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Hepatology (Baltimore, Md.) Feb 2023
Topics: Humans; Alagille Syndrome
PubMed: 36036191
DOI: 10.1002/hep.32760 -
Fetal and Pediatric Pathology Feb 2021This review aims to highlight the clinicopathological characteristics and differential diagnosis of central hepatic regenerative nodules (CHRNs) in patients with... (Review)
Review
OBJECTIVE
This review aims to highlight the clinicopathological characteristics and differential diagnosis of central hepatic regenerative nodules (CHRNs) in patients with Alagille syndrome.
METHODS
A review of the literature for cases of CHRNs and their differential diagnoses in patients with Alagille syndrome was performed and the main findings were collated.
RESULTS
Large, regenerative hepatic nodules are seen in approximately 30% of patients with Alagille syndrome. They are thought to be a functional adaptation to vascular changes rather than a neoplastic process. The nodules are typically centrally located, and normal hepatic vasculature coursing through the lesions are noted radiologically. Microscopically, they are characterized by well-circumscribed hepatic lesions with preserved architecture, lesser degrees of fibrosis and relative preservation of interlobular bile ducts compared to the background cirrhotic liver.
CONCLUSION
Regenerative nodules are common in Alagille's syndrome, and should be distinguished from hepatocellular carcinomas and adenomas for appropriate management and prognostication.
Topics: Alagille Syndrome; Carcinoma, Hepatocellular; Diagnosis, Differential; Humans; Liver; Liver Neoplasms
PubMed: 31608763
DOI: 10.1080/15513815.2019.1675834 -
Transgender Health Feb 2023Alagille syndrome is a rare autosomal dominant disorder with variable expression. Liver damage, especially cholestatic, is the most common feature of the syndrome....
Alagille syndrome is a rare autosomal dominant disorder with variable expression. Liver damage, especially cholestatic, is the most common feature of the syndrome. Transgender patients may suffer from a great distress due to the discrepancy between assigned sex at birth and unaffirmed gender identity. Gender affirmation treatment options for these patients include hormone therapy (HT) to induce secondary sexual characteristics and various surgical procedures. Estrogen-based hormonal treatments have been linked to an increased risk of liver enzyme elevation and disruption of bilirubin metabolism, especially in those with a genetic susceptibility. The case presented here is the first described Alagille syndrome transgender patient to undergo gender affirmation treatment, including (HT) and vulvo-vaginoplasty surgery.
PubMed: 36895310
DOI: 10.1089/trgh.2021.0023 -
Hepatology (Baltimore, Md.) Feb 2023Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for...
BACKGROUND AND AIMS
Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.
APPROACH AND RESULTS
A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS.
CONCLUSIONS
Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.
Topics: Humans; Child; Liver; Matrix Metalloproteinase 7; Endoglin; Interleukin-8; Cholestasis; Liver Cirrhosis; Liver Diseases; Biomarkers; Alagille Syndrome; Elasticity Imaging Techniques
PubMed: 36069569
DOI: 10.1002/hep.32777 -
Bone Dec 2020Alagille syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility...
Alagille syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. This was a cross-sectional study of 10 children (9 females), ages 8-18 years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20 years (n = 247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p < .05), were significantly less than zero. DXA bone Z-scores were not significantly different from zero, but were highly variable. For pQCT bone measures, Z-scores for total bone mineral content at the distal 3% site and cortical bone mineral content, cortical area, and cortical thickness at the distal 38% site were significantly less than zero (all p < .05). There was good correspondence between pQCT measures of cortical thickness Z-scores and DXA Z-scores for aBMD at the whole body less head, 1/3 radius, and femoral neck (all p < .05). Compared to healthy children, those with ALGS generally had lower trabecular number and greater trabecular separation despite having greater trabecular thickness (measured via HR-pQCT). Bilirubin and bile acids, markers of hepatic cholestasis, were associated with poorer bone measures. For example, greater bilirubin was associated with lower trabecular number (Spearman's rho [ρ] = -0.82, p = .023) and greater trabecular separation (ρ = 0.82, p = .023) measured via HR-pQCT, and greater bile acids were associated with lower cortical area measured via pQCT (ρ = -0.78, p = .041) and lower serum insulin-like growth factor-1 (ρ = -0.86, p = .002). In summary, deficits in cortical bone size and trabecular bone microarchitecture were evident in children with ALGS. Further investigation is needed to understand the factors contributing to these skeletal inadequacies, and the manner in which these deficits contribute to increased fracture risk.
