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1. Blood-Based Non-Invasive Tests of Hepatic Fibrosis in Autoimmune Hepatitis: Application among Selected Patients Leads to Higher Accuracy

Author

Marco Ferronato, Marco Lenzi, Paolo Muratori, and Luigi Muratori

Subjects
autoimmune hepatitis, fibrosis, non-invasive test, FIB-4, spleen diameter, platelet count, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background. Assessment of liver fibrosis is essential to guide treatment in autoimmune hepatitis (AIH), but non-invasive tests (NITs) showed poor accuracy. Our study aims to evaluate the performance of NITs among different AIH presentations. Methods. Monocentric retrospective study among 122 AIH patients. NITs were compared to histological grading of liver fibrosis. We performed an accuracy analysis among acute (jaundice and/or transaminases > 10 times upper limit of normal) and non-acute patients. Results. A significant difference in the distribution of NIT values for each Ishak stage was found for spleen-diameter-to-platelet-count ratio (SD/PC) (p < 0.001), fibrosis-4-score (FIB-4) (p = 0.002), AST-to-ALT ratio (AAR) (p = 0.002), red-blood-cell-width-distribution-to-platelet-count ratio (RDW/PC) (p = 0.008) and AST-to-platelet-count ratio (APRI) (p = 0.029). The AUC for advanced fibrosis of SD/PC, FIB-4, RDW/PC, APRI and AAR were, respectively, 0.814, 0.770, 0.768, 0.708 and 0.694. The AUC of SD/PC, FIB-4 and APRI in non-acute subgroup were 0.902, 0.834 and 0.758, while in acute patients they were 0.754, 0.724 and 0.716. RDW/PC and AAR weren’t different among the two subgroups. Conclusions. For SD/PC, FIB-4 and APRI, diagnostic accuracy is higher in patients with non-acute presentation. In this context, SD/PC and FIB-4 showed an overall performance that could be of interest in clinical practice alongside other non-invasive techniques.

Published
2022
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2. COVID‐19 and Immunological Dysregulation: Can Autoantibodies be Useful?

Author

Simona Pascolini, Antonio Vannini, Gaia Deleonardi, Michele Ciordinik, Annamaria Sensoli, Ilaria Carletti, Lorenza Veronesi, Chiara Ricci, Alessia Pronesti, Laura Mazzanti, Ana Grondona, Tania Silvestri, Stefano Zanuso, Marcello Mazzolini, Claudine Lalanne, Chiara Quarneti, Marco Fusconi, Fabrizio Giostra, Alessandro Granito, Luigi Muratori, Marco Lenzi, and Paolo Muratori

Subjects
Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270
Abstract

Coronavirus disease 2019 (COVID‐19) is often associated with interstitial pneumonia. However, there is insufficient knowledge on the presence of autoimmune serological markers in patients with COVID‐19. We analyzed the presence and role of autoantibodies in patients with COVID‐19‐associated pneumonia. We prospectively studied 33 consecutive patients with COVID‐19, 31 (94%) of whom had interstitial pneumonia, and 25 age‐matched and sex‐matched patients with fever and/or pneumonia with etiologies other than COVID‐19 as the pathological control group. All patients were tested for the presence of antinuclear antibodies (ANAs), anti‐antiphospholipid antibodies, and anti‐cytoplasmic neutrophil antibodies (ANCAs). Clinical, biochemical, and radiological parameters were also collected. Fifteen of 33 patients (45%) tested positive for at least one autoantibody, including 11 who tested positive for ANAs (33%), 8 who tested positive for anti‐cardiolipin antibodies (immunoglobulin (Ig)G and/or IgM; 24%), and 3 who tested positive for anti‐β2‐glycoprotein antibodies (IgG and/or IgM; 9%). ANCA reactivity was not detected in any patient. Patients that tested positive for auto‐antibodies had a significantly more severe prognosis than other patients did: 6 of 15 patients (40%) with auto‐antibodies died due to COVID‐19 complications during hospitalization, whereas only 1 of 18 patients (5.5%) who did not have auto‐antibodies died (P = 0.03). Patients with poor prognosis (death due to COVID‐19 complications) had a significantly higher respiratory rate at admission (23 breaths per minute vs. 17 breaths per minute; P = 0.03) and a higher frequency of auto‐antibodies (86% vs. 27%; P = 0.008). In conclusion, auto‐antibodies are frequently detected in patients with COVID‐19 possibly reflecting a pathogenetic role of immune dysregulation. However, given the small number of patients, the association of auto‐antibodies with an unfavorable prognosis requires further multicenter studies.

Published
2021
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3. Autoantibodies to speckled protein family in primary biliary cholangitis

Author

Alessandro Granito, Luigi Muratori, Francesco Tovoli, and Paolo Muratori

Subjects
Speckled proteins, Multiple nuclear dots, Antinuclear antibodies, Primary biliary cholangitis, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract The autoantibody profile of primary biliary cholangitis (PBC) includes antinuclear antibodies (ANA) which are detectable by indirect immunofluorescence in more than 50% of PBC patients. One of the two immunofluorescence patterns which are historically considered “PBC-specific” is the so-called “multiple nuclear dots” (MND) targeting nuclear body proteins such as Sp100, Sp140, Sp140L proteins, promyelocytic leukemia protein (PML) and small ubiquitin-related modifier proteins (SUMO). It has been hypothesized a role of nuclear body protein alterations in immune disorders such as PBC, thus suggesting novel and more refined therapeutic approaches.

Published
2021
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4. Decompensated Cirrhosis as Presentation of LKM1/LC1 Positive Type 2 Autoimmune Hepatitis in Adulthood. A Rare Clinical Entity of Difficult Management

Author

Alessandro Granito, Simona Pascolini, Chiara Ricci, Marco Ferronato, Luigi Muratori, Francesco Vasuri, Tania Franceschini, Marco Lenzi, and Paolo Muratori

Subjects
autoimmune hepatitis (AIH), anti-liver/kidney microsomal antibody type 1 (anti-LKM1), antiliver cytosol antibody type 1 (anti-LC1), immunosuppressive therapy, autoimmune cirrhosis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background: Autoimmune hepatitis (AIH) is a chronic and aggressive liver disease that rapidly evolves into cirrhosis and end-stage liver disease if not timely diagnosed and treated with immunosuppressive therapy. AIH is classified into type 1 and type 2 according to the autoantibody pattern, with smooth muscle antibodies and/or antinuclear antibodies as serological markers of AIH-1, while antiliver cytosol antibody type 1 and/or antiliver/kidney microsomal antibody type 1 characterize type 2 AIH, which mainly affects children, including infants, and adolescents. Case Summary: We describe a case of type 2 AIH, clinically onset in a 34-year-old woman with decompensated cirrhosis. Only a thorough analysis of the autoantibody profile allowed for a diagnosis of an AIH-2 evolved into cirrhosis. The patient received a moderate corticosteroid therapy without achieving optimal disease control. We discuss the controversial decision of whether or not to treat the patient with immunosuppressive therapy, which should be balanced with the potential risk of infectious and other complications. A review of the literature on the management of patients with autoimmune cirrhosis is also presented. Conclusions: AIH-2 can be clinically onset in adult patients with cirrhosis and its complications, without being preceded by major clinical signs. Due to the difficult management of cirrhosis with immunosuppressive treatments, a patient-tailored strategy with a case-by-case approach is needed to prevent major complications such as infections, potentially precluding liver transplantation the only curative therapy.

Published
2021
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8. Cutaneous small vessel vasculitis associated with palpable purpura after COVID 19 Vaccination: A case report and a literature review

Author

Daniela Tirotta, Francesco Girelli, Maurizio Tassinari, and Paolo Muratori

Subjects
Small vessel vasculitis, Covid-19 vaccination, Adverse reaction, Cutaneous reaction, General Medicine
Abstract

Coronavirus disease 19 (Covid-19) vaccination is mostly safe and effective: adverse events following Covid-19 vaccination are generally mild and well tolerated. Adverse reactions may include cutaneous reactions and, rarely, cutaneous small vessel vasculitis associated with palpable purpura. We present the case of a small-vessel vasculitis after Covid-19 vaccination that manifested with no organ involvement or systemic symptoms, associated with self-resolution, and a review of the cases described in literature. We have collected the epidemiological and clinical features of these cases.

Published
2022

9. Acute-on-chronic liver failure: A complex clinical entity in patients with autoimmune hepatitis

Author

Paolo Muratori, Luigi Muratori, Alessandro Granito, Granito A., Muratori P., and Muratori L.

Subjects
Liver Cirrhosis, Hepatitis B virus, medicine.medical_specialty, Cirrhosis, Liver Cirrhosi, MEDLINE, Autoimmune hepatitis, Gastroenterology, Text mining, AIH, immune system diseases, ACLF, Internal medicine, medicine, Humans, Acute on chronic liver failure, In patient, Hepatology, business.industry, liver failure, Liver failure, Acute-On-Chronic Liver Failure, Hepatitis B viru, medicine.disease, digestive system diseases, Hepatitis, Autoimmune, business, cirrhosi, Human
Abstract

In their comprehensive and stimulating review, Moreau et al. report the distinctive features of “acute-on-chronic liver failure” (ACLF) based on different geographic definitions (European,North American, Chinese, Asian Pacific) and suggest that ACLF should be considered a unique clinical syndrome.1 However, in discussing hallmarks, causes and precipitating factors of ACLF, they do not consider the case of autoimmune hepatitis (AIH), which can initiate as acute hepatitis in more than 40% of cases.2 It is well recognized that AIH patients may develop ACLF either as hyperacute exacerbation of undiagnosed or misdiagnosed AIH, or in response to a second exogenous insult (viral, drug-induced, toxic) on typical AIH, possibly favored by long-term immunosuppression.

Published
2021

10. Cutaneous small vessel vasculitis associated to palpable purpura after Covid 19 Vaccination: a case report and a literature review

Author

daniela tirotta, Francesco Girelli, maurizio tassinari, Vincenzo Mazzeo, and Paolo Muratori

Abstract

Covid-19 vaccination is mostly safe and effective: adverse events to vaccinations are usually mild and well tolerated. These adverse reactions may include cutaneous reactions and, rarely, cutaneous small vessel vasculitis associated to palpable purpura.We present a case of a small-vessel vasculitis after covid-19 vaccination, that manifested without evidence organ involvement and systemic symptoms, associated to self-resolution, and a review of the cases described in literatureWe have collected the epidemiological and clinical features of these cases.

Published
2022

11. COVID‐19 and Immunological Dysregulation: Can Autoantibodies be Useful?

Author

Marco Fusconi, Marco Lenzi, Alessia Pronesti, Luigi Muratori, Chiara Ricci, Simona Pascolini, Antonio Vannini, Lorenza Veronesi, Michele Ciordinik, Laura Mazzanti, Chiara Quarneti, Paolo Muratori, A.G. Grondona, Claudine Lalanne, Fabrizio Giostra, Alessandro Granito, Annamaria Sensoli, Ilaria Carletti, Stefano Zanuso, Tania Silvestri, Marcello Mazzolini, Gaia Deleonardi, Pascolini S., Vannini A., Deleonardi G., Ciordinik M., Sensoli A., Carletti I., Veronesi L., Ricci C., Pronesti A., Mazzanti L., Grondona A., Silvestri T., Zanuso S., Mazzolini M., Lalanne C., Quarneti C., Fusconi M., Giostra F., Granito A., Muratori L., Lenzi M., and Muratori P.

