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1. Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

Author

Lucena, M.I., Villanueva-Paz, M., Alvarez-Alvarez, I., Aithal, G.P., Björnsson, E.S., Cakan-Akdogan, G., Cubero, F.J., Esteves, F., Falcon-Perez, J.M., Fromenty, B., Garcia-Ruiz, C., Grove, J.I., Konu, O., Kranendonk, M., Kullak-Ublick, G.A., Miranda, J.P., Remesal-Doblado, A., Sancho-Bru, P., Nelson, L., Andrade, R.J., Daly, A.K., and Fernandez-Checa, J.C.

Published
2024
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2. Noninvasive assessment of liver disease severity in patients with nonalcoholic fatty liver disease and type 2 diabetes

Author

Pennisi, G., primary, Enea, M., additional, Falco, V., additional, Aithal, G.P., additional, Palaniyappan, N., additional, Yilmaz, Y., additional, Boursier, J., additional, Cassinotto, C., additional, de Lédinghen, V., additional, Chan, W.K., additional, Mahadeva, S., additional, Eddowes, P., additional, Newsome, P., additional, Karlas, T., additional, Wiegand, J., additional, Wong, V. Wai-Sun, additional, Schattenberg, J.M., additional, Labenz, C., additional, Kim, W., additional, Lee, M.S., additional, Lupsor-Platon, M., additional, Cobbold, J.F.L., additional, Fan, J., additional, Shen, F., additional, Staufer, K., additional, Trauner, M., additional, Stauber, R., additional, Nakajima, A., additional, Yoneda, M., additional, Bugianesi, E., additional, Younes, R., additional, Gaia, S., additional, Zheng, M., additional, Cammà, C., additional, Anstee, Q.M., additional, Mózes, F.E., additional, Pavlides, M., additional, and Petta, S., additional

Published
2023
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4. Therapeutic management of idiosyncratic drug-induced liver injury and acetaminophen hepatotoxicity in the paediatric population: a systematic review

Author

Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Niu, H.; Atallah, E.; Alvarez-Alvarez, I.; Medina-Caliz, I.; Aithal, G.P.; Andrade, R.J.; Lucena, M.I., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Koç University Hospital, School of Medicine, Arıkan, Çiğdem (ORCID 0000-0002-0794-2741 & YÖK ID 240198), Niu, H.; Atallah, E.; Alvarez-Alvarez, I.; Medina-Caliz, I.; Aithal, G.P.; Andrade, R.J.; Lucena, M.I., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Koç University Hospital, and School of Medicine

Abstract

Introduction: Drug-induced liver injury (DILI) is a rare but serious adverse event that can progress to acute liver failure (ALF). The evidence for treatment of DILI in children is scarce. Objective We aimed to comprehensively review the available literature on the therapies for both acetaminophen overdose (APAP) and idiosyncratic DILI in the paediatric population. Methods: we included original articles conducted in a paediatric population (< 18 years) in which a therapeutic intervention was described to manage APAP or idiosyncratic DILI. Findings were summarized based on age groups (preterm newborn neonates, term and post-term neonates, infants, children and adolescents). Results: overall, 25 publications (fifteen case reports, six case series and four retrospective cohort studies) were included, including a total of 140 paediatric DILI cases, from preterm newborn neonates to adolescents. N-acetylcysteine was used to treat 19 APAP cases. N-acetylcysteine (n = 14), ursodeoxycholic acid (n = 3), corticosteroids (n = 31), carnitine (n = 16) and the combination of glycyrrhizin, reduced glutathione, polyene phosphatidylcholine and S-adenosylmethionine (n = 31) were the therapeutic options for treating idiosyncratic DILI. The molecular adsorbent recirculating system was used in the management of either APAP (n = 4) or idiosyncratic DILI (n = 2), while 20 paediatric ALF cases received continuous renal replacement therapy. Conclusions: this systematic review identified DILI in the paediatric population who have received specific treatment. These interventions appear to be mainly extrapolated from low-quality evidence from the adult population. Thus, there is a need for high-quality studies to test the efficacy of known and novel therapies to treat DILI specifically addressed to the paediatric population., European Union (EU); Instituto de Salud Carlos III (ISCIII); Fondo Europeo de Desarrollo Regional-FEDER; Consejería de Salud de Junta de Andalucía; Junta de Andalucia; COST Action; Prospective European Drug-Induced Liver Injury Network; Agencia Española del Medicamento; CIBERehd; Plataforma ISCIII Ensayos Clínicos; Sara Borrell; ISCIII

Published
2022

5. Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease

Author

Govaere, O. Petersen, S.K. Martinez-Lopez, N. Wouters, J. Van Haele, M. Mancina, R.M. Jamialahmadi, O. Bilkei-Gorzo, O. Lassen, P.B. Darlay, R. Peltier, J. Palmer, J.M. Younes, R. Tiniakos, D. Aithal, G.P. Allison, M. Vacca, M. Göransson, M. Berlinguer-Palmini, R. Clark, J.E. Drinnan, M.J. Yki-Järvinen, H. Dufour, J.-F. Ekstedt, M. Francque, S. Petta, S. Bugianesi, E. Schattenberg, J.M. Day, C.P. Cordell, H.J. Topal, B. Clément, K. Romeo, S. Ratziu, V. Roskams, T. Daly, A.K. Anstee, Q.M. Trost, M. Härtlova, A.

Abstract

Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. © 2021 The Authors

Published
2022

6. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: An individual patient data meta-analysis

