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Zhonghua Gan Zang Bing Za Zhi =... Sep 2023This study focuses on Na(+)-taurocholate cotransporting polypeptide (NTCP) deficiency to analyze and investigate the value of the serum bile acid profile for...
This study focuses on Na(+)-taurocholate cotransporting polypeptide (NTCP) deficiency to analyze and investigate the value of the serum bile acid profile for facilitating the diagnosis and differential diagnosis. Clinical data of 66 patients with cholestatic liver diseases (CLDs) diagnosed and treated in the Department of Pediatrics of the First Affiliated Hospital of Jinan University from early April 2015 to the end of December 2021 were collected, including 32 cases of NTCP deficiency (16 adults and 16 children), 16 cases of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), 8 cases of Alagille syndrome, and 10 cases of biliary atresia. At the same time, adult and pediatric healthy control groups (15 cases each) were established. The serum bile acid components of the study subjects were qualitatively and quantitatively analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry. The data were plotted and compared using statistical SPSS 19.0 and GraphPad Prism 5.0 software. The clinical and bile acid profiles of children with NTCP deficiency and corresponding healthy controls, as well as differences between NTCP deficiency and other CLDs, were compared using statistical methods such as t-tests, Wilcoxon rank sum tests, and Kruskal-Wallis H tests. Compared with the healthy control, the levels of total conjugated bile acids, total primary bile acids, total secondary bile acids, glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were increased in NTCP deficiency patients ( < 0.05). Compared with adults with NTCP deficiency, the levels of total conjugated bile acids and total primary bile acids were significantly increased in children with NTCP deficiency ( < 0.05). The serum levels of taurochenodeoxycholic acid, glycolithocholate, taurohyocholate, and tauro-α-muricholic acid were significantly increased in children with NTCP deficiency, but the bile acid levels such as glycodeoxycholic acid, glycolithocholate, and lithocholic acid were decreased ( < 0.05). The serum levels of secondary bile acids such as lithocholic acid, deoxycholic acid, and hyodeoxycholic acid were significantly higher in children with NTCP deficiency than those in other CLD groups such as NICCD, Alagille syndrome, and biliary atresia ( < 0.05). Total primary bile acids/total secondary bile acids, total conjugated bile acids/total unconjugated bile acids, taurocholic acid, serum taurodeoxycholic acid, and glycodeoxycholic acid effectively distinguished children with NTCP deficiency from other non-NTCP deficiency CLDs. This study confirms that serum bile acid profile analysis has an important reference value for facilitating the diagnosis and differential diagnosis of NTCP deficiency. Furthermore, it deepens the scientific understanding of the changing characteristics of serum bile acid profiles in patients with CLDs such as NTCP deficiency, provides a metabolomic basis for in-depth understanding of its pathogenesis, and provides clues and ideas for subsequent in-depth research.
Topics: Humans; Infant, Newborn; Child; Bile Acids and Salts; Citrullinemia; Diagnosis, Differential; Biliary Atresia; Alagille Syndrome; Symporters; Cholestasis; Taurocholic Acid; Glycodeoxycholic Acid; Lithocholic Acid; Peptides
PubMed: 37872088
DOI: 10.3760/cma.j.cn501113-20230717-00007 -
Stem Cell Research Oct 2023Alagille syndrome (ALGS) is a multisystem disease with high variability in clinical features. ALGS is predominantly caused by pathogenic variants in the Notch ligand...
Alagille syndrome (ALGS) is a multisystem disease with high variability in clinical features. ALGS is predominantly caused by pathogenic variants in the Notch ligand JAG1. An iPSC line, NCHi011-A, was generated from a ALGS patient with complex cardiac phenotypes consisting of pulmonic valve and branch pulmonary artery stenosis. NCHi011-A is heterozygous for a single base duplication causing a frameshift in the JAG1 gene. This iPSC line demonstrates normal cellular morphology, expression of pluripotency markers, trilineage differentiation potential, and identity to the source patient. NCHi011-A provides a resource for modeling ALGS and investigating the role of Notch signaling in the disease.
Topics: Female; Humans; Young Adult; Adult; Alagille Syndrome; Induced Pluripotent Stem Cells; Jagged-1 Protein; Heart; Cell Differentiation
PubMed: 37774637
DOI: 10.1016/j.scr.2023.103213 -
Radiology Case Reports Nov 2023A man in his 40s presented to our Hospital with abdominal pain, jaundice, and pruritus. He had a history of Alagille Syndrome treated with cholecystojejunostomy in the...
