Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 828
Filtrar
1.
J Med Case Rep ; 18(1): 434, 2024 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-39243110

RESUMO

BACKGROUND: Progressive familial intrahepatic cholestasis is an autosomal recessive genetic disorder that manifests primarily with jaundice and pruritus and can progresses from persistent cholestasis to cirrhosis and late childhood liver failure. Classically, progressive familial intrahepatic cholestasis is classified into three subtypes: 1, 2, and 3 and results from a defect in a biliary protein responsible for bile formation and circulation in the liver. In the last decade and with the increased use of genetic testing, more types have been known. CASE PRESENTATION: A 6-month-old Afrocentric boy presented with progressive jaundice and pruritus that started since the age of 2 months. He was thoroughly investigated to be finally diagnosed as progressive familial intrahepatic cholestasis type 4. A low-fat diet, ursodeoxycholic acid, fat-soluble vitamins, and cholestyramine were started. He showed initial improvement then had refractory pruritus and impaired quality of life. He underwent surgical biliary diversion at the age of 1 year with marked improvement of manifestations. CONCLUSION: Owing to the increased technology of genetic testing, more clinical subtypes of progressive familial intrahepatic cholestasis were diagnosed other than the classical three types. Surgical management using biliary diversion could be beneficial and delays or may even obviate the need for liver transplantation.


Assuntos
Colestase Intra-Hepática , Prurido , Ácido Ursodesoxicólico , Humanos , Masculino , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/diagnóstico , Prurido/etiologia , Lactente , Ácido Ursodesoxicólico/uso terapêutico , Dieta com Restrição de Gorduras , Icterícia/etiologia , Resina de Colestiramina/uso terapêutico , Colagogos e Coleréticos/uso terapêutico , Vitaminas/uso terapêutico , Resultado do Tratamento , Qualidade de Vida
2.
J Lipid Res ; 65(9): 100616, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39111549

RESUMO

Progressive familial intrahepatic cholestasis (PFIC) is a liver disease that occurs during childhood and requires liver transplantation. ABCB4 is localized along the canalicular membranes of hepatocytes, transports phosphatidylcholine into bile, and its mutation causes PFIC3. Abcb4 gene-deficient mice established as animal models of PFIC3 exhibit cholestasis-induced liver injury. However, their phenotypes are often milder than those of human PFIC3, partly because of the existence of large amounts of less toxic hydrophilic bile acids synthesized by the rodent-specific enzymes Cyp2c70 and Cyp2a12. Mice with double deletions of Cyp2c70/Cyp2a12 (CYPDKO mice) have a human-like hydrophobic bile acid composition. PFIC-related gene mutations were induced in CYPDKO mice to determine whether these triple-gene-deficient mice are a better model for PFIC. To establish a PFIC3 mouse model using CYPDKO mice, we induced abcb4 gene deletion in vivo using adeno-associated viruses expressing SaCas9 under the control of a liver-specific promoter and abcb4-target gRNAs. Compared to Abcb4-deficient wild-type mice, Abcb4-deficient CYPDKO mice showed more pronounced liver injury along with an elevation of inflammatory and fibrotic markers. The proliferation of intrahepatic bile ductal cells and hematopoietic cell infiltration were also observed. CYPDKO/abcb4-deficient mice show a predominance of taurine-conjugated chenodeoxycholic acid and lithocholic acid in the liver. In addition, phospholipid levels in the gallbladder bile were barely detectable. Mice with both human-like bile acid composition and Abcb4-defect exhibit severe cholestatic liver injury and are useful for studying human cholestatic diseases and developing new treatments.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Ácidos e Sais Biliares , Modelos Animais de Doenças , Deleção de Genes , Fígado , Animais , Ácidos e Sais Biliares/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Camundongos , Fígado/metabolismo , Colestase Intra-Hepática/metabolismo , Colestase Intra-Hepática/genética , Interações Hidrofóbicas e Hidrofílicas , Humanos , Masculino , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Camundongos Knockout , Sistema Enzimático do Citocromo P-450
3.
Sci Rep ; 14(1): 18876, 2024 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-39143102