Author

Mózes, F.E. Lee, J.A. Selvaraj, E.A. Jayaswal, A.N.A. Trauner, M. Boursier, J. Fournier, C. Staufer, K. Stauber, R.E. Bugianesi, E. Younes, R. Gaia, S. Lupșor-Platon, M. Petta, S. Shima, T. Okanoue, T. Mahadeva, S. Chan, W.-K. Eddowes, P.J. Newsome, P.N. Wong, V.W.-S. de Ledinghen, V. Fan, J. Shen, F. Cobbold, J.F. Sumida, Y. Okajima, A. Schattenberg, J.M. Labenz, C. Kim, W. Lee, M.S. Wiegand, J. Karlas, T. Yılmaz, Y. Aithal, G.P. Palaniyappan, N. Cassinotto, C. Aggarwal, S. Garg, H. Ooi, G.J. Nakajima, A. Yoneda, M. Ziol, M. Barget, N. Geier, A. Tuthill, T. Brosnan, M.J. Anstee, Q.M. Neubauer, S. Harrison, S.A. Bossuyt, P.M. Pavlides, M. Anstee, Q. Daly, A. Johnson, K. Govaere, O. Cockell, S. Tiniakos, D. Bedossa, P. Oakley, F. Cordell, H. Day, C. Wonders, K. Bossuyt, P. Zafarmand, H. Vali, Y. Lee, J. Ratziu, V. Clement, K. Pais, R. Schuppan, D. Schattenberg, J. Schuppan, D. Schattenberg, J. Vidal-Puig, T. Vacca, M. Rodrigues-Cuenca, S. Allison, M. Kamzolas, I. Petsalaki, E. Oresic, M. Hyötyläinen, T. McGlinchey, A. Mato, J.M. Millet, O. Dufour, J.-F. Berzigotti, A. Pavlides, M. Harrison, S. Neubauer, S. Cobbold, J. Mozes, F. Akhtar, S. Banerjee, R. Kelly, M. Shumbayawonda, E. Dennis, A. Erpicum, C. Graham, M. Romero-Gómez, M. Gómez-González, E. Ampuero, J. Castell, J. Gallego-Durán, R. Fernández, I. Montero-Vallejo, R. Karsdal, M. Erhardtsen, E. Rasmussen, D. Leeming, D.J. Fisker, M.J. Sinisi, A. Musa, K. Betsou, F. Sandt, E. Tonini, M. Bugianesi, E. Rosso, C. Armandi, A. Marra, F. Gastaldelli, A. Svegliati, G. Boursier, J. Francque, S. Vonghia, L. Ekstedt, M. Kechagias, S. Yki-Jarvinen, H. Porthan, K. van Mil, S. Papatheodoridis, G. Cortez-Pinto, H. Valenti, L. Petta, S. Miele, L. Geier, A. Trautwein, C. Aithal, G. Hockings, P. Newsome, P. Wenn, D. Rodrigues, C.M.P. Chaumat, P. Hanf, R. Trylesinski, A. Ortiz, P. Duffin, K. Brosnan, J. Tuthill, T. McLeod, E. Ertle, J. Younes, R. Ostroff, R. Alexander, L. Kjær, M.S. Mikkelsen, L.F. Balp, M.-M. Brass, C. Jennings, L. Martic, M. Loeffler, J. Hanauer, G. Shankar, S. Fournier, C. Pepin, K. Ehman, R. Myers, J. Ho, G. Torstenson, R. Myers, R. Doward, L. LITMUS Investigators

Abstract

Objective Liver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies. Design Individual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations. Results Data were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (

Published
2021

7. Diagnostic accuracy of elastography and magnetic resonance imaging in patients with NAFLD: A systematic review and meta-analysis

Author

Selvaraj, E.A. Mózes, F.E. Jayaswal, A.N.A. Zafarmand, M.H. Vali, Y. Lee, J.A. Levick, C.K. Young, L.A.J. Palaniyappan, N. Liu, C.-H. Aithal, G.P. Romero-Gómez, M. Brosnan, M.J. Tuthill, T.A. Anstee, Q.M. Neubauer, S. Harrison, S.A. Bossuyt, P.M. Pavlides, M. Daly, A. Johnson, K. Govaere, O. Cockell, S. Tiniakos, D. Bedossa, P. Oakley, F. Cordell, H. Day, C. Wonders, K. Bossuyt, P. Zafarmand, H. Lee, J. Ratziu, V. Clement, K. Pais, R. Schuppan, D. Schattenberg, J. Vidal-Puig, T. Vacca, M. Rodrigues-Cuenca, S. Allison, M. Kamzolas, I. Petsalaki, E. Oresic, M. Hyötyläinen, T. McGlinchey, A. Mato, J.M. Millet, O. Dufour, J.-F. Berzigotti, A. Harrison, S. Cobbold, J. Mozes, F. Akhtar, S. Banerjee, R. Kelly, M. Shumbayawonda, E. Dennis, A. Erpicum, C. Gómez-González, E. Ampuero, J. Castell, J. Gallego-Durán, R. Fernández, I. Montero-Vallejo, R. Karsdal, M. Erhardtsen, E. Rasmussen, D. Leeming, D.J. Fisker, M.J. Sinisi, A. Musa, K. Betsou, F. Sandt, E. Tonini, M. Bugianesi, E. Rosso, C. Armandi, A. Marra, F. Gastaldelli, A. Svegliati, G. Boursier, J. Francque, S. Vonghia, L. Ekstedt, M. Kechagias, S. Yki-Jarvinen, H. Luukkonen, P. van Mil, S. Papatheodoridis, G. Cortez-Pinto, H. Valenti, L. Petta, S. Miele, L. Geier, A. Trautwein, C. Aithal, G. Hockings, P. Newsome, P. Wenn, D. Pereira Rodrigues, C.M. Chaumat, P. Hanf, R. Trylesinski, A. Ortiz, P. Duffin, K. Brosnan, J. Tuthill, T. McLeod, E. Ertle, J. Younes, R. Ostroff, R. Alexander, L. Kjær, M.S. Mikkelsen, L.F. Balp, M.-M. Brass, C. Jennings, L. Martic, M. Loeffler, J. Hanauer, G. Shankar, S. Fournier, C. Pepin, K. Ehman, R. Myers, J. Ho, G. Torstenson, R. Myers, R. Doward, L. LITMUS Investigators

Abstract

Background and Aims: Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH). Methods: PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model. Results: We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs. Conclusions: When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking. Lay summary: Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring. © 2021 The Author(s)

Published
2021

8. Corrigendum to: 'Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort'☆ (J Hepatol [2020] 505–515) (Journal of Hepatology (2020) 73(3) (505–515), (S0168827820302130), (10.1016/j.jhep.2020.04.003))

Author

Anstee, Q.M. Darlay, R. Cockell, S. Meroni, M. Govaere, O. Tiniakos, D. Burt, A.D. Bedossa, P. Palmer, J. Liu, Y.-L. Aithal, G.P. Allison, M. Yki-Järvinen, H. Vacca, M. Dufour, J.-F. Invernizzi, P. Prati, D. Ekstedt, M. Kechagias, S. Francque, S. Petta, S. Bugianesi, E. Clement, K. Ratziu, V. Schattenberg, J.M. Valenti, L. Day, C.P. Cordell, H.J. Daly, A.K. EPoS Consortium Investigators

Abstract

It has come to our attention that there is a typographical error in Table 5 of our manuscript. In line 6 of column 2, “rs11852624” should read "rs11858624”. We apologise for any inconvenience caused. © 2020 European Association for the Study of the Liver

Published
2021

9. The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease

Author

Hardy, T. Wonders, K. Younes, R. Aithal, G.P. Aller, R. Allison, M. Bedossa, P. Betsou, F. Boursier, J. Brosnan, M.J. Burt, A. Cobbold, J. Cortez-Pinto, H. Day, C.P. Dufour, J.-F. Ekstedt, M. Francque, S. Harrison, S. Miele, L. Nasr, P. Papatheodoridis, G. Petta, S. Tiniakos, D. Torstenson, R. Valenti, L. Holleboom, A.G. Yki-Jarvinen, H. Geier, A. Romero-Gomez, M. Ratziu, V. Bugianesi, E. Schattenberg, J.M. Anstee, Q.M. on behalf of the LITMUS Consortium

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS ‘Liver Investigation: Testing Marker Utility in Steatohepatitis’ consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace. © 2020 The Author(s)

Published
2020

11. Short-term changes observed in multi-parametric liver MRI following therapy with direct acting antivirals in chronic hepatitis C virus patients

Author

Bradley, C., Scott, R.A., Cox, E., Palaniyappan, N., Thompson, B.J., Ryder, D., Irving, W.L., Aithal, G.P., Guha, I.N., and Francis, S.

