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1. European Society for Organ Transplantation (ESOT) Consensus Statement on Outcome Measures in Liver Transplantation According to Value-Based Health Care

Author: Marco Carbone, James Neuberger, Ian Rowe, Wojciech G. Polak, Anna Forsberg, Constantino Fondevila, Lorenzo Mantovani, Alessandra Nardi, Agostino Colli, Karen Rockell, Liz Schick, Laura Cristoferi, Gabriel C. Oniscu, Mario Strazzabosco, and Umberto Cillo
Subjects: liver transplantation, value-based health care, PROM, wait-list, outcomes ATS, Specialties of internal medicine, RC581-951
Abstract: Liver transplantation is a highly complex, life-saving, treatment for many patients with advanced liver disease. Liver transplantation requires multidisciplinary teams, system-wide adaptations and significant investment, as well as being an expensive treatment. Several metrics have been proposed to monitor processes and outcomes, however these lack patient focus and do not capture all aspects of the process. Most of the reported outcomes do not capture those outcomes that matter to the patients. Adopting the principles of Value-Based Health Care (VBHC), may provide an opportunity to develop those metrics that matter to patients. In this article, we present a Consensus Statement on Outcome Measures in Liver Transplantation following the principles of VBHC, developed by a dedicated panel of experts under the auspices of the European Society of Organ Transplantation (ESOT) Guidelines’ Taskforce. The overarching goal is to provide a framework to facilitate the development of outcome measures as an initial step to apply the VMC paradigm to liver transplantation.
Published: 2024
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2. Artificial intelligence for precision medicine in autoimmune liver disease

Author: Alessio Gerussi, Miki Scaravaglio, Laura Cristoferi, Damiano Verda, Chiara Milani, Elisabetta De Bernardi, Davide Ippolito, Rosanna Asselta, Pietro Invernizzi, Jakob Nikolas Kather, and Marco Carbone
Subjects: machine learning, genomics, radiomics, digital pathology, autoimmunity, deep learning, Immunologic diseases. Allergy, RC581-607
Abstract: Autoimmune liver diseases (AiLDs) are rare autoimmune conditions of the liver and the biliary tree with unknown etiology and limited treatment options. AiLDs are inherently characterized by a high degree of complexity, which poses great challenges in understanding their etiopathogenesis, developing novel biomarkers and risk-stratification tools, and, eventually, generating new drugs. Artificial intelligence (AI) is considered one of the best candidates to support researchers and clinicians in making sense of biological complexity. In this review, we offer a primer on AI and machine learning for clinicians, and discuss recent available literature on its applications in medicine and more specifically how it can help to tackle major unmet needs in AiLDs.
Published: 2022
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3. Role of ductular reaction and ductular–canalicular junctions in identifying severe primary biliary cholangitis

Author: Diletta Overi, Guido Carpino, Laura Cristoferi, Paolo Onori, Lindsey Kennedy, Heather Francis, Nicola Zucchini, Cristina Rigamonti, Mauro Viganò, Annarosa Floreani, Daphne D’Amato, Alessio Gerussi, Rosanna Venere, Gianfranco Alpini, Shannon Glaser, Domenico Alvaro, Pietro Invernizzi, Eugenio Gaudio, Vincenzo Cardinale, and Marco Carbone
Subjects: Ursodeoxycholic acid, Cholestasis, Histology, Cholangiopathy, Regeneration, Liver biopsy, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & Aims: Primary biliary cholangitis (PBC) is a chronic cholangiopathy characterised by immuno-mediated injury of interlobular bile ducts leading to intrahepatic cholestasis and progressive liver fibrosis. PBC histology is characterised by portal inflammation, progressive fibrosis, ductopenia, and the appearance of the so-called ductular reaction. The aim of the present study was to investigate the pathogenetic relevance of ductular reaction in PBC. Methods: Liver biopsies were collected from naïve people with PBC (N = 87). Clinical–serological parameters were obtained at diagnosis and after 1 year of ursodeoxycholic acid (UDCA) treatment. Histological staging was performed on all slides according to multiple scoring systems and criteria for PBC. Liver samples were obtained from Mdr2−/− mice treated with or without UDCA. Samples were processed for histology, immunohistochemistry, and immunofluorescence. Results: Ductular reaction in people with PBC correlated with the disease stage and liver fibrosis, but not with disease activity; an extensive ductular reaction correlated with serum alkaline phosphatase levels at diagnosis, response to UDCA, and individuals’ estimated survival, independently from other histological parameters, including disease stage. In people with PBC, reactive ductules were associated with the establishment of junctions with bile canaliculi and with fibrogenetic cell activation. Consistently, in a mouse model of intrahepatic cholestasis, UDCA treatment was effective in reducing ductular reaction and fibrosis and increasing ductular–canalicular junctions. Conclusions: Extensive ductular reaction outlines a severe histologic phenotype in PBC and is associated with an inadequate therapy response and a worse estimated prognosis. Lay summary: In people affected by primary biliary cholangitis (PBC), the histological appearance of extensive ductular reaction identifies individuals at risk of progressive fibrosis. Ductular reaction at diagnosis correlates with the lack of response to first-line therapy with ursodeoxycholic acid and serves to restore ductular–canalicular junctions in people with PBC. Assessing ductular reaction extension at diagnosis may add valuable information for clinicians.
Published: 2022
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4. Clinical treatment of cholangiocarcinoma: an updated comprehensive review

Author: Alessandra Elvevi, Alice Laffusa, Miki Scaravaglio, Roberta Elisa Rossi, Raffaella Longarini, Anna Maria Stagno, Laura Cristoferi, Antonio Ciaccio, Diego Luigi Cortinovis, Pietro Invernizzi, and Sara Massironi
Subjects: primary liver cancers, cholangiocarcinoma, biliary tract neoplasm, therapies, treatment, Specialties of internal medicine, RC581-951
Abstract: Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA).The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types.When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor.In order to ameliorate patients’ survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.
Published: 2022
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5. Coronavirus Disease 2019 in Autoimmune Hepatitis: A Lesson From Immunosuppressed Patients

Author: Alessio Gerussi, Cristina Rigamonti, Chiara Elia, Nora Cazzagon, Annarosa Floreani, Roberta Pozzi, Pietro Pozzoni, Ernesto Claar, Luisa Pasulo, Stefano Fagiuoli, Laura Cristoferi, Marco Carbone, and Pietro Invernizzi
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Chronic immunosuppression is associated with increased and more severe viral infections. However, little is known about the association between immunosuppression and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Our aim was to describe the clinical course of patients with immunosuppressed autoimmune hepatitis (AIH) during coronavirus disease 2019 (COVID‐19) infection in Italy. Our study is a case series of patients with AIH treated with immunosuppression, who tested positive for SARS‐CoV‐2 in March 2020 during the outbreak of COVID‐19. Ten patients from seven different hospitals in Italy were diagnosed with COVID‐19 during the outbreak of SARS‐CoV‐2 in March 2020. Seven subjects were female (70%), and age ranged from 27 to 73 years. Before the onset of SARS‐CoV‐2 infection, all patients were taking immunosuppressive therapy for AIH, and eight of them were on biochemical remission. Two other patients had recent acute onset of their AIH, and consequently started high‐dose steroids, as per induction protocol. All patients had a respiratory syndrome and a positive nasal swab for SARS‐CoV‐2. Five patients developed a computed tomography–confirmed COVID‐19 pneumonia. Six subjects received a combination of antiretroviral and antimalarial drugs. In seven patients, the dosage of immunosuppressive medication was changed. Liver enzymes were repeated during SARS‐CoV‐2 infection in all hospitalized cases; they remained within the normal range in all cases, and improved in the two acute cases treated with high‐dose steroids. The clinical outcome was comparable to the reported cases occurring in non‐immunosuppressed subjects. Conclusion: Patients under immunosuppressive therapy for AIH developing COVID‐19 show a disease course presumptively similar to that reported in the non‐immunosuppressed population. These data might aid in medical decisions when dealing with SARS‐CoV‐2 infection in immunocompromised patients.
Published: 2020
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6. Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies

Author: Alessio Gerussi, Daphne D’Amato, Laura Cristoferi, Sarah Elizabeth O’Donnell, Marco Carbone, and Pietro Invernizzi
Subjects: Primary biliary cholangitis, Primary sclerosing cholangitis, Precision medicine, Bile acids, FXR agonists, Fibrates, Specialties of internal medicine, RC581-951
Abstract: Primary biliary cholangitis and primary sclerosing cholangitis are rare diseases affecting the bile ducts and the liver. The limited knowledge of their pathogenesis leads to limited therapeutic options. Nevertheless, the landscape of novel therapies for these cholangiopathies is now rapidly changing, providing new treatment opportunities for patients and clinicians involved in their care. The aim of this review is to summarize the evidence of novel molecules under investigation for primary biliary cholangitis and primary sclerosing cholangitis and to discuss how they can potentially change current treatment paradigms.
Published: 2020
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7. A quantitative MRCP-derived score for medium-term outcome prediction in primary sclerosing cholangitis

Author: Laura Cristoferi, Marco Porta, Davide Paolo Bernasconi, Filippo Leonardi, Alessio Gerussi, Giacomo Mulinacci, Andrea Palermo, Camilla Gallo, Miki Scaravaglio, Eliana Stucchi, Cesare Maino, Davide Ippolito, Daphne D'Amato, Carlos Ferreira, Alessandra Nardi, Rajarshi Banerjee, Maria Grazia Valsecchi, Laura Antolini, Rocco Corso, Sandro Sironi, Stefano Fagiuoli, Pietro Invernizzi, Marco Carbone, Cristoferi, L, Porta, M, Bernasconi, D, Leonardi, F, Gerussi, A, Mulinacci, G, Palermo, A, Gallo, C, Scaravaglio, M, Stucchi, E, Maino, C, Ippolito, D, D'Amato, D, Ferreira, C, Nardi, A, Banerjee, R, Valsecchi, M, Antolini, L, Corso, R, Sironi, S, Fagiuoli, S, Invernizzi, P, and Carbone, M
Subjects: sclerosing cholangitis, Artificial intelligence, Hepatology, Prognostic score, Gastroenterology, Primary sclerosing cholangiti, MRCP
Abstract: Background: Magnetic resonance cholangiopancreatography (MRCP) is the gold standard for diagnosis of patients with primary sclerosing cholangitis (PSC). The semi-quantitative MRCP-derived Anali scores proposed for risk stratification, have poor-to-moderate inter-reader agreement. Aims: To evaluate the prognostic performance of quantitative MRCP metrics in PSC. Methods: This is a retrospective study of PSC patients undergoing MRCP. Images were processed using MRCP+ software (Perspectum Ltd, Oxford) that provides quantitative biliary features, semi-automatically extracted by artificial intelligence-driven analysis of MRCP-3D images. The prognostic value of biliary features has been assessed for all hepato-biliary complications. Results: 87 PSC patients have been included in the analysis. Median follow-up from MRCP to event/censoring of 30.9 months (Q1-Q3=13.6–46.6). An adverse outcome occurred in 27 (31.0%) patients. The number of biliary strictures (HR=1.05 per unit, 95%CI 1.02–1.08, p < 0.0001), spleen length (HR=1.16 per cm, 95%CI 1.01–1.34, p = 0.039), adjusted for height, age at MRCP, and time from diagnosis to MRCP predicted higher risk of hepatobiliary complications. These were incorporated into a the quantitative MRCP-derived PSC (qMRCP-PSC) score (C-statistic=0.80). After 3-fold cross-validation, qMRCP-PSC outperformed the Anali score in our cohort (C-statistic of 0.78 vs 0.64) and enabled the discrimination of survival of PSC patients (log-rank p < 0.0001). Conclusions: The qMRCP-PSC score identified patients at higher risk of hepatobiliary complications and outperformed the available radiological scores. It represents a novel quantitative biomarker for disease monitoring and a potential surrogate endpoint for clinical trials.
Published: 2023

8. Real-world experience with obeticholic acid in patients with primary biliary cholangitis

Author: Daphne D’Amato, Antonio De Vincentis, Federica Malinverno, Mauro Viganò, Domenico Alvaro, Maurizio Pompili, Antonino Picciotto, Valeria Pace Palitti, Maurizio Russello, Silvia Storato, Marie Graciella Pigozzi, Vincenza Calvaruso, Elisabetta De Gasperi, Ana Lleo, Antonino Castellaneta, Adriano Pellicelli, Nora Cazzagon, Annarosa Floreani, Luigi Muratori, Stefano Fagiuoli, Grazia Anna Niro, Valentina Feletti, Raffaele Cozzolongo, Natalia Terreni, Marco Marzioni, Rinaldo Pellicano, Pietro Pozzoni, Leonardo Baiocchi, Luchino Chessa, Floriano Rosina, Gaetano Bertino, Maria Vinci, Anna Morgando, Ester Vanni, Gaetano Scifo, Rodolfo Sacco, Maria D’Antò, Valentina Bellia, Roberto Boldizzoni, Silvia Casella, Barbara Omazzi, Guido Poggi, Laura Cristoferi, Alessio Gerussi, Vincenzo Ronca, Rosanna Venere, Francesca Ponziani, Maria Cannavò, Alessandro Mussetto, Rosanna Fontana, Francesco Losito, Evelise Frazzetto, Marco Distefano, Francesca Colapietro, Sara Labanca, Giulia Marconi, Giuseppe Grassi, Giovanni Galati, Sarah Elizabeth O’Donnell, Clara Mancuso, Giacomo Mulinacci, Andrea Palermo, Ernesto Claar, Antonio Izzi, Antonio Picardi, Pietro Invernizzi, Marco Carbone, and Umberto Vespasiani-Gentilucci
Subjects: Cholestasis, Cirrhosis, Overlap PBC-AIH, Autoimmunity, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & aims: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. Lay summary: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.
Published: 2021
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9. Geoepidemiology and (epi-)genetics in primary biliary cholangitis

Author: Roberto, Rosa, Laura, Cristoferi, Atsushi, Tanaka, and Pietro, Invernizzi
Published: 2018
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10. Quality of life in patients with primary biliary cholangitis: A cross-geographical comparison

Author: Lorenzo Montali, Andrea Gragnano, Massimo Miglioretti, Alessandra Frigerio, Luca Vecchio, Alessio Gerussi, Laura Cristoferi, Vincenzo Ronca, Daphne D’Amato, Sarah Elizabeth O’Donnell, Clara Mancuso, Martina Lucà, Minami Yagi, Anna Reig, Laura Jopson, Sesé Pilar, Dave Jones, Albert Pares, George Mells, Atsushi Tanaka, Marco Carbone, and Pietro Invernizzi
Subjects: Autoimmunity, Liver, Cholestasis, Fatigue, Immunologic diseases. Allergy, RC581-607
Abstract: Background & aims: Several symptoms impair the quality of life (QoL) of patients with primary biliary cholangitis (PBC). They are reported to vary significantly in different countries. Aim of our study was to explore whether there is a geographical clustering that accounts for symptoms in PBC. Methods: Data was analysed from four cohorts of PBC patients from the UK, Spain, Japan and Italy using the PBC-27 scale. Results: Overall, 569 patients from four cohorts were identified, including 515 females (90.5%) with a mean age of 61 years. The analysis provided evidence for strict factorial invariance of the scale, a robust indicator of its validity for cross-cultural research. The mean of the fatigue domain of British patients was significantly greater than that of the Japanese (p
Published: 2021
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11. Takayasu arteritis and primary sclerosing cholangitis: A casual association or different phenotypes of the same disease?

Author: Giacomo Mulinacci, Andrea Palermo, Laura Cristoferi, Pietro Invernizzi, and Marco Carbone
Subjects: Primary sclerosing cholangitis, Takayasu arteritis, Vasculitis, Inflammatory bowel disease, Immunologic diseases. Allergy, RC581-607
Abstract: Takayasu arteritis and primary sclerosing cholangitis are two rare disorders. The pathogenesis of Takayasu arteritis involves immune-mediated mechanisms, and corticosteroids represent the mainstay for treatment. Conversely, the aetiology of primary sclerosing cholangitis remains elusive, even if dysimmunity seems to be one of the contributors to bile duct damage. Despite this, immunosuppressants do not alter disease course. In this paper we describe the association of these two rare disorders, with an unexpected normalization of cholestatic enzymes following steroid treatment. This might hint a novel subtype of sclerosing cholangitis with a prevalent immunebackground, or a local manifestation of Takayasu arteritis.
Published: 2021
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12. The Role of Epigenetics in Primary Biliary Cholangitis

Author: Alessio Gerussi, Elvezia Maria Paraboschi, Claudio Cappadona, Chiara Caime, Eleonora Binatti, Laura Cristoferi, Rosanna Asselta, and Pietro Invernizzi
Subjects: chromosome X, non-coding RNA, autoimmunity, sex bias, somatic mosaicism, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Primary Biliary Cholangitis (PBC) is a rare autoimmune disease of the liver, affecting mostly females. There is evidence that epigenetic changes have a pathogenic role in PBC. Epigenetic modifications are related to methylation of CpG DNA islands, post-translational modifications of histone proteins, and non-coding RNAs. In PBC, there are data showing a dysregulation of all these levels, especially in immune cells. In addition, epigenetics seems to be involved in complex phenomena such as X monosomy or abnormalities in the process of X chromosome inactivation, which have been reported in PBC and appear to influence its sex imbalance and pathogenesis. We review here historical data on epigenetic modifications in PBC, present new data, and discuss possible links among X-chromosome abnormalities at a genetic and epigenetic level, PBC pathogenesis, and PBC sex imbalance.
Published: 2022
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13. New Therapeutic Targets in Autoimmune Cholangiopathies

Author: Alessio Gerussi, Martina Lucà, Laura Cristoferi, Vincenzo Ronca, Clara Mancuso, Chiara Milani, Daphne D'Amato, Sarah Elizabeth O'Donnell, Marco Carbone, and Pietro Invernizzi
Subjects: primary biliary cholangitis, primary sclerosing cholangitis, liver, FXR agonists, fibrates, microbiome, Medicine (General), R5-920
Abstract: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune cholangiopathies characterized by limited treatment options. A more accurate understanding of the several pathways involved in these diseases has fostered the development of novel and promising targeted drugs. For PBC, the characterization of the role of farnesoid X receptor (FXR) and perixosome-proliferator activated receptor (PPAR) has paved the way to several clinical trials including different molecules with choleretic and antinflammatory action. Conversely, different pathogenetic models have been proposed in PSC such as the “leaky gut” hypothesis, a dysbiotic microbiota or a defect in mechanisms protecting against bile acid toxicity. Along these theories, new treatment approaches have been developed, ranging from drugs interfering with trafficking of lymphocytes from the gut to the liver, fecal microbiota transplantation or new biliary acids with possible immunomodulatory potential. Finally, for both diseases, antifibrotic agents are under investigation. In this review, we will illustrate current understanding of molecular mechanisms in PBC and PSC, focusing on actionable biological pathways for which novel treatments are being developed.
Published: 2020
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14. Endocrinology and Metabolic Diseases (Including Diabetes)

