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The Lancet. Child & Adolescent Health Jan 2024Children with Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) experience debilitating pruritus, for which there have been few effective... (Review)
Review
Children with Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC) experience debilitating pruritus, for which there have been few effective treatment options. In the past 2 years, the ileal bile acid transporter (IBAT) inhibitors maralixibat and odevixibat have been approved for the management of cholestatic pruritus in these individuals, representing an important step forward in improving their quality of life. Emerging data suggest these drugs might also improve event-free survival, therefore potentially altering the typical disease course currently seen in these disorders. This Review will discuss how genetic advances have clarified the molecular basis of cholestatic disorders, facilitating the development of new therapeutic options that have only been evaluated in children. We focus specifically on the newly licensed IBAT inhibitors for patients with Alagille syndrome and PFIC and explore the next steps for these drugs in relation to other paediatric and adult cholestatic disorders, recognising that they have the potential to benefit a wider group of patients with gastrointestinal and liver disease.
Topics: Child; Humans; Alagille Syndrome; Quality of Life; Cholestasis; Pruritus
PubMed: 38006895
DOI: 10.1016/S2352-4642(23)00259-6 -
Liver International : Official Journal... Feb 2024Alagille syndrome (ALGS) manifests with peripheral intrahepatic bile duct (IHBD) paucity, which can spontaneously resolve. In a model for ALGS, Jag1 mice, this occurs...
BACKGROUND & AIMS
Alagille syndrome (ALGS) manifests with peripheral intrahepatic bile duct (IHBD) paucity, which can spontaneously resolve. In a model for ALGS, Jag1 mice, this occurs with distinct architectural mechanisms in hilar and peripheral IHBDs. Here, we investigated region-specific IHBD characteristics and addressed whether IGF1, a cholangiocyte mitogen that is downregulated in ALGS and in Jag1 mice, can improve biliary outcomes.
METHODS
Intrahepatic cholangiocyte organoids (ICOs) were derived from hilar and peripheral adult Jag1 and Jag1 livers (hICOs and pICOs, respectively). ICOs were grown in Matrigel or microwell arrays, and characterized using bulk RNA sequencing, immunofluorescence, and high throughput analyses of nuclear sizes. ICOs were treated with IGF1, followed by analyses of growth, proliferation, and death. CellProfiler and Python scripts were custom written for image analyses. Key results were validated in vivo by immunostaining.
RESULTS
Cell growth assays and transcriptomics demonstrated that Jag1 ICOs were less proliferative than Jag1 ICOs. IGF1 specifically rescued survival and growth of Jag1 pICOs. Jag1 hICOs were the least proliferative, with lower Notch signalling and an enrichment of hepatocyte signatures and IGF uptake/transport pathways. In vitro (Jag1 hICOs) and in vivo (Jag1 hilar portal tracts) analyses revealed ectopic HNF4a hepatocytes.
CONCLUSIONS
Hilar and peripheral Jag1 ICOs exhibit differences in Notch signalling status, proliferation, and cholangiocyte commitment which may result in cholangiocyte-to-hepatocyte transdifferentiation. While Jag1 pICOs can be rescued by IGF1, hICOs are unresponsive, perhaps due to their hepatocyte-like state and/or expression of IGF transport components. IGF1 represents a potential therapeutic for peripheral bile ducts.
Topics: Mice; Animals; Alagille Syndrome; Bile Ducts; Biliary Tract; Bile Ducts, Intrahepatic; Organoids
PubMed: 38014627
DOI: 10.1111/liv.15789 -
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 -
Nature Metabolism Dec 2023The thyroid functions as an apex endocrine organ that controls growth, differentiation and metabolism, and thyroid diseases comprise the most common endocrine disorders....
The thyroid functions as an apex endocrine organ that controls growth, differentiation and metabolism, and thyroid diseases comprise the most common endocrine disorders. Nevertheless, high-resolution views of the cellular composition and signals that govern the thyroid have been lacking. Here, we show that Notch signalling controls homeostasis and thermoregulation in adult mammals through a mitochondria-based mechanism in a subset of thyrocytes. We discover two thyrocyte subtypes in mouse and human thyroids, identified in single-cell analyses by different levels of metabolic activity and Notch signalling. Therapeutic antibody blockade of Notch in adult mice inhibits a thyrocyte-specific transcriptional program and induces thyrocyte defects due to decreased mitochondrial activity and ROS production. Thus, disrupting Notch signalling in adult mice causes hypothyroidism, characterized by reduced levels of circulating thyroid hormone and dysregulation of whole-body thermoregulation. Inducible genetic deletion of Notch1 and 2 in thyrocytes phenocopies this antibody-induced hypothyroidism, establishing a direct role for Notch in adult murine thyrocytes. We confirm that hypothyroidism is enriched in children with Alagille syndrome, a genetic disorder marked by Notch mutations, suggesting that these findings translate to humans.
