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Journal of Pediatric Gastroenterology... Aug 2018Alagille syndrome (ALGS) is an inherited multisystem disorder typically manifesting as cholestasis, and potentially leading to end-stage liver disease and death. The aim...
BACKGROUND AND AIM
Alagille syndrome (ALGS) is an inherited multisystem disorder typically manifesting as cholestasis, and potentially leading to end-stage liver disease and death. The aim of the study was to perform the first systematic review of the epidemiology, natural history, and burden of ALGS with a focus on the liver component.
METHODS
Electronic databases and proceedings from key congresses were searched in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines. This analysis included publications reporting epidemiology, natural history, economic burden or health-related quality of life (HRQoL) outcomes in patients with ALGS.
RESULTS
Of 525 screened publications, 20 met the inclusion criteria. Liver-related features included cholestasis (87%-100% of patients), jaundice (66%-85%), and cirrhosis (44%-95%). Between 15% and 47% of patients underwent liver transplantation and 4% to 14% received partial biliary diversion. Pruritus affected the majority of patients (59%-88%, of whom up to 45% had severe pruritus) and manifested during the first 10 years of life. Children with ALGS had significantly impaired HRQoL compared with healthy controls and those with other diseases. Itching was the symptom that most affected children with ALGS. No study assessed the economic burden of ALGS.
CONCLUSIONS
Our findings consolidate information on the clinical course of ALGS, and highlight gaps in knowledge, most notably the absence of any research on the economic consequences of the disease. Further research is needed to establish the incidence of genetically confirmed ALGS. Disease-specific tools are also needed to improve the measurement of symptoms, such as itching, and better understand the impact of ALGS on HRQoL.
Topics: Alagille Syndrome; Child; Humans
PubMed: 29543694
DOI: 10.1097/MPG.0000000000001958 -
Cardiology in the Young Jan 2016CHD is frequently associated with a genetic syndrome. These syndromes often present specific cardiovascular and non-cardiovascular co-morbidities that confer significant... (Review)
Review
CHD is frequently associated with a genetic syndrome. These syndromes often present specific cardiovascular and non-cardiovascular co-morbidities that confer significant peri-operative risks affecting multiple organ systems. Although surgical outcomes have improved over time, these co-morbidities continue to contribute substantially to poor peri-operative mortality and morbidity outcomes. Peri-operative morbidity may have long-standing ramifications on neurodevelopment and overall health. Recognising the cardiovascular and non-cardiovascular risks associated with specific syndromic diagnoses will facilitate expectant management, early detection of clinical problems, and improved outcomes--for example, the development of syndrome-based protocols for peri-operative evaluation and prophylactic actions may improve outcomes for the more frequently encountered syndromes such as 22q11 deletion syndrome.
Topics: 22q11 Deletion Syndrome; Alagille Syndrome; Heart Defects, Congenital; Heart Diseases; Heterotaxy Syndrome; Humans; Infant; Marfan Syndrome; Noonan Syndrome; Risk Factors; Syndrome; Time Factors; Treatment Outcome; Turner Syndrome; Williams Syndrome
PubMed: 26345374
DOI: 10.1017/S1047951115001389 -
Annals of Medicine and Surgery (2012) Apr 2023Alagille syndrome has been described as a multisystemic clinical spectrum caused by an autosomal dominant genetic disorder. Although it is estimated that there is 1 case...
UNLABELLED
Alagille syndrome has been described as a multisystemic clinical spectrum caused by an autosomal dominant genetic disorder. Although it is estimated that there is 1 case per 100 000 live births, the prognosis for survival and quality of life for these patients is varied but tends to be negative. In Colombia, this condition is considered an orphan disease with difficult management due to the lack of specialized centers that have all the medical specialties and subspecialties. Some reports state that no more than 30 cases have been published in this country.
