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3. OC-030 Effective Stratification of Hepatocellular Carcinoma Risk in Primary Biliary Cirrhosis: Results of a Multi-centre International Study

Author

Trivedi, PJ, Lammers, W, van Buuren, H, Janssen, H, Invernizzi, P, Battezzati, PM, Floreani, A, Pares, A, Ponsioen, C, Corpechot, C, Poupon, R, Mayo, M, Talwalkar, J, Burroughs, A, Nevens, F, Mason, A, Bruns, T, Li, K-K, Kowdley, K, Kumagi, T, Cheung, A, Lleo, A, Cazagon, N, Franceschet, I, Caballería, L, Boonstra, K, de Vries, E, Imam, M, Pieri, G, Kanwar, P, Lindor, K, Hansen, B, and Hirschfield, G

Published
2014
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4. Range of Normal Liver Stiffness and Factors Associated With Increased Stiffness Measurements in Apparently Healthy Individuals

Author

Bazerbachi, F. Haffar, S. Wang, Z. Cabezas, J. Arias-Loste, M.T. Crespo, J. Darwish-Murad, S. Ikram, M.A. Olynyk, J.K. Gan, E. Petta, S. Berzuini, A. Prati, D. de Lédinghen, V. Wong, V.W. Del Poggio, P. Chávez-Tapia, N.C. Chen, Y.-P. Cheng, P.-N. Yuen, M.-F. Das, K. Chowdhury, A. Caballeria, L. Fabrellas, N. Ginès, P. Kumar, M. Sarin, S.K. Conti, F. Andreone, P. Sirli, R. Cortez-Pinto, H. Carvalhana, S. Sugihara, T. Kim, S.U. Parikh, P. Chayama, K. Corpechot, C. Kim, K.M. Papatheodoridis, G. Alsebaey, A. Kamath, P.S. Murad, M.H. Watt, K.D.

Abstract

Background & Aims: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. Methods: We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index

Published
2019

6. Changes in serum bile acid levels associated with bezafibrate add-on therapy in patients with primary biliary cholangitis and inadequate biochemical response to ursodeoxycholic acid: results from the BEZURSO trial (NCT01654731)

Author

Corpechot, C., Chazouilleres, O., Humbert, L., Rousseau, A., Le Gruyer, A., Habersetzer, F., Philippe Mathurin, Goria, O., Potier, P., Anne, M., Silvain, C., Abergel, A., Debette-Gratien, M., Larrey, D. G., Roux, O., Bronowicki, J. P., Boursier, J., Ledinghen, V., Heurgue-Berlot, A., Nguyen-Khac, E., Zoulim, F., Ollivier-Hourmand, I., Zarski, J. P. H., Nkontchou, G., Gaouar, F., Simon, T., Poupon, R., Rainteau, D., CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Pôle Hépato-digestif, Les Hôpitaux Universitaires de Strasbourg (HUS), Service des Maladies de l'Appareil Digestif et de la Nutrition [CHRU Lille], Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Régional d'Orléans (CHRO), Unité d'Hépatologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Department of Digestive and Hepatobiliary Medecine, University Medical Hospital, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Pharmacologie des Immunosuppresseurs et de la Transplantation (PIST), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro-Entérologie et Nutrition [CHU Limoges], CHU Limoges, Département d'Hépato-Gastroentérologie et de Transplantation Hépatique [CHU Saint-Eloi], Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Méthodes Formelles pour la Bioinformatique (LS2N - équipe MéForBio), Laboratoire des Sciences du Numérique de Nantes (LS2N), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital universitaire Robert Debré [Reims], Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’Hépato-Gastroentérologie [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Jean Verdier [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

68th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) / Liver Meeting, Washington, DC, OCT 20-24, 2017; International audience

Published
2017

7. Clustering Reveals the Prognostic Role of Serum Albumin Values Within the Normal Range in Patients with Primary Biliary Cholangitis

Author

Gerussi, A., Verda, D., Bernasconi, D.P., Carbone, M., Komori, A., Abe, M., Inao, M., Namisaki, T., Mochida, S., Yoshiji, H., Hirschfield, G., Lindor, K., Pares, A., Corpechot, C., Cazzagon, N., Floreani, A., Marzioni, M., Alvaro, D., Vespasiani-Gentilucci, U., Cristoferi, L., Valsecchi, M.G., Muselli, M., Study Group, the Japan PBC, Study Group, the Global PBC, study Group, the Italian PBC, Hansen, B.E., Tanaka, A., and Invernizzi, P.

Published
2021
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8. Serum gamma-glutamyltransferase is a prognostic biomarker in primary biliary cholangitis and improves risk stratification based on alkaline phosphatase

Author

Gerussi, A., Bernasconi, D., O’donnell, S.E., Lammers, W.J., Van Buuren, H., Hirschfield, G., Janssen, H., Corpechot, C., Reig, A., Pares, A., Battezzati, P.M., Zuin, M.G., Cazzagon, N., Floreani, A., Nevens, F., Gatselis, N., Dalekos, G., Mayo, M.J., Thorburn, D., Bruns, T., Mason, A.L., Xavier, V., Kowdley, K., Invernizzi, P., Hansen, B., and Carbone, M.