Topics: Adult; Child; Humans; Mice; Animals; Thyroid Epithelial Cells; Mammals; Hypothyroidism; Homeostasis
PubMed: 38123718
DOI: 10.1038/s42255-023-00937-1 -
Ophthalmic Genetics Mar 2024Alagille syndrome (AGS) is a genetic disease with multisystemic affection, including ocular manifestations. Recently, a high frequency of posterior segment findings,...
INTRODUCTION
Alagille syndrome (AGS) is a genetic disease with multisystemic affection, including ocular manifestations. Recently, a high frequency of posterior segment findings, including macular changes, has been reported. This publication aims to report an unusual finding of macular atrophy and a focal choroidal excavation in a patient with JAG1 related AGS.
METHODS
Case report.
RESULTS
This publication describes an atypical presentation of focal choroidal excavation (FCE) and unilateral macular atrophy in a 7-year-old male with Alagille syndrome (AGS). Genetic analysis revealed a pathogenic variant in the JAG1 gene. Ophthalmological examination and imaging findings demonstrated characteristic ocular manifestations of AGS, including posterior embryotoxon, chorioretinal atrophy, and thinning of the choroid.
CONCLUSION
The presence of FCE in AGS is uncommon, and the underlying mechanisms remain unclear. Further exploration of similar cases is necessary to better understand the evolution and visual prognosis in patients with AGS and FCE.
PubMed: 38526149
DOI: 10.1080/13816810.2024.2303786 -
Pharmacological Research Jan 2024Gallbladder and biliary diseases (GBDs) are one of the most common digestive diseases. The connections between GBDs and several organs other than the liver have... (Review)
Review
Gallbladder and biliary diseases (GBDs) are one of the most common digestive diseases. The connections between GBDs and several organs other than the liver have gradually surfaced accompanied by the changes in people's diet structure and the continuous improvement of medical diagnosis technology. Among them, cholecardia syndrome that takes the heart as the important target of GBDs complications has been paid close attention. However, there are still no systematic report about its corresponding clinical manifestations and pathogenesis. This review summarized recent reported types of cholecardia syndrome and found that arrhythmia, myocardial injury, acute coronary syndrome and heart failure are common in the general population. Besides, the clinical diagnosis rate of intrahepatic cholestasis of pregnancy (ICP) and Alagille syndrome associated with gene mutation is also increasing. Accordingly, the underlying pathogenesis including abnormal secretion of bile acid, gene mutation, translocation and deletion (JAG1, NOTCH2, ABCG5/8 and CYP7A1), nerve reflex and autonomic neuropathy were further revealed. Finally, the potential treatment measures and clinical medication represented by ursodeoxycholic acid were summarized to provide assistance for clinical diagnosis and treatment.
Topics: Female; Pregnancy; Humans; Alagille Syndrome; Cholestasis, Intrahepatic; Ursodeoxycholic Acid; Pregnancy Complications
PubMed: 38000562
DOI: 10.1016/j.phrs.2023.107006 -
Journal of Pediatric Gastroenterology... Mar 2024Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in... (Review)
Review
OBJECTIVE
Maralixibat, an ileal bile acid transporter inhibitor, is the first drug approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients aged ≥3 months with Alagille syndrome (ALGS). Approval was based on reductions in pruritus from the pivotal ICONIC trial, information from two additional trials (ITCH and IMAGO), and long-term extension studies. Although participants in these trials met strict inclusion and exclusion criteria, patients have received maralixibat under broader circumstances as part of an expanded access program or commercially. The expanded access and postapproval settings inform a real-world understanding of effectiveness and safety. The objective was to report on the use of maralixibat in the real-world setting in eight patients who otherwise would not have met entrance criteria for the clinical trials, providing unique insights into its effectiveness in the management of ALGS.
METHODS
We reviewed records of patients with ALGS who received maralixibat but would have been excluded from trials due to surgical biliary diversion, reduction of antipruritic/cholestatic concomitant medications, administration of medication through a gastrostomy or nasogastric tube, or use in patients under consideration for transplantation.
RESULTS
Maralixibat appeared to be effective with reductions in pruritus compared to baseline. Consistent with clinical trials, maralixibat was well tolerated without appreciable gastrointestinal complications. Liver enzyme elevations were observed but were interpreted as consistent with normal fluctuations observed in ALGS, with no increases in bilirubin.
CONCLUSION
Maralixibat may be effective and well tolerated in patients with ALGS in broader clinical contexts than previously reported.
Topics: Humans; Alagille Syndrome; Benzothiepins; Cholestasis; Longitudinal Studies; Pruritus; Clinical Trials as Topic; Infant
PubMed: 38334237
DOI: 10.1002/jpn3.12101 -
Hepatology Communications Nov 2023Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The...
