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3.
Histopathology ; 69(2): 315-21, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26826338

RESUMO

AIMS: Liver pathology is a challenging subspeciality, with histopathologists frequently seeking specialist opinions. This study aims to determine the impact of specialist reviews on the final diagnosis and patient management. METHODS AND RESULTS: Agreement with the initial reporting centre in the histopathological diagnosis of 1265 liver biopsies was determined. The nature of differences was explored in more depth for 103 discrepant cases. Differences in the histopathological interpretation were present in 749 of 1265 (59%) biopsies, of which 505 of 749 (67%) were predicted at the time of reporting to impact upon patient management. Agreement was good in cases with chronic viral hepatitis, fatty liver disease, malignancy and minimal pathological changes, while diagnostic differences occurred in more than 70% with biliary disease, autoimmune hepatitis or vascular/architectural changes. A clinical review of a subset of reports with histopathological differences predicted changes in patient management in 63 of 103 (61%). CONCLUSIONS: Clinically significant differences in liver biopsy interpretation between local pathologists and subspecialists are common. Diagnoses with frequent discrepancies, such as biliary disease, may benefit from a specialist review as standard when diagnosed initially, while cases requiring specialist advice from disease subgroups where discrepancies are less common, such as chronic viral hepatitis, could be selected during the clinicopathological conference process.


Assuntos
Fígado Gorduroso/diagnóstico , Hepatite Autoimune/diagnóstico , Hepatopatias/diagnóstico , Fígado/patologia , Encaminhamento e Consulta/normas , Biópsia , Erros de Diagnóstico/prevenção & controle , Fígado Gorduroso/patologia , Hepatite Autoimune/patologia , Humanos , Hepatopatias/patologia , Especialização
4.
Liver Transpl ; 21(4): 487-99, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25545865

RESUMO

Ischemia/reperfusion injury (IRI) that develops after liver implantation may prejudice long-term graft survival, but it remains poorly understood. Here we correlate the severity of IRIs that were determined by histological grading of time-zero biopsies sampled after graft revascularization with patient and graft outcomes. Time-zero biopsies of 476 liver transplants performed at our center between 2000 and 2010 were graded as follows: nil (10.5%), mild (58.8%), moderate (26.1%), and severe (4.6%). Severe IRI was associated with donor age, donation after circulatory death, prolonged cold ischemia time, and liver steatosis, but it was also associated with increased rates of primary nonfunction (9.1%) and retransplantation within 90 days (22.7%). Longer term outcomes in the severe IRI group were also poor, with 1-year graft and patient survival rates of only 55% and 68%, respectively (cf. 90% and 93% for the remainder). Severe IRI on the time-zero biopsy was, in a multivariate analysis, an independent determinant of 1-year graft survival and was a better predictor of 1-year graft loss than liver steatosis, early graft dysfunction syndrome, and high first-week alanine aminotransferase with a positive predictive value of 45%. Time-zero biopsies predict adverse clinical outcomes after liver transplantation, and severe IRI upon biopsy signals the likely need for early retransplantation.


Assuntos
Transplante de Fígado/efeitos adversos , Traumatismo por Reperfusão/patologia , Adulto , Fatores Etários , Idoso , Alanina Transaminase/sangue , Aloenxertos , Biomarcadores/sangue , Biópsia , Isquemia Fria/efeitos adversos , Feminino , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Transplante de Fígado/mortalidade , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/mortalidade , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Doadores de Tecidos , Resultado do Tratamento , Adulto Jovem
5.
J Antimicrob Chemother ; 69(8): 2238-45, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24788657