Published
2020
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14. THU-226 - Stratification of hepatocellular carcinoma risk using the GLOBE score in patients with primary biliary cholangitis– the Global PBC Study Group

Author

Lammers, W.J., Trivedi, P., Hirschfield, G., Corpechot, C., Floreani, A., Nevens, F., Thorburn, D., Pares, A., Kowdley, K.V., Larusso, N., Battezzati, P.M., Ponsioen, C., Mason, A.L., Mayo, M.J., Invernizzi, P., Bruns, T., Dalekos, G., Xavier, V., Harms, M., Goet, J., Lindor, K., Janssen, H., Hansen, B., and Van Buuren, H.

Published
2018
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15. THU-211 - Younger age is associated with lower transplant-free survival relative to a general population in patients with Primary Biliary Cholangitis

Author

Perez, C.F.M., Lammers, W.J., Van Buuren, H., Gulamhusein, A., Cheung, A., Ponsioen, C., Carbone, M., Mason, A.L., Corpechot, C., Mayo, M.J., Invernizzi, P., Battezzati, P.M., Floreani, A., Pares, A., Nevens, F., Kowdley, K.V., Bruns, T., Dalekos, G., Zachou, K., Thorburn, D., Larusso, N., Poupon, R., Trivedi, P., Xavier, V., Janssen, H., Hirschfield, G., Lindor, K., and Hansen, B.

Published
2018
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16. THU-204 - Histologic stage is a stronger predictor of transplant free survival than APRI and FIB-4 in patients with primary biliary cholangitis

Author

Gulamhusein, A., Perez, C.F.M., Van Buuren, H., Corpechot, C., Trivedi, P., Carbone, M., Pares, A., Lammers, W.J., Harms, M., Floreani, A., Lindor, K., Ponsioen, C., Invernizzi, P., Mayo, M.J., Battezzati, P.M., Nevens, F., Bruns, T., Dalekos, G., Thorburn, D., Larusso, N., Zachou, K., Poupon, R., Xavier, V., Mason, A.L., Kowdley, K.V., Janssen, H., Hirschfield, G., and Hansen, B.

Published
2018
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17. A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis.

Author

Corpechot, C., Chazouillères, O., Rousseau, A., Le Gruyer, A., Habersetzer, F., Mathurin, P., Goria, O., Potier, P., Minello, A., Silvain, C., Abergel, A., Debette-Gratien, M., Larrey, D., Roux, O., Bronowicki, J.-P., Boursier, J., de Ledinghen, V., Heurgue-Berlot, A., Nguyen-Khac, E., and Zoulim, F.

Abstract

BACKGROUND Patients with primary biliary cholangitis who have an inadequate response to therapy with ursodeoxycholic acid are at high risk for disease progression. Fibrates, which are agonists of peroxisome proliferator-activated receptors, in combination with ursodeoxycholic acid, have shown potential benefit in patients with this condition. METHODS In this 24-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 100 patients who had had an inadequate response to ursodeoxycholic acid according to the Paris 2 criteria to receive bezafibrate at a daily dose of 400 mg (50 patients), or placebo (50 patients), in addition to continued treatment with ursodeoxycholic acid. The primary outcome was a complete biochemical response, which was defined as normal levels of total bilirubin, alkaline phosphatase, aminotransferases, and albumin, as well as a normal prothrombin index (a derived measure of prothrombin time), at 24 months. RESULTS The primary outcome occurred in 31% of the patients assigned to bezafibrate and in 0% assigned to placebo (difference, 31 percentage points; 95% confidence interval, 10 to 50; P<0.001). Normal levels of alkaline phosphatase were observed in 67% of the patients in the bezafibrate group and in 2% in the placebo group. Results regarding changes in pruritus, fatigue, and noninvasive measures of liver fibrosis, including liver stiffness and Enhanced Liver Fibrosis score, were consistent with the results of the primary outcome. Two patients in each group had complications from end-stage liver disease. The creatinine level increased 5% from baseline in the bezafibrate group and decreased 3% in the placebo group. Myalgia occurred in 20% of the patients in the bezafibrate group and in 10% in the placebo group. CONCLUSIONS Among patients with primary biliary cholangitis who had had an inadequate response to ursodeoxycholic acid alone, treatment with bezafibrate in addition to ursodeoxycholic acid resulted in a rate of complete biochemical response that was significantly higher than the rate with placebo and ursodeoxycholic acid therapy. [ABSTRACT FROM AUTHOR]

Published
2018
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21. Neurosteroids: Deficient cognitive performance in aged rats depends on low pregnenolone sulfate levels in the hippocampus