RESUMO

Progressive familial intrahepatic cholestasis (PFIC) is a rare childhood manifested disease associated with impaired bile secretion with severe pruritus yellow stool, and sometimes hepatosplenomegaly. PFIC is caused by mutations in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, SLC51A, USP53, KIF12, ZFYVE19, and MYO5B genes depending on its type. ABCB11 mutations lead to PFIC2 that encodes the bile salt export pump (BSEP). Different mutations of ABCB11 have been reported in different population groups but no data available in Pakistani population being a consanguineous one. We sequenced coding exons of the ABCB11 gene along with its flanking regions in 66 unrelated Pakistani children along with parents with PFIC2 phenotype. We identified 20 variations of ABCB11: 12 in homozygous form, one compound heterozygous, and seven heterozygous. These variants include 11 missenses, two frameshifts, two nonsense mutations, and five splicing variants. Seven variants are novel candidate variants and are not detected in any of the 120 chromosomes from normal ethnically matched individuals. Insilico analysis revealed that four homozygous missense variations have high pathogenic scores. Minigene analysis of splicing variants showed exon skipping and the addition of exon. This data is a useful addition to the disease variants genomic database and would be used in the future to build a diagnostic algorithm.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Colestase Intra-Hepática , Humanos , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Colestase Intra-Hepática/genética , Paquistão , Masculino , Feminino , Criança , Pré-Escolar , Lactente , Mutação , Éxons/genética , Estudos de Coortes , Homozigoto
4.
Tokai J Exp Clin Med ; 49(3): 133-136, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39182182

RESUMO

Abnormalities in MYO5B, which encodes an unconventional myosin Vb, not only cause microvillus inclusion disease but also cholestatic liver disease, including benign recurrent intrahepatic cholestasis (BRIC). However, MYO5B-related cholestasis has not yet been reported in Japan. In this study, we present the case of a female patient in her thirties, who had developed jaundice, without diarrhea, in the first year after birth. The jaundice spontaneously subsided and occasionally recurred. Whole-exome sequencing identified two pathogenic variants in MYO5B: a nonsense mutation (c. G1124A: p. W375X) and a missense mutation (c.C2470T: p.R824C). Therefore, the patient was diagnosed with MYO5B-associated BRIC. This is the first reported case of cholestasis with a defined MYO5B defect in Japan.


Assuntos
Colestase Intra-Hepática , Códon sem Sentido , Sequenciamento do Exoma , Mutação de Sentido Incorreto , Miosina Tipo V , Recidiva , Humanos , Miosina Tipo V/genética , Miosina Tipo V/deficiência , Feminino , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/etiologia , Adulto , Cadeias Pesadas de Miosina/genética , Japão , Icterícia/etiologia
6.
Curr Opin Pediatr ; 36(5): 524-536, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-38957097

RESUMO

PURPOSE OF REVIEW: To highlight recent advances in pediatric cholestatic liver disease, including promising novel prognostic markers and new therapies. FINDINGS: Additional genetic variants associated with the progressive familial intrahepatic cholestasis (PFIC) phenotype and new genetic cholangiopathies, with an emerging role of ciliopathy genes, are increasingly being identified. Genotype severity predicts outcomes in bile salt export pump (BSEP) deficiency, and post-biliary diversion serum bile acid levels significantly affect native liver survival in BSEP and progressive familial intrahepatic cholestasis type 1 (FIC1 deficiency) patients. Heterozygous variants in the MDR3 gene have been associated with various cholestatic liver disease phenotypes in adults. Ileal bile acid transporter (IBAT) inhibitors, approved for pruritus in PFIC and Alagille Syndrome (ALGS), have been associated with improved long-term quality of life and event-free survival. SUMMARY: Next-generation sequencing (NGS) technologies have revolutionized diagnostic approaches, while discovery of new intracellular signaling pathways show promise in identifying therapeutic targets and personalized strategies. Bile acids may play a significant role in hepatic damage progression, suggesting their monitoring could guide cholestatic liver disease management. IBAT inhibitors should be incorporated early into routine management algorithms for pruritus. Data are emerging as to whether IBAT inhibitors are impacting disease biology and modifying the natural history of the cholestasis.


