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1.
Sci Rep ; 14(1): 15796, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38982277

RESUMO

The clinical diagnosis of biliary atresia (BA) poses challenges, particularly in distinguishing it from cholestasis (CS). Moreover, the prognosis for BA is unfavorable and there is a dearth of effective non-invasive diagnostic models for detection. Therefore, the aim of this study is to elucidate the metabolic disparities among children with BA, CS, and normal controls (NC) without any hepatic abnormalities through comprehensive metabolomics analysis. Additionally, our objective is to develop an advanced diagnostic model that enables identification of BA. The plasma samples from 90 children with BA, 48 children with CS, and 47 NC without any liver abnormalities children were subjected to metabolomics analysis, revealing significant differences in metabolite profiles among the 3 groups, particularly between BA and CS. A total of 238 differential metabolites were identified in the positive mode, while 89 differential metabolites were detected in the negative mode. Enrichment analysis revealed 10 distinct metabolic pathways that differed, such as lysine degradation, bile acid biosynthesis. A total of 18 biomarkers were identified through biomarker analysis, and in combination with the exploration of 3 additional biomarkers (LysoPC(18:2(9Z,12Z)), PC (22:5(7Z,10Z,13Z,16Z,19Z)/14:0), and Biliverdin-IX-α), a diagnostic model for BA was constructed using logistic regression analysis. The resulting ROC area under the curve was determined to be 0.968. This study presents an innovative and pioneering approach that utilizes metabolomics analysis to develop a diagnostic model for BA, thereby reducing the need for unnecessary invasive examinations and contributing to advancements in diagnosis and prognosis for patients with BA.


Assuntos
Atresia Biliar , Biomarcadores , Colestase , Redes e Vias Metabólicas , Metabolômica , Atresia Biliar/sangue , Atresia Biliar/diagnóstico , Atresia Biliar/metabolismo , Humanos , Metabolômica/métodos , Colestase/sangue , Colestase/diagnóstico , Colestase/metabolismo , Feminino , Masculino , Biomarcadores/sangue , Lactente , Pré-Escolar , Diagnóstico Diferencial , Curva ROC , Metaboloma , Estudos de Casos e Controles , Criança
2.
Medicine (Baltimore) ; 103(28): e38757, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38996159

RESUMO

To evaluate the efficacy and safety of indocyanine green (ICG)-guided near-infrared fluorescence (NIRF) imaging during surgery to diagnose the cause of neonatal cholestasis (NC). Data on NC patients who underwent both NIRF with ICG and conventional laparoscopic bile duct exploration (the gold standard) at our institute from January 2022 to December 2022 were retrospectively analyzed. The patients' baseline characteristics and liver function outcomes were collected and analyzed, and the diagnostic consistency was compared between the 2 methods. In total, 16 NC patients were included in the study, comprising 8 (50%) male and 8 (50%) female patients, ranging in age from 42 to 93 days, with a median age of 54.4 ±â€…21 days. During surgery, all the patients underwent NIRF with ICG, followed by conventional laparoscopic bile duct exploration. Finally, 15 of the patients were diagnosed with biliary atresia (BA) (1 with type-I BA, and 14 with type-II BA). The other patient was diagnosed with cholestasis. The diagnostic results from fluorescence imaging with ICG were consistent with those from conventional laparoscopic bile duct exploration. ICG-guided NIRF is associated with an easy operation, less trauma, and good safety. Also, its diagnostic accuracy is similar to conventional laparoscopic bile duct exploration.


Assuntos
Colestase , Verde de Indocianina , Imagem Óptica , Humanos , Verde de Indocianina/administração & dosagem , Feminino , Masculino , Estudos Retrospectivos , Colestase/diagnóstico por imagem , Colestase/etiologia , Imagem Óptica/métodos , Lactente , Recém-Nascido , Atresia Biliar/cirurgia , Atresia Biliar/diagnóstico por imagem , Laparoscopia/métodos , Corantes/administração & dosagem , Espectroscopia de Luz Próxima ao Infravermelho/métodos
3.
PLoS One ; 19(7): e0303786, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38950046