Author: Laura Cristoferi, Stefano Ciardullo, Pietro Invernizzi, Gianluca Perseghin, Marco Carbone, Hirschfield, GM, Gill, P, Neuberger, J, Cristoferi, L, Ciardullo, S, Invernizzi, P, Perseghin, G, and Carbone, M
Subjects: endocrinology, type 2 diabetes mellitu, altered liver function test, non-alcohol fatty liver disease, liver disease, drug-induced liver injury
Abstract: The central function of the liver in the regulation of the metabolisms of hormones and nutrients makes it an integral part of the endocrine system. In everyday clinical practice, the endocrinologist usually encounters patients with altered liver function tests. This condition might be a cause or a consequence of the endocrine disease (e.g. type 2 diabetes mellitus, polycystic ovary syndrome), an associated condition as in the case of concomitant autoimmune diseases, a consequence of a specific pharmacological treatment, or an unrelated condition. In this chapter, we focus on the most common causes of alteration of liver function tests and provide indications on how to perform the first assessment of liver disease and when to refer patients to a hepatologist.
Published: 2022

15. Endocrinology and Metabolic Diseases (Including Diabetes)

Author: Hirschfield, GM, Gill, P, Neuberger, J, Cristoferi, L, Ciardullo, S, Invernizzi, P, Perseghin, G, Carbone, M, Laura Cristoferi, Stefano Ciardullo, Pietro Invernizzi, Gianluca Perseghin, Marco Carbone, Hirschfield, GM, Gill, P, Neuberger, J, Cristoferi, L, Ciardullo, S, Invernizzi, P, Perseghin, G, Carbone, M, Laura Cristoferi, Stefano Ciardullo, Pietro Invernizzi, Gianluca Perseghin, and Marco Carbone
Abstract: The central function of the liver in the regulation of the metabolisms of hormones and nutrients makes it an integral part of the endocrine system. In everyday clinical practice, the endocrinologist usually encounters patients with altered liver function tests. This condition might be a cause or a consequence of the endocrine disease (e.g. type 2 diabetes mellitus, polycystic ovary syndrome), an associated condition as in the case of concomitant autoimmune diseases, a consequence of a specific pharmacological treatment, or an unrelated condition. In this chapter, we focus on the most common causes of alteration of liver function tests and provide indications on how to perform the first assessment of liver disease and when to refer patients to a hepatologist.
Published: 2023

16. The Time is Ripe for a Randomized Controlled Trial of Oral Vancomycin in Primary Sclerosing Cholangitis

Author: Christine Halma, J, Cristoferi, L, Carbone, M, Jennifer Christine Halma, Laura Cristoferi, Marco Carbone, Christine Halma, J, Cristoferi, L, Carbone, M, Jennifer Christine Halma, Laura Cristoferi, and Marco Carbone
Published: 2023

17. X marks the spot in autoimmunity

Author: Alessio Gerussi, Chiara Caime, Eleonora Binatti, Claudio Cappadona, Laura Cristoferi, Rosanna Asselta, M. Eric Gershwin, Pietro Invernizzi, Gerussi, A, Caime, C, Binatti, E, Cappadona, C, Cristoferi, L, Asselta, R, Gershwin, M, and Invernizzi, P
Subjects: autoimmunity, Immunology, X-chromosome inactivation, escape from X-chromosome inactivation, Autoimmune Diseases, mammalian evolution, Genes, X-Linked, X Chromosome Inactivation, sex bia, Autoimmune disease, Humans, Immunology and Allergy, Female, sex chromosome
Abstract: Introduction: Autoimmune diseases mostly affect females. Besides hormones, several factors related to chromosome X have been called in action to explain this sex predominance. Areas covered: This paper provides an overview on the role of chromosome X (chrX) in explaining why females have higher susceptibility to autoimmunity. The work outlines some essential concepts regarding chrX inactivation, escape from chrX inactivation and the evolutionary history of chrX. In addition, we will discuss the concept of gene escape in immune cells, with examples related to specific X-linked genes and autoimmune diseases. Expert opinion: There is growing evidence that many genes present on chrX escape inactivation, and some of them have significant immune-mediated functions. In immune cells of female individuals the escape of these genes is not constant, but the knowledge of the mechanisms controlling this plasticity are not completely understood. Future studies aimed at the characterization of these modifications at single-cell resolution, together with conformational 3D studies of the inactive X chromosome, will hopefully help to fill this gap of knowledge.
Published: 2022

18. An update on novel pharmacological agents for primary sclerosing cholangitis

Author: Camilla Gallo, Bright Oworae Howardson, Laura Cristoferi, Marco Carbone, M. Eric Gershwin, Pietro Invernizzi, Gallo, C, Howardson, B, Cristoferi, L, Carbone, M, Gershwin, M, and Invernizzi, P
Subjects: Pharmacology, Cholangitis, Sclerosing, Clinical Biochemistry, fecal microbiota transplantation, gut–liver axi, Primary sclerosing cholangiti, anti-inflammatory agent, Gastrointestinal Microbiome, Liver Transplantation, Bile Acids and Salts, antibiotic, Drug Discovery, bile acid, Humans, Molecular Medicine
Abstract: Introduction: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic disease with heterogeneous phenotypes that may lead to liver transplantation and/or end-stage liver disease. Its multifactorial etiopathogenesis remains uncertain, but gut–liver axis and bile composition and excretion are widely demonstrated to influence the immune-mediated fibrogenic reactive cascade. Areas covered: Different experimental therapeutic options are under investigation, mainly aiming at modulating bile acids excretion, limiting inflammatory-cascade reactions, and changing intestinal microbiota composition; none of them yet demonstrated to prolong transplant-free survival. This review provides a comprehensive description of the experimental drugs recently tested and/or currently under investigation. A bibliographical search was performed in PubMed, MEDLINE, EMBASE, OVID, and clinicaltrial.gov until July 2021. Expert opinion: The heterogeneity and poor prevalence of PSC, its uncertain pathophysiology, and the lack of surrogate endpoints are the major challenges in drug discovery. Strategies that synergistically target microbiota, bile acids, and liver fibrosis are needed. In parallel, we must enhance biomarkers discovery to develop surrogate endpoints, as biochemical markers’ fluctuations over the time hamper their effectiveness. Magnetic resonance cholangiopancreatography tools that accurately measure bile duct changes represent a potential marker for disease monitoring. A collaboration between academia, research consortia, patient’s associations, and industry is required.
Published: 2022

19. Risk stratification in primary sclerosing cholangitis

Author: Pietro Invernizzi, Giacomo Mulinacci, Andrea Palermo, Martina Lucà, Marco Carbone, Laura Cristoferi, Alessio Gerussi, Mulinacci, G, Cristoferi, L, Palermo, A, Lucà, M, Gerussi, A, Invernizzi, P, and Carbone, M
Subjects: medicine.medical_specialty, sclerosing, business.industry, Endocrinology, Diabetes and Metabolism, Cholangiti, MEDLINE, Gastroenterology, Biomarker, medicine.disease, Primary sclerosing cholangitis, Liver disorder, Disease course, Clinical Practice, Liver disease, Risk stratification, Internal Medicine, Medicine, Diagnostic imaging, Biomarker discovery, business, Intensive care medicine
Abstract: Primary Sclerosing Cholangitis (PSC) is a chronic liver disorder commonly affecting young patients and associated with uncertain prognosis and elevated risk of end-stage liver disease and hepatobiliary cancer. Rate of progression in PSC is heterogeneous and accurately predicting the disease course is of paramount importance to clinical practice and interventional trial design. So far, efforts have brought to the development of models looking at short-to-middle-term outcome using composite models including clinical, laboratory, radiological and histological parameters with limited performance. In the era of whole genome sequencing and digital innovation, the time is ripe for the development of stratified medicine in PSC. Efforts should be directed toward developing wellphenotyped cohorts of patients with longitudinal follow-up across sustained periods of time, application of novel image-processing technology, and biomarker discovery using multi-omics platforms.
Published: 2023

20. 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

21. The Time is Ripe for a Randomized Controlled Trial of Oral Vancomycin in Primary Sclerosing Cholangitis

Author: Jennifer Christine Halma, Laura Cristoferi, Marco Carbone, Christine Halma, J, Cristoferi, L, and Carbone, M
Subjects: Hepatology, Primary Sclerosing Cholangitis, Gastroenterology
Published: 2022

22. Systematic review-pancreatic involvement in inflammatory bowel disease

Author: Sara Massironi, Ilaria Fanetti, Chiara Viganò, Lorena Pirola, Maria Fichera, Laura Cristoferi, Gabriele Capurso, Pietro Invernizzi, Silvio Danese, Massironi, S, Fanetti, I, Vigano, C, Pirola, L, Fichera, M, Cristoferi, L, Capurso, G, Invernizzi, P, and Danese, S
Subjects: Hepatology, Gastroenterology, Gallstones, Inflammatory Bowel Diseases, Inflammatory bowel disease, Autoimmune Diseases, Pancreatitis, Chronic, Acute Disease, Chronic Disease, Humans, Pharmacology (medical), Colitis, Ulcerative, Exocrine Pancreatic Insufficiency, pancreas
Abstract: Background: Inflammatory bowel disease (IBD) is a chronic inflammatory immune-mediated disorder of the gut with frequent extra-intestinal complications. Pancreatic involvement in IBD is not uncommon and comprises a heterogeneous group of conditions, including acute pancreatitis (AP), chronic pancreatitis (CP), autoimmune pancreatitis (AIP) and pancreatic exocrine insufficiency (PEI); however, data on such an association remain sparse and heterogeneous. Method: PubMed/MEDLINE and EMBASE databases were searched for studies investigating pancreatic involvement in patients with IBD. Results: Four thousand one hundred and twenty-one records were identified and 547 screened; finally, 124 studies were included in the review. AP is the most frequent pancreatic manifestation in IBD; the majority of AP cases in IBD are due to gallstones and drugs but cases of idiopathic AP are increasingly reported. AIP is a rare disease, but a strong association with IBD has been demonstrated, especially for type 2 and ulcerative colitis. The pathogenetic link between IBD and AIP remains unclear, but an immune-mediated pathway seems plausible. An association between CP and PEI with IBD has also been suggested, but data are to date scarce and conflicting. Conclusion: This is the first systematic review of the association between IBD and pancreatic diseases. Gallstones and drugs should be considered the most probable causes of AP in IBD, with type 2 AIP also being possible.
Published: 2022

23. Issue Cover

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, and Pietro Invernizzi
Subjects: Hepatology
Published: 2022

24. 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

25. LLM-PBC: Logic Learning Machine-Based Explainable Rules Accurately Stratify the Genetic Risk of Primary Biliary Cholangitis

Author: Alessio, Gerussi, Damiano, Verda, Claudio, Cappadona, Laura, Cristoferi, Davide Paolo, Bernasconi, Sandro, Bottaro, Marco, Carbone, Marco, Muselli, Pietro, Invernizzi, Rosanna, Asselta, On Behalf Of The Italian Pbc Genetics Study Group, Gerussi, A, Verda, D, Cappadona, C, Cristoferi, L, Bernasconi, D, Bottaro, S, Carbone, M, Muselli, M, Invernizzi, P, and Asselta, R
Subjects: genomic, genome-wide association study, machine learning, Hepatology, explainable artificial intelligence, precision medicine, autoimmunity, Gastroenterology, Medicine (miscellaneous), risk stratification, primary biliary cholangitis, liver, genomics, primary biliary cholangiti
Abstract: Background: The application of Machine Learning (ML) to genetic individual-level data represents a foreseeable advancement for the field, which is still in its infancy. Here, we aimed to evaluate the feasibility and accuracy of an ML-based model for disease risk prediction applied to Primary Biliary Cholangitis (PBC). Methods: Genome-wide significant variants identified in subjects of European ancestry in the recently released second international meta-analysis of GWAS in PBC were used as input data. Quality-checked, individual genomic data from two Italian cohorts were used. The ML included the following steps: import of genotype and phenotype data, genetic variant selection, supervised classification of PBC by genotype, generation of “if-then” rules for disease prediction by logic learning machine (LLM), and model validation in a different cohort. Results: The training cohort included 1345 individuals: 444 were PBC cases and 901 were healthy controls. After pre-processing, 41,899 variants entered the analysis. Several configurations of parameters related to feature selection were simulated. The best LLM model reached an Accuracy of 71.7%, a Matthews correlation coefficient of 0.29, a Youden’s value of 0.21, a Sensitivity of 0.28, a Specificity of 0.93, a Positive Predictive Value of 0.66, and a Negative Predictive Value of 0.72. Thirty-eight rules were generated. The rule with the highest covering (19.14) included the following genes: RIN3, KANSL1, TIMMDC1, TNPO3. The validation cohort included 834 individuals: 255 cases and 579 controls. By applying the ruleset derived in the training cohort, the Area under the Curve of the model was 0.73. Conclusions: This study represents the first illustration of an ML model applied to common variants associated with PBC. Our approach is computationally feasible, leverages individual-level data to generate intelligible rules, and can be used for disease prediction in at-risk individuals.
Published: 2022

26. Accuracy of Transient Elastography in Assessing Fibrosis at Diagnosis in Naïve Patients With Primary Biliary Cholangitis: A Dual Cut-Off Approach

Author: Cristina Rigamonti, Rosanna Venere, Carla De Benedittis, Guido Carpino, Pietro Invernizzi, Italian Pbc Registry, Elisabetta Degasperi, Giacomo Mulinacci, Marco Carbone, Sarah Elisabeth O’Donnell, Diletta Overi, Sara Labanca, Vito Di Marco, A. Ciaccio, Vincenzo Cardinale, Mauro Viganò, Andrea Palermo, Annarosa Floreani, Daphne D’Amato, Nora Cazzagon, Vincenzo Ronca, Donatella Barisani, Laura Cristoferi, Federica Malinverno, Marco Marzioni, Domenico Alvaro, Clara Mancuso, Vincenza Calvaruso, Anna Fichera, Martina Lucà, Federica Cerini, Alessandra Nardi, Eugenio Gaudio, Antonino Picciotto, Nicola Zucchini, Monica Leutner, Alessio Gerussi, Laura Cristoferi, Vincenza Calvaruso, Diletta Overi 5 , Mauro Viganò 6 , Cristina Rigamonti 7 , Elisabetta Degasperi 8 , Vincenzo Cardinale 9 , Sara Labanca 10 , Nicola Zucchini 11 , Anna Fichera, Vito Di Marco, Monica Leutner 12 , Rosanna Venere 13 , Antonino Picciotto 10 , Martina Lucà 1 2 , Giacomo Mulinacci 1 2 , Andrea Palermo 1 2 , Alessio Gerussi 1 2 , Daphne D'Amato 1 2 , Sarah Elisabeth O'Donnell 1 2 , Federica Cerini 6 , Carla De Benedittis 7 , Federica Malinverno 1 2 , Vincenzo Ronca 1 2 , Clara Mancuso 1 2 , Nora Cazzagon 14 , Antonio Ciaccio 1 2 , Donatella Barisani 1 , Marco Marzioni 15 , Annarosa Floreani 16 17 , Domenico Alvaro 9 , Eugenio Gaudio 5 , Pietro Invernizzi 1 2 , Guido Carpino # 18 , Alessandra Nardi # 19 , Marco Carbone, Cristoferi, L, Calvaruso, V, Overi, D, Viganò, M, Rigamonti, C, Degasperi, E, Cardinale, V, Labanca, S, Zucchini, N, Fichera, A, Di Marco, V, Leutner, M, Venere, R, Picciotto, A, Lucà, M, Mulinacci, G, Palermo, A, Gerussi, A, D'Amato, D, O'Donnell, S, Cerini, F, De Benedittis, C, Malinverno, F, Ronca, V, Mancuso, C, Cazzagon, N, Ciaccio, A, Barisani, D, Marzioni, M, Floreani, A, Alvaro, D, Gaudio, E, Invernizzi, P, Carpino, G, Nardi, A, and Carbone, M
Subjects: area under curve, 0301 basic medicine, medicine.medical_specialty, liver cirrhosis, Diagnostic accuracy, risk stratification, PBC, Gastroenterology, primary biliary cholangiti, elasticity imaging techniques, female, humans, biliary, male, middle aged, ROC curve, sensitivity and specificity, Therapy naive, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, medicine, Hepatology, Receiver operating characteristic, medicine.diagnostic_test, Liver Cirrhosis, Biliary, business.industry, Original Articles, medicine.disease, transient elastography, Autoimmune, Cholestatic and Biliary Disease, 030104 developmental biology, Liver biopsy, Cohort, Original Article, 030211 gastroenterology & hepatology, diagnostic accuracy, Cut-off, Transient elastography, business, fibrosi
Abstract: Background & aims Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis at disease presentation in PBC. Approach & results We collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy(LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves(AUROCs) for advanced fibrosis (Ludwig stage≥III). The effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. Derivation cohort consisted of 126 patients with valid LSM and LB, VCTE identified patients with advanced fibrosis with AUROC of 0.89. LSM cut-offs ≤6.5kPa and >11.0kPa enabled to exclude and confirm, respectively, advanced fibrosis (negative predictive value[NPV]=0.94, positive predictive value[PPV]=0.89, error rate=5.6%). These values were externally validated in an independent cohort of 91 PBC patients(NPV=0.93, PPV=0.89, error rate=8.6%). Multivariable analysis found the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions In a multicenter study of treatment-naive PBC patients, we identified two cut-offs (LSM≤6.5kPa and>11.0kPa) able to discriminate at diagnosis the presence or the absence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with LSM between these two cut-offs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.
Published: 2021