Abstract

Methods: We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before DAA therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed).Results: We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35±4 ms), transverse relaxation time (T2, 2.5±0.8 ms; T2* 3.0±0.7 ms) and liver perfusion (28.1±19.7ml/100g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or SMA blood flow.Conclusion: For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2, T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms.

Published
2019

13. Obesity in acute alcoholic hepatitis increases morbidity and mortality

Author

Parker, Richard, primary, Kim, S.J., additional, Im, G.Y., additional, Nahas, J., additional, Dhesi, B., additional, Vergis, N., additional, Sinha, A., additional, Ghezzi, A., additional, Rink, M.R., additional, McCune, A., additional, Aithal, G.P., additional, Newsome, P.N., additional, Weston, C.J., additional, Holt, A., additional, and Gao, B., additional

Published
2019
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18. Sprint interval exercise training reduces intrahepatic, visceral and subcutaneous abdominal fat despite no change in body weight, but has variable effects on whole-body insulin sensitivity

Author

Sargeant, J.A., primary, Bawden, S., additional, Simpson, E.J., additional, Kaviani, M., additional, Gowland, P., additional, Dorling, J.L., additional, Nimmo, M.A., additional, MacDonald, I., additional, Aithal, G.P., additional, and King, J.A., additional

Published
2017
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24. G01 : Liraglutide is effective in the histological clearance of non-alcoholic steatohepatitis in a multicentre, doubleblinded, randomised, placebo-controlled phase II trial

Author

Armstrong, M.J., primary, Gaunt, P., additional, Aithal, G.P., additional, Parker, R., additional, Barton, D., additional, Hull, D., additional, Guo, K., additional, Abouda, G., additional, Aldersley, M., additional, Gough, S.C., additional, Tomlinson, J.W., additional, Brown, R.M., additional, Hübscher, S.G., additional, and Newsome, P.N., additional

Published
2015
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25. When acquired thrombophilia mattered

Author

Hammond, J.S., Jackson, L., Zaitoun, A.B., Rowlands, B.J., and Aithal, G.P.

Subjects
Sepsis -- Patient outcomes, Health
Published
2005

26. P801 DO SERUM MARKERS OF CELL INJURY AND DEATH HAVE POTENTIAL TO BECOME MECHANISTIC MARKERS IN NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)?

Author

Grove, J.I., primary, Antoine, D.J., additional, Kaye, P., additional, Miller, M.H., additional, Dillon, J.F., additional, Allison, M.E., additional, James, M.W., additional, Wilkes, E.A., additional, Jackson, A.P., additional, Guha, I.N., additional, Williams, D.P., additional, and Aithal, G.P., additional

Published
2014
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30. 703 QUANTITATIVE MAGNETIC RESONANCE IMAGING (MRI) IN THE EVALUATION OF THE DEGREE OF STEATOSIS, IRON ACCUMULATION AND FIBROSIS IN CHRONIC LIVER DISEASE (MRker STUDY)

Author

Hoad, C.L., primary, Palaniyappan, N., additional, Kaye, P., additional, Stephenson, M., additional, Bawden, S., additional, Dolman, G., additional, James, M.W., additional, Costigan, C., additional, Austin, A., additional, Chernova-Chernaya, Y., additional, Gowland, P.A., additional, Guha, I.N., additional, Francis, S.T., additional, and Aithal, G.P., additional

Published
2013
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40. Accuracy of EUS for detection of intraductal papillary mucinous tumor of the pancreas

Author

Aithal, G.P., Chen, R.Y.M., Cunningham, J.T., Durkalski, V., Kim, E.Y., Patel, R.S., Wallace, M.B., Hawes, R.H., and Hoffman, B.J.

Abstract

Background: Patients with intraductal papillary mucinous tumors of the pancreas (IPMT) present with symptoms similar to those of chronic pancreatitis. This study assessed the accuracy of EUS for detection of IPMT and identified features that discriminate IPMT from chronic pancreatitis. Methods: EUS accuracy for detecting IPMT was determined with characteristic findings by endoscopic retrograde pancreatography as the reference standard. To determine EUS features characteristic of IPMT, EUS images from patients with IPMT were compared with those from patients (similar age, gender) with chronic pancreatitis. Results: Thirty-eight patients (23 men, 15 women; age range 40-90 years) with IPMT were identified between 1994 and 2001. For EUS, the sensitivity was 86%, specificity 99%, positive predictive value 78%, and negative predictive value 99% for detection of IPMT. When compared with patients with chronic pancreatitis, the EUS features of dilation of pancreatic duct (89% vs. 42%, p < 0.0001), cysts (45% vs. 11%, p = 0.002), and pancreatic atrophy (32% vs. 3%, p = 0.002) were more common, whereas parenchymal features of chronic pancreatitis were less common with IPMT (21% vs. 97%, p < 0.0001). By multivariate analysis, the presence of no more than one parenchymal feature of chronic pancreatitis suggested the diagnosis of IPMT (odds ratio 43.84; 95% CI [4.13, 465.74]). Conclusions: EUS may be useful in the initial evaluation of patients suspected to have IPMT. Paucity of parenchymal features of chronic pancreatitis is important in differentiating IPMT from other causes of chronic pancreatitis. (Gastrointest Endosc 2002;56:701-7.)

Published
2002
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41. Helical CT versus EUS with fine needle aspiration for celiac nodal assessment in patients with esophageal cancer

Author

Romagnuolo, J., Scott, J., Hawes, R.H., Hoffman, B.J., Reed, C.E., Aithal, G.P., Breslin, N.P., Chen, R.Y.M., Gumustop, B., Hennessey, W., Van Velse, A., and Wallace, M.B.

Abstract

Background: Conventional CT is insensitive for detection of metastatic involvement of celiac lymph nodes in esophageal cancer. Helical CT has theoretical advantages over ''slice'' CT in this regard, but its performance has not yet been prospectively studied. Methods: Consecutive patients with untreated esophageal cancer were recruited after obtaining informed consent. Helical CT was performed on all patients and TNM staging was performed by a single radiologist. Subsequently, all patients underwent esophageal radial and, as needed, curvilinear array EUS with fine needle aspiration (FNA), for evaluation of celiac lymph nodes and TNM staging. Test performance characteristics with 95% confidence intervals were calculated, assuming EUS with FNA as the reference standard. Results: Forty-eight patients were recruited, of whom 37 (77%) were men. The mean (SD) age was 63.6 (10) years. Excluding 5 patients in whom a confirmatory FNA was not available (n = 43), helical CT identified celiac lymph nodes in 12 (28%) patients. The reference standard of EUS with FNA identified 15 (35%) patients with metastatic celiac lymph nodes, giving a sensitivity, specificity, and positive and negative predictive values for helical CT of 53% (95% CI [28%, 79%]), 86% (95% CI [73%, 99%]), 67% (95% CI [40%, 93%]), and 77% (95% CI [63%, 92%]), respectively, for assessing celiac lymph nodal involvement. The sensitivity and specificity of helical CT in detecting T4 disease were 25% (95% CI [3.8%, 46%]) and 94% (95% CI [85%, 100%]), respectively. There were 12 patients (25%; 95% CI [13%, 37%]) who were felt to have resectable disease by helical CT but had either metastatic involvement of celiac lymph nodes or T4 disease by EUS/FNA. Conclusions: Despite technological advances, helical CT still appears unreliable, mainly because of insensitivity, for the identification of inoperable T4 or metastatic involvement of celiac lymph node disease in esophageal cancer. (Gastrointest Endosc 2002;55:648-54.)