RESUMO

A prevailing animal model currently used to study severe human diseases like obstructive cholestasis, primary biliary or sclerosing cholangitis, biliary atresia, and acute liver injury is the common bile duct ligation (cBDL). Modifications of this model include ligation of the left hepatic bile duct (pBDL) or ligation of the left bile duct with the corresponding left hepatic artery (pBDL+pAL). Both modifications induce cholestasis only in the left liver lobe. After induction of total or partial cholestasis in mice, the well-being of these animals was evaluated by assessing burrowing behavior, body weight, and a distress score. To compare the pathological features of these animal models, plasma levels of liver enzymes, bile acids, bilirubin, and within the liver tissue, necrosis, fibrosis, inflammation, as well as expression of genes involved in the synthesis or transport of bile acids were assessed. The survival rate of the animals and their well-being was comparable between pBDL+pAL and pBDL. However, surgical intervention by pBDL+pAL caused confluent necrosis and collagen depositions at the edge of necrotic tissue, whereas pBDL caused focal necrosis and fibrosis in between portal areas. Interestingly, pBDL animals had a higher survival rate and their well-being was significantly improved compared to cBDL animals. On day 14 after cBDL liver aspartate, as well as alanine aminotransferase, alkaline phosphatase, glutamate dehydrogenase, bile acids, and bilirubin were significantly elevated, but only glutamate dehydrogenase activity was increased after pBDL. Thus, pBDL may be primarily used to evaluate local features such as inflammation and fibrosis or regulation of genes involved in bile acid synthesis or transport but does not allow to study all systemic features of cholestasis. The pBDL model also has the advantage that fewer mice are needed, because of its high survival rate, and that the well-being of the animals is improved compared to the cBDL animal model.


Assuntos
Colestase , Modelos Animais de Doenças , Fígado , Animais , Ligadura , Camundongos , Colestase/metabolismo , Colestase/patologia , Fígado/metabolismo , Fígado/patologia , Ductos Biliares/cirurgia , Ductos Biliares/patologia , Ductos Biliares/metabolismo , Ácidos e Sais Biliares/metabolismo , Masculino , Bilirrubina/sangue , Bilirrubina/metabolismo , Camundongos Endogâmicos C57BL , Ducto Colédoco/cirurgia
4.
J Biomed Sci ; 31(1): 66, 2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-38951890

RESUMO

BACKGROUND: Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. METHODS: Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. RESULTS: Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-ß-muricholic acid (Tß-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. CONCLUSIONS: Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism.


Assuntos
Colestase , Neoplasias Colorretais , Neoplasias Hepáticas , Neutrófilos , Animais , Neutrófilos/imunologia , Camundongos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Colestase/imunologia , Colestase/metabolismo , Microambiente Tumoral , Masculino , Camundongos Endogâmicos C57BL , Humanos , Modelos Animais de Doenças
5.
J Dig Dis ; 25(5): 310-317, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38973135

RESUMO

OBJECTIVES: Unresectable ampullary cancer (AC) is a rare disease entity. The risk factors for recurrent biliary obstruction (RBO) following endoscopic biliary stenting (EBS) for unresectable AC remain unknown. In this study we aimed to evaluate the cumulative RBO rate and to identify risk factors for RBO following palliative EBS in patients with unresectable AC. METHODS: This multicenter retrospective observational study enrolled consecutive patients with unresectable AC who had undergone palliative EBS between April 2011 and December 2021. The cumulative rate of and risk factors for RBO following palliative EBS were evaluated via multivariate analysis. RESULTS: The study analysis comprised 107 patients with a median age of 84 years (interquartile range 79-88 years). Plastic stents (PSs) and self-expandable metal stents (SEMSs) were placed in 53 and 54 patients, respectively. Functional success was accomplished in 104 (97.2%) patients. Of these, RBO occurred in 62 (59.6%) patients, with obstruction and complete/partial migration occurring in 47 and 15 patients, respectively. The median time to RBO was 190 days. Multivariate analysis showed that PS was associated with a higher rate of RBO compared to SEMS (hazard ratio [HR] 2.48; P < 0.01) and that the presence of common bile duct stones/sludge immediately after EBS was an independent risk factor for RBO (HR 1.99; P = 0.04). CONCLUSIONS: The use of SEMS compared to PS during EBS reduced the time to RBO in patients with unresectable AC. Common bile duct stones/sludge immediately after EBS was a risk factor for RBO.