Topics: Absorptiometry, Photon; Adolescent; Adult; Alagille Syndrome; Bone Density; Child; Child, Preschool; Cross-Sectional Studies; Female; Humans; Radius; Tibia; Tomography, X-Ray Computed; Young Adult
PubMed: 32791330
DOI: 10.1016/j.bone.2020.115576 -
Genes Oct 2023Axenfeld-Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. and variants explain the majority of...
Axenfeld-Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. and variants explain the majority of individuals with Axenfeld-Rieger syndrome (ARS) but leave ~30% unsolved. Here, we present pathogenic/likely pathogenic variants in nine families with ARA/ARS or similar phenotypes affecting five different genes/regions. and explained three families each. was recently linked with syndromic cognitive impairment that includes hearing loss, dental defects, ventriculomegaly, Dandy-Walker malformation, skeletal anomalies (hip dysplasia), and other features showing a significant overlap with -ARS. Anterior segment anomalies are not currently associated with , yet our cases demonstrate ARA, congenital glaucoma, corneal neovascularization, and cataracts. The identification of variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA/ARS highlights the overlapping features and high variability of these two phenotypes. Finally, intragenic variants in , , and an X chromosome deletion encompassing and (linked with ocular and dental anomalies, correspondingly) were identified in three additional cases with ARS. Accurate diagnosis has important implications for clinical management. We suggest that broad testing such as exome sequencing be applied as a second-tier test for individuals with ARS with normal results for sequencing and copy number analysis, with attention to the described genes/regions.
Topics: Humans; Transcription Factors; Homeodomain Proteins; Anterior Eye Segment; Eye Abnormalities; Ubiquitin Thiolesterase
PubMed: 37895297
DOI: 10.3390/genes14101948 -
Pediatric Radiology Apr 2022Although radiographs are generally performed in the neonatal period to evaluate for causes of respiratory distress or to evaluate line placement, close attention to the... (Review)
Review
Although radiographs are generally performed in the neonatal period to evaluate for causes of respiratory distress or to evaluate line placement, close attention to the osseous structures can provide important clues to an underlying diagnosis. Although segmentation anomalies can be random, they are frequently associated with more complex entities such as VACTERL association. A butterfly vertebral body can hint at a possible diagnosis of Alagille syndrome even before jaundice develops in an infant with a murmur. Close evaluation of the sacrum can identify abnormalities that point to caudal regression or Currarino triad. Other classic musculoskeletal abnormalities in the extremities are readily apparent on physical exam but require radiographic evaluation to define anatomy. Diagnoses such as congenital pseudoarthrosis of the clavicle, Apert syndrome, constriction band syndrome, and proximal focal femoral deficiency have pathognomonic imaging findings. Given that treatment for these is usually delayed until later in life, extremity imaging might not occur in the neonatal period.
Topics: Anal Canal; Digestive System Abnormalities; Humans; Infant; Infant, Newborn; Limb Deformities, Congenital; Musculoskeletal Abnormalities; Sacrum
PubMed: 34731287
DOI: 10.1007/s00247-021-05200-x -
Biochemical Pharmacology Jan 2023Metabolic bone diseases is the third most common endocrine diseases after diabetes and thyroid diseases. More than 500 million people worldwide suffer from metabolic... (Review)
Review
Metabolic bone diseases is the third most common endocrine diseases after diabetes and thyroid diseases. More than 500 million people worldwide suffer from metabolic bone diseases. The generation and development of bone metabolic diseases is a complex process regulated by multiple signaling pathways, among which the Notch signaling pathway is one of the most important pathways. The Notch signaling pathway regulates the differentiation and function of osteoblasts and osteoclasts, and affects the process of cartilage formation, bone formation and bone resorption. Genetic mutations in upstream and downstream of Notch signaling genes can lead to a series of metabolic bone diseases, such as Alagille syndrome, Adams-Oliver syndrome and spondylocostal dysostosis. In this review, we analyzed the mechanisms of Notch ligands, Notch receptors and signaling molecules in the process of signal transduction, and summarized the progress on the pathogenesis and clinical manifestations of bone metabolic diseases caused by Notch gene mutation. We hope to draw attention to the role of the Notch signaling pathway in metabolic bone diseases and provide new ideas and approaches for the diagnosis and treatment of metabolic bone diseases.