Author

Mayo, W., Darnaudéry, M, Corpéchot, C, Young, J., Koehl, Muriel, Le Moal, M., Baulieu, E.-E., Robel, P., Simon, H., Vallée, M., Darnaudery, M., Corpechot, C., Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, Différenciation, interaction, activation et migration des sous-populations lymphocitaires humaines, Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie et des Maladies de la Reproduction, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Aging, medicine.medical_specialty, Neuroactive steroid, MESH: Hippocampus, MESH: Rats, Morris water navigation task, Hippocampus, MESH: Cognition, Water maze, MESH: Rats, Sprague-Dawley, Hippocampal formation, Rats, Sprague-Dawley, 03 medical and health sciences, chemistry.chemical_compound, Cognition, 0302 clinical medicine, Internal medicine, medicine, Animals, MESH: Aging, MESH: Animals, Prefrontal cortex, 030304 developmental biology, 0303 health sciences, Multidisciplinary, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, Biological Sciences, MESH: Pregnenolone, MESH: Male, Rats, Endocrinology, chemistry, Pregnenolone, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Pregnenolone sulfate, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Pregnenolone sulfate (PREG S) is synthesized in the nervous system and is a major neurosteroid in the rat brain. Its concentrations were measured in the hippocampus and other brain areas of single adult and aged (22–24 month-old) male Sprague–Dawley rats. Significantly lower levels were found in aged rats, although the values were widely scattered and reached, in about half the animals, the same range as those of young ones. The spatial memory performances of aged rats were investigated in two different spatial memory tasks, the Morris water maze and Y-maze. Performances in both tests were significantly correlated and, accompanied by appropriate controls, likely evaluated genuine memory function. Importantly, individual hippocampal PREG S and distance to reach the platform in the water maze were linked by a significant correlation, i.e., those rats with lower memory deficit had the highest PREG S levels, whereas no relationship was found with the PREG S content in other brain areas (amygdala, prefrontal cortex, parietal cortex, striatum). Moreover, the memory deficit of cognitively impaired aged rats was transiently corrected after either intraperitoneal or bilateral intrahippocampal injection of PREG S. PREG S is both a γ-aminobutyric acid antagonist and a positive allosteric modulator at the N -methyl- d -aspartate receptor, and may reinforce neurotransmitter system(s) that decline with age. Indeed, intracerebroventricular injection of PREG S was shown to stimulate acetylcholine release in the adult rat hippocampus. In conclusion, it is proposed that the hippocampal content of PREG S plays a physiological role in preserving and/or enhancing cognitive abilities in old animals, possibly via an interaction with central cholinergic systems. Thus, neurosteroids should be further studied in the context of prevention and/or treatment of age-related memory disorders.

Published
1997
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22. P1184 : Age, bilirubin and albumin, regardless of sex, are the strongest independent predictors of biochemical response and transplantation-free survival in patients with primary biliary cirrhosis

Author

Cheung, A.C., Lammers, W.J., Hirschfield, G.M., Invernizzi, P., Mason, A.L., Ponsioen, C.Y., Floreani, A., Corpechot, C., Mayo, M.J., Pares, A., Battezzati, P.M., Nevens, F., Thorburn, D., Kowdley, K.V., Trivedi, P.J., Kumagi, T., Lleo, A., LaRusso, N., Boonstra, K., Cazzagon, N., Franceschet, I., Poupon, R., Caballeria, L., Lindor, K.D., Hansen, B.E., Janssen, H.L., and Van Buuren, H.

Published
2015
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24. P1180 : Identification of pbc patients in need of additional therapy during the course of UDCA treatment -an international multicenter study

Author

Lammers, W.J., Parés, A., Corpechot, C., Nevens, F., Janssen, H.L., Ponsioen, C.Y., Hirschfield, G.M., Floreani, A., Mayo, M.J., Invernizzi, P., Battezzati, P.M., Thorburn, D., Mason, A.L., Kowdley, K.V., Larusso, N.F., Caballeria, L., Poupon, R., Cheung, A., Boonstra, K., Trivedi, P.J., Kumagi, T., Cazzagon, N., Franceschet, I., Lleo, A., Pieri, G., Imam, M.H., Lindor, K.D., Harms, M.H., van Buuren, H.R., and Hansen, B.E.

Published
2015
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25. P1177 : Risk factors for hepatic decompensation in primary biliary cirrhosis - results of an international follow up study of 2326 patients

Author

Harms, M.H., Lammers, W.J., Invernizzi, P., Battezzati, P.M., Floreani, A., Pares, A., Nevens, F., Thorburn, D., Mason, A.L., Kowdley, K.V., Ponsioen, C., Corpechot, C., Janssen, H.L., Hirschfield, G.M., Mayo, M., LaRusso, N.F., Lleo, A., Cazzagon, N., Franceschet, I., Caballeria, L., Poupon, R., Cheung, A., Trivedi, P., Lindor, K., van Buuren, H.R., and Hansen, B.E.

Published
2015
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26. P1147 : Validation of an alkaline phosphatase and bilirubin response criterion as biomarker for transplant-free survival in primary biliary cirrhosis in the world's two largest cohorts

Author

Carbone, M., Harms, M.H., Lindor, K., Hirschfield, G.M., Lammers, W.J., Heneghan, M., Janssen, H.L., Neuberger, J.M., Thorburn, D., Pares, A., Sharp, S., Invernizzi, P., Warheam, N., Floreani, A., Bathgate, A., Corpechot, C., Aldersley, M., Mayo, M., LaRusso, N.F., Nevens, F., Alexander, G.J., Kowdley, K.V., Sandford, R.N., Mason, A.L., Jones, D., van Buuren, H.R., Mells, G., and Hansen, B.E.