27. Effects of immunosuppressive drugs on COVID-19 severity in patients with autoimmune hepatitis

Author: George N. Dalekos, Cristina Rigamonti, Godolfino Miranda Zazueta, Ali Rıza Calışkan, Annarosa Floreani, Berat Ebik, Kadri Atay, Aylin Demirezer Bolat, Nazım Ekin, Eric M. Yoshida, Graciela Castro Narro, Fatih Güzelbulut, Murat Biyik, Manuel Mendizabal, Renumathy Dhanasekaran, Stefano Fagiuoli, Thomas D. Schiano, Ellina Lytvyak, Shalom Frager, Nataly Chris Escajadillo Vargas, Yucel Ustundag, Ramazan Idilman, Andreea M. Catana, Alvaro Urzúa, Ahmet Yavuz, Staffan Wahlin, Mesut Aydin, Cumali Efe, Laura Cristoferi, Hatef Massoumi, Maria Vincent, Sandro Ruiz Garcia, Evrim Kahramanoğlu-Aksoy, Natalia Ratusnu, Craig Lammert, Sümeyra Yıldırım, Mário Reis Álvares-da-Silva, Murat Harputoğlu, Marina Silveira, Murat Kiyici, Fátima Higuera-de la Tijera, Nurhan Demir, Cynthia Levy, Einar Bjornsson, Javier Brahm, Rotonya M. Carr, Nidah S. Khakoo, Andres Jose Gomez Aldana, Murat Akyildiz, Leyla Nazal, Alessio Gerussi, Tuğçe Eşkazan, Zeynep Ellik, Pietro Invernizzi, Fulya Gunsar, Ezequiel Ridruejo, Eleonora De Martin, Tugrul Purnak, Fatih Eren, Hüseyin Kaçmaz, Margarita Anders, Nikolaos K. Gatselis, Romee Snijders, Sezgin Barutçu, Costica Aloman, Alexandra Heurgue-Berlot, Bianca Magro, Jonathan Aguirre, Kader Irak, Koray Tascilar, Aldo J. Montano-Loza, Marcelo Silva, David N. Assis, Joost P.H. Drenth, Eira Cerda Reyes, Ibrahim Hatemi, Mirta Peralta, Sanjaya K. Satapathy, James L. Boyer, Yasemin H. Balaban, Efe, C, Lammert, C, Tascilar, K, Dhanasekaran, R, Ebik, B, Higuera-de la Tijera, F, Caliskan, A, Peralta, M, Gerussi, A, Massoumi, H, Catana, A, Purnak, T, Rigamonti, C, Aldana, A, Khakoo, N, Nazal, L, Frager, S, Demir, N, Irak, K, Melekoglu-Ellik, Z, Kacmaz, H, Balaban, Y, Atay, K, Eren, F, Alvares-da-Silva, M, Cristoferi, L, Urzua, A, Eskazan, T, Magro, B, Snijders, R, Barutcu, S, Lytvyak, E, Zazueta, G, Demirezer-Bolat, A, Aydin, M, Heurgue-Berlot, A, De Martin, E, Ekin, N, Yildirim, S, Yavuz, A, Biyik, M, Narro, G, Kiyici, M, Akyildiz, M, Kahramanoglu-Aksoy, E, Vincent, M, Carr, R, Gunsar, F, Reyes, E, Harputluoglu, M, Aloman, C, Gatselis, N, Ustundag, Y, Brahm, J, Vargas, N, Guzelbulut, F, Garcia, S, Aguirre, J, Anders, M, Ratusnu, N, Hatemi, I, Mendizabal, M, Floreani, A, Fagiuoli, S, Silva, M, Idilman, R, Satapathy, S, Silveira, M, Drenth, J, Dalekos, G, Assis, D, Bjornsson, E, Boyer, J, Yoshida, E, Invernizzi, P, Levy, C, Montano-Loza, A, Schiano, T, Ridruejo, E, Wahlin, S, Akyıldız, Murat (ORCID 0000-0002-2080-7528 & YÖK ID 123080), Efe, Cumalı, Lammert, Craig, Taşçılar, Koray, Dhanasekaran, Renumathy, Ebik, Berat, Higuera-de la Tijera, Fatima, Çalışkan, Ali R., Peralta, Mirta, Gerussi, Alessio, Massoumi, Hatef, Catana, Andreea M., Purnak, Tuğrul, Rigamonti, Cristina, Aldana, Andres J. G., Khakoo, Nidah, Nazal, Leyla, Frager, Shalom, Demir, Nurhan, Irak, Kader, Melekoğlu-Ellik, Zeynep, Kaçmaz, Hüseyin, Balaban, Yasemin, Atay, Kadri, Eren, Fatih, Alvares-da-Silva, Mario R., Cristoferi, Laura, Urzua, Alvaro, Eskazan, Tugce, Magro, Bianca, Snijders, Romee, Barutçu, Sezgin, Lytvyak, Ellina, Zazueta, Godolfino M., Demirezer-Bolat, Aylin, Aydın, Mesut, Heurgue-Berlot, Alexandra, De Martin, Eleonora, Ekin, Nazım, Yıldırım, Sumeyra, Yavuz, Ahmet, Bıyık, Murat, Narro, Graciela C., Kıyıcı, Murat, Kahramanoğlu-Aksoy, Evrim, Vincent, Maria, Carr, Rotonya M., Günsar, Fulya, Reyes, Eira C., Harputluoğlu, Murat, Aloman, Costica, Gatselis, Nikolaos K., Üstündağ, Yücel, Brahm, Javier, Vargas, Nataly C. E., Güzelbulut, Fatih, Garcia, Sandro R., Aguirre, Jonathan, Anders, Margarita, Ratusnu, Natalia, Hatemi, İbrahim, Mendizabal, Manuel, Floreani, Annarosa, Fagiuoli, Stefano, Silva, Marcelo, İdilman, Ramazan, Satapathy, Sanjaya K., Silveira, Marina, Drenth, Joost P. H., Dalekos, George N., Assis, David N., Bjornsson, Einar, Boyer, James L., Yoshida, Eric M., Invernizzi, Pietro, Levy, Cynthia, Montano-Loza, Aldo J., Schiano, Thomas D., Ridruejo, Ezequiel, Wahlin, Staffan, and School of Medicine
Subjects: Adult, Male, medicine.medical_specialty, budesonide, Cirrhosis, Adolescent, Gastroenterology and hepatology, medicine.medical_treatment, Azathioprine, Autoimmune hepatitis, mercaptopurine, Liver transplantation, Gastroenterology, Young Adult, Sars-Cov-2 Infection, Internal medicine, medicine, Humans, Autoimmunity, Budesonide, Mercaptopurine, SARS-CoV-2, Aged, Retrospective Studies, Mechanical ventilation, Aged, 80 and over, azathioprine, liver transplantation, Hepatology, business.industry, autoimmunity, COVID-19, Immunosuppression, Odds ratio, Middle Aged, medicine.disease, Tacrolimus, Liver-Transplant Recipients, Hospitalization, Hepatitis, Autoimmune, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Pharmaceutical Preparations, Female, business, medicine.drug
Abstract: Background We investigated associations between baseline use of immunosuppressive drugs and severity of Coronavirus Disease 2019 (COVID-19) in autoimmune hepatitis (AIH). Patients and methods Data of AIH patients with laboratory confirmed COVID-19 were retrospectively collected from 15 countries. The outcomes of AIH patients who were on immunosuppression at the time of COVID-19 were compared to patients who were not on AIH medication. The clinical courses of COVID-19 were classified as (i)-no hospitalization, (ii)-hospitalization without oxygen supplementation, (iii)-hospitalization with oxygen supplementation by nasal cannula or mask, (iv)-intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v)-ICU admission with invasive mechanical ventilation or (vi)-death and analysed using ordinal logistic regression. Results We included 254 AIH patients (79.5%, female) with a median age of 50 (range, 17-85) years. At the onset of COVID-19, 234 patients (92.1%) were on treatment with glucocorticoids (n = 156), thiopurines (n = 151), mycophenolate mofetil (n = 22) or tacrolimus (n = 16), alone or in combinations. Overall, 94 (37%) patients were hospitalized and 18 (7.1%) patients died. Use of systemic glucocorticoids (adjusted odds ratio [aOR] 4.73, 95% CI 1.12-25.89) and thiopurines (aOR 4.78, 95% CI 1.33-23.50) for AIH was associated with worse COVID-19 severity, after adjusting for age-sex, comorbidities and presence of cirrhosis. Baseline treatment with mycophenolate mofetil (aOR 3.56, 95% CI 0.76-20.56) and tacrolimus (aOR 4.09, 95% CI 0.69-27.00) were also associated with more severe COVID-19 courses in a smaller subset of treated patients. Conclusion Baseline treatment with systemic glucocorticoids or thiopurines prior to the onset of COVID-19 was significantly associated with COVID-19 severity in patients with AIH., Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic), A. Gerussi, L. Cristoferi, and P. Invernizzi acknowledge that this research was partially supported by the Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic).
Published: 2021

28. Corrigendum to ‘An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs’ [J Hepatol 2021;75(3):572–581]

Author: Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byun, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, Maria Consiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton V.J. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris D.J. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom J.W. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch'ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, and Charles Millson
Subjects: Science & Technology, Hepatology, Gastroenterology & Hepatology, Italian PBC Study Group, Japan-PBC-GWAS Consortium, UK-PBC Consortium, Chinese PBC Consortium, 1103 Clinical Sciences, US PBC Consortium, Canadian PBC Consortium, Life Sciences & Biomedicine, PBC Consortia, 1117 Public Health and Health Services
Published: 2021

29. PTU-46 Safety and efficacy of fully covered metallic stent placement for patients with primary sclerosing cholangitis

Author: Giulia Bonato, Richard Sturgess, Laura Cristoferi, Sinan Sadalla, Massimiliano Mutignani, Douglas Thorburn, Jonathan Potts, Pietro Invernizzi, Leonardo Henry Eusebi, and Laura K. Dwyer
Subjects: medicine.medical_specialty, Stent placement, business.industry, medicine, business, medicine.disease, Surgery, Primary sclerosing cholangitis
Published: 2021

30. SARS-CoV-2 vaccination and risk of severe COVID-19 outcomes in patients with autoimmune hepatitis

Author: Cumali Efe, Koray Taşçılar, Alessio Gerussi, Francesca Bolis, Craig Lammert, Berat Ebik, Albert Friedrich Stättermayer, Mustafa Cengiz, Dilara Turan Gökçe, Laura Cristoferi, Mirta Peralta, Hatef Massoumi, Pedro Montes, Eira Cerda, Cristina Rigamonti, Suna Yapalı, Gupse Adali, Ali Rıza Çalışkan, Yasemin Balaban, Fatih Eren, Tuğçe Eşkazan, Sezgin Barutçu, Ellina Lytvyak, Godolfino Miranda Zazueta, Meral Akdogan Kayhan, Alexandra Heurgue-Berlot, Eleonora De Martin, Ahmet Yavuz, Murat Bıyık, Graciela Castro Narro, Serkan Duman, Nelia Hernandez, Nikolaos K. Gatselis, Jonathan Aguirre, Ramazan Idilman, Marcelo Silva, Manuel Mendizabal, Kadri Atay, Fatih Güzelbulut, Renumathy Dhanasekaran, Aldo J. Montano-Loza, George N. Dalekos, Ezequiel Ridruejo, Pietro Invernizzi, Staffan Wahlin, Acibadem University Dspace, Efe, C, Tascilar, K, Gerussi, A, Bolis, F, Lammert, C, Ebik, B, Stattermayer, A, Cengiz, M, Gokce, D, Cristoferi, L, Peralta, M, Massoumi, H, Montes, P, Cerda, E, Rigamonti, C, Yapali, S, Adali, G, Caliskan, A, Balaban, Y, Eren, F, Eskazan, T, Barutcu, S, Lytvyak, E, Zazueta, G, Kayhan, M, Heurgue-Berlot, A, De Martin, E, Yavuz, A, Biyik, M, Narro, G, Duman, S, Hernandez, N, Gatselis, N, Aguirre, J, Idilman, R, Silva, M, Mendizabal, M, Atay, K, Guzelbulut, F, Dhanasekaran, R, Montano-Loza, A, Dalekos, G, Ridruejo, E, Invernizzi, P, and Wahlin, S
Subjects: Adult, Aged, 80 and over, Male, COVID-19 Vaccines, Adolescent, SARS-CoV-2, Vaccination, Immunology, Liver failure, COVID-19, Autoimmunity, Middle Aged, Breakthrough infection, Young Adult, Hepatitis, Autoimmune, COVID-19 Testing, Humans, Immunology and Allergy, Female, Vaccine, BNT162 Vaccine, Immunosuppression, Aged, Retrospective Studies
Abstract: Background: Data regarding outcome of Coronavirus disease 2019 (COVID-19) in vaccinated patients with autoimmune hepatitis (AIH) are lacking. We evaluated the outcome of COVID-19 in AIH patients who received at least one dose of Pfizer- BioNTech (BNT162b2), Moderna (mRNA-1273) or AstraZeneca (ChAdOx1-S) vaccine. Patients and methods: We performed a retrospective study on AIH patients with COVID-19. The outcomes of AIH patients who had acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection after at least one dose of COVID-19 vaccine were compared to unvaccinated patients with AIH. COVID-19 outcome was classified according to clinical state during the disease course as: (i) no hospitalization, (ii) hospitalization without oxygen supplementation, (iii) hospitalization with oxygen supplementation by nasal cannula or mask, (iv) intensive care unit (ICU) admission with non-invasive mechanical ventilation, (v) ICU admission with invasive mechanical ventilation or (vi) death, and data was analyzed using ordinal logistic regression. Results: We included 413 (258 unvaccinated and 155 vaccinated) patients (81\%, female) with a median age of 52 (range: 17-85) years at COVID-19 diagnosis. The rates of hospitalization were (36.4\% vs. 14.2\%), need for any supplemental oxygen (29.5\% vs. 9\%) and mortality (7\% vs. 0.6\%) in unvaccinated and vaccinated AIH patients with COVID-19. Having received at least one dose of SARS-CoV-2 vaccine was associated with a significantly lower risk of worse COVID-19 severity, after adjusting for age, sex, comorbidities and presence of cirrhosis (adjusted odds ratio {[}aOR] 0.18, 95\% confidence interval {[}CI], 0.10-0.31). Overall, vaccination against SARSCoV-2 was associated with a significantly lower risk of mortality from COVID-19 (aOR 0.20, 95\% CI 0.11-0.35). Conclusions: SARS-CoV-2 vaccination significantly reduced the risk of COVID-19 severity and mortality in patients with AIH.
Published: 2022

31. Precision medicine in primary biliary cholangitis

Author: Marco Carbone, Laura Cristoferi, Alessio Gerussi, Vincenzo Ronca, Pietro Invernizzi, Ronca, V, Gerussi, A, Cristoferi, L, Carbone, M, and Invernizzi, P
Subjects: medicine.medical_specialty, precision medicine, omic, risk stratification, Chenodeoxycholic Acid, primary biliary cholangiti, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Gastrointestinal Agents, Health care, medicine, Humans, Intensive care medicine, Liver Cirrhosis, Biliary, business.industry, Gastroenterology, Obeticholic acid, Precision medicine, Omics, Clinical Practice, chemistry, 030220 oncology & carcinogenesis, Precision Medicine Initiative, Risk stratification, Disease Progression, 030211 gastroenterology & hepatology, business
Abstract: For many years the one-size-fits-all approach has been the only one available to manage patients affected by primary biliary cholangitis. The introduction of obeticholic acid in 2016 as a second-line treatment, together with the creation and validation of several biochemically based scores to stratify the risk of progressive disease, has opened up the need to redefine clinical practice by changing the actual paradigm. The precision medicine initiative is a model of patient-centered health care that aims to improve medicine based on genotypic and molecular characteristics that correlate to specific phenotypic, individual characteristics. In summary, the aim of the precision medicine is to define the right treatment for the right person at the right time. The availability of a second-line disease-modifying drug and new molecules in phase 2 or 3 trials makes this an exciting time for the precision medicine initiative in primary biliary cholangitis. In this review we describe the current risk stratification tools and we track a possible path towards the application of precision medicine in clinical daily life.
Published: 2019

32. Prognostic models in primary biliary cholangitis

Author: George F. Mells, Ronca, Marco Carbone, Pietro Invernizzi, Alessandra Nardi, Laura Cristoferi, Cristoferi, L, Nardi, A, Ronca, V, Invernizzi, P, Mells, G, and Carbone, M
Subjects: 0301 basic medicine, Cholagogues and Choleretics, medicine.medical_specialty, Prognostic variable, Prognostic models, Immunology, Disease, Risk Assessment, Settore MED/01 - Statistica Medica, Machine Learning, 03 medical and health sciences, 0302 clinical medicine, MED/12 - GASTROENTEROLOGIA, Risk Factors, medicine, Animals, Humans, Metabolomics, Immunology and Allergy, Precision Medicine, Biomarker discovery, Intensive care medicine, Risk management, Settore MED/12 - Gastroenterologia, Models, Statistical, Whole Genome Sequencing, Liver Cirrhosis, Biliary, business.industry, Alkaline phosphatase, Personalised medicine, Primary biliary cholangitis, Risk prediction, Ursodeoxycholic Acid, Genomics, Alkaline Phosphatase, Prognosis, Molecular diagnostics, Omics, Clinical trial, Treatment Outcome, 030104 developmental biology, Primary biliary cholangiti, 030211 gastroenterology & hepatology, Prognostic model, business, Risk assessment, Biomarkers
Abstract: Risk prediction modelling is important to better understand the determinants of the course and outcome of PBC and to inform the risk across the disease continuum in PBC enabling risk-stratified follow-up care and personalised therapy. Current prognostic models in PBC are based on treatment response to ursodeoxycholic acid because of the well-established relationship between alkaline phosphatase on treatment and long-term outcome. In addition, serum alkaline phosphatase correlates with ductular reaction and biliary metaplasia, which are hallmark of biliary injury. Considering the waiting time for treatment failure in high-risk patients is not inconsequential, efforts are focused on bringing forward risk stratification at diagnosis by predicting treatment response at onset. There is a need for better prognostic variables that are central to the disease process. We should take an integrative approach that incorporates multiple layers of information including genetic and environmental influences, host characteristics, clinical data, and molecular alterations for risk assessments. Biomarker discovery has an accelerated pace taking advantage of the emergence of large-scale omics platforms (genomics, epigenomics, transcriptomics, proteomics, metabolomics, and others) and whole-genome sequencing. In the digital era, applications of artificial intelligence, such as machine learning, can support the computing power required to analyse the vast amount of data produced by omics. The information is then used for the development of personalised risk prediction models that through clinical trials and hopefully industry partnerships can guide risk management strategies. We are facing an unprecedented opportunity for the integration of molecular diagnostics into the clinic, which promotes progress toward the personalised management of patients with PBC.
Published: 2018

33. The immunobiology of female predominance in primary biliary cholangitis

Author: Alessio Gerussi, Rosanna Asselta, Laura Cristoferi, Marco Carbone, Pietro Invernizzi, Gerussi, A, Cristoferi, L, Carbone, M, Asselta, R, and Invernizzi, P
Subjects: Male, 0301 basic medicine, Immunology, ARE-Del−/− mice, Gene Expression, Autoimmunity, Disease, Biology, medicine.disease_cause, Bioinformatics, Autoimmune Diseases, Epigenesis, Genetic, Interferon-gamma, Mice, 03 medical and health sciences, Sex Factors, 0302 clinical medicine, HLA Antigens, T-Lymphocyte Subsets, medicine, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Epigenetics, Microbiome, Gonadal Steroid Hormones, X chromosome, Mice, Knockout, Chromosomes, Human, X, Liver Cirrhosis, Biliary, Epigenetic, Microchimerism, Epigenome, Phenotype, Female preponderance, Disease Models, Animal, 030104 developmental biology, Primary biliary cholangiti, 030220 oncology & carcinogenesis, Female, Sex chromosome
Abstract: Primary biliary cholangitis (PBC) is an autoimmune liver disease with a striking female preponderance. The mechanisms behind this predominance are still to be elucidated, although multiple theories have been postulated and investigated. Among the proposed involved factors, sex hormones have been the first to be studied, but unfortunately data have been inconclusive or conflicting. Similarly, fetal microchimerism has received a huge attention in the past, but data in PBC have been unsatisfactory especially if compared to other autoimmune diseases like systemic lupus erythematosus. Studies focused on genetic factors have generated more intriguing and robust data, reporting a few abnormalities on the X chromosome in PBC patients. However, these data are able to explain only a part of the phenotypic variability attributed to the genetic component, and most importantly, need to be validated in larger series. More recently, a novel mice model of PBC, characterised by a constitutive expression of Interferon-γ (IFN-γ), has been developed and it is notable for being the first one with female predominance. At the same time, there has been a wide interest in the role of microbiome in health and disease, as well as in epigenetics, which have tried to explain differences in biological phenotypes not covered by genetics. The aim of this review is to outline established knowledge on the topic and try to provide novel perspectives on the potential future applications of newer techniques addressing microbiome and epigenome, in order to further understand the biology of sex divergence in PBC.
Published: 2018

34. Transient elastography in chronic liver disease: Beware of the cut-offs!

Author: Laura Cristoferi, Alessandra Nardi, Marco Carbone, Cristoferi, L, Nardi, A, and Carbone, M
Subjects: Liver Cirrhosis, Pathology, medicine.medical_specialty, Hepatology, business.industry, Liver fibrosis, Liver Diseases, liver fibrosi, Chronic liver disease, medicine.disease, non-invasive liver fibrosis marker, transient elastography, dual cut-off, medicine, Elasticity Imaging Techniques, Humans, Transient elastography, business
Published: 2021

35. Issue Cover

Author: Laura Cristoferi, Alessio Gerussi, and Pietro Invernizzi
Subjects: Hepatology
Published: 2021

36. AF.63 PANCREATIC INVOLVEMENT IN INFLAMMATORY BOWEL DISEASE: AUTOIMMUNITY AND BEYOND

Author: I. Fanetti, L. Pirola, M. Fichera, Chiara Viganò, Pietro Invernizzi, Sara Massironi, and Laura Cristoferi
Subjects: Hepatology, business.industry, Immunology, Gastroenterology, Medicine, business, medicine.disease_cause, medicine.disease, Inflammatory bowel disease, Autoimmunity
Published: 2021

37. Elastography in Autoimmune Liver Diseases

Author: Marco Carbone, Laura Cristoferi, and Pietro Invernizzi
Subjects: medicine.medical_specialty, Cirrhosis, medicine.diagnostic_test, business.industry, Retrospective cohort study, Autoimmune hepatitis, medicine.disease, Gastroenterology, Primary sclerosing cholangitis, Cholestasis, Fibrosis, Internal medicine, Medicine, Elastography, business, Transient elastography
Abstract: Non-invasive assessment of fibrosis is a key step in prognostication and monitoring of patients with autoimmune liver diseases (AILDs). Vibration-controlled transient elastography (VCTE) has been the most widely used tool of fibrosis staging which showed high accuracy in identifying advanced fibrosis and cirrhosis in AILD. However, evidence about its accuracy are often based on retrospective cohort studies with small samples. Furthermore, the role of potential confounding factors (i.e. liver inflammation and cholestasis) has not been fully established yet. In this chapter, we review the evidence on the use of VCTE in AILDs focusing on strengths and limitations.
Published: 2021

38. Takayasu arteritis and primary sclerosing cholangitis: A casual association or different phenotypes of the same disease?

