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Zhongguo Dang Dai Er Ke Za Zhi =... Nov 2014Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is an autosomal dominant disease with multisystem involvement. In this disease, the Notch signalling... (Review)
Review
Alagille syndrome (ALGS), also known as arteriohepatic dysplasia, is an autosomal dominant disease with multisystem involvement. In this disease, the Notch signalling pathway is impaired due to mutation in JAG1 (ALGS type 1) or NOTCH2 (ALGS type 2) gene, affecting multiple organs or systems such as liver, heart, eyes, vertebrate and face. The main clinical features of ALGS include chronic cholestasis, congenital heart disease, mild vertebral segmentation abnormalities, characteristic face, postcorneal embryotoxon and poor kidney development. This article reviews the recent advances in the pathogenesis, clinical presentations, diagnosis and treatment of this syndrome.
Topics: Alagille Syndrome; Humans
PubMed: 25406571
DOI: No ID Found -
Advanced Science (Weinheim,... Jan 2022Patients with Alagille syndrome carry monogenic mutations in the Notch signaling pathway and face complications such as jaundice and cholestasis. Given the presence of...
Patients with Alagille syndrome carry monogenic mutations in the Notch signaling pathway and face complications such as jaundice and cholestasis. Given the presence of intrahepatic ductopenia in these patients, Notch2 receptor signaling is implicated in driving normal biliary development and downstream branching morphogenesis. As a result, in vitro model systems of liver epithelium are needed to further mechanistic insight of biliary tissue assembly. Here, primary human intrahepatic cholangiocytes as a candidate population for such a platform are systematically evaluated, and conditions that direct their branching morphogenesis are described. It is found that extracellular matrix presentation, coupled with mitogen stimulation, promotes biliary branching in a Notch-dependent manner. These results demonstrate the utility of using 3D scaffolds for mechanistic investigation of cholangiocyte branching and provide a gateway to integrate biliary architecture in additional in vitro models of liver tissue.
Topics: Adult; Alagille Syndrome; Biliary Tract; Biocompatible Materials; Cells, Cultured; Epithelial Cells; Humans; Liver; Morphogenesis; Organoids; Signal Transduction; Tissue Scaffolds
PubMed: 34786888
DOI: 10.1002/advs.202102698 -
Ocular Oncology and Pathology Oct 2016Alagille syndrome is an autosomal dominant disorder characterized by neonatal cholestasis, characteristic facies, and cardiac abnormalities. Ocular abnormalities include...
BACKGROUND
Alagille syndrome is an autosomal dominant disorder characterized by neonatal cholestasis, characteristic facies, and cardiac abnormalities. Ocular abnormalities include posterior embryotoxon, mosaic pattern of iris stromal hypoplasia, microcornea, optic disc drusen, and pigmentary retinopathy. We present the second report of ocular pathology in two cases of Alagille syndrome.
METHODS
Gross and histologic preparations of four eyes of two patients.
RESULTS
Posterior embryotoxon is seen in both cases, with iris processes extending to the embryotoxon in case 1. Case 1 exhibited distinctly abnormal iris stroma with a prominent cleft separating the anterior and posterior stroma. Lacy vacuolization of the iris pigment epithelium was seen in case 2.
CONCLUSIONS
Alagille syndrome is primarily a hepatic disorder but presents with several distinct ocular pathologic features, most specifically posterior embryotoxon. This and the unusual iris stroma may be caused by improper migration of neural crest cells due to mutation in the gene that causes Alagille syndrome. Patients with Alagille syndrome rarely present to ocular autopsy. Pathology findings may help us better understand the pathophysiology of the ocular abnormalities in this disorder.
PubMed: 27843908
DOI: 10.1159/000446804 -
Nature Reviews. Gastroenterology &... Aug 2019Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells... (Review)
Review
Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.
Topics: Alagille Syndrome; Bile Duct Diseases; Cystic Fibrosis; Cysts; Gastrointestinal Microbiome; Humans; Liver Diseases; Molecular Targeted Therapy; Receptors, Notch; Signal Transduction
PubMed: 31165788
DOI: 10.1038/s41575-019-0156-4 -
Journal of Clinical Medicine Dec 2022Alagille syndrome (ALGS) is a rare, debilitating inheritable disease that is associated with refractory pruritus due to chronic cholestasis. The following systemic...