Subjects
Adult, Male, 030213 general clinical medicine, medicine.medical_specialty, Anti-nuclear antibody, Respiratory rate, autoantibodies, medicine.disease_cause, 030226 pharmacology & pharmacy, Gastroenterology, Article, General Biochemistry, Genetics and Molecular Biology, Serology, coronavirus disease 2019, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, pneumonia, General Pharmacology, Toxicology and Pharmaceutics, Aged, Aged, 80 and over, biology, SARS-CoV-2, business.industry, lcsh:Public aspects of medicine, General Neuroscience, lcsh:RM1-950, Autoantibody, COVID-19, lcsh:RA1-1270, Articles, General Medicine, Middle Aged, Immunological Dysregulation, Immune dysregulation, medicine.disease, Autoantibodie, Pneumonia, lcsh:Therapeutics. Pharmacology, Immune System Diseases, biology.protein, Etiology, Female, prognosis, Antibody, business
Abstract

Coronavirus disease 2019 (COVID-19) is often associated with interstitial pneumonia. However, there is insufficient knowledge on the presence of autoimmune serological markers in patients with COVID-19. We analyzed the presence and role of autoantibodies in patients with COVID-19-associated pneumonia. We prospectively studied 33 consecutive patients with COVID-19, 31 (94%) of whom had interstitial pneumonia, and 25 age-matched and sex-matched patients with fever and/or pneumonia with etiologies other than COVID-19 as the pathological control group. All patients were tested for the presence of antinuclear antibodies (ANAs), anti-antiphospholipid antibodies, and anti-cytoplasmic neutrophil antibodies (ANCAs). Clinical, biochemical, and radiological parameters were also collected. Fifteen of 33 patients (45%) tested positive for at least one autoantibody, including 11 who tested positive for ANAs (33%), 8 who tested positive for anti-cardiolipin antibodies (immunoglobulin (Ig)G and/or IgM; 24%), and 3 who tested positive for anti-β2-glycoprotein antibodies (IgG and/or IgM; 9%). ANCA reactivity was not detected in any patient. Patients that tested positive for auto-antibodies had a significantly more severe prognosis than other patients did: 6 of 15 patients (40%) with auto-antibodies died due to COVID-19 complications during hospitalization, whereas only 1 of 18 patients (5.5%) who did not have auto-antibodies died (P=0.03). Patients with poor prognosis (death due to COVID-19 complications) had a significantly higher respiratory rate at admission (23 breaths per minute vs. 17 breaths per minute; P=0.03) and a higher frequency of auto-antibodies (86% vs. 27%; P=0.008). In conclusion, auto-antibodies are frequently detected in patients with COVID-19 possibly reflecting a pathogenetic role of immune dysregulation. However, given the small number of patients, the association of auto-antibodies with an unfavorable prognosis requires further multicenter studies.

Published
2021

12. Limitation of the simplified scoring system for the diagnosis of autoimmune Hepatitis with acute onset

Author

Marco Lenzi, Alessandro Granito, Luigi Muratori, Paolo Muratori, Muratori P., Granito A., Lenzi M., and Muratori L.

Subjects
IgG serum levels, medicine.medical_specialty, Scoring system, Interface hepatitis, anti-smooth muscle antibodies (SMA), Autoimmune hepatitis, Gastroenterology, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Acute onset, Fulminant hepatic failure, autoimmune hepatitis (AIH), anti-nuclear antibodies (ANA), Internal medicine, Humans, Medicine, Autoantibodies, Hepatology, business.industry, Autoantibody, Specific igg, medicine.disease, digestive system diseases, AIH scoring system, Hepatitis, Autoimmune, 030220 oncology & carcinogenesis, Acute Disease, 030211 gastroenterology & hepatology, business
Abstract

Autoimmune Hepatitis (AIH) is a chronic inflammatory liver disease of unknown aetiology characterized by the presence of autoantibodies, hypergammaglobulinaemia with specific IgG increase and interface hepatitis on liver histology. The clinical course of AIH is classically characterized by fluctuating periods of decreased or increased disease activity and therefore its clinical spectrum is variable ranging from no symptoms to severe acute hepatitis and even fulminant hepatic failure. Acute presentation may not differ from acute hepatitis of other causes and diagnosis can be difficult. We describe our experience on diagnostic performance of the two AIH scoring systems in acute onset of AIH and found that revised version of the original criteria (1999) achieves the diagnosis in about 30% of patients who presented with normal IgG serum levels and lower frequency of autoantibody positivity in whom the simplified score did not allow the diagnosis.

Published
2021

13. Imaging-based diagnosis of benign lesions and pseudolesions in the cirrhotic liver

Author

Matteo Renzulli, Giovanni Marasco, Giulio Vara, Stefano Brocchi, Fabio Piscaglia, Rita Golfieri, Francesco Tovoli, Anna Maria Ierardi, Paolo Muratori, Gianpaolo Carrafiello, Irene Pettinari, Alessandro Granito, Vincenzo Lucidi, Caterina Balacchi, Matteo Milandri, Renzulli M., Brocchi S., Ierardi A.M., Milandri M., Pettinari I., Lucidi V., Balacchi C., Muratori P., Marasco G., Vara G., Tovoli F., Granito A., Carrafiello G., Piscaglia F., and Golfieri R.

Subjects
Diagnostic Imaging, Liver Cirrhosis, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, Fibrosi, medicine.medical_treatment, Biomedical Engineering, Biophysics, Liver transplantation, 030218 nuclear medicine & medical imaging, Diagnosis, Differential, 03 medical and health sciences, Magnetic resonance imaging, 0302 clinical medicine, Fibrosis, Neoplasms, medicine, Humans, Radiology, Nuclear Medicine and imaging, Cause of death, Cirrhosi, medicine.diagnostic_test, business.industry, Liver Neoplasms, medicine.disease, Primary tumor, Portal vein thrombosis, Hepatocellular carcinoma, Radiology, business, 030217 neurology & neurosurgery, Diagnosi
Abstract

Liver cirrhosis is a leading cause of death worldwide, with 1-year mortality rates of up to 57% in decompensated patients. Hepatocellular carcinoma (HCC) is the most common primary tumor in cirrhotic livers and the second leading cause of cancer-related mortality worldwide. Annually, up to 8% of patients with cirrhosis develop HCC. The diagnosis of HCC rarely requires histological confirmation: in fact, according to the most recent guidelines, the imaging features of HCC are almost always sufficient for a certain diagnosis. Thus, the role of the radiologist is pivotal because the accurate detection and characterization of focal liver lesions in patients with cirrhosis are essential in improving clinical outcomes. Despite recent technical innovations in liver imaging, several issues remain for radiologists regarding the differentiation of HCC from other hepatic lesions, particularly benign lesions and pseudolesions. It is important to avoid misdiagnosis of benign liver lesions as HCC (false-positive cases) because this diagnostic misinterpretation may lead to ineligibility of a patient for potentially curative treatments or inappropriate assignment of high priority scores to patients on waiting lists for liver transplantation. This review presents a pocket guide that could be useful for the radiologist in the diagnosis of benign lesions and pseudolesions in cirrhotic livers, highlighting the imaging features that help in making the correct diagnosis of macroregenerative nodules; siderotic nodules; arterioportal shunts; hemangiomas, including fast-filling hemangiomas, hemangiomas with pseudowashout, and sclerosed hemangiomas; confluent fibrosis; pseudomasses in chronic portal vein thrombosis; and focal fatty changes.

Published
2021

14. Combination of Problem Solving and Multi-organ Ultrasound. A Case Report of AL Amyloidosis Associated to Cardiac, Renal, Peritoneal, Mesenteric and Gastrointestinal Involvement

Author

Daniela Tirotta, Delia Cangini, Francesco Girelli, Vincenzo Mazzeo, Maurizio Tassinari, and Paolo Muratori

Abstract

Introduction. Systemic amyloidosis AL is unusual disease that is heterogeneous in presentation. Clinical case. We present a case of systemic amyloidosis AL with unusual cardiac, mesenteric, renal, peritoneal and gastrointestinal involvement, in which the diagnostic hypothesis was formulated on the basis of problem solving and ultrasound (abdomen, lung, heart US).Conclusion. This case shows that multi-organ ultrasound, associated with problem solving, may be of very helpful in the diagnosis of systemic diseases, even unusual ones and even associated to non-specific clinical aspect, avoiding a long diagnostic interval length.

Published
2022

15. Update of the simplified criteria for autoimmune hepatitis: Evaluation of the methodology for immunoserological testing

Author

George N Dalekos, Paolo Muratori, Marco Lenzi, Christoph Schramm, Friedrich Haag, Kalliopi Zachou, Johanna Galaski, Ansgar W. Lohse, Christina Weiler-Normann, Sibylle Lampalzer, Miriam Schakat, Johanna Galaski, Christina Weiler-Normann, Miriam Schakat, Kalliopi Zachou, Paolo Muratori, Sibylle Lampalzer, Friedrich Haag, Christoph Schramm, Marco Lenzi, George N Daleko, and Ansgar W Lohse

Subjects
0301 basic medicine, Anti-nuclear antibody, Fluorescent Antibody Technique, Autoimmune hepatitis, Immunofluorescence, Sensitivity and Specificity, SMA, autoimmune hepatitis, 03 medical and health sciences, 0302 clinical medicine, Antigen, immune system diseases, Cell Line, Tumor, medicine, Animals, Humans, Autoantibodies, Hepatology, medicine.diagnostic_test, business.industry, Carcinoma, Area under the curve, Autoantibody, Reproducibility of Results, Work Simplification, medicine.disease, SMA, Rats, Hepatitis, Autoimmune, Titer, 030104 developmental biology, Antibodies, Antinuclear, Immunology, 030211 gastroenterology & hepatology, sense organs, business
Abstract

Background & Aims The simplified criteria for the diagnosis of autoimmune hepatitis (AIH) include immunofluorescence testing (IFT) of antinuclear and smooth muscle autoantibodies (ANA and SMA) on rodent tissue sections. We aimed to establish scoring criteria for the implementation of ANA IFT on human epithelioma-2 (HEp-2) cells and ELISA-based testing. Methods ANA and SMA reactivity of 61 AIH sera and 72 non-alcoholic fatty liver disease controls were separately assessed on tissue sections and HEp-2 cells to compare the diagnostic value at increasing titers. A total of 113 patients with AIH at diagnosis and 202 controls from 3 European centers were assessed by IFT as well as 3 different commercially available ANA ELISA and 1 anti-F-actin ELISA. Results ANA assessment by IFT on liver sections had 83.6% sensitivity and 69.4% specificity for AIH at a titer of 1:40. On HEp-2 cells, sensitivity and specificity were 75.4% and 73.6%, respectively, at an adjusted titer of 1:160. Area under the curve (AUC) values of ANA ELISA ranged from 0.70–0.87, with ELISA coated with HEp-2 extracts in addition to selected antigens performing significantly better. SMA assessment by IFT had the highest specificity for the SMA-VG/T pattern and anti-microfilament reactivity on HEp-2 cells. ELISA-based anti-F-actin evaluation was a strong predictor of AIH (AUC 0.88) and performed better than SMA assessment by IFT (AUC 0.77–0.87). Conclusion At adjusted cut-offs, both ANA IFT using HEp-2 cells and ELISA-based autoantibody evaluation for ANA and SMA are potential alternatives to tissue-based IFT for the diagnosis of AIH. Lay summary Autoantibodies are a hallmark of autoimmune hepatitis and are traditionally tested for by immunofluorescence assays on rodent tissue sections. Herein, we demonstrate that human epithelioma cells can be used as a reliable substrate for immunofluorescence testing. ELISA-based testing is also a potentially reliable alternative for autoantibody assessment in autoimmune hepatitis. We propose the implementation of these testing methods into the simplified criteria for the diagnosis of autoimmune hepatitis.