Published
2015
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30. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

Author

Kowdley, K. V., Bowlus, C. L., Levy, C., Akarca, U. S., Alvares-da-Silva, M. R., Andreone, P., Arrese, M., Corpechot, C., Francque, S. M., Heneghan, M. A., Invernizzi, P., Jones, D., Kruger, F. C., Lawitz, E., Mayo, M. J., Shiffman, M. L., Swain, M. G., Valera, J. M., Vargas, V., and Vierling, J. M.

Subjects
*CHOLANGITIS, *HEPATIC fibrosis, *PEROXISOME proliferator-activated receptors, *ALKALINE phosphatase, *BILE ducts, *URSODEOXYCHOLIC acid
Abstract

BACKGROUND Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P=0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P=0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.) [ABSTRACT FROM AUTHOR]

Published
2024
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31. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis.

Author

Hirschfield, G. M., Bowlus, C. L., Mayo, M. J., Kremer, A. E., Vierling, J. M., Kowdley, K. V., Levy, C., Villamil, A., de Guevara Cetina, A. L. Ladrón, Janczewska, E., Zigmond, E., Jeong, S.-H., Yilmaz, Y., Kallis, Y., Corpechot, C., Buggisch, P., Invernizzi, P., Londoño Hurtado, M. C., Bergheanu, S., and Yang, K.

Subjects
*CLINICAL trials, *CHOLANGITIS, *PEROXISOME proliferator-activated receptors, *ALKALINE phosphatase, *URSODEOXYCHOLIC acid
Abstract

BACKGROUND Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P=0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733. opens in new tab; EudraCT number, 2020-004348-27.) [ABSTRACT FROM AUTHOR]

Published
2024
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32. Acute Renal Failure Associated with Nonfulminant Hepatitis A Viral Infection.

Author

Cadranel, J. F., Corpechot, C., Di Martino, V., Bernard, B., Lunel, F., and Øpolon, P.

Subjects
LETTERS to the editor, HEPATITIS
Abstract

Presents a letter to the editor regarding the case of a 38-year-old nonalcoholic man with acute cholestatic nonfulminant viral A hepatitis associated with acute renal failure.

Published
1996

44. Geographical region and clinical outcomes of patients with primary biliary cholangitis from Western Europe

Author

Carla F, Murillo Perez, Alessio, Gerussi, Palak J, Trivedi, Christophe, Corpechot, Adriaan J, van der Meer, Pier, Maria Battezzati, Keith D, Lindor, Frederik, Nevens, Kris V, Kowdley, Tony, Bruns, Nora, Cazzagon, Annarosa, Floreani, Atsushi, Tanaka, Xiong, Ma, Andrew L, Mason, Aliya, Gulamhusein, Cyriel Y, Ponsioen, Marco, Carbone, Ana, Lleo, Marlyn J, Mayo, George N, Dalekos, Nikolaos K, Gatselis, Douglas, Thorburn, Xavier, Verhelst, Albert, Parés, Harry L A, Janssen, Gideon M, Hirschfield, Bettina E, Hansen, Pietro, Invernizzi, Willem J, Lammers, Gastroenterology & Hepatology, Murillo Perez, C, Gerussi, A, Trivedi, P, Corpechot, C, Van Der Meer, A, Maria Battezzati, P, Lindor, K, Nevens, F, Kowdley, K, Bruns, T, Cazzagon, N, Floreani, A, Tanaka, A, Ma, X, Mason, A, Gulamhusein, A, Ponsioen, C, Carbone, M, Lleo, A, Mayo, M, Dalekos, G, Gatselis, N, Thorburn, D, Verhelst, X, Pares, A, Janssen, H, Hirschfield, G, Hansen, B, Invernizzi, P, and Lammers, W

Subjects
Male, Europe, Liver Cirrhosis, Databases, Factual, risk factor, Liver Cirrhosis, Biliary, environmental factor, Graft Survival, Humans, Female, Middle Aged, geography
Abstract

Background and aims The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region. Methods Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate. Results One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris). Conclusion We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors.