Assuntos
Ampola Hepatopancreática , Colestase , Neoplasias do Ducto Colédoco , Cuidados Paliativos , Recidiva , Stents , Humanos , Masculino , Feminino , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Idoso , Ampola Hepatopancreática/cirurgia , Fatores de Risco , Colestase/etiologia , Colestase/cirurgia , Stents/efeitos adversos , Neoplasias do Ducto Colédoco/cirurgia , Neoplasias do Ducto Colédoco/complicações , Cuidados Paliativos/métodos , Stents Metálicos Autoexpansíveis/efeitos adversos , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos
6.
J Transl Med ; 22(1): 636, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978022

RESUMO

BACKGROUND: Prompt and precise differential diagnosis of biliary atresia (BA) among cholestatic patients is of great importance. Matrix metalloproteinase-7 (MMP-7) holds great promise as a diagnostic marker for BA. This study aimed to investigate the accuracy of age-specific serum MMP-7 for discriminating BA from other cholestatic pediatric patients. METHODS: This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases (n = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients (n = 318, with 172 BA) and validated in a prospective cohort (n = 687, including 395 BA). RESULTS: The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946-0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0-90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9-93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6-96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0-30 days, which was 86.4% (95% CI: 75.0-94.0%), 95.5% (95% CI: 77.2-99.9%), 98.1% (95% CI: 89.7-100%), and 72.4% (95% CI: 52.8-87.3%), respectively. CONCLUSIONS: The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.


Assuntos
Atresia Biliar , Metaloproteinase 7 da Matriz , Curva ROC , Humanos , Atresia Biliar/sangue , Atresia Biliar/diagnóstico , Metaloproteinase 7 da Matriz/sangue , Lactente , Masculino , Feminino , Recém-Nascido , Reprodutibilidade dos Testes , Estudos Retrospectivos , Diagnóstico Diferencial , Pré-Escolar , Colestase/sangue , Colestase/diagnóstico , Estudos Prospectivos
7.
Front Cell Infect Microbiol ; 14: 1402329, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38947125

RESUMO

Introduction: In infants with cholestasis, variations in the enterohepatic circulation of bile acids and the gut microbiota (GM) characteristics differ between those with biliary atresia (BA) and non-BA, prompting a differential analysis of their respective GM profiles. Methods: Using 16S rDNA gene sequencing to analyse the variance in GM composition among three groups: infants with BA (BA group, n=26), non-BA cholestasis (IC group, n=37), and healthy infants (control group, n=50). Additionally, correlation analysis was conducted between GM and liver function-related indicators. Results: Principal component analysis using Bray-Curtis distance measurement revealed a significant distinction between microbial samples in the IC group compared to the two other groups. IC-accumulated co-abundance groups exhibited positive correlations with aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, and total bile acid serum levels. These correlations were notably reinforced upon the exclusion of microbial samples from children with BA. Conclusion: The varying "enterohepatic circulation" status of bile acids in children with BA and non-BA cholestasis contributes to distinct GM structures and functions. This divergence underscores the potential for targeted GM interventions tailored to the specific aetiologies of cholestasis.


Assuntos
Ácidos e Sais Biliares , Atresia Biliar , Colestase , Microbioma Gastrointestinal , RNA Ribossômico 16S , Humanos , Atresia Biliar/microbiologia , Colestase/microbiologia , Lactente , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/sangue , Masculino , Feminino , RNA Ribossômico 16S/genética , Bilirrubina/sangue , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , DNA Ribossômico/genética , Fezes/microbiologia
8.
Medicina (B Aires) ; 84(3): 564-568, 2024.
Artigo em Espanhol | MEDLINE | ID: mdl-38907975