Author: Laura Cristoferi, Andrea Palermo, Marco Carbone, Giacomo Mulinacci, Pietro Invernizzi, Mulinacci, G, Palermo, A, Cristoferi, L, Invernizzi, P, and Carbone, M
Subjects: Vasculitis, medicine.medical_specialty, Vasculiti, Short communication, Immunology, Takayasu arteritis, Disease, Gastroenterology, Inflammatory bowel disease, Disease course, Primary sclerosing cholangitis, Takayasu arteriti, Pathogenesis, Internal medicine, medicine, Immunology and Allergy, cardiovascular diseases, skin and connective tissue diseases, Bile duct, business.industry, Primary sclerosing cholangiti, RC581-607, medicine.disease, Phenotype, medicine.anatomical_structure, Etiology, Immunologic diseases. Allergy, business
Abstract: Takayasu arteritis and primary sclerosing cholangitis are two rare disorders. The pathogenesis of Takayasu arteritis involves immune-mediated mechanisms, and corticosteroids represent the mainstay for treatment. Conversely, the aetiology of primary sclerosing cholangitis remains elusive, even if dysimmunity seems to be one of the contributors to bile duct damage. Despite this, immunosuppressants do not alter disease course. In this paper we describe the association of these two rare disorders, with an unexpected normalization of cholestatic enzymes following steroid treatment. This might hint a novel subtype of sclerosing cholangitis with a prevalent immunebackground, or a local manifestation of Takayasu arteritis., Highlights • Unusual association of two rare entities: PSC (supported by the presence of IBD) and TA. • Onset of Takayasu after PSC diagnosis. • Lack of response to UDCA and fibrates. • Improvement of liver function tests after steroid treatment. • No changes on biliary tree reported on MRCP.
Published: 2021

39. Outcome of COVID-19 in Patients With Autoimmune Hepatitis: An International Multicenter Study

Author: Fátima Higuera-de la Tijera, Renumathy Dhanasekaran, Mirta Peralta, C. Levy, Laura Cristoferi, Hüseyin Kaçmaz, Romee Snijders, David N. Assis, Cristina Rigamonti, Ali Rıza Calışkan, Nidah S. Khakoo, Alessio Gerussi, Alvaro Urzúa, Ezequiel Ridruejo, Yasemin H. Balaban, Craig Lammert, Ersin Batıbay, Kader Irak, Thomas D. Schiano, Marina Silveira, Fatih Eren, Berat Ebik, Kadri Atay, Andreea M. Catana, Cumali Efe, Staffan Wahlin, Murat Harputluoglu, Ibrahim Hatemi, Einar Bjornsson, Nurhan Demir, Murat Akyildiz, Manuel Mendizabal, Murat Kiyici, Costica Aloman, Rotonya M. Carr, Nazım Ekin, Ramazan Idilman, Marcelo Silva, Andres Jose Gomez Aldana, James L. Boyer, Murat Torgutalp, Tugrul Purnak, Zeynep Ellik, Leyla Nazal, Shalom Frager, Joost P.H. Drenth, Hatef Massoumi, Pietro Invernizzi, Efe, C, Dhanasekaran, R, Lammert, C, Ebik, B, Higuera-de la Tijera, F, Aloman, C, Riza Caliskan, A, Peralta, M, Gerussi, A, Massoumi, H, Catana, A, Torgutalp, M, Purnak, T, Rigamonti, C, Gomez Aldana, A, Khakoo, N, Kacmaz, H, Nazal, L, Frager, S, Demir, N, Irak, K, Ellik, Z, Balaban, Y, Atay, K, Eren, F, Cristoferi, L, Batibay, E, Urzua, A, Snijders, R, Kiyici, M, Akyildiz, M, Ekin, N, Carr, R, Harputluoglu, M, Hatemi, I, Mendizabal, M, Silva, M, Idilman, R, Silveira, M, Drenth, J, Assis, D, Bjornsson, E, Boyer, J, Invernizzi, P, Levy, C, Schiano, T, Ridruejo, E, Wahlin, S, Akyıldız, Murat, Efe, C., Dhanasekaran, R., Lammert, C., Ebi, B., Higuera-de la Tijera, F., Aloman, C., Çalışkan, A. R., Peralta, M., Gerussi, A., Massoumi, H., Catana, A. M., Torgutalp, M., Pürnak T., Rigamonti, C., Aldana, A. J. G., Khakoo, N., Kaçmaz, H., Nazal, L., Frager, S., Demir, N., Irak, K., Ellik, Z. M., Balaban, Y., Atay, K., Eren, F., Cristoferi, L., Batıbay, E., Urzua, Á., Snijders, R., Kıyıcı, M., Ekin, N., Carr, R. M., Harputoğlu, M., Hatemi, İ., Mendizabal, M., Silva, M., İdilman, R., Silveira, M., Drenth, J. P. H., Assis, D. N., Björnsson, E., Boyer, J. L., Invernizzi, P., Levy, C., Schiano, T. D., Ridruejo, E., Wahlin, S., and School of Medicine
Subjects: Adult, Male, medicine.medical_specialty, Cirrhosis, Adolescent, medicine.medical_treatment, America, Autoimmune hepatitis, Liver transplantation, liver, Gastroenterology, Young Adult, AIH, Retrospective Studie, Internal medicine, purl.org/becyt/ford/3.2 [https], medicine, Humans, Propensity Score, Determinants, Retrospective Studies, Aged, Hepatitis, Liver injury, Aged, 80 and over, Hepatology, business.industry, COVID-19, Immunosuppression, Retrospective cohort study, Middle Aged, medicine.disease, Autoimmunity, Liver failure, Mycophenolate mofetil, Steroids, Tacrolimus, Europe, Hepatitis, Autoimmune, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Cohort, Female, purl.org/becyt/ford/3 [https], Americas, Erratum, business, Rapid Communication, Human
Abstract: Background: data regarding outcome of Coronavirus disease 2019 (COVID-19) in patients with autoimmune hepatitis (AIH) are lacking. Patients and methods: we performed a retrospective study on AIH patients with COVID-19 from 34 centres in Europe and the Americas. We analyzed factors associated with severe COVID-19 outcomes defined as the need for mechanical ventilation, intensive care admission, and/or death. The outcomes of patients with AIH were compared to a propensity-score matched cohort of non-AIH patients with chronic liver diseases (CLD) and COVID-19. The frequency and clinical significance of new-onset liver injury (alanine aminotransferase>2xupper limit of normal) during COVID-19 was also evaluated. Results: we included 110 AIH patients (80%,female) with a median age of 49 (range:18-85) years at COVID-19 diagnosis. New-onset liver injury was observed in 37.1% (33/89) of the patients. Use of antivirals was associated with liver injury (p=0.041; odds ratio (OR) 3.36[1.05-10.78]) while continued immunosuppression during COVID-19 was associated with a lower rate of liver injury (p=0.009; OR 0.26[0.09-0.71]). The rates of severe COVID-19 (15.5% vs 20.2% p=0.231) and all-cause mortality (10% vs 11.5%; p=0.852) were not different between AIH and non-AIH CLD. Cirrhosis was an independent predictor of severe COVID-19 in patients with AIH (p, Italian Ministry of University; Research (MIUR)-Department of Excellence Project PREMIA; AMAF Monza ONLUS; AIRCS
Published: 2021

40. Primary Sclerosing Cholangitis

Author: Pietro Invernizzi, Marco Carbone, Alessio Gerussi, Laura Cristoferi, Floreani, A, Cristoferi, L, Gerussi, A, Carbone, M, and Invernizzi, P
Subjects: medicine.medical_specialty, endocrine system diseases, Colorectal cancer, Inflammation, digestive system, Inflammatory bowel disease, Gastroenterology, Primary sclerosing cholangitis, Cholangiocarcinoma, Fibrosis, Internal medicine, Medicine, Risk stratification, business.industry, Gallbladder, digestive, oral, and skin physiology, Primary sclerosing cholangiti, medicine.disease, digestive system diseases, Gut-liver axi, medicine.anatomical_structure, Hepatocellular carcinoma, Cholestatic liver disease, medicine.symptom, business
Abstract: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive biliary inflammation and fibrosis. PSC has a strong association with inflammatory bowel disease (IBD), which is diagnosed in 60-80% of patients. The coexistence of the PSC and IBD increases the risk for colorectal cancer (CRC). Furthermore, PSC predisposes to the occurrence of other neoplastic conditions, such as cholangiocarcinoma (CCA), gallbladder, and hepatocellular carcinoma. The pathogenesis of PSC is still unclear. Current evidence supports a multifactorial etiology, where genetic predisposition, altered gut microbiota, and immune-mediated phenomena play a crucial role. The highly variable natural history of PSC, with possible intercurrent clinical events (e.g., cholangitis, biliary lithiasis) that could be dissociated from the severity of underlying liver disease with consequent fluctuant clinical symptoms and serum cholestasis marker, makes the prognostic assessment of these patients challenging. To date, no effective medical therapy has been registered, and liver transplantation is the only therapeutic option in patients developing end-stage liver disease. In this chapter, we describe epidemiological and clinical features of PSC, current understanding of its pathogenesis, and address challenges and opportunities associated with its management while focusing on risk stratification.
Published: 2021

41. Real-world experience with obeticholic acid in patients with primary biliary cholangitis

Author: Anna Morgando, Mauro Viganò, Ana Lleo, Maurizio Pompili, Elisabetta De Gasperi, Daphne D’Amato, Alessandro Mussetto, Nora Cazzagon, Pietro Invernizzi, Francesca Colapietro, Vincenzo Ronca, Sara Labanca, Ester Vanni, M.R. Cannavò, Francesco Losito, Ernesto Claar, G. Scifo, Giovanni Galati, Umberto Vespasiani-Gentilucci, Silvia Storato, Alessio Gerussi, Grazia Anna Niro, Antonio Izzi, Barbara Omazzi, Antonio De Vincentis, Valentina Feletti, Giuseppe Grassi, Valeria Pace Palitti, Clara Mancuso, Vincenza Calvaruso, Evelise Frazzetto, Roberto Boldizzoni, Marco Marzioni, Floriano Rosina, Andrea Palermo, Antonino Picciotto, Valentina Bellia, Gaetano Bertino, Italian Pbc Registry, Guido Poggi, Rodolfo Sacco, Domenico Alvaro, Luigi Muratori, Maria Vinci, Marie Graciella Pigozzi, Raffaele Cozzolongo, Natalia Terreni, Annarosa Floreani, Maurizio Russello, Marco Distefano, Rinaldo Pellicano, Maria D'Antò, Marco Carbone, Rosanna Venere, R. Fontana, Antonio Picardi, Silvia Casella, S. E. O'Donnell, Federica Malinverno, Stefano Fagiuoli, Laura Cristoferi, Luchino Chessa, Giacomo Mulinacci, Pietro Pozzoni, Antonino Castellaneta, Giulia Marconi, Adriano M. Pellicelli, Francesca Romana Ponziani, Leonardo Baiocchi, D'Amato, D, De Vincentis, A, Malinverno, F, Vigano, M, Alvaro, D, Pompili, M, Picciotto, A, Palitti, V, Russello, M, Storato, S, Pigozzi, M, Calvaruso, V, De Gasperi, E, Lleo, A, Castellaneta, A, Pellicelli, A, Cazzagon, N, Floreani, A, Muratori, L, Fagiuoli, S, Niro, G, Feletti, V, Cozzolongo, R, Terreni, N, Marzioni, M, Pellicano, R, Pozzoni, P, Baiocchi, L, Chessa, L, Rosina, F, Bertino, G, Vinci, M, Morgando, A, Vanni, E, Scifo, G, Sacco, R, D'Anto, M, Bellia, V, Boldizzoni, R, Casella, S, Omazzi, B, Poggi, G, Cristoferi, L, Gerussi, A, Ronca, V, Venere, R, Ponziani, F, Cannavo, M, Mussetto, A, Fontana, R, Losito, F, Frazzetto, E, Distefano, M, Colapietro, F, Labanca, S, Marconi, G, Grassi, G, Galati, G, O'Donnell, S, Mancuso, C, Mulinacci, G, Palermo, A, Claar, E, Izzi, A, Picardi, A, Invernizzi, P, Carbone, M, Vespasiani-Gentilucci, U, D'Amato D, De Vincentis A, Malinverno F, Viganò M, Alvaro D, Pompili M, Picciotto A, Palitti VP, Russello M, Storato S, Pigozzi MG, Calvaruso V, De Gasperi E, Lleo A, Castellaneta A, Pellicelli A, Cazzagon N, Floreani A, Muratori L, Fagiuoli S, Niro GA, Feletti V, Cozzolongo R, Terreni N, Marzioni M, Pellicano R, Pozzoni P, Baiocchi L, Chessa L, Rosina F, Bertino G, Vinci M, Morgando A, Vanni E, Scifo G, Sacco R, D'Antò M, Bellia V, Boldizzoni R, Casella S, Omazzi B, Poggi G, Cristoferi L, Gerussi A, Ronca V, Venere R, Ponziani F, Cannavò M, Mussetto A, Fontana R, Losito F, Frazzetto E, Distefano M, Colapietro F, Labanca S, Marconi G, Grassi G, Galati G, O'Donnell SE, Mancuso C, Mulinacci G, Palermo A, Claar E, Izzi A, Picardi A, Invernizzi P, Carbone M, Vespasiani-Gentilucci U, and Italian PBC Registry and the Club Epatologi Ospedalieri (CLEO)/Associazione Italiana Gastroenterologi ed Endoscopisti Digestivi Ospedalieri (AIGO) PBC Study Group.
Subjects: upper limit of normal, Cirrhosis, ALT, AMA, Autoimmunity, antinuclear antibodies, ULN, PBC, Gastroenterology, UDCA, Settore MED/12, ULN, upper limit of normal, obeticholic acid, aRR, adjusted risk ratio, CRFs, case record form, AST, aspartate transferase, Clinical endpoint, GGT, gamma-glutamyl transferase, QC, primary biliary cholangitis, Ursodeoxycholic acid, ANA, TCC, Cholestasi, TIPS, Treatment Completer Cohort, ANA, antinuclear antibodie, medicine.medical_specialty, RR, UDCA, ursodeoxycholic acid, TIPS, transjugular intrahepatic portosystemic shunt, OCA, Cirrhosi, ALP, alkaline phosphatase, autoimmune hepatitis, medicine.disease, digestive system diseases, Discontinuation, Keywords: AIH, autoimmune hepatiti, QC, quality control, chemistry, gamma-glutamyl transferase, randomised controlled trial, electronic data capture, antimitochondrial antibodies, aspartate transferase, Autoimmune hepatitis, chemistry.chemical_compound, AIH, CRFs, Immunology and Allergy, adjusted risk ratio, ANA, antinuclear antibodies, RR, risk ratio, Overall cohort, ALT, alanine transferase, AMA, antimitochondrial antibodie, Cholestasis, CRFs, case record forms, Obeticholic acid, Overlap PBC-AIH, ursodeoxycholic acid, OCA, obeticholic acid, Tolerability, alkaline phosphatase, RCT, Research Article, medicine.drug, case record forms, Context (language use), AMA, antimitochondrial antibodies, Internal medicine, EDC, electronic data capture, transjugular intrahepatic portosystemic shunt, Internal Medicine, medicine, RCT, randomised controlled trial, OC, lcsh:RC799-869, quality control, alanine transferase, AST, aRR, Hepatology, business.industry, AIH, autoimmune hepatitis, TCC, Treatment Completer Cohort, PBC, primary biliary cholangiti, GGT, risk ratio, OC, Overall cohort, ALP, lcsh:Diseases of the digestive system. Gastroenterology, PBC, primary biliary cholangitis, business, EDC
Abstract: Background & aims Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. Methods Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. Results We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). Conclusions Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. Lay summary Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis., Graphical abstract, Highlights • Under real-world conditions, OCA was effective in ~43% of patients who were non-responders to UDCA, according to Poise criteria. • Patients with cirrhosis showed lower efficacy (29.5%), mainly attributed to reduced tolerability and higher discontinuation rate. • Patients with overlap AIH-PBC showed a comparable efficacy to pure PBC, with a higher ALT reduction at 6 months. • Most patients with PBC are still in need of additional therapy if aiming to normalise liver biochemistry.
Published: 2021