Published
2021

16. 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

17. Autoantibodies to speckled protein family in primary biliary cholangitis

Author

Luigi Muratori, Francesco Tovoli, Alessandro Granito, Paolo Muratori, Granito A., Muratori L., Tovoli F., and Muratori P.

Subjects
lcsh:Immunologic diseases. Allergy, Allergy, Anti-nuclear antibody, Protein family, Nuclear dots, Immunofluorescence, digestive system, Speckled proteins, Promyelocytic leukemia protein, Immune system, Medicine, Multiple nuclear dot, skin and connective tissue diseases, Letter to the Editor, medicine.diagnostic_test, biology, business.industry, Primary biliary cholangitis, Autoantibody, General Medicine, medicine.disease, digestive system diseases, Antinuclear antibodies, Primary biliary cholangiti, Immunology, biology.protein, lcsh:RC581-607, Multiple nuclear dots, business, Antinuclear antibodie
Abstract

The autoantibody profile of primary biliary cholangitis (PBC) includes antinuclear antibodies (ANA) which are detectable by indirect immunofluorescence in more than 50% of PBC patients. One of the two immunofluorescence patterns which are historically considered “PBC-specific” is the so-called “multiple nuclear dots” (MND) targeting nuclear body proteins such as Sp100, Sp140, Sp140L proteins, promyelocytic leukemia protein (PML) and small ubiquitin-related modifier proteins (SUMO). It has been hypothesized a role of nuclear body protein alterations in immune disorders such as PBC, thus suggesting novel and more refined therapeutic approaches.

Published
2021

18. Decompensated cirrhosis as presentation of LKM1/LC1 positive type 2 autoimmune hepatitis in adulthood. A rare clinical entity of difficult management

Author

Marco Ferronato, Francesco Vasuri, Simona Pascolini, Luigi Muratori, Alessandro Granito, Chiara Ricci, Paolo Muratori, Tania Franceschini, Marco Lenzi, Granito A., Pascolini S., Ricci C., Ferronato M., Muratori L., Vasuri F., Franceschini T., Lenzi M., and Muratori P.

Subjects
medicine.medical_specialty, Cirrhosis, Anti-nuclear antibody, medicine.medical_treatment, autoimmune cirrhosis, Autoimmune hepatitis, RC799-869, Liver transplantation, Gastroenterology, Autoimmune hepatitis (AIH), Serology, 03 medical and health sciences, Liver disease, 0302 clinical medicine, immune system diseases, Internal medicine, Autoimmune cirrhosi, medicine, Anti-liver/kidney microsomal antibody type 1 (anti-LKM1), Hepatology, biology, Antiliver cytosol antibody type 1 (anti-LC1), business.industry, Autoantibody, Diseases of the digestive system. Gastroenterology, medicine.disease, digestive system diseases, Immunosuppressive therapy, 030220 oncology & carcinogenesis, biology.protein, 030211 gastroenterology & hepatology, Antibody, business
Abstract

Background: Autoimmune hepatitis (AIH) is a chronic and aggressive liver disease that rapidly evolves into cirrhosis and end-stage liver disease if not timely diagnosed and treated with immunosuppressive therapy. AIH is classified into type 1 and type 2 according to the autoantibody pattern, with smooth muscle antibodies and/or antinuclear antibodies as serological markers of AIH-1, while antiliver cytosol antibody type 1 and/or antiliver/kidney microsomal antibody type 1 characterize type 2 AIH, which mainly affects children, including infants, and adolescents. Case Summary: We describe a case of type 2 AIH, clinically onset in a 34-year-old woman with decompensated cirrhosis. Only a thorough analysis of the autoantibody profile allowed for a diagnosis of an AIH-2 evolved into cirrhosis. The patient received a moderate corticosteroid therapy without achieving optimal disease control. We discuss the controversial decision of whether or not to treat the patient with immunosuppressive therapy, which should be balanced with the potential risk of infectious and other complications. A review of the literature on the management of patients with autoimmune cirrhosis is also presented. Conclusions: AIH-2 can be clinically onset in adult patients with cirrhosis and its complications, without being preceded by major clinical signs. Due to the difficult management of cirrhosis with immunosuppressive treatments, a patient-tailored strategy with a case-by-case approach is needed to prevent major complications such as infections, potentially precluding liver transplantation the only curative therapy.

Published
2021

19. Anti-neutrophil cytoplasm antibodies (ANCA) in autoimmune diseases: A matter of laboratory technique and clinical setting

Author

Luigi Muratori, Francesco Tovoli, Paolo Muratori, Alessandro Granito, Granito A., Muratori P., Tovoli F., and Muratori L.

Subjects
Cytoplasm, biology, Neutrophils, business.industry, Immunology, Neutrophil, Autoantibody, Autoantibodie, digestive system diseases, Antibodies, Antineutrophil Cytoplasmic, Autoimmune Diseases, biology.protein, Humans, Immunology and Allergy, Medicine, Antibody, Laboratories, business, Laboratorie, Autoantibodies, Laboratory technique, Human
Abstract

Perinuclear anti-neutrophil cytoplasm antibodies (pANCA) detected by IIF represent a useful tool conveying the diagnosis of type 1 AIH and/or PSC. As other serological markers of autoimmune diseases, pANCA detection can suggest, but not supersede the clinical and imaging diagnosis.

Published
2021

20. Hepatocellular carcinoma in viral and autoimmune liver diseases: Role of CD4+ CD25+ Foxp3+ regulatory T cells in the immune microenvironment

Author

Claudine Lalanne, Chiara Quarneti, M. Guidi, S. Ferri, Marco Lenzi, Paolo Muratori, Luigi Muratori, Alessandro Granito, Granito A., Muratori L., Lalanne C., Quarneti C., Ferri S., Guidi M., Lenzi M., and Muratori P.

Subjects
Carcinoma, Hepatocellular, Hepatocellular carcinoma, Transcription Factor, medicine.medical_treatment, chemical and pharmacologic phenomena, Hepatitis C virus-related chronic hepatiti, Review, medicine.disease_cause, T-Lymphocytes, Regulatory, Autoimmunity, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, medicine, Humans, Cytotoxic T cell, Tumor microenvironment, business.industry, Liver Neoplasms, Gastroenterology, FOXP3, Forkhead Transcription Factors, General Medicine, Immunotherapy, Forkhead Transcription Factor, Hepatitis C virus-related chronic hepatitis, Tumor progression, Autoimmune liver disease, 030220 oncology & carcinogenesis, Cancer research, Hepatitis B virus-related chronic hepatitis, Hepatitis B virus-related chronic hepatiti, 030211 gastroenterology & hepatology, business, Transcription Factors, Human
Abstract

More than 90% of cases of hepatocellular carcinoma (HCC) occurs in patients with cirrhosis, of which hepatitis B virus and hepatitis C virus are the leading causes, while the tumor less frequently arises in autoimmune liver diseases. Advances in understanding tumor immunity have led to a major shift in the treatment of HCC, with the emergence of immunotherapy where therapeutic agents are used to target immune cells rather than cancer cells. Regulatory T cells (Tregs) are the most abundant suppressive cells in the tumor microenvironment and their presence has been correlated with tumor progression, invasiveness, as well as metastasis. Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function. Notably, Tregs amply express checkpoint molecules such as cytotoxic T lymphocyte-associated antigen 4 and programmed cell-death 1 receptor and therefore represent a direct target of immune checkpoint inhibitor (ICI) immunotherapy. Taking into consideration the critical role of Tregs in maintenance of immune homeostasis as well as avoidance of autoimmunity, it is plausible that targeting of Tregs by ICI immunotherapy results in the development of immune-related adverse events (irAEs). Since the use of ICI becomes common in oncology, with an increasing number of new ICI currently under clinical trials for cancer treatment, the occurrence of irAEs is expected to dramatically rise. Herein, we review the current literature focusing on the role of Tregs in HCC evolution taking into account their opposite etiological function in viral and autoimmune chronic liver disease, and we discuss their involvement in irAEs due to the new immunotherapies.

Published
2021

21. Diagnostic role of anti-dsDNA antibodies: do not forget autoimmune hepatitis

Author

Paolo Muratori, Alessandro Granito, Francesco Tovoli, Luigi Muratori, Granito A., Muratori L., Tovoli F., and Muratori P.

Subjects
biology, business.industry, Anti-dsDNA antibodies, Autoimmune hepatitis, Immunologic Tests, medicine.disease, Hepatitis, Autoimmune, Rheumatology, immune system diseases, Antibodies, Antinuclear, Immunology, biology.protein, Medicine, Humans, Lupus Erythematosus, Systemic, Immunologic Test, business, skin and connective tissue diseases, Human
Abstract

In their Review, Pisetsky and Lipsky highlight the clinical role of antinuclear antibody (ANA) testing in patients with systemic lupus erythematosus (SLE) and properly state that anti-double-stranded DNA (dsDNA) antibodies are highly specific for the diagnosis of SLE; however, they refer to two papers that do not take into account the widely and historically recognized presence of these autoantibodies in individuals with autoimmune hepatitis. In this regard, we would like to discuss that knowledge of anti-dsDNA antibody positivity in autoimmune hepatitis dates back to 1956 when, because of the similarities to SLE, Mackay etal. proposed that this chronic liver disease be named ‘lupoid hepatitis’.

Published
2021

22. Surrogate Markers for Antimitochondrial Antibody-Negative Primary Biliary Cholangitis

Author

Luigi Muratori, Alessandro Granito, Paolo Muratori, Francesco Tovoli, Granito, Alessandro, Muratori, Luigi, Tovoli, Francesco, and Muratori, Paolo

Subjects
medicine.medical_specialty, Primary (chemistry), Hepatology, Anti-nuclear antibody, Cholangitis, Liver Cirrhosis, Biliary, business.industry, Antimitochondrial Antibody, Gastroenterology, antinuclear antibodies, Prognosis, anti-HK1 or antiKLHL12 antibodie, Hexokinase, Internal medicine, medicine, Antimitochondrial antibody, Humans, Primary Biliary Cholangiti, business, skin and connective tissue diseases, Biomarkers
Abstract

New Antibodies to hexokinase 1 (HK1) and kelch-like 12 (KLHL12) has been reported by Reig et al as potential biomarkers in primary biliary cholangitis (PBC). They also reported changes of these antibodies over time, and described the association with clinical outcomes. The authors found that anti-HK1 and anti-KLHL12 were positive in 46.1% and 22.8% of patients, respectively, and changed overtime in 13.3% and 5.5% of patients, respectively. Interestingly, anti-HK1 or antiKLHL12 antibodies were detected in 6 (37.5%) of the 16 patients with antimitochondrial antibody (AMA), and in 4 (40%) of the 10 AMA, anti-gp210– and anti-sp100–seronegative patients. Moreover, a lower response to ursodeoxycholic acid was observed in antiHK1–positive patients according only to Toronto criteria (74% vs 87%, P , 0.02). It is well known that antinuclear antibodies (ANA) demonstrated high PBC specificity and high diagnostic value in AMA-negative PBC patients, particularly the anti-sp100 and anti-gp210 antibodies corresponding to the immunofluorescence PBC-specific ANA patterns of multiple nuclear dots (MND) and rim-like membranous (RL/M), respectively. It would therefore be relevant to test the new antibodies described by Reig et al. in multicenter studies in different geographical areas on a subgroup of patients who are negative for both AMA and all ANAs as detected by immunofluorescence and/or by immunoenzymatic assays with recombinant antigens.