RESUMO

A case is presented of a 64-year-old male patient who was admitted because of delirium, jaundice, a pattern of cholestasis in the liver profile and a right lung mass in the context of a constitutional syndrome and weight loss in the last eight months. The lung mass was punctured and the culture of the obtained material developed white colonies, identified by mass spectrometry (MALDI-TOF) as Nocardia cyriacigeorgica. Regarding the clinical diagnosis, it was considered as systemic lupus erythematosus (SLE), on the basis of fulfilling 8 criteria according to SLICC 2012 group, and 24 points according to EULAR/ACR 2019. The liver biopsy showed a mixt cellular infiltrate in portal spaces, with absence of interphase hepatitis and presence of peripheral ductular reaction. These findings were interpreted as liver compromise relate to SLE. Delirium was also considered as a neurological manifestation related to SLE on the basis of ruling out other causes. After being treated with antibiotics and documenting a reduction in the size of the lung mass he received cyclophosphamide in intravenous pulses, achieving normalization of his liver profile and his state of consciousness, and a progressively weight recovering. A year after he was in good health. The report of this case is justified because of the rare presenting form of late onset SLE, as well as the concomitant pulmonary nocardiosis in the absence of previous immunosuppressant treatment.


Se presenta el caso de un varón de 64 años que fue internado por delirium asociado a ictericia con patrón de colestasis en el hepatograma, y una masa en el pulmón derecho en el contexto de pérdida de peso y síndrome constitucional de 8 meses de evolución. Se realizó punción de la masa pulmonar cuyo cultivo desarrolló colonias blanquecinas identificadas como Nocardia cyriacigeorgica por espectrometría de masas (MALDI-TOF MS). Se llegó al diagnóstico de lupus eritematosos sistémico (LES) por presentar 8 de los criterios de acuerdo con el grupo SLICC 2012 y 24 puntos de acuerdo a los criterios EULAR/ACR 2019. La biopsia hepática mostró leve y variable infiltrado inflamatorio mixto en espacios porta, con ausencia de hepatitis de interfase y presencia de reacción ductular periférica. Se interpretaron estos hallazgos como vinculados a hepatopatía por LES. El delirium fue interpretado como afectación neurológica por LES en base al descarte de otras enfermedades. Recibió tratamiento antibiótico y tras constatarse reducción del tamaño de la masa pulmonar se administraron pulsos de ciclofosfamida intravenosa. Evolucionó favorablemente, con normalización del hepatograma y el estado de conciencia, y recuperación del peso en forma progresiva. Al año se lo encontró en buen estado de salud. Justifica el reporte del caso la rara forma de presentación del LES de comienzo tardío, así como la nocardiosis pulmonar concomitante sin tratamiento inmunosupresor previo.


Assuntos
Colestase , Delírio , Lúpus Eritematoso Sistêmico , Nocardiose , Humanos , Masculino , Pessoa de Meia-Idade , Lúpus Eritematoso Sistêmico/complicações , Nocardiose/diagnóstico , Nocardiose/complicações , Delírio/etiologia , Colestase/etiologia , Pneumopatias/microbiologia
10.
Toxins (Basel) ; 16(6)2024 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-38922135

RESUMO

The aim of this study was to investigate the effects of aflatoxin B1 (AFB1) on cholestasis in duck liver and its nutritional regulation. Three hundred sixty 1-day-old ducks were randomly divided into six groups and fed for 4 weeks. The control group was fed a basic diet, while the experimental group diet contained 90 µg/kg of AFB1. Cholestyramine, atorvastatin calcium, taurine, and emodin were added to the diets of four experimental groups. The results show that in the AFB1 group, the growth properties, total bile acid (TBA) serum levels and total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and glutathione (GSH) liver levels decreased, while the malondialdehyde (MDA) and TBA liver levels increased (p < 0.05). Moreover, AFB1 caused cholestasis. Cholestyramine, atorvastatin calcium, taurine, and emodin could reduce the TBA serum and liver levels (p < 0.05), alleviating the symptoms of cholestasis. The qPCR results show that AFB1 upregulated cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and cytochrome P450 family 8 subfamily B member 1 (CYP8B1) gene expression and downregulated ATP binding cassette subfamily B member 11 (BSEP) gene expression in the liver, and taurine and emodin downregulated CYP7A1 and CYP8B1 gene expression (p < 0.05). In summary, AFB1 negatively affects health and alters the expression of genes related to liver bile acid metabolism, leading to cholestasis. Cholestyramine, atorvastatin calcium, taurine, and emodin can alleviate AFB1-induced cholestasis.


