XXIII Children's Hospital, Bari, Italy
| | - Viviana V. Palmieri
- Pediatric Section, Department of Biomedicine and Human Oncology, University A. Moro, Bari, Italy
| | - Maria E. Tripaldi
- Pediatric Section, Department of Biomedicine and Human Oncology, University A. Moro, Bari, Italy
| | - Alberto Gaeta
- PediatricRadiology Unit, Giovanni XXIII Children's Hospital, Bari, Italy
| | - Angela Michelucci
- Laboratory of Molecular Genetics, University Hospital of Pisa, Pisa, Italy
| | | | - Ruggiero Francavilla
- Pediatric Section, Department of Biomedicine and Human Oncology, University A. Moro, Bari, Italy
| | - Paola Giordano
- Pediatric Section, Department of Biomedicine and Human Oncology, University A. Moro, Bari, Italy
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21
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Abstract
Mouse is broadly used as a model organism to study biliary diseases. To evaluate the development and function of the biliary system, various techniques are used, including serum chemistry, histological analysis, and immunostaining for specific markers. Although these techniques can provide important information about the biliary system, they often do not present a full picture of bile duct (BD) developmental defects across the whole liver. This is in part due to the robust ability of the mouse liver to drain the bile even in animals with significant impairment in biliary development. Here we present a simple method to calculate the average number of BDs associated with each portal vein (PV) in sections covering all lobes of mutant/transgenic mice. In this method, livers are mounted and sectioned in a stereotypic manner to facilitate comparison among various genotypes and experimental conditions. BDs are identified via light microscopy of cytokeratin-stained cholangiocytes, and then counted and divided by the total number of PVs present in liver section. As an example, we show how this method can clearly distinguish between wild-type mice and a mouse model of Alagille syndrome. The method presented here cannot substitute for techniques that visualize the three-dimensional structure of the biliary tree. However, it offers an easy and direct way to quantitatively assess BD development and the degree of ductular reaction formation in mice.
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Affiliation(s)
- Joshua M Adams
- Program in Developmental Biology, Baylor College of Medicine; Medical Scientist Training Program (MSTP), Baylor College of Medicine; Department of Molecular and Human Genetics, Baylor College of Medicine
| | - Hamed Jafar-Nejad
- Program in Developmental Biology, Baylor College of Medicine; Department of Molecular and Human Genetics, Baylor College of Medicine;
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22
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P Singh S, K Pati G. Alagille Syndrome and the Liver: Current Insights. Euroasian J Hepatogastroenterol 2019; 8:140-147. [PMID: 30828556 PMCID: PMC6395485 DOI: 10.5005/jp-journals-10018-1280] [Citation(s) in RCA: 7] [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: 06/14/2018] [Accepted: 09/07/2018] [Indexed: 01/11/2023] Open
Abstract
Alagille syndrome (ALGS) is an autosomal dominant disorder, with multisystem involvement, which usually occurs due to Notch signaling pathway defects, mostly due to JAG1 mutation (ALGS type 1), but rarely due to neurogenic locus notch homolog protein (NOTCH2) mutation (ALGS type 2). It was suspected in cases having at least three out of five major clinical criteria: cholestasis with a paucity of the bile duct, congenital cardiac defects, ocular posterior embryotoxon, typical facial features, and skeletal malformation. Till date, no early predictive marker for hepatic outcome in ALGS has found. No genotypic or, phenotype features or correlation could predict the development of endstage liver disease, which poses a unique management challenge. Cases with progressive liver damage, unremitting cholestasis and intractable pruritus often depend on liver transplantation as last resort. The cardiac, and renal status should be well accessed before liver transplant for the better post-transplantation outcome. Most of the clinical manifestations usually improve the following transplant, except any change in stature. The post liver transplantation outcome was usually comparable with other conditions which require liver transplantation as a last resort, but in this disease the effect of long term immunosuppression on other affected systems not evaluated well till date. Therefore long term post transplant prospective study is required to address these issues. How to cite this article: Singh SP, Pati GK. Alagille Syndrome and the Liver: Current Insights. Euroasian J Hepatogastroenterol, 2018;8(2):140-147
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Affiliation(s)
- Shivaram P Singh
- Department of Gastroenterology, Sriram Chandra Bhanj Medical College, Cuttack, Odisha, India
| | - Girish K Pati
- Department of Gastroenterology, Institute of Medical Sciences and Sum Hospital, Bhubaneswar, Odisha, India
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23
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Abstract
Alagille syndrome is a complex multisystem autosomal dominant disorder with a wide variability in penetrance of clinical features. A majority of patients have pathogenic mutations in either the JAG1 gene, encoding a Notch pathway ligand, or the receptor NOTCH2. No genotype-phenotype correlations have been found in any organ system. Liver disease is a major cause of morbidity in this population, whereas cardiac and vascular involvement accounts for most of the mortality. Current therapies are supportive, but the future is promising for the development of targeted interventions to augment Notch pathway signaling in involved tissues.