Published
2021

23. 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. 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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. S., 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. -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.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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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

24. 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

25. Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome

Author

Fredrik Rorsman, Ellina Lytvyak, Mårten Werner, Aldo J. Montano-Loza, Fatema Alalkim, Benedetta Terziroli Beretta-Piccoli, Paolo Muratori, Thomas Berg, Thomas D. Schiano, Emma Nilsson, Tugrul Purnak, Ida Henriksson, David Semela, Staffan Wahlin, Eric M. Yoshida, Luigi Muratori, Alan Bonder, Murat Kiyici, Kristina Önnerhag, Janett Fischer, Ersan Ozaslan, Maneerat Chayanupatkul, Hanns-Ulrich Marschall, Murat Torgutalp, Claudia Coppo, Alexandra Heurgué-Berlot, Hirsh D. Trivedi, Nurhan Demir, Cumali Efe, Fatih Eren, Efe C., Torgutalp M., Henriksson I., Alalkim F., Lytvyak E., Trivedi H., Eren F., Fischer J., Chayanupatkul M., Coppo C., Purnak T., Muratori L., Werner M., Muratori P., Rorsman F., Onnerhag K., Nilsson E., Heurgue-Berlot A., Demir N., Semela D., Kiyici M., Schiano T.D., Montano-Loza A.J., Berg T., Ozaslan E., Yoshida E.M., Bonder A., Marschall H.-U., Beretta-Piccoli B.T., Wahlin S., Bursa Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı., CPU-6796-2022, and Eren, Fatih

Subjects
Male, Anti-nuclear antibody, PBC, Gastroenterology, Inflammatory bowel disease, 0302 clinical medicine, Lichen sclerosus et atrophicus, Antiphospholipid syndrome, Ascites, Undifferentiated connective tissue disease, Temporal arteritis, Myasthenia gravis, Hepatic encephalopathy, Hashimoto disease, Addison disease, Crohn disease, Pemphigus vulgaris, IgA nephropathy, Prognosis, Liver cell carcinoma, Management, Risk-factors, Retrospective study, Blood, Cirrhosis, Smooth muscle antibody, Biochemical response, Ursodeoxycholic acid, Primary biliary cirrhosis, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Graves disease, Systemic sclerosis, 030211 gastroenterology & hepatology, Cohort analysis, Lichen planus, Anti-phospholipid syndrome, Human, Sex factor, medicine.medical_specialty, Cholangitis, Biliary Liver Cirrhosis, Obeticholic Acid, Sarcoidosis, Immunology, Major clinical study, Aspartate aminotransferase, Article, Dermatomyositis, Multiple sclerosis, 03 medical and health sciences, Humans, Clinical significance, Aspartate Aminotransferases, Autoimmune hemolytic anemia, Autoantibodies, Polymyositi, Ankylosing spondylitis, Bullous pemphigoid, Wegener granulomatosis, Medical record, Biliary cirrhosis, Follow up, medicine.disease, Event free survival, Ankylosing spondyliti, Ulcerative colitis, Pernicious anemia, Idiopathic thrombocytopenic purpura, Gastroenterology & hepatology, Complication, Biomarkers, Sarcoidosi, Autoantibody, Immunoglobulin A nephropathy, Autoimmune disease, Prevalence, Celiac disease, Middle aged, Variceal bleeding, Liver Cirrhosis, Biliary, Chronic urticaria, Mitochondria, Gastritis, Antibodies, Antinuclear, Female, medicine.symptom, Adult, Vitiligo, Autoimmune Diseases, Antinuclear antibody, Systemic lupus erythematosus, Sex Factors, Decompensated liver cirrhosis, Mitochondrion antibody, Internal medicine, Psoriasis, medicine, Multiple sclerosi, Collagenous colitis, Mitochondrion, Membranous glomerulonephritis, Hepatology, business.industry, Bleeding, Bilirubin, Polyarteritis nodosa, Alkaline Phosphatase, Polymyositis, Biological marker, business, Controlled study, Sjoegren syndrome
Abstract

Background and Aim: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P&nbsp

Published
2021

26. A practical histological approach to the diagnosis of autoimmune hepatitis: experience of an Italian tertiary referral center

Author

Maria Guido, Antonia D'Errico, Marco Lenzi, Paolo Muratori, Francesco Vasuri, Luigi Muratori, Tania Franceschini, Franceschini T., Vasuri F., Muratori P., Muratori L., Guido M., Lenzi M., and D'Errico A.

Subjects
0301 basic medicine, Liver Cirrhosis, Male, Time Factors, Fibrosi, Biopsy, Apoptosis, Autoimmune hepatitis, Gastroenterology, Serology, Tertiary Care Centers, 0302 clinical medicine, Fibrosis, immune system diseases, Referral and Consultation, Aged, 80 and over, medicine.diagnostic_test, General Medicine, Middle Aged, Liver biopsy, Apoptotic body, Prognosis, Hepatitis, Autoimmune, Italy, Liver, 030220 oncology & carcinogenesis, Female, Original Article, Adult, medicine.medical_specialty, Histopathology, Autoimmune hepatiti, Pathology and Forensic Medicine, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, Molecular Biology, Aged, Retrospective Studies, business.industry, Apoptosi, Reproducibility of Results, Cell Biology, medicine.disease, digestive system diseases, 030104 developmental biology, Portal fibrosis, business
Abstract

Liver biopsy is crucial for the diagnosis of autoimmune hepatitis (AIH), and new reproducible histological criteria would be highly desirable, especially in acute-on-chronic cases. The aims of the present study were (i) to evaluate the AIH histopathological criteria as a function of the time and modality of AIH onset, and (ii) to validate the count of apoptotic bodies in the portal tracts as a histopathological criterion for AIH diagnosis. Sixty-five patients were retrospectively enrolled: 20 underwent biopsy for the first diagnosis and 45 had a previous histological AIH diagnosis. Biopsies were revised, and all histological variables were collected, including the lymphocytic apoptotic bodies in the portal tracts. Clinical and serological data were revised as well. First-diagnosis patients showed a higher grade of inflammation (p = 0.001), but also worse portal fibrosis (p = 0.001). The apoptotic body count was higher in first-diagnosis patients than in follow-up patients (p = 0.002), and it was strongly correlated to inflammation. Using the apoptotic body count among the simplified AIH score variables, the first-biopsy patients in the “definite” category rose from 42 to 68%. Our results confirm the histopathological criteria proposed by the literature and introduce the count of portal apoptotic bodies for the diagnosis of active AIH, especially in first biopsies without other classic features, as well as in AIH diagnostic score, albeit future studies are required to find a definite cutoff.

Published
2020

27. Permanent immunosuppression in SLA/LP-positive autoimmune hepatitis is required although overall response and survival are similar

Author

Luigi Muratori, George N. Dalekos, Christina Weiler-Normann, Paolo Muratori, Kalliopi Zachou, Ansgar W. Lohse, Zachou K., Weiler-Normann C., Muratori L., Muratori P., Lohse A.W., and Dalekos G.N.

Subjects
medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, Azathioprine, Enzyme-Linked Immunosorbent Assay, Disease, Autoimmune hepatitis, Asymptomatic, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Germany, medicine, Humans, Clinical significance, anti-SLA/LP antibodie, Autoantibodies, Retrospective Studies, autoimmune hepatiti, Immunosuppression Therapy, azathioprine, Hepatology, biology, Greece, business.industry, fungi, mycophenolate mofetil, Immunosuppression, medicine.disease, Hepatitis, Autoimmune, Italy, 030220 oncology & carcinogenesis, biology.protein, Corticosteroid, 030211 gastroenterology & hepatology, medicine.symptom, Antibody, business, medicine.drug
Abstract

Background and aims: Antibodies against soluble liver antigen/liver pancreas (anti-SLA/LP) are highly specific for autoimmune hepatitis (AIH) and have been linked with a more severe clinical course of the disease, frequent relapses after treatment withdrawal and worse outcome. To address definitely the clinical significance of anti-SLA/LP, we investigated a large number of anti-SLA/LP-positive and -negative patients followed in three referral centres. Methods: Prospectively collected data from 89 anti-SLA/LP-positive AIH patients (29 from Hamburg-Germany, 20 from Bologna-Italy and 40 from Larissa-Greece) were analysed retrospectively. Age- and sex-matched anti-SLA/LP-negative patients served as disease controls (n=230; 1:2.5 ratio). Results: In respect to baseline characteristics, anti-SLA/LP-positive patients were more frequently asymptomatic compared to anti-SLA/LP-negative (P&nbsp

Published
2020

28. Editorial: gut microbiota profile in patients with autoimmune hepatitis—a clue for adjunctive probiotic therapy?

Author

Luigi Muratori, Alessandro Granito, Paolo Muratori, Granito A., Muratori P., and Muratori L.

Subjects
Hepatitis, Probiotic therapy, Hepatology, biology, business.industry, Probiotics, Gastrointestinal Microbiome, Gastroenterology, Autoimmune hepatitis, Gut flora, Ribosomal RNA, biology.organism_classification, medicine.disease, Hepatitis, Autoimmune, RNA, Ribosomal, 16S, Immunology, medicine, Humans, Pharmacology (medical), In patient, Bifidobacterium, business, microbiota, autoimmune hepatitis, probiotic therapy
Abstract

LINKED CONTENT This article is linked to Liwinski et al and Liwinski and Shcramm papers. To view these articles, visit and .

Published
2020

29. Standardization of Autoantibody Testing in Autoimmune Hepatitis

Author

Luigi Muratori, Marco Lenzi, Paolo Muratori, Muratori, Paolo, Lenzi, Marco, and Muratori, Luigi

Subjects
Allergy, business.industry, Autoantibody, Autoimmunity, General Medicine, Autoimmune hepatitis, Autoimmune hepatiti, medicine.disease, Autoantibodie, Hepatitis, Autoimmune, Anti-smooth muscle antibodie, Immunology, Humans, Medicine, Immunology and Allergy, Disease Susceptibility, Anti-actin, business, Autoantibodies
Abstract

It is a comment on a recent review published on the Journal.