Assuntos
Aflatoxina B1 , Colestase , Patos , Fígado , Animais , Aflatoxina B1/toxicidade , Colestase/induzido quimicamente , Colestase/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ácidos e Sais Biliares/metabolismo , Ácidos e Sais Biliares/sangue , Doenças das Aves Domésticas/induzido quimicamente , Resina de Colestiramina/farmacologia , Ração Animal
11.
Hepatol Commun ; 8(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38934703

RESUMO

BACKGROUND: The incidence of gallbladder diseases is as high as 20%, but whether gallbladder diseases contribute to hepatic disorders remains unknown. METHODS: Here, we established an animal model of gallbladder dysfunction and assessed the role of a diseased gallbladder in cholestasis-induced hepatic fibrosis (CIHF). RESULTS: Mice with smooth muscle-specific deletion of Mypt1, the gene encoding the main regulatory subunit of myosin light chain phosphatase (myosin phosphatase target subunit 1 [MYPT1]), had apparent dysfunction of gallbladder motility. This dysfunction was evidenced by abnormal contractile responses, namely, inhibited cholecystokinin 8-mediated contraction and nitric oxide-resistant relaxation. As a consequence, the gallbladder displayed impaired bile filling and biliary tract dilation comparable to the alterations in CIHF. Interestingly, the mutant animals also displayed CIHF features, including necrotic loci by the age of 1 month and subsequently exhibited progressive fibrosis and hyperplastic/dilated bile ducts. This pathological progression was similar to the phenotypes of the animal model with bile duct ligation and patients with CIHF. The characteristic biomarker of CIHF, serum alkaline phosphatase activity, was also elevated in the mice. Moreover, we observed that the myosin phosphatase target subunit 1 protein level was able to be regulated by several reagents, including lipopolysaccharide, exemplifying the risk factors for gallbladder dysfunction and hence CIHF. CONCLUSIONS: We propose that gallbladder dysfunction caused by myosin phosphatase target subunit 1 ablation is sufficient to induce CIHF in mice, resulting in impairment of the bile transport system.


Assuntos
Colestase , Modelos Animais de Doenças , Cirrose Hepática , Fosfatase de Miosina-de-Cadeia-Leve , Animais , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/genética , Camundongos , Cirrose Hepática/fisiopatologia , Cirrose Hepática/genética , Colestase/complicações , Doenças da Vesícula Biliar/genética , Doenças da Vesícula Biliar/fisiopatologia , Doenças da Vesícula Biliar/patologia , Vesícula Biliar/patologia , Vesícula Biliar/fisiopatologia , Masculino , Camundongos Knockout
13.
Pharmacol Res Perspect ; 12(4): e1220, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38899589

RESUMO

Cholestasis, a chronic liver condition, disrupts bile acid homeostasis and complicates drug disposition, posing significant challenges in medicating cholestatic patients. Drug metabolism enzymes and transporters (DMETs) are pivotal in drug clearance. Research indicates that cholestasis leads to alterations in both hepatic and extrahepatic DMETs, with changes in expression and function documented in rodents and humans. This review synthesizes the modifications in key drug disposition components within cholestasis, focusing on cytochrome P450 (CYP450), drug transporters, and their substrates. Additionally, we briefly discuss certain drugs that have demonstrated efficacy in restoring DMET expression in cholestatic conditions. Ultimately, these insights necessitate a reevaluation of drug selection and dosing guidelines for patients with cholestasis.


Assuntos
Colestase , Sistema Enzimático do Citocromo P-450 , Humanos , Colestase/metabolismo , Colestase/tratamento farmacológico , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Preparações Farmacêuticas/metabolismo , Preparações Farmacêuticas/administração & dosagem , Proteínas de Membrana Transportadoras/metabolismo , Fígado/metabolismo , Ácidos e Sais Biliares/metabolismo
17.
S Afr J Surg ; 62(2): 50-53, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38838120