Assuntos
Colestase Intra-Hepática , Humanos , Criança , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/terapia , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/sangue , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Síndrome de Alagille/terapia , Fenótipo , Prognóstico , Sequenciamento de Nucleotídeos em Larga Escala
7.
Commun Biol ; 7(1): 898, 2024 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-39048674

RESUMO

ABCB4 is located at the canalicular membrane of hepatocytes and is responsible for the secretion of phosphatidylcholine into bile. Genetic variations of this transporter are correlated with rare cholestatic liver diseases, the most severe being progressive familial intrahepatic cholestasis type 3 (PFIC3). PFIC3 patients most often require liver transplantation. In this context of unmet medical need, we developed a high-content screening approach to identify small molecules able to correct ABCB4 molecular defects. Intracellularly-retained variants of ABCB4 were expressed in cell models and their maturation, cellular localization and function were analyzed after treatment with the molecules identified by high-content screening. In total, six hits were identified by high-content screening. Three of them were able to correct the maturation and canalicular localization of two distinct intracellularly-retained ABCB4 variants; one molecule was able to significantly restore the function of two ABCB4 variants. In addition, in silico molecular docking calculations suggest that the identified hits may interact with wild type ABCB4 residues involved in ATP binding/hydrolysis. Our results pave the way for their optimization in order to provide new drug candidates as potential alternative to liver transplantation for patients with severe forms of ABCB4-related diseases, including PFIC3.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Simulação de Acoplamento Molecular , Humanos , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/metabolismo , Transporte Proteico , Ensaios de Triagem em Larga Escala/métodos , Células HEK293
8.
Zhonghua Er Ke Za Zhi ; 62(7): 649-654, 2024 Jul 02.
Artigo em Chinês | MEDLINE | ID: mdl-38955683

RESUMO

Objective: To investigate the pathogenic mechanism and clinical characteristics of the novel splicing variant of ATP-binding cassette subfamily B member 4 (ABCB4) and provide a basis for subsequent genetic diagnosis. Methods: The clinical data of a 5-year-old child with cholestatic liver disease admitted to the Beijing Children's Hospital of Capital Medical University was retrospectively analyzed. The pathogenic variations were detected by whole exome sequencing and verified by Sanger sequencing, and bioinformatics was used to predict the pathogenicity of the mutation sites. Possible pathogenic variations were verified in vitro by Minigene assay. The clinical outcome was followed after discharge from hospital. Results: The 5-year-old boy had developed cholestasis at the age of 11 months. His physical examination showed obvious enlargement of the liver and spleen. Cholestatic cirrhosis was diagnosed by liver function tests, abdominal ultrasonography, liver biopsy and pathology. The results of genetic analysis showed that the patient was a complex heterozygote of the ABCB4 gene, with a pathogenic mutation c.2860G>A and a novel mutation c.2065-8T>G, derived from the mother and father respectively. The conservative prediction of the c.2065-8T>G site showed that this region was highly conserved and may affect splicing. Minigene assay results confirmed that the c.2065-8T>G mutation resulted in a 7 bp retention of intron 16 in the mature mRNA. In the absence of nonsense-mediated mRNA decay, the amino acid frameshift forms a truncated protein, which is represented by p.Glu689ValfsTer19. The patient was diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3) and treated with ursodeoxycholic acid (UDCA). His clinical symptoms improved during 18 months of follow-up. Conclusions: The c.2065-8T>G variant is confirmed to affect the splicing process and exhibits complex heterozygosity with c.2860G>A, which is identified as the cause of the disease. PFIC3 children with this variant showed cholestatic liver disease as the main manifestation with a slow progression and was sensitive to treatment with UDCA.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Colestase Intra-Hepática , Mutação , Fenótipo , Humanos , Masculino , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/diagnóstico , Pré-Escolar , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Sequenciamento do Exoma , Genótipo , Heterozigoto , Estudos Retrospectivos , Ácido Ursodesoxicólico/uso terapêutico , Fígado/patologia
9.
Pediatr Transplant ; 28(5): e14804, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38853137