Published
2020

30. Clinical implications of antimitochondrial antibody seropositivity in autoimmune hepatitis

Author

Alexandra Heurgué-Berlot, Ersan Ozaslan, Staffan Wahlin, Marco Lenzi, Thomas D. Schiano, Luigi Muratori, Claudine Lalanne, Cumali Efe, Paolo Muratori, Eric M. Yoshida, Muratori, Paolo, Efe, Cumali, Muratori, Luigi, Ozaslan, Ersan, Schiano, Thoma, Yoshida, Eric M., Heurgué-Berlot, Alexandra, Lalanne, Claudine, Lenzi, Marco, and Wahlin, Staffan

Subjects
Male, 0301 basic medicine, Cholangitis, medicine.medical_treatment, Autoimmune hepatitis, medicine.disease_cause, Gastroenterology, Serology, Autoimmunity, primary biliary cirrhosi, 0302 clinical medicine, immune system diseases, Child, autoimmune hepatiti, Aged, 80 and over, Univariate analysis, Immunosuppression, Middle Aged, autoantibodie, Mitochondria, Europe, Hepatitis, Autoimmune, Treatment Outcome, Child, Preschool, antimitochondrial antibodie, Antimitochondrial antibody, Female, 030211 gastroenterology & hepatology, Immunosuppressive Agents, Adult, medicine.medical_specialty, Adolescent, Young Adult, 03 medical and health sciences, Internal medicine, parasitic diseases, medicine, Humans, Serologic Tests, Clinical significance, Aged, Autoantibodies, Chi-Square Distribution, Hepatology, business.industry, Autoantibody, medicine.disease, digestive system diseases, Logistic Models, 030104 developmental biology, Case-Control Studies, North America, Immunology, business, Biomarkers
Abstract

Background/aim Antimitochondrial antibody (AMA) positivity is the serological marker of primary biliary cholangitis (PBC), but can also be sporadically detected in autoimmune hepatitis (AIH). Little is known about the clinical significance of AMA in AIH. Patients and methods We recruited 47 AMA-positive AIH cases from several centres and compared them with 264 well-characterized Italian AIH patients. Cases with any features of PBC were excluded. Results In univariate analysis, AMA-positive AIH patients were older (46 vs. 36, P=0.002) and more responsive to immunosuppression (74 vs. 59%, P=0.05), but no differences were observed between the two groups after logistic regression using AMA as a dependent variable. None of the AMA-positive AIH patients showed signs of evolving PBC features after a median follow-up of up 47 months. AMA was detected in combination with all serological AIH markers except antiliver kidney microsome type 1 and antiliver cytosol type 1. AMA was the only marker of autoimmunity in eight cases. Conclusion We found no differences between AIH with and without AMA. The groups had similar clinical, biochemical and histological features. AMA-positive AIH patients did not evolve towards PBC. In some cases, AMA was the only autoantibody.

Published
2017

31. Validation of risk scoring systems in ursodeoxycholic acid-treated patients with primary biliary Cholangitis

Author

Fatema Alalkim, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Cumali Efe, Fulya Gunsar, Ellina Lytvyak, Janett Fischer, Fredrik Rorsman, Ali Riza Caliskan, Hanns-Ulrich Marschall, Kristina Önnerhag, Tugrul Purnak, Ida Henriksson, Maneerat Chayanupatkul, Claudia Coppo, Can Gonen, David Semela, Staffan Wahlin, Murat Kiyici, Ersan Ozaslan, Alexandra Heurgué-Berlot, Emma Nilsson, Alan Bonder, Koray Tascilar, Luigi Muratori, Fatih Güzelbulut, Murat Aladağ, Aldo J. Montano-Loza, Fatih Eren, Mårten Werner, Nurhan Demir, Henriette Ytting, Paolo Muratori, Thomas D. Schiano, Hirsh D. Trivedi, Eric M. Yoshida, Johanna Eliasson, Bursa Uludağ Üniversitesi/Tıp Fakültesi/Dahili Tıp Bilimleri., Eren, Fatih, AAS-6286-2020, Ege Üniversitesi, Efe C., Tascilar K., Henriksson I., Lytvyak E., Alalkim F., Trivedi H., Eren F., Eliasson J., Beretta-Piccoli B.T., Fischer J., Caliskan A.R., Chayanupatkul M., Coppo C., Ytting H., Purnak T., Muratori L., Werner M., Muratori P., Rorsman F., Onnerhag K., Gunsar F., Nilsson E., Heurgue-Berlot A., Guzelbulut F., Demir N., Gonen C., Semela D., Aladag M., Kiyici M., Schiano T.D., Montano-Loza A.J., Berg T., Ozaslan E., Yoshida E.M., Bonder A., Marschall H.-U., and Wahlin S.

Subjects
Male, Scoring system, Survival rate, Kaplan Meier method, Cholagogues and choleretics, Gastroenterology, 0302 clinical medicine, Cholagogue, Pathology, Histological progression, Treatment outcome, Child, Hepatic encephalopathy, Prognosis, Ursodeoxycholic acid, Multicenter study, Clinical trial, Retrospective study, Cirrhosis, Biochemical response, Primary biliary cirrhosis, liver, autoimmune, human, 030220 oncology & carcinogenesis, Predictive value of tests, Risk stratification, Disease Progression, Dose-response relationship, drug, Cohort studies, 030211 gastroenterology & hepatology, Cohort analysis, Human, medicine.medical_specialty, Sex factor, Cholangitis, Biliary Liver Cirrhosis, Obeticholic Acid, Major clinical study, Article, Adverse outcome, 03 medical and health sciences, Age, Severity of illness, Dose response, Humans, Disease exacerbation, Survival analysis, Confidence interval, Biliary cirrhosis, Follow up, Globe, digestive system diseases, Event free survival, United States, Retrospective studies, International cooperation, Gastroenterology & hepatology, Internationality, Survival, Middle aged, Priority journal, Risk assessment, Liver Cirrhosis, Biliary, Ascites, Validation study, Europe, Female, France, Sex factors, Age factors, medicine.drug, Adult, Canada, Proportional hazards models, Adolescent, Kaplan-Meier estimate, Hazard ratio, Placebo-controlled trial, Predictive value, macromolecular substances, Outcomes, Proportional hazards model, Internal medicine, medicine, Mortality, Hepatology, business.industry, Drug administration, Bleeding, Drug administration schedule, Retrospective cohort study, Severity of illness index, Spain, Bezafibrate, business, Prediction, Controlled study
Abstract

EgeUn###, INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.

Published
2019

33. Diagnosis of primary biliary cholangitis in a 'teen' male patient

Author

Marco Lenzi, Luigi Muratori, Paolo Muratori, Muratori, Paolo, Lenzi, Marco, and Muratori, Luigi

Subjects
Pediatrics, medicine.medical_specialty, Primary (chemistry), Text mining, Hepatology, Male patient, business.industry, Gastroenterology, medicine, Primary biliary cholangitis, autoimmunity, medicine.disease_cause, business, Autoimmunity
Abstract

not available

Published
2019

34. Predictive factors of poor response to therapy in Autoimmune Hepatitis

Author

Luigi Muratori, Giampaolo Bianchi, Claudine Lalanne, Paolo Muratori, Marco Lenzi, Muratori, Paolo, Lalanne, Claudine, Bianchi, Giampaolo, Lenzi, Marco, and Muratori, Luigi

Subjects
Liver Cirrhosis, Male, Cirrhosis, Databases, Factual, Drug Resistance, Azathioprine, Autoimmune hepatitis, Antibodies, Viral, Gastroenterology, 0302 clinical medicine, Liver Function Tests, Adrenal Cortex Hormones, Young adult, Child, Aged, 80 and over, biology, medicine.diagnostic_test, Medicine (all), Age Factors, Alanine Transaminase, Middle Aged, Prognosis, Hepatitis, Autoimmune, Treatment Outcome, Italy, Liver, Autoimmune liver disease, Child, Preschool, Liver function test, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, Adolescent, Immunology, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Aspartate Aminotransferases, Aged, Cirrhosi, Hepatology, business.industry, Stepwise regression, medicine.disease, Logistic Models, Alanine transaminase, Immunoglobulin G, biology.protein, business, Liver function tests
Abstract

Aim To evaluate “ex ante” the predictive factors of incomplete/absent response to the standard therapy in a well characterized series of Autoimmune Hepatitis (AIH) patients from Italy. Methods Of 282 AIH patients screened from our database 166 (59%) had a sustained response and 116 (41%) had an incomplete/absent response to the therapy; all patients were analyzed for the clinical, serological and histological parameters at diagnosis. Results The patients with incomplete/absent response were characterized by significantly younger age (30 aa vs 42 aa p = 0.001) and a significantly higher frequency of cirrhosis at diagnosis than patients who had a complete response to therapy (26% vs 3% p

Published
2016

35. Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis

Author

Alessandro Granito, Marco Lenzi, Claudine Lalanne, Fabio Cassani, Luigi Muratori, G. Pappas, Angela Fabbri, Chiara Masi, R. Menichella, Paolo Muratori, Chiara Quarneti, Chiara Quarneti, Paolo Muratori, Claudine Lalanne, Angela Fabbri, Rita Menichella, Alessandro Granito, Chiara Masi, Marco Lenzi, Fabio Cassani, Georgios Pappa, Luigi Muratori, DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, DIPARTIMENTO DI SCIENZE PER LA QUALITA' DELLA VITA, Facolta' di MEDICINA e CHIRURGIA, AREA MIN. 06 - Scienze mediche, and Da definire

Subjects
Liver Cirrhosis, Male, Cirrhosis, Fluorescent Antibody Technique, Kaplan-Meier Estimate, Gastroenterology, Cohort Studies, Pruritu, Primary biliary cirrhosis, Fluorescent Antibody Technique, Indirect, Fatigue, Blotting, Liver Cirrhosis, Biliary, Medicine (all), Biliary, Ursodeoxycholic Acid, Middle Aged, Autoantibodie, Ursodeoxycholic acid, Italy, Cohort, Disease Progression, Female, medicine.symptom, Western, Human, medicine.drug, Cohort study, Adult, Indirect, medicine.medical_specialty, Antimitochondrial antibodies, Blotting, Western, Symptomatic, Enzyme-Linked Immunosorbent Assay, Transaminase, Asymptomatic, Follow-Up Studie, Internal medicine, medicine, Humans, Transaminases, Autoantibodies, Cirrhosi, Hepatology, business.industry, Pruritus, Autoantibody, Alkaline Phosphatase, medicine.disease, Therapy, Follow-Up Studies, Antimitochondrial antibodie, Cohort Studie, business
Abstract

none 11 no First published: 23 April 2014 Background & Aims: In recent years, primary biliary cirrhosis is mostly diagnosed in patients who are asymptomatic; however, a proportion of cases still present with typical complaints such as fatigue and/or pruritus. We compared biochemical, histological and immunological features of patients with or without fatigue and/or pruritus at onset to see whether the different clinical presentation may eventually impact on disease progression. Methods: We analysed the Bologna cohort of 216 patients with primary biliary cirrhosis referred to our Centre between 1997 and 2007, according to symptomatic (fatigue and/or pruritus) or asymptomatic presentation. Clinical, biochemical, histological and immunological feature at diagnosis, response to ursodeoxycholic acid and progression of the disorder were compared after a mean follow-up of 81 ± 75 months. Results: At diagnosis, symptomatic patients were significantly more often women (98.6% vs. 87.2%, P = 0.004), younger (mean age 49 ± 12 vs. 55 ± 12 years, P = 0.003) and with more pronounced biochemical activity, as indicated by higher alkaline phosphatase (mean 2.93 ± 2 vs. 2.12, P = 0.002) and aminotransferase (mean 1.92 ± 1 vs. 1.47 ± 1.27, P = 0.014) levels, whereas histological stage and autoantibody profile were similar. Symptomatic patients were less likely to respond to ursodeoxycholic acid therapy (63% vs. 81%, P = 0.006) and developed more often cirrhosis and its complications (31% vs. 13%, P = 0.004). Conclusions: Fatigue and/or pruritus at onset identify a subset of patients with primary biliary cirrhosis who preferentially are women, younger, with a particularly active disease, less responsive to ursodeoxycholic acid treatment, and more inclined to evolve to cirrhosis and its complications. Chiara Quarneti; Paolo Muratori; Claudine Lalanne; Angela Fabbri; Rita Menichella; Alessandro Granito; Chiara Masi; Marco Lenzi; Fabio Cassani; Georgios Pappas; Luigi Muratori Chiara Quarneti; Paolo Muratori; Claudine Lalanne; Angela Fabbri; Rita Menichella; Alessandro Granito; Chiara Masi; Marco Lenzi; Fabio Cassani; Georgios Pappas; Luigi Muratori