Alagille syndrome (ALGS) is a rare, debilitating inheritable disease that is associated with refractory pruritus due to chronic cholestasis. The following systemic review and meta-analysis presents the latest evidence for ileal bile acid transport (IBAT) blockers in AGLS patients in order to improve their efficacy. This study adhered to PRISMA 2020 Statement guidelines. A systematic search of PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane library was conducted from inception until 23 October 2022. A combination of the following keywords was used: Alagille syndrome, therapeutics, treatment, therapy. Meta-analytical outcomes included effect directions of end-line changes in serum bile acids (sBAs), Itch Scale scores (ItchRO), Multidimensional Fatigue Scale scores, pediatric quality of life (QL), alanine aminotransferase (ALT), and total bilirubin. A total of 94 patients across four trials were enrolled and received maralixibat, odevixibat, or a placebo. There was a significant reduction in ItchRO scores by 1.8 points, as well as in sBAs by 75.8 μmol/L. Both the Multidimensional Fatigue Scale and Pediatric QL scale were also improved by 11.4 and 8.3 points, respectively. However, ALT levels were raised by 40 U/L. The efficacy of IBAT inhibitors across current trials was noted. Future trials may focus on the optimization of dosing regimens, considering gastrointestinal side effects and drug-induced ALT elevation in AGLS patients.
PubMed: 36556142
DOI: 10.3390/jcm11247526 -
Biomolecules Oct 2019The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development,... (Review)
Review
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.
Topics: Animals; Humans; Liver; Liver Diseases; Receptors, Notch; Signal Transduction
PubMed: 31615106
DOI: 10.3390/biom9100608 -
The Journal of Pediatrics Feb 2023To assess and characterize health care resource utilization (HRU) in children with the rare, genetic, multisystem disorder, Alagille syndrome.
OBJECTIVE
To assess and characterize health care resource utilization (HRU) in children with the rare, genetic, multisystem disorder, Alagille syndrome.
STUDY DESIGN
This retrospective analysis reviewed commercially insured and Medicaid-insured claims from October 1, 2015 to December 31, 2019 to assess HRU in patients with Alagille syndrome. As there is no specific International Classification ofDiseases-10 code for Alagille syndrome, patients were identified using the following algorithm: ≥1 claim with diagnosis code Q44.7 (other congenital malformations of the liver); <18 years of age, with no history of biliary atresia (International Classification ofDiseases-10 code: Q44.2); and ≥6 months of insurance eligibility prior to diagnosis. HRU was summarized per patient per year over all available claims postdiagnosis.
RESULTS
A total of 171 commercially insured and 215 Medicaid-insured patients with Alagille syndrome were available for analysis. Annually, commercially insured and Medicaid-insured patients averaged 31 medical visits (range, 1.5-237) and 48 medical visits (range, 0.7-690), respectively. The most common visits were outpatient with the majority encompassing lab/imaging and primary care visits (commercially insured: 21 [range, 0.0-183]; Medicaid-insured: 26 [range, 0.0-609]). Inpatient visits were the highest driver of costs in both the commercial and Medicaid populations.
CONCLUSIONS
Patients with Alagille syndrome have a substantial HRU burden driven largely by numerous outpatient visits and costly inpatient stays. Given the complexity and variability of Alagille syndrome presentation, patients may benefit from multidisciplinary and subspecialized care.