RESUMO

BACKGROUND: Kinesin family member 12 (KIF12) mutation-related cholestatic disorder represents a rare subtype of progressive familial intrahepatic cholestasis (PFIC), referred to as PFIC Type 8, with only 21 reported cases globally to date. METHODS: Here, we present a unique case of a 6-month-old boy diagnosed with homozygous KIF12 gene mutation, who successfully underwent a living donor liver transplant at our center for end-stage liver disease. RESULTS: This case marks the youngest patient of KIF12-related cholestatic disorder necessitating a liver transplant to date. The child initially presented with neonatal cholestasis and then developed infantile hepatic decompensation. Our report discusses the diagnostic process and management strategies employed. It underscores the importance of prompt diagnosis through clinical suspicion, biochemical parameters, and genetic testing, as well as the adoption of suitable management strategies, including the early contemplation of liver transplant in such exceptional and rare cases of genetic intrahepatic cholestasis. CONCLUSION: KIF12-related genetic disease should be considered in neonatal cholestasis cases with high gamma glutamyl transpeptidase to differentiate from conditions like biliary atresia. Favorable outcomes post liver transplant stress the importance of early genetic testing and referral to liver transplant centers for unresponsive patients, potentially saving lives.


Assuntos
Colestase Intra-Hepática , Doença Hepática Terminal , Cinesinas , Transplante de Fígado , Doadores Vivos , Mutação , Humanos , Masculino , Cinesinas/genética , Lactente , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/cirurgia , Doença Hepática Terminal/cirurgia , Doença Hepática Terminal/genética
10.
J Hepatol ; 81(2): 303-325, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38851996

RESUMO

Genetic cholestatic liver diseases are caused by (often rare) mutations in a multitude of different genes. While these diseases differ in pathobiology, clinical presentation and prognosis, they do have several commonalities due to their cholestatic nature. These Clinical Practice Guidelines (CPGs) offer a general approach to genetic testing and management of cholestatic pruritus, while exploring diagnostic and treatment approaches for a subset of genetic cholestatic liver diseases in depth. An expert panel appointed by the European Association for the Study of the Liver has created recommendations regarding diagnosis and treatment, based on the best evidence currently available in the fields of paediatric and adult hepatology, as well as genetics. The management of these diseases generally takes place in a tertiary referral centre, in order to provide up-to-date approaches and expertise. These CPGs are intended to support hepatologists (for paediatric and adult patients), residents and other healthcare professionals involved in the management of these patients with concrete recommendations based on currently available evidence or, if not available, on expert opinion.


Assuntos
Colestase Intra-Hepática , Humanos , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/terapia , Europa (Continente) , Testes Genéticos/métodos , Adulto , Colestase/genética , Colestase/diagnóstico , Colestase/terapia , Gastroenterologia/métodos , Gastroenterologia/normas
11.
J Matern Fetal Neonatal Med ; 37(1): 2361278, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38835155

RESUMO

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) can cause adverse perinatal outcomes. Previous studies have demonstrated that the placenta of an ICP pregnancy differs in morphology and gene expression from the placenta of a normal pregnancy. To date, however, the genetic mechanism by which ICP affects the placenta is poorly understood. Therefore, the aim of this study was to investigate the differences in main cell types, gene signatures, cell ratio, and functional changes in the placenta between ICP and normal pregnancy. METHODS: Single-cell RNA sequencing (scRNA-seq) technology was used to detect the gene expression of all cells at the placental maternal-fetal interface. Two individuals were analyzed - one with ICP and one without ICP. The classification of cell types was determined by a graph-based clustering algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the R software phyper () function and DAVID website. The differentially expressed genes (DEGs) encoding transcription factors (TFs) were identified using getorf and DIAMOND software. RESULTS: We identified 14 cell types and 22 distinct cell subtypes that showed unique functional properties. Additionally, we found differences in the proportions of fibroblasts 1, helper T (Th) cells, extravillous trophoblasts, and villous cytotrophoblasts, and we observed heterogeneity of gene expression between ICP and control placentas. Furthermore, we identified 263 DEGs that belonged to TF families, including zf-C2H2, HMGI/HMGY, and Homeobox. In addition, 28 imprinted genes were preferentially expressed in specific cell types, such as PEG3 and PEG10 in trophoblasts as well as DLK1 and DIO3 in fibroblasts. CONCLUSIONS: Our results revealed the differences in cell-type ratios, gene expression, and functional changes between ICP and normal placentas, and heterogeneity was found among cell subgroups. Hence, the imbalance of various cell types affects placental activity to varying degrees, indicating the complexity of the cell networks that form the placental tissue system, and this alteration of placental function is associated with adverse events in the perinatal period.