Published
2014

36. Antimitochondrial antibodies in patients with autoimmune hepatitis: a large multicenter study

Author

Nikolaos Gatselis, Kalliopi Zachou, Aldo Montano-Loza, Eduardo Luiz Rachid Cançado, Teruko Arinaga-Hino, Paolo Muratori, Cumali Efe, Annarosa Floreani, Pietro Invernizzi, Atsushi Takahashi, Akinobu Takaki, Benedetta Terziroli Beretta-Piccoli, Bart Van Hoek, Ellina Lytvyak, Laura Vilar Guedes, Tuğrul Purnak, Nora Cazzagon, Vasiliki Lygoura, Pinelopi Arvaniti, Eirini Rigopoulou, Luigi Muratori, and George Dalekos

Subjects
Hepatology
Published
2020

37. Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis

Author

Mårten Werner, Hannes Hagström, Cumali Efe, Luigi Muratori, Naim Alkhouri, Tugrul Purnak, Thomas Berg, Paolo Muratori, Haider Al Taii, Thomas D. Schiano, Fin Stolze Larsen, Aldo J. Montano-Loza, Niklas Aehling, Eric M. Yoshida, Ersan Ozaslan, Rahima A. Bhanji, Michael A. Heneghan, Henriette Ytting, Staffan Wahlin, Daniel Klintman, Efe, Cumali, Taii, Haider Al, Ytting, Henriette, Aehling, Nikla, Bhanji, Rahima A., Hagström, Hanne, Purnak, Tugrul, Muratori, Luigi, Werner, Mårten, Muratori, Paolo, Klintman, Daniel, Schiano, Thomas D., Montano-Loza, Aldo J., Berg, Thoma, Larsen, Fin Stolze, Alkhouri, Naim, Ozaslan, Ersan, Heneghan, Michael A., Yoshida, Eric M., and Wahlin, Staffan

Subjects
Male, Cirrhosis, Physiology, medicine.medical_treatment, Autoimmune hepatitis, Liver transplantation, Mycophenolate, Gastroenterology, Immunosuppressive Agent, 0302 clinical medicine, Transplant surgery, Second line, immune system diseases, Retrospective Studie, Child, Pediatric, Mycophenolate mofetil, Hepatitis, Autoimmune, surgical procedures, operative, Treatment Outcome, 030220 oncology & carcinogenesis, Tacrolimu, 030211 gastroenterology & hepatology, Female, Immunosuppressive Agents, Human, medicine.medical_specialty, Adolescent, chemical and pharmacologic phenomena, Second-line, Autoimmune hepatiti, Tacrolimus, Drug Administration Schedule, Follow-Up Studie, 03 medical and health sciences, Internal medicine, medicine, Humans, Retrospective Studies, Cirrhosi, business.industry, Hepatology, Mycophenolic Acid, medicine.disease, digestive system diseases, business, Follow-Up Studies
Abstract

Background: We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine). Patients and Methods: We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8–182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy. Results: Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal. Conclusions: Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.

Published
2018

38. Clinical and prognostic implications of acute onset of Autoimmune Hepatitis: An Italian multicentre study

Author

Giampaolo Bianchi, Paolo Muratori, Pietro Invernizzi, Claudine Lalanne, Giorgia Stangos, Marco Lenzi, Vincenzo Ronca, Marco Carbone, Luigi Muratori, Annarosa Floreani, L. Perini, Nora Cazzagon, Muratori, Paolo, Carbone, Marco, Stangos, Giorgia, Perini, Lisa, Lalanne, Claudine, Ronca, Vincenzo, Cazzagon, Nora, Bianchi, Giampaolo, Lenzi, Marco, Floreani, Annarosa, Invernizzi, Pietro, Muratori, Luigi, Muratori, P, Carbone, M, Stangos, G, Perini, L, Lalanne, C, Ronca, V, Cazzagon, N, Bianchi, G, Lenzi, M, Floreani, A, Invernizzi, P, and Muratori, L

Subjects
Liver Cirrhosis, Male, Cirrhosis, medicine.medical_treatment, Azathioprine, Autoimmune hepatitis, Adrenal Cortex Hormone, Gastroenterology, Liver disease, 0302 clinical medicine, Adrenal Cortex Hormones, Retrospective Studie, Autoimmune disease, Child, Aged, 80 and over, Immunosuppression, Middle Aged, Prognosis, Hepatitis, Autoimmune, Liver, Italy, 030220 oncology & carcinogenesis, Child, Preschool, Acute Disease, Disease Progression, 030211 gastroenterology & hepatology, Female, medicine.drug, Human, Adult, medicine.medical_specialty, Adolescent, Logistic Model, Prognosi, Liver Cirrhosi, Transaminase, 03 medical and health sciences, Young Adult, Internal medicine, Hepatology, medicine, Humans, International Normalized Ratio, Transaminases, Retrospective Studies, Aged, business.industry, Retrospective cohort study, Bilirubin, medicine.disease, digestive system diseases, Logistic Models, business
Abstract

Autoimmune Hepatitis (AIH) can present under clinical profile as acute hepatitis of unexplained cause. We analyzed clinical, therapeutical and prognostic implications of AIH presenting as acute hepatitis in a cohort of patients admitted to 3 referral Centres in Italy. AIH onset was considered acute when transaminases were higher than 10 times the normal limit and/or bilirubin higher than 5 mg/ml (irrespectively from the histology, available only in 62% of cases). Among 479 patients diagnosed as AIH, 202 (43%) met the criteria of acute onset. This former group of patients on the basis of the histology has been subdivided in the "genuine" acute onset (83 pts) and acute "on chronic" onset (45 pts) At onset, clinical acute AIH showed significantly higher ALT, bilirubin and INR levels (p < 0.001 for all), lower albumin values (p = 0.001), similar IgG levels; Response to treatment was similar between the two groups. The progression to liver cirrhosis or its complications was significantly less frequent in acute onset AIH (13% vs. 22%, p = 0.02). The "genuine" acute patients showed a higher albumin serum levels (40 vs. 36, p = 0.001), lower INR levels (1.12 vs. 1.26, p = 0.002) and less tendency to the progression of liver disease (7% vs. 12%, p = NS) with respect to acute "on chronic" onset patients. Clinical acute hepatitis represents a common presentation of AIH, responds to standard immunosuppression regimen and would seem to be correlated with a better long-term prognosis.

Published
2018

39. Diagnostic approach to autoimmune hepatitis

Author

Luigi Muratori, Paolo Muratori, Marco Lenzi, Fabio Cassani, Claudine Lalanne, Muratori, Paolo, Lenzi, Marco, Cassani, Fabio, Lalanne, Claudine, and Muratori, Luigi

Subjects
0301 basic medicine, Cirrhosis, Anti-nuclear antibody, Immunology, Myocytes, Smooth Muscle, MEDLINE, Disease, Autoimmune hepatitis, Autoimmune hepatiti, Immunologic Tests, pattern, anti smooth muscle antibodie, 03 medical and health sciences, Liver disease, 0302 clinical medicine, medicine, Immunology and Allergy, Animals, Humans, interface hepatiti, Pathology, Molecular, Autoantibodies, business.industry, Autoantibody, medicine.disease, autoantibodie, Hepatitis, Autoimmune, 030104 developmental biology, Liver, Antibodies, Antinuclear, 030211 gastroenterology & hepatology, Differential diagnosis, liver kidney microsome type 1, business, antinuclear antibodie, hypergammaglobulinemia, Biomarkers
Abstract

Introduction: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if left without treatment, can evolve into cirrhosis and possibly liver failure. The diagnosis of AIH is hampered by the lack of specific and reliable markers of the disease and a number of clinical, biochemical, immunological, histological and genetic factors should be considered to reach a confident diagnosis Areas covered: Clinical expression of AIH, histological features, serological and genetic profiles, differential diagnosis, overlap with other autoimmune liver diseases, assessed on the basis of personal experience and review of published literature in the last 10Â years through a systematic Medline search (keywords: autoimmune hepatitis, diagnosis) Expert commentary: Notwithstanding numerous efforts to identify simple and reliable markers of the disease, the diagnosis of AIH is still based on the combination of histological, immunological and biochemical features and often can represent a real challenge for the hepatologist.

Published
2017

40. Rebounds after discharge from the emergency department for community-acquired pneumonia: focus on the usefulness of severity scoring systems

Author

Rodolfo, Ferrari, Pierluigi, Viale, Paolo, Muratori, Fabrizio, Giostra, Daniela, Agostinelli, Roberto, Lazzari, Riccardo, Voza, Mario, Cavazza, and Ferrari R, Viale P, Muratori P, Giostra F, Agostinelli D, Lazzari R, Voza R, Cavazza M

Subjects
Adult, Male, community-acquired pneumonia, Adolescent, emergency department, CRB-65 score, risk stratification, Patient Readmission, Severity of Illness Index, Young Adult, continuity of care, CURB-65 score, Humans, Aged, Aged, 80 and over, admit versus discharge, community-acquired pneumonia, severity scoring systems, rebounds, CURB-65 score, CRB-65 score, emergency department, clinical judgment, risk stratification, admit versus discharge, continuity of care, Pneumonia, Middle Aged, rebounds, Patient Discharge, severity scoring systems, Community-Acquired Infections, Female, Original Article, Emergency Service, Hospital, clinical judgment
Abstract

Summary. Background: Community-acquired pneumonia (CAP) is common cause of hospital admission and leading cause of morbidity and mortality. Severity scoring systems are used to predict risk profile, outcome and mortality, and to help decisions about management strategies. Aim of the work and Methods: To critically analyze pneumonia “rebound” cases, once discharged from the emergency department (ED) and afterwards admitted. We conducted an observational clinical study in the acute setting of a university teaching hospital, prospectively analyzing, in a 1 year period, demographic, medical, clinical and laboratory data, and the outcome. Results: 249 patients were discharged home with diagnosis of CAP; 80 cases (32.1%) resulted in the high-intermediate risk class according to CURB-65 or CRB-65. Twelve patients (4.8%) presented to the ED twice and were then admitted. At their first visit 5 were in the high-intermediate risk group; just 4 of them were in the non-low risk group at the time of their admission. The rebound cohort showed some peculiar abnormalities in laboratory parameters (coagulation and renal function) and severe chest X-rays characteristics. None died in 30 days. Conclusions: The power of CURB-65 to correctly predict mortality for CAP patients discharged home from the ED is not confirmed by our results; careful clinical judgement seems to be irreplaceable in the management process. Many patients with a high-intermediate risk according to CURB-65 can be safely treated as outpatients, according to adequate welfare conditions; we identified a subgroup of cases that should worth a special attention and, therefore, a brief observation period in the ED before the final decision to safely discharge or admit. (www.actabiomedica.it)

Published
2017

41. Safety and efficacy of direct-acting antivirals for the treatment of chronic hepatitis C in a real-world population aged 65 years and older

Author

Lorenzo Badia, Pietro Andreone, Paolo Caraceni, Paolo Muratori, Elisa Negri, Gian Maria Prati, Maria Cristina Morelli, Federica Buonfiglioli, A. Porro, Giuseppe Mazzella, Ilaria Serio, Fabio Conti, Ranka Vukotic, Francesco Giuseppe Foschi, Claudine Lalanne, Stefano Brillanti, Veronica Bernabucci, Giovanni Vitale, Marco Massari, Marta Morotti, DIPARTIMENTO DI SCIENZE BIOMEDICHE E NEUROMOTORIE, DIPARTIMENTO DI SCIENZE MEDICHE E CHIRURGICHE, DIPARTIMENTO DI SCIENZE PER LA QUALITA' DELLA VITA, Facolta' di MEDICINA e CHIRURGIA, AREA MIN. 06 - Scienze mediche, Da definire, Conti, F., Brillanti, S., Buonfiglioli, F., Vukotic, R., Morelli, M.C., Lalanne, C., Massari, M., Foschi, F.G., Bernabucci, V., Serio, I., Prati, G.M., Negri, E., Badia, L., Caraceni, P., Muratori, P., Vitale, G., Porro, A., Morotti, M., Mazzella, G., and Andreone, P.

