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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 -
Revue Medicale Suisse Aug 2019Alagille syndrome is a rare disorder with low physician awareness. It affects multiple organs and thus patient management involves several medical specialties. It is an... (Review)
Review
Alagille syndrome is a rare disorder with low physician awareness. It affects multiple organs and thus patient management involves several medical specialties. It is an autosomal dominant disorder with significant intrafamilial variability. The most frequent clinical manifestations are neonatal jaundice, chronic cholestasis as well as cardiac, ocular and skeletal malformations associated with characteristic facial features. Inherited mutations affect the Notch pathway. Although the molecular basis of Alagille syndrome is well defined, no specific targeted therapy exists.
Topics: Alagille Syndrome; Humans
PubMed: 31496175
DOI: No ID Found -
Hepatology (Baltimore, Md.) Dec 2023Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated...
BACKGROUND AND AIMS
Refractory pruritus and other complications of cholestasis are indications for liver transplantation (LT) in patients with Alagille syndrome (ALGS). We evaluated predictors of event-free survival and transplant-free survival in patients with ALGS treated with maralixibat (MRX), an ileal bile acid transporter inhibitor.
APPROACH AND RESULTS
We assessed patients with ALGS from 3 clinical trials of MRX with up to 6 years of follow-up. Event-free survival was defined as the absence of LT, surgical biliary diversion, hepatic decompensation, or death; transplant-free survival was the absence of LT or death. Forty-three potential predictors were evaluated, including age, pruritus (ItchRO[Obs] 0-4 scale), biochemistries, platelets, and serum bile acids. Harrell's concordance statistic assessed goodness-of-fit, and then, Cox proportional hazard models confirmed the statistical significance of the predictors identified. A further analysis was performed to identify cutoffs using a grid search. Seventy-six individuals met the criteria of receiving MRX for ≥48 weeks with laboratory values available at week 48 (W48). The median duration of MRX was 4.7 years (IQR: 1.6-5.8); 16 had events (10 LT, 3 decompensation, 2 death, and 1 surgical biliary diversion). The 6-year event-free survival improved with a clinically meaningful >1-point ItchRO(Obs) reduction from baseline to W48 (88% vs. 57%; p = 0.005), W48 bilirubin < 6.5 mg/dL (90% vs. 43%; p < 0.0001), and W48 serum bile acid < 200 µmol/L (85% vs. 49%; p = 0.001). These parameters were also predictive of 6-year transplant-free survival.
CONCLUSIONS
Improvement in pruritus by 48 weeks, and lower W48 bilirubin and serum bile acid levels were associated with fewer events. These data may help identify potential markers of disease progression for ALGS patients treated with MRX.
Topics: Humans; Alagille Syndrome; Progression-Free Survival; Retrospective Studies; Bilirubin; Pruritus; Bile Acids and Salts
PubMed: 37278241
DOI: 10.1097/HEP.0000000000000502 -
Current Gastroenterology Reports Nov 2023Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and... (Review)
Review
PURPOSE OF REVIEW
Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies.
RECENT FINDINGS
Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge.
Topics: Humans; Child; Infant; Child, Preschool; Cholestasis; Cholestasis, Intrahepatic; Alagille Syndrome; Pruritus
PubMed: 37651067
DOI: 10.1007/s11894-023-00891-8 -
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 -
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 -
Lancet (London, England) Aug 2023
Topics: Humans; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Peptides
PubMed: 37369233
DOI: 10.1016/S0140-6736(23)01201-1 -
Diagnostics (Basel, Switzerland) Nov 2020Alagille syndrome (ALGS) is a multisystem disease characterized by cholestasis and bile duct paucity on liver biopsy in addition to variable involvement of the heart,... (Review)
Review
Alagille syndrome (ALGS) is a multisystem disease characterized by cholestasis and bile duct paucity on liver biopsy in addition to variable involvement of the heart, eyes, skeleton, face, kidneys, and vasculature. The identification of and as disease-causing genes has deepened our understanding of the molecular mechanisms underlying ALGS. However, the variable expressivity of the clinical phenotype and the lack of genotype-phenotype relationships creates significant diagnostic and therapeutic challenges. In this review, we provide a comprehensive overview of the clinical characteristics and management of ALGS, and the molecular basis of ALGS pathobiology. We further describe unique diagnostic considerations that pose challenges to clinicians and outline therapeutic concepts and treatment targets that may be available in the near future.
PubMed: 33172025
DOI: 10.3390/diagnostics10110907 -
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