CLAUDIA PINTO MARQUES SOUZA DE OLIVEIRA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Gastroenterologia, Faculdade de Medicina - Docente
LIM/07 - Laboratório de Gastroenterologia Clínica e Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/07 - Laboratório de Gastroenterologia Clínica e Experimental, Hospital das Clínicas, Faculdade de Medicina - Líder
16 resultados
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- Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease(2022) MCGLINCHEY, Aidan J.; GOVAERE, Olivier; GENG, Dawei; RATZIU, Vlad; ALLISON, Michael; BOUSIER, Jerome; PETTA, Salvatore; OLIVIERA, Claudia de; BUGIANESI, Elisabetta; SCHATTENBERG, Jorn M.; DALY, Ann K.; HYOTYLAINEN, Tuulia; ANSTEE, Quentin M.; ORESIC, MatejBackground & Aims: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis). Methods: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis. Results: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered. Conclusions: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress. Clinical Trials registration: The study is registered at Clinicaltrials.gov (NCT04442334). Lay summary: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases. (c) 2022 The Author(s).
conferenceObject IMPACT OF BASELINE STEATOSIS AND SEVERITY OF ISCHAEMIA-REPERFUSION INJURY IN PREDICTING HCV RECURRENCE POST TRANSPLANTATION(2013) JOSHI, D.; QUAGLIA, A.; HEATON, N.; OLIVEIRA, C.; ALVARES-DA-SILVA, M.; SANCHEZ-FUEYO, A.; AGARWAL, K.; HENEGHAN, M. A.Introduction: Recurrent HCV (rHCV) infection is universal post-transplantation and is associated with significant morbidity and mortality. HCV recurrence is influenced by a combination of donor, recipient, viral and immunosuppressive factors. Methods: We hypothesised that baseline steatosis and the severity of ischaemia–reperfusion (IR) injury can predict slow and rapid fibrosis progression at 12 months. IR injury and steatosis was graded as none (0) – severe (3). Predictive ability was assessed using area under the curve generated by receiver operator characteristic analysis (AUROC). Results: During January 2000 and January 2011, 303 patients (> 18 years) with chronic HCV underwent primary liver transplantation at King’s College Hospital, London. Of these 303 patients, 141 had an IR liver biopsy performed. Median age at transplant was 53 years (19–67), median donor age was 46 years (15–85). Median IR grade was 1 (0–3) and median grade of steatosis was 0 (0–3). Median peak AST was 1218 IU/ml (236–5045). Patients were followed up for 46 months (4–143). Patients were then divided into groups according to the result of their 12 month biopsy result (slow fibrosis progression rate – F < 2 Ishak; fast fibrosis progression rate – F≥2). Patients with slow fibrosis progression at 12 months were male, had younger donors, and a longer time to F≥4 post-LT (p < 0.04). Moderate/severe IR injury was a poor predictor of fast fibrosis progression (AUROC 0.54, 95%CI 0.36–0.71, p=0.67), although the presence of steatosis along with moderate/severe IR injury was a sensitive predictor of F≥2 at 12 month (0.79, 0.66–0.89, p < 0.0001). Patients with the combination of steatosis and moderate/severe IR injury were more likely to develop F≥2 at 12 months (86% vs. 30%, p < 0.0001). Conclusion: The combination of steatosis and moderate/severe degree of IR injury appears to correctly identify patients with rapid fibrosis of rHCV in the post-transplant setting.- Diagnostic performance of FibroTest, SteatoTest and ActiTest in patients with NAFLD using the SAF score as histological reference(2016) MUNTEANU, M.; TINIAKOS, D.; ANSTEE, Q.; CHARLOTTE, F.; MARCHESINI, G.; BUGIANESI, E.; TRAUNER, M.; GOMEZ, M. Romero; OLIVEIRA, C.; DAY, C.; DUFOUR, J. -F.; BELLENTANI, S.; NGO, Y.; TRAUSSNIG, S.; PERAZZO, H.; DECKMYN, O.; BEDOSSA, P.; RATZIU, V.; POYNARD, T.Background Blood tests of liver injury are less well validated in non-alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis. Aims To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading. Methods We pre-included new NAFLD patients with biopsy and blood tests from a single-centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary-ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing. Results A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864-0.892) for FibroTest and fibrosis stages, 0.846 (0.830-0.862) for ActiTest and activity grades, and 0.822 (0.804-0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820-0.852; P = 0.0001), FIB4 (0.845; 0.829-0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850-0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05). Conclusions In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non-invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis.