Published
2023

45. Simplified care-pathway selection for nonspecialist practice

Author

Aliya Gulamhusein, Nora Cazzagon, Xavier Verhelst, Andrew Mason, Cyriel Y. Ponsioen, George N. Dalekos, Keith D. Lindor, Frederik Nevens, Palak J. Trivedi, Adriaan J. van der Meer, Kris V. Kowdley, Willem J Lammers, Olivier Chazouillères, Ana Lleo, Douglas Thorburn, Nikolaos K. Gatselis, Bettina E. Hansen, Carla F. Murillo Perez, Tony Bruns, Gideon M. Hirschfield, Pietro Invernizzi, Annarosa Floreani, Christophe Corpechot, Marco Carbone, Marlyn J. Mayo, Albert Parés, Pier Maria Battezzati, Harry L.A. Janssen, Gastroenterology & Hepatology, Murillo Perez, C, Gulamhusein, A, Carbone, M, Trivedi, P, van der Meer, A, Corpechot, C, Battezzati, P, Lammers, W, Cazzagon, N, Floreani, A, Pares, A, Nevens, F, Lleo, A, Mayo, M, Kowdley, K, Ponsioen, C, Dalekos, G, Gatselis, N, Thorburn, D, Mason, A, Janssen, H, Verhelst, X, Bruns, T, Lindor, K, Chazouilleres, O, Invernizzi, P, Hansen, B, Hirschfield, G, Gastroenterology and Hepatology, and Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Cholagogues and Choleretics, medicine.medical_specialty, Bilirubin, Risk management tools, Risk Assessment, chemistry.chemical_compound, Risk groups, Internal medicine, medicine, Care pathway, Humans, In patient, Hepatology, Liver Cirrhosis, Biliary, business.industry, Ursodeoxycholic Acid, Gastroenterology, Fibrosis stage, Middle Aged, Alkaline Phosphatase, pbc, Young age, chemistry, Critical Pathways, Alkaline phosphatase, business
Abstract

BACKGROUND: Opportunity to redefine the care journeys for those living with primary biliary cholangitis (PBC) includes facilitating access to enhanced (PBC-dedicated) programmes by nonspecialist risk 'flagging' of patients. OBJECTIVE: To develop a nonexpert PBC stratification tool to help care pathway choices (standard vs. enhanced) choices in PBC. METHODS: We included ursodeoxycholic acid-treated patients with PBC from the Global PBC Study Group. The performance of baseline and 1-year clinical markers with transplant-free survival was assessed to develop the 'ABA' tool using Age (A), Bilirubin (B), and Alkaline phosphatase (A). Added value of fibrosis estimation was assessed. RESULTS: 'ABA' classification mapped three risk groups (n = 2226): low [Age > 50 years, bilirubin ≤ 1 × ULN, alkaline phosphatase (ALP) ≤ 3 × ULN], high (Age ≤ 50 years, bilirubin > 1 × ULN, ALP > 3 × ULN), and intermediate (other). Transplant-free survival at 10 years in the low-, intermediate-, and high-risk groups were 89, 77, and 59% at baseline and 86, 76, and 40% at 1 year, respectively. We propose that high-risk patients at baseline be directly triaged to enhanced (PBC-dedicated) care and the remaining be reassessed at 1 year. Modelling showed after 1 year 46% patients were proposed to enhanced care and 54% to standard care. The 'ABA' mapped pathways facilitated identification of patients at risk based on a young age, as compared to traditional liver biochemical stratification. In patients proposed to standard care, estimated fibrosis stage had ongoing prognostic value. CONCLUSION: Nonspecialist use of the 'ABA' risk tool could prioritize care journey choices for patients with PBC.

Published
2021

46. Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis

Author

Christophe Corpechot, Fabrice Carrat, Farid Gaouar, Frederic Chau, Gideon Hirschfield, Aliya Gulamhusein, Aldo J. Montano-Loza, Ellina Lytvyak, Christoph Schramm, Albert Pares, Ignasi Olivas, John E. Eaton, Karim T. Osman, George Dalekos, Nikolaos Gatselis, Frederik Nevens, Nora Cazzagon, Alessandra Zago, Francesco Paolo Russo, Nadir Abbas, Palak Trivedi, Douglas Thorburn, Francesca Saffioti, Laszlo Barkai, Davide Roccarina, Vicenza Calvaruso, Anna Fichera, Adèle Delamarre, Esli Medina-Morales, Alan Bonder, Vilas Patwardhan, Cristina Rigamonti, Marco Carbone, Pietro Invernizzi, Laura Cristoferi, Adriaan van der Meer, Rozanne de Veer, Ehud Zigmond, Eyal Yehezkel, Andreas E. Kremer, Ansgar Deibel, Jérôme Dumortier, Tony Bruns, Karsten Große, Georges-Philippe Pageaux, Aaron Wetten, Jessica Dyson, David Jones, Olivier Chazouillères, Bettina Hansen, Victor de Lédinghen, Corpechot, Christophe, Carrat, Fabrice, Gaouar, Farid, Chau, Frederic, Hirschfield, Gideon, Gulamhusein, Aliya, Montano-Loza, Aldo J, Lytvyak, Ellina, Schramm, Christoph, Pares, Albert, Olivas, Ignasi, Eaton, John E, Osman, Karim T, Dalekos, George, Gatselis, Nikolao, Nevens, Frederik, Cazzagon, Nora, Zago, Alessandra, Russo, Francesco Paolo, Abbas, Nadir, Trivedi, Palak, Thorburn, Dougla, Saffioti, Francesca, Barkai, Laszlo, Roccarina, Davide, Calvaruso, Vincenza, Fichera, Anna, Delamarre, Adèle, Medina-Morales, Esli, Bonder, Alan, Patwardhan, Vila, Rigamonti, Cristina, Carbone, Marco, Invernizzi, Pietro, Cristoferi, Laura, van der Meer, Adriaan, de Veer, Rozanne, Zigmond, Ehud, Yehezkel, Eyal, Kremer, Andreas E, Deibel, Ansgar, Dumortier, Jérôme, Bruns, Tony, Große, Karsten, Pageaux, Georges-Philippe, Wetten, Aaron, Dyson, Jessica, Jones, David, Chazouillères, Olivier, Hansen, Bettina, de Lédinghen, Victor, Corpechot, C, Carrat, F, Gaouar, F, Chau, F, Hirschfield, G, Gulamhusein, A, Montano-Loza, A, Lytvyak, E, Schramm, C, Pares, A, Olivas, I, Eaton, J, Osman, K, Dalekos, G, Gatselis, N, Nevens, F, Cazzagon, N, Zago, A, Russo, F, Abbas, N, Trivedi, P, Thorburn, D, Saffioti, F, Barkai, L, Roccarina, D, Calvaruso, V, Fichera, A, Delamarre, A, Medina-Morales, E, Bonder, A, Patwardhan, V, Rigamonti, C, Carbone, M, Invernizzi, P, Cristoferi, L, van der Meer, A, de Veer, R, Zigmond, E, Yehezkel, E, Kremer, A, Deibel, A, Dumortier, J, Bruns, T, Große, K, Pageaux, G, Wetten, A, Dyson, J, Jones, D, Chazouillères, O, Hansen, B, de Lédinghen, V, and Gastroenterology & Hepatology