RESUMO

BACKGROUND: Human immunodeficiency virus (HIV) infection, low cluster of differentiation (CD)4 counts and antiretroviral therapy can cause cholestasis and raised transaminases. In acute pancreatitis, this may render biochemical predictors of a gallstone aetiology inaccurate. METHODS: In a prospective observational study, acute pancreatitis was diagnosed by standard criteria. Cholecystolithiasis and bile duct diameter were diagnosed by ultrasound. Cholestasis was defined as two of the following: bilirubin ≥ 21 umol/l, γ glutamyl transferase ≥ 78 U/l, alkaline phosphatase ≥ 121 U/l. Cholangitis was defined as cholestasis and any two sepsis criteria: (temperature > 38˚C, WCC > 12.6 ×109/L, pulse > 90 beats/min). Cholangitis, cholestasis, and bile duct diameter greater that 1 cm were indications for endoscopic retrograde cholangiopancreatography (ERCP). These parameters' ability to predict gallstone pancreatitis (GSP) and choledocholithiasis were compared in HIV+ve and HIV-ve patients. RESULTS: Sixty-two (26%) of 216 patients had GSP. Twenty four were HIV+ve patients. More HIV+ve patients had cholestasis (p = 0.059) and ERCP (p = 0.004). In HIV+ve patients alanine aminotransferase (ALT) > 100 U/L, gamma glutamyl transferase (GGT) > 2 upper limit of normal and cholestasis had a negative predictive value of 92%, 96.7% and 95.2% respectively. In HIV-ve patients, negative predictive value (NPV) was 84%, 83.8% and 84.6% respectively. Bile duct stones were demonstrated at ERCP in 6 (25%) and 3 (8%) of HIV+ve and HIV-ve patients respectively (p = 0.077). Five of 14 ERCP patients had no bile duct stones. HIV+ve and HIV-ve groups had two deaths each. CONCLUSION: Absence at presentation of the abnormal parameters analysed were good predictors of a non-gallstone aetiology particularly in HIV+ve patients. Prior, magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) would reduce the number of non-therapeutic ERCPs.


Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Cálculos Biliares , Infecções por HIV , Pancreatite , Humanos , Masculino , Feminino , Estudos Prospectivos , Infecções por HIV/complicações , Cálculos Biliares/complicações , Cálculos Biliares/diagnóstico por imagem , Adulto , Pessoa de Meia-Idade , Pancreatite/etiologia , Pancreatite/diagnóstico , Valor Preditivo dos Testes , Doença Aguda , Coledocolitíase/complicações , Coledocolitíase/diagnóstico por imagem , Colestase/etiologia , Colestase/diagnóstico por imagem
18.
Exp Clin Transplant ; 22(4): 311-313, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38742323

RESUMO

Biliary strictures afterlivertransplant are amenable to endoscopic dilatation or percutaneous dilatation and stenting in most cases. In rare cases, for recurrence or tight stricture, surgery is required, and hepaticojejunostomy is the favored procedure. We report a case of posttransplant stricture in a duct-to-duct anastomosis that could not be accessed due to prior gastric bypass. Despite multiple percutaneous transhepatic cholangiography dilatations, the stricture recurred, and the patient was taken up for bilioenteric bypass. During surgery, dense adhesions in the infracolic compartment with chronically twisted jejunal loops, due to prior mini gastric bypass, were encountered, which prevented the creation of a jejunal Roux limb. Hepaticoduodenostomy was performed with no recurrence of stricture at 12 months. Hepaticoduodenostomy is a viable option for surgical management of recurrent biliary strictures, especially in a setting of prior bariatric/diversion procedures.


Assuntos
Duodenostomia , Transplante de Fígado , Recidiva , Reoperação , Humanos , Transplante de Fígado/efeitos adversos , Constrição Patológica , Resultado do Tratamento , Colestase/etiologia , Colestase/cirurgia , Colestase/diagnóstico por imagem , Pessoa de Meia-Idade , Anastomose Cirúrgica , Feminino , Masculino , Colangiografia
19.
Biochim Biophys Acta Mol Basis Dis ; 1870(6): 167266, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38806072