MATERIALS AND METHODS
The authors report a case of a male baby who, at 8 days old, he was taken to the general practitioner's outpatient clinic for persistent jaundice. At 3 months of age, he was reviewed by the pediatric gastroenterology department, which requested liver and biliary tract scintigraphy, showing atresia of the biliary tract, hepatomegaly, and the absence of a gallbladder.
RESULTS
Liver transplantation is the definitive solution. However, in low- and middle-income countries, where there are no well-established organ transplantation programs, the prognosis for these patients is presumed to be worse.
CONCLUSION
Alagille syndrome is a rare disease that requires an accurate and early diagnosis and timely multidisciplinary management to reduce the impact of multisystemic complications. It is necessary to advance in transplant programs in low- and middle-income countries, to provide a solution to cases where there are no other therapeutic alternatives, and to contribute to the quality of life of the affected patient.
PubMed: 37113962
DOI: 10.1097/MS9.0000000000000473 -
Journal of Clinical Research in... Jun 2020Studies examining changes in thyroid function in the course of chronic liver disease have mostly been conducted in adults. The aim of this study was to investigate...
OBJECTIVE
Studies examining changes in thyroid function in the course of chronic liver disease have mostly been conducted in adults. The aim of this study was to investigate thyroid dysfunction in children with chronic liver diseases.
METHODS
Between 2005 and 2018, patients aged up to 18 years of age, diagnosed with chronic liver disease and had thyroid function test results available were included. Anthropometric characteristics, liver and thyroid function results were collected and analyzed.
RESULTS
The study included 107 (53 female; 49.5%) patients aged between one month and 18 years-old. Of the 107 patients, 96 (89.7%) had normal thyroid function results, seven (6.5%) had subclinical hypothyroidism (SH) and four (3.7%) had euthyroid sick syndrome. Of the patients with SH, one (14.2%) had glycogen storage diasease, one (14.2%) had biliary atresia, one (14.2%) had undiagnosed cholestatic liver disease, one (14.2%) had Alagille syndrome, one (14.2%) had idiopatic hepatitis, one (14.2%) had progressive familial intra-hepatic cholestasis and one (14.2%) had congenital hepatic fibrosis. Spearman correlation analysis showed a negative correlation between free tri-iodothyronine and direct bilirubin (r=-0.329, p=0.027).
CONCLUSION
In conclusion, euthyroid sick syndrome or SH may affect up to 10% of children with chronic liver diseases. It is suggested that thyroid function should be evaluated in cases of pediatric chronic liver disease at diagnosis and during follow-up. Moreover, this study is the first to show a negative correlation between free T3 levels and direct bilirubin, suggesting a possible association between liver disease severity and thyroid function.
Topics: Adolescent; Biliary Atresia; Child; Child, Preschool; Cholestasis, Intrahepatic; Chronic Disease; Comorbidity; Euthyroid Sick Syndromes; Female; Glycogen Storage Disease; Hepatitis; Humans; Hypothyroidism; Infant; Liver Diseases; Liver Function Tests; Male; Thyroid Function Tests
PubMed: 31486329
DOI: 10.4274/jcrpe.galenos.2019.2019.0029 -
PloS One 2023Alagille syndrome (ALGS) is an autosomal dominant disease characterized by a multisystem involvement including bile duct paucity and cholestasis, caused by JAG1 or...
INTRODUCTION
Alagille syndrome (ALGS) is an autosomal dominant disease characterized by a multisystem involvement including bile duct paucity and cholestasis, caused by JAG1 or NOTCH2 mutations in most of the cases. Jagged1-Notch2 interactions are known to be crucial for intrahepatic biliary tract development, but the Notch signaling pathway is also involved in the juxtacrine transmission of senescence and in the induction and modulation of the senescence-associated secretory phenotype (SASP).
AIM
Our aim was to investigate premature senescence and SASP in ALGS livers.
METHODS
Liver tissue from ALGS patients was prospectively obtained at the time of liver transplantation (n = 5) and compared to control livers (n = 5).