Published
2002
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45. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Author

Raluca Pais, Rachel Ostroff, Stephen Harrison, Lars Friis Mikkelsen, Elisabeth Erhardtsen, Sudha Shankar, Kimmo Porthan, Jérôme Boursier, Antonia Sinisi, Michael Kalutkiewicz, Sven Francque, Miljen Martic, Vanessa Pellegrinelli, Phil N. Newsome, Guido Hanauer, Hannele Yki-Järvinen, Rebecca Darlay, Joel Myers, Carla Yunis, Salvatore Petta, Mette Skalshøi Kjær, Pablo Ortiz, Ann K. Daly, James H. Clark, Dina Tiniakos, Yasaman Vali, Hadi Zafarmand, Matej Orešič, Maurizio Parola, Estelle Sandt, Lori L. Jennings, Matt Kelly, Tuulia Hyötyläinen, Detlef Schuppan, Céline Fournier, Chiara Rosso, Diane E. Shevell, Maria Manuela Tonini, Paul Hockings, Aidan McGlinchey, Salma Akhtar, Mette Juul Fisker, Morten A. Karsdal, Diane Whalley, Melissa R. Miller, Aldo Trylesinski, Mattias Ekstedt, Stefan Neubauer, Jeremy M. Palmer, Partho Sen, Michael Pavlides, Per Qvist, Isabel Fernández, Luca Miele, Fabio Marra, Stergios Kechagias, Richard Torstenson, Katherine Johnson, Jean-François Dufour, Elisabetta Bugianesi, M. Julia Brosnan, George V. Papatheodoridis, Kay M. Pepin, Daniel Guldager Kring Rasmussen, Henrik Landgren, Rachel Queen, Simon Cockell, Michael Allison, Patrick M.M. Bossuyt, Rocío Gallego-Durán, Christian Rosenquist, Leigh Alexander, Elizabeth Shumbayawonda, Michele Vacca, Antonio Vidal-Puig, David Wenn, Rémy Hanf, Oscar Millet, Michalina Zatorska, R. Myers, José M. Mato, Jenny Lee, Theresa Tuthill, James Twiss, Ramy Younes, Peter Leary, Lynda Doward, Kristy Wonders, Guruprasad P. Aithal, Sarah Charlton, Vlad Ratziu, Cecília M. P. Rodrigues, Christian Trautwein, Helena Cortez-Pinto, Gideon Ho, Matt J. Barter, Judith Ertle, Jörn M. Schattenberg, Maria-Magdalena Balp, Yang-Lin Liu, Clifford A. Brass, Olivier Govaere, Amalia Gastaldelli, Sergio Rodriguez Cuenca, Pierre Chaumat, Fiona Oakley, Luca Valenti, Simon J. Cockell, Saskia W.C. van Mil, Ferenc E. Mózes, Andreas Geier, Timothy Hardy, Pierre Bedossa, Andrea Dennis, Richard L. Ehman, Charlotte Erpicum, Karine Clément, Jeremy F. L. Cobbold, Christopher P. Day, Rajarshi Banerjee, Manuel Romero-Gómez, Quentin M. Anstee, Adriaan G. Holleboom, Heather J. Cordell, Kevin L. Duffin, Diana Julie Leeming, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Graduate School, Investigators, LITMUS Consortium, Johnson K., Leary P.J., Govaere O., Barter M.J., Charlton S.H., Cockell S.J., Tiniakos D., Zatorska M., Bedossa P., Brosnan M.J., Cobbold J.F., Ekstedt M., Aithal G.P., Clement K., Schattenberg J.M., Boursier J., Ratziu V., Bugianesi E., Anstee Q.M., Daly A.K., Clark J., Cordell H.J., Darlay R., Day C.P., Hardy T., Liu Y.-L., Oakley F., Palmer J., Queen R., Wonders K., Bossuyt P.M., Holleboom A.G., Zafarmand H., Vali Y., Lee J., Pais R., Schuppan D., Allison M., Cuenca S.R., Pellegrinelli V., Vacca M., Vidal-Puig A., Hyotylainen T., McGlinchey A., Oresic M., Sen P., Mato J., Millet O., Dufour J.-F., Harrison S., Neubauer S., Pavlides M., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Romero-Gomez M., Gallego-Duran R., Fernandez I., Karsdal M., Leeming D., Fisker M.J., Erhardtsen E., Rasmussen D., Qvist P., Sinisi A., Sandt E., Tonini M.M., Parola M., Rosso C., Marra F., Gastaldelli A., Francque S., Kechagias S., Yki-Jarvinen H., Porthan K., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Petta S., Miele L., Geier A., Trautwein C., Hockings P., Newsome P., Wenn D., Pereira Rodrigues C.M., Hanf R., Chaumat P., Rosenquist C., Trylesinski A., Ortiz P., Duffin K., Yunis C., Miller M., Tuthill T., Ertle J., Younes R., Alexander L., Ostroff R., Kjaer M.S., Mikkelsen L.F., Brass C., Jennings L., Balp M.-M., Martic M., Hanauer G., Shankar S., Torstenson R., Fournier C., Ehman R., Kalutkiewicz M., Pepin K., Myers J., Shevell D., Ho G., Landgren H., Myers R., Doward L., Whalley D., Twiss J., Miller, Melissa, Tuthill, Theresa, Ertle, Judith, Younes, Ramy, Alexander, Leigh, Ostroff, Rachel, Kjær, Mette Skalshøi, Mikkelsen, Lars Friis, Brass, Clifford, Jennings, Lori, Balp, Maria-Magdalena, Martic, Miljen, Hanauer, Guido, Shankar, Sudha, Torstenson, Richard, Fournier, Céline, Ehman, Richard, Kalutkiewicz, Michael, Pepin, Kay, Myers, Joel, Shevell, Diane, Ho, Gideon, Landgren, Henrik, Myers, Rob, Doward, Lynda, Whalley, Diane, Twiss, James, Clark, James, Cordell, Heather J., Darlay, Rebecca, Day, Christopher P., Hardy, Tim, Liu, Yang-Lin, Oakley, Fiona, Palmer, Jeremy, Queen, Rachel, Wonders, Kristy, Bossuyt, Patrick M., Holleboom, Adriaan G., Zafarmand, Hadi, Vali, Yasaman, Lee, Jenny, Clement, Karine, Pais, Raluca, Schuppan, Detlef, Allison, Michael, Cuenca, Sergio Rodriguez, Pellegrinelli, Vanessa, Vacca, Michele, Vidal-Puig, Antonio, Hyötyläinen, Tuulia, McGlinchey, Aidan, Orešič, Matej, Sen, Partho, Mato, Jose, Millet, Óscar, Dufour, Jean-Francois, Harrison, Stephen, Neubauer, Stefan, Pavlides, Michael, Mozes, Ferenc, Akhtar, Salma, Banerjee, Rajarshi, Kelly, Matt, Shumbayawonda, Elizabeth, Dennis, Andrea, Erpicum, Charlotte, Romero-Gomez, Manuel, Gallego-Durán, Rocío, Fernández, Isabel, Karsdal, Morten, Leeming, Diana, Fisker, Mette Juul, Erhardtsen, Elisabeth, Rasmussen, Daniel, Qvist, Per, Sinisi, Antonia, Sandt, Estelle, Tonini, Maria Manuela, Parola, Maurizio, Rosso, Chiara, Marra, Fabio, Gastaldelli, Amalia, Francque, Sven, Kechagias, Stergios, Yki-Järvinen, Hannele, Porthan, Kimmo, van Mil, Saskia, Papatheodoridis, George, Cortez-Pinto, Helena, Valenti, Luca, Petta, Salvatore, Miele, Luca, Geier, Andreas, Trautwein, Christian, Hockings, Paul, Newsome, Phil, Wenn, David, Pereira Rodrigues, Cecília Maria, Hanf, Rémy, Chaumat, Pierre, Rosenquist, Christian, Trylesinski, Aldo, Ortiz, Pablo, Duffin, Kevin, and Yunis, Carla