- Impact of Baseline Steatosis and Severity of Ischaemia-Reperfusion Injury in Predicting HCV Recurrence Post Liver Transplantation(2013) JOSHI, Deepak; QUAGLIA, Alberto; HEATON, Nigel; OLIVEIRA, Claudia P.; ALVARES-DA-SILVA, Mario R.; SANCHEZ-FUEYO, Alberto; AGARWAL, Kosh; HENEGHAN, Michael A.Introduction: Recurrent HCV (rHCV) infection is universal post-transplantation and is associated with significant morbidity and mortality. HCV recurrence is influenced by a combination of donor, recipient, viral and immunosuppressive factors. Methods: We hypothesised that baseline steatosis and the severity of ischaemia-reperfusion (IR) injury can predict slow and rapid fibrosis (F>2) progression at 12 months. IR injury and steatosis was graded as none (0) to severe (3). Predictive ability was assessed using the area under the curve generated by receiver operator characteristic analysis (AUROC). Results: During January 2000 and January 2011, 303 adult patients (> 18 years) with chronic HCV underwent primary liver transplantation at King’s College Hospital NHS Foundation Trust, London. Of these 303 patients, 141 had an IR liver biopsy performed. Median age at transplant was 53 years (19-67), median donor age was 46 years (15-85). Median IR grade was 1(0-3) and median grade of steatosis was 0(0-3). Median peak AST was 1218 IU/ml (236-5045). Patients were followed up for 46 months (4-143). Patients were then divided into groups according to the result of their 12 month biopsy result (slow fibrosis progression rate - F<2 Ishak; fast fibrosis progression rate - F≥2). Patients with slow fibrosis progression at 12 months were male, had younger donors, and a longer time to F≥4 post-LT (p<0.04). Moderate/severe IR injury was a poor predictor of fast fibrosis progression (AUROC 0.54, 95% CI 0.36-0.71, p=0.67), although the presence of steatosis along with moderate/severe IR injury was a sensitive predictor of F≥2 at 12 month (0.79, 0.66-0.89, p<0.0001). Patients with the combination of steatosis and moderate/severe IR injury were more likely to develop F≥2 at 12 months (86% vs. 30%, p<0.0001). Conclusion: The combination of steatosis and moderate/severe degree of IR injury appears to correctly identify patients with rapid fibrosis of rHCV in the post-transplant setting.
- Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis(2021) PINYOL, Roser; TORRECILLA, Sara; WANG, Huan; MONTIRONI, Carla; PIQUE-GILI, Marta; TORRES-MARTIN, Miguel; WEI-QIANG, Leow; WILLOUGHBY, Catherine E.; RAMADORI, Pierluigi; ANDREU-OLLER, Carmen; TAIK, Patricia; LEE, Youngmin A.; MOEINI, Agrin; PEIX, Judit; FAURE-DUPUY, Suzanne; RIEDL, Tobias; SCHUEHLE, Svenja; OLIVEIRA, Claudia P.; ALVES, Venancio A.; BOFFETTA, Paolo; LACHENMAYER, Anja; ROESSLER, Stephanie; MINGUEZ, Beatriz; SCHIRMACHER, Peter; DUFOUR, Jean-Francois; THUNG, Swan N.; REEVES, Helen L.; CARRILHO, Flair J.; CHANG, Charissa; V, Andrew Uzilov; HEIKENWALDER, Mathias; SANYAL, Arun; FRIEDMAN, Scott L.; SIA, Daniela; LLOVET, Josep M.Background and Aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/ TGF-beta proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. Lay summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.