RESULTS
We evidenced advanced premature senescence in the livers of five JAG1 mutated ALGS pediatric patients through increased senescence-associated beta-galactosidase activity (p<0.05), increased p16 and p21 gene expression (p<0.01), and increased p16 and γH2AX protein expression (p<0.01). Senescence was located in hepatocytes of the whole liver parenchyma as well as in remaining bile ducts. The classical SASP markers TGF-β1, IL-6, and IL-8 were not overexpressed in the livers of our patients.
CONCLUSIONS
We demonstrate for the first time that ALGS livers display important premature senescence despite Jagged1 mutation, underlying the complexity of senescence and SASP development pathways.
Topics: Humans; Liver; Alagille Syndrome; Bile Ducts; Jagged-1 Protein; Mutation; Biliary Atresia; Cellular Senescence
PubMed: 37099537
DOI: 10.1371/journal.pone.0285019 -
Hepatology Communications Aug 2022There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine...
There is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo-controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0-100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo-controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] -1.59 [-1.81, -1.36], CSS -1.36 [-1.67, -1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment-emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome.
Topics: Alagille Syndrome; Bilirubin; Child; Cholestasis; Fatigue; Humans; Pruritus; Quality of Life
PubMed: 35672955
DOI: 10.1002/hep4.1992 -
World Journal of Clinical Cases Sep 2022Alagille syndrome (ALGS) is an autosomal dominant genetic disorder caused by mutations in the or gene. It is characterized by decreased intrahepatic bile ducts...
BACKGROUND
Alagille syndrome (ALGS) is an autosomal dominant genetic disorder caused by mutations in the or gene. It is characterized by decreased intrahepatic bile ducts associated with a variety of abnormalities in many other organ systems, such as the cardiovascular, skeletal, and urinary systems.
CASE SUMMARY
We report a rare case of ALGS. A 1-month-old male infant presented with sustained jaundice and had a rare congenital heart disease: Total anomalous pulmonary venous connection (TAPVC). Sustained jaundice, particularly with cardiac murmur, caught our attention. Laboratory tests revealed elevated levels of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, total bilirubin, and total bile acids, indicating serious intrahepatic cholestasis. Imaging confirmed the presence of butterfly vertebra at the seventh thoracic vertebra. This suggested ALGS, which was confirmed by genetic testing with a c.3197dupC mutation in the gene. Ursodiol was administered immediately after confirmation of the diagnosis, and cardiac surgery was performed when the patient was 1.5 month old. He recovered well after treatment and was discharged at the age of 3 mo. At the age of two years, the patient returned to our clinic because multiple cutaneous nodules with xanthomas appeared, and their size and number increased over time.
CONCLUSION
We report a unique case of ALGS associated with TAPVC and severe xanthomas. This study has enriched the clinical manifestations of ALGS and emphasized the association between gene and TAPVC.
PubMed: 36157644
DOI: 10.12998/wjcc.v10.i25.8932 -
Multimedia Manual of Cardiothoracic... Dec 2022This tutorial describes in detail the surgical technique of bilateral branch pulmonary arterial reconstruction in a 10-month-old boy with Alagille syndrome and advanced...
This tutorial describes in detail the surgical technique of bilateral branch pulmonary arterial reconstruction in a 10-month-old boy with Alagille syndrome and advanced liver disease. The procedure was performed via a standard median sternotomy and moderate hypothermia and involves bilateral pulmonary branch arterioplasties combined with relief of valvular and supravalvular pulmonary stenosis and subtotal closure of secundum atrial septal defect. The patient presented with systemic/suprasystemic right ventricular pressure.
Topics: Male; Humans; Infant; Alagille Syndrome; Hypertension, Pulmonary; Pulmonary Artery; Vascular Surgical Procedures; Plastic Surgery Procedures
PubMed: 36458898
DOI: 10.1510/mmcts.2022.088 -
Hepatology Communications Sep 2023We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of...