Subjects
SCORING SYSTEM, CPM, counts per million, AUROC, area under the receiver operating characteristic, RC799-869, AST, aspartate aminotransferase, MicroRNA, Non-alcoholic fatty liver disease, Biomarker, Sequencing, TGF-β, transforming growth factor-beta, Gastroenterology, STEATOHEPATITIS, Liver disease, 0302 clinical medicine, Fibrosis, miRNA, microRNA, logFC, log2 fold change, FIBROSIS, Immunology and Allergy, 0303 health sciences, education.field_of_study, NAS, NAFLD activity score, medicine.diagnostic_test, Fatty liver, GTEx, Genotype-Tissue Expression, Diseases of the digestive system. Gastroenterology, 3. Good health, Real-time polymerase chain reaction, Biomarker, MicroRNA, Non-alcoholic fatty liver disease, Sequencing, Liver biopsy, ACID, Biomarker (medicine), 030211 gastroenterology & hepatology, Life Sciences & Biomedicine, Research Article, EXPRESSION, medicine.medical_specialty, NAFLD, non-alcoholic fatty liver disease, NASH, non-alcoholic steatohepatitis, Population, Gastroenterology and Hepatology, SAF, steatosis–activity–fibrosis, VALIDATION, ER, endoplasmic reticulum, 03 medical and health sciences, cDNA, complementary DNA, Internal medicine, ALT, alanine aminotransferase, Gastroenterologi, Internal Medicine, medicine, NAFL, non-alcoholic fatty liver, ALGORITHM, FIB-4, fibrosis-4, education, 030304 developmental biology, PCA, principal component analysis, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, FC, fold change, medicine.disease, digestive system diseases, FLIP, fatty liver inhibition of progression, Ct, cycle threshold, Steatosis, qPCR, quantitative PCR, business
Abstract

Background & Aims Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages. Methods We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR. Results Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2–4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5–8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2–4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p. Conclusions Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD. Lay summary MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy., Graphical abstract, Highlights • Serum miRNA was sequenced in 183 NAFLD cases of varying severity and 10 population controls. • Plasma levels of miR-193a-5p were significantly increased in patients with advanced fibrosis, high NAS scores, or high SAF scores. • Other miRNAs including miR378d and miR378e were also significantly increased in certain comparisons. • The findings for miR-193a-5p were replicated in a cohort of 372 additional NAFLD cases.

Published
2022
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46. Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD : an individual patient data meta-analysis

