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JPGN Reports Aug 2023Intractable pruritus is one of the most prominent and debilitating features of Alagille syndrome. Maralixibat is the first US Food and Drug Administration-approved drug...
Intractable pruritus is one of the most prominent and debilitating features of Alagille syndrome. Maralixibat is the first US Food and Drug Administration-approved drug for the treatment of cholestatic pruritus in children with Alagille syndrome aged 3 months and older. Clinical trials of maralixibat have reported follow-up to 4 years and reported a ≥1-pt reduction using the Itch-Reported Outcome (Observer) (ItchRO[Obs]) instrument (0-4 scale), as this decrease was previously defined as a clinically meaningful improvement in pruritus; participants in clinical trials were expected to be maintained on stable doses of antipruritic agents. We report on a patient with 3 notable features: (1) complete resolution of her pruritus; (2) durability of this response for over 7 years; and (3) ability to discontinue all other antipruritic medications.
PubMed: 37600618
DOI: 10.1097/PG9.0000000000000335 -
JPGN Reports Aug 2023
PubMed: 37600608
DOI: 10.1097/PG9.0000000000000338 -
Hepatology International Oct 2023Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is... (Review)
Review
Alagille syndrome (ALGS) is a complex rare genetic disorder that involves multiple organ systems and is historically regarded as a disease of childhood. Since it is inherited in an autosomal dominant manner in 40% of patients, it carries many implications for genetic counselling of patients and screening of family members. In addition, the considerable variable expression and absence of a clear genotype-phenotype correlation, results in a diverse range of clinical manifestations, even in affected individuals within the same family. With recent therapeutic advancements in cholestasis treatment and the improved survival rates with liver transplantation (LT), many patients with ALGS survive into adulthood. Although LT is curative for liver disease secondary to ALGS, complications secondary to extrahepatic involvement remain problematic lifelong. This review is aimed at providing a comprehensive review of ALGS to adult clinicians who will take over the medical care of these patients following transition, with particular focus on certain aspects of the condition that require lifelong surveillance. We also provide a diagnostic framework for adult patients with suspected ALGS and highlight key aspects to consider when determining eligibility for LT in patients with this syndrome.
Topics: Adult; Humans; Alagille Syndrome; Liver Transplantation
PubMed: 37584849
DOI: 10.1007/s12072-023-10578-x -
Gastroenterology Nursing : the Official...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...
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.
Topics: Male; Child; Infant, Newborn; Humans; Adolescent; Alagille Syndrome; Standardized Nursing Terminology; Nursing Diagnosis; Patient Care
PubMed: 37581873
DOI: 10.1097/SGA.0000000000000755 -
Advanced Biomedical Research 2023Alagille syndrome (ALGS) is an autosomal dominant disease caused by or mutation. It is diagnosed by the presence of three out of five features: characteristic facies,...
BACKGROUND
Alagille syndrome (ALGS) is an autosomal dominant disease caused by or mutation. It is diagnosed by the presence of three out of five features: characteristic facies, posterior embryotoxon, peripheral pulmonary stenosis, vertebral defects, and interlobular bile duct paucity. This study aimed to review the prevalence, clinical presentations, diagnosis, treatment, and outcome of patients with ALGS.
MATERIALS AND METHODS
This is a retrospective review of patients with ALGS at the Pediatric Department, Salmaniya Medical Complex, Bahrain, between August 1994 and October 2022. The diagnosis was based on clinical, laboratory, radiological, histopathological, and genetic findings.
RESULTS
Five patients were found to have ALGS. The prevalence of ALGS in Bahrain was 1.04 patients per 100,000 (0.001%). Four were Bahraini and three were females. Median birth weight was 2.3 (2.3-2.5) kg. All patients presented at the time of birth with low birth weight, cholestatic jaundice, clay-colored stool, heart murmur, and dysmorphic facial features. All had congenital heart diseases, two had butterfly vertebrae, and one had posterior embryotoxon. All had elevated liver enzymes and normal abdominal ultrasound. Three had positive hepatobiliary iminodiacetic acid scan and one had bile duct paucity in liver biopsy. Three had intraoperative cholangiogram. Four were positive for mutation. All received ursodeoxycholic acid and fat-soluble vitamins. Two required liver transplantation.
CONCLUSION
ALGS is a rare disorder in Bahrain. Diagnosis is challenging as the disease can be associated with or misdiagnosed as biliary atresia. Patients with ALGS are at high risk of morbidity either by unnecessary intraoperative cholangiogram or unavoidable liver transplantation.
PubMed: 37564457
DOI: 10.4103/abr.abr_201_22 -
Hepatology Communications Sep 2023We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of...
BACKGROUND
We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPKO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity.
METHODS
We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAPKO mice, resulting in YAP/TAZ double knockout (DKO) and YAPKO with TAZ heterozygosity (YAPKO TAZHET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing.
RESULTS
DKO mice were embryonic lethal, but their livers were similar to YAPKO, suggesting an extrahepatic cause of death. Male YAPKO TAZHET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAPKO TAZHET females survived and were phenotypically similar to YAPKO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAPKO impacted the expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment.
CONCLUSIONS
YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAPKO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.
Topics: Animals; Male; Mice; Adaptor Proteins, Signal Transducing; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cholestasis; Endoderm; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Trans-Activators; Transcription Factors; YAP-Signaling Proteins; Female
PubMed: 37556373
DOI: 10.1097/HC9.0000000000000220 -
Stem Cell Research Sep 2023Alagille syndrome (ALGS) is an autosomal dominant disease affecting the liver, heart and other organs with high variability. About 95% of ALGS cases are associated with...
Alagille syndrome (ALGS) is an autosomal dominant disease affecting the liver, heart and other organs with high variability. About 95% of ALGS cases are associated with pathogenic variants in JAG1, encoding the Jagged1 ligand that binds to Notch receptors. The iPSC line NCHi012-A was derived from an ALGS patient with cholestatic liver disease and mild pulmonary stenosis, who is heterozygous for a 2 bp deletion in the JAG1 coding sequence. We report here an initial characterization of NCHi012-A to evaluate its morphology, pluripotency, differentiation potential, genotype, karyotype and identity to the source patient.
Topics: Humans; Alagille Syndrome; Induced Pluripotent Stem Cells; Receptors, Notch; Heart; Jagged-1 Protein
PubMed: 37549562
DOI: 10.1016/j.scr.2023.103177 -
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 -
Pediatric Nephrology (Berlin, Germany) Oct 2023
Topics: Child; Humans; Liver Diseases; Renal Insufficiency, Chronic
PubMed: 37405491
DOI: 10.1007/s00467-023-05949-3