BACKGROUND
We previously showed that loss of yes-associated protein 1 (YAP) in early liver development (YAPKO) leads to an Alagille syndrome-like phenotype, with failure of intrahepatic bile duct development, severe cholestasis, and chronic hepatocyte adaptations to reduce liver injury. TAZ, a paralog of YAP, was significantly upregulated in YAPKO hepatocytes and interacted with TEA domain family member (TEAD) transcription factors, suggesting possible compensatory activity.
METHODS
We deleted both Yap1 and Wwtr1 (which encodes TAZ) during early liver development using the Foxa3 promoter to drive Cre expression, similar to YAPKO mice, resulting in YAP/TAZ double knockout (DKO) and YAPKO with TAZ heterozygosity (YAPKO TAZHET). We evaluated these mice using immunohistochemistry, serum biochemistry, bile acid profiling, and RNA sequencing.
RESULTS
DKO mice were embryonic lethal, but their livers were similar to YAPKO, suggesting an extrahepatic cause of death. Male YAPKO TAZHET mice were also embryonic lethal, with insufficient samples to determine the cause. However, YAPKO TAZHET females survived and were phenotypically similar to YAPKO mice, with increased bile acid hydrophilicity and similar global gene expression adaptations but worsened the hepatocellular injury. TAZ heterozygosity in YAPKO impacted the expression of canonical YAP targets Ctgf and Cyr61, and we found changes in pathways regulating cell division and inflammatory signaling correlating with an increase in hepatocyte cell death, cell cycling, and macrophage recruitment.
CONCLUSIONS
YAP loss (with or without TAZ loss) aborts biliary development. YAP and TAZ play a codependent critical role in foregut endoderm development outside the liver, but they are not essential for hepatocyte development. TAZ heterozygosity in YAPKO livers increased cell cycling and inflammatory signaling in the setting of chronic injury, highlighting genes that are especially sensitive to TAZ regulation.
Topics: Animals; Male; Mice; Adaptor Proteins, Signal Transducing; Carcinoma, Hepatocellular; Cell Cycle Proteins; Cholestasis; Endoderm; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Trans-Activators; Transcription Factors; YAP-Signaling Proteins; Female
PubMed: 37556373
DOI: 10.1097/HC9.0000000000000220 -
Annals of Hepatology 2020Liver and eyes are interlinked to each other in various medical conditions. There are certain ocular findings which directly indicate specific liver disorders. Thus, it... (Review)
Review
Liver and eyes are interlinked to each other in various medical conditions. There are certain ocular findings which directly indicate specific liver disorders. Thus, it becomes critical to identify disorders of liver and eyes early in the course of illness, so that prompt management may be initiated before the commencement of complications. It is highly advantageous in metabolic liver disorders as it offers prognostic value and spares the patient of unnecessary invasive and detailed work up. However, due to its silent and heterogeneous presentation, it is often unrecognized and ignored. Eye abnormalities could be due to, either direct toxic effects of abnormal metabolites, excess of normal metabolites, or by deficient energy metabolism. A number of inherited liver conditions have associated ocular lesions such as Kayser-Fleischer rings in Wilson's disease, posterior embryotoxon or optic drusen in Alagille's syndrome, and cherry-red spot in Niemann-Pick's type A. A thorough eye examination is important in distinguishing between several different forms of familial intrahepatic cholestasis which are associated with anomalies of the heart, bones, or kidneys. Early diagnosis is important, as in most cases, dietary restriction and early therapy prevents the onset of disability. The aim of this review is to sensitize and make pediatricians, hepatologists and ophthalmologists aware of specific ocular findings, suggestive of certain hepatobiliary disorders, thus helping in early referral. The pediatric and adult literature was thoroughly reviewed to organize the present review.
Topics: Child; Child, Preschool; Eye Diseases; Female; Humans; Infant; Liver Diseases; Male
PubMed: 31901314
DOI: 10.1016/j.aohep.2019.11.009