Subjects
Liver Cirrhosis, FibroScan, Mortality, PBC, Prognosis, Transplantation, Hepatology, Prognosi, Liver Cirrhosis, Biliary, Liver Cirrhosi, Vibration, Follow-Up Studie, Cohort Studies, Liver, Elasticity Imaging Technique, Retrospective Studie, Humans, Elasticity Imaging Techniques, Cohort Studie, Retrospective Studies, Follow-Up Studies, Human
Abstract

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p

Published
2022

47. Long-term impact of preventive UDCA therapy after transplantation for primary biliary cholangitis

Author

Gideon M. Hirschfield, Maryam Ebadi, Xavier Verhelst, Federica Malinverno, Nora Cazzagon, Pierre Belnou, Christophe Corpechot, Falk Rauchfuss, Olivier Boillot, Raoul Poupon, Jérôme Dumortier, Palak J. Trivedi, Maria Francesca Donato, Sascha Chopra, Dennis Eurich, Francesco Paolo Russo, Martina Sterneck, Aldo J. Montano-Loza, Maren H. Harms, Fabrice Carrat, Philipp A. Reuken, Christoph Schramm, Alexie Bosch, Albert Parés, Patrick McDowell, Davide Roccarina, Andrew Mason, Jorn C Goet, Bettina E. Hansen, Emiliano Giostra, Anna Reig, Annarosa Floreani, Dietmar Jacob, Douglas Thorburn, Olivier Chazouillères, Tony Bruns, Alessio Gerussi, Henk R. van Buuren, Filomena Conti, Frederik Nevens, Corpechot, C, Chazouilleres, O, Belnou, P, Montano-Loza, A, Mason, A, Ebadi, M, Eurich, D, Chopra, S, Jacob, D, Schramm, C, Sterneck, M, Bruns, T, Reuken, P, Rauchfuss, F, Roccarina, D, Thorburn, D, Gerussi, A, Trivedi, P, Hirschfield, G, Mcdowell, P, Nevens, F, Boillot, O, Bosch, A, Giostra, E, Conti, F, Poupon, R, Pares, A, Reig, A, Donato, M, Malinverno, F, Floreani, A, Russo, F, Cazzagon, N, Verhelst, X, Goet, J, Harms, M, van Buuren, H, Hansen, B, Carrat, F, Dumortier, J, Gastroenterology & Hepatology, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Graft Rejection, Male, 0301 basic medicine, Cholagogues and Choleretics, Cirrhosis, Survival, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Placebo-controlled study, Liver transplantation, PBC, Gastroenterology, UDCA, 0302 clinical medicine, MED/12 - GASTROENTEROLOGIA, Recurrence, Liver Cirrhosis, Biliary, Ursodeoxycholic Acid, Hazard ratio, Middle Aged, Ursodeoxycholic acid, 3. Good health, Survival Rate, Treatment Outcome, Tacrolimu, Cyclosporine, Tacrolimus, Transplantation, Drug Therapy, Combination, Female, 030211 gastroenterology & hepatology, Immunosuppressive Agents, medicine.drug, Risk, medicine.medical_specialty, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, Retrospective Studies, Hepatology, business.industry, Retrospective cohort study, medicine.disease, digestive system diseases, Liver Transplantation, Regimen, 030104 developmental biology, MED/09 - MEDICINA INTERNA, business, Follow-Up Studies
Abstract

Background & Aims: Recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT) is frequent and can impair graft and patient survival. Ursodeoxycholic acid (UDCA) is the current standard therapy for PBC. We investigated the effect of preventive exposure to UDCA on the incidence and long-term consequences of PBC recurrence after LT. Methods: We performed a retrospective cohort study in 780 patients transplanted for PBC, between 1983–2017 in 16 centers (9 countries), and followed-up for a median of 11 years. Among them, 190 received preventive UDCA (10–15 mg/kg/day). The primary outcome was histological evidence of PBC recurrence. The secondary outcomes were graft loss, liver-related death, and all-cause death. The association between preventive UDCA and outcomes was quantified using multivariable-adjusted Cox and restricted mean survival time (RMST) models. Results: While recurrence of PBC significantly shortened graft and patient survival, preventive exposure to UDCA was associated with reduced risk of PBC recurrence (adjusted hazard ratio [aHR] 0.41; 95% CI 0.28–0.61; p