42. X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis

Author: S. Abiru, John F. Dillon, Yasuhiro Miyake, Piero Portincasa, Giancarlo Spinzi, R. Harvey, T. Ngatchu, Agostino Colli, M. Taniai, K. Flahive, Masanori Abe, B. Hoeroldt, S. Holder, Howard Curtis, María Isabel Colombo, C. MacNicol, Gang Xie, Andrew Chilton, H. Hussaini, Cristina Rigamonti, M. Kato, Shintaro Yagi, G. Abouda, D. Tyrer, Chris D. Evans, Christopher I. Amos, K. Koss, Kazuaki Chayama, P. Premchand, K. Migita, Simon Panter, Marco Marzioni, Silvia Colombo, Konstantinos N. Lazaridis, M. Yagura, Ashley Brown, D. Gocher, Domenico Alvaro, K. Murata, Mark Wright, Piero Luigi Almasio, C. Healey, A. Ciaccio, N. Wheatley, Vincenzo Cardinale, T. Delahooke, Chiara Milani, T. Shewan, W. Stableforth, S. Levi, Mark L. Green, James V. Jones, Y. Baird, Aftab Ala, Burroughs Ak, D. Williams, K. Ario, P. Sanghi, Hemant Gupta, P. Southern, L. Farrington, M. Hamilton, Andrew D. Higham, I. Yabuuchi, H. Yatsuhashi, Lorenzo Morini, T. Yamamoto, Douglas Thorburn, M. Carnahan, N. Nishida, Susan Slininger, M. Koga, K. Honda, Annarosa Floreani, Andrew Douglass, K. Netherton, M. Yasunami, Hirohito Tsubouchi, F. Donato, K. Walker, U. Shmueli, Paolo Muratori, Ray Mathew, J. Maiden, E. Dungca, Subramaniam Ramakrishnan, S. Vyas, Helen Sweeting, Subrata Saha, T. Komeda, T. Komatsu, H. J. Lee, Maria Consiglia Bragazzi, T. Komura, C. Thomas, C. Shallcross, C. Duggan, J. Kordula, F. Muscariu, Lourdes Cumlat, Imran Patanwala, Giulia Cardamone, L. Morgan, J. Brighton, Masao Honda, H. Nakamura, David Jones, Raj Srirajaskanthan, M. E. Gershwin, T. Muro, L. Stafford, N. Fukushima, Graham P. Butcher, Andrea Crosignani, George Lipscomb, K. Hirata, Y. Nagaoki, S. Mann, Paul G. Richardson, David A Elphick, M. Mupudzi, Y. Ohara, E. Grieve, Gayle Clifford, Claudio Tiribelli, M. Quinn, G. Van Duyvenvoorde, E. Archer, Tatsuki Ichikawa, J. Maltby, T. Arinaga-Hino, Simon Williams, A. King, Yasuni Nakanuma, H. Doyle, A. Brind, Nora Cazzagon, H. Ota, Daphne D’Amato, K. Hogben, H. Wooldridge, J. Wilkins, Shuichi Kaneko, L. Hankey, Gordon Wood, Andrew Fraser, K. Martin, A. Naqvi, M. Ninkovic, M. Patel, Yoshihiko Maehara, Kapil Kapur, I. Amey, Vincenza Calvaruso, Kenichi Harada, T. Yamashita, James Neuberger, N. Taylor, T. Lee, J. Featherstone, C. Lawlor, K. Seward, Satoshi Yamagiwa, Andrea Galli, L. Tan, Kentaro Kikuchi, K. Furuta, Mark A. Ainsworth, Hiromasa Ohira, Esther Unitt, Yosuke Kawai, N. Lancaster, D. Simpson, R. Shidrawi, I. Salam, A.J. Bell, Pietro Andreone, J. Ishida, Voi Shim Wong, N Fisher, Andrew C. Douds, R. Penn, Matthew Foxton, A. Watson, Andrew Mason, S. Walsh, Hiromi Ishibashi, Daniel M. Forton, Giovanni Casella, H. Takaki, K. Yamauchi, Pietro Lampertico, Osamu Yokosuka, M. Koda, M. Davies, H. Mitchison, P. Gyawali, G. Bird, M. Hughes, L. Jones, C. Hamilton, A. Hynes, R. Galaska, Fabio Marra, Debasish Das, C. Cowley, A. Fouracres, Yasuhiko Sugawara, E. Mita, T. Saoshiro, Akinobu Taketomi, Robert P. Myers, R. Przemioslo, F. Wright, L. Hobson, L. Currie, J. Allison, J. Hails, Noriyo Yamashiki, Massimo Zuin, C. Grimley, Alessio Gerussi, S. Besley, Stefano Duga, A. Piotrowicz, H. Kouno, L. Dali-kemmery, H. Sakai, M. Mizokami, Stefano Fagiuoli, Amy Davis, Pier Maria Battezzati, Masao Nagasaki, Luigi Muratori, A. Mori, S. Desmennu, S. Jones, R. Abrahams, Keith George, F. Makita, J. Brown, D. Gorard, Satoru Joshita, M. Mills, Pierluigi Toniutto, S. Campbell, J. Butterworth, S. Dyer, Filomena Morisco, Norihiro Kokudo, T. Yapp, C. Shorrock, Floriano Rosina, E. Walker, Shinji Uemoto, H. Takahashi, Simon M. Rushbrook, K. Amor, E. Marshall, J. Browning, S. Batham, Luca Fabris, Paul R. Banim, Meenakshi Narain, M. Harada, Dermot Gleeson, N. Hirashima, M. Kikuchi, T. Nikami, Gideon M. Hirschfield, Carlo Ferrari, G. Prasad, O. Chirag, Katsushi Tokunaga, M. Nasseri, Rosanna Asselta, Y. Lu, Ken Shirabe, D. Sirdefield, George F. Mells, K. Sugi, R. Ayres, G. Whatley, A. Singhal, M. Leoni, N. Sivaramakrishnan, T. Harding, Rupert Ransford, Anton V J Gunasekera, C. Mulvaney-Jones, D. Ramanaden, M. Mendall, Muhammad F. Dawwas, Dave Jones, Luca Valenti, Earl J. Williams, Markus Gess, Peter Bramley, A. McNair, E. Hashimoto, P. Townshend, C. Ford, Mario Strazzabosco, Luca Miele, Matthew J Brookes, J. Colley, Mark Wilkinson, H. Dewhurst, Charles Millson, E. Shpuza, Shinji Shimoda, T. Himoto, P. Kitchen, M. Nakamuta, Hiroaki Nishimura, Martin Lombard, Kevork M. Peltekian, M. Pitcher, G. Lim, L. Graves, C. Palmer, S. Lord, S. Katsushima, S. Tripoli, Andrew Austin, N. White, B. Grover, S. Congreave, M. Prince, Rebecca Jones, K. Hirano, A. Shepherd, Y. Mano, Michael A. Heneghan, Richard Sandford, L. O'Donohoe, Marco Carbone, S. A. Rolls, Patrick Goggin, M. L. Cowan, M. Crossey, A. Loftus, K. Young, Mesbah Rahman, Cameron N. Ghent, E. Nambela, M. Xiong, L. Grellier, Sunil Dolwani, Antonio Picciotto, Gill Watts, Alberto Mattalia, Elvezia Maria Paraboschi, J. Orpe, Takeji Umemura, Yuki Hitomi, Fiona H. Gordon, Shotaro Sakisaka, A. Dias, Chin Lye Ch'ng, M. Carter, A. Mandal, Yufang Shi, Takafumi Ichida, N. Masaki, M. Oblak, S. Nagaoka, Kevin Yoong, O. Gervais, Minoru Nakamura, Kazuhiko Nakao, S. Taylor-Robinson, L. Kent, Sushma Saksena, A. Affronti, K. Boulton, R. Ede, H. Pateman, K. Yoshizawa, G. Bray, H. Ebinuma, Yeng Ang, Akio Ido, John Ramage, Richard Sturgess, C. Gray, E. Durant, M. Hayes, A. Saeed, J. Keggans, J. Gitahi, T. Valliani, Edoardo G. Giannini, C. Foale, A. Palegwala, Lory Saveria Crocè, K. Matsushita, S. Shaukat, J. Mclindon, S. Pearson, A. Barnardo, A. Wright, Mirko Tarocchi, R Marley, M. Kent, C. Dickson, A. Gibbins, J. Whiteman, S. Singhal, Richard Aspinall, M. Ito, Laura Cristoferi, Maurizia Rossana Brunetto, J. Booth, A. Bathgate, Morikazu Onji, A. Grant, A. Paton, Y. Aiba, P. Chan, J. Sayer, S. Whalley, T. Mathialahan, J. Gotto, T. Kanda, B. Williams, K. Elliott, P. Raymode, Akinobu Takaki, V. Silvestre, I. Gee, C. Hovell, Graham R. Foster, D. Cotterill, G. Stansfield, Grazia Anna Niro, J. Conder, Yoshiyuki Ueno, A. Shah, Jane Metcalf, S. Hayashi, T. Sato, S. Jain, J. Subhani, Donatella Barisani, A. McKay, Kuniaki Arai, Jeremy Shearman, Torao Tanaka, S. Glenn, S. E. O'Donnell, Federica Malinverno, Denise O'Donnell, R. Casey, N. Sharer, J. Bowles, J. Kendall, Maria Cristina Vinci, Antonio Benedetti, George MacFaul, K. Houghton, Vincenzo Ronca, P. Desousa, B. Holbrook, F. Ali, B. Longhurst, Atsushi Tanaka, Marek Czajkowski, R. Tang, Kazuhide Yamamoto, Y. Watanabe, Graeme J.M. Alexander, R. Cloudsdale, F. Hines, M. Karmo, Brian D. Juran, I. Gooding, Y. Takeyama, J. Fraser, A. Mukhopadhya, Sumihito Tamura, Hajime Takikawa, R. Damant, E. Wilhelmsen, M. Kobayashi, J. Tregonning, V. Lambourne, D. Clement, D. Braim, M. Shimada, S. Sen, Shaun Greer, C. Innes, E. Gunter, C. Brown, H. Klass, A. Komori, Andy Li, H. Fairlamb, N. Ncube, Yoshinori Shimada, M. Harrison, S. Marriott, I. Grattagliano, Savino Bruno, A. Naganuma, Xiangjun Gu, Michael F. Seldin, S. Thornthwaite, Peter R. Mills, Katherine A. Siminovitch, X. Liu, Masataka Seike, J. Curtis, Carmela Cursaro, Z. Li, Mikio Zeniya, K. Warner, B. Bird, Jane Collier, Bridget Gunson, S. Tsuruta, E. Tanqueray, Richard Evans, H. Kamitsukasa, R. Sugimoto, Jeremy Tibble, D. Neal, S. Ducker, Francesco Azzaroli, K. Spurdle, K. Ocker, M. Senju, C. Collins, Y. Nakamura, Matthew E. Cramp, Yuji Soejima, I. Drake, K. Ueno, T. Mannami, Clara Mancuso, M. Kawashima, M. Cox, S. S. Kohn, H. Shibata, Stephen D. Ryder, Christopher Macdonald, J. Ridpath, Stephen P. Pereira, L. March, Barbara Coco, J. Morrison, A. Broad, J. Verheyden, Angelo Andriulli, N. Higuchi, J. Musselwhite, R. Bishop, Gwen Baxter, Richard A. Miller, Guido Colloredo, A. Eastick, I. Rees, Deb Ghosh, L. Winter, Sara Massironi, R. McCorry, Gianfranco Elia, T. Kobata, N. Naeshiro, K. Pollock, J. Gasem, S. Gallagher, K. Jing, S. Misra, B. Shinder, Harriet Gordon, E. Takesaki, J. Sadeghian, S. Tsunematsu, Ana Lleo, M. Aldersley, Elizabeth J. Atkinson, Pietro Invernizzi, Heather J. Cordell, Asselta, R., Paraboschi, E. M., Gerussi, A., Cordell, H. J., Mells, G. F., Sandford, R. N., Jones, D. E., Nakamura, M., Ueno, K., Hitomi, Y., Kawashima, M., Nishida, N., Tokunaga, K., Nagasaki, M., Tanaka, A., Tang, R., Li, Z., Shi, Y., Liu, X., Xiong, M., Hirschfield, G., Siminovitch, K. A., Walker, E., Xie, G., Mason, A., Myers, R., Peltekian, K., Ghent, C., Atkinson, E., Juran, B., Lazaridis, K., Lu, Y., Gu, X., Jing, K., Amos, C., Affronti, A., Brunetto, M., Coco, B., Spinzi, G., Elia, G., Ferrari, C., Lleo, A., Muratori, L., Muratori, P., Portincasa, P., Colli, A., Bruno, S., Colloredo, G., Azzaroli, F., Andreone, P., Bragazzi, M., Alvaro, D., Cardinale, V., Cazzagon, N., Rigamonti, C., Floreani, A., Rosina, F., Ciaccio, A., Cristoferi, L., D'Amato, D., Malinverno, F., Mancuso, C., Massironi, S., Milani, C., O'Donnell, S. E., Ronca, V., Barisani, D., Lampertico, P., Donato, F., Fagiuoli, S., Almasio, P. L., Giannini, E., Cursaro, C., Colombo, M., Valenti, L., Miele, L., Andriulli, A., Niro, G. A., Grattagliano, I., Morini, L., Casella, G., Vinci, M., Battezzati, P. M., Crosignani, A., Zuin, M., Mattalia, A., Calvaruso, V., Colombo, S., Benedetti, A., Marzioni, M., Galli, A., Marra, F., Tarocchi, M., Picciotto, A., Morisco, F., Fabris, L., Croce, L. S., Tiribelli, C., Toniutto, P., Strazzabosco, M., Ch'Ng, C. L., Rahman, M., Yapp, T., Sturgess, R., Healey, C., Czajkowski, M., Gunasekera, A., Gyawali, P., Premchand, P., Kapur, K., Marley, R., Foster, G., Watson, A., Dias, A., Subhani, J., Harvey, R., Mccorry, R., Ramanaden, D., Gasem, J., Evans, R., Mathialahan, T., Shorrock, C., Lipscomb, G., Southern, P., Tibble, J., Gorard, D., Palegwala, A., Jones, S., Dawwas, M., Alexander, G., Dolwani, S., Prince, M., Foxton, M., Elphick, D., Mitchison, H., Gooding, I., Karmo, M., Saksena, S., Mendall, M., Patel, M., Ede, R., Austin, A., Sayer, J., Hankey, L., Hovell, C., Fisher, N., Carter, M., Koss, K., Piotrowicz, A., Grimley, C., Neal, D., Lim, G., Levi, S., Ala, A., Broad, A., Saeed, A., Wood, G., Brown, J., Wilkinson, M., Gordon, H., Ramage, J., Ridpath, J., Ngatchu, T., Grover, B., Shaukat, S., Shidrawi, R., Abouda, G., Ali, F., Rees, I., Salam, I., Narain, M., Brown, A., Taylor-Robinson, S., Williams, S., Grellier, L., Banim, P., Das, D., Chilton, A., Heneghan, M., Curtis, H., Gess, M., Drake, I., Aldersley, M., Davies, M., Jones, R., Mcnair, A., Srirajaskanthan, R., Pitcher, M., Sen, S., Bird, G., Barnardo, A., Kitchen, P., Yoong, K., Chirag, O., Sivaramakrishnan, N., Macfaul, G., Jones, D., Shah, A., Evans, C., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Fraser, A., Mills, P., Shallcross, C., Campbell, S., Bathgate, A., Shepherd, A., Dillon, J., Rushbrook, S., Przemioslo, R., Macdonald, C., Metcalf, J., Shmueli, U., Davis, A., Naqvi, A., Lee, T., Ryder, S. D., Collier, J., Klass, H., Ninkovic, M., Cramp, M., Sharer, N., Aspinall, R., Goggin, P., Ghosh, D., Douds, A., Hoeroldt, B., Booth, J., Williams, E., Hussaini, H., Stableforth, W., Ayres, R., Thorburn, D., Marshall, E., Burroughs, A., Mann, S., Lombard, M., Richardson, P., Patanwala, I., Maltby, J., Brookes, M., Mathew, R., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Panter, S., Shearman, J., Bray, G., Butcher, G., Forton, D., Mclindon, J., Cowan, M., Whatley, G., Mandal, A., Gupta, H., Sanghi, P., Jain, S., Pereira, S., Prasad, G., Watts, G., Wright, M., Neuberger, J., Gordon, F., Unitt, E., Grant, A., Delahooke, T., Higham, A., Brind, A., Cox, M., Ramakrishnan, S., King, A., Collins, C., Whalley, S., Li, A., Fraser, J., Bell, A., Wong, V. 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E., Seldin, M. F., Invernizzi, P., Asselta R., Paraboschi E.M., Gerussi A., Cordell H.J., Mells G.F., Sandford R.N., Jones D.E., Nakamura M., Ueno K., Hitomi Y., Kawashima M., Nishida N., Tokunaga K., Nagasaki M., Tanaka A., Tang R., Li Z., Shi Y., Liu X., Xiong M., Hirschfield G., Siminovitch K.A., Walker E., Xie G., Mason A., Myers R., Peltekian K., Ghent C., Atkinson E., Juran B., Lazaridis K., Lu Y., Gu X., Jing K., Amos C., Affronti A., Brunetto M., Coco B., Spinzi G., Elia G., Ferrari C., Lleo A., Muratori L., Muratori P., Portincasa P., Colli A., Bruno S., Colloredo G., Azzaroli F., Andreone P., Bragazzi M., Alvaro D., Cardinale V., Cazzagon N., Rigamonti C., Floreani A., Rosina F., Ciaccio A., Cristoferi L., D'Amato D., Malinverno F., Mancuso C., Massironi S., Milani C., O'Donnell S.E., Ronca V., Barisani D., Lampertico P., Donato F., Fagiuoli S., Almasio P.L., Giannini E., Cursaro C., Colombo M., Valenti L., Miele L., Andriulli A., Niro G.A., Grattagliano I., Morini L., Casella G., Vinci M., Battezzati P.M., Crosignani A., Zuin M., Mattalia A., Calvaruso V., Colombo S., Benedetti A., Marzioni M., Galli A., Marra F., Tarocchi M., Picciotto A., Morisco F., Fabris L., Croce L.S., Tiribelli C., Toniutto P., Strazzabosco M., Ch'ng C.L., Rahman M., Yapp T., Sturgess R., Healey C., Czajkowski M., Gunasekera A., Gyawali P., Premchand P., Kapur K., Marley R., Foster G., Watson A., Dias A., Subhani J., Harvey R., McCorry R., Ramanaden D., Gasem J., Evans R., Mathialahan T., Shorrock C., Lipscomb G., Southern P., Tibble J., Gorard D., Palegwala A., Jones S., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali 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Sadeghian J., Williams B., Rolls S.-A., Hynes A., Duggan C., Crossey M., Stansfield G., MacNicol C., Wilkins J., Wilhelmsen E., Raymode P., Lee H.-J., Durant E., Bishop R., Ncube N., Tripoli S., Casey R., Cowley C., Miller R., Houghton K., Ducker S., Wright F., Bird B., Baxter G., Keggans J., Hughes M., Grieve E., Young K., Williams D., Ocker K., Hines F., Martin K., Innes C., Valliani T., Fairlamb H., Thornthwaite S., Eastick A., Tanqueray E., Morrison J., Holbrook B., Browning J., Walker K., Congreave S., Verheyden J., Slininger S., Stafford L., O'Donnell D., Ainsworth M., Lord S., Kent L., March L., Dickson C., Simpson D., Longhurst B., Hayes M., Shpuza E., White N., Besley S., Pearson S., Wright A., Jones L., Gunter E., Dewhurst H., Fouracres A., Farrington L., Graves L., Marriott S., Leoni M., Tyrer D., Dali-kemmery L., Lambourne V., Green M., Sirdefield D., Amor K., Colley J., Shinder B., Jones J., Mills M., Carnahan M., Taylor N., Boulton K., Tregonning J., Brown C., Clifford G., Archer E., Hamilton M., Curtis J., Shewan T., Walsh S., Warner K., Netherton K., Mupudzi M., Gunson B., Gitahi J., Gocher D., Batham S., Pateman H., Desmennu S., Conder J., Clement D., Gallagher S., Orpe J., Chan P., Currie L., O'Donohoe L., Oblak M., Morgan L., Quinn M., Amey I., Baird Y., Cotterill D., Cumlat L., Winter L., Greer S., Spurdle K., Allison J., Dyer S., Sweeting H., Kordula J., Aiba Y., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Kawai Y., Kohn S.-S., Gervais O., Migita K., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Higuchi N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Takikawa H., Ohira H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Carbone M., Cardamone G., Duga S., Gershwin M.E., Seldin M.F., Invernizzi P., Asselta, R, Paraboschi, E, Gerussi, A, Cordell, H, Mells, G, Sandford, R, Jones, D, Nakamura, M, Ueno, K, Hitomi, Y, Kawashima, M, Nishida, N, Tokunaga, K, Nagasaki, M, Tanaka, A, Tang, R, Li, Z, Shi, Y, Liu, X, Xiong, M, Hirschfield, G, Siminovitch, K, Walker, E, Xie, G, Mason, A, Myers, R, Peltekian, K, Ghent, C, Atkinson, E, Juran, B, Lazaridis, K, Lu, Y, Gu, X, Jing, K, Amos, C, Affronti, A, Brunetto, M, Coco, B, Spinzi, G, Elia, G, Ferrari, C, Lleo, A, Muratori, L, Muratori, P, Portincasa, P, Colli, A, Bruno, S, Colloredo, G, Azzaroli, F, Andreone, P, Bragazzi, M, Alvaro, D, Cardinale, V, Cazzagon, N, Rigamonti, C, Floreani, A, Rosina, F, Ciaccio, A, Cristoferi, L, D'Amato, D, Malinverno, F, Mancuso, C, Massironi, S, Milani, C, O'Donnell, S, Ronca, V, Barisani, D, Lampertico, P, Donato, F, Fagiuoli, S, Almasio, P, Giannini, E, Cursaro, C, Colombo, M, Valenti, L, Miele, L, Andriulli, A, Niro, G, Grattagliano, I, Morini, L, Casella, G, Vinci, M, Battezzati, P, Crosignani, A, Zuin, M, Mattalia, A, Calvaruso, V, Colombo, S, Benedetti, A, Marzioni, M, Galli, A, Marra, F, Tarocchi, M, Picciotto, A, Morisco, F, Fabris, L, Croce, L, Tiribelli, C, Toniutto, P, Strazzabosco, M, Ch'Ng, C, Rahman, M, Yapp, T, Sturgess, R, Healey, C, Czajkowski, M, Gunasekera, A, Gyawali, P, Premchand, P, Kapur, K, Marley, R, Foster, G, Watson, A, Dias, A, Subhani, J, Harvey, R, Mccorry, R, Ramanaden, D, Gasem, J, Evans, R, Mathialahan, T, Shorrock, C, Lipscomb, G, Southern, P, Tibble, J, Gorard, D, Palegwala, A, Jones, S, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, I, Narain, M, Brown, A, Taylor-Robinson, S, Williams, S, Grellier, L, Banim, P, Das, D, Chilton, A, Heneghan, M, Curtis, H, Gess, M, Drake, I, Aldersley, M, Davies, M, Jones, R, Mcnair, A, Srirajaskanthan, R, Pitcher, M, Sen, S, Bird, G, Barnardo, A, Kitchen, P, Yoong, K, Chirag, O, Sivaramakrishnan, N, Macfaul, G, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Fraser, A, Mills, P, Shallcross, C, Campbell, S, Bathgate, A, Shepherd, A, Dillon, J, Rushbrook, S, Przemioslo, R, Macdonald, C, Metcalf, J, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Ninkovic, M, Cramp, M, Sharer, N, Aspinall, R, Goggin, P, Ghosh, D, Douds, A, Hoeroldt, B, Booth, J, Williams, E, Hussaini, H, Stableforth, W, Ayres, R, Thorburn, D, Marshall, E, Burroughs, A, Mann, S, Lombard, M, Richardson, P, Patanwala, I, Maltby, J, Brookes, M, Mathew, R, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Panter, S, Shearman, J, Bray, G, Butcher, G, Forton, D, Mclindon, J, Cowan, M, Whatley, G, Mandal, A, Gupta, H, Sanghi, P, Jain, S, Pereira, S, Prasad, G, Watts, G, Wright, M, Neuberger, J, Gordon, F, Unitt, E, Grant, A, Delahooke, T, Higham, A, Brind, A, Cox, M, Ramakrishnan, S, King, A, Collins, C, Whalley, S, Li, A, Fraser, J, Bell, A, Wong, V, Singhal, A, Gee, I, Ang, Y, Ransford, R, Gotto, J, Millson, C, Bowles, J, Thomas, C, Harrison, M, Galaska, R, Kendall, J, Whiteman, J, Lawlor, C, Gray, C, Elliott, K, Mulvaney-Jones, C, Hobson, L, Van Duyvenvoorde, G, Loftus, A, Seward, K, Penn, R, Maiden, J, Damant, R, Hails, J, Cloudsdale, R, Silvestre, V, Glenn, S, Dungca, E, Wheatley, N, Doyle, H, Kent, M, Hamilton, C, Braim, D, Wooldridge, H, Abrahams, R, Paton, A, Lancaster, N, Gibbins, A, Hogben, K, Desousa, P, Muscariu, F, Musselwhite, J, Mckay, A, Tan, L, Foale, C, Brighton, J, Flahive, K, Nambela, E, Townshend, P, Ford, C, Holder, S, Palmer, C, Featherstone, J, Nasseri, M, Sadeghian, J, Williams, B, Rolls, S, Hynes, A, Duggan, C, Crossey, M, Stansfield, G, Macnicol, C, Wilkins, J, Wilhelmsen, E, Raymode, P, Lee, H, Durant, E, Bishop, R, Ncube, N, Tripoli, S, Casey, R, Cowley, C, Miller, R, Houghton, K, Ducker, S, Wright, F, Bird, B, Baxter, G, Keggans, J, Hughes, M, Grieve, E, Young, K, Williams, D, Ocker, K, Hines, F, Martin, K, Innes, C, Valliani, T, Fairlamb, H, Thornthwaite, S, Eastick, A, Tanqueray, E, Morrison, J, Holbrook, B, Browning, J, Walker, K, Congreave, S, Verheyden, J, Slininger, S, Stafford, L, O'Donnell, D, Ainsworth, M, Lord, S, Kent, L, March, L, Dickson, C, Simpson, D, Longhurst, B, Hayes, M, Shpuza, E, White, N, Besley, S, Pearson, S, Wright, A, Jones, L, Gunter, E, Dewhurst, H, Fouracres, A, Farrington, L, Graves, L, Marriott, S, Leoni, M, Tyrer, D, Dali-kemmery, L, Lambourne, V, Green, M, Sirdefield, D, Amor, K, Colley, J, Shinder, B, Jones, J, Mills, M, Carnahan, M, Taylor, N, Boulton, K, Tregonning, J, Brown, C, Clifford, G, Archer, E, Hamilton, M, Curtis, J, Shewan, T, Walsh, S, Warner, K, Netherton, K, Mupudzi, M, Gunson, B, Gitahi, J, Gocher, D, Batham, S, Pateman, H, Desmennu, S, Conder, J, Clement, D, Gallagher, S, Orpe, J, Chan, P, Currie, L, O'Donohoe, L, Oblak, M, Morgan, L, Quinn, M, Amey, I, Baird, Y, Cotterill, D, Cumlat, L, Winter, L, Greer, S, Spurdle, K, Allison, J, Dyer, S, Sweeting, H, Kordula, J, Aiba, Y, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Kawai, Y, Kohn, S, Gervais, O, Migita, K, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Higuchi, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Takikawa, H, Ohira, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Carbone, M, Cardamone, G, Duga, S, Gershwin, M, Seldin, M, Invernizzi, P, Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P, and LiveR North
Subjects: Canadian-US PBC Consortium, 0301 basic medicine, Male, Linkage disequilibrium, Genome-wide association study, Disease, PBC, Settore MED/03 - GENETICA MEDICA, Linkage Disequilibrium, 0302 clinical medicine, UK-PBC Consortium, Genotype, Mitochondrial Precursor Protein Import Complex Proteins, Italian PBC Genetics Study Group, Odds Ratio, X-Wide Association Study, Japan PBC-GWAS Consortium, X chromosome, Genetics, Liver Cirrhosis, Biliary, Gastroenterology, Forkhead Transcription Factors, DNA-Binding Proteins, Shal Potassium Channels, 030211 gastroenterology & hepatology, Female, Adult, Monosaccharide Transport Proteins, Superenhancer, Locus (genetics), Single-nucleotide polymorphism, Biology, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Asian People, Proto-Oncogene Proteins, Endopeptidases, Humans, Cell Lineage, Genetic Predisposition to Disease, Meta-analysi, Genetic association, Chromosomes, Human, X, Gastroenterology & Hepatology, Hepatology, 1103 Clinical Sciences, Meta-analysis, 030104 developmental biology, Genetic Loci, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, Carrier Proteins, Genome-Wide Association Study
Abstract: Background & aims: Genome-wide association studies in primary biliary cholangitis (PBC) have failed to find X chromosome (chrX) variants associated with the disease. Here, we specifically explore the chrX contribution to PBC, a sexually dimorphic complex autoimmune disease. Methods: We performed a chrX-wide association study, including genotype data from 5 genome-wide association studies (from Italy, United Kingdom, Canada, China, and Japan; 5244 case patients and 11,875 control individuals). Results: Single-marker association analyses found approximately 100 loci displaying P < 5 × 10-4, with the most significant being a signal within the OTUD5 gene (rs3027490; P = 4.80 × 10-6; odds ratio [OR], 1.39; 95% confidence interval [CI], 1.028-1.88; Japanese cohort). Although the transethnic meta-analysis evidenced only a suggestive signal (rs2239452, mapping within the PIM2 gene; OR, 1.17; 95% CI, 1.09-1.26; P = 9.93 × 10-8), the population-specific meta-analysis showed a genome-wide significant locus in East Asian individuals pointing to the same region (rs7059064, mapping within the GRIPAP1 gene; P = 6.2 × 10-9; OR, 1.33; 95% CI, 1.21-1.46). Indeed, rs7059064 tags a unique linkage disequilibrium block including 7 genes: TIMM17B, PQBP1, PIM2, SLC35A2, OTUD5, KCND1, and GRIPAP1, as well as a superenhancer (GH0XJ048933 within OTUD5) targeting all these genes. GH0XJ048933 is also predicted to target FOXP3, the main T-regulatory cell lineage specification factor. Consistently, OTUD5 and FOXP3 RNA levels were up-regulated in PBC case patients (1.75- and 1.64-fold, respectively). Conclusions: This work represents the first comprehensive study, to our knowledge, of the chrX contribution to the genetics of an autoimmune liver disease and shows a novel PBC-related genome-wide significant locus.
Published: 2021