Assuntos
Colestase Intra-Hepática , Placenta , Complicações na Gravidez , Análise de Célula Única , Humanos , Feminino , Gravidez , Análise de Célula Única/métodos , Placenta/metabolismo , Estudos de Casos e Controles , Colestase Intra-Hepática/genética , Complicações na Gravidez/genética , Análise de Sequência de RNA , Adulto
12.
Orphanet J Rare Dis ; 19(1): 171, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38641832

RESUMO

BACKGROUND: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. METHODS: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. RESULTS: Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. CONCLUSIONS: We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.


Assuntos
Colestase Intra-Hepática , Colestase , Humanos , Recém-Nascido , Lactente , Estudos Retrospectivos , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/terapia , Colestase/genética
13.
Zhonghua Er Ke Za Zhi ; 62(5): 462-466, 2024 May 02.
Artigo em Chinês | MEDLINE | ID: mdl-38623015

RESUMO

Objective: To analyze the clinical manifestations, pathology, and gene variant characteristics in children with progressive familial intrahepatic cholestasis type 3 (PFIC3). Methods: This retrospective study assessed the clinical manifestations, pathological features, gene variants, and prognosis data of 11 children with PFIC3 hospitalized in the Department of Hepatology, Fifth Medical Center, PLA General Hospital, from January 2015 to December 2022. Panel or whole exome sequencing was performed on the probands, followed by Sanger sequencing for verification within the family. Detected pathogenic variants were compared with known disease databases. Additionally, the new variants were predicted the deleteriousness and protein structure using relevant software to evaluate their pathogenicity. Results: Among the 11 PFIC3 children, 8 were boys and 3 were girls. The age of onset was 3.1 (0.2, 15.6) years. The main complaint of onset was different in the 11 patients;5 of them were abnormal liver function, 3 of them were liver and spleen enlargement, 2 of them were abdominal distension, and 1 of them was jaundice. Alanine aminotransferase, asparate aminotransferase and γ-glutamyltransferase increased in all the patients, which were(113±40), (150±44) and (270±156) U/L respectively. Moreover, direct bilirubin increased in 9 patients, and cholestasis was showed in 8 patients. All patients showed liver fibrosis on imaging, and 8 patients had cirrhosis. The pathological features of 8 cases by liver biopsy were as follows: 8 cases of fibrosis in the portal area, 7 cases of small bile duct hyperplasia, 4 cases of positive copper staining, and 5 cases of cirrhosis. A total of 17 ABCB4 gene variants were detected, including 9 new variants: c.589C>T(p.Q197X), c.1230+1G>A(Splicing), c.2914G>A(P.D972N), c.1058G>A(p.C353Y), c.956G>T(p.G319V), c.473T>A(p.L158Q), c.164T>C(p.L55S), c.2493G>C(p.R831S), and c.1150G>C(p.G384R). All 11 patients were treated with ursodeoxycholic acid and followed up for 5.1(0.6, 7.4) years. Among them, 4 cases of cirrhosis progressed continuously, 3 cases had liver transplantations, and the remaining 4 cases were stable after medical treatment. Conclusions: Children with PFIC3 have early onset, diverse clinical manifestations, rapid progression of fibrotic and cholestasis, as well as poor prognosis. Genetic testing helps to confirm the diagnosis.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Colestase Intra-Hepática , Sequenciamento do Exoma , Humanos , Masculino , Feminino , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/diagnóstico , Estudos Retrospectivos , Criança , Pré-Escolar , Lactente , Adolescente , Mutação , Fígado/patologia , gama-Glutamiltransferase/sangue , Alanina Transaminase/sangue , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Prognóstico , Aspartato Aminotransferases/sangue
14.
Orphanet J Rare Dis ; 19(1): 157, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38610052