RESUMO

BACKGROUND: The term 'zero tolerance' has recently been applied to healthcare-associated infections, implying that such events are always preventable. This may not be the case for healthcare-associated infections such as methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. METHODS: We combined information from an epidemiological investigation and bacterial whole-genome sequencing to evaluate a cluster of five MRSA bacteraemia episodes in four patients in a specialist hepatology unit. RESULTS: The five MRSA bacteraemia isolates were highly related by multilocus sequence type (ST) (four isolates were ST22 and one isolate was a single-locus variant, ST2046). Whole-genome sequencing demonstrated unequivocally that the bacteraemia cases were unrelated. Placing the MRSA bacteraemia isolates within a local and global phylogenetic tree of MRSA ST22 genomes demonstrated that the five bacteraemia isolates were highly diverse. This was consistent with the acquisition and importation of MRSA from the wider referral network. Analysis of MRSA carriage and disease in patients within the hepatology service demonstrated a higher risk of both initial MRSA acquisition compared with the nephrology service and a higher risk of progression from MRSA carriage to bacteraemia, compared with patients in nephrology or geriatric services. A root cause analysis failed to reveal any mechanism by which three of five MRSA bacteraemia episodes could have been prevented. CONCLUSIONS: This study illustrates the complex nature of MRSA carriage and bacteraemia in patients in a specialized hepatology unit. Despite numerous ongoing interventions to prevent MRSA bacteraemia in healthcare settings, these are unlikely to result in a zero incidence in referral centres that treat highly complex patients.


Assuntos
Bacteriemia/mortalidade , Infecção Hospitalar/prevenção & controle , Atenção à Saúde/normas , Infecções Estafilocócicas/prevenção & controle , Infecções Estafilocócicas/transmissão , Antibacterianos/farmacologia , Bacteriemia/microbiologia , Bacteriemia/prevenção & controle , Técnicas de Tipagem Bacteriana , Sequência de Bases , Infecção Hospitalar/microbiologia , DNA Bacteriano/genética , Surtos de Doenças , Doença Hepática Terminal/microbiologia , Humanos , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Filogenia , Análise de Sequência de DNA , Infecções Estafilocócicas/microbiologia
6.
Transplantation ; 108(6): 1383-1393, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38409681

RESUMO

BACKGROUND: Bile chemistry during normothermic ex situ liver perfusion (NESLiP) has been suggested to be an indicator of cholangiopathy. The normal range of biochemical variables in bile of livers undergoing NESLiP has not been defined, nor have published biliary viability criteria been assessed against instances of posttransplant nonanastomotic bile strictures (NASs). METHODS: The bile and perfusate chemistry of 200 livers undergoing NESLiP between February 1, 2018, and October 30, 2023, was compared. In addition, 11 livers that underwent NESLiP and later developed NAS were selected and their bile chemistry was also examined. RESULTS: In livers that did not develop cholangiopathy, concentrations of sodium, potassium, and chloride were slightly higher in bile than in perfusate, whereas the concentration of calcium was slightly lower. Bile was alkali and had a lower glucose concentration than perfusate. Cholangiocyte glucose reabsorption was shown to saturate at high perfusate concentrations and was more impaired in livers donated after circulatory death than in livers donated after brain death. Published criteria failed to identify all livers that went on to develop NASs. CONCLUSIONS: A significant false-negative rate exists with current biliary viability criteria, probably reflecting the patchy and incomplete nature of the development of NASs in the biliary tree. The data presented here provide a benchmark for future assessment of bile duct chemistry during NESLiP.


Assuntos
Bile , Transplante de Fígado , Fígado , Preservação de Órgãos , Perfusão , Humanos , Transplante de Fígado/efeitos adversos , Bile/metabolismo , Bile/química , Preservação de Órgãos/métodos , Fígado/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Colestase , Adulto , Estudos Retrospectivos , Constrição Patológica
7.
Mol Metab ; 48: 101210, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33722690

RESUMO

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. METHODS AND RESULTS: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. CONCLUSIONS: Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.


Assuntos
Colesterol/biossíntese , Progressão da Doença , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipogênese/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Biomarcadores/metabolismo , Dieta Ocidental , Feminino , Humanos , Resistência à Insulina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Transcriptoma
8.
Sci Transl Med ; 13(624): eabk2267, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34910547

RESUMO

The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that ß2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)­binding protein (SREBP)­stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased SPTBN1 and CASPASE-3 expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.