Author

Mozes, F. E., Lee, J. A., Selvaraj, E. A., Jayaswal, A. N. A., Trauner, M., Boursier, J., Fournier, C., Staufer, K., Stauber, R. E., Bugianesi, E., Younes, R., Gaia, S., Lupsor-Platon, M., Petta, S., Shima, T., Okanoue, T., Mahadeva, S., Chan, W. -K., Eddowes, P. J., Newsome, P. N., Wong, V. W. -S., de Ledinghen, V., Fan, J., Shen, F., Cobbold, J. F., Sumida, Y., Okajima, A., Schattenberg, J. M., Labenz, C., Kim, W., Lee, M. S., Wiegand, J., Karlas, T., Yilmaz, Y., Aithal, G. P., Palaniyappan, N., Cassinotto, C., Aggarwal, S., Garg, H., Ooi, G. J., Nakajima, A., Yoneda, M., Ziol, M., Barget, N., Geier, A., Tuthill, T., Brosnan, M. J., Anstee, Q. M., Neubauer, S., Harrison, S. A., Bossuyt, P. M., Pavlides, M., Anstee, Q., Daly, A., Johnson, K., Govaere, O., Cockell, S., Tiniakos, D., Bedossa, P., Oakley, F., Cordell, H., Day, C., Wonders, K., Bossuyt, P., Zafarmand, H., Vali, Y., Lee, J., Ratziu, V., Clement, K., Pais, R., Schuppan, D., Schattenberg, J., Vidal-Puig, T., Vacca, M., Rodrigues-Cuenca, S., Allison, M., Kamzolas, I., Petsalaki, E., Oresic, M., Hyotylainen, T., Mcglinchey, A., Mato, J. M., Millet, O., Dufour, J. -F., Berzigotti, A., Harrison, S., Cobbold, J., Mozes, F., Akhtar, S., Banerjee, R., Kelly, M., Shumbayawonda, E., Dennis, A., Erpicum, C., Graham, M., Romero-Gomez, M., Gomez-Gonzalez, E., Ampuero, J., Castell, J., Gallego-Duran, R., Fernandez, I., Montero-Vallejo, R., Karsdal, M., Erhardtsen, E., Rasmussen, D., Leeming, D. J., Fisker, M. J., Sinisi, A., Musa, K., Betsou, F., Sandt, E., Tonini, M., Rosso, C., Armandi, A., Marra, F., Gastaldelli, A., Svegliati, G., Francque, S., Vonghia, L., Ekstedt, M., Kechagias, S., Yki-Jarvinen, H., Porthan, K., van Mil, S., Papatheodoridis, G., Cortez-Pinto, H., Valenti, L., Miele, L., Trautwein, C., Aithal, G., Hockings, P., Newsome, P., Wenn, D., Rodrigues, C. M. P., Chaumat, P., Hanf, R., Trylesinski, A., Ortiz, P., Duffin, K., Brosnan, J., Mcleod, E., Ertle, J., Ostroff, R., Alexander, L., Kjaer, M. S., Mikkelsen, L. F., Balp, M. -M., Brass, C., Jennings, L., Martic, M., Loeffler, J., Hanauer, G., Shankar, S., Pepin, K., Ehman, R., Myers, J., Ho, G., Torstenson, R., Myers, R., Doward, L., LITMUS Investigators, University of Denver, Medizinische Universität Wien = Medical University of Vienna, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), SUACI Alpes du Nord, Medical University Graz, Mozes, Ferenc Emil, Lee, Jenny A., Selvaraj, Emmanuel Anandraj, Jayaswal, Arjun Narayan Ajmer, Trauner, Michael, Boursier, Jerome, Fournier, Celine, Staufer, Katharina, Stauber, Rudolf E., Bugianesi, Elisabetta, Younes, Ramy, Gaia, Silvia, Lupsor-Platon, Monica, Petta, Salvatore, Shima, Toshihide, Okanoue, Takeshi, Mahadeva, Sanjiv, Chan, Wah-Kheong, Eddowes, Peter J., Hirschfield, Gideon M., Newsome, Philip Noel, Wong, Vincent Wai-Sun, de Ledinghen, Victor, Fan, Jiangao, Shen, Feng, Cobbold, Jeremy F., Sumida, Yoshio, Okajima, Akira, Schattenberg, Joern M., Labenz, Christian, Kim, Won, Lee, Myoung Seok, Wiegand, Johannes, Karlas, Thomas, Yilmaz, Yusuf, Aithal, Guruprasad Padur, Palaniyappan, Naaventhan, Cassinotto, Christophe, Aggarwal, Sandeep, Garg, Harshit, Ooi, Geraldine J., Nakajima, Atsushi, Yoneda, Masato, Ziol, Marianne, Barget, Nathalie, Geier, Andreas, Tuthill, Theresa, Brosnan, M. Julia, Anstee, Quentin Mark, Neubauer, Stefan, Harrison, Stephen A., Bossuyt, Patrick M., Pavlides, Michael, Epidemiology and Data Science, APH - Methodology, APH - Personalized Medicine, ACS - Atherosclerosis & ischemic syndromes, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, Graduate School, Mozes F.E., Lee J.A., Selvaraj E.A., Jayaswal A.N.A., Trauner M., Boursier J., Fournier C., Staufer K., Stauber R.E., Bugianesi E., Younes R., Gaia S., Lupsor-Platon M., Petta S., Shima T., Okanoue T., Mahadeva S., Chan W.-K., Eddowes P.J., Newsome P.N., Wong V.W.-S., de Ledinghen V., Fan J., Shen F., Cobbold J.F., Sumida Y., Okajima A., Schattenberg J.M., Labenz C., Kim W., Lee M.S., Wiegand J., Karlas T., Yilmaz Y., Aithal G.P., Palaniyappan N., Cassinotto C., Aggarwal S., Garg H., Ooi G.J., Nakajima A., Yoneda M., Ziol M., Barget N., Geier A., Tuthill T., Brosnan M.J., Anstee Q.M., Neubauer S., Harrison S.A., Bossuyt P.M., Pavlides M., Anstee Q., Daly A., Johnson K., Govaere O., Cockell S., Tiniakos D., Bedossa P., Oakley F., Cordell H., Day C., Wonders K., Bossuyt P., Zafarmand H., Vali Y., Lee J., Ratziu V., Clement K., Pais R., Schuppan D., Schattenberg J., Vidal-Puig T., Vacca M., Rodrigues-Cuenca S., Allison M., Kamzolas I., Petsalaki E., Oresic M., Hyotylainen T., McGlinchey A., Mato J.M., Millet O., Dufour J.-F., Berzigotti A., Harrison S., Cobbold J., Mozes F., Akhtar S., Banerjee R., Kelly M., Shumbayawonda E., Dennis A., Erpicum C., Graham M., Romero-Gomez M., Gomez-Gonzalez E., Ampuero J., Castell J., Gallego-Duran R., Fernandez I., Montero-Vallejo R., Karsdal M., Erhardtsen E., Rasmussen D., Leeming D.J., Fisker M.J., Sinisi A., Musa K., Betsou F., Sandt E., Tonini M., Rosso C., Armandi A., Marra F., Gastaldelli A., Svegliati G., Francque S., Vonghia L., Ekstedt M., Kechagias S., Yki-Jarvinen H., Porthan K., van Mil S., Papatheodoridis G., Cortez-Pinto H., Valenti L., Miele L., Trautwein C., Aithal G., Hockings P., Newsome P., Wenn D., Rodrigues C.M.P., Chaumat P., Hanf R., Trylesinski A., Ortiz P., Duffin K., Brosnan J., McLeod E., Ertle J., Ostroff R., Alexander L., Kjaer M.S., Mikkelsen L.F., Balp M.-M., Brass C., Jennings L., Martic M., Loeffler J., Hanauer G., Shankar S., Pepin K., Ehman R., Myers J., Ho G., Torstenson R., Myers R., and Doward L.

Subjects
Liver Cirrhosis, Male, Cirrhosis, LIVER STIFFNESS MEASUREMENT, Biopsy, [SDV]Life Sciences [q-bio], biostatistics, Gastroenterology, DISEASE, clinical decision making, fatty liver, hepatic fibrosis, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, 2. Zero hunger, 0303 health sciences, medicine.diagnostic_test, NONALCOHOLIC STEATOHEPATITIS, TRANSIENT ELASTOGRAPHY, Fatty liver, CHRONIC HEPATITIS, Middle Aged, 3. Good health, Settore AGR/03 - Arboricoltura Generale E Coltivazioni Arboree, Liver, Liver biopsy, BIOPSY, Elasticity Imaging Techniques, Female, 030211 gastroenterology & hepatology, Median body, medicine.medical_specialty, CONTROLLED ATTENUATION PARAMETER, 610 Medicine & health, 03 medical and health sciences, Internal medicine, SCORE, medicine, Humans, biostatistics, clinical decision making, fatty liver, hepatic fibrosis, 030304 developmental biology, Receiver operating characteristic, business.industry, medicine.disease, Diabetes Mellitus, Type 2, XL PROBE, business, Hepatic fibrosis, Transient elastography, Biomarkers, PROSPECTIVE DERIVATION
Abstract

ObjectiveLiver biopsy is still needed for fibrosis staging in many patients with non-alcoholic fatty liver disease. The aims of this study were to evaluate the individual diagnostic performance of liver stiffness measurement by vibration controlled transient elastography (LSM-VCTE), Fibrosis-4 Index (FIB-4) and NAFLD (non-alcoholic fatty liver disease) Fibrosis Score (NFS) and to derive diagnostic strategies that could reduce the need for liver biopsies.DesignIndividual patient data meta-analysis of studies evaluating LSM-VCTE against liver histology was conducted. FIB-4 and NFS were computed where possible. Sensitivity, specificity and area under the receiver operating curve (AUROC) were calculated. Biomarkers were assessed individually and in sequential combinations.ResultsData were included from 37 primary studies (n=5735; 45% women; median age: 54 years; median body mass index: 30 kg/m2; 33% had type 2 diabetes; 30% had advanced fibrosis). AUROCs of individual LSM-VCTE, FIB-4 and NFS for advanced fibrosis were 0.85, 0.76 and 0.73. Sequential combination of FIB-4 cut-offs (ConclusionSequential combinations of markers with a lower cut-off to rule-out advanced fibrosis and a higher cut-off to rule-in cirrhosis can reduce the need for liver biopsies.