RESUMO

BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. CONCLUSION: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Colestase Intra-Hepática , Colestase , Adulto , Criança , Humanos , Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , China , Colestase/genética , Colestase Intra-Hepática/genética , Cirrose Hepática , Estudos Retrospectivos
15.
Arch Gynecol Obstet ; 310(2): 1037-1048, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38441603

RESUMO

PURPOSE: To determine the association between fetal fraction (FF) levels in cell-free fetal DNA (cffDNA) testing and adverse pregnancy outcomes. METHODS: This retrospective cohort study, conducted at a single center, involved 2063 pregnant women with normal 1st and 2nd trimester non-invasive prenatal test (NIPT) results between 2016 and 2021. Pregnancy outcomes were examined by determining the < 4% and < 5th percentile (3.6%) cut-off values for low fetal fraction (LFF). Pregnancy outcomes were also examined by dividing the FF into population-based quartiles. Adverse pregnancy outcomes were pregnancy-induced hypertensive diseases (PIHD), gestational diabetes mellitus (GDM), spontaneous preterm birth (PTB), intrahepatic cholestasis of pregnancy (ICP), small for gestational age (SGA), large for gestational age (LGA), low birth weight (LBW), macrosomia, and 1st and 5th minutes low APGAR scores (< 7). RESULTS: PIHD was significantly higher in LFF (< 4% and < 5th percentile) cases (p = 0.015 and p < 0.001, respectively). However, in population-based quartiles of FF, PIHD did not differ significantly between groups. Composite adverse maternal outcomes were significantly higher in the FF < 4% group (p = 0.042). When analyzes were adjusted for maternal age, BMI, and gestational age at NIPT, significance was maintained at < 4%, < 5th percentile LFF for PIHD, and < 4% LFF for composite adverse maternal outcomes. However, there was no significant relationship between LFF with GDM, ICP and PTB. Additionally, there was no significant association between low APGAR scores, SGA, LGA, LBW, macrosomia, and LFF concerning neonatal outcomes. CONCLUSION: Our study showed that LFF in pregnant women with normal NIPT results may be a predictor of subsequent PIHD.


Assuntos
Ácidos Nucleicos Livres , Resultado da Gravidez , Humanos , Feminino , Gravidez , Ácidos Nucleicos Livres/sangue , Estudos Retrospectivos , Adulto , Complicações na Gravidez , Recém-Nascido , Diabetes Gestacional , Teste Pré-Natal não Invasivo , Nascimento Prematuro , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/sangue , Macrossomia Fetal , Recém-Nascido Pequeno para a Idade Gestacional , Hipertensão Induzida pela Gravidez
16.
Nature ; 628(8006): 130-138, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38448586

RESUMO

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.


Assuntos
Biomarcadores , Estudo de Associação Genômica Ampla , Metabolômica , Feminino , Humanos , Gravidez , Acetona/sangue , Acetona/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/metabolismo , Estudos de Coortes , Estudo de Associação Genômica Ampla/métodos , Hipertensão/sangue , Hipertensão/genética , Hipertensão/metabolismo , Lipoproteínas/genética , Lipoproteínas/metabolismo , Espectroscopia de Ressonância Magnética , Análise da Randomização Mendeliana , Redes e Vias Metabólicas/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Complicações na Gravidez/sangue , Complicações na Gravidez/genética , Complicações na Gravidez/metabolismo
17.
Hepatology ; 80(3): 511-526, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38447037