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Affiliation(s)
- Ellen Mitchell
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, 4401 Penn Avenue, Pittsburgh, PA 15224, USA
| | - Melissa Gilbert
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA
| | - Kathleen M Loomes
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA.
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24
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A Novel c.91dupG JAG1 Gene Mutation Is Associated with Early Onset and Severe Alagille Syndrome. Case Rep Genet 2018; 2018:1369413. [PMID: 30046498 PMCID: PMC6036836 DOI: 10.1155/2018/1369413] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 04/30/2018] [Accepted: 05/22/2018] [Indexed: 11/18/2022] Open
Abstract
Alagille syndrome (MIM 118450) is an autosomal dominant disorder characterized by paucity of intrahepatic bile ducts, chronic cholestasis, pulmonary stenosis, butterfly-like vertebrae, posterior embryotoxon, and dysmorphic facial features. Most cases are caused by JAG1 gene mutations. We report the case of a 2-year-old Mexican mestizo patient with Alagille syndrome, having exhibited jaundice and cholestatic syndrome as of three weeks of age. Sequencing analysis of the JAG1 gene revealed the novel heterozygous mutation c.91dupG that originates a truncated protein and therefore a possibly diminished activation of the Notch signaling pathway. The latter may explain the severe phenotype of the patient. Since the mutation was not identified in the parents, it was considered a de novo event, highlighting the importance of molecular diagnosis and genetic counseling. In conclusion, this report widens the spectrum of JAG1 gene mutations associated with Alagille syndrome.
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25
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Alagille syndrome: Genetics and Functional Models. CURRENT PATHOBIOLOGY REPORTS 2017; 5:233-241. [PMID: 29270332 DOI: 10.1007/s40139-017-0144-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Purpose of review We review the genetics of the autosomal dominant, multi-system disorder, Alagille syndrome and provide a summary on how current functional models and emerging biotechnologies are equipped to guide scientists towards novel therapies. The importance of haploinsufficiency as a disease mechanism will be underscored throughout this discussion. Recent findings Alagille syndrome, a human disorder affecting the liver, heart, vasculature, kidney, and other systems, is caused by mutations in the Notch signaling pathway ligand, Jagged1 (JAG1) or the receptor, NOTCH2. Current advances in animal modeling, in vitro cell culture, and human induced pluripotent stem cells, provide new opportunities in which to study disease mechanisms and manifestations. Summary We anticipate that the availability of innovative functional models will allow scientists to test new gene therapies or small molecule treatments in physiologically-relevant systems. With these advances, we look forward to the development of new methods to help Alagille syndrome patients.