- THE EMERGING IMPACT OF HEPATOCELLULAR CARCINOMA ARISING ON A BACKGROUND OF NAFLD(2012) REEVES, H.; VILLA, E.; BELLENTANI, S.; DIONIGI, E.; DUFOUR, J. -F.; OLIVEIRA, C. de; FRACANZANI, A.; BARCHETI, A.; MERLE, P.; BOURSIER, J.; SCHATTENBERG, J.; FEDCHUK, L.; HOLST, C.; RATZIU, V.
conferenceObject MOLECULAR AND MUTATIONAL LANDSCAPE OF HEPATOCELLULAR CARCINOMA (HCC) RELATED TO NONALCOHOLIC STEATOHEPATITIS (NASH)(2020) PIQUE-GILI, Marta; PINYOL, Roser; TORRECILLA, Sara; WANG, Huan; MONTIRONI, Carla; RAMADORI, Pierluigi; WILLOUGHBY, Catherine E.; ANDREU-OLLER, Carmen; TORRES-MARTIN, Miguel; LEOW, Wei-Qiang; MOEINI, Agrin; TAIK, Patricia; GALLOFRE, Judit Peix; OLIVEIRA, Claudia P. M. S.; ALVES, Venancio A. F.; LACHENMAYER, Anja; ROESSLER, Stephanie; MINGUEZ, Beatriz; SCHIRMACHER, Peter; BOFFETTA, Paolo; DUFOUR, Jean-Francois; THUNG, Swan N.; REEVES, Helen; UZILOV, Andrew; CARRILHO, Flair J.; CHANG, Charissa Y.; HEIKENWAELDER, Mathias; SANYAL, Arun J.; FRIEDMAN, Scott L.; SIA, Daniela; LLOVET, Josep M.- Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis (vol 75, pg 865, 2021)(2021) PINYOL, Roser; TORRECILLA, Sara; WANG, Huan; MONTIRONI, Carla; PIQUE-GILI, Marta; TORRES-MARTIN, Miguel; WEI-QIANG, Leow; WILLOUGHBY, Catherine E.; RAMADORI, Pierluigi; ANDREU-OLLER, Carmen; TAIK, Patricia; LEE, Youngmin A.; MOEINI, Agrin; PEIX, Judit; FAURE-DUPUY, Suzanne; RIEDL, Tobias; SCHUEHLE, Svenja; OLIVEIRA, Claudia P.; ALVES, Venancio A.; BOFFETTA, Paolo; LACHENMAYER, Anja; ROESSLER, Stephanie; MINGUEZ, Beatriz; SCHIRMACHER, Peter; DUFOUR, Jean-Francois; THUNG, Swan N.; REEVES, Helen L.; CARRILHO, Flair J.; CHANG, Charissa; UZILOV, Andrew V.; HEIKENWALDER, Mathias; SANYAL, Arun; FRIEDMAN, Scott L.; SIA, Daniela; LLOVET, Josep M.
conferenceObject Diagnostic performance of FibroTest, SteatoTest, and ActiTest in patients with NAFLD using the SAF-score as histological reference(2016) MUNTEANU, Mona; TINIAKOS, Dina; ANSTEE, Quentin; CHARLOTTE, Frederic; MARCHESINI, Giulio; BUGIANESI, Elisabetta; TRAUNER, Michael H.; OLIVEIRA, Claudia P.; DAY, Christofer; DUFOUR, Jean-Francois; BELLENTANI, Stefano; NGO, Yen; TRAUSSNIGG, Stefan; BEDOSSA, Pierre; RATZIU, Vlad; POYNARD, ThierryconferenceObject Substantial variability of the diagnostic accuracy of serum fibrosis markers across multiple cohorts of nash patients in various centers : the case for the negative predictive value(2015) NASCIMBENI, Fabio; PETTA, Salvatore; ROMERO-GOMEZ, Manuel; MARCHESINI, Giulio; BUGIANESI, Elisabetta; BELLENTANI, Stefano; DAY, Christopher P.; BEDOSSA, Pierre; OLIVEIRA, Claudia P.; TRAUNER, Michael; DUFOUR, Jean-Francois; PAIS, Raluca; RATZIU, Vlad