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Seminars in Liver Disease Nov 2021Alagille syndrome (ALGS) is an autosomal dominant disorder caused by pathogenic variants in or , which encode fundamental components of the Notch signaling pathway.... (Review)
Review
Alagille syndrome (ALGS) is an autosomal dominant disorder caused by pathogenic variants in or , which encode fundamental components of the Notch signaling pathway. Clinical features span multiple organ systems including hepatic, cardiac, vascular, renal, skeletal, craniofacial, and ocular, and occur with variable phenotypic penetrance. Genotype-phenotype correlation studies have not yet shown associations between mutation type and clinical manifestations or severity, and it has been hypothesized that modifier genes may modulate the effects of and pathogenic variants. Medical management is supportive, focusing on clinical manifestations of disease, with liver transplant indicated for severe pruritus, liver synthetic dysfunction, portal hypertension, bone fractures, and/or growth failure. New therapeutic approaches are under investigation, including ileal bile acid transporter (IBAT) inhibitors and other approaches that may involve targeted interventions to augment the Notch signaling pathway in involved tissues.
Topics: Alagille Syndrome; Humans; Jagged-1 Protein; Mutation; Receptor, Notch2; Signal Transduction
PubMed: 34215014
DOI: 10.1055/s-0041-1730951 -
Clinics in Liver Disease Aug 2022Alagille syndrome (ALGS) is a complex heterogenous disease with a wide array of clinical manifestations in association with cholestatic liver disease. Major clinical and... (Review)
Review
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.
Topics: Alagille Syndrome; Humans; Jagged-1 Protein; Phenotype; Receptor, Notch2
PubMed: 35868679
DOI: 10.1016/j.cld.2022.03.002 -
Drugs Jan 2022Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the... (Review)
Review
Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.
Topics: Humans; Alagille Syndrome; Biliary Atresia; Carrier Proteins; Cholestasis, Intrahepatic; Clinical Trials as Topic; Drug Approval; Membrane Glycoproteins; United States; United States Food and Drug Administration; Benzothiepins
PubMed: 34813049
DOI: 10.1007/s40265-021-01649-0 -
Indian Journal of Pediatrics Sep 2019Hyperbilirubinemia is a common occurrence in neonates; it may be physiological or pathological. Conjugated hyperbilirubinemia may result from medical or surgical causes,... (Review)
Review
Hyperbilirubinemia is a common occurrence in neonates; it may be physiological or pathological. Conjugated hyperbilirubinemia may result from medical or surgical causes, and can result in irreversible liver damage if untreated. The aim of imaging is the timely diagnosis of surgical conditions like biliary atresia and choledochal cysts. Abdominal ultrasound is the first line imaging modality, and Magnetic resonance cholangiopancreatography (MRCP) also has a role, especially in pre-operative assessment of choledochal cysts (CDCs). For biliary atresia, the triangular cord sign and gallbladder abnormalities are the two most useful ultrasound features, with a combined sensitivity of 95%. Liver biopsy has an important role in pre-operative evaluation; however, the gold standard for diagnosis of biliary atresia remains an intra-operative cholangiogram. Choledochal cysts are classified into types according to the number, location, extent and morphology of the areas of cystic dilatation. They are often associated with an abnormal pancreaticobiliary junction, which is best assessed on MRCP. Caroli's disease or type 5 CDC comprises of multiple intrahepatic cysts. CDCs, though benign, require surgery as they may be associated with complications like cholelithiasis, cholangitis and development of malignancy. Severe unconjugated hyperbilirubinemia puts neonates at high risk of developing bilirubin induced brain injury, which may be acute or chronic. Magnetic resonance imaging of the brain is the preferred modality for evaluation, and shows characteristic involvement of the globus pallidi, subthalamic nuclei and cerebellum - in acute cases, these areas show T1 hyperintensity, while chronic cases typically show hyperintensity on T2 weighted images.
Topics: Alagille Syndrome; Biliary Atresia; Bilirubin; Biopsy; Brain Injuries; Cholangiography; Cholangiopancreatography, Magnetic Resonance; Cholangitis; Choledochal Cyst; Diagnostic Imaging; Hepatitis; Humans; Infant, Newborn; Jaundice, Neonatal; Liver; Magnetic Resonance Imaging; Ultrasonography
PubMed: 30790186
DOI: 10.1007/s12098-019-02856-0 -
Lancet (London, England) Oct 2021Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Alagille syndrome is a rare genetic disease that often presents with severe cholestasis and pruritus. There are no approved drugs for management. Maralixibat, an apical, sodium-dependent, bile acid transport inhibitor, prevents enterohepatic bile acid recirculation. We evaluated the safety and efficacy of maralixibat for children with cholestasis in Alagille syndrome.