BACKGROUND
Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes.
METHODS
Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed.
RESULTS
eSMM was calculated in 127 participants (5-18 y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 ± 1.3) and ALGS (-2.1 ± 1.0) than BASD (-0.1 ± 1.1) and a1ATd (-0.5 ± 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score ≤- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd.
CONCLUSION
Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis.
Topics: Humans; Child; Quality of Life; Sarcopenia; Cholestasis; Bone Diseases, Metabolic; Cholestasis, Intrahepatic
PubMed: 37902507
DOI: 10.1097/HC9.0000000000000293 -
JPGN Reports Nov 2023Biliary atresia (BA) remains the most common indication for pediatric liver transplantation. Early diagnosis is essential for a favorable long-term prognosis for...
BACKGROUND
Biliary atresia (BA) remains the most common indication for pediatric liver transplantation. Early diagnosis is essential for a favorable long-term prognosis for patients with BA. Preliminary data suggests that measurement of direct bilirubin (DB) in newborns may be an effective screening tool for neonatal cholestasis, particularly BA, allowing for early referral and diagnosis. The objective of our study was to establish a cutoff DB value to predict diagnosis of cholestatic liver disease (CLD) with high sensitivity and specificity, as well as, to evaluate whether newborns with elevated DB received appropriate follow-up in our health system.
METHODS
Baseline data were collected on infants born between 2016 and 2019 who had serum total bilirubin and DB drawn in the nursery, and who continued to follow in our health system. Sensitivity, specificity, and positive and negative predictive values were examined using cutoff values of 0.5, 0.6, and 0.7 mg/dL for identifying infants at risk for CLD. Patients' charts were reviewed to note whether they had follow-up levels drawn by their pediatrician or by the hepatology team within 2 months of age and whether they were diagnosed with CLD.
RESULTS
Serum total bilirubin and DB levels were drawn from 11 965 infants during their hospitalizations. Three infants from this cohort were diagnosed with CLD: 2 with BA and 1 with Alagille syndrome. DB cutoff values of 0.5, 0.6, and 0.7 mg/dL had sensitivity of 100% and specificity of 96.83% (95% confidence interval [CI], 96.69%-97.53%), 99.08% (95% CI, 98.81%-99.30%), and 99.63% (95% CI, 99.4%-99.7%), respectively. Given that a DB of 0.6 mg/dL had a sensitivity of 100% and specificity of 99%, this value was chosen as the cutoff value to monitor for DB follow-up and diagnosis of CLD. Out of 60 infants who met criteria for DB ≥0.6 mg/dL, only 15 (25%) had a repeat level drawn after nursery discharge; 3 (5%) were eventually diagnosed with CLD.
CONCLUSIONS
A DB cutoff value of 0.6 mg/dL yielded high sensitivity and specificity for identifying patients with CLD. All 3 patients diagnosed with CLD had elevated DB at hospital discharge. The data revealed that the majority (75%) of eligible newborns did not receive follow-up for their elevated DB in the outpatient setting.
PubMed: 38034462
DOI: 10.1097/PG9.0000000000000345 -
Neuroradiology Feb 2024Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with highly variable expression. Intracranial arterial and venous anomalies have a reported...
PURPOSE
Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with highly variable expression. Intracranial arterial and venous anomalies have a reported prevalence of 30-40% and can increase the risk of stroke by 16%. Few reports document the frequency and evolution of cerebrovascular abnormalities (CVAs) in children with ALGS. We aimed to define the spectrum, frequency, and evolution of CVAs in a series of children with ALGS using magnetic resonance angiography (MRA).
METHODS
We conducted a single-center, retrospective study in a large tertiary pediatric hospital. CVAs were grouped into 4 categories: 1) Stenosis or narrowing; 2) Aneurysms and ectasias; 3) Tortuosity; and 4) Vascular anomalies and anatomical variants.
RESULTS
Thirty-two children met the inclusion criteria. The median age at initial diagnosis was 6 (3.8-10.3) years. Thirteen (40%) had follow-up MRI at a mean of 55 (31.5-66) months. Eighteen (56%) had CVAs; the most frequent fell into group 1 (n = 12, 37.5%). CVAs were stable over time, except for one patient with Moyamoya arteriopathy (MMA). One patient developed a transient ischemic attack secondary to an embolic event. Three (9.3%) had microhemorrhages at the initial diagnosis secondary to Tetralogy of Fallot. Another patient had recurrent subdural hematomas of unknown cause.
CONCLUSION
CVAs were stable except in the presence of MMA. Vascular strokes, which are reported in older patients with ALGS, were not a common feature in children under 16 years of age, either at presentation or over the 31.5-66 month follow-up period.
PubMed: 38400955
DOI: 10.1007/s00234-024-03316-z