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26
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Tsai EA, Gilbert MA, Grochowski CM, Underkoffler LA, Meng H, Zhang X, Wang MM, Shitaye H, Hankenson KD, Piccoli D, Lin H, Kamath BM, Devoto M, Spinner NB, Loomes KM. THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome. Cell Mol Gastroenterol Hepatol 2016; 2:663-675.e2. [PMID: 28090565 PMCID: PMC5042888 DOI: 10.1016/j.jcmgh.2016.05.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/17/2016] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Alagille syndrome is an autosomal-dominant, multisystem disorder caused primarily by mutations in JAG1, resulting in bile duct paucity, cholestasis, cardiac disease, and other features. Liver disease severity in Alagille syndrome is highly variable, however, factors influencing the hepatic phenotype are unknown. We hypothesized that genetic modifiers may contribute to the variable expressivity of this disorder. METHODS We performed a genome-wide association study in a cohort of Caucasian subjects with known pathogenic JAG1 mutations, comparing patients with mild vs severe liver disease, followed by functional characterization of a candidate locus. RESULTS We identified a locus that reached suggestive genome-level significance upstream of the thrombospondin 2 (THBS2) gene. THBS2 codes for a secreted matricellular protein that regulates cell proliferation, apoptosis, and angiogenesis, and has been shown to affect Notch signaling. By using a reporter mouse line, we detected thrombospondin 2 expression in bile ducts and periportal regions of the mouse liver. Examination of Thbs2-null mouse livers showed increased microvessels in the portal regions of adult mice. We also showed that thrombospondin 2 interacts with NOTCH1 and NOTCH2 and can inhibit JAG1-NOTCH2 interactions. CONCLUSIONS Based on the genome-wide association study results, thrombospondin 2 localization within bile ducts, and demonstration of interactions of thrombospondin 2 with JAG1 and NOTCH2, we propose that changes in thrombospondin 2 expression may further perturb JAG1-NOTCH2 signaling in patients harboring a JAG1 mutation and lead to a more severe liver phenotype. These results implicate THBS2 as a plausible candidate genetic modifier of liver disease severity in Alagille syndrome.
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Key Words
- ALGS, Alagille syndrome
- BSA, bovine serum albumin
- CK19, cytokeratin 19
- ChiLDReN, Childhood Liver Disease Research Network
- Cholestasis
- GFP, green fluorescent protein
- GWAS, genome-wide association study
- Gene Modifier
- Genome-Wide Association Study
- JAG1
- NOTCH2
- PCR, polymerase chain reaction
- SNP, single-nucleotide polymorphism
- THBS2, thrombospondin 2
- cDNA, complementary DNA
- ddPCR, droplet digital polymerase chain reaction
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Affiliation(s)
- Ellen A Tsai
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania; Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Melissa A Gilbert
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Christopher M Grochowski
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lara A Underkoffler
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | - He Meng
- Department of Neurology, University of Michigan, Ann Arbor, Michigan
| | - Xiaojie Zhang
- Department of Neurology, University of Michigan, Ann Arbor, Michigan
| | - Michael M Wang
- Department of Neurology, University of Michigan, Ann Arbor, Michigan; Department of Physiology, University of Michigan, Ann Arbor, Michigan; VA Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Hailu Shitaye
- Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan
| | - Kurt D Hankenson
- Department of Physiology, Department of Small Animal Clinical Sciences, Colleges of Natural Science, Osteopathic Medicine, and Veterinary Medicine, Michigan State University, East Lansing, Michigan; Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David Piccoli
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Henry Lin
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Marcella Devoto
- Division of Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Molecular Medicine, University La Sapienza, Rome, Italy
| | - Nancy B Spinner
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kathleen M Loomes
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
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27
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Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. APPLICATION OF CLINICAL GENETICS 2016; 9:75-82. [PMID: 27418850 PMCID: PMC4935120 DOI: 10.2147/tacg.s86420] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Alagille syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with bile duct paucity on liver biopsy, congenital cardiac defects (with particular involvement of the pulmonary arteries), posterior embryotoxon in the eye, characteristic facial features, and butterfly vertebrae. Renal and vascular abnormalities can also occur. Inter- and intrafamilial variabilities in the clinical manifestations are common. We reviewed the clinical features and management as well as the molecular basis of Alagille syndrome.
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Affiliation(s)
- Maha Saleh
- Division of Clinical and Metabolic Genetics
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children
| | - David Chitayat
- Division of Clinical and Metabolic Genetics; Department of Obstetrics and Gynecology, Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
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