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Journal of Clinical Gastroenterology Aug 2023Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed... (Review)
Review
Children with cholestatic liver diseases are increasingly living into adulthood, thanks to innovations in medical and surgical therapies. The excellent outcomes observed in pediatric liver transplantation for diseases, such as biliary atresia, have transformed the life trajectory of children born with once-fatal liver diseases. The evolution of molecular genetic testing, has helped expedite the diagnosis of other cholestatic disorders, improving the clinical management, disease prognosis, and family planning for inherited disorders, such as progressive familial intrahepatic cholestasis and bile acid synthesis disorders. The expanding list of therapeutics, including bile acids and the newer ileal bile acid transport inhibitors, has also helped slow the progression of disease and improve the quality of life for certain diseases, like Alagille syndrome. More and more children with cholestatic disorders are expected to require care from adult providers familiar with the natural history and potential complications of these childhood diseases. The aim of this review is to bridge the gap between pediatric and adult care in children with cholestatic disorders. The present review addresses the epidemiology, clinical features, diagnostic testing, treatment, prognosis, and transplant outcomes of 4 hallmark childhood cholestatic liver diseases: biliary atresia, Alagille syndrome, progressive familial intrahepatic cholestasis, and bile acid synthesis disorders.
Topics: Child; Adult; Humans; Biliary Atresia; Alagille Syndrome; Gastroenterologists; Quality of Life; Cholestasis; Cholestasis, Intrahepatic; Bile Acids and Salts
PubMed: 37022007
DOI: 10.1097/MCG.0000000000001850 -
Hepatology (Baltimore, Md.) Nov 2023Paucity of intrahepatic bile ducts (BDs) is caused by various etiologies and often leads to cholestatic liver disease. For example, in patients with Alagille syndrome...
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.
Topics: Animals; Mice; Alagille Syndrome; Bile Ducts, Intrahepatic; Calcium-Binding Proteins; Cholestasis; Gene Silencing; Glucosyltransferases; Glycosyltransferases; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Liver; Membrane Proteins; Oligonucleotides, Antisense; Phenotype; Serrate-Jagged Proteins
PubMed: 37021797
DOI: 10.1097/HEP.0000000000000380 -
Retinal Cases & Brief Reports Mar 2024To report a case of atypical Alagille syndrome with progressive chorioretinal atrophy.
PURPOSE
To report a case of atypical Alagille syndrome with progressive chorioretinal atrophy.
METHODS
Case Report.
RESULTS
A 42-year-old Japanese man presented with atypical Alagille syndrome. At the first visit, funduscopy revealed anterior circumferential chorioretinal atrophy in the peripheral retina and peripapillary region with posterior pole sparing in both eyes. Fundus autofluorescence showed hypoautofluorescence in the peripheral and peripapillary regions, but normal findings in the macular region. After follow-up for 3 years, hypopigmented area with well visualized large choroidal vessels extended to mid-peripheral region. On Fundus autofluorescence images, hypoautofluorescence newly appeared in macular region in both eyes. Perivascular hypoautofluorescence and granular hyperautofluorescence scattering within the posterior pole were also observed. BCVA deteriorated and concentric visual field contraction worsened progressively.
CONCLUSION
Alagille syndrome is known to have many ophthalmic manifestations, most of which are stable with minimal threat to vision. In the present case, chorioretinal atrophy progressed during 3-year follow-up, suggesting that progression of chorioretinal atrophy with vision loss may occur over time in Alagille syndrome.
Topics: Male; Humans; Adult; Alagille Syndrome; Follow-Up Studies; Retina; Retinal Degeneration; Atrophy; Fluorescein Angiography; Retrospective Studies; Choroid Diseases
PubMed: 36730824
DOI: 10.1097/ICB.0000000000001368