Subjects
Cirrhosis, antiviral therapy, cirrhosis, elderly, hepatitis C virus, interferon-free, Adult, Aged, Aged, 80 and over, Antiviral Agents, Genotype, Hepacivirus, Hepatitis C, Chronic, Humans, Italy, Middle Aged, Retrospective Studies, Sustained Virologic Response, Tertiary Care Centers, Treatment Outcome, Young Adult, Hepatology, Infectious Diseases, Virology, Antiviral therapy, 0302 clinical medicine, Elderly, Clinical endpoint, 80 and over, 030212 general & internal medicine, Young adult, Chronic, Hepatitis C virus, Hepatitis C, Tolerability, 030211 gastroenterology & hepatology, medicine.medical_specialty, Renal function, Infectious Disease, 03 medical and health sciences, Internal medicine, medicine, Interferon-free, Cirrhosi, business.industry, Retrospective cohort study, medicine.disease, Surgery, Regimen, business, Hepatitis C viru
Abstract

none 20 no The availability of direct-acting antiviral agents (DAA) regimens has expanded the pool of patients eligible for treatment. However, data on the virologic response and tolerability of DAAs in elderly patients are lacking. We evaluated the efficacy and safety of DAAs in patients with advanced fibrosis/cirrhosis in real-life practice with the focus on those aged ≥65 years. Between January and December 2015, all consecutive patients with HCV-related advanced fibrosis/cirrhosis treated with DAA at eleven tertiary referral centres in Emilia Romagna (Italy) were enrolled. Regimen choice was based on viral genotype and stage of disease, according to guidelines. The primary end point was sustained virologic response 12 weeks after the end of treatment (SVR12). Overall, 282 of 556 (50.7%) patients evaluated were elderly, most of them with cirrhosis. Antiviral therapy was stopped prematurely in four (1.4%) patients. Two patients, both with cirrhosis, died during treatment due to worsening of liver/renal function. SVR12 was achieved by 94.7% and was comparable to that obtained in patients aged

Published
2017

42. Autoantibodies in antimithocondrial antibodies negative primary biliary cholangitis

Author

Paolo Muratori, Luigi Muratori, Muratori, Paolo, and Muratori, Luigi

Subjects
0301 basic medicine, medicine.medical_specialty, Cholangitis, Cholangitis, Sclerosing, Gastroenterology, Autoimmune Diseases, 03 medical and health sciences, CHOLANGITIS SCLEROSING, 0302 clinical medicine, Internal medicine, medicine, Humans, Autoantibodies, Primary (chemistry), Hepatology, biology, business.industry, Liver Cirrhosis, Biliary, Autoantibody, 030104 developmental biology, 030220 oncology & carcinogenesis, autoantobodies, liver, biology.protein, Antibody, business
Abstract

NA

Published
2017

43. Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis

Author

Rahima A. Bhanji, Daniel Klintman, Hanns-Ulrich Marschall, Eric M. Yoshida, Albert Parés, Thomas D. Schiano, Aldo J. Montano-Loza, Niklas F. Müller, Fin Stolze Larsen, Mustafa Cengiz, Cumali Efe, Mårten Werner, Xiong Ma, Fulya Gunsar, Tugrul Purnak, Hannes Hagström, Henriette Ytting, Michael A. Heneghan, Staffan Wahlin, Michele M. Tana, Qixia Wang, Sumita Verma, Ersan Ozaslan, Luigi Muratori, Paolo Muratori, Thomas Berg, Alexandra Heurgué-Berlot, Ege Üniversitesi, Efe, C, Hagström, H, Ytting, H, Bhanji, Ra, Müller, Nf, Wang, Q, Purnak, T, Muratori, Luigi, Werner, M, Marschall, Hu, Muratori, Paolo, Gunşar, F, Klintman, D, Parés, A, Heurgué-Berlot, A, Schiano, Td, Cengiz, M, May-Sien Tana, M, Ma, X, Montano-Loza, Aj, Berg, T, Verma, S, Larsen, F, Ozaslan, E, Heneghan, Ma, Yoshida, Em, and Wahlin, S.

Subjects
Male, medicine.medical_treatment, Azathioprine, Autoimmune hepatitis, Liver transplantation, Mycophenolate, Gastroenterology, 0302 clinical medicine, Medicine, Child, Autoimmune Liver Disease, Middle Aged, Europe, Hepatitis, Autoimmune, Treatment Outcome, surgical procedures, operative, 030220 oncology & carcinogenesis, Female, 030211 gastroenterology & hepatology, Immunosuppressive Agents, psychological phenomena and processes, medicine.drug, Adult, inorganic chemicals, Canada, China, medicine.medical_specialty, Standard of care, Adolescent, Drug-Related Side Effects and Adverse Reactions, behavioral disciplines and activities, Tacrolimus, Young Adult, 03 medical and health sciences, Internal medicine, otorhinolaryngologic diseases, Humans, Autoimmune liver disease, Aged, Retrospective Studies, Simplified Criteria, Second-line therapy, Hepatology, business.industry, Mycophenolic Acid, medicine.disease, United States, Liver Transplantation, Immunology, sense organs, business, Liver Failure, RC
Abstract

WOS: 000415165200027, PubMed ID: 28603052, BACKGROUND & AIMS: Predniso(lo) ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo) ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.

Published
2017

44. Factors Associated With Response to Therapy and Outcome of Patients With Primary Biliary Cirrhosis With Features of Autoimmune Hepatitis

Author

Thomas D. Schiano, Chiara Masi, Gérard Thiéfin, Cumali Efe, Tugrul Purnak, Taylan Kav, Paolo Muratori, Alexandra Heurgue Berlot, Solange Bresson–Hadni, Yucel Ustundag, Staffan Wahlin, Luigi Muratori, Ersan Ozaslan, Zonguldak Bülent Ecevit Üniversitesi, Ozaslan, E, Efe, C, Heurgué-Berlot, A, Kav, T, Masi, C, Purnak, T, Muratori, L, Ustündag, Y, Bresson-Hadni, S, Thiéfin, G, Schiano, Td, Wahlin, S, and Muratori, P.

Subjects
Adult, Male, Cholagogues and Choleretics, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Autoimmunity, Autoimmune hepatitis, Malignancy, Gastroenterology, Cohort Studies, Young Adult, Primary biliary cirrhosis, Internal medicine, medicine, Humans, Aged, Retrospective Studies, Aged, 80 and over, Hepatology, Liver Cirrhosis, Biliary, business.industry, Ursodeoxycholic Acid, Immunosuppression, Retrospective cohort study, Odds ratio, Mycophenolate-Mofetil, Middle Aged, medicine.disease, digestive system diseases, Tacrolimus, Ursodeoxycholic acid, Hepatitis, Autoimmune, Paris Criteria, Treatment Outcome, Immunology, Female, business, Immunosuppressive Agents, medicine.drug
Abstract

Background & Aims: For patients with primary biliary cirrhosis (PBC) with features of autoimmune hepatitis (AIH), treatment with ursodeoxycholic acid (UDCA) alone or in combination with immunosuppression is controversial. Little is known about the factors associated with initial response to therapy or outcome. We performed a retrospective analysis of treatment strategies and factors associated with outcomes of patients with PBC-AIH. Methods: We analyzed data from 88 patients who were diagnosed with PBC-AIH according to Paris criteria, from 7 centers in 5 countries. First-line therapies included UDCA alone (n= 30) or a combination of UDCA and immunosuppression (n= 58). Results: Of patients who received UDCA alone as the first-line therapy, 37% did not respond to treatment. Severe interface hepatitis was independently associated with lack of response to treatment (P= .024; odds ratio, 0.05; 95% confidence interval, 0.004-0.68). The combination of UDCA and immunosuppression was effective in 73% of patients who had not been previously treated or had not responded to UDCA. The presence of advanced fibrosis was associated with lack of response to the combination of UDCA and immunosuppression (P= .003; odds ratio, 0.13; 95% confidence interval, 0.03-0.48). Second-line immunosuppressive agents (cyclosporine, tacrolimus, and mycophenolate mofetil) led to biochemical remission in 54% of patients who did not respond to initial immunosuppression. Liver transplants were given to 4patients with PBC-AIH. Five patients died during follow-up (3 from liver-related causes). Conclusions: In a retrospective study of a large cohort of patients with PBC-AIH, UDCA alone did not produce a biochemical response in most patients with severe interface hepatitis; these patients require additional therapy with immunosuppression. Second-line immunosuppressive agents are effective in controlling disease activity in patients who do not respond to conventional immunosuppression. © 2014 AGA Institute.

Published
2014

45. Imbalance of Neutrophils and Lymphocyte Counts Can Be Predictive of Hepatocellular Carcinoma Occurrence in Hepatitis C-related Cirrhosis Treated With Direct-acting Antivirals

Author

Andrea Casadei Gardini, Paolo Caraceni, Maria Cristina Morelli, Fabio Conti, Marco Lenzi, Mauro Bernardi, Stefano Brillanti, Cristina Crespi, Paolo Muratori, Lorenzo Badia, Pietro Andreone, Francesco Giuseppe Foschi, Giuseppe Mazzella, Gabriella Verucchi, Sonia Berardi, Federico Ravaioli, Federica Buonfiglioli, Luigi Bolondi, Casadei Gardini, Andrea, Conti, Fabio, Foschi, Francesco Giuseppe, Brillanti, Stefano, Andreone, Pietro, Mazzella, Giuseppe, Ravaioli, Federico, Buonfiglioli, Federica, Bolondi, Luigi, Crespi, Cristina, Lenzi, Marco, Muratori, Paolo, Verucchi, Gabriella, Badia, Lorenzo, Bernardi, Mauro, Caraceni, Paolo, Morelli, Maria Cristina, and Berardi, Sonia

Subjects
Liver Cirrhosis, 0301 basic medicine, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, Neutrophils, Liver Cirrhosi, Lymphocyte, DIRECT ACTING ANTIVIRALS, Antiviral Agents, Hepatology, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Carcinoma, Humans, Lymphocyte Count, Antiviral Agent, business.industry, Neutrophil, Liver Neoplasms, Hepatocellular, Hepatitis C, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Liver Neoplasm, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, business, Human
Abstract

N/A

Published
2018

46. Immune inflammation indicators and ALBI score to predict occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals

Author

Cristina Crespi, Giuseppe Mazzella, Fabio Conti, F.G. Foschi, P. Andreone, M. Lenzi, Paolo Muratori, Luigi Bolondi, Stefano Brillanti, Gabriella Verucchi, Giorgia Marisi, Andrea Casadei Gardini, Federica Buonfiglioli, Matteo Ravaioli, Elisabetta Petracci, Giovanni Vitale, Lorenzo Badia, and Ranka Vukotic