A man in his 40s presented to our Hospital with abdominal pain, jaundice, and pruritus. He had a history of Alagille Syndrome treated with cholecystojejunostomy in the neonatal period because of initial misdiagnosis of biliary atresia. Laboratory investigations showed hyperbilirubinemia (total bilirubin 1.76 mg/dL [<1.2 mg/dL]; conjugated 1.06 mg/dL [<0.3 mg/dL]) and cholestasis (GGT 78 U/L [<50 U/L]; ALP 200 U/L [<50 U/L]). Transabdominal ultrasound was limited by aerobilia due to the cholecystojejuno-anastomosis. Subsequent basal CT scan revealed an impacted stone within the patient's native common bile duct (CBD). Aerobilia in intrahepatic bile ducts and gallbladder was reported. Magnetic Resonance cholangiopancreatography confirmed the gallstone in the CBD compressing cystic duct and common hepatic duct, with dilation of the upstream bile ducts. Furthermore, the native CBD was obstructed by other gallstones. In Mirizzi syndrome, gallstones impacted in gallbladder's Hartmann's pouch or cystic duct extrinsically compress CBD. We suggest naming the present condition "Reverse Mirizzi Syndrome" (Renzulli Matteo Syndrome, RMS) because it is the exact opposite of Mirizzi syndrome.
PubMed: 37745768
DOI: 10.1016/j.radcr.2023.08.077 -
Journal of the American College of... Sep 2023We have followed a consistent, albeit evolving, strategy for the management of patients with pulmonary atresia or severe stenosis and major aortopulmonary collateral...
BACKGROUND
We have followed a consistent, albeit evolving, strategy for the management of patients with pulmonary atresia or severe stenosis and major aortopulmonary collateral arteries (MAPCAs) that aims to achieve complete repair with low right ventricular pressure by completely incorporating blood supply and relieving stenoses to all lung segments.
OBJECTIVES
The purpose of this study was to characterize our 20-year institutional experience managing patients with MAPCAs.
METHODS
We reviewed all patients who underwent surgery for MAPCAs and biventricular heart disease from November 2001 through December 2021.
RESULTS
During the study period, 780 unique patients underwent surgery. The number of new patients undergoing surgery annually was relatively steady during the first 15 years, then increased substantially thereafter. Surgery before referral had been performed in almost 40% of patients, more often in our recent experience than earlier. Complete repair was achieved in 704 patients (90%), 521 (67%) during the first surgery at our center, with a median right ventricular to aortic pressure ratio of 0.34 (25th, 75th percentiles: 0.28, 0.40). The cumulative incidence of mortality was 15% (95% CI: 12%-19%) at 10 years, with no difference according to era of surgery (P = 0.53). On multivariable Cox regression, Alagille syndrome (HR: 2.8; 95% CI: 1.4-5.7; P = 0.004), preoperative respiratory support (HR: 2.0; 95% CI: 1.2-3.3; P = 0.008), and palliative first surgery at our center (HR: 3.5; 95% CI: 2.3-5.4; P < 0.001) were associated with higher risk of death.
CONCLUSIONS
In a growing pulmonary artery reconstruction program, with increasing volumes and an expanding population of patients who underwent prior surgery, outcomes of patients with pulmonary atresia or stenosis and MAPCAs have continued to improve.
Topics: Humans; Aorta; Constriction, Pathologic; Heart Defects, Congenital; Pulmonary Artery; Pulmonary Atresia
PubMed: 37704311
DOI: 10.1016/j.jacc.2023.06.041 -
Expert Review of Gastroenterology &... 2023Alagille syndrome (ALGS) is an autosomal dominant, multisystem genetic disorder with wide phenotypic variability caused by mutations in the Notch signaling pathway,... (Review)
Review
INTRODUCTION
Alagille syndrome (ALGS) is an autosomal dominant, multisystem genetic disorder with wide phenotypic variability caused by mutations in the Notch signaling pathway, specifically from mutations in either the Jagged1 (JAG1) or NOTCH2 gene. The range of clinical features in ALGS can involve various organ systems including the liver, heart, eyes, skeleton, kidney, and vasculature. Despite the genetic mutations being well-defined, there is variable expressivity and individuals with the same mutation may have different clinical phenotypes.
AREAS COVERED
While no clear genotype-phenotype correlation has been identified in ALGS, this review will summarize what is currently known about the genotype-phenotype relationship and how this relationship influences the treatment of the multisystemic disorder. This review includes discussion of numerous studies which have focused on describing the genotype-phenotype relationship of different organ systems in ALGS as well as relevant basic science and population studies of ALGS. A thorough literature search was completed via the PubMed and National Library of Medicine GeneReviews databases including dates from 1969, when ALGS was first identified, to February 2023.