43. Quality of life in patients with primary biliary cholangitis: A cross-geographical comparison

Author: Marco Carbone, Daphne D’Amato, L. Jopson, Luca Vecchio, Sesé Pilar, Massimo Miglioretti, Lorenzo Montali, Martina Lucà, S. E. O'Donnell, A Gerussi, Clara Mancuso, Pietro Invernizzi, Andrea Gragnano, Albert Parés, Dave Jones, Anna Reig, Alessandra Frigerio, Minami Yagi, George F. Mells, Vincenzo Ronca, Atsushi Tanaka, Laura Cristoferi, Montali, L, Gragnano, A, Miglioretti, M, Frigerio, A, Vecchio, L, Gerussi, A, Cristoferi, L, Ronca, V, D’Amato, D, O’Donnell, S, Mancuso, C, Lucà, M, Yagi, M, Reig, A, Jopson, L, Pilar, S, Jones, D, Pares, A, Mells, G, Tanaka, A, Carbone, M, and Invernizzi, P
Subjects: Factorial invariance, Research paper, Cholestasis, business.industry, Cognitive domain, Immunology, Mean age, Cognition, Autoimmunity, RC581-607, Quality of life, Liver, Cholestasi, Immunology and Allergy, Medicine, In patient, Sun exposure, Immunologic diseases. Allergy, business, Emotional dysfunction, Fatigue, Demography
Abstract: Background & aims Several symptoms impair the quality of life (QoL) of patients with primary biliary cholangitis (PBC). They are reported to vary significantly in different countries. Aim of our study was to explore whether there is a geographical clustering that accounts for symptoms in PBC. Methods Data was analysed from four cohorts of PBC patients from the UK, Spain, Japan and Italy using the PBC-27 scale. Results Overall, 569 patients from four cohorts were identified, including 515 females (90.5%) with a mean age of 61 years. The analysis provided evidence for strict factorial invariance of the scale, a robust indicator of its validity for cross-cultural research. The mean of the fatigue domain of British patients was significantly greater than that of the Japanese (p , Graphical abstract Image 1, Highlights • Primary Biliary Cholangitis (PBC) is a rare liver disease characterised by several symptoms that impair quality of life; • This study includes data from questionnaires provided to individuals with PBC in Italy, Japan, Spain and United Kingdom; • It shows a clear geographical pattern of distribution of PBC-related symptoms, with a significant difference based on latitude.
Published: 2021

44. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Author: Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, Yosuke Kawai, Masao Nagasaki, Katsushi Tokunaga, Ruqi Tang, Yongyong Shi, Zhiqiang Li, Brian D. Juran, Elizabeth J. Atkinson, Alessio Gerussi, Marco Carbone, Rosanna Asselta, Angela Cheung, Mariza de Andrade, Aris Baras, Julie Horowitz, Manuel A.R. Ferreira, Dylan Sun, David E. Jones, Steven Flack, Ann Spicer, Victoria L. Mulcahy, Jinyoung Byan, Younghun Han, Richard N. Sandford, Konstantinos N. Lazaridis, Christopher I. Amos, Gideon M. Hirschfield, Michael F. Seldin, Pietro Invernizzi, Katherine A. Siminovitch, Xiong Ma, Minoru Nakamura, George F. Mells, Andrew Mason, Catherine Vincent, Gang Xie, Jinyi Zhang, Andrea Affronti, Piero L. Almasio, Domenico Alvaro, Pietro Andreone, Angelo Andriulli, Francesco Azzaroli, Pier Maria Battezzati, Antonio Benedetti, MariaConsiglia Bragazzi, Maurizia Brunetto, Savino Bruno, Vincenza Calvaruso, Vincenzo Cardinale, Giovanni Casella, Nora Cazzagon, Antonio Ciaccio, Barbara Coco, Agostino Colli, Guido Colloredo, Massimo Colombo, Silvia Colombo, Laura Cristoferi, Carmela Cursaro, Lory Saveria Crocè, Andrea Crosignani, Daphne D’Amato, Francesca Donato, Gianfranco Elia, Luca Fabris, Stefano Fagiuoli, Carlo Ferrari, Annarosa Floreani, Andrea Galli, Edoardo Giannini, Ignazio Grattagliano, Pietro Lampertico, Ana Lleo, Federica Malinverno, Clara Mancuso, Fabio Marra, Marco Marzioni, Sara Massironi, Alberto Mattalia, Luca Miele, Chiara Milani, Lorenzo Morini, Filomena Morisco, Luigi Muratori, Paolo Muratori, Grazia A. Niro, Sarah O’Donnell, Antonio Picciotto, Piero Portincasa, Cristina Rigamonti, Vincenzo Ronca, Floriano Rosina, Giancarlo Spinzi, Mario Strazzabosco, Mirko Tarocchi, Claudio Tiribelli, Pierluigi Toniutto, Luca Valenti, Maria Vinci, Massimo Zuin, Hitomi Nakamura, Seigo Abiru, Shinya Nagaoka, Atsumasa Komori, Hiroshi Yatsuhashi, Hiromi Ishibashi, Masahiro Ito, Kiyoshi Migita, Hiromasa Ohira, Shinji Katsushima, Atsushi Naganuma, Kazuhiro Sugi, Tatsuji Komatsu, Tomohiko Mannami, Kouki Matsushita, Kaname Yoshizawa, Fujio Makita, Toshiki Nikami, Hideo Nishimura, Hiroshi Kouno, Hirotaka Kouno, Hajime Ota, Takuya Komura, Yoko Nakamura, Masaaki Shimada, Noboru Hirashima, Toshiki Komeda, Keisuke Ario, Makoto Nakamuta, Tsutomu Yamashita, Kiyoshi Furuta, Masahiro Kikuchi, Noriaki Naeshiro, Hironao Takahashi, Yutaka Mano, Seiji Tsunematsu, Iwao Yabuuchi, Yusuke Shimada, Kazuhiko Yamauchi, Rie Sugimoto, Hironori Sakai, Eiji Mita, Masaharu Koda, Satoru Tsuruta, Hiroshi Kamitsukasa, Takeaki Sato, Naohiko Masaki, Tatsuro Kobata, Nobuyoshi Fukushima, Yukio Ohara, Toyokichi Muro, Eiichi Takesaki, Hitoshi Takaki, Tetsuo Yamamoto, Michio Kato, Yuko Nagaoki, Shigeki Hayashi, Jinya Ishida, Yukio Watanabe, Masakazu Kobayashi, Michiaki Koga, Takeo Saoshiro, Michiyasu Yagura, Keisuke Hirata, Atsushu Tanaka, Hajime Takikawa, Mikio Zeniya, Masanori Abe, Morikazu Onji, Shuichi Kaneko, Masao Honda, Kuniaki Arai, Teruko Arinaga-Hino, Etsuko Hashimoto, Makiko Taniai, Takeji Umemura, Satoru Joshita, Kazuhiko Nakao, Tatsuki Ichikawa, Hidetaka Shibata, Satoshi Yamagiwa, Masataka Seike, Koichi Honda, Shotaro Sakisaka, Yasuaki Takeyama, Masaru Harada, Michio Senju, Osamu Yokosuka, Tatsuo Kanda, Yoshiyuki Ueno, Kentaro Kikuchi, Hirotoshi Ebinuma, Takashi Himoto, Michio Yasunami, Kazumoto Murata, Masashi Mizokami, Kazuhito Kawata, Shinji Shimoda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto, Katsuji Hirano, Takafumi Ichida, Akio Ido, Hirohito Tsubouchi, Kazuaki Chayama, Kenichi Harada, Yasuni Nakanuma, Yoshihiko Maehara, Akinobu Taketomi, Ken Shirabe, Yuji Soejima, Akira Mori, Shintaro Yagi, Shinji Uemoto, Egawa H, Tomohiro Tanaka, Noriyo Yamashiki, Sumito Tamura, Yasuhiro Sugawara, Norihiro Kokudo, Naga Chalasani, Vel Luketic, Joseph Odin, Kapil Chopra, Goncalo Abecasis, Michael Cantor, Giovanni Coppola, Aris Economides, Luca A. Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Christina Beechert, Caitlin Forsythe, Erin D. Fuller, Zhenhua Gu, Michael Lattari, Alexander Lopez, Thomas D. Schleicher, Maria Sotiropoulos Padilla, Karina Toledo, Louis Widom, Sarah E. Wolf, Manasi Pradhan, Kia Manoochehri, Ricardo H. Ulloa, Xiaodong Bai, Suganthi Balasubramanian, Leland Barnard, Andrew Blumenfeld, Gisu Eom, Lukas Habegger, Alicia Hawes, Shareef Khalid, Evan K. Maxwell, William Salerno, Jeffrey C. Staples, Marcus B. Jones, Lyndon J. Mitnaul, Richard Sturgess, Christopher Healey, Andrew Yeoman, Anton VJ. Gunasekera, Paul Kooner, Kapil Kapur, V. Sathyanarayana, Yiannis Kallis, Javaid Subhani, Rory Harvey, Roger McCorry, Paul Rooney, David Ramanaden, Richard Evans, Thiriloganathan Mathialahan, Jaber Gasem, Christopher Shorrock, Mahesh Bhalme, Paul Southern, Jeremy A. Tibble, David A. Gorard, Susan Jones, George Mells, Victoria Mulcahy, Brijesh Srivastava, Matthew R. Foxton, Carole E. Collins, David Elphick, Mazn Karmo, Francisco Porras-Perez, Michael Mendall, Tom Yapp, Minesh Patel, Roland Ede, Joanne Sayer, James Jupp, Neil Fisher, Martyn J. Carter, Konrad Koss, Jayshri Shah, Andrzej Piotrowicz, Glyn Scott, Charles Grimley, Ian R. Gooding, Simon Williams, Judith Tidbury, Guan Lim, Kuldeep Cheent, Sass Levi, Dina Mansour, Matilda Beckley, Coral Hollywood, Terry Wong, Richard Marley, John Ramage, Harriet M. Gordon, Jo Ridpath, Theodore Ngatchu, Vijay Paul Bob Grover, Ray G. Shidrawi, George Abouda, L. Corless, Mark Narain, Ian Rees, Ashley Brown, Simon Taylor-Robinson, Joy Wilkins, Leonie Grellier, Paul Banim, Debasish Das, Michael A. Heneghan, Howard Curtis, Helen C. Matthews, Faiyaz Mohammed, Mark Aldersley, Raj Srirajaskanthan, Giles Walker, Alistair McNair, Amar Sharif, Sambit Sen, George Bird, Martin I. Prince, Geeta Prasad, Paul Kitchen, Adrian Barnardo, Chirag Oza, Nurani N. Sivaramakrishnan, Prakash Gupta, Amir Shah, Chris DJ. Evans, Subrata Saha, Katharine Pollock, Peter Bramley, Ashis Mukhopadhya, Stephen T. Barclay, Natasha McDonald, Andrew J. Bathgate, Kelvin Palmer, John F. Dillon, Simon M. Rushbrook, Robert Przemioslo, Chris McDonald, Andrew Millar, Cheh Tai, Stephen Mitchell, Jane Metcalf, Syed Shaukat, Mary Ninkovic, Udi Shmueli, Andrew Davis, Asifabbas Naqvi, Tom JW. Lee, Stephen Ryder, Jane Collier, Howard Klass, Matthew E. Cramp, Nichols Sharer, Richard Aspinall, Deb Ghosh, Andrew C. Douds, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Steven Mann, Douglas Thorburn, Aileen Marshall, Imran Patanwala, Aftab Ala, Julia Maltby, Ray Matthew, Chris Corbett, Sam Vyas, Saket Singhal, Dermot Gleeson, Sharat Misra, Jeff Butterworth, Keith George, Tim Harding, Andrew Douglass, Harriet Mitchison, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Graham Butcher, Daniel Forton, Zahid Mahmood, Matthew Cowan, Debashis Das, Chin Lye Ch’ng, Mesbah Rahman, Gregory C.A. Whatley, Emma Wesley, Aditya Mandal, Sanjiv Jain, Stephen P. Pereira, Mark Wright, Palak Trivedi, Fiona H. Gordon, Esther Unitt, Altaf Palejwala, Andrew Austin, Vishwaraj Vemala, Allister Grant, Andrew D. Higham, Alison Brind, Ray Mathew, Mark Cox, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Jocelyn Fraser, S.J. Thomson, Andrew Bell, Voi Shim Wong, Richard Kia, Ian Gee, Richard Keld, Rupert Ransford, James Gotto, Charles Millson, Cordell, H. J., Fryett, J. J., Ueno, K., Darlay, R., Aiba, Y., Hitomi, Y., Kawashima, M., Nishida, N., Khor, S. -S., Gervais, O., Kawai, Y., Nagasaki, M., Tokunaga, K., Tang, R., Shi, Y., Li, Z., Juran, B. D., Atkinson, E. J., Gerussi, A., Carbone, M., Asselta, R., Cheung, A., de Andrade, M., Baras, A., Horowitz, J., Ferreira, M. A. R., Sun, D., Jones, D. E., Flack, S., Spicer, A., Mulcahy, V. L., Byan, J., Han, Y., Sandford, R. N., Lazaridis, K. N., Amos, C. I., Hirschfield, G. M., Seldin, M. F., Invernizzi, P., Siminovitch, K. A., Ma, X., Nakamura, M., Mells, G. F., Mason, A., Vincent, C., Xie, G., Zhang, J., Affronti, A., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Azzaroli, F., Battezzati, P. M., Benedetti, A., Bragazzi, M., Brunetto, M., Bruno, S., Calvaruso, V., Cardinale, V., Casella, G., Cazzagon, N., Ciaccio, A., Coco, B., Colli, A., Colloredo, G., Colombo, M., Colombo, S., Cristoferi, L., Cursaro, C., Croce, L. S., Crosignani, A., D'Amato, D., Donato, F., Elia, G., Fabris, L., Fagiuoli, S., Ferrari, C., Floreani, A., Galli, A., Giannini, E., Grattagliano, I., Lampertico, P., Lleo, A., Malinverno, F., Mancuso, C., Marra, F., Marzioni, M., Massironi, S., Mattalia, A., Miele, L., Milani, C., Morini, L., Morisco, F., Muratori, L., Muratori, P., Niro, G. A., O'Donnell, S., Picciotto, A., Portincasa, P., Rigamonti, C., Ronca, V., Rosina, F., Spinzi, G., Strazzabosco, M., Tarocchi, M., Tiribelli, C., Toniutto, P., Valenti, L., Vinci, M., Zuin, M., Nakamura, H., Abiru, S., Nagaoka, S., Komori, A., Yatsuhashi, H., Ishibashi, H., Ito, M., Migita, K., Ohira, H., Katsushima, S., Naganuma, A., Sugi, K., Komatsu, T., Mannami, T., Matsushita, K., Yoshizawa, K., Makita, F., Nikami, T., Nishimura, H., Kouno, H., Ota, H., Komura, T., Nakamura, Y., Shimada, M., Hirashima, N., Komeda, T., Ario, K., Nakamuta, M., Yamashita, T., Furuta, K., Kikuchi, M., Naeshiro, N., Takahashi, H., Mano, Y., Tsunematsu, S., Yabuuchi, I., Shimada, Y., Yamauchi, K., Sugimoto, R., Sakai, H., Mita, E., Koda, M., Tsuruta, S., Kamitsukasa, H., Sato, T., Masaki, N., Kobata, T., Fukushima, N., Ohara, Y., Muro, T., Takesaki, E., Takaki, H., Yamamoto, T., Kato, M., Nagaoki, Y., Hayashi, S., Ishida, J., Watanabe, Y., Kobayashi, M., Koga, M., Saoshiro, T., Yagura, M., Hirata, K., Tanaka, A., Takikawa, H., Zeniya, M., Abe, M., Onji, M., Kaneko, S., Honda, M., Arai, K., Arinaga-Hino, T., Hashimoto, E., Taniai, M., Umemura, T., Joshita, S., Nakao, K., Ichikawa, T., Shibata, H., Yamagiwa, S., Seike, M., Honda, K., Sakisaka, S., Takeyama, Y., Harada, M., Senju, M., Yokosuka, O., Kanda, T., Ueno, Y., Kikuchi, K., Ebinuma, H., Himoto, T., Yasunami, M., Murata, K., Mizokami, M., Kawata, K., Shimoda, S., Miyake, Y., Takaki, A., Yamamoto, K., Hirano, K., Ichida, T., Ido, A., Tsubouchi, H., Chayama, K., Harada, K., Nakanuma, Y., Maehara, Y., Taketomi, A., Shirabe, K., Soejima, Y., Mori, A., Yagi, S., Uemoto, S., H, E., Tanaka, T., Yamashiki, N., Tamura, S., Sugawara, Y., Kokudo, N., Chalasani, N., Luketic, V., Odin, J., Chopra, K., Abecasis, G., Cantor, M., Coppola, G., Economides, A., Lotta, L. A., Overton, J. D., Reid, J. G., Shuldiner, A., Beechert, C., Forsythe, C., Fuller, E. D., Gu, Z., Lattari, M., Lopez, A., Schleicher, T. D., Padilla, M. S., Toledo, K., Widom, L., Wolf, S. E., Pradhan, M., Manoochehri, K., Ulloa, R. H., Bai, X., Balasubramanian, S., Barnard, L., Blumenfeld, A., Eom, G., Habegger, L., Hawes, A., Khalid, S., Maxwell, E. K., Salerno, W., Staples, J. C., Jones, M. B., Mitnaul, L. J., Sturgess, R., Healey, C., Yeoman, A., Gunasekera, A. V., Kooner, P., Kapur, K., Sathyanarayana, V., Kallis, Y., Subhani, J., Harvey, R., Mccorry, R., Rooney, P., Ramanaden, D., Evans, R., Mathialahan, T., Gasem, J., Shorrock, C., Bhalme, M., Southern, P., Tibble, J. A., Gorard, D. A., Jones, S., Mells, G., Mulcahy, V., Srivastava, B., Foxton, M. R., Collins, C. E., Elphick, D., Karmo, M., Porras-Perez, F., Mendall, M., Yapp, T., Patel, M., Ede, R., Sayer, J., Jupp, J., Fisher, N., Carter, M. J., Koss, K., Shah, J., Piotrowicz, A., Scott, G., Grimley, C., Gooding, I. R., Williams, S., Tidbury, J., Lim, G., Cheent, K., Levi, S., Mansour, D., Beckley, M., Hollywood, C., Wong, T., Marley, R., Ramage, J., Gordon, H. M., Ridpath, J., Ngatchu, T., Bob Grover, V. P., Shidrawi, R. G., Abouda, G., Corless, L., Narain, M., Rees, I., Brown, A., Taylor-Robinson, S., Wilkins, J., Grellier, L., Banim, P., Das, D., Heneghan, M. A., Curtis, H., Matthews, H. C., Mohammed, F., Aldersley, M., Srirajaskanthan, R., Walker, G., Mcnair, A., Sharif, A., Sen, S., Bird, G., Prince, M. I., Prasad, G., Kitchen, P., Barnardo, A., Oza, C., Sivaramakrishnan, N. N., Gupta, P., Shah, A., Evans, C. D., Saha, S., Pollock, K., Bramley, P., Mukhopadhya, A., Barclay, S. T., Mcdonald, N., Bathgate, A. J., Palmer, K., Dillon, J. F., Rushbrook, S. M., Przemioslo, R., Mcdonald, C., Millar, A., Tai, C., Mitchell, S., Metcalf, J., Shaukat, S., Ninkovic, M., Shmueli, U., Davis, A., Naqvi, A., Lee, T. J., Ryder, S., Collier, J., Klass, H., Cramp, M. E., Sharer, N., Aspinall, R., Ghosh, D., Douds, A. C., Booth, J., Williams, E., Hussaini, H., Christie, J., Mann, S., Thorburn, D., Marshall, A., Patanwala, I., Ala, A., Maltby, J., Matthew, R., Corbett, C., Vyas, S., Singhal, S., Gleeson, D., Misra, S., Butterworth, J., George, K., Harding, T., Douglass, A., Mitchison, H., Panter, S., Shearman, J., Bray, G., Roberts, M., Butcher, G., Forton, D., Mahmood, Z., Cowan, M., Ch'Ng, C. L., Rahman, M., Whatley, G. C. A., Wesley, E., Mandal, A., Jain, S., Pereira, S. P., Wright, M., Trivedi, P., Gordon, F. H., Unitt, E., Palejwala, A., Austin, A., Vemala, V., Grant, A., Higham, A. D., Brind, A., Mathew, R., Cox, M., Ramakrishnan, S., King, A., Whalley, S., Fraser, J., Thomson, S. J., Bell, A., Wong, V. S., Kia, R., Gee, I., Keld, R., Ransford, R., Gotto, J., Millson, C., Cordell H.J., Fryett J.J., Ueno K., Darlay R., Aiba Y., Hitomi Y., Kawashima M., Nishida N., Khor S.-S., Gervais O., Kawai Y., Nagasaki M., Tokunaga K., Tang R., Shi Y., Li Z., Juran B.D., Atkinson E.J., Gerussi A., Carbone M., Asselta R., Cheung A., de Andrade M., Baras A., Horowitz J., Ferreira M.A.R., Sun D., Jones D.E., Flack S., Spicer A., Mulcahy V.L., Byan J., Han Y., Sandford R.N., Lazaridis K.N., Amos C.I., Hirschfield G.M., Seldin M.F., Invernizzi P., Siminovitch K.A., Ma X., Nakamura M., Mells G.F., Mason A., Vincent C., Xie G., Zhang J., Affronti A., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Azzaroli F., Battezzati P.M., Benedetti A., Bragazzi M., Brunetto M., Bruno S., Calvaruso V., Cardinale V., Casella G., Cazzagon N., Ciaccio A., Coco B., Colli A., Colloredo G., Colombo M., Colombo S., Cristoferi L., Cursaro C., Croce L.S., Crosignani A., D'Amato D., Donato F., Elia G., Fabris L., Fagiuoli S., Ferrari C., Floreani A., Galli A., Giannini E., Grattagliano I., Lampertico P., Lleo A., Malinverno F., Mancuso C., Marra F., Marzioni M., Massironi S., Mattalia A., Miele L., Milani C., Morini L., Morisco F., Muratori L., Muratori P., Niro G.A., O'Donnell S., Picciotto A., Portincasa P., Rigamonti C., Ronca V., Rosina F., Spinzi G., Strazzabosco M., Tarocchi M., Tiribelli C., Toniutto P., Valenti L., Vinci M., Zuin M., Nakamura H., Abiru S., Nagaoka S., Komori A., Yatsuhashi H., Ishibashi H., Ito M., Migita K., Ohira H., Katsushima S., Naganuma A., Sugi K., Komatsu T., Mannami T., Matsushita K., Yoshizawa K., Makita F., Nikami T., Nishimura H., Kouno H., Ota H., Komura T., Nakamura Y., Shimada M., Hirashima N., Komeda T., Ario K., Nakamuta M., Yamashita T., Furuta K., Kikuchi M., Naeshiro N., Takahashi H., Mano Y., Tsunematsu S., Yabuuchi I., Shimada Y., Yamauchi K., Sugimoto R., Sakai H., Mita E., Koda M., Tsuruta S., Kamitsukasa H., Sato T., Masaki N., Kobata T., Fukushima N., Ohara Y., Muro T., Takesaki E., Takaki H., Yamamoto T., Kato M., Nagaoki Y., Hayashi S., Ishida J., Watanabe Y., Kobayashi M., Koga M., Saoshiro T., Yagura M., Hirata K., Tanaka A., Takikawa H., Zeniya M., Abe M., Onji M., Kaneko S., Honda M., Arai K., Arinaga-Hino T., Hashimoto E., Taniai M., Umemura T., Joshita S., Nakao K., Ichikawa T., Shibata H., Yamagiwa S., Seike M., Honda K., Sakisaka S., Takeyama Y., Harada M., Senju M., Yokosuka O., Kanda T., Ueno Y., Kikuchi K., Ebinuma H., Himoto T., Yasunami M., Murata K., Mizokami M., Kawata K., Shimoda S., Miyake Y., Takaki A., Yamamoto K., Hirano K., Ichida T., Ido A., Tsubouchi H., Chayama K., Harada K., Nakanuma Y., Maehara Y., Taketomi A., Shirabe K., Soejima Y., Mori A., Yagi S., Uemoto S., H E., Tanaka T., Yamashiki N., Tamura S., Sugawara Y., Kokudo N., Chalasani N., Luketic V., Odin J., Chopra K., Abecasis G., Cantor M., Coppola G., Economides A., Lotta L.A., Overton J.D., Reid J.G., Shuldiner A., Beechert C., Forsythe C., Fuller E.D., Gu Z., Lattari M., Lopez A., Schleicher T.D., Padilla M.S., Toledo K., Widom L., Wolf S.E., Pradhan M., Manoochehri K., Ulloa R.H., Bai X., Balasubramanian S., Barnard L., Blumenfeld A., Eom G., Habegger L., Hawes A., Khalid S., Maxwell E.K., Salerno W., Staples J.C., Jones M.B., Mitnaul L.J., Sturgess R., Healey C., Yeoman A., Gunasekera A.V., Kooner P., Kapur K., Sathyanarayana V., Kallis Y., Subhani J., Harvey R., McCorry R., Rooney P., Ramanaden D., Evans R., Mathialahan T., Gasem J., Shorrock C., Bhalme M., Southern P., Tibble J.A., Gorard D.A., Jones S., Mells G., Mulcahy V., Srivastava B., Foxton M.R., Collins C.E., Elphick D., Karmo M., Porras-Perez F., Mendall M., Yapp T., Patel M., Ede R., Sayer J., Jupp J., Fisher N., Carter M.J., Koss K., Shah J., Piotrowicz A., Scott G., Grimley C., Gooding I.R., Williams S., Tidbury J., Lim G., Cheent K., Levi S., Mansour D., Beckley M., Hollywood C., Wong T., Marley R., Ramage J., Gordon H.M., Ridpath J., Ngatchu T., Bob Grover V.P., Shidrawi R.G., Abouda G., Corless L., Narain M., Rees I., Brown A., Taylor-Robinson S., Wilkins J., Grellier L., Banim P., Das D., Heneghan M.A., Curtis H., Matthews H.C., Mohammed F., Aldersley M., Srirajaskanthan R., Walker G., McNair A., Sharif A., Sen S., Bird G., Prince M.I., Prasad G., Kitchen P., Barnardo A., Oza C., Sivaramakrishnan N.N., Gupta P., Shah A., Evans C.D., Saha S., Pollock K., Bramley P., Mukhopadhya A., Barclay S.T., McDonald N., Bathgate A.J., Palmer K., Dillon J.F., Rushbrook S.M., Przemioslo R., McDonald C., Millar A., Tai C., Mitchell S., Metcalf J., Shaukat S., Ninkovic M., Shmueli U., Davis A., Naqvi A., Lee T.J., Ryder S., Collier J., Klass H., Cramp M.E., Sharer N., Aspinall R., Ghosh D., Douds A.C., Booth J., Williams E., Hussaini H., Christie J., Mann S., Thorburn D., Marshall A., Patanwala I., Ala A., Maltby J., Matthew R., Corbett C., Vyas S., Singhal S., Gleeson D., Misra S., Butterworth J., George K., Harding T., Douglass A., Mitchison H., Panter S., Shearman J., Bray G., Roberts M., Butcher G., Forton D., Mahmood Z., Cowan M., Ch'ng C.L., Rahman M., Whatley G.C.A., Wesley E., Mandal A., Jain S., Pereira S.P., Wright M., Trivedi P., Gordon F.H., Unitt E., Palejwala A., Austin A., Vemala V., Grant A., Higham A.D., Brind A., Mathew R., Cox M., Ramakrishnan S., King A., Whalley S., Fraser J., Thomson S.J., Bell A., Wong V.S., Kia R., Gee I., Keld R., Ransford R., Gotto J., Millson C., Medical Research Council (MRC), LiveR North, Cordell, H, Fryett, J, Ueno, K, Darlay, R, Aiba, Y, Hitomi, Y, Kawashima, M, Nishida, N, Khor, S, Gervais, O, Kawai, Y, Nagasaki, M, Tokunaga, K, Tang, R, Shi, Y, Li, Z, Juran, B, Atkinson, E, Gerussi, A, Carbone, M, Asselta, R, Cheung, A, de Andrade, M, Baras, A, Horowitz, J, Ferreira, M, Sun, D, Jones, D, Flack, S, Spicer, A, Mulcahy, V, Byan, J, Han, Y, Sandford, R, Lazaridis, K, Amos, C, Hirschfield, G, Seldin, M, Invernizzi, P, Siminovitch, K, Ma, X, Nakamura, M, Mells, G, Mason, A, Vincent, C, Xie, G, Zhang, J, Affronti, A, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Azzaroli, F, Battezzati, P, Benedetti, A, Bragazzi, M, Brunetto, M, Bruno, S, Calvaruso, V, Cardinale, V, Casella, G, Cazzagon, N, Ciaccio, A, Coco, B, Colli, A, Colloredo, G, Colombo, M, Colombo, S, Cristoferi, L, Cursaro, C, Croce, L, Crosignani, A, D'Amato, D, Donato, F, Elia, G, Fabris, L, Fagiuoli, S, Ferrari, C, Floreani, A, Galli, A, Giannini, E, Grattagliano, I, Lampertico, P, Lleo, A, Malinverno, F, Mancuso, C, Marra, F, Marzioni, M, Massironi, S, Mattalia, A, Miele, L, Milani, C, Morini, L, Morisco, F, Muratori, L, Muratori, P, Niro, G, O'Donnell, S, Picciotto, A, Portincasa, P, Rigamonti, C, Ronca, V, Rosina, F, Spinzi, G, Strazzabosco, M, Tarocchi, M, Tiribelli, C, Toniutto, P, Valenti, L, Vinci, M, Zuin, M, Nakamura, H, Abiru, S, Nagaoka, S, Komori, A, Yatsuhashi, H, Ishibashi, H, Ito, M, Migita, K, Ohira, H, Katsushima, S, Naganuma, A, Sugi, K, Komatsu, T, Mannami, T, Matsushita, K, Yoshizawa, K, Makita, F, Nikami, T, Nishimura, H, Kouno, H, Ota, H, Komura, T, Nakamura, Y, Shimada, M, Hirashima, N, Komeda, T, Ario, K, Nakamuta, M, Yamashita, T, Furuta, K, Kikuchi, M, Naeshiro, N, Takahashi, H, Mano, Y, Tsunematsu, S, Yabuuchi, I, Shimada, Y, Yamauchi, K, Sugimoto, R, Sakai, H, Mita, E, Koda, M, Tsuruta, S, Kamitsukasa, H, Sato, T, Masaki, N, Kobata, T, Fukushima, N, Ohara, Y, Muro, T, Takesaki, E, Takaki, H, Yamamoto, T, Kato, M, Nagaoki, Y, Hayashi, S, Ishida, J, Watanabe, Y, Kobayashi, M, Koga, M, Saoshiro, T, Yagura, M, Hirata, K, Tanaka, A, Takikawa, H, Zeniya, M, Abe, M, Onji, M, Kaneko, S, Honda, M, Arai, K, Arinaga-Hino, T, Hashimoto, E, Taniai, M, Umemura, T, Joshita, S, Nakao, K, Ichikawa, T, Shibata, H, Yamagiwa, S, Seike, M, Honda, K, Sakisaka, S, Takeyama, Y, Harada, M, Senju, M, Yokosuka, O, Kanda, T, Ueno, Y, Kikuchi, K, Ebinuma, H, Himoto, T, Yasunami, M, Murata, K, Mizokami, M, Kawata, K, Shimoda, S, Miyake, Y, Takaki, A, Yamamoto, K, Hirano, K, Ichida, T, Ido, A, Tsubouchi, H, Chayama, K, Harada, K, Nakanuma, Y, Maehara, Y, Taketomi, A, Shirabe, K, Soejima, Y, Mori, A, Yagi, S, Uemoto, S, H, E, Tanaka, T, Yamashiki, N, Tamura, S, Sugawara, Y, Kokudo, N, Chalasani, N, Luketic, V, Odin, J, Chopra, K, Abecasis, G, Cantor, M, Coppola, G, Economides, A, Lotta, L, Overton, J, Reid, J, Shuldiner, A, Beechert, C, Forsythe, C, Fuller, E, Gu, Z, Lattari, M, Lopez, A, Schleicher, T, Padilla, M, Toledo, K, Widom, L, Wolf, S, Pradhan, M, Manoochehri, K, Ulloa, R, Bai, X, Balasubramanian, S, Barnard, L, Blumenfeld, A, Eom, G, Habegger, L, Hawes, A, Khalid, S, Maxwell, E, Salerno, W, Staples, J, Jones, M, Mitnaul, L, Sturgess, R, Healey, C, Yeoman, A, Gunasekera, A, Kooner, P, Kapur, K, Sathyanarayana, V, Kallis, Y, Subhani, J, Harvey, R, Mccorry, R, Rooney, P, Ramanaden, D, Evans, R, Mathialahan, T, Gasem, J, Shorrock, C, Bhalme, M, Southern, P, Tibble, J, Gorard, D, Jones, S, Srivastava, B, Foxton, M, Collins, C, Elphick, D, Karmo, M, Porras-Perez, F, Mendall, M, Yapp, T, Patel, M, Ede, R, Sayer, J, Jupp, J, Fisher, N, Carter, M, Koss, K, Shah, J, Piotrowicz, A, Scott, G, Grimley, C, Gooding, I, Williams, S, Tidbury, J, Lim, G, Cheent, K, Levi, S, Mansour, D, Beckley, M, Hollywood, C, Wong, T, Marley, R, Ramage, J, Gordon, H, Ridpath, J, Ngatchu, T, Bob Grover, V, Shidrawi, R, Abouda, G, Corless, L, Narain, M, Rees, I, Brown, A, Taylor-Robinson, S, Wilkins, J, Grellier, L, Banim, P, Das, D, Heneghan, M, Curtis, H, Matthews, H, Mohammed, F, Aldersley, M, Srirajaskanthan, R, Walker, G, Mcnair, A, Sharif, A, Sen, S, Bird, G, Prince, M, Prasad, G, Kitchen, P, Barnardo, A, Oza, C, Sivaramakrishnan, N, Gupta, P, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Barclay, S, Mcdonald, N, Bathgate, A, Palmer, K, Dillon, J, Rushbrook, S, Przemioslo, R, Mcdonald, C, Millar, A, Tai, C, Mitchell, S, Metcalf, J, Shaukat, S, Ninkovic, M, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Ryder, S, Collier, J, Klass, H, Cramp, M, Sharer, N, Aspinall, R, Ghosh, D, Douds, A, Booth, J, Williams, E, Hussaini, H, Christie, J, Mann, S, Thorburn, D, Marshall, A, Patanwala, I, Ala, A, Maltby, J, Matthew, R, Corbett, C, Vyas, S, Singhal, S, Gleeson, D, Misra, S, Butterworth, J, George, K, Harding, T, Douglass, A, Mitchison, H, Panter, S, Shearman, J, Bray, G, Roberts, M, Butcher, G, Forton, D, Mahmood, Z, Cowan, M, Ch'Ng, C, Rahman, M, Whatley, G, Wesley, E, Mandal, A, Jain, S, Pereira, S, Wright, M, Trivedi, P, Gordon, F, Unitt, E, Palejwala, A, Austin, A, Vemala, V, Grant, A, Higham, A, Brind, A, Mathew, R, Cox, M, Ramakrishnan, S, King, A, Whalley, S, Fraser, J, Thomson, S, Bell, A, Wong, V, Kia, R, Gee, I, Keld, R, Ransford, R, Gotto, J, Millson, C, Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF, PBC Consortia, Canadian PBC Consortium, Chinese PBC Consortium, Italian PBC Study Group, Japan-PBC-GWAS Consortium, US PBC Consortium, UK-PBC Consortium, and Calvaruso V. .
Subjects: Liver Cirrhosis, ALSPAC, ERN RARE-LIVER, Genomic co-localization, Network-based in silico drug efficacy screening, UK-PBC, 0301 basic medicine, Candidate gene, Genome-Wide Association Study, Humans, Liver Cirrhosis, Biliary, Italian PBC Study Group, LD SCORE REGRESSION, Japan-PBC-GWAS Consortium, Genome-wide association study, Locus (genetics), Disease, SUSCEPTIBILITY, PBC, Chronic liver disease, Bioinformatics, GENETIC ASSOCIATION, 1117 Public Health and Health Services, 03 medical and health sciences, 0302 clinical medicine, UK-PBC Consortium, Genotype, Medicine, Genetic association, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Biliary, Chinese PBC Consortium, 1103 Clinical Sciences, medicine.disease, PBC Consortia, 030104 developmental biology, Meta-analysis, ERN RARE LIVER, 030211 gastroenterology & hepatology, US PBC Consortium, Canadian PBC Consortium, business, Life Sciences & Biomedicine, Human
Abstract: [BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.
Published: 2021