RESUMO

Acute cholestatic liver injury (ACLI) is a disease associated with bile duct obstruction that causes liver inflammation and apoptosis. Although G protein-coupled bile acid receptor1 (Gpbar-1) has diverse metabolic roles, its involvement in ACLI-associated immune activation remains unclear. Liver tissues and blood samples from 20 patients with ACLI and 20 healthy individuals were analyzed using biochemical tests, H&E staining, western blotting, and immunohistochemistry to verify liver damage and expression of Gpbar-1. The expression of Gpbar-1, cAMP/PKA signaling, and the NLRP3 inflammasome was tested in wild-type (WT) and Gpbar-1 knockdown (si-Gpbar-1) mice with ACLI induced by bile duct ligation (BDL) and in primary Kupffer cells (KCs) with or without Gpbar-1-siRNA. The results showed that total bile acids and Gpbar-1 expressions were elevated in patients with ACLI. Gpbar-1 knockdown significantly worsened BDL-induced acute hepatic damage, inflammation, and liver apoptosis in vivo. Knockdown of Gpbar-1 heightened KC sensitivity to lipopolysaccharide (LPS) stimulation. Gpbar-1 activation inhibited LPS-induced pro-inflammatory responses in normal KCs but not in Gpbar-1-knockdown KCs. Notably, NLRP3-ASC inflammasome expression was effectively enhanced by Gpbar-1 deficiency. Additionally, Gpbar-1 directly increased intracellular cAMP levels and PKA phosphorylation, thus disrupting the NLRP3-ASC inflammasome. The pro-inflammatory characteristic of Gpbar-1 deficiency was almost neutralized by the NLRP3 inhibitor CY-09. In vitro, M1 polarization was accelerated in LPS-stimulated Gpbar-1-knockdown KCs. Therapeutically, Gpbar-1 deficiency exacerbated BDL-induced ACLI, which could be rescued by inhibition of the NLRP3-ASC inflammasome. Our study reveal that Gpbar-1 may act as a novel immune-mediated regulator of ACLI by inhibiting the NLRP3-ASC inflammasome.


Assuntos
Colestase , Proteínas Quinases Dependentes de AMP Cíclico , AMP Cíclico , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Receptores Acoplados a Proteínas G , Transdução de Sinais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Animais , Humanos , Inflamassomos/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Camundongos , Masculino , Colestase/metabolismo , Colestase/patologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Células de Kupffer/metabolismo , Camundongos Endogâmicos C57BL , Feminino , Macrófagos/metabolismo , Macrófagos/imunologia , Fígado/metabolismo , Fígado/patologia , Fígado/lesões , Lipopolissacarídeos/toxicidade , Adulto , Pessoa de Meia-Idade
20.
Stem Cells Transl Med ; 13(7): 648-660, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38736295

RESUMO

Cholestatic liver disease (CLD) is a severe disease, which can progress to liver cirrhosis, even liver cancer. Hepatic stellate cells (HSCs) activation plays a crucial role in CLD development. Bone mesenchymal stem cells (BMSCs) treatment was demonstrated to be beneficial in liver diseases. However, the therapeutic effect and mechanism of BMSCs on CLD are poorly known. In the present study, we investigated the therapeutic effects and underlying mechanisms of BMSCs transplantation in mouse models of bile duct ligation-induced cholestatic liver fibrosis (CLF). The results revealed that BMSCs significantly improved liver function and reduced the formation of fibrosis after portal vein transplantation. Mechanistically, after coculturing BMSCs and HSCs, we identified that BMSCs alleviated starvation-induced HSCs activation. Further, BMSCs inhibited HSCs activation by decreasing autophagy, and PI3K/AKT/mTOR pathway was involved in the regulation. More importantly, ULK1 is identified as the main autophagy-related gene regulated by BMSCs in HSCs autophagy. Overexpression of ULK1 reversed the suppression of HSCs autophagy by BMSCs. Collectively, our results provide a theoretical basis for BMSCs targeting ULK1 to attenuate HSCs autophagy and activation and suggest that BMSCs or ULK1 may be an alternative therapeutic approach/target for the treatment of CLF.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia , Autofagia , Cirrose Hepática , Células-Tronco Mesenquimais , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Animais , Autofagia/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Células-Tronco Mesenquimais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/terapia , Cirrose Hepática/patologia , Transdução de Sinais , Transplante de Células-Tronco Mesenquimais/métodos , Masculino , Camundongos Endogâmicos C57BL , Células Estreladas do Fígado/metabolismo , Colestase/metabolismo , Colestase/patologia
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