Published
2022
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47. The European NAFLD Registry: A real-world longitudinal cohort study of nonalcoholic fatty liver disease

Author

Hardy, Timothy, Wonders, Kristy, Younes, Ramy, Aithal, Guruprasad P, Aller, Rocio, Allison, Michael, Bedossa, Pierre, Betsou, Fay, Boursier, Jerome, Brosnan, M Julia, Burt, Alastair, Cobbold, Jeremy, Cortez-Pinto, Helena, Day, Chris P, Dufour, Jean-Francois, Ekstedt, Mattias, Francque, Sven, Harrison, Stephen, Miele, Luca, Nasr, Patrik, Papatheodoridis, George, Petta, Salvatore, Tiniakos, Dina, Torstenson, Richard, Valenti, Luca, Holleboom, Adriaan G, Yki-Jarvinen, Hannele, Geier, Andreas, Romero-Gomez, Manuel, Ratziu, Vlad, Bugianesi, Elisabetta, Schattenberg, Jörn M, Anstee, Quentin M, LITMUS Consortium, Newcastle University [Newcastle], Università degli studi di Torino (UNITO), University of Nottingham, UK (UON), Universidad de Valladolid [Valladolid] (UVa), Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Integrated BioBank of Luxembourg (IBBL), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Pfizer, Oxford University Hospitals NHS Trust, University of Oxford [Oxford], Universidade de Lisboa (ULISBOA), University of Bern, Linköping University (LIU), University of Antwerp (UA), Università cattolica del Sacro Cuore [Roma] (Unicatt), National and Kapodistrian University of Athens (NKUA), Università degli studi di Palermo - University of Palermo, University of Milan, University of Helsinki, University of Würzburg, Hospital Universitario Virgen del Rocío [Sevilla], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University Medical Center [Mainz], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Vascular Medicine, ACS - Diabetes & metabolism, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, LITMUS Consortium, Innovative Medicines Initiative, European Commission, Department of Medicine, HUS Internal Medicine and Rehabilitation, Helsinki University Hospital Area, Hardy T., Wonders K., Younes R., Aithal G.P., Aller R., Allison M., Bedossa P., Betsou F., Boursier J., Brosnan M.J., Burt A., Cobbold J., Cortez-Pinto H., Day C.P., Dufour J.-F., Ekstedt M., Francque S., Harrison S., Miele L., Nasr P., Papatheodoridis G., Petta S., Tiniakos D., Torstenson R., Valenti L., Holleboom A.G., Yki-Jarvinen H., Geier A., Romero-Gomez M., Ratziu V., Bugianesi E., Schattenberg J.M., Anstee Q.M., Harrison, Seamus Conor [0000-0003-1480-1143], and Apollo - University of Cambridge Repository

Subjects
Liver Cirrhosis, PROGNOSIS, Cirrhosis, SCORING SYSTEM, [SDV]Life Sciences [q-bio], PROGRESSION, Disease, Biomarker, Cirrhosis, NAFLD, NASH, STEATOHEPATITIS, DEFINITIONS, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Nonalcoholic fatty liver disease, Pharmacology (medical), 030212 general & internal medicine, Longitudinal Studies, Registries, ComputingMilieux_MISCELLANEOUS, media_common, Pharmacology. Therapy, Fatty liver, Liver Neoplasms, NASH, General Medicine, 3. Good health, Liver, 317 Pharmacy, Cohort, 0305 other medical science, Cohort study, medicine.medical_specialty, Settore MED/12 - GASTROENTEROLOGIA, Geriatrik, QUESTIONNAIRE, NAFLD, Biomarker, 610 Medicine & health, 03 medical and health sciences, medicine, STEATOSIS, media_common.cataloged_instance, Humans, ALGORITHM, European union, Intensive care medicine, 030505 public health, business.industry, CONSUMPTION, STAGING SYSTEM, medicine.disease, Diabetes Mellitus, Type 2, Geriatrics, 3121 General medicine, internal medicine and other clinical medicine, 3111 Biomedicine, Human medicine, Steatohepatitis, business
Abstract

© 2020 The Author(s)., Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS ‘Liver Investigation: Testing Marker Utility in Steatohepatitis’ consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace., The European NAFLD Registry is supported by the LITMUS (Liver Investigation: Testing Biomarker Utility in Steatohepatitis) consortium funded by the European Union Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement 777377, which receives support from the Horizon 2020 Framework Program of European Union and EFPIA. It has also received support from the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413, the FLIP consortium funded by the Framework Program 7 of the European Union under grant agreement 241762, and an EASL Registry Grant from the European Association for the Study of the Liver.

Published
2020
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48. Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort☆

Author

Jeremy M. Palmer, Michael Allison, Guruprasad P. Aithal, Simon Cockell, Vlad Ratziu, Alastair D. Burt, Yang-Lin Liu, Christopher P. Day, Jörn M. Schattenberg, Michele Vacca, Quentin M. Anstee, Pietro Invernizzi, Heather J. Cordell, Olivier Govaere, Stergios Kechagias, Sven Francque, Ann K. Daly, Dina Tiniakos, Jean-François Dufour, Rebecca Darlay, Salvatore Petta, Karine Clément, Luca Valenti, Daniele Prati, Pierre Bedossa, Mattias Ekstedt, Hannele Yki-Järvinen, Marica Meroni, Elisabetta Bugianesi, Anstee, Q, Darlay, R, Cockell, S, Meroni, M, Govaere, O, Tiniakos, D, Burt, A, Bedossa, P, Palmer, J, Liu, Y, Aithal, G, Allison, M, Yki-Jarvinen, H, Vacca, M, Dufour, J, Invernizzi, P, Prati, D, Ekstedt, M, Kechagias, S, Francque, S, Petta, S, Bugianesi, E, Clement, K, Ratziu, V, Schattenberg, J, Valenti, L, Day, C, Cordell, H, Daly, A, EPoS Consortium Investigators, Department of Medicine, HUS Internal Medicine and Rehabilitation, University of Helsinki, Helsinki University Hospital Area, Anstee Q.M., Darlay R., Cockell S., Meroni M., Govaere O., Tiniakos D., Burt A.D., Bedossa P., Palmer J., Liu Y.-L., Aithal G.P., Allison M., Yki-Jarvinen H., Vacca M., Dufour J.-F., Invernizzi P., Prati D., Ekstedt M., Kechagias S., Francque S., Petta S., Bugianesi E., Clement K., Ratziu V., Schattenberg J.M., Valenti L., Day C.P., Cordell H.J., and Daly A.K.