Assuntos
Neoplasias , Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Espectrina/metabolismo
9.
Cell Death Differ ; 27(5): 1457-1474, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32231246

RESUMO

Methionine-1 (M1)-linked polyubiquitin chains conjugated by the linear ubiquitin chain assembly complex (LUBAC) control NF-κB activation, immune homoeostasis, and prevents tumour necrosis factor (TNF)-induced cell death. The deubiquitinase OTULIN negatively regulates M1-linked polyubiquitin signalling by removing the chains conjugated by LUBAC, and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. However, the cellular pathways and physiological functions controlled by OTULIN remain poorly understood. Here, we show that OTULIN prevents development of liver disease in mice and humans. In an ORAS patient, OTULIN deficiency caused spontaneous and progressive steatotic liver disease at 10-13 months of age. Similarly, liver-specific deletion of OTULIN in mice leads to neonatally onset steatosis and hepatitis, akin to the ORAS patient. OTULIN deficiency triggers metabolic alterations, apoptosis, and inflammation in the liver. In mice, steatosis progresses to steatohepatitis, fibrosis and pre-malignant tumour formation by 8 weeks of age, and by the age of 7-12 months the phenotype has advanced to malignant hepatocellular carcinoma. Surprisingly, the pathology in OTULIN-deficient livers is independent of TNFR1 signalling. Instead, we find that steatohepatitis in OTULIN-deficient livers is associated with aberrant mTOR activation, and inhibition of mTOR by rapamycin administration significantly reduces the liver pathology. Collectively, our results reveal that OTULIN is critical for maintaining liver homoeostasis and suggest that M1-linked polyubiquitin chains may play a role in regulation of mTOR signalling and metabolism in the liver.


Assuntos
Endopeptidases/metabolismo , Inflamação/complicações , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Fígado/patologia , Animais , Animais Recém-Nascidos , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Morte Celular , Proliferação de Células , Endopeptidases/deficiência , Fígado Gorduroso/complicações , Feminino , Deleção de Genes , Hematopoese , Humanos , Inflamação/patologia , Fígado/efeitos dos fármacos , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Sirolimo , Serina-Treonina Quinases TOR/metabolismo
10.
Nat Metab ; 2(6): 514-531, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32694734

RESUMO

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFß)-BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFß-BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Intoxicação por Tetracloreto de Carbono/metabolismo , Dieta Hiperlipídica , Dieta Ocidental , Células Estreladas do Fígado/metabolismo , Humanos , Inflamação/genética , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/genética , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas Recombinantes/farmacologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Cicatrização/genética
11.
Hosp Med ; 65(10): 609-12, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15524341

RESUMO

Fatty liver is increasingly becoming more problematic from a clinical perspective. This article describes fatty liver and its clinical presentation. The current understanding of processes underlying fatty liver is reviewed, as well as the evidence for therapeutic options.


Assuntos
Fígado Gorduroso , Biópsia/métodos , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Fígado Gorduroso/terapia , Hepatomegalia/etiologia , Humanos , Fígado/enzimologia , Fígado/patologia , Testes de Função Hepática , Fatores de Risco , Esplenomegalia/etiologia
12.
Nat Commun ; 5: 4309, 2014 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-24978903

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition, strongly associated with the metabolic syndrome, that can lead to progressive hepatic fibrosis, cirrhosis and hepatic failure. Subtle inter-patient genetic variation and environmental factors combine to determine variation in disease progression. A common non-synonymous polymorphism in TM6SF2 (rs58542926 c.449 C>T, p.Glu167Lys) was recently associated with increased hepatic triglyceride content, but whether this variant promotes clinically relevant hepatic fibrosis is unknown. Here we confirm that TM6SF2 minor allele carriage is associated with NAFLD and is causally related to a previously reported chromosome 19 GWAS signal that was ascribed to the gene NCAN. Furthermore, using two histologically characterized cohorts encompassing steatosis, steatohepatitis, fibrosis and cirrhosis (combined n=1,074), we demonstrate a new association, independent of potential confounding factors (age, BMI, type 2 diabetes mellitus and PNPLA3 rs738409 genotype), with advanced hepatic fibrosis/cirrhosis. These findings establish new and important clinical relevance to TM6SF2 in NAFLD.