Topics: Child; United States; Humans; Health Care Costs; Retrospective Studies; Alagille Syndrome; Delivery of Health Care; Patient Acceptance of Health Care; Medicaid; Insurance, Health
PubMed: 36179890
DOI: 10.1016/j.jpeds.2022.09.033 -
Seminars in Liver Disease Feb 2022Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the... (Review)
Review
Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the Hippo signaling pathway, to regulate biological processes like proliferation, survival, and differentiation. YAP1 is most prominently expressed in biliary epithelial cells (BECs) in normal adult livers and during development. In the current review, we will discuss the multiple roles of YAP1 in the development and morphogenesis of bile ducts inside and outside the liver, as well as in orchestrating the cholangiocyte repair response to biliary injury. We will review how biliary repair can occur through the process of hepatocyte-to-BEC transdifferentiation and how YAP1 is pertinent to this process. We will also discuss the liver's capacity for metabolic reprogramming as an adaptive mechanism in extreme cholestasis, such as when intrahepatic bile ducts are absent due to YAP1 loss from hepatic progenitors. Finally, we will discuss the roles of YAP1 in the context of pediatric pathologies afflicting bile ducts, such as Alagille syndrome and biliary atresia. In conclusion, we will comprehensively discuss the spatiotemporal roles of YAP1 in biliary development and repair after biliary injury while describing key interactions with other well-known developmental pathways.
Topics: Bile Ducts, Intrahepatic; Biliary Tract; Biological Phenomena; Child; Humans; Liver; Transcription Factors; YAP-Signaling Proteins
PubMed: 35073587
DOI: 10.1055/s-0041-1742277 -
International Journal of Molecular... Jul 2023Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton,...
Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton, eyes, kidneys, and face and caused by pathogenic variants in the or gene. The variable expressivity of the clinical phenotype and the lack of genotype-phenotype correlations lead to significant diagnostic difficulties. Here we present an analysis of 18 patients with cholestasis who were diagnosed with ALGS. We used an NGS panel targeting coding exons of 52 genes, including the and genes. Sanger sequencing was used to verify the mutation in the affected individuals and family members. The specific facial phenotype was seen in 16/18 (88.9%). Heart defects were seen in 8/18 (44.4%) patients (pulmonary stenosis in 7/8). Butterfly vertebrae were seen in 5/14 (35.7%) patients. Renal involvement was detected in 2/18 (11.1%) cases-one patient had renal cysts, and one had obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only one had posterior embryotoxon (8.3%). A percutaneous liver biopsy was performed in nine cases. Bile duct paucity was detected in six/nine cases (66.7%). Two patients required liver transplantation because of cirrhosis. We identified nine novel variants in the gene-eight frameshift variants (c.1619_1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168_3169delAG (p.R1056Sfs*51), c.2688delG (p.896CysfsTer49), c.164dupG (p.Cys55fs)) and one missense variant, c.2806T > G (p.Cys936Gly). None of the patients presented with variants. In accordance with the classical criteria, only six patients could meet the diagnostic criteria in our cohort without genetic analysis. Genetic testing is important in the diagnosis of ALGS and can help differentiate it from other types of cholestasis.
Topics: Humans; Alagille Syndrome; Cholestasis; Mutation; Mutation, Missense; Phenotype; Jagged-1 Protein
PubMed: 37511516
DOI: 10.3390/ijms241411758 -
Cancers Jul 2022The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport... (Review)
Review
The family of inherited intrahepatic cholestasis includes autosomal recessive cholestatic rare diseases of childhood involved in bile acids secretion or bile transport defects. Specific genetic pathways potentially cause many otherwise unexplained cholestasis or hepatobiliary tumours in a healthy liver. Lately, next-generation sequencing and whole-exome sequencing have improved the diagnostic procedures of familial intrahepatic cholestasis (FIC), as well as the discovery of several genes responsible for FIC. Moreover, mutations in these genes, even in the heterozygous status, may be responsible for cryptogenic cholestasis in both young and adults. Mutations in FIC genes can influence serum and hepatic levels of bile acids. Experimental studies on the gene have shown that high bile acids concentrations cause excessive production of inflammatory cytokines, resistance to apoptosis, and increased cell regeneration, all risk conditions for developing hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). gene encodes farnesoid X-activated receptor having a pivotal role in bile salts synthesis. Moreover, HCC and CCA can emerge in patients with several FIC genes such as , and . Herein, we reviewed the available data on FIC-related hepatobiliary cancers, reporting on genetics to the pathophysiology, the risk factors and the clinical presentation.
PubMed: 35884482
DOI: 10.3390/cancers14143421