Published
2020
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48. Goals of Treatment for Improved Survival in Primary Biliary Cholangitis: Treatment Target Should Be Bilirubin Within the Normal Range and Normalization of Alkaline Phosphatase

Author

George N. Dalekos, Harry L.A. Janssen, Albert Parés, Willem J Lammers, Keith D. Lindor, Frederik Nevens, Jordan J. Feld, Maren H. Harms, Pier Maria Battezzati, Henk R. van Buuren, Marlyn J. Mayo, Pietro Invernizzi, Carla F. Murillo Perez, Christophe Corpechot, Annarosa Floreani, Douglas Thorburn, Tony Bruns, Palak J. Trivedi, Kris V. Kowdley, Xavier Verhelst, Ana Lleo, Aliya Gulamhusein, Cyriel Y. Ponsioen, Nikolaos K. Gatselis, Andrew Mason, Bettina E. Hansen, Gideon M. Hirschfield, Adriaan J. van der Meer, Marco Carbone, Murillo Perez, C, Harms, M, Lindor, K, van Buuren, H, Hirschfield, G, Corpechot, C, van der Meer, A, Feld, J, Gulamhusein, A, Lammers, W, Ponsioen, C, Carbone, M, Mason, A, Mayo, M, Invernizzi, P, Battezzati, P, Floreani, A, Lleo, A, Nevens, F, Kowdley, K, Bruns, T, Dalekos, G, Gatselis, N, Thorburn, D, Trivedi, P, Verhelst, X, Parés, A, Janssen, H, Hansen, B, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology & Hepatology

Subjects
Male, medicine.medical_specialty, Cholagogues and Choleretics, Cirrhosis, Bilirubin, Cholangitis, medicine.medical_treatment, Autoimmune hepatitis, Liver transplantation, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, MED/12 - GASTROENTEROLOGIA, Reference Values, Internal medicine, medicine, Humans, Primary Biliary Cholangiti, Survival rate, Hepatology, business.industry, Hazard ratio, Ursodeoxycholic Acid, Middle Aged, medicine.disease, Alkaline Phosphatase, Prognosis, Survival Rate, chemistry, 030220 oncology & carcinogenesis, Cohort, Alkaline phosphatase, 030211 gastroenterology & hepatology, Female, business, Biomarkers
Abstract

INTRODUCTION: In primary biliary cholangitis (PBC), bilirubin and alkaline phosphatase (ALP) are widely established as independent predictors of prognosis. Current treatment goals do not aim for normalization of surrogate markers because their association with survival has not been defined. METHODS: The patient cohort from the GLOBAL PBC Study Group was used, comprising of long-term follow-up data from European and North American centers. Ursodeoxycholic acid-treated and untreated patients with bilirubin levels ≤1 × upper limit of normal (ULN) at baseline or 1 year were included. The association of normal ALP with transplant-free survival was assessed in a subgroup with ALP ≤1.67 × ULN at 1 year. Optimal thresholds of bilirubin and ALP to predict liver transplantation (LT) or death were evaluated. RESULTS: There were 2,281 patients included in the time zero cohort and 2,555 patients in the 1-year cohort. The bilirubin threshold with the highest ability to predict LT or death at 1 year was 0.6 × ULN (hazard ratio 2.12, 95% CI 1.69-2.66, P < 0.001). The 10-year survival rates of patients with bilirubin ≤0.6 × ULN and >0.6 × ULN were 91.3% and 79.2%, respectively (P < 0.001). The risk for LT or death was stable below the bilirubin levels of 0.6 × ULN, yet increased beyond this threshold. Ursodeoxycholic acid-induced reduction in bilirubin below this threshold was associated with an 11% improvement in 10-year survival. Furthermore, ALP normalization was optimal, with 10-year survival rates of 93.2% in patients with ALP ≤ 1 × ULN and 86.1% in those with ALP 1.0-1.67 × ULN. DISCUSSION: Attaining bilirubin levels ≤0.6 × ULN or normal ALP are associated with the lowest risk for LT or death in patients with PBC. This has important implications for treatment targets.