Subjects
0301 basic medicine, Male, Cirrhosis, 17-Hydroxysteroid Dehydrogenases, Fibrosi, VARIANT, LOCI, PROGRESSION, Genome-wide association study, Disease, Bioinformatics, DISEASE, Cohort Studies, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Risk Factors, GWAS, INCREASED RISK, CONFERS SUSCEPTIBILITY, education.field_of_study, Fatty liver, NASH, Middle Aged, 3. Good health, NAFLD, Fibrosis, PNPLA3, TM6SF2, GCKR, HSD17B13, SNP, Phenotype, Liver, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, Adult, Population, 610 Medicine & health, Gastroenterology and Hepatology, Polymorphism, Single Nucleotide, 03 medical and health sciences, medicine, Gastroenterologi, Humans, Genetic Predisposition to Disease, education, Adaptor Proteins, Signal Transducing, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, nutritional and metabolic diseases, Membrane Proteins, Lipase, medicine.disease, POLYMORPHISM, LEPTIN RECEPTOR GENE, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Case-Control Studies, Human medicine, Steatosis, Steatohepatitis, business, Genome-Wide Association Study
Abstract

Background & Aims: Genetic factors associated with nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. Methods: The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Results: Case-control analysis identified signals showing p values = F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. Conclusions: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Lay summary: Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individuals risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. Funding Agencies|EPoS (Elucidating Pathways of Steatohepatitis) consortium - Horizon 2020 Framework Program of the European Union [634413]; FLIP consortium(EuropeanUnion FP7 grant) [241762]; Newcastle NIHR Biomedical Research Centre

Published
2020
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49. Validation of a model for identification of patients with compensated cirrhosis at high risk of decompensation

Author

Rebecca Harris, Audrey Dillon, Imad Waked, Philip J. Johnson, David J. Harman, Stephen Stewart, Alessandro Cucchetti, Sarah Berhane, Guruprasad P. Aithal, Omar Elshaarawy, Lisa Coffey, Indra Neil Guha, Martin W. James, Guha I.N., Harris R., Berhane S., Dillon A., Coffey L., James M.W., Cucchetti A., Harman D.J., Aithal G.P., Elshaarawy O., Waked I., Stewart S., and Johnson P.J.

Subjects
Liver Cirrhosis, Alcohol-Associated Liver Disease Outcome, Male, medicine.medical_specialty, Cirrhosis, Prognosi, Liver Cirrhosi, liver failure, prognostic factor, alcohol-associated liver disease outcome, NAFLD prediction, Predictive Value of Test, Risk Assessment, Severity of Illness Index, Follow-Up Studie, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Model for End-Stage Liver Disease, Predictive Value of Tests, Risk Factors, Internal medicine, medicine, Humans, Decompensation, Prospective Studies, NAFLD Prediction, Aged, Framingham Risk Score, Hepatology, business.industry, Prognostic Factor, Risk Factor, Hazard ratio, Gastroenterology, Middle Aged, Prognosis, medicine.disease, Prospective Studie, Liver, 030220 oncology & carcinogenesis, Cohort, Disease Progression, Egypt, Female, 030211 gastroenterology & hepatology, Liver function, business, Ireland, Liver Failure, Follow-Up Studies, Human
Abstract

Background & Aims It is important to rapidly identify patients with advanced liver disease. Routine tests to assess liver function and fibrosis provide data that can be used to determine patients’ prognoses. We tested the validated the ability of combined data from the ALBI and FIB-4 scoring systems to identify patients with compensated cirrhosis at highest risk for decompensation. Methods We collected data from 145 patients with compensated cirrhosis (91% Child A cirrhosis and median MELD scores below 8) from a cohort in Nottingham, United Kingdom, followed for a median 4.59 years (development cohort). We collected baseline clinical features and recorded decompensation events. We used these data to develop a model based on liver function (assessed by the ALBI score) and extent of fibrosis (assessed by the FIB-4 index) to determine risk of decompensation. We validated the model in 2 independent external cohorts (1 in Dublin, Ireland and 1 in Menoufia, Egypt) comprising 234 patients. Results In the development cohort, 19.3% of the patients developed decompensated cirrhosis. Using a combination of ALBI and FIB-4 scores, we developed a model that identified patients at low vs high risk of decompensation (hazard ratio [HR] for decompensation in patients with high risk score was 7.10). When we tested the scoring system in the validation cohorts, the HR for decompensation in patients with a high-risk score was 12.54 in the Ireland cohort and 5.10 in the Egypt cohort. Conclusion We developed scoring system, based on a combination of ALBI and FIB-4 scores, that identifies patients at risk for liver decompensation. We validated the scoring system in 2 independent international cohorts (Europe and the Middle East), so it appears to apply to diverse populations.

Published
2019

50. Prediction of Survival Among Patients Receiving Transarterial Chemoembolization for Hepatocellular Carcinoma: A Response-Based Approach

Author

Guru Aithal, Markus Peck-Radosavljevic, Philip J. Johnson, Waleed Fateen, Omar Elshaarawy, Imam Waked, Diego Ottaviani, R B Takkenberg, Stephen L. Chan, David J. Pinato, Mario Pirisi, Martha M. Kirstein, Cristina Mosconi, Asmaa Gomaa, Jeong W Jang, Tim A. Labeur, Anthony W.H. Chan, Bruno Sangro, Dominik Bettinger, Masatoshi Kudo, Otto M. van Delden, Nick Stern, Eman Rewisha, Simon Travis, Arndt Vogel, Guohong Han, Daniel H. Palmer, Marta García-Fiñana, Hidenori Toyoda, Tim Meyer, Rohini Sharma, Sarah Berhane, Alessandro Cucchetti, F. Hucke, Wellcome Trust, Gastroenterology and Hepatology, Graduate School, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Radiology and Nuclear Medicine, CCA -Cancer Center Amsterdam, CCA - Cancer Treatment and Quality of Life, Han G., Berhane S., Toyoda H., Bettinger D., Elshaarawy O., Chan A.W.H., Kirstein M., Mosconi C., Hucke F., Palmer D., Pinato D.J., Sharma R., Ottaviani D., Jang J.W., Labeur T.A., van Delden O.M., Pirisi M., Stern N., Sangro B., Meyer T., Fateen W., Garcia-Finana M., Gomaa A., Waked I., Rewisha E., Aithal G.P., Travis S., Kudo M., Cucchetti A., Peck-Radosavljevic M., Takkenberg R.B., Chan S.L., Vogel A., and Johnson P.J.

Subjects
0301 basic medicine, Oncology, Male, EXTERNAL VALIDATION, ARTERIAL CHEMOEMBOLIZATION, Prognostic score, Cohort Studies, 0302 clinical medicine, Training set, Liver Neoplasms, hepatocellular carcinoma, Arteries, Middle Aged, EMBOLIZATION, Prognosis, Survival Rate, DRUG-ELUTING BEADS, 1101 Medical Biochemistry and Metabolomics, 1107 Immunology, Response Evaluation Criteria in Solid Tumors, SAFETY, Hepatocellular carcinoma, Original Article, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Carcinoma, Hepatocellular, RETREATMENT, mRECIST, survival, 03 medical and health sciences, Internal medicine, SCORE, medicine, Overall survival, Humans, Internal validation, Chemoembolization, Therapeutic, Aged, TACE, Science & Technology, Models, Statistical, Gastroenterology & Hepatology, Hepatology, business.industry, External validation, 1103 Clinical Sciences, Patient survival, Original Articles, EFFICACY, medicine.disease, 030104 developmental biology, LIVER-FUNCTION, business
Abstract

Background and Aims: The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. Approach and Results: Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model (“Pre-TACE-Predict”) and a post-TACE model (“Post-TACE-Predict”) that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7months to more than 4years. Conclusions: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.

Published
2019

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