METHODS
ICONIC was a placebo-controlled, randomised withdrawal period (RWD), phase 2b study with open-label extension in children (aged 1-18 years) with Alagille syndrome (NCT02160782). Eligible participants had more than three times the normal serum bile acid (sBA) levels and intractable pruritus. After 18 weeks of maralixibat 380 μg/kg once per day, participants were randomly assigned (1:1) to continue maralixibat or receive placebo for 4 weeks. Subsequently, all participants received open-label maralixibat until week 48. During the long-term extension (204 weeks reported), doses were increased up to 380 μg/kg twice per day. The primary endpoint was the mean sBA change during the RWD in participants with at least 50% sBA reduction by week 18. Cholestastic pruritus was assessed using observer-rated, patient-rated, and clinician-rated 0-4 scales. The safety population was defined as all participants who had received at least one dose of maralixibat. This trial was registered with ClinicalTrials.gov, NCT02160782, and is closed to recruitment.
FINDINGS
Between Oct 28, 2014, and Aug 14, 2015, 31 participants (mean age 5·4 years [SD 4·25]) were enrolled and 28 analysed at week 48. Of the 29 participants who entered the randomised drug withdrawal period, ten (34%) were female and 19 (66%) were male. In the RWD, participants switched to placebo had significant increases in sBA (94 μmol/L, 95% CI 23 to 164) and pruritus (1·7 points, 95% CI 1·2 to 2·2), whereas participants who continued maralixibat maintained treatment effect. This study met the primary endpoint (least square mean difference -117 μmol/L, 95% CI -232 to -2). From baseline to week 48, sBA (-96 μmol/L, -162 to -31) and pruritus (-1·6 pts, -2·1 to -1·1) improved. In participants who continued to week 204 (n=15) all improvements were maintained. Maralixibat was generally safe and well tolerated throughout. The most frequent adverse events were gastrointestinal related. Most adverse events were self-limiting in nature and mild-to-moderate in severity.
INTERPRETATION
In children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome.
FUNDING
Mirum Pharmaceuticals.
Topics: Adolescent; Alagille Syndrome; Carrier Proteins; Child; Child, Preschool; Female; Humans; Infant; Male; Membrane Glycoproteins; Pruritus; Treatment Outcome
PubMed: 34755627
DOI: 10.1016/S0140-6736(21)01256-3 -
Seminars in Pediatric Surgery Aug 2020Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic... (Review)
Review
Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic disorders. A timely evaluation for its etiology is critical in order to quickly identify treatable causes such as biliary atresia, many of which benefit from early therapy. An expanding group of molecularly defined disorders involving bile formation, canalicular transporters, tight junction proteins and inborn errors of metabolism are being continuously discovered because of advances in genetic testing and bioinformatics. The advent of next generation sequencing has transformed our ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks, enabling rapid and affordable molecular diagnosis for disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Thus, our diagnostic algorithms for neonatal cholestasis are undergoing transformation, moving genetic sequencing to earlier in the evaluation pathway once biliary atresia, "red flag" disorders and treatable disorders are excluded. Current therapies focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, without addressing the underlying cause of cholestasis in most instances. Our improved understanding of bile formation and the enterohepatic circulation of bile acids has led to emerging therapies for cholestasis which require appropriate pediatric clinical trials. Despite these advances, the cause and optimal therapy for biliary atresia remain elusive. The goals of this review are to outline the etiologies, diagnostic pathways and current and emerging management strategies for neonatal cholestasis.
Topics: Cholestasis; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases
PubMed: 32861449
DOI: 10.1016/j.sempedsurg.2020.150945 -
Human Mutation Dec 2019Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1...
Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1 (JAG1), but also by variants in NOTCH2. The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants. Conversely, the majority of NOTCH2 variants are missense, though fewer of these variants have been described. In addition, there is a small group of patients with a clear clinical phenotype in the absence of a pathogenic variant. Here, we catalog our single-center study, which includes 401 probands and 111 affected family members amassed over a 27-year period, to provide updated mutation frequencies in JAG1 and NOTCH2 as well as functional validation of nine missense variants. Combining our cohort of 86 novel JAG1 and three novel NOTCH2 variants with previously published data (totaling 713 variants), we present the most comprehensive pathogenic variant overview for Alagille syndrome. Using this data set, we developed new guidance to help with the classification of JAG1 missense variants. Finally, we report clinically consistent cases for which a molecular etiology has not been identified and discuss the potential for next generation sequencing methodologies in novel variant discovery.
Topics: Alagille Syndrome; Female; Genetic Predisposition to Disease; Humans; Jagged-1 Protein; Loss of Function Mutation; Male; Mutation Rate; Mutation, Missense; Pedigree; Receptor, Notch2
PubMed: 31343788
DOI: 10.1002/humu.23879 -
Hepatology (Baltimore, Md.) Feb 2023Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data...
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.
Topics: Humans; Child; Male; Female; Alagille Syndrome; Retrospective Studies; Cholestasis; Hypertension, Portal
PubMed: 36036223
DOI: 10.1002/hep.32761