Topics: Humans; Bone Diseases, Metabolic; Bone Resorption; Cell Differentiation; Osteoblasts; Osteoclasts; Receptors, Notch; Signal Transduction
PubMed: 36513140
DOI: 10.1016/j.bcp.2022.115377 -
Indian Journal of Pediatrics Nov 2016Jaundice with pruritus is a manifestation of cholestasis. The defective biliary drainage causes accumulation of substances that are usually excreted in bile, which in... (Review)
Review
Jaundice with pruritus is a manifestation of cholestasis. The defective biliary drainage causes accumulation of substances that are usually excreted in bile, which in turn causes pruritus. The exact nature of the pruritogen is under evaluation. However, lysophosphatidic acid is the current favourite. The causes of cholestasis can be broadly classified as intra or extrahepatic, with intrahepatic disorders being more often associated with pruritus. Cholestatic phase of acute viral hepatitis, progressive familial intrahepatic cholestasis, syndromic and non-syndromic paucity of intralobular bile ductules, drug induced cholestasis and sclerosing cholangitis (SC) are the common causes in children. An algorithmic approach facilitates early etiological diagnosis by careful clinical evaluation combined with investigations including gamma glutamyl transpeptidase, radiological imaging (ultrasonography, magnetic resonance cholangiopancreatography), liver biopsy and genetic analysis. Management is largely supportive and includes nutritional rehabilitation with supplement of fat soluble vitamins and calcium, stepwise therapy of pruritus with drugs (ursodeoxycholic acid, rifampicin, bile acid sequestrants and/or opioid antagonists) and biliary diversion surgery. Complications of advanced liver disease and portal hypertension need to be addressed. Liver transplantation is required in children with refractory pruritus affecting the quality of life or those with end stage liver disease. Relief of biliary obstruction by endoscopy or surgery and treatment of diseases associated with SC like histiocytosis may be rewarding. Long-term follow-up for development of complications of liver disease and hepatocellular/ cholangiocarcinoma is essential. Thus, an early diagnosis and stepwise treatment with an understanding of the pathogenesis of pruritus in cholestatic disorders may decrease morbidity and mortality.
Topics: Carcinoma, Hepatocellular; Child; Cholestasis; Cholestasis, Intrahepatic; Humans; Jaundice; Liver Neoplasms; Pruritus; Quality of Life
PubMed: 26932879
DOI: 10.1007/s12098-016-2058-6 -
Biology May 2023Pruritus in the setting of cholestatic liver disease is difficult to treat and occurs in patients ranging in age from infancy to adulthood. Likely multifactorial in... (Review)
Review
Pruritus in the setting of cholestatic liver disease is difficult to treat and occurs in patients ranging in age from infancy to adulthood. Likely multifactorial in etiology, this symptom often involves multimodal therapy targeting several pathways and mechanisms proposed in the underlying etiology of cholestatic pruritus. Many patients in both the pediatric and adult populations continue to experience unrelenting pruritus despite maximal conventional therapy. Options are further limited in treating pediatric patients due to sparse data regarding medication safety and efficacy in younger patients. Conventional therapies for the treatment of cholestatic pruritus in children include ursodeoxycholic acid, cholestyramine, hydroxyzine, and rifampin. Certain therapies are more routinely used in the adult populations but with limited data available for use in child and adolescent patients, including opioid antagonists and selective serotonin reuptake inhibitors. Recently, ileal bile acid transport inhibitors have been shown to alleviate pruritus in many children with Alagille syndrome and progressive familial intrahepatic cholestasis and is an additional therapy available for consideration for these patients. Ultimately, surgical options such as biliary diversion or liver transplantation are considered in specific circumstances when medical therapies have been exhausted and pruritus remains debilitating. While further investigation regarding underlying etiologies and effective therapies are needed to better understand itch pathogenesis and treatment in pediatric cholestasis, current considerations beyond conventional management include the use of opioid antagonists, selective serotonin reuptake inhibitors, ileal bile acid transport inhibitors, and surgical intervention.
PubMed: 37237568
DOI: 10.3390/biology12050756