45. Primary Sclerosing Cholangitis

Author: Floreani, A, Cristoferi, L, Gerussi, A, Carbone, M, Invernizzi, P, Laura Cristoferi, Alessio Gerussi, Marco Carbone, Pietro Invernizzi, Floreani, A, Cristoferi, L, Gerussi, A, Carbone, M, Invernizzi, P, Laura Cristoferi, Alessio Gerussi, Marco Carbone, and Pietro Invernizzi
Abstract: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive biliary inflammation and fibrosis. PSC has a strong association with inflammatory bowel disease (IBD), which is diagnosed in 60-80% of patients. The coexistence of the PSC and IBD increases the risk for colorectal cancer (CRC). Furthermore, PSC predisposes to the occurrence of other neoplastic conditions, such as cholangiocarcinoma (CCA), gallbladder, and hepatocellular carcinoma. The pathogenesis of PSC is still unclear. Current evidence supports a multifactorial etiology, where genetic predisposition, altered gut microbiota, and immune-mediated phenomena play a crucial role. The highly variable natural history of PSC, with possible intercurrent clinical events (e.g., cholangitis, biliary lithiasis) that could be dissociated from the severity of underlying liver disease with consequent fluctuant clinical symptoms and serum cholestasis marker, makes the prognostic assessment of these patients challenging. To date, no effective medical therapy has been registered, and liver transplantation is the only therapeutic option in patients developing end-stage liver disease. In this chapter, we describe epidemiological and clinical features of PSC, current understanding of its pathogenesis, and address challenges and opportunities associated with its management while focusing on risk stratification.
Published: 2021

46. Anti-gp210 and other anti-nuclear pore complex autoantibodies in primary biliary cholangitis: What we know and what we should know

Author: Alessio Gerussi, Pietro Invernizzi, Laura Cristoferi, Cristoferi, L, Gerussi, A, and Invernizzi, P
Subjects: glycoprotein, glycoprotein 210 antibody, Pore complex, nucleoporin antibody, Anti nuclear, protein antibody, Autoantigens, Sequestosome 1, DNA glycosylase MutY, Medicine, Humans, sequestosome 1, Laminin receptor, education, laminin B receptor, Autoantibodies, epitope, education.field_of_study, Hepatology, business.industry, Liver Cirrhosis, Biliary, aminotransferase, pyruvate dehydrogenase complex, Autoantibody, Nuclear Proteins, glycoprotein 210, nucleoporin, Ursodeoxycholic acid, unclassified drug, ursodeoxycholic acid, Protein antibody, Antibodies, Antinuclear, Immunology, Nucleoporin, bilirubin, CD4 antigen, business, cell nucleus antigen, autoantibody, laminin receptor, mitochondrion antibody, medicine.drug
Published: 2020

47. EP1211: RADIOMICS-BASED MODEL FOR OUTCOME PREDICTION IN PRIMARY SCLEROSING CHOLANGITIS

Author: Laura Cristoferi, Marco Porta, Davide Paolo Bernasconi, Filippo Leonardi, Giacomo Mulinacci, Andrea Palermo, Alessio Gerussi, Camilla Gallo, Miki Scaravaglio, Eliana Stucchi, Cesare Maino, Davide Ippolito, Daphne D'Amato, Carlos Ferreira, Marija Mavar, Rajarshi Banerjee, Laura Antolini, Maria Grazia Valsecchi, Stefano Fagiuoli, Pietro Invernizzi, and Marco Carbone
Subjects: Hepatology, Gastroenterology
Published: 2022

48. Primary Sclerosing Cholangitis: Burden of Disease and Mortality Using Data from the National Rare Diseases Registry in Italy

Author: Giada Minelli, Laura Cristoferi, Marco Carbone, Pietro Invernizzi, Annarosa Floreani, Alessio Gerussi, Valerio Manno, Yllka Kodra, Federica Malinverno, Adele Rocchetti, Vincenzo Ronca, Domenica Taruscio, Susanna Conti, Carbone, M, Kodra, Y, Rocchetti, A, Manno, V, Minelli, G, Gerussi, A, Ronca, V, Malinverno, F, Cristoferi, L, Floreani, A, Invernizzi, P, Conti, S, and Taruscio, D
Subjects: Male, Pediatrics, Delayed Diagnosis, endocrine system diseases, Health, Toxicology and Mutagenesis, lcsh:Medicine, Disease, registry, State Medicine, 0302 clinical medicine, Cost of Illness, Epidemiology, Registries, 030212 general & internal medicine, Child, Cause of death, education.field_of_study, Incidence (epidemiology), digestive, oral, and skin physiology, autoimmune liver disease, rare diseases, primary sclerosing cholangitis, Middle Aged, Primary sclerosing cholangiti, Italy, Child, Preschool, Cohort, Female, 030211 gastroenterology & hepatology, epidemiology, Adult, medicine.medical_specialty, cholestatic liver disease, Adolescent, Cholangitis, Sclerosing, Population, digestive system, Article, Primary sclerosing cholangitis, Young Adult, 03 medical and health sciences, medicine, Humans, Gallbladder cancer, education, Aged, Retrospective Studies, business.industry, lcsh:R, Infant, Newborn, Public Health, Environmental and Occupational Health, Infant, medicine.disease, digestive system diseases, business, Rare disease
Abstract: Introduction: Studies on the epidemiology of primary sclerosing cholangitis (PSC) are mainly based on tertiary referral centers, and are retrospective case series susceptible to selection bias. The aim of this study was to estimate incidence, survival and cause of mortality of PSC in Italy, using population-based data. Methods: Data collected from the National Rare Diseases Registry (RNMR) and the National Mortality Database (NMD) were integrated and analyzed. Results: We identified 502 PSC incident cases. The crude incidence rate between 2012 and 2014 was 0.10 per 100,000 individuals. Sixty percent were male, mean age at disease onset and at diagnosis were 33 and 37 years, respectively, highlighting a mean diagnostic delay of 4 years. The rate of interregional mobility was 12%. Ten-year survival was 92%. In 32% of cases the cause of death was biliary-related, 12% died of biliary or gallbladder cancer. Conclusions: For rare diseases such as PSC, population-based cohort&rsquo, s studies are of paramount importance. Incidence rates of PSC in Italy are markedly lower and survival much longer than the ones reported from tertiary, single-centre series. Moreover, the diagnostic delay and the patient interregional mobility highlights the need for increasing awareness on the disease and for resource reallocation among Italian regions within the National Health Service
Published: 2020
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49. Additive beneficial effects of Fibrates combined with Obeticholic acid in the treatment of patients with Primary Biliary Cholangitis and inadequate response to second-line therapy: data from the Italian PBC Study Group

Author: G. Marconi, Clara Mancuso, Chiara Milani, Nora Cazzagon, A. Floreani, Laura Cristoferi, Alessio Gerussi, Marco Marzioni, S. E. O'Donnell, Federica Malinverno, Marco Carbone, Pietro Invernizzi, Daphne D’Amato, D'Amato, D, O'Donnell, S, Cazzagon, N, Marconi, G, Gerussi, A, Cristoferi, L, Malinverno, F, Mancuso, C, Milani, C, Marzioni, M, Floreani, A, Invernizzi, P, and Carbone, M
Subjects: medicine.medical_specialty, Second-line therapy, Hepatology, business.industry, Obeticholic Acid, Gastroenterology, Obeticholic acid, chemistry.chemical_compound, chemistry, Internal medicine, Medicine, Primary Biliary Cholangiti, Fibrate, New Therapy, business, Beneficial effects
Published: 2020

50. Glycomic analysis of antibody indicates distinctive glycosylation profile in patients with autoimmune cholangitis

Author: Laura Cristoferi, Sandeep Dhaliwal, Ying Sun, Weici Zhang, Christopher L. Bowlus, Aftab A. Ansari, Xing Zhou, Pietro Invernizzi, William M. Ridgway, M. Eric Gershwin, Patrick S.C. Leung, Zongwen Shuai, Guo-Xiang Yang, Carlito B. Lebrilla, Muchena J. Kailemia, Zhou, X, Kailemia, M, Sun, Y, Shuai, Z, Yang, G, Dhaliwal, S, Cristoferi, L, Leung, P, Invernizzi, P, Bowlus, C, Lebrilla, C, Ansari, A, Ridgway, W, Zhang, W, and Gershwin, M
Subjects: Adult, Male, 0301 basic medicine, Glycan, Cirrhosis, Glycosylation, Cholangitis, Sclerosing, Immunology, Severity of Illness Index, digestive system, Autoimmune Diseases, Primary sclerosing cholangitis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, Polysaccharides, medicine, Humans, Immunology and Allergy, Glycomics, Antibody, Aged, Autoantibodies, 030203 arthritis & rheumatology, Inflammation, biology, Liver Cirrhosis, Biliary, Middle Aged, medicine.disease, Healthy Volunteers, digestive system diseases, J chain, Sialic acid, carbohydrates (lipids), 030104 developmental biology, chemistry, Primary biliary cholangiti, Case-Control Studies, Immunoglobulin G, biology.protein, Female, Biomarkers
Abstract: Glycosylation of antibodies, particularly in the Fc domain, critically modulate the ability of antibodies to bind to FcRs, maintaining immune quiescence to achieve a finely orchestrated immune response. The removal of sialic acid and galactose residues dramatically alters the physiological function of IgGs, and alterations of Ig glycosylation have been associated with several autoimmune disorders. However, Ig glycosylation has not been extensively studied in autoimmune cholangitis. We applied triple quadruple mass spectroscopy with subsequent multiple reaction monitoring to elucidate the profile, composition and linkage of sugar residues of antibody glycans in patients with primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and healthy controls (HC). Agalactosylated, HexNAc terminated IgG1 glycoforms were enriched in both PBC and PSC. Levels of IgM glycans at site N439 and fucosylated glycans in J chain, were significantly decreased in PBC compared to PSC and HC. PSC patients had decreased bisecting glycoforms and increased biantennary glycoforms on IgA compared to PBC. Importantly, our data demonstrate the association of distinct branching and composition patterns of Ig glycoforms with disease severity and liver cirrhosis, which highlight the importance of glycan biology as a potential mechanism and/or a disease specific signal of inflammation.
Published: 2020

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