RESUMO

BACKGROUND AND AIMS: The study aimed to describe the clinical course and outcomes, and analyze the genotype-phenotype correlation in patients with tight junction protein 2 (TJP2) deficiency. APPROACH AND RESULTS: Data from all children with chronic cholestasis and either homozygous or compound heterozygous mutations in TJP2 were extracted and analyzed. The patients were categorized into 3 genotypes: TJP2-A (missense mutations on both alleles), TJP2-B (missense mutation on one allele and a predicted protein-truncating mutation [PPTM] on the other), and TJP2-C (PPTMs on both alleles). A total of 278 cases of genetic intrahepatic cholestasis were studied, with TJP2 deficiency accounting for 44 cases (15.8%). Of these, 29 were homozygous and 15 were compound heterozygous variants of TJP2 . TJP2-A genotype was identified in 21 (47.7%), TJP2-B in 7 cases (15.9%), and TJP2-C in 16 cases (36.4%), respectively. Patients with the TJP2-C genotype were more likely to experience early infantile cholestasis (87.5% vs. 53.5%, p =0.033), less likely to clear jaundice (12.5% vs. 52.2%, p =0.037), more likely to develop ascites, and had higher serum bile acids. Patients with the TJP2-C genotype were more likely to die or require liver transplantation (native liver survival: 12.5% vs. 78.6%, p <0.001), with a median age at death/liver transplantation of 2.5 years. Cox regression analysis revealed that TJP2-C mutations ( p =0.003) and failure to resolve jaundice ( p =0.049) were independent predictors of poor outcomes. CONCLUSIONS: Patients with the TJP2-C genotype carrying PPTMs in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.


Assuntos
Colestase Intra-Hepática , Genótipo , Proteína da Zônula de Oclusão-2 , Humanos , Proteína da Zônula de Oclusão-2/genética , Masculino , Feminino , Lactente , Colestase Intra-Hepática/genética , Pré-Escolar , Criança , Transplante de Fígado , Mutação , Estudos de Associação Genética
18.
Placenta ; 148: 20-30, 2024 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-38346375

RESUMO

BACKGROUND: Abnormal bile acid metabolism leading to changes in placental function during pregnancy. To determine whether endoplasmic reticulum protein 29 (ERp29) can mediate the pregnancy effects of cholestasis by altering the level of trophoblast cell apoptosis. METHODS: ERp29 in serum of 66 intrahepatic cholestasis of pregnancy (ICP) pregnant women and 74 healthy were detected by ELISA. Subcutaneous injection of ethinyl estradiol (E2) was used to induce ICP in pregnant rats. Taurocholic acid (TCA) was used to simulate the ICP environment, and TGF-ß1 was added to induce the epithelial mesenchymal transformation (EMT) process. The scratch, migration, and invasion test were used to detect the EMT process. ERp29 overexpression/knockdown vector were constructed and transfected to verify the role of ERp29 in the EMT process. Downstream gene was obtained through RNA-seq. RESULTS: Compared with the healthy pregnant women, the expression levels of ERp29 in serum of ICP pregnancy women were significantly increased (P < 0.001). ERp29 in the placenta tissue of the ICP pregnant rats increased significantly, and the level of apoptosis increased. The placental tissues of the ICP had high expression of E-cadherin and low expression of N-cadherin, snail1, vimentin. After HTR-8/SVneo cells were induced by TCA, EMT was inhibited, while the ERp29 increased. Cell and animal experiments showed that, knockdown of ERp29 reduced the inhibition of EMT, the ICP progress was alleviated. Overexpression of FOS salvaged the inhibitory effects of ERp29 on cell EMT. DISCUSSION: The high level of ERp29 in placental trophoblast cells reduced FOS mRNA levels, inhibited the EMT process and aggravated the occurrence and development of ICP.


Assuntos
Colestase Intra-Hepática , Complicações na Gravidez , Feminino , Gravidez , Humanos , Ratos , Animais , Placenta/metabolismo , Trofoblastos/metabolismo , Complicações na Gravidez/metabolismo , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/metabolismo , Ácido Taurocólico/metabolismo , Ácido Taurocólico/farmacologia , Apoptose/fisiologia , Transição Epitelial-Mesenquimal/fisiologia
19.
J Crohns Colitis ; 18(7): 1134-1146, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-38366839