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, Hepatocellular carcinoma, Internal medicine, Gastroenterology, medicine, medicine.disease, DIRECT ACTING ANTIVIRALS, business, Immune inflammation
Published
2018

47. Celiac disease in autoimmune cholestatic liver disorders

Author

Umberto Volta, Paolo Muratori, Dolores Fuentes, Luigi Muratori, A. Linares, Francesco B. Bianchi, Daniela Zauli, N. Petrolini, Alessandro Granito, Luis Rodrigo, Lorenza Veronesi, and Umberto Volta, Luis Rodrigo, Alessandro Granito, Nunzio Petrolini, Paolo Muratori, Luigi Muratori, Antonio Linares, Lorenza Veronesi, Dolores Fuentes, Daniela Zauli, Francesco B Bianchi

Subjects
Adult, Male, Celiac disease autoimmune cholestatic liver diseases, medicine.medical_specialty, Glutens, Cholangitis, Tissue transglutaminase, Biopsy, Cholangitis, Sclerosing, medicine.disease_cause, Gastroenterology, Gliadin, Coeliac disease, Autoimmune Diseases, Autoimmunity, Primary sclerosing cholangitis, Liver disease, Primary biliary cirrhosis, Cholestasis, GTP-Binding Proteins, Internal medicine, medicine, Humans, Protein Glutamine gamma Glutamyltransferase 2, Intestinal Mucosa, Aged, Autoantibodies, Aged, 80 and over, Transglutaminases, Hepatology, biology, Liver Cirrhosis, Biliary, business.industry, Middle Aged, medicine.disease, Immunoglobulin A, Celiac Disease, Immunoglobulin G, Immunology, biology.protein, Female, business
Abstract

OBJECTIVES: In this study, serological screening for celiac disease (CD) was performed in patients with autoimmune cholestasis to define the prevalence of such an association and to evaluate the impact of gluten withdrawal on liver disease associated with gluten sensitive enteropathy. METHODS: Immunoglobulin A endomysial, human and guinea pig tissue transglutaminase antibodies, and immunoglobulin A and G gliadin antibodies were sought in 255 patients with primary biliary cirrhosis, autoimmune cholangitis, and primary sclerosing cholangitis. RESULTS: Immunoglobulin A endomysial and human tissue transglutaminase antibodies were positive in nine patients (seven primary biliary cirrhosis, one autoimmune cholangitis, and one primary sclerosing cholangitis), whose duodenal biopsy results showed villous atrophy consistent with CD. Two of these patients had a malabsorption syndrome, and one had iron-deficiency anemia. Clinical and biochemical signs of cholestasis did not improve after gluten withdrawal in the three patients with severe liver disease. A longer follow-up of the six celiac patients with mild liver damage is needed to clarify whether gluten restriction can contribute to slow down the progression of liver disease. CONCLUSIONS: The high prevalence of CD (3.5%) in autoimmune cholestasis suggests that serological screening for CD should be routinely performed in such patients by immunoglobulin A endomysial or human tissue transglutaminase antibodies.

Published
2002

48. Direct acting antivirals for the treatment of elderly patients with HCV advanced disease in the real life practice

Author

F.G. Foschi, Arianna Lanzi, Gabriella Verucchi, Marianna Mastroroberto, L. Appolloni, Ilaria Serio, Giovanni Vitale, Cristina Crespi, Stefano Brillanti, A. Scuteri, Giuseppe Mazzella, M. Morotti, G. Lazzarini, A. Porro, Fabio Conti, Paolo Muratori, Lorenzo Badia, Pietro Andreone, M. Lenzi, M.C. Morelli, Federica Buonfiglioli, Conti, F., Scuteri, A., Vitale, G., Lazzarini, G., Porro, A., Muratori, P., Serio, I., Buonfiglioli, F., Badia, L., Lanzi, A., Mastroroberto, M., Appolloni, L., Morotti, M., Morelli, M.C., Foschi, F.G., Verucchi, G., Brillanti, S., Crespi, C., Lenzi, M., Mazzella, G., and Andreone, P.

Subjects
Simeprevir, medicine.medical_specialty, direct acting antivirals, HCV, fibrosis, cirrhosis, Sofosbuvir, viruses, Pharmacology, DIRECT ACTING ANTIVIRALS, Gastroenterology, chemistry.chemical_compound, Internal medicine, medicine, Advanced disease, In patient, High prevalence, Hepatology, business.industry, Ribavirin, virus diseases, direct acting antivirals, HCV, fibrosis, cirrhosis, biochemical phenomena, metabolism, and nutrition, digestive system diseases, chemistry, business, medicine.drug
Abstract

Introduction: The availability of interferon-sparing therapy with direct acting antivirals (DAAs) has expanded the pool of patients eligible for treatment. Despite this, data on the efficacy and safety of these treatments in elderly are lacking. Aim: To evaluate the efficacy and safety of the treatment with DAA-based regimens in HCV patients aged ≥65 years with advanced fibrosis/cirrhosis in a real life clinical setting. Methods: Retrospective data of elderly patients treated with DAAs from January to November 2015 in 7 tertiary referral center of Emilia-Romagna Region (Italy) were collected. Patients received: sofosbuvir (SOF) [n = 35], SOF + simeprevir (SMV) [n = 78], SOF + daclatasvir (DCV) [n = 21], SOF + ledipasvir [n = 17], SMV + DCV [n = 4], ombitasvir/paritaprevir/ritonavir only [n = 3] or with dasasbuvir [n = 42]. Ribavirin was added at the physician's discretion according weight. The primary efficacy endpoint was sustained virological response 12 weeks after the last dose of study drug (SVR12). Results: Overall, 200 consecutive elderly patients were treated. The median age was 74 years (range: 65-85) and 90 (45%) aged ≥75 years; 49% were male, 50.5% were treatment experienced and 85% had cirrhosis. The majority (76%) had genotype (GT) 1b. To date, 155 patients completed treatment. Two cirrhotics died during the therapy and were excluded from final analysis because the cause of death was unrelated to the treatment. Overall, 94 have reached week 12 of post-treatment and the SVR12 was 91.5% (86/94). According to GT, the SVR12 was achieved in 69/73 (94.5%) with GT1, in 16/18 (88.9%) with GT2 and in 1/3 (33.4%) with GT4 infection. Relapse occurred more commonly in cirrhotic patients. No serious adverse events have been reported until now. Complete safety data for the cohort and updated SVR data will be presented. Conclusions: This preliminary data indicate that DAA-based regimen have a similar efficacy compared to registrative studies and without significant side effects in HCV elderly patients in a real-world setting.

Published
2016

49. Treatment with direct acting antiviral agents-based regimen in HCV patients with advanced liver disease: Analysis of an Italian multicenter observational study

Author

Marco Lenzi, Giuseppe Mazzella, Ilaria Serio, A. Scuteri, Lorenzo Badia, Pietro Andreone, F.G. Foschi, Fabio Conti, A. Porro, Paolo Muratori, M. Morotti, R. Di Donato, Arianna Lanzi, Cristina Crespi, Gabriella Verucchi, Marianna Mastroroberto, Stefano Brillanti, L. Appolloni, G. Lazzarini, M.C. Morelli, Federica Buonfiglioli, Conti, F., Scuteri, A., Di Donato, R., Lazzarini, G., Porro, A., Muratori, P., Serio, I., Buonfiglioli, F., Badia, L., Lanzi, A., Mastroroberto, M., Appolloni, L., Morotti, M., Morelli, M.C., Foschi, F.G., Verucchi, G., Brillanti, S., Crespi, C., Lenzi, M., Mazzella, G., and Andreone, P.

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, direct acting antiviral agents, HCV, fibrosis, cirrhosis, Gastroenterology, medicine.disease, Surgery, Liver disease, Regimen, direct acting antiviral agents, HCV, fibrosis, cirrhosis, Fibrosis, Internal medicine, Medicine, Observational study, business, Direct acting
Abstract

Introduction: Non-interferon-based therapy with direct acting antiviral agents (DAA) have become an integral component of treatment for HCV infection but little is known about their real-world effectiveness. Aim: To evaluate the efficacy and safety of the treatment with DAA-based regimen in HCV patients with advanced fibrosis/cirrhosis in a real life clinical setting. Methods: Retrospective data of patients treated with DAA from January to November 2015 in 7 tertiary referral centers in the Emilia-Romagna Region (Italy) were collected. Patients on the waiting list for orthotopic liver transplantation and with HIV co-infection were excluded. Patients received: sofosbuvir (SOF) [n = 74], SOF + simeprevir (SMV) [n = 149], SOF + daclatasvir (DCV) [n = 69], SOF + ledipasvir [n = 43], SMV + DCV [n = 4], ombitasvir/paritaprevir/ritonavir only [n = 11] or with dasasbuvir [n = 84]. Ribavirin was added at the physician's discretion according to weight. The primary efficacy endpoint was sustained virological response 12 weeks after the last dose of study drug (SVR12). Results: Overall, 435 consecutive patients were treated. The median age was 63 years (range: 29–85); 60% were male, 55.2% were treatment experienced and 81.1% had cirrhosis. The majority (56.6%) had genotype (GT) 1b, 12.4% GT1a, 11.3% GT2, 12.6% GT3 and 7.1% GT4. To date, 347 patients completed treatment and 179 the week 12 of post-treatment follow-up. Three cirrhotics died during treatment and were excluded from analysis. Overall, the SVR12 was 88.8% (159/179). According to GT, the SVR12 was achieved in 17/19 (89.5%) GT1a, in 100/111 (90.1%) GT1b, in 24/26 (92.3%) GT2, in 9/11 (81.8%) GT3 and in 9/12 (75%) GT4. Patients with cirrhosis had a lower response rate than those with advanced fibrosis (86.7% vs 97.2%; p = 0.082). Complete safety data for the entire cohort, updated SVR12 will be presented. Conclusions: The DAA-based regimen was efficacious with low relapse rates in HCV patients in a real-world setting. Patients with cirrhosis seems to respond less well to the different regimens used.

Published
2016

50. Asymptomatic Onset of Autoimmune Hepatitis does not Mean Better Prognosis

Author

Luigi Muratori, Marco Lenzi, Claudine Lalanne, and Paolo Muratori

Subjects
medicine.medical_specialty, Cirrhosis, Bilirubin, business.industry, Thyroid, Autoantibody, Autoimmune hepatitis, medicine.disease, Gastroenterology, Asymptomatic, Natural history, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Internal medicine, Immunology, medicine, medicine.symptom, business, Grading (tumors)
Abstract

Clinical presentation of autoimmune hepatitis can be either acute or chronic or totally asymptomatic. The aim of this study was to assess the impact of asymptomatic onset on AIH natural history. Ninety asymptomatic patients were retrospectively compared to 215 with symptoms. Asymptomatic presentation was characterized by lower histological grading and lower mean levels of aminotransferases, bilirubin, gamma-globulins, IgG and anti-dsDNA. On the other hand, asymptomatic patients were more often positive for anti-LKM1 autoantibodies and were more often affected by extrahepatic autoimmune conditions, particularly thyroid and skin disorders. Despite these differences, asymptomatic and symptomatic subjects had similar response to immunosuppressive treatment and comparable prognosis, with a low but considerable rate of progression (23%) towards cirrhosis or its complications.

Published
2016

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