EXPERT OPINION
The genetics of ALGS are well defined; however, ongoing investigation to identify genotype-phenotype relationships as well as genetic modifiers as potential therapeutic targets is needed. Clinicians and patients alike would benefit from identification of a correlation to aid in diagnostic evaluation and management.
Topics: Humans; Alagille Syndrome; Mutation; Phenotype; Genotype
PubMed: 37668532
DOI: 10.1080/17474124.2023.2255518 -
SAGE Open Medical Case Reports 2023A female infant, born at 37 week 5 days to a mother via induced vaginal delivery for preeclampsia, was prenatally diagnosed with a right aortic arch with vascular ring....
A female infant, born at 37 week 5 days to a mother via induced vaginal delivery for preeclampsia, was prenatally diagnosed with a right aortic arch with vascular ring. On the third day of life, the infant exhibited a bronze-gray coloration, and a direct bilirubin of 1.7 mg/dL was detected. The abdominal ultrasound did not visualize the gallbladder. Clinically, the infant displayed features consistent with Alagille syndrome, including unusual facial appearance, butterfly vertebrae, cardiovascular defects, and cholestasis. The geneticist noted that the mother of the patient also exhibited similar features. Both the infant and the mother were diagnosed with Alagille syndrome, both having the same heterozygous JAG1 gene (NM_000214.2) variant (c.1890_1893del, p.Ile630Metfs*112). We believe that the vascular ring observed in our patient is the first reported instance of a vascular ring associated with Alagille syndrome.
PubMed: 37667743
DOI: 10.1177/2050313X231197321 -
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 -
Journal of Indian Association of... 2023Severe pruritus caused by progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (AGS) is refractory to medical treatment. Surgical interruption of...
BACKGROUND
Severe pruritus caused by progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (AGS) is refractory to medical treatment. Surgical interruption of the enterohepatic circulation is considered the mainstay of alleviating distressing symptoms and delaying cirrhosis.
AIM AND OBJECTIVES
This study aims to evaluate the short-term effect of partial external biliary diversion (PEBD) on pruritus, liver disease progression, patient's growth, and quality of life.
MATERIAL AND METHODS
This prospective cohort study enrolled children with PFIC and AGS from July 2019 to July 2021, whose guardians consented to the PEBD procedure. A standard surgical approach was performed by a single surgeon. Outcomes were measured subjectively and objectively pre- and post-procedure using the pruritus 5-D itching score, Paediatric Quality of Life Inventory scale (PedsQL), growth parameters, bile acids level, and liver function tests. Patients' follow-up period ranged from 6 to 12 months.
RESULTS
Seven patients had PEBD procedure; five with PFIC and two with AGS. A significant improvement was detected in the 5-D itching score (p-value < 0.001), PedsQL (p-value < 0.001), and bile acids level (p-value 0.013). The preexisting growth failure was ameliorated. The downward trend in the bilirubin level was not significant. No influential difference in the other liver function tests occurred. No intra-operative complications encountered. Only one case had a post-operative stoma prolapse which was managed surgically.
CONCLUSION
PEBD procedure could be considered as an effective and safe treatment options for intractable pruritus in patients with PFIC or AGS, providing preserved synthetic liver functions.
PubMed: 37635886
DOI: 10.4103/jiaps.jiaps_49_23 -
JPGN Reports Aug 2023Intractable pruritus is one of the most prominent and debilitating features of Alagille syndrome. Maralixibat is the first US Food and Drug Administration-approved drug...
Intractable pruritus is one of the most prominent and debilitating features of Alagille syndrome. Maralixibat is the first US Food and Drug Administration-approved drug for the treatment of cholestatic pruritus in children with Alagille syndrome aged 3 months and older. Clinical trials of maralixibat have reported follow-up to 4 years and reported a ≥1-pt reduction using the Itch-Reported Outcome (Observer) (ItchRO[Obs]) instrument (0-4 scale), as this decrease was previously defined as a clinically meaningful improvement in pruritus; participants in clinical trials were expected to be maintained on stable doses of antipruritic agents. We report on a patient with 3 notable features: (1) complete resolution of her pruritus; (2) durability of this response for over 7 years; and (3) ability to discontinue all other antipruritic medications.
PubMed: 37600618
DOI: 10.1097/PG9.0000000000000335 -
JPGN Reports Aug 2023
PubMed: 37600608
DOI: 10.1097/PG9.0000000000000338