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Hepatology (Baltimore, Md.) Jun 2024Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter... (Comparative Study)
Comparative Study
BACKGROUND AND AIMS
Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study.
APPROACH AND RESULTS
Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings.
CONCLUSIONS
This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.
Topics: Humans; Alagille Syndrome; Female; Male; Retrospective Studies; Child; Infant; Child, Preschool; Progression-Free Survival; Adolescent; Carrier Proteins; Membrane Glycoproteins
PubMed: 38146932
DOI: 10.1097/HEP.0000000000000727 -
The Application of Clinical Genetics 2016Alagille syndrome is an autosomal dominant, complex multisystem disorder characterized by the presence of three out of five major clinical criteria: cholestasis with... (Review)
Review
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.
PubMed: 27418850
DOI: 10.2147/TACG.S86420 -
World Journal of Gastroenterology Mar 2024Several diseases originate from bile duct pathology. Despite studies on these diseases, certain etiologies of some of them still cannot be concluded. The most common... (Review)
Review
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.
Topics: Infant; Child; Infant, Newborn; Humans; Bile Ducts; Biliary Atresia; Choledochal Cyst; Bile Duct Diseases; Cholangiography
PubMed: 38577180
DOI: 10.3748/wjg.v30.i9.1043 -
Indian Journal of Otolaryngology and... Dec 2022Alagille Syndrome (ALGS) is a rare, autosomal dominant inherited disorder that causes abnormalities of liver, eye, heart, skeleton and distinctive facial appearance....
Alagille Syndrome (ALGS) is a rare, autosomal dominant inherited disorder that causes abnormalities of liver, eye, heart, skeleton and distinctive facial appearance. ALGS is caused by mutation in one of two genes: JAG1 and NOTCH2. There are some reports of Hearing Loss in patients with ALGS raising the possibility of involvement of both structural components of middle ear and sensorineural components of the inner ear. The present case study was to emphasize audiological perspectives of Alagille Syndrome in a nine year old female child. Audiologists must be well aware of the typical features and clinical perspectives of ALGS and should be an expert in selecting appropriate tests and in interpreting findings.
PubMed: 36742831
DOI: 10.1007/s12070-020-02293-y -
World Journal of Gastroenterology Jul 2014Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic... (Review)
Review
Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have "silent" progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.
Topics: Alagille Syndrome; Biliary Atresia; Chemical and Drug Induced Liver Injury; Cholestasis; Cholestasis, Intrahepatic; Female; Genetic Predisposition to Disease; Heredity; Humans; Male; Parenteral Nutrition, Total; Pedigree; Phenotype; Pregnancy; Pregnancy Complications; Prognosis; Recurrence; Risk Factors; Sepsis
PubMed: 25071336
DOI: 10.3748/wjg.v20.i28.9418 -
Cardiovascular Diagnosis and Therapy Apr 2018A variety of syndromes are associated with thoracoabdominal aortic pathologies. While these diseases are collectively rare, the presence of advanced or unusual aortic... (Review)
Review
A variety of syndromes are associated with thoracoabdominal aortic pathologies. While these diseases are collectively rare, the presence of advanced or unusual aortic disease at a young age should raise suspicion of an underlying syndrome. Similarly, patients with a known syndrome require close monitoring in anticipation of future aortic disease. In this article, the syndromes most commonly encountered in clinical practice are reviewed, including Marfan syndrome (MFS) and other connective tissue disorders, Turner syndrome (TS), autosomal dominant polycystic kidney disease (ADPKD), neurofibromatosis (NF), Williams syndrome (WS), Alagille syndrome (AGS), and DiGeorge syndrome (DGS). The distinct clinical, imaging, and management features of each disorder are discussed. Attention is focused on the unique patterns of aortic disease in each syndrome, emphasizing the role of recent imaging modalities and treatment strategies. Ancillary and distinguishing aspects of the syndromes that aid in diagnosis are also highlighted.
PubMed: 29850420
DOI: 10.21037/cdt.2017.09.14 -
Hepatology Communications Dec 2023Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the...
Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis.