Published
2020
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49. Machine learning in primary biliary cholangitis: A novel approach for risk stratification

Author

Alessio Gerussi, Damiano Verda, Davide Paolo Bernasconi, Marco Carbone, Atsumasa Komori, Masanori Abe, Mie Inao, Tadashi Namisaki, Satoshi Mochida, Hitoshi Yoshiji, Gideon Hirschfield, Keith Lindor, Albert Pares, Christophe Corpechot, Nora Cazzagon, Annarosa Floreani, Marco Marzioni, Domenico Alvaro, Umberto Vespasiani‐Gentilucci, Laura Cristoferi, Maria Grazia Valsecchi, Marco Muselli, Bettina E. Hansen, Atsushi Tanaka, Pietro Invernizzi, Gerussi, A, Verda, D, Bernasconi, D, Carbone, M, Komori, A, Abe, M, Inao, M, Namisaki, T, Mochida, S, Yoshiji, H, Hirschfield, G, Lindor, K, Pares, A, Corpechot, C, Cazzagon, N, Floreani, A, Marzioni, M, Alvaro, D, Vespasiani‐gentilucci, U, Cristoferi, L, Valsecchi, M, Muselli, M, Hansen, B, Tanaka, A, and Invernizzi, P

Subjects
Cholagogues and Choleretics, Hepatology, Cholangitis, Liver Cirrhosis, Biliary, Ursodeoxycholic Acid, autoimmune liver disease, Prognosis, artificial intelligence, Risk Assessment, Machine Learning, cluster analysi, Humans, cluster analysis, prognosis, prognosi
Abstract

Background & Aims: Machine learning (ML) provides new approaches for prognostication through the identification of novel subgroups of patients. We explored whether ML could support disease sub-phenotyping and risk stratification in primary biliary cholangitis (PBC). Methods: ML was applied to an international dataset of PBC patients. The dataset was split into a derivation cohort (training set) and a validation cohort (validation set), and key clinical features were analysed. The outcome was a composite of liver-related death or liver transplantation. ML and standard survival analysis were performed. Results: The training set was composed of 11,819 subjects, while the validation set was composed of 1,069 subjects. ML identified four clusters of patients characterized by different phenotypes and long-term prognosis. Cluster 1 (n = 3566) included patients with excellent prognosis, whereas Cluster 2 (n = 3966) consisted of individuals at worse prognosis differing from Cluster 1 only for albumin levels around the limit of normal. Cluster 3 (n = 2379) included young patients with florid cholestasis and Cluster 4 (n = 1908) comprised advanced cases. Further sub-analyses on the dynamics of albumin within the normal range revealed that ursodeoxycholic acid-induced increase of albumin >1.2 x lower limit of normal (LLN) is associated with improved transplant-free survival. Conclusions: Unsupervised ML identified four novel groups of PBC patients with different phenotypes and prognosis and highlighted subtle variations of albumin within the normal range. Therapy-induced increase of albumin >1.2 x LLN should be considered a treatment goal.

Published
2022

50. Ursodeoxycholic acid therapy and liver transplant-free survival in patients with primary biliary cholangitis

Author

Willem J Lammers, Keith D. Lindor, Maren H. Harms, Albert Parés, Gideon M. Hirschfield, Henk R. van Buuren, Douglas Thorburn, Cyriel Y. Ponsioen, Adriaan J. van der Meer, Harry L.A. Janssen, Christophe Corpechot, Pietro Invernizzi, Annarosa Floreani, Pier Maria Battezzati, Frederik Nevens, Marlyn J. Mayo, Andrew Mason, B.E. Hansen, Kris V. Kowdley, Harms, M, van Buuren, H, Corpechot, C, Thorburn, D, Janssen, H, Lindor, K, Hirschfield, G, Pares, A, Floreani, A, Mayo, M, Invernizzi, P, Battezzati, P, Nevens, F, Ponsioen, C, Mason, A, Kowdley, K, Lammers, W, Hansen, B, van der Meer, A, Gastroenterology & Hepatology, Gastroenterology and Hepatology, AGEM - Digestive immunity, and AGEM - Endocrinology, metabolism and nutrition

Subjects
0301 basic medicine, medicine.medical_specialty, Gastroenterology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Cholestasis, law, Interquartile range, Internal medicine, medicine, Mortality, Patient Management, Treatment, Stage (cooking), Hepatology, Proportional hazards model, business.industry, Cholestasis, Clinical trials, Mortality, Patient management, Treatment, UDCA, transplantation, medicine.disease, Ursodeoxycholic acid, 3. Good health, Clinical trial, 030104 developmental biology, 030211 gastroenterology & hepatology, business, Cohort study, medicine.drug
Abstract

BACKGROUND & AIMS: The clinical efficacy of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) remains subject to debate as definitive randomized controlled trials are lacking. We aimed to determine whether UDCA prolongs liver transplant (LT)-free survival in patients with PBC. METHODS: This international cohort study included patients from the Global PBC Study Group database, originating from 8 countries in Europe and North America. Both UDCA-treated and untreated patients were included. LT and death were assessed as a combined endpoint through Cox regression analyses, with inverse probability treatment weighting (IPTW). RESULTS: In the 3,902 patients included, the mean (SD) age was 54.3 (11.9) years, 3,552 patients (94.0%) were female, 3,529 patients (90.4%) were treated with UDCA and 373 patients (9.6%) were not treated. The median (interquartile range) follow-up was 7.8 (4.1-12.1) years. In total, 721 UDCA-treated patients and 145 untreated patients died or underwent LT. After IPTW, the 10-year cumulative LT-free survival was 79.7% (95% CI 78.1-81.2) among UDCA-treated patients and 60.7% (95% CI 58.2-63.4) among untreated patients (p

Published
2019
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