Assuntos
Cirrose Hepática/genética , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Proteoglicanas de Sulfatos de Condroitina/genética , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Estudos de Coortes , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurocam , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia
13.
Liver Transpl ; 13(12): 1694-702, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18044728

RESUMO

Renal impairment is common in patients after liver transplantation and is attributable in large part to the use of calcineurin inhibitor (CNI)-based immunosuppression. We sought to determine whether conversion to sirolimus-based immunosuppression was associated with improved renal function. In a single-center, randomized, controlled trial, 30 patients at least 6 months post liver transplantation were randomized to remain on CNI-based immunosuppression or to switch to sirolimus-based immunosuppression. The primary outcome measure was change in measured glomerular filtration rate (GFR) between baseline and 12 months. Of 30 patients randomized, 3 were withdrawn at randomization, leaving 14 patients on CNI and 13 on sirolimus. There was a significant improvement in delta GFR following conversion to sirolimus at 3 months (7.7 mL/minute/1.73 m2; 95% confidence interval, 3.5-11.9) and 1 yr (6.1 mL/minute/1.73 m2; 95% confidence interval, 0.9-11.4). The difference in absolute GFR between the 2 study groups was significant at 3 months (P=0.02), but not at 12 months (P=0.07). The principal adverse events following conversion were the development of skin rash (9 of 13 patients, 69%) and mouth ulcers (5 of 13 patients, 38%). Two patients developed acute rejection at 2 and 3 months following conversion, 1 in association with low sirolimus levels and 1 having stopped the drug inadvertently. In conclusion, overall, this study suggests that conversion to sirolimus immunosuppression is associated with a modest improvement in renal function. Side effects were common, but tolerable in most patients and controlled with dose reduction.


Assuntos
Inibidores de Calcineurina , Ciclosporina/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Imunossupressores/efeitos adversos , Nefropatias/induzido quimicamente , Transplante de Fígado , Sirolimo/efeitos adversos , Tacrolimo/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Nefropatias/sangue , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Fatores de Tempo , Resultado do Tratamento
14.
Liver Transpl ; 13(6): 853-6, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17539005

RESUMO

Sirolimus-induced pneumonitis has emerged as a potentially serious complication in renal transplantation but only single case reports of this condition have been described after liver transplantation (LT), where experience with sirolimus is relatively limited. We report our experience, the largest to date, of sirolimus-induced pneumonitis following LT. Between 1999 and 2006, 186 liver transplant patients received sirolimus-based immunosuppression, after initial therapy with calcineurin inhibitors (CNIs). All cases of sirolimus-induced pneumonitis were recorded and a retrospective review of the case notes of such patients was undertaken for the purpose of this analysis. Of 186 liver transplant patients receiving sirolimus, 4 (2.2%) developed pneumonitis that was attributed to the drug; the time from starting sirolimus to presentation was varied (1.5-30 months). The most common presenting symptoms were dyspnea, cough and fatigue. The median sirolimus level at the time of diagnosis was 9.7 ng/mL (range, 7-19.5 ng/mL). All patients in the series underwent thoracic computed tomography, which showed similar changes in all patients, and lung biopsy, which revealed features consistent with a drug-induced pneumonitis. In all 4 patients, sirolimus-induced pneumonitis resolved following cessation of therapy but took weeks to months for complete recovery. In conclusion, sirolimus-induced pneumonitis occurred in at least 2% of liver transplant recipients and should be suspected in patients who develop respiratory symptoms while on sirolimus. Although it may be life threatening, early recognition and cessation of sirolimus can lead to complete resolution of pneumonitis.


Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/efeitos adversos , Transplante de Fígado/efeitos adversos , Pneumonia/induzido quimicamente , Sirolimo/efeitos adversos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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