Topics: Humans; Alagille Syndrome; Quality of Life; Cholestasis; Pruritus
PubMed: 38055640
DOI: 10.1097/HC9.0000000000000314 -
Annual Review of Pathology Jan 2024Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert.... (Review)
Review
Cholestasis is the predominate feature of many pediatric hepatobiliary diseases. The physiologic flow of bile requires multiple complex processes working in concert. Bile acid (BA) synthesis and excretion, the formation and flow of bile, and the enterohepatic reuptake of BAs all function to maintain the circulation of BAs, a key molecule in lipid digestion, metabolic and cellular signaling, and, as discussed in the review, a crucial mediator in the pathogenesis of cholestasis. Disruption of one or several of these steps can result in the accumulation of toxic BAs in bile ducts and hepatocytes leading to inflammation, fibrosis, and, over time, biliary and hepatic cirrhosis. Biliary atresia, progressive familial intrahepatic cholestasis, primary sclerosing cholangitis, and Alagille syndrome are four of the most common pediatric cholestatic conditions. Through understanding the commonalities and differences in these diseases, the important cellular mechanistic underpinnings of cholestasis can be greater appreciated.
Topics: Child; Humans; Cholestasis; Cholestasis, Intrahepatic; Hepatocytes; Inflammation
PubMed: 38265882
DOI: 10.1146/annurev-pathmechdis-031521-025623 -
Euroasian Journal of... 2018Alagille syndrome (ALGS) is an autosomal dominant disorder, with multisystem involvement, which usually occurs due to Notch signaling pathway defects, mostly due to... (Review)
Review
Alagille syndrome (ALGS) is an autosomal dominant disorder, with multisystem involvement, which usually occurs due to Notch signaling pathway defects, mostly due to 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. Singh SP, Pati GK. Alagille Syndrome and the Liver: Current Insights. Euroasian J Hepatogastroenterol, 2018;8(2):140-147.
PubMed: 30828556
DOI: 10.5005/jp-journals-10018-1280 -
Therapeutic Advances in Gastroenterology 2023Pruritus is a symptom of several cholestatic liver diseases (CLDs) that can impair health-related quality of life (HRQoL). Despite evidence-based guideline therapy,... (Review)
Review
BACKGROUND
Pruritus is a symptom of several cholestatic liver diseases (CLDs) that can impair health-related quality of life (HRQoL). Despite evidence-based guideline therapy, managing cholestatic pruritus (CP) remains challenging, thus making the need for newer, more effective therapeutic agents more evident.
OBJECTIVE
Our study evaluated the efficacy of existing CP therapies.
DESIGN
Systematic review.
DATA SOURCES
From inception until March 2023, we conducted a comprehensive search of MEDLINE, Cochrane, EMBASE, Scopus, ClinicalTrial.gov, and other sources, including pharmaceutical webpages and conference proceedings published in English that reported on CP interventions.
METHODS
Two reviewers independently conducted screening and full-text review of articles with extraction conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The methodological quality of studies included in our qualitative synthesis was assessed by using the Cochrane ROBINS-I and ROBINS-II tools for interventional studies and the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The primary outcome assessed in our systematic review was the severity of CP after therapy.
RESULTS
Of 3293 screened articles, 92 studies were eligible for inclusion in the qualitative synthesis. Some patients' HRQoL improved with evidence-based standard therapy. Others, particularly those with severe and refractory CP, often required conversion to or addition of experimental noninvasive (e.g., ondansetron) or extracorporeal liver support to alleviate CP. In addition, studies investigating a newer class drug, the ileal bile acid transporter inhibitor (IBATi), demonstrate its effectiveness in reducing serum bile acid and alleviating CP with sustained improvement noted in patients with the inherited childhood cholestatic disorders - progressive familial intrahepatic cholestasis and Alagille syndrome.
CONCLUSION
Our findings consolidate data on the efficacy of guideline-based approaches and newer therapies for CP. While the initial findings are promising, additional clinical trials will be needed to determine the full extent of IBATi's efficacy and potential use in treating other common CLDs. These results provide a foundation for future research and highlight the need for continued investigation into the management and treatment of CLDs.
PubMed: 37255856
DOI: 10.1177/17562848231172829