RESUMO

AIMS: Patients with mutations in ATP8B1 develop progressive familial intrahepatic cholestasis type 1 [PFIC1], a severe liver disease that requires life-saving liver transplantation. PFIC1 patients also present with gastrointestinal problems, including intestinal inflammation and diarrhoea, which are aggravated after liver transplantation. Here we investigate the intestinal function of ATP8B1 in relation to inflammatory bowel diseases. METHODS: ATP8B1 expression was investigated in intestinal samples of patients with Crohn's disease [CD] or ulcerative colitis [UC] as well as in murine models of intestinal inflammation. Colitis was induced in ATP8B1-deficient mice with dextran sodium sulphate [DSS] and intestinal permeability was investigated. Epithelial barrier function was assessed in ATP8B1 knockdown Caco2-BBE cells. Co-immunoprecipitation experiments were performed in Caco2-BBE cells overexpressing ATP8B1-eGFP. Expression and localization of ATP8B1 and tight junction proteins were investigated in cells and in biopsies of UC and PFIC1 patients. RESULTS: ATP8B1 expression was decreased in UC and DSS-treated mice, and was associated with a decreased tight junctional pathway transcriptional programme. ATP8B1-deficient mice were extremely sensitive to DSS-induced colitis, as evidenced by increased intestinal barrier leakage. ATP8B1 knockdown cells showed delayed barrier establishment that affected Claudin-4 [CLDN4] levels and localization. CLDN4 immunohistochemistry showed a tight junctional staining in control tissue, whereas in UC and intestinal PFIC1 samples, CLDN4 was not properly localized. CONCLUSION: ATP8B1 is important in the establishment of the intestinal barrier. Downregulation of ATP8B1 levels in UC, and subsequent altered localization of tight junctional proteins, including CLDN4, might therefore be an important mechanism in UC pathophysiology.


Assuntos
Colite Ulcerativa , Função da Barreira Intestinal , Animais , Feminino , Humanos , Masculino , Camundongos , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/genética , Células CACO-2 , Colestase Intra-Hepática/metabolismo , Colestase Intra-Hepática/genética , Claudina-4/metabolismo , Claudina-4/genética , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colite Ulcerativa/genética , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Função da Barreira Intestinal/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade , Proteínas de Transferência de Fosfolipídeos/metabolismo , Proteínas de Transferência de Fosfolipídeos/genética , Junções Íntimas/metabolismo
20.
J Pediatr Gastroenterol Nutr ; 78(2): 339-349, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38374565

RESUMO

OBJECTIVES: Biallelic variants in the adenosine triphosphate binding cassette subfamily B member 4 (ABCB4) gene which encodes the multidrug resistance 3 protein (MDR3) leads to progressive familiar intrahepatic cholestasis type 3. However, monoallelic variants are increasingly recognized as contributing to liver disease in adults. Our aim was to describe the clinical characteristics of MDR3 heterozygous variants in a large cohort of infants and children with cholestatic liver disease. METHODS: The clinical and genotypic data on pediatric patients seen at King's College Hospital, London, between 2004 and 2022 and found to harbour heterozygous variants in ABCB4 were reviewed. RESULTS: Ninety-two patients amongst 1568 tested were identified with a monoallelic variant (5.9%). The most common presenting problem was conjugated hyperbilirubinemia (n = 46; 50%) followed by cholelithiasis (n = 12; 13%) and cholestatic hepatitis (n = 10; 11%). The median values of liver biochemistry at presentation were: GGT 105 IU/L and total bilirubin 86 µmol/L. Thirty-two genetic variants were identified including 22 missense (69%), 4 deletions (13%), 5 splice site (16%) and 1 termination (3%). At a median follow up of 1 year there was resolution of liver disease. CONCLUSIONS: Rare variants in ABCB4 were found amongst infants and children with cholestatic liver disease. The presenting problems were variable and abnormalities tended to normalize over time. Those with severe mutations could develop liver disease later in life when exposed to further insult and should be counseled appropriately.


Assuntos
Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Colestase Intra-Hepática , Colestase , Adulto , Criança , Humanos , Lactente , Colestase/genética , Colestase Intra-Hepática/genética , Colestase Intra-Hepática/metabolismo , Heterozigoto , Mutação , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA