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1. Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis

Author

Nicola E. Owen, Graeme J. Alexander, Sambit Sen, Katherine Bunclark, Gary Polwarth, Joanna Pepke-Zaba, Anthony P. Davenport, Nicholas, W. Morrell, and Paul. D. Upton

Subjects
Bone morphogenetic protein 9, BMP10, Cirrhosis, Endoglin, ELISA, Medicine, Medicine (General), R5-920
Abstract

Background: BMP9, originating from the liver, and BMP10 are circulating BMPs that preserve vascular endothelial integrity. We assessed BMP9, BMP10 and soluble endoglin (sEng) levels and their relationships to liver disease severity and associated pulmonary vascular syndromes in a cohort of well-characterised liver disease patients. Methods: Plasma samples from patients with liver disease (n = 83) and non-disease controls (n = 21) were assayed for BMP9, BMP10 and sEng. Levels were also assessed in a separate cohort of controls (n = 27) and PoPH patients (n = 8). Expression of mRNA and immunohistochemical staining was undertaken in liver biopsy specimens. Plasma BMP activity was assessed using an endothelial cell bioassay. Findings: Plasma BMP9 and BMP10 levels were normal in patients with compensated cirrhosis or fibrosis without cirrhosis, but markedly reduced in patients with decompensated cirrhosis, including those with hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PoPH). Liver biopsy specimens revealed reduced mRNA expression and immunostaining for these ligands. Patient plasma samples with reduced BMP9 and BMP10 levels exhibited low BMP activity that was restored with exogenous BMP9. Endoglin mRNA expression was increased in cirrhotic livers and elevated circulating sEng levels in PoPH and HPS patients suggested increased endothelial sEng shedding in these syndromes. Interpretation: Plasma BMP9 and BMP10 levels are reduced in decompensated cirrhosis, leading to reduced circulating BMP activity on the vascular endothelium. The pulmonary complications of cirrhosis, PoPH and HPS, are associated with markedly reduced BMP9 and BMP10 and increased sEng levels, suggesting that supplementation with exogenous ligands might be a therapeutic approach for PoPH and HPS.

Published
2020
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2. Pulmonary vascular clearance of harmful endogenous macromolecules in a porcine model of acute liver failure

Author

Geir I. Nedredal, Kjetil Elvevold, Marcio F. Chedid, Lars M. Ytrebø, Christopher F. Rose, Sambit Sen, Bård Smedsrød, Rajiv Jalan, and Arthur Revhaug

Subjects
Systemic inflammatory response syndrome, Hyaluronic acid, Liver sinusoidal endothelial cells, Pulmonary intravascular macrophages, Specialties of internal medicine, RC581-951
Abstract

Background. Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake.Results. As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups.Conclusion. Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.

Published
2016
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3. Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls

Author

C. Fiorella Murillo Perez, Holly Fisher, Shaun Hiu, Dorcas Kareithi, Femi Adekunle, Tracy Mayne, Elizabeth Malecha, Erik Ness, Adriaan J. van der Meer, Willem J. Lammers, Palak J. Trivedi, Pier Maria Battezzati, Frederik Nevens, Kris V. Kowdley, Tony Bruns, Nora Cazzagon, Annarosa Floreani, Andrew L. Mason, Albert Parés, Maria-Carlota Londoño, Pietro Invernizzi, Marco Carbone, Ana Lleo, Marlyn J. Mayo, George N. Dalekos, Nikolaos K. Gatselis, Douglas Thorburn, Xavier Verhelst, Aliya Gulamhusein, Harry L.A. Janssen, Rachel Smith, Steve Flack, Victoria Mulcahy, Michael Trauner, Christopher L. Bowlus, Keith D. Lindor, Christophe Corpechot, David Jones, George Mells, Gideon M. Hirschfield, James Wason, Bettina E. Hansen, Richard Sturgess, Christopher Healey, Anton Gunasekera, Yiannis Kallis, Gavin Wright, Thiriloganathan Mathialahan, Richard Evans, Jaber Gasem, David Ramanaden, Emma Ward, Mahesh Bhalme, Paul Southern, James Maggs, Mohamed Yousif, Brijesh Srivastava, Matthew Foxton, Carole Collins, Yash Prasad, Francisco Porras-Perez, Tom Yapp, Minesh Patel, Roland Ede, Martyn Carte, Konrad Koss, Prayman Sattianayagam, Charles Grimley, Jude Tidbury, Dina Mansour, Matilda Beckley, Coral Hollywood, John Ramag, Harriet Gordon, Joanne Ridpath, Bob Grover, George Abouda, Ian Rees, Mark Narain, Imroz Salam, Paul Banim, Debasish Das, Helen Matthews, Faiyaz Mohammed, Rebecca Jones, Sambit Sen, George Bird, Martin Prince, Geeta Prasad, Paul Kitchen, John Hutchinson, Prakash Gupta, Amir Shah, Subrata Saha, Katharine Pollock, Stephen Barclay, Natasha McDonald, Simon Rushbrook, Robert Przemioslo, Andrew Millar, Steven Mitchell, Andrew Davis, Asifabbas Naqvi, Tom Lee, Stephen Ryder, Jane Collier, Matthew Cramp, Richard Aspinal, Jonathan Booth, Earl Williams, Hyder Hussaini, John Christie, Tehreem Chaudhry, Stephen Mann, Aftab Ala, Julia Maltby, Chris Corbett, Saket Singhal, Barbara Hoeroldt, Jeff Butterworth, Andrew Douglas, Rohit Sinha, Simon Panter, Jeremy Shearman, Gary Bray, Michael Roberts, Daniel Forton, Nicola Taylor, Wisam Jafar, Matthew Cowan, Chin Lye Ch'ng, Mesbah Rahman, Emma Wesley, Sanjiv Jain, Aditya Mandal, Mark Wright, Palak Trivedi, Fiona Gordon, Esther Unitt, Andrew Austin, Altaf Palegwala, Vishwaraj Vemala, Andrew Higham, Jocelyn Fraser, Andy Li, Subramaniam Ramakrishnan, Alistair King, Simon Whalley, Ian Gee, Richard Keld, Helen Fellows, James Gotto, Charles Millson, Gastroenterology & Hepatology, and Public Health

Subjects
Liver Cirrhosis, Settore MED/12 - Gastroenterologia, Hepatology, UK PBC, Liver Cirrhosis, Biliary, Obeticholic Acid, Ursodeoxycholic Acid, Gastroenterology, Global PBC, Propensity Score, Transplant-Free Survival, UK-PBC, Chenodeoxycholic Acid, transplant-free survival, obeticholic acid, Humans, propensity score
Abstract

BACKGROUND & AIMS: The Primary Biliary Cholangitis (PBC) Obeticholic Acid (OCA) International Study of Efficacy (POISE) randomized, double-blind, placebo-controlled trial demonstrated that OCA reduced biomarkers associated with adverse clinical outcomes (ie, alkaline phosphatase, bilirubin, aspartate aminotransferase, and alanine aminotransferase) in patients with PBC. The objective of this study was to evaluate time to first occurrence of liver transplantation or death in patients with OCA in the POISE trial and open-label extension vs comparable non-OCA-treated external controls. METHODS: Propensity scores were generated for external control patients meeting POISE eligibility criteria from 2 registry studies (Global PBC and UK-PBC) using an index date selected randomly between the first and last date (inclusive) on which eligibility criteria were met. Cox proportional hazards models weighted by inverse probability of treatment assessed time to death or liver transplantation. Additional analyses (Global PBC only) added hepatic decompensation to the composite end point and assessed efficacy in patients with or without cirrhosis. RESULTS: During the 6-year follow-up, there were 5 deaths or liver transplantations in 209 subjects in the POISE cohort (2.4%), 135 of 1381 patients in the Global PBC control (10.0%), and 281 of 2135 patients in the UK-PBC control (13.2%). The hazard ratios (HRs) for the primary outcome were 0.29 (95% CI, 0.10-0.83) for POISE vs Global PBC and 0.30 (95% CI, 0.12-0.75) for POISE vs UK-PBC. In the Global PBC study, HR was 0.20 (95% CI, 0.03-1.22) for patients with cirrhosis and 0.31 (95% CI, 0.09-1.04) for those without cirrhosis; HR was 0.42 (95% CI, 0.21-0.85) including hepatic decompensation. CONCLUSIONS: Patients treated with OCA in a trial setting had significantly greater transplant-free survival than comparable external control patients. ispartof: Gastroenterology vol:163 issue:6 pages:1630-1642.e3 ispartof: location:United States status: published

Published
2022

4. 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

5. P002 The role of Transient elastography and Platelets count in predicting patients who can avoid Oesophagogastroduodenoscopy for variceal screening. Validating the Baveno VI criteria – experience from a District General Hospital (DGH) for a cohort of patients with heterogonous aetiology of chronic liver disease

Author

Pooja Khanna, Zaw Aung, Luis Neto Pereira, Omar Farouk, Dipal Juthani, Sambit Sen, and Martin Mcgrath

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Cohort, medicine, Etiology, Platelet, General hospital, Transient elastography, Chronic liver disease, medicine.disease, business
Published
2021
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6. Giant Cell Hepatitis – A Rare Association with Connective Tissue Disease

Author

Muhammad K. Nisar, Sambit Sen, Adam Levene, and Maria Rauf

Subjects
Lupus anticoagulant, Pathology, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, medicine.diagnostic_test, Anti-nuclear antibody, business.industry, Undifferentiated connective tissue disease, antiphospholipid antibodies, Case Report, medicine.disease, Connective tissue disease, Scleroderma, giant cell hepatitis, Liver disease, Rheumatology, connective tissue disease, Liver biopsy, medicine, lcsh:RC925-935, Liver function tests, business
Abstract

A 68-year-old gentleman presented to hepatology department with asymptomatic year-long history of stably deranged liver function tests. His peak alkaline phosphatase (ALP), was 828 with alanine transaminase (ALT) of 141. Full liver workup was negative; hence, a liver biopsy was organised, which confirmed giant cell hepatitis (GCH). A computed tomography (CT) scan revealed non-specific interstitial pneumonitis (NSIP) pattern interstitial lung disease supported by lung function tests. Antibody testing showed strongly positive antinuclear antibody (ANA) with anti-polymyositis/scleroderma (anti-PM-SCL) antibody. Clinical picture was in keeping with likely undifferentiated connective tissue disease (UCTD) with polyarthralgia, early morning stiffness, Raynaud’s and nailfold infarcts with capillaritis on nail bed examination. Further testing confirmed triple-positive antiphospholipid antibodies twice 12 weeks apart (immunoglobulin M [IgM] anti beta-2 glycoprotein antibodies, lupus anticoagulant and IgM anticardiolipin antibody). He was treated with mycophenolate and hydroxychloroquine with resolution of symptoms. Giant cell hepatitis is uncommon, with only 100 cases reported worldwide. To our knowledge, this is the only report of GCH in the context of UCTD, highlighting the significance of careful evaluation of liver disease overlap and the successful role of mycophenolate mofetil (MMF) in this setting.

Published
2019

7. 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. 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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. 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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

8. ‘Double-hit’ pegylated interferon-alpha successfully treats Hepatitis B and Hepatitis D co-infection

Author

Meha Bhuva, Sambit Sen, and Marie Moore

Subjects
omcrep/800, medicine.medical_specialty, viruses, Case Report, 030204 cardiovascular system & hematology, medicine.disease_cause, Microbiology, Gastroenterology, omcrep/2000, 03 medical and health sciences, 0302 clinical medicine, Pegylated interferon, Internal medicine, Medicine, 030212 general & internal medicine, Liver injury, business.industry, virus diseases, Hepatitis B, medicine.disease, Hepatitis D, digestive system diseases, Infectious Diseases, Superinfection, Hepatocellular carcinoma, Parasitology, AcademicSubjects/MED00010, business, Viral hepatitis, Viral load, medicine.drug
Abstract

Hepatitis delta (HDV) infection is either acquired simultaneously with, or as a superinfection to, existing Hepatitis B (HBV). It leads to a serious form of chronic viral hepatitis and accelerated liver-related morbidity and mortality including hepatocellular carcinoma. Current treatment regimes propose Pegylated interferon-alpha for 48 weeks however sustained virological response (SVR) rates remain low. We report a patient who initially responded to Pegylated interferon treatment for HBV-HDV co-infection. Although initial improvement in viraemia from both virsues was seen, SVR was not achieved with ongoing progression of liver injury biochemically. However, the summative effect of a second course of Pegylated interferon 2 years later led to HDV cure (SVR 12 months post-treatment), very low level HBV carrier status (with persistently undetectable viral load) and ongoing biochemical normalization. This case illustrates a successful treatment strategy for persistent HBV-HDV co-infection where proposed treatment regimes elicit an initial response but SVR is not achieved.

Published
2020
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9. Reduced circulating BMP10 and BMP9 and elevated endoglin are associated with disease severity, decompensation and pulmonary vascular syndromes in patients with cirrhosis

Author

Paul D. Upton, Gary Polwarth, Sambit Sen, Anthony P. Davenport, Graeme J.M. Alexander, Katherine Bunclark, W. Morrell Nicholas, Joanna Pepke-Zaba, Nicola E. Owen, Davenport, Anthony [0000-0002-2096-3117], Morrell, Nicholas [0000-0001-5700-9792], Upton, Paul [0000-0003-2716-4921], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Liver Cirrhosis, Male, Cirrhosis, Biopsy, Bone morphogenetic protein 9, lcsh:Medicine, Gastroenterology, Severity of Illness Index, Liver disease, Mice, 0302 clinical medicine, Growth Differentiation Factor 2, Hepatopulmonary syndrome, Mice, Knockout, lcsh:R5-920, Portopulmonary hypertension, medicine.diagnostic_test, Endoglin, General Medicine, Middle Aged, 030220 oncology & carcinogenesis, Liver biopsy, Bone Morphogenetic Proteins, ELISA, Female, lcsh:Medicine (General), Adult, medicine.medical_specialty, Hypertension, Pulmonary, Down-Regulation, General Biochemistry, Genetics and Molecular Biology, Cell Line, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Animals, Humans, Decompensation, Aged, business.industry, lcsh:R, medicine.disease, Pulmonary hypertension, BMP10, Disease Models, Animal, 030104 developmental biology, Case-Control Studies, Commentary, business, Hepatopulmonary Syndrome
Abstract

Background BMP9, originating from the liver, and BMP10 are circulating BMPs that preserve vascular endothelial integrity. We assessed BMP9, BMP10 and soluble endoglin (sEng) levels and their relationships to liver disease severity and associated pulmonary vascular syndromes in a cohort of well-characterised liver disease patients. Methods Plasma samples from patients with liver disease (n = 83) and non-disease controls (n = 21) were assayed for BMP9, BMP10 and sEng. Levels were also assessed in a separate cohort of controls (n = 27) and PoPH patients (n = 8). Expression of mRNA and immunohistochemical staining was undertaken in liver biopsy specimens. Plasma BMP activity was assessed using an endothelial cell bioassay. Findings Plasma BMP9 and BMP10 levels were normal in patients with compensated cirrhosis or fibrosis without cirrhosis, but markedly reduced in patients with decompensated cirrhosis, including those with hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PoPH). Liver biopsy specimens revealed reduced mRNA expression and immunostaining for these ligands. Patient plasma samples with reduced BMP9 and BMP10 levels exhibited low BMP activity that was restored with exogenous BMP9. Endoglin mRNA expression was increased in cirrhotic livers and elevated circulating sEng levels in PoPH and HPS patients suggested increased endothelial sEng shedding in these syndromes. Interpretation Plasma BMP9 and BMP10 levels are reduced in decompensated cirrhosis, leading to reduced circulating BMP activity on the vascular endothelium. The pulmonary complications of cirrhosis, PoPH and HPS, are associated with markedly reduced BMP9 and BMP10 and increased sEng levels, suggesting that supplementation with exogenous ligands might be a therapeutic approach for PoPH and HPS.

Published
2020
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10. Pulmonary vascular clearance of harmful endogenous macromolecules in a porcine model of acute liver failure

Author

Kjetil Elvevold, Bård Smedsrød, Lars M. Ytrebø, Marcio F. Chedid, Rajiv Jalan, Arthur Revhaug, Geir I. Nedredal, Sambit Sen, and Christopher F. Rose

Subjects
0301 basic medicine, medicine.medical_specialty, Pathology, Time Factors, Hyaluronic acid, Sus scrofa, Specialties of internal medicine, Tissue plasminogen activator, 03 medical and health sciences, Liver disease, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Macrophages, Alveolar, medicine, Animals, Liver sinusoidal endothelial cells, Receptor, Lung, Serum Albumin, Pulmonary intravascular macrophages, Leukopenia, Hepatology, business.industry, Albumin, Endothelial Cells, Biological Transport, Lung Injury, General Medicine, Liver Failure, Acute, medicine.disease, Systemic inflammatory response syndrome, Disease Models, Animal, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, chemistry, RC581-951, 030211 gastroenterology & hepatology, Tumor necrosis factor alpha, Inflammation Mediators, medicine.symptom, business, Fluorescein-5-isothiocyanate, medicine.drug
Abstract

Background. Pulmonary complications are common in acute liver failure (ALF). The role of the lungs in the uptake of harmful soluble endogenous macromolecules was evaluated in a porcine model of ALF induced by hepatic devascularization (n = 8) vs. controls (n = 8). In additional experiments, pulmonary uptake was investigated in healthy pigs. Fluorochrome-labeled modified albumin (MA) was applied to investigate the cellular uptake. Results. As compared to controls, the ALF group displayed a 4-fold net increased lung uptake of hyaluronan, and 5-fold net increased uptake of both tissue plasminogen activator and lysosomal enzymes. Anatomical distribution experiments in healthy animals revealed that radiolabeled MA uptake (taken up by the same receptor as hyaluronan) was 53% by the liver, and 24% by the lungs. The lung uptake of LPS was 14% whereas 60% remained in the blood. Both fluorescence and electron microscopy revealed initial uptake of MA by pulmonary endothelial cells (PECs) with later translocation to pulmonary intravascular macrophages (PIMs). Moreover, the presence of PIMs was evident 10 min after injection. Systemic inflammatory markers such as leukopenia and increased serum TNF-α levels were evident after 20 min in the MA and LPS groups. Conclusion. Significant lung uptake of harmful soluble macromolecules compensated for the defect liver scavenger function in the ALF-group. Infusion of MA induced increased TNF-α serum levels and leukopenia, similar to the effect of the known inflammatory mediator LPS. These observations suggest a potential mechanism that may contribute to lung damage secondary to liver disease.

Published
2016

11. Sequence analysis of exon 1 of the ferritin light chain (FTL) gene can reveal the rare disorder ‘hereditary hyperferritinaemia without cataracts’

Author

Sambit Sen, Charlotte Bradbury, Wale Atoyebi, Helene Dreau, Terence S. Elsey, P Bignell, Meha Bhuva, Rosalynd Johnston, and William J.H. Griffiths

Subjects
Genetics, 030213 general clinical medicine, Sequence analysis, Exons, Hematology, Biology, medicine.disease, Iron Metabolism Disorders, Cataract, Ferritin light chain, 03 medical and health sciences, Exon, 0302 clinical medicine, Cataracts, haemochromatosis, 030220 oncology & carcinogenesis, Apoferritins, medicine, Humans, genetics, iron overload, Gene
Abstract

[no abstract]

Published
2018
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12. Pretreatment prediction of response to ursodeoxycholic acid in primary biliary cholangitis: development and validation of the UDCA Response Score

Author

Marco Carbone, Alessandra Nardi, Steve Flack, Guido Carpino, Nikoletta Varvaropoulou, Caius Gavrila, Ann Spicer, Jonathan Badrock, Francesca Bernuzzi, Vincenzo Cardinale, Holly F Ainsworth, Michael A Heneghan, Douglas Thorburn, Andrew Bathgate, Rebecca Jones, James M Neuberger, Pier Maria Battezzati, Massimo Zuin, Simon Taylor-Robinson, Maria F Donato, John Kirby, Robert Mitchell-Thain, Annarosa Floreani, Fotios Sampaziotis, Luigi Muratori, Domenico Alvaro, Marco Marzioni, Luca Miele, Fabio Marra, Edoardo Giannini, Eugenio Gaudio, Vincenzo Ronca, Giulia Bonato, Laura Cristoferi, Federica Malinverno, Alessio Gerussi, Deborah D Stocken, Heather J Cordell, Gideon M Hirschfield, Graeme J Alexander, Richard N Sandford, David E Jones, Pietro Invernizzi, George F Mells, Caradog Thomas, Meshbah Rahman, Tom Yapp, Chin Lye Ch'ng, Melanie Harrison, Richard Sturgess, Roman Galaska, Chris Healey, Jessica Whiteman, Marek Czaijkowski, Catherine Gray, Anton Gunasekera, Pranab Gyawli, Purushothaman Premchand, Steven Mann, Keith Elliott, Kapil Kapur, Alan Watson, Graham Foster, Paul Trembling, Javaid Subhani, Rory Harvey, Roger McCorry, Carolyn Adgey, Lucie Hobson, Caroline Mulvaney-Jones, Richard Evans, Thiriloganathan Mathialahan, David Ramanaden, Jaber Gasem, Greta Van Duyvenvoorde, Christopher Shorrock, Katie Seward, Paul Southern, Jeremy Tibble, Ruth Penn, David Gorard, Jane Maiden, Rose Damant, Altaf Palegwala, Susan Jones, Graeme Alexander, George Mells, Richard Sandford, Sunil Dolwani, Martin Prince, Valeria Silvestre, Matthew Foxton, Eleanor Dungca, Harriet Mitchison, Natalie Wheatley, Ian Gooding, Helen Doyle, Mazn Karmo, Melanie Kent, Sushma Saksena, Delyth Braim, Minesh Patel, Susan Lord, Roland Ede, Alison Paton, Andrew Austin, Nicola Lancaster, Joanna Sayer, Andrew Gibbins, Karen Hogben, Chris Hovell, Neil Fisher, Martyn Carter, Konrad Koss, Janine Musselwhite, Florin Muscariu, Andrzej Piotreowicz, Alexandra McKay, Charles Grimley, David Neal, Lai Ting Tan, Guan Lim, Jacqueline Brighton, Carole Foale, Aftab Ala, Athar Saeed, Kerry Flahive, Gordon Wood, Paula Townshend, Chris Ford, Jonathan Brown, Jean Kordula, Jane Bowles, Mark Wilkinson, Caroline Palmer, John Ramage, Harriet Gordon, James Featherstone, Jo Ridpath, Theodore Ngatchu, Sass Levi, Syed Shaukat, Joy Sadeghian, Ray Shidrawi, Bronwen Williams, George Abouda, Sarah Jones, Claire Duggan, Abigail Hynes, Mark Narain, Ian Rees, Imroz Salam, Mary Crossey, Ashley Brown, Carolyn MacNicol, Simon Williams, Elva Wilhelmsen, Paul Banim, Parizade Raymode, Andrew Chilton, Debasish Das, Hye-Jeong Lee, Howard Curtis, Michael Heneghan, Markus Gess, Emma Durant, IM Drake, Rebecca Bishop, Mervyn Davies, Mark Aldersley, Noma Ncube, Alistair McNair, Raj Srirajaskanthan, Sambit Sen, Rebecca Casey, George Bird, Mike Mendall, Caroline Cowley, Adrian Barnardo, Paul Kitchen, Kevin Yoong, Kelly Amore, Dawn Sirdefield, Jacky Orpe, Ray Mathew, George MacFaul, Aruna Wrigth, Amir Shah, Chris Evans, Janie Keggans, Bridget Bird, Gwen Baxter, Subrata Saha, Katharine Pollock, Maggie Hughes, Peter Bramley, Emma Grieve, Karin Young, Andrew Fraser, Ashis Mukhopadhya, Kate Ocker, Peter Mills, Francis Hines, Chris Shallcross, Joy Wilkins, Leonie Grellier, Stewart Campbell, Kirsty Martin, Caron Innes, Alan Shepherd, Simon Rushbrook, Talal Valliani, Robert Przemioslo, Helen Fairlamb, Chris Macdonald, Anne Eastick, Jane Metcalf, Elizabeth Tanqueray, Udi Shmueli, Becky Holbrook, Andrew Davis, Julie Browning, Asifabbas Naqvi, Kirsten Walker, Tom Lee, Juliette Verheyden, Susan Slininger, Stephen D Ryder, Roger Chapman, Jane Collier, Denise O'Donnell, Lizzie Stafford, Kate Williamson, Linda Kent, Howard Klass, Mary Ninkovic, Linda March, Matthew Cramp, Diane Simpson, Christine Dickson, Nicholas Sharer, Maria Hayes, Patrick Goggin, Mary Quinne, Sallyanne Pearson, Barbara Hoeroldt, Linda Jones, Alice Wright, Jonathan Booth, Alison Loftus, George Lipscomb, Hannah Dewhurst, Emma Gunter, Earl Williams, Anna Fouracres, Liz Farrington, Lyn Graves, Hyder Hussaini, Bill Stableforth, Suzie Marriott, Reuben Ayres, Marina Leoni, Andrew Burroughs, Eileen Marshall, David Tyrer, Kate Martin, Martin Lombard, Imran Patanwala, Lola Dali-Kemmery, Victoria Lambourne, Julia Maltby, Samir Vyas, Julie Colley, Bal Shinder, Saket Singhal, Jayne Jones, Marisa Mills, Dermot Gleeson, Mandy Carnahan, Jeff Butterworth, Kerenza Boulton, Natalie Taylor, Keith George, Tim Harding, Julie Tregonning, Andrew Douglass, Carly Brown, Gayle Clifford, Simon Panter, Denise Gocher, Jeremy Shearman, Gary Bray, Maria Hamilton, Graham Butcher, Daniel Forton, John Mclindon, Janette Curtis, Debashis Das, Tracey Shewan, Matthew Cowan, Gregory Whatley, Mariam Nasseri, Bob Grover, Nurani Sivaramakrishnan, Samantha Ducker, Kathryn Houghton, David Jones, Laura Griffiths, Sherill Tripoli, Maxton Pitcher, Ervin Shpuza, Nikki White, Deb Ghosh, Andrew Douds, Marie Green, Matthew Brookes, Lourdes Cumlat, Voi Shim Wong, Karen Warner, Kimberley Netherton, Adtya Mandal, Snjiv Jain, Hemant Gupta, Pradeep Sanghi, Steve Pereira, James Neuberger, Bridget Gunson, Gideon Hirschfield, Reina Teegan Lim, Susan Gallagher, Darren Clement, Alison Brind, Gill Watts, Mcdonald Mupudzi, Mark Wright, Jane Gitahi, Fiona Gordon, Denis Gocher, Esther Unitt, Hilary Pateman, Sally Batham, Toby Delahooke, Allister Grant, Jill Conder, Andrew Higham, Mark Cox, Lynn O'Donohoe, Lynn Currie, Alistair King, Metod Oblak, Carole Collins, Simon Whalley, Marie Quinn, Yolanda Baird, Isobel Amey, Jocelyn Fraser, Andy Li, Donna Cotterill, Andrew Bell, Amit Singhal, Ian Gee, Sandra Greer, Yeng Ang, Rupert Ransford, Joanna Allison, James Gotto, Simon Dyer, Helen Sweeting, Charles Millson, Giancarlo Labbadia, Maria Consiglia Bragazzi, Pietro Andreone, Francesco Azzaroli, Andrea Galli, Mirko Tarocchi, Antonio Gasbarrini, Antonio Grieco, Giuseppe Marrone, Maria Francesca Donato, Luca Valenti, Luca Maroni, Cristina Rigamonti, Antonino Picciotto, Carbone, M, Nardi, A, Flack, S, Carpino, G, Varvaropoulou, N, Gavrila, C, Spicer, A, Badrock, J, Bernuzzi, F, Cardinale, V, Ainsworth, H, Heneghan, M, Thorburn, D, Bathgate, A, Jones, R, Neuberger, J, Battezzati, P, Zuin, M, Taylor-Robinson, S, Donato, M, Kirby, J, Mitchell-Thain, R, Floreani, A, Sampaziotis, F, Muratori, L, Alvaro, D, Marzioni, M, Miele, L, Marra, F, Giannini, E, Gaudio, E, Ronca, V, Bonato, G, Cristoferi, L, Malinverno, F, Gerussi, A, Stocken, D, Cordell, H, Hirschfield, G, Alexander, G, Sandford, R, Jones, D, Invernizzi, P, Mells, G, Thomas, C, Rahman, M, Yapp, T, Lye Ch'ng, C, Harrison, M, Sturgess, R, Galaska, R, Healey, C, Whiteman, J, Czaijkowski, M, Gray, C, Gunasekera, A, Gyawli, P, Premchand, P, Mann, S, Elliott, K, Kapur, K, Watson, A, Foster, G, Trembling, P, Subhani, J, Harvey, R, Mccorry, R, Adgey, C, Hobson, L, Mulvaney-Jones, C, Evans, R, Mathialahan, T, Ramanaden, D, Gasem, J, Van Duyvenvoorde, G, Shorrock, C, Seward, K, Southern, P, Tibble, J, Penn, R, Gorard, D, Maiden, J, Damant, R, Palegwala, A, Jones, S, Dolwani, S, Prince, M, Silvestre, V, Foxton, M, Dungca, E, Mitchison, H, Wheatley, N, Gooding, I, Doyle, H, Karmo, M, Kent, M, Saksena, S, Braim, D, Patel, M, Lord, S, Ede, R, Paton, A, Austin, A, Lancaster, N, Sayer, J, Gibbins, A, Hogben, K, Hovell, C, Fisher, N, Carter, M, Koss, K, Musselwhite, J, Muscariu, F, Piotreowicz, A, Mckay, A, Grimley, C, Neal, D, Ting Tan, L, Lim, G, Brighton, J, Foale, C, Ala, A, Saeed, A, Flahive, K, Wood, G, Townshend, P, Ford, C, Brown, J, Kordula, J, Bowles, J, Wilkinson, M, Palmer, C, Ramage, J, Gordon, H, Featherstone, J, Ridpath, J, Ngatchu, T, Levi, S, Shaukat, S, Sadeghian, J, Shidrawi, R, Williams, B, Abouda, G, Duggan, C, Hynes, A, Narain, M, Rees, I, Salam, I, Crossey, M, Brown, A, Macnicol, C, Williams, S, Wilhelmsen, E, Banim, P, Raymode, P, Chilton, A, Das, D, Lee, H, Curtis, H, Gess, M, Durant, E, Drake, I, Bishop, R, Davies, M, Aldersley, M, Ncube, N, Mcnair, A, Srirajaskanthan, R, Sen, S, Casey, R, Bird, G, Mendall, M, Cowley, C, Barnardo, A, Kitchen, P, Yoong, K, Amore, K, Sirdefield, D, Orpe, J, Mathew, R, Macfaul, G, Wrigth, A, Shah, A, Evans, C, Keggans, J, Bird, B, Baxter, G, Saha, S, Pollock, K, Hughes, M, Bramley, P, Grieve, E, Young, K, Fraser, A, Mukhopadhya, A, Ocker, K, Mills, P, Hines, F, Shallcross, C, Wilkins, J, Grellier, L, Campbell, S, Martin, K, Innes, C, Shepherd, A, Rushbrook, S, Valliani, T, Przemioslo, R, Fairlamb, H, Macdonald, C, Eastick, A, Metcalf, J, Tanqueray, E, Shmueli, U, Holbrook, B, Davis, A, Browning, J, Naqvi, A, Walker, K, Lee, T, Verheyden, J, Slininger, S, Ryder, S, Chapman, R, Collier, J, O'Donnell, D, Stafford, L, Williamson, K, Kent, L, Klass, H, Ninkovic, M, March, L, Cramp, M, Simpson, D, Dickson, C, Sharer, N, Hayes, M, Goggin, P, Quinne, M, Pearson, S, Hoeroldt, B, Jones, L, Wright, A, Booth, J, Loftus, A, Lipscomb, G, Dewhurst, H, Gunter, E, Williams, E, Fouracres, A, Farrington, L, Graves, L, Hussaini, H, Stableforth, B, Marriott, S, Ayres, R, Leoni, M, Burroughs, A, Marshall, E, Tyrer, D, Lombard, M, Patanwala, I, Dali-Kemmery, L, Lambourne, V, Maltby, J, Vyas, S, Colley, J, Shinder, B, Singhal, S, Jones, J, Mills, M, Gleeson, D, Carnahan, M, Butterworth, J, Boulton, K, Taylor, N, George, K, Harding, T, Tregonning, J, Douglass, A, Brown, C, Clifford, G, Panter, S, Gocher, D, Shearman, J, Bray, G, Hamilton, M, Butcher, G, Forton, D, Mclindon, J, Curtis, J, Shewan, T, Cowan, M, Whatley, G, Nasseri, M, Grover, B, Sivaramakrishnan, N, Ducker, S, Houghton, K, Griffiths, L, Tripoli, S, Pitcher, M, Shpuza, E, White, N, Ghosh, D, Douds, A, Green, M, Brookes, M, Cumlat, L, Wong, V, Warner, K, Netherton, K, Mandal, A, Jain, S, Gupta, H, Sanghi, P, Pereira, S, Gunson, B, Lim, R, Gallagher, S, Clement, D, Brind, A, Watts, G, Mupudzi, M, Wright, M, Gitahi, J, Gordon, F, Unitt, E, Pateman, H, Batham, S, Delahooke, T, Grant, A, Conder, J, Higham, A, Cox, M, O'Donohoe, L, Currie, L, King, A, Oblak, M, Collins, C, Whalley, S, Quinn, M, Baird, Y, Amey, I, Fraser, J, Li, A, Cotterill, D, Bell, A, Singhal, A, Gee, I, Greer, S, Ang, Y, Ransford, R, Allison, J, Gotto, J, Dyer, S, Sweeting, H, Millson, C, Labbadia, G, Bragazzi, M, Andreone, P, Azzaroli, F, Galli, A, Tarocchi, M, Gasbarrini, A, Grieco, A, Marrone, G, Valenti, L, Maroni, L, Rigamonti, C, Picciotto, A, Sampaziotis, Fotios [0000-0003-0812-7586], Sandford, Richard [0000-0002-7437-0560], Apollo - University of Cambridge Repository, Carbone, Marco, Nardi, Alessandra, Flack, Steve, Carpino, Guido, Varvaropoulou, Nikoletta, Gavrila, Caiu, Spicer, Ann, Badrock, Jonathan, Bernuzzi, Francesca, Cardinale, Vincenzo, Ainsworth, Holly F, Heneghan, Michael A, Thorburn, Dougla, Bathgate, Andrew, Jones, Rebecca, Neuberger, James M, Battezzati, Pier Maria, Zuin, Massimo, Taylor-Robinson, Simon, Donato, Maria F, Kirby, John, Mitchell-Thain, Robert, Floreani, Annarosa, Sampaziotis, Fotio, Muratori, Luigi, Alvaro, Domenico, Marzioni, Marco, Miele, Luca, Marra, Fabio, Giannini, Edoardo, Gaudio, Eugenio, Ronca, Vincenzo, Bonato, Giulia, Cristoferi, Laura, Malinverno, Federica, Gerussi, Alessio, Stocken, Deborah D, Cordell, Heather J, Hirschfield, Gideon M, Alexander, Graeme J, Sandford, Richard N, Jones, David E, Invernizzi, Pietro, Mells, George F, Thomas, Caradog, Rahman, Meshbah, Yapp, Tom, Lye Ch'ng, Chin, Harrison, Melanie, Sturgess, Richard, Galaska, Roman, Healey, Chri, Whiteman, Jessica, Czaijkowski, Marek, Gray, Catherine, Gunasekera, Anton, Gyawli, Pranab, Premchand, Purushothaman, Mann, Steven, Elliott, Keith, Kapur, Kapil, Watson, Alan, Foster, Graham, Trembling, Paul, Subhani, Javaid, Harvey, Rory, McCorry, Roger, Adgey, Carolyn, Hobson, Lucie, Mulvaney-Jones, Caroline, Evans, Richard, Mathialahan, Thiriloganathan, Ramanaden, David, Gasem, Jaber, Van Duyvenvoorde, Greta, Shorrock, Christopher, Seward, Katie, Southern, Paul, Tibble, Jeremy, Penn, Ruth, Gorard, David, Maiden, Jane, Damant, Rose, Palegwala, Altaf, Jones, Susan, Alexander, Graeme, Mells, George, Sandford, Richard, Dolwani, Sunil, Prince, Martin, Silvestre, Valeria, Foxton, Matthew, Dungca, Eleanor, Mitchison, Harriet, Wheatley, Natalie, Gooding, Ian, Doyle, Helen, Karmo, Mazn, Kent, Melanie, Saksena, Sushma, Braim, Delyth, Patel, Minesh, Lord, Susan, Ede, Roland, Paton, Alison, Austin, Andrew, Lancaster, Nicola, Sayer, Joanna, Gibbins, Andrew, Hogben, Karen, Hovell, Chri, Fisher, Neil, Carter, Martyn, Koss, Konrad, Musselwhite, Janine, Muscariu, Florin, Piotreowicz, Andrzej, McKay, Alexandra, Grimley, Charle, Neal, David, Ting Tan, Lai, Lim, Guan, Brighton, Jacqueline, Foale, Carole, Ala, Aftab, Saeed, Athar, Flahive, Kerry, Wood, Gordon, Townshend, Paula, Ford, Chri, Brown, Jonathan, Kordula, Jean, Bowles, Jane, Wilkinson, Mark, Palmer, Caroline, Ramage, John, Gordon, Harriet, Featherstone, Jame, Ridpath, Jo, Ngatchu, Theodore, Levi, Sa, Shaukat, Syed, Sadeghian, Joy, Shidrawi, Ray, Williams, Bronwen, Abouda, George, Jones, Sarah, Duggan, Claire, Hynes, Abigail, Narain, Mark, Rees, Ian, Salam, Imroz, Crossey, Mary, Brown, Ashley, MacNicol, Carolyn, Williams, Simon, Wilhelmsen, Elva, Banim, Paul, Raymode, Parizade, Chilton, Andrew, Das, Debasish, Lee, Hye-Jeong, Curtis, Howard, Heneghan, Michael, Gess, Marku, Durant, Emma, Drake, I.M., Bishop, Rebecca, Davies, Mervyn, Aldersley, Mark, Ncube, Noma, McNair, Alistair, Srirajaskanthan, Raj, Sen, Sambit, Casey, Rebecca, Bird, George, Mendall, Mike, Cowley, Caroline, Barnardo, Adrian, Kitchen, Paul, Yoong, Kevin, Amore, Kelly, Sirdefield, Dawn, Orpe, Jacky, Mathew, Ray, MacFaul, George, Wrigth, Aruna, Shah, Amir, Evans, Chri, Keggans, Janie, Bird, Bridget, Baxter, Gwen, Saha, Subrata, Pollock, Katharine, Hughes, Maggie, Bramley, Peter, Grieve, Emma, Young, Karin, Fraser, Andrew, Mukhopadhya, Ashi, Ocker, Kate, Mills, Peter, Hines, Franci, Shallcross, Chri, Wilkins, Joy, Grellier, Leonie, Campbell, Stewart, Martin, Kirsty, Innes, Caron, Shepherd, Alan, Rushbrook, Simon, Valliani, Talal, Przemioslo, Robert, Fairlamb, Helen, Macdonald, Chri, Eastick, Anne, Metcalf, Jane, Tanqueray, Elizabeth, Shmueli, Udi, Holbrook, Becky, Davis, Andrew, Browning, Julie, Naqvi, Asifabba, Walker, Kirsten, Lee, Tom, Verheyden, Juliette, Slininger, Susan, Ryder, Stephen D, Chapman, Roger, Collier, Jane, O'Donnell, Denise, Stafford, Lizzie, Williamson, Kate, Kent, Linda, Klass, Howard, Ninkovic, Mary, March, Linda, Cramp, Matthew, Simpson, Diane, Dickson, Christine, Sharer, Nichola, Hayes, Maria, Goggin, Patrick, Quinne, Mary, Pearson, Sallyanne, Hoeroldt, Barbara, Jones, Linda, Wright, Alice, Booth, Jonathan, Loftus, Alison, Lipscomb, George, Dewhurst, Hannah, Gunter, Emma, Williams, Earl, Fouracres, Anna, Farrington, Liz, Graves, Lyn, Hussaini, Hyder, Stableforth, Bill, Marriott, Suzie, Ayres, Reuben, Leoni, Marina, Burroughs, Andrew, Marshall, Eileen, Tyrer, David, Martin, Kate, Lombard, Martin, Patanwala, Imran, Dali-Kemmery, Lola, Lambourne, Victoria, Maltby, Julia, Vyas, Samir, Colley, Julie, Shinder, Bal, Singhal, Saket, Jones, Jayne, Mills, Marisa, Gleeson, Dermot, Carnahan, Mandy, Butterworth, Jeff, Boulton, Kerenza, Taylor, Natalie, George, Keith, Harding, Tim, Tregonning, Julie, Douglass, Andrew, Brown, Carly, Clifford, Gayle, Panter, Simon, Gocher, Denise, Shearman, Jeremy, Bray, Gary, Hamilton, Maria, Butcher, Graham, Forton, Daniel, Mclindon, John, Curtis, Janette, Das, Debashi, Shewan, Tracey, Cowan, Matthew, Whatley, Gregory, Nasseri, Mariam, Grover, Bob, Sivaramakrishnan, Nurani, Ducker, Samantha, Houghton, Kathryn, Jones, David, Griffiths, Laura, Tripoli, Sherill, Pitcher, Maxton, Shpuza, Ervin, White, Nikki, Ghosh, Deb, Douds, Andrew, Green, Marie, Brookes, Matthew, Cumlat, Lourde, Wong, Voi Shim, Warner, Karen, Netherton, Kimberley, Mandal, Adtya, Jain, Snjiv, Gupta, Hemant, Sanghi, Pradeep, Pereira, Steve, Neuberger, Jame, Gunson, Bridget, Hirschfield, Gideon, Lim, Reina Teegan, Gallagher, Susan, Clement, Darren, Brind, Alison, Watts, Gill, Mupudzi, Mcdonald, Wright, Mark, Gitahi, Jane, Gordon, Fiona, Gocher, Deni, Unitt, Esther, Pateman, Hilary, Batham, Sally, Delahooke, Toby, Grant, Allister, Conder, Jill, Higham, Andrew, Cox, Mark, O'Donohoe, Lynn, Currie, Lynn, King, Alistair, Oblak, Metod, Collins, Carole, Whalley, Simon, Quinn, Marie, Baird, Yolanda, Amey, Isobel, Fraser, Jocelyn, Li, Andy, Cotterill, Donna, Bell, Andrew, Singhal, Amit, Gee, Ian, Greer, Sandra, Ang, Yeng, Ransford, Rupert, Allison, Joanna, Gotto, Jame, Dyer, Simon, Sweeting, Helen, Millson, Charle, Labbadia, Giancarlo, Bragazzi, Maria Consiglia, Andreone, Pietro, Azzaroli, Francesco, Galli, Andrea, Tarocchi, Mirko, Gasbarrini, Antonio, Grieco, Antonio, Marrone, Giuseppe, Donato, Maria Francesca, Valenti, Luca, Maroni, Luca, Rigamonti, Cristina, Picciotto, Antonino, and Medical Research Council (MRC)

Subjects
Male, Cholagogues and Choleretics, Cirrhosis, medicine.medical_treatment, PROGRESSION, Liver transplantation, PHENOTYPE, Gastroenterology, UDCA, 0302 clinical medicine, Primary biliary cirrhosis, Risk Factors, Medicine, Age of Onset, CIRRHOSIS, TREE, OUTCOMES, Settore MED/12 - Gastroenterologia, medicine.diagnostic_test, Liver Cirrhosis, Biliary, Ursodeoxycholic Acid, Area under the curve, URSODIOL, Middle Aged, Ursodeoxycholic acid, Treatment Outcome, Primary biliary cholangitis, ursodeoxycholic acid, 030220 oncology & carcinogenesis, Liver biopsy, Area Under Curve, 030211 gastroenterology & hepatology, Female, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, CONTROLLED-TRIAL, Hepatology, Decision Support Techniques, Time-to-Treatment, Biliary injury, 03 medical and health sciences, Internal medicine, Humans, Transaminases, Science & Technology, Gastroenterology & Hepatology, Italian PBC Study Group and the UK–PBC Consortium, business.industry, Bilirubin, medicine.disease, Alkaline Phosphatase, ROC Curve, CELLS, Linear Models, business
Abstract

Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p

Published
2018
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13. Artificial Liver Support Systems in the Management of Complications of Cirrhosis

Author

Sambit Sen, Nathan Davies, Rajiv Jalan, and Vanessa Stadlbauer

Subjects
Liver Cirrhosis, medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, Bioartificial liver device, Equipment Design, medicine.disease, Systemic inflammation, Liver, Artificial, law.invention, Survival Rate, Treatment Outcome, Spontaneous bacterial peritonitis, Hepatorenal syndrome, law, Intensive care, medicine, Humans, Liver function, medicine.symptom, Intensive care medicine, business, Hepatic encephalopathy, Liver Failure
Abstract

Acute-on-chronic liver failure (ACLF) is associated with multiorgan dysfunction requiring intensive care support and carries an exceptionally high risk of mortality. Decompensation of liver cirrhosis is triggered by different precipitating events but the final common pathway is hypothesized to be unregulated systemic inflammation. The concept of an artificial liver that may impact favorably upon the inflammatory response and provide liver function to prevent complications seems to be promising. This article aims to describe the currently available artificial and bioartificial systems and reviews their effect on different complications of cirrhosis, such as liver function and hepatic hemodynamics, renal function and systemic hemodynamics, hepatic encephalopathy, inflammation/infection, and coagulation. Due to the difficulties in studying large patient numbers with ACLF and the heterogeneity of this patient group, only limited data on survival are available. The currently available studies indicate that there is a survival benefit for artificial and bioartificial liver support in certain subgroups of patients; however, further studies are warranted. At present several studies in this field are under way. In this review several of the companies interested in the manufacture of the respective devices provide an up-to-date report of ongoing trials. In summary, artificial and bioartificial liver support are already playing important roles in the treatment of complications of ACLF. Better understanding of the pathophysiology of ACLF, further development of the current systems, and their evaluation in appropriately controlled clinical studies are necessary to translate their application to improvement in outcome of patients with ACLF.

Published
2008
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14. International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways

Author

Cordell, Heather J., Younghun, Han, Mells, George F., Yafang, Li, Hirschfield, Gideon M., Greene, Casey S., Gang, Xie, Juran 7, Brian D., Dakai Zhu, 2, Qian 2, David C., Floyd, James A. B., Morley, Katherine I., Daniele Prati 11, Ana Lleo 12, Daniele, Cusi, Eric Gershwin 15, M., Anderson 8, Carl A., Lazaridis 7, Konstantinos N., Pietro, Invernizzi, Seldin 15, Michael F., Sandford, Richard N., Amos 2, Christopher I., Siminovitch, Katherine A., Schlicht 7, Erik M., Craig Lammert, 7, Atkinson 19, Elizabeth J., Chan 19, Landon L., Mariza de Andrade 19, Tobias Balschun 20, Mason 21, Andrew L., Myers 22, Robert P., Jinyi Zhang 23, Piotr Milkiewicz 24, Jia Qu 25, Odin 26, Joseph A., Luketic 27, Velimir A., Bacon 28, Bruce R., Bodenheimer Jr 29, Henry C., Valentina Liakina 30, Catherine Vincent 31, Cynthia Levy 32, Gregersen, Peter K., Almasio, 33 Piero L., Domenico Alvaro 35, Pietro Andreone 36, Angelo Andriulli 37, Cristina Barlassina 38, Pier Maria Battezzati 39, Antonio Benedetti 40, Francesca Bernuzzi 41, Ilaria Bianchi 41, Maria Consiglia Bragazzi 42, Maurizia Brunetto 43, Savino Bruno 41, Giovanni Casella 44, Barbara Coco 43, Agostino Colli 45, Massimo Colombo 46, Silvia Colombo 47, Carmela Cursaro 36, Lory Saveria Croce, ` 48, Andrea Crosignani 39, Maria Francesca Donato 46, Gianfranco Elia 49, Luca Fabris 50, Carlo Ferrari 49, Annarosa Floreani 51, Barbara Foglieni 11, Rosanna Fontana 37, Galli, Andrea, Roberta Lazzari 51, Fabio Macaluso 34, Federica Malinverno 46, Marra, Fabio, Marco Marzioni 40, Alberto Mattalia 54, Renzo Montanari 55, Lorenzo Morini 56, Filomena Morisco 57, Mousa Hani S., 41, Luigi Muratori 36, Paolo Muratori 36, Niro 37, Grazia A., Palmieri 58, Vincenzo O., Antonio Picciotto 59, Mauro Podda 41, Piero Portincasa 58, Vincenzo Ronca 41, Floriano Rosina 60, Sonia Rossi 41, Ilaria Sogno 41, Giancarlo Spinzi 61, Marta Spreafico 11, Mario, Strazzabosco, Sonia Tarallo 60, Tarocchi, Mirko, Claudio Tiribelli 48, Pierluigi Toniutto 64, Maria Vinci 65, Massimo, Zuin, Chin Lye Ch’ng, Mesbah Rahman 68, Tom Yapp 69, Richard Sturgess 70, Christopher Healey 71, Marek, Czajkowski, Anton, Gunasekera, Pranab Gyawali 77, Purushothaman Premchand 78, Kapil Kapur 79, Richard Marley 80, Graham Foster 80, Alan Watson 81, Aruna Dias 82, Javaid Subhani 83, Rory Harvey 84, Roger McCorry 85, David Ramanaden 86, Jaber Gasem 87, Richard Evans 88, Thiriloganathan Mathialahan 89, Christopher Shorrock 90, George Lipscomb 91, Paul Southern 92, Jeremy Tibble 93, David, Gorard, Altaf Palegwala 98, Susan, Jones, Marco Carbone 101, Mohamed Dawwas 101, Graeme Alexander 101, Sunil, Dolwani, Martin Prince 104, Matthew Foxton 105, David Elphick 106, Harriet Mitchison 107, Ian Gooding 108, Mazn Karmo 109, Sushma, Saksena, Mike, Mendall, Minesh, Patel, Roland, Ede, Andrew Austin 119, Joanna, Sayer, Lorraine Hankey 122, Christopher Hovell 122, Neil Fisher 123, Martyn, Carter, Konrad Koss 126, Andrzej, Piotrowicz, Charles, Grimley, David, Neal, Guan Lim 135, Sass, Levi, Aftab Ala 138, Andrea Broad 139, Athar Saeed 139, Gordon Wood 140, Jonathan, Brown, Mark, Wilkinson, Harriet Gordon 145, John Ramage 146, Jo Ridpath 147, Theodore, Ngatchu, Bob Grover 151, Syed Shaukat 152, Ray Shidrawi 153, George, Abouda, Faiz Ali 156, Ian Rees 157, Imroz Salam 158, Mark Narain 159, Ashley, Brown, Simon Taylor Robinson 162, Simon Williams 163, Leonie Grellier 164, Paul Banim 165, Debasish Das 166, Andrew Chilton 166, Michael Heneghan 167, Howard, Curtis, Markus Gess 170, Ian, Drake, Mark, Aldersley, Mervyn, Davies, Rebecca, Jones, Alastair McNair 175, Raj Srirajaskanthan 176, Maxton, Pitcher, Sambit Sen 179, George, Bird, Adrian Barnardo 182, Paul Kitchen 182, Kevin Yoong 183, Oza, Chirag, Nurani Sivaramakrishnan 186, George MacFaul 187, David Jones 188, Amir Shah 189, Chris Evans 190, Subrata Saha 191, Katharine, Pollock, Peter, Bramley, Ashis, Mukhopadhya, Andrew, Fraser, Peter, Mills, Christopher, Shallcross, Stewart, Campbell, Andrew, Bathgate, Alan Shepherd 213, John Dillon 214, Simon Rushbrook 215, Robert Przemioslo 216 Christopher Macdonald, Jane, Metcalf, Udi Shmueli 221, Andrew, Davis, Asifabbas, Naqvi, Tom, Lee, Ryder, Stephen D., Jane Collier 231, Howard, Klass, Mary, Ninkovic, Matthew Cramp 238, Nicholas Sharer 239, Richard Aspinall 240, Patrick Goggin 240, Deb, Ghosh, Andrew Douds 243, Barbara Hoeroldt 244, Jonathan Booth 245, Earl Williams 246, Hyder Hussaini 247, William Stableforth 247, Reuben Ayres 248, Douglas Thorburn 249, Eileen Marshall 249, Andrew Burroughs 249, Steven, Mann, Martin Lombard 252, Paul Richardson 252, Imran Patanwala 252, Julia Maltby 253, Matthew Brookes 254, Ray, Mathew, Samir Vyas 257, Saket Singhal 258, Dermot, Gleeson, Sharat, Misra, Jeff, Butterworth, Keith George 265, Tim, Harding, Andrew, Douglass, Simon Panter 270, Jeremy Shearman 271, Gary Bray 272, Graham, Butcher, Daniel Forton 275, John, Mclindon, Matthew Cowan 279, Gregory Whatley 280, Aditya, Mandal, Hemant, Gupta, Pradeep, Sanghi, Sanjiv Jain 283, Steve Pereira 284, Geeta Prasad 285, Gill Watts 285, Mark Wright 286, James Neuberger 287, Fiona Gordon 288, Esther Unitt 289, Allister, Grant, Toby, Delahooke, Andrew Higham 293, Alison Brind 294, Mark Cox 295, Subramaniam Ramakrishnan 296, Alistair, King, Carole Collins 300, Simon, Whalley, Andy Li 303, Jocelyn Fraser 304, Andrew Bell 305, Voi Shim Wong 306, Amit, Singhal, Ian, Gee, Yeng Ang 312, Rupert Ransford 313, James Gotto 314, Charles, Millson, Jane Bowles 318, Caradog, Thomas, Melanie Harrison 70, Roman Galaska 71, Jennie, Kendall, Jessica, Whiteman, Caroline, Lawlor, Catherine, Gray, Keith Elliott 79, Caroline Mulvaney Jones, Lucie, Hobson, Greta Van Duyvenvoorde 90, Alison Loftus 91, Katie Seward 92, Ruth, Penn, Jane Maiden 98, Rose Damant 98, Janeane Hails 101, Rebecca, Cloudsdale, Valeria Silvestre 105, Sue Glenn 106, Eleanor Dungca 107, Natalie Wheatley 108, Helen Doyle 109, Melanie, Kent, Caroline, Hamilton, Delyth, Braim, Helen Wooldridge 117, Rachel Abrahams 117, Alison Paton 119, Nicola, Lancaster, Andrew Gibbins 122, Karen Hogben 122, Phillipa, Desousa, Florin, Muscariu, Janine, Musselwhite, Alexandra McKay 132, LaiTing Tan 135, Carole Foale 138, Jacqueline Brighton 138, Kerry Flahive 140, Estelle, Nambela, Paula, Townshend, Chris, Ford, Sophie, Holder, Caroline, Palmer, James Featherstone 147, Mariam Nasseri 151, Joy Sadeghian 153, Bronwen, Williams, Carol Thomas 156, Sally Ann Rolls 156, Abigail Hynes 159, Claire Duggan 159, Sarah Jones 159, Mary, Crossey, Glynis Stansfield 163, Carolyn MacNicol 163, Joy Wilkins 164, Elva Wilhelmsen 165, Parizade Raymode 166, Hye Jeong Lee 167, Emma, Durant, Rebecca, Bishop, Noma, Ncube, Sherill, Tripoli, Rebecca, Casey, Caroline Cowley 182, Richard Miller 183, Kathryn Houghton 188, Samantha Ducker 188, Fiona Wright 189, Bridget Bird 191, Gwen Baxter 191, Janie Keggans 191, Maggie, Hughes, Emma Grieve 196, Karin Young 196, Williams 197, D., Kate Ocker 199, Frances, Hines, Kirsty, Martin, Caron, Innes, Talal Valliani 216, Helen, Fairlamb, Sarah, Thornthwaite, Anne, Eastick, Elizabeth Tanqueray 221, Jennifer Morrison 222, Becky Holbrook 222, Julie, Browning, Kirsten, Walker, Susan, Congreave, Juliette, Verheyden, Susan, Slininger, Lizzie Stafford 231, Denise O’Donnell 231, Mark Ainsworth 231, Susan Lord 118, Linda, Kent, Linda March 238, Christine Dickson 239, Diane Simpson 239, Beverley Longhurst 240, Maria Hayes 240, Ervin, Shpuza, Nikki, White, Sarah, Besley, Sallyanne Pearson 244, Alice Wright 245, Linda Jones 245, Emma Gunter 246, Hannah Dewhurst 246, Anna Fouracres 247, Liz Farrington 247, Lyn Graves 247, Suzie Marriott 248, Marina Leoni 249, David Tyrer 252, Kate Martin 252, Lola Dali kemmery 253, Victoria Lambourne 253, Marie Green 254, Dawn, Sirdefield, Kelly Amor 255, Julie Colley 258, Bal Shinder 258, Jayne Jones 260, Marisa Mills 260, Mandy, Carnahan, Natalie Taylor 265, Kerenza Boulton 265, Julie, Tregonning, Carly Brown 270, Gayle Clifford 270, Emily Archer 271, Maria, Hamilton, Janette Curtis 278, Tracey Shewan 279, Sue Walsh 280, Karen, Warner, Kimberley Netherton 283, Mcdonald Mupudzi 286, Bridget Gunson 287, Jane Gitahi 288, Denise Gocher 289, Sally, Batham, Hilary, Pateman, Senayon, Desmennu, Jill Conder 293, Darren Clement 294, Susan Gallagher 294, Jacky Orpe 256, PuiChing Chan 296, Lynn, Currie, Lynn, O’Donohoe, Metod Oblak 300, Lisa Morgan 302, Marie Quinn 303, Isobel Amey 304, Yolanda Baird 304, Donna Cotterill 305, Lourdes Cumlat 306, Louise Winter 312, Sandra Greer 312, Katie, Spurdle, Joanna, Allison, Simon, Dyer, Helen, Sweeting, Jean, Kordula, Cordell, H. J., Han, Y., Mells, G. F., Li, Y., Hirschfield, G. M., Greene, C. S., Xie, G., Juran, B. D., Zhu, D., Qian, D. C., Floyd, J. A. B., Morley, K. I., Prati, D., Lleo, A., Cusi, D., Gershwin, M. E., Anderson, C. A., Lazaridis, K. N., Invernizzi, P., Seldin, M. F., Sandford, R. N., Amos, C. I., Siminovitch, K. A., Schlicht, E. M., Lammert, C., Atkinson, E. J., Chan, L. L., De Andrade, M., Balschun, T., Mason, A. L., Myers, R. P., Zhang, J., Milkiewicz, P., Qu, J., Odin, J. A., Luketic, V. A., Bacon, B. R., Bodenheimer, H. C., Liakina, V., Vincent, C., Levy, C., Gregersen, P. K., Almasio, P. L., Alvaro, D., Andreone, P., Andriulli, A., Barlassina, C., Battezzati, P. M., Benedetti, A., Bernuzzi, F., Bianchi, I., Bragazzi, M. C., Brunetto, M., Bruno, S., Casella, G., Coco, B., Colli, A., Colombo, M., Colombo, S., Cursaro, C., Croce, L. S., Crosignani, A., Donato, M. 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B., Morley, Katherine I., Prati, Daniele, Lleo, Ana, Cusi, Daniele, Gershwin, M. Eric, Anderson, Carl A., Lazaridis, Konstantinos N., Invernizzi, Pietro, Seldin, Michael F., Sandford, Richard N., Amos, Christopher I., Siminovitch, Katherine A., Schlicht, Erik M., Lammert, Craig, Atkinson, Elizabeth J., Chan, Landon L., De Andrade, Mariza, Balschun, Tobia, Mason, Andrew L., Myers, Robert P., Zhang, Jinyi, Milkiewicz, Piotr, Qu, Jia, Odin, Joseph A., Luketic, Velimir A., Bacon, Bruce R., Bodenheimer, Henry C., Liakina, Valentina, Vincent, Catherine, Levy, Cynthia, Gregersen, Peter K., Almasio, Piero L., Alvaro, Domenico, Andreone, Pietro, Andriulli, Angelo, Barlassina, Cristina, Battezzati, Pier Maria, Benedetti, Antonio, Bernuzzi, Francesca, Bianchi, Ilaria, Bragazzi, Maria Consiglia, Brunetto, Maurizia, Bruno, Savino, Casella, Giovanni, Coco, Barbara, Colli, Agostino, Colombo, Massimo, Colombo, Silvia, Cursaro, Carmela, Crocè, Lory Saveria, Crosignani, Andrea, Donato, Maria Francesca, Elia, Gianfranco, Fabris, Luca, Ferrari, Carlo, Floreani, Annarosa, Foglieni, 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B., Floyd, Katherine I., Morley, Daniele, Prati, Ana, Lleo, Daniele, Cusi, Canadian US PBC, Consortium, Italian PBC Genetics Study, Group, UK PBC, Consortium, M., Eric Gershwin, Carl A., Anderson, Konstantinos N., Lazaridi, Pietro, Invernizzi, Michael F., Seldin, Richard N., Sandford, Christopher I., Amo, Katherine A., Siminovitch, Cordell H.J., Han Y., Mells G.F., Li Y., Hirschfield G.M., Greene C.S., Xie G., Juran B.D., Zhu D., Qian D.C., Floyd J.A.B., Morley K.I., Prati D., Lleo A., Cusi D., Gershwin M.E., Anderson C.A., Lazaridis K.N., Invernizzi P., Seldin M.F., Sandford R.N., Amos C.I., Siminovitch K.A., Schlicht E.M., Lammert C., Atkinson E.J., Chan L.L., De Andrade M., Balschun T., Mason A.L., Myers R.P., Zhang J., Milkiewicz P., Qu J., Odin J.A., Luketic V.A., Bacon B.R., Bodenheimer H.C., Liakina V., Vincent C., Levy C., Gregersen P.K., Almasio P.L., Alvaro D., Andreone P., Andriulli A., Barlassina C., Battezzati P.M., Benedetti A., Bernuzzi F., Bianchi I., Bragazzi M.C., Brunetto M., Bruno S., Casella G., Coco B., Colli A., Colombo M., Colombo S., Cursaro C., Croce L.S., Crosignani A., Donato M.F., Elia G., Fabris L., Ferrari C., Floreani A., Foglieni B., Fontana R., Galli A., Lazzari R., Macaluso F., Malinverno F., Marra F., Marzioni M., Mattalia A., Montanari R., Morini L., Morisco F., Mousa Hani S., Muratori L., Muratori P., Niro G.A., Palmieri V.O., Picciotto A., Podda M., Portincasa P., Ronca V., Rosina F., Rossi S., Sogno I., Spinzi G., Spreafico M., Strazzabosco M., Tarallo S., Tarocchi M., Tiribelli C., Toniutto P., Vinci M., Zuin 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., Carbone M., Dawwas M., Alexander G., Dolwani S., Prince M., Foxton M., Elphick D., Mitchison H., Gooding I., Karmo M., Saksena S., Mendall M., Patel M., Ede R., Austin A., Sayer J., Hankey L., Hovell C., Fisher N., Carter M., Koss K., Piotrowicz A., Grimley C., Neal D., Lim G., Levi S., Ala A., Broad A., Saeed A., Wood G., Brown J., Wilkinson M., Gordon H., Ramage J., Ridpath J., Ngatchu T., Grover B., Shaukat S., Shidrawi R., Abouda G., Ali F., Rees I., Salam I., Narain M., Brown A., Taylor-Robinson S., Williams S., Grellier L., Banim P., Das D., Chilton A., Heneghan M., Curtis H., Gess M., Drake I., Aldersley M., Davies M., Jones R., McNair A., Srirajaskanthan R., Pitcher M., Sen S., Bird G., Barnardo A., Kitchen P., Yoong K., Chirag O., Sivaramakrishnan N., MacFaul G., Jones D., Shah A., Evans C., Saha S., Pollock K., Bramley P., Mukhopadhya A., Fraser A., Mills P., Shallcross C., Campbell S., Bathgate A., Shepherd A., Dillon J., Rushbrook S., Przemioslo R., Macdonald C., Metcalf J., Shmueli U., Davis A., Naqvi A., Lee T., Stephen 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., Cordell, H, Han, Y, Mells, G, Li, Y, Hirschfield, G, Greene, C, Xie, G, Juran, B, Zhu, D, Qian, D, Floyd, J, Morley, K, Prati, D, Lleo, A, Cusi, D, Gershwin, M, Anderson, C, Lazaridis, K, Invernizzi, P, Seldin, M, Sandford, R, Amos, C, Siminovitch, K, Schlicht, E, Lammert, C, Atkinson, E, Chan, L, De Andrade, M, Balschun, T, Mason, A, Myers, R, Zhang, J, Milkiewicz, P, Qu, J, Odin, J, Luketic, V, Bacon, B, Bodenheimer, H, Liakina, V, Vincent, C, Levy, C, Gregersen, P, Almasio, P, Alvaro, D, Andreone, P, Andriulli, A, Barlassina, C, Battezzati, P, Benedetti, A, Bernuzzi, F, Bianchi, I, Bragazzi, M, Brunetto, M, Bruno, S, Casella, G, Coco, B, Colli, A, Colombo, M, Colombo, S, Cursaro, C, Crocè, L, Crosignani, A, Donato, M, Elia, G, Fabris, L, Ferrari, C, Floreani, A, Foglieni, B, Fontana, R, Galli, A, Lazzari, R, Macaluso, F, Malinverno, F, Marra, F, Marzioni, M, Mattalia, A, Montanari, R, Morini, L, Morisco, F, Mousa Hani, S, Muratori, L, Muratori, P, Niro, G, Palmieri, V, Picciotto, A, Podda, M, Portincasa, P, Ronca, V, Rosina, F, Rossi, S, Sogno, I, Spinzi, G, Spreafico, M, Strazzabosco, M, Tarallo, S, Tarocchi, M, Tiribelli, C, Toniutto, P, Vinci, M, Zuin, 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, Carbone, M, Dawwas, M, Alexander, G, Dolwani, S, Prince, M, Foxton, M, Elphick, D, Mitchison, H, Gooding, I, Karmo, M, Saksena, S, Mendall, M, Patel, M, Ede, R, Austin, A, Sayer, J, Hankey, L, Hovell, C, Fisher, N, Carter, M, Koss, K, Piotrowicz, A, Grimley, C, Neal, D, Lim, G, Levi, S, Ala, A, Broad, A, Saeed, A, Wood, G, Brown, J, Wilkinson, M, Gordon, H, Ramage, J, Ridpath, J, Ngatchu, T, Grover, B, Shaukat, S, Shidrawi, R, Abouda, G, Ali, F, Rees, I, Salam, I, Narain, M, Brown, A, Taylor Robinson, S, Williams, S, Grellier, L, Banim, P, Das, D, Chilton, A, Heneghan, M, Curtis, H, Gess, M, Drake, I, Aldersley, M, Davies, M, Jones, R, Mcnair, A, Srirajaskanthan, R, Pitcher, M, Sen, S, Bird, G, Barnardo, A, Kitchen, P, Yoong, K, Chirag, O, Sivaramakrishnan, N, Macfaul, G, Jones, D, Shah, A, Evans, C, Saha, S, Pollock, K, Bramley, P, Mukhopadhya, A, Fraser, A, Mills, P, Shallcross, C, Campbell, S, Bathgate, A, Shepherd, A, Dillon, J, Rushbrook, S, Przemioslo, R, Macdonald, C, Metcalf, J, Shmueli, U, Davis, A, Naqvi, A, Lee, T, Stephen, 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, 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, and Kordula, J

Subjects
Liver Cirrhosis, Genetics and Molecular Biology (all), pathogenesi, risk assessment EMTREE medical terms: Article, genetic association, genotype, EMTREE drug terms: chemokine receptor CCR6, genetic risk, Biochemistry, meta-analysi, primary biliary cirrhosi, chemokine receptor CCR6 [EMTREE drug terms], single nucleotide polymorphism, genetic variability, Article [risk assessment EMTREE medical terms], Liver Cirrhosis, Biliary, pathogenesis, Biliary, Chemistry (all), STAT protein GEOBASE Subject Index: disease treatment, cohort analysis, genome wide meta analysis PBC, signal transduction, gene locus, cohort analysi, CBP, Article, Physics and Astronomy (all), macrophage inflammatory protein 3alpha, Humans, controlled study, human, interleukin 27, genome, Biochemistry, Genetics and Molecular Biology (all), meta analysi, interleukin 12p40, interleukin 12, Janus kinase, meta-analysis, pathogen, genetic predisposition, major clinical study, meta analysis, primary biliary cirrhosis, disease treatment [STAT protein GEOBASE Subject Index], Genome-Wide Association Study, gene locu
Abstract

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined, Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.

Published
2015
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15. Effect of albumin dialysis on intracranial pressure increase in pigs with acute liver failure: a randomized study

Author

Roger F. Butterworth, Frits W. Prinzen, Arthur Revhaug, Geir I. Nedredal, Roger Williams, Nathan Davies, Nicolaas E. P. Deutz, Christopher F. Rose, Lars M. Ytrebø, Rajiv Jalan, Sambit Sen, Synnøve Sæterstad Drevland, Stephen J. Hodges, Marianne Kjønnø, Fysiologie, Algemene Heelkunde, RS: NUTRIM School of Nutrition and Translational Research in Metabolism, Université de Montréal. Faculté de médecine, and Université de Montréal. Faculté de médecine. Centre de recherche du CHUM

Subjects
Circulation sanguine cérébrale, Intracranial Pressure, medicine.medical_treatment, Sus scrofa, Brain Edema, Hemodiafiltration, Critical Care and Intensive Care Medicine, Sensitivity and Specificity, Cerebral edema, Random Allocation, Ammonia, Risk Factors, Intensive care, Albumins, Hemofiltration, medicine, Animals, Oedème cérébral, Dialysis, Intracranial pressure, Inflammation, business.industry, digestive, oral, and skin physiology, Albumin, Liver Failure, Acute, Cerebral blood flow, medicine.disease, Survival Rate, Disease Models, Animal, Anesthesia, Cerebrovascular Circulation, Liver ischemia, Female, Hemodialysis, Inflammation Mediators, Intracranial Hypertension, business, Ischémie hépatique
Abstract

Background: Increased intracranial pressure (ICP) worsens the outcome of acute liver failure (ALF). This study investigates the underlying pathophysiological mechanisms and evaluates the therapeutic effect of albumin dialysis in ALF with use of the Molecular Adsorbents Recirculating System without hemofiltration/dialysis (modified, M-MARS). Methods: Pigs were randomized into three groups: sham, ALF, and ALF + M-MARS. ALF was induced by hepatic devascularization (time = 0). M-MARS began at time = 2 and ended with the experiment at time = 6. ICP, arterial ammonia, brain water, cerebral blood flow (CBF), and plasma inflammatory markers were measured. Results: ICP and arterial ammonia increased significantly over 6 hrs in the ALF group, in comparison with the sham group. M-MARS attenuated (did not normalize) the increased ICP in the ALF group, whereas arterial ammonia was unaltered by M-MARS. Brain water in the frontal cortex (grey matter) and in the subcortical white matter at 6 hrs was significantly higher in the ALF group than in the sham group. M-MARS prevented a rise in water content, but only in white matter. CBF and inflammatory mediators remained unchanged in all groups. Conclusion: The initial development of cerebral edema and increased ICP occurs independently of CBF changes in this non-inflammatory model of ALF. Factor(s) other than or in addition to hyperammonemia are important, however, and may be more amenable to alteration by albumin dialysis.

Published
2006
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16. Interorgan ammonia, glutamate and glutamine trafficking in pigs with acute liver failure

Author

Manuel Romero-Gómez, Arthur Revhaug, Geir I. Nedredal, Nathan Davies, Sambit Sen, LM Ytrebo, Rajiv Jalan, Gabrie A. M. Ten Have, Christopher F. Rose, Nicolaas E. P. Deutz, Roger Williams, Stephen J. Hodges, Algemene Heelkunde, and RS: NUTRIM School of Nutrition and Translational Research in Metabolism

Subjects
medicine.medical_specialty, Physiology, Swine, Glutamine, Biological Transport, Active, Glutamic Acid, Biology, Kidney, Ammonia production, Ammonia, Physiology (medical), Internal medicine, medicine, Animals, Hyperammonemia, Tissue Distribution, Hepatic encephalopathy, Lung, Hepatology, digestive, oral, and skin physiology, Gastroenterology, Kidney metabolism, Metabolism, Liver Failure, Acute, medicine.disease, medicine.anatomical_structure, Endocrinology, Liver, Organ Specificity, Urea cycle, Female
Abstract

Background/Aims: Ammonia reduction is the target for therapy of hepatic encephalopathy (HE) but lack of quantitative data about how the individual organs handle ammonia limit our ability to develop novel therapeutic strategies. The study aims were to evaluate interorgan ammonia metabolism quantitatively in a devascularised pig model of acute liver failure (ALF). Methods: Ammonia and amino acid fluxes were measured across the portal drained viscera (PDV), kidneys, hind-leg, and lungs in ALF pigs. Results: ALF pigs developed hyperammonemia and increased glutamine levels, while glutamate levels were decreased. PDV contributed to the hyperammonemic state mainly through increased shunting and not as a result of increased glutamine breakdown. The kidneys were quantitatively as important as PDV in systemic ammonia release, while muscle took up ammonia. Data suggest that the lungs are able to remove ammonia from the circulation during the initial stage of ALF. Conclusions: Our study provides the novel observation of glutamate deficiency in a pig model of ALF. Furthermore, the kidneys are quantitatively as important as PDV in ammonia production and the muscles play an important role in ammonia removal. AD - Digestive Surgery, University Hospital Northern Norway, Norway. AU - Ytrebo LM AU - Sen S AU - Rose C AU - Ten Have GA AU - Davies NA AU - Hodges S AU - Nedredal GI AU - Romero-Gomez M AU - Williams R AU - Revhaug A AU - Jalan R AU - Deutz NE LA - ENG PT - JOURNAL ARTICLE DEP - 20060615 TA - Am J Physiol Gastrointest Liver Physiol JID - 100901227

Published
2006
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17. Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis

Author

Mohammed Malaki, Patrick Vallance, Charles Turner, Roger Williams, Rajeshwar P. Mookerjee, Nathan Davies, James Leiper, Stephen J. Hodges, Rajiv Jalan, Sambit Sen, and R. Neil Dalton

Subjects
Adult, Male, Protein-Arginine N-Methyltransferases, medicine.medical_specialty, Alcoholic liver disease, Cirrhosis, Portal venous pressure, Alcoholic hepatitis, Arginine, Sensitivity and Specificity, Amidohydrolases, chemistry.chemical_compound, Liver Cirrhosis, Alcoholic, Predictive Value of Tests, Internal medicine, Hypertension, Portal, medicine, Humans, Aged, Hepatitis, Hepatology, Hepatitis, Alcoholic, business.industry, Middle Aged, Prognosis, medicine.disease, Repressor Proteins, Survival Rate, Endocrinology, Gene Expression Regulation, chemistry, Case-Control Studies, Portal hypertension, Female, Acute Alcoholic Hepatitis, Asymmetric dimethylarginine, business, Biomarkers
Abstract

Previous studies suggest reduced hepatic endothelial nitric oxide synthase activity contributes to increased intrahepatic resistance. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, undergoes hepatic metabolism via dimethylarginine-dimethylamino-hydrolase, and is derived by the action of protein-arginine-methyltransferases. Our study assessed whether ADMA, and its stereo-isomer symmetric dimethylarginine (SDMA), are increased in alcoholic hepatitis patients, and determined any relationship with severity of portal hypertension (hepatic venous pressure gradient measurement) and outcome. Fifty-two patients with decompensated alcoholic cirrhosis were studied, 27 with acute alcoholic hepatitis and cirrhosis, in whom hepatic venous pressure gradient was higher (P = 0.001) than cirrhosis alone, and correlated with ADMA measurement. Plasma ADMA and SDMA were significantly higher in alcoholic hepatitis patients and in nonsurvivors. Dimethylarginine-dimethylamino-hydrolase protein expression was reduced and protein-arginine-methyltransferase-1 increased in alcoholic hepatitis livers. ADMA, SDMA and their combined sum, which we termed a dimethylarginine score, were better predictors of outcome compared with Pugh score, MELD and Maddrey's discriminant-function. Conclusion: Alcoholic hepatitis patients have higher portal pressures associated with increased ADMA, which may result from both decreased breakdown (decreased hepatic dimethylarginine-dimethylamino-hydrolase) and/or increased production. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic hepatitis.

Published
2006
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18. Albumin dialysis reduces portal pressure acutely in patients with severe alcoholic hepatitis

Author

L Cheshire, Sambit Sen, Roger Williams, Rajeshwar P. Mookerjee, Nathan Davies, and Rajiv Jalan

Subjects
Adult, Male, medicine.medical_specialty, Time Factors, Cirrhosis, medicine.medical_treatment, Portal venous pressure, Alcoholic hepatitis, Blood Pressure, Hepatic Veins, Cardiovascular System, Severity of Illness Index, Gastroenterology, Hepatorenal syndrome, Renal Dialysis, Albumins, Internal medicine, Hypertension, Portal, Hemofiltration, medicine, Humans, Renal Insufficiency, Dialysis, Hepatology, Hepatitis, Alcoholic, business.industry, Hemodynamics, Middle Aged, medicine.disease, Surgery, Portal System, Treatment Outcome, Blood pressure, Hepatic Encephalopathy, Portal hypertension, Female, business, Venous Pressure, Liver Circulation
Abstract

Background/Aims In patients with alcoholic hepatitis (AH), inflammation contributes to the severity of portal hypertension. This study evaluates the acute effects of albumin dialysis, using the Molecular Adsorbents Recirculating System (MARS), on portal pressure in AH. Methods Eleven patients with AH and portal hypertension were treated with MARS (n=8) or haemofiltration (n=3). All patients had associated organ failure manifested by hepatic encephalopathy (Grade 2 or more) or renal failure. Hepatic venous pressure gradient (HVPG) was measured before, during and after the treatment session. Results A rapid significant reduction of HVPG was observed by 6 h (falling by ≥20% in 7/8 patients, reaching 12 mmHg in 6/8), which was sustained up to 18 h after stopping dialysis. Similar rapid sustained improvements of systemic haemodynamics were also observed. No changes occurred in three patients receiving haemofiltration alone. Conclusions Albumin dialysis produces clinically significant, acute reduction in portal pressure but the mechanism by which this effect is achieved is not clear. Our results suggest that MARS may be a useful adjunct in management of portal hypertension, particularly in patients with severe AH with associated organ failure.

Published
2005
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19. Emerging Indications for Albumin Dialysis

Author

Rajiv Jalan, Sambit Sen, and Roger Williams

Subjects
medicine.medical_specialty, medicine.medical_treatment, Encephalopathy, Renal function, Pharmacology, law.invention, Hepatorenal syndrome, Renal Dialysis, law, Albumins, Internal medicine, Humans, Medicine, Dialysis, Kidney, Hepatology, business.industry, Gastroenterology, Bioartificial liver device, Albumin, medicine.disease, medicine.anatomical_structure, Endocrinology, Sorption Detoxification, business, Liver Failure
Abstract

The accumulation of albumin-bound toxins in liver failure is believed to be responsible for the development of associated end-organ dysfunctions (kidney, circulation, brain). Albumin dialysis utilizes the scavenging functions of albumin for the removal of toxins. The Molecular Adsorbents Recirculating System (MARS) is one such extracorporeal liver support device where blood is dialyzed across an albumin-impregnated membrane against 20% albumin. Charcoal and anion exchange resin columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies in the last decade have demonstrated proven reduction in hyperbilirubinemia, along with an improvement in encephalopathy in liver failure patients, as well as apparent improvement in survival. Some studies have also reported improvement of systemic hemodynamics and renal function in these patients. Amelioration of intractable pruritus and treatment of toxicities with albumin-bound substances are some of the newer indications emerging. However, the specific underlying pathophysiological mechanisms are still not clear. Two other systems based on the removal of albumin-bound toxins, the Prometheus (using the principle of fractionated plasma separation and adsorption [FPSA]), and the single pass albumin dialysis (SPAD) are also currently under development but available clinical data are limited.

Published
2005
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20. Ideal hepatocyte: Quest for the Holy Grail

Author

Sambit Sen and Rajiv Jalan

Subjects
Transplantation, Ideal (set theory), Hepatology, Porcine endogenous retrovirus, business.industry, Immunology, Gastroenterology, Liver failure, Medicine, Theology, business, Holy Grail
Published
2005
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21. PROSPECTS FOR EXTRACORPOREAL LIVER SUPPORT

Author

Sambit Sen, Rajiv Jalan, and Roger Williams

Subjects
Extracorporeal Circulation, medicine.medical_specialty, medicine.medical_treatment, Liver transplantation, Chronic liver disease, Liver disorder, law.invention, Liver disease, Fulminant hepatic failure, Hepatorenal syndrome, law, Recent Advances in Clinical Practice, medicine, Humans, Intensive care medicine, Clinical Trials as Topic, Bioartificial Organs, business.industry, Extracorporeal circulation, Gastroenterology, Bioartificial liver device, Equipment Design, medicine.disease, Liver, Artificial, Surgery, business, Liver Failure
Abstract

This present review is timely with the increasing use of the molecular adsorbents recirculating system (MARS) for the management of liver failure, with over 3000 patients having been treated with this device worldwide. In the UK, MARS is being used for the treatment of individual patients both in the National Health Service and also in the private sector. In order to investigate the latest position with respect to bioartificial liver devices, a meeting was held at University College London Hospital in September 2003 and this article is based on the most up to date data presented there. Liver failure, whether of the acute variety with no pre-existing liver disease (acute liver failure (ALF)) or an acute episode of decompensation superimposed on a chronic liver disorder (acute on chronic liver failure (ACLF)), carries a high mortality. In patients with ALF, lack of detoxification, metabolic, and regulatory functions of the liver leads to life threatening complications, including kidney failure, encephalopathy, cerebral oedema, severe hypotension, and susceptibility to infections culminating in multiorgan failure.1 The only established therapy for such patients is liver transplantation (LTx) but currently one third of these patients die while waiting for a transplant and the organ shortage is increasing (fig 1).2 However, liver failure, whether of the acute or acute on chronic variety, is potentially reversible, and considerable work has been carried out over many years to develop effective liver support devices. Figure 1 Annual death rates on the waiting list for liver transplantation between 1997 and 2001 in UNOS categories 1 (acute/fulminant liver failure), 2a (decompensated chronic liver disease urgently requiring transplant), and 2b (decompensated chronic liver disease requiring transplant less urgently). (Source: OPTN/SRTR data, as of 1 August 2002.) The development of these devices has been approached in two very different ways. The biological devices, which aim …

Published
2004
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22. Binding of bilirubin and bromosulphthalein to albumin: Implications for understanding the pathophysiology of liver failure and its management

Author

Sambit Sen, Jan Stange, Roger Williams, Christian Steiner, and Rajiv Jalan

Subjects
medicine.medical_specialty, Cirrhosis, Bilirubin, Serum albumin, Alcoholic hepatitis, Sulfobromophthalein, Liver disease, chemistry.chemical_compound, stomatognathic system, Hepatorenal syndrome, In vivo, Albumins, Internal medicine, medicine, Humans, Registries, Coloring Agents, Serum Albumin, Transplantation, Hepatology, biology, business.industry, Albumin, Biological Transport, Membranes, Artificial, medicine.disease, Endocrinology, chemistry, Injections, Intravenous, biology.protein, Surgery, Adsorption, business, Dialysis, Liver Failure
Abstract

The binding/transporting functions of albumin provide the rationale for using albumin dialysis (e.g., molecular adsorbents recirculating system [MARS]) in liver failure. This study investigates these properties in vitro, validating the findings in vivo. In vitro bromosulphthalein (BSP) and bilirubin-spiked plasma were dialyzed against albumin and sampled. In vivo serum biochemistry was analyzed in: 7 MARS-treated liver failure patients; 98 MARS-treated patients from the MARS Registry; and 8 patients receiving albumin infusion. In vitro BSP concentrations did not equilibrate, but the molar ratio of BSP to albumin (C(BSP)/C(alb)) did, with no subsequent transmembrane transport, suggesting that the C(BSP)/C(alb) gradient (rather than simple diffusion) drives BSP transport. Bilirubin was transported similarly. In vivo serum bilirubin reduction during MARS sessions (n = 26) correlated with pre-treatment bilirubin (r = 0.42), but better (r = 0.85) with pre-treatment molar ratio of bilirubin to albumin (C(bilirubin)/C(alb)). The strongest correlation was between C(bilirubin)/C(alb) reduction and pre-treatment C(bilirubin)/C(alb) (r = 0.9). A similar pattern was observed in the MARS Registry patients. After albumin infusion (n = 8), both serum albumin and bilirubin increased, while C(bilirubin)/C(alb) remained unchanged. C(bilirubin)/C(alb) appears to be important in albumin dialysis, and generally in liver disease patients, reinforcing the importance of the toxin-binding functions of albumin in liver disease.

Published
2004
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23. Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: A randomized controlled study

Author

Rajiv Jalan, Nathan Davies, Roger Williams, Rajeshwar P. Mookerjee, Sambit Sen, Stephen J. Hodges, and L Cheshire

Subjects
Adult, Male, Extracorporeal Circulation, medicine.medical_specialty, Mean arterial pressure, medicine.medical_treatment, Encephalopathy, Renal function, Liver transplantation, Thiobarbituric Acid Reactive Substances, Gastroenterology, Nitric oxide, chemistry.chemical_compound, Albumins, Malondialdehyde, Internal medicine, medicine, Humans, Prospective Studies, Dialysis, Transplantation, Nitrates, Hepatology, business.industry, Albumin, Liver Failure, Acute, Middle Aged, medicine.disease, Blood pressure, chemistry, Chronic Disease, Immunology, Cytokines, Female, Sorption Detoxification, Surgery, business, Liver Failure
Abstract

The pathophysiological basis of acute-on-chronic liver failure (ACLF) is unclear but systemic inflammatory response is thought to be important. In patients with ACLF, the molecular adsorbents recirculating system (MARS) improves individual organ function, but the effect of MARS on the proposed mediators of systemic inflammatory response is unclear. The present study was designed to determine the effect of MARS on the cytokine profile, oxidative stress, nitric oxide, and ammonia. A total of 18 patients with alcohol-related ACLF due to inflammation-related precipitants were randomized to receive standard medical therapy (SMT) alone, or with MARS therapy over 7 days. Plasma cytokines, malondialdehyde (MDA), free radical production, nitrate / nitrite (NOx), and ammonia were measured. Encephalopathy improved significantly with MARS (P < .01), but not with SMT. Mean arterial pressure and renal function remained unchanged. No significant change of plasma cytokines and ammonia levels were observed in either group. Plasma MDA levels did not change either. There was a fall in NOx (P < .05) with MARS, but not with SMT. In conclusion, in inflammation-related ACLF patients, albumin dialysis using MARS results in improvement of encephalopathy, independent of changes of ammonia or cytokines, without improving blood pressure or renal function. These results should temper the liberal use of MARS until further data is available. (Liver Transpl 2004;10:1109–1119.)

Published
2004
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24. Tumour necrosis factor is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis

Author

Rajiv Jalan, Sambit Sen, Roger Williams, Nathan Davies, R.P. Mookerjee, and Stephen J. Hodges

Subjects
Adult, Male, medicine.medical_specialty, Cirrhosis, Portal venous pressure, Alcoholic hepatitis, Blood Pressure, Gastroenterology, Renal Circulation, Proinflammatory cytokine, Liver disease, Gastrointestinal Agents, Heart Rate, Internal medicine, Hypertension, Portal, medicine, Humans, Nitrites, Aged, Nitrates, Hepatitis, Alcoholic, Tumor Necrosis Factor-alpha, business.industry, Vascular disease, Hemodynamics, Antibodies, Monoclonal, Middle Aged, medicine.disease, Infliximab, Endocrinology, Liver, Renal blood flow, Portal hypertension, Female, business, Liver Circulation
Abstract

The role of proinflammatory cytokines in the pathogenesis of portal hypertension is unclear.This study tests the hypothesis that tumour necrosis factor alpha (TNF-alpha) is an important mediator of the circulatory disturbances in alcoholic hepatitis (AH) and evaluates the acute and short term effect of a single infusion of the monoclonal chimeric anti-TNF-alpha antibody (Infliximab) on portal and systemic haemodynamics in 10 patients with severe biopsy proven AH. Cardiovascular haemodynamics, hepatic venous pressure gradient (HVPG), and hepatic and renal blood flow were measured before, 24 hours after Infliximab, and prior to hospital discharge.Serum bilirubin (p0.05), C reactive protein (p0.001), and white cell count (p0.01) were reduced significantly, as were plasma levels of interleukin (IL)-6 and IL-8 after treatment. Of the 10 patients, nine were alive at 28 days. Mean HVPG decreased significantly at 24 hours (23.4 (2.8) to 14.3 (1.9) mm Hg; p0.001) with a sustained reduction prior to discharge (12.8 (1.9) mm Hg; p0.001). Mean arterial pressure and systemic vascular resistance increased significantly (p0.001and p0.01, respectively), mirrored by a reduction in cardiac index (5.9 (0.5) to 4.7 (0.5) l/min/m(2); p0.05) prior to discharge. Hepatic and renal blood flow also increased significantly (506.2 (42.9) to 646.3 (49.2) ml/min (p=0.001) and 424.3 (65.12) to 506.3 (85.7) ml/min (p=0.001), respectively) prior to discharge.The results of this study illustrate that anti-TNF-alpha treatment in AH patients produces a highly significant, early, and sustained reduction in HVPG, possibly through a combination of a reduction in cardiac output and intrahepatic resistance. In addition, there was a reduction in hepatic inflammation and improved organ blood flow, suggesting an important role for TNF-alpha in mediating the circulatory disturbances in AH.

Published
2003
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25. Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis

Author

Roger Williams, Sambit Sen, Christian Steiner, Akeel Alisa, Dharmesh Kapoor, and Rajiv Jalan

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Encephalopathy, Renal function, Blood Pressure, Severity of Illness Index, Gastroenterology, Extracorporeal, Hepatorenal syndrome, Internal medicine, medicine, Humans, Cardiac Output, Dialysis, Prothrombin time, Hepatitis, Hepatology, medicine.diagnostic_test, Hepatitis, Alcoholic, business.industry, Bilirubin, Middle Aged, medicine.disease, Survival Analysis, Thrombocytopenia, Surgery, Creatinine, Hepatic Encephalopathy, Acute Disease, Prothrombin Time, Feasibility Studies, Sorption Detoxification, Vascular Resistance, business, Acute Alcoholic Hepatitis
Abstract

Background/Aims : The mortality of patients with severe acute alcoholic hepatitis (AH) remains high, leading to interest in the use of extracorporeal liver support. The molecular adsorbents recirculating system (MARS) is a liver support device based upon a hollow fibre module in which the patient's blood is dialyzed across an albumin-impregnated membrane. The aim of this paper is to assess the safety, efficacy and feasibility of using MARS in patients with severe AH. Methods : Eight patients (all encephalopathic; hepatorenal syndrome: Type 1, five patients; Type 2, two patients) were treated with MARS. Clinical, biochemical and haemodynamic assessments were done. Results : Five patients were discharged from hospital, and four are alive at 3 months of follow-up, compared with an estimated survival of about 20%. There were significant improvement in serum bilirubin ( P =0.008), creatinine ( P =0.02), prothrombin time ( P =0.04), and grade of encephalopathy ( P =0.05). Sustained improvements in mean arterial pressure, systemic vascular resistance and cardiac output were observed. Thrombocytopaenia was the only MARS-related adverse event observed. Conclusions : MARS resulted in improved liver biochemistry, cardiovascular haemodynamics, renal function and encephalopathy in patients with severe AH, with an apparent reduction in mortality. On this basis, a multi-centre, randomized clinical trial has been initiated.

Published
2003
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26. Review article: the Molecular Adsorbents Recirculating System (MARS) in liver failure

Author

Rajiv Jalan, Rajeshwar P. Mookerjee, Nathan Davies, Roger Williams, and Sambit Sen

Subjects
medicine.medical_specialty, Hepatology, medicine.diagnostic_test, business.industry, Gastroenterology, Bioartificial liver device, Primary Graft Dysfunction, medicine.disease, Chronic liver disease, law.invention, Hepatorenal syndrome, law, medicine, Pharmacology (medical), Decompensation, Liver function, Liver function tests, business, Intensive care medicine, Hepatic encephalopathy
Abstract

In recent years different artificial liver support systems are being developed for use in patients with acute decompensation of chronic liver disease or acute liver failure. The molecular adsorbents recirculating system (MARS), a device in which patient's blood is dialysed across an albumin-impregnated membrane against a recirculated albumin-containing solution, seems to be effective in removing albumin-bound toxins, such as fatty acids, bile acids and bilirubin. Although the clinical experience with MARS is scarce, some pilot studies have reported its effectiveness at improving liver function and hepatic encephalopathy in patients with acute decompensation of chronic liver disease, and renal function in patients with hepatorenal syndrome type I. Data regarding MARS experience in acute liver failure and in primary graft dysfunction are encouraging but limited. Its real usefulness in these settings is, at present, under evaluation in randomized controlled clinical trials.

Published
2002
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27. Albumin dialysis and Molecular Adsorbents Recirculating System (MARS) for acute Wilson's disease

Author

Roger Williams, Michael Olausson, Bo Larsson, Marie Felldin, Christian Steiner, Godfrey T. Gillett, Sambit Sen, and Rajiv Jalan

Subjects
Adult, medicine.medical_specialty, Poor prognosis, Time Factors, medicine.medical_treatment, Encephalopathy, Serum copper, Liver transplantation, Gastroenterology, Serum bilirubin, Hepatolenticular Degeneration, Renal Dialysis, Albumins, Dialysis Solutions, Internal medicine, medicine, Humans, Dialysis, Transplantation, Hepatology, business.industry, Albumin, Bilirubin, Membranes, Artificial, medicine.disease, Liver Transplantation, Surgery, Wilson's disease, Hepatic Encephalopathy, Acute Disease, Female, Adsorption, business, Copper, Liver Failure
Abstract

Wilson's disease presenting as acute liver failure (ALF) is potentially fatal, and liver transplantation (LTx) is the only option. We report two patients with Wilson's disease and ALF treated with the Molecular Adsorbents Recirculating System (MARS). Both patients fulfilled criteria for poor prognosis. Because LTx was not available immediately in either case, MARS was used as a bridge to LTx. In Case 1, serum bilirubin decreased from 803 to 425 micromol/L after 3 treatments, but increased to 656 micromol/L during a break, decreasing again to 457 micromol/L with further treatment. Serum copper decreased from 53.7 micromol/L, to 35.8 micromol/L after first treatment session, and 17.4 micromol/L at treatment completion. In Case 2, MARS treatment over 2 weeks reduced serum bilirubin from 1200 to 450 micromol/L and copper from 35 to 13 micromol/L with marked improvement in encephalopathy and reduction in ammonia (59 to 34 micromol/L). Both patients were successfully bridged to LTx (days 9 and 28, respectively). Analysis of albumin-dialysate from the MARS circuit suggested that copper removal occurred mostly in the first few hours of treatment, partly being adsorbed by albumin and partly by the MARSFlux membrane (Teraklin AG, Rostock, Germany). These data suggest that MARS removes copper efficiently and can be used to bridge patients with Wilson's disease and ALF to LTx.

Published
2002
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28. The pathophysiological basis of acute-on-chronic liver failure

Author

S Sen, R Williams, R. Jalan, Sambit Sen, Roger Williams, and Rajiv Jalan

Subjects
medicine.medical_specialty, Gastrointestinal bleeding, Hepatology, business.industry, medicine.disease, Chronic liver disease, Pathophysiology, Sepsis, Fulminant hepatic failure, Hepatorenal syndrome, Supportive psychotherapy, medicine, Liver function, business, Intensive care medicine
Abstract

The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short and long-term prognosis. This review focuses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that the liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver support strategies to enhance the recovery process.

Published
2002
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29. Glucose-6-phosphate dehydrogenase deficiency: an unusual cause of acute jaundice after paracetamol overdose

Author

Simon Phillpotts, Sambit Sen, and Elliot Tash

Subjects
Adult, medicine.medical_specialty, Antipyretics, Jaundice, Dehydrogenase, Gastroenterology, chemistry.chemical_compound, hemic and lymphatic diseases, Internal medicine, Coagulopathy, medicine, Glucose-6-phosphate dehydrogenase, Humans, Acetaminophen, business.industry, Hematology, General Medicine, medicine.disease, Haemolysis, Surgery, Glucosephosphate Dehydrogenase Deficiency, chemistry, Acute Disease, Transaminitis, Female, medicine.symptom, Drug Overdose, Complication, business, Glucose-6-phosphate dehydrogenase deficiency
Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest human enzyme defect causing haemolytic anaemia after exposure to specific triggers. Paracetamol-induced haemolysis in G6PD deficiency is a rare complication and mostly reported in children. We report the first case (to the best of our knowledge) of acute jaundice without overt clinical features of a haemolytic crisis, in an otherwise healthy adult female following paracetamol overdose, due to previously undiagnosed G6PD deficiency. It is important that clinicians consider this condition when a patient presents following a paracetamol overdose with significant and disproportionate jaundice, without transaminitis or coagulopathy.

Published
2014

30. Propranolol in primary and secondary prophylaxis of variceal bleeding among cirrhotics in India: a hemodynamic evaluation

Author

Pranab K Biswas, Amal Santra, Ajit K Maity, Binay K De, Sambit Sen, Jayanta Biswas, Baburam Hazra, and Debapriya Sengupta

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Adrenergic beta-Antagonists, Administration, Oral, India, Hemodynamics, Hemorrhage, Propranolol, Hepatic Veins, Esophageal and Gastric Varices, Gastroenterology, Internal medicine, medicine, Humans, Varix, Dose-Response Relationship, Drug, Hepatology, Vascular disease, business.industry, Middle Aged, medicine.disease, Surgery, Echocardiography, Chemoprophylaxis, Female, Preventive Medicine, Complication, Varices, business, Venous Pressure, Follow-Up Studies, medicine.drug
Abstract

In the present study, we attempted to complete the hemodynamic assessment of propranolol response in cirrhotics with esophageal varices at high risk of bleeding, in one sitting, so as to identify nonresponders at the earliest. Some noninvasive indicators of this response were also evaluated.Hepatic venous pressure gradient (HVPG) was measured in 33 such cases (18 nonbleeders, 15 bleeders) before and 90 min after an oral dose of 80 mg propranolol, and reduction byor =20% taken as responder.Twenty-two patients (66.67%) responded (HVPG reductionor =26%), whereas 11 (33.33%) did not (HVPG reductionor =6%). Postdrug HVPG between responders and nonresponders showed a significant difference (p0.001). Neither baseline HVPG (p0.1), baseline CI (p = 0.665), nor baseline stroke volume index (p0.1) could predict responder status. Difference of HVPG reduction (percent) between bleeders (21.49 +/- 35.53) and nonbleeders (40.58 +/- 23.95) approached, but did not reach, statistical significance (p = 0.076). However, logistic regression showed this difference to be significant (p = 0.026). Age of responders was found to be significantly lower than that of nonresponders (p approximately equals 0.05). During a follow-up of 9-38 months, only one of 22 responders (on propranolol) had an episode of variceal bleed. None in whom HVPG fell toor = 12 mm Hg bled.The study suggests that single-sitting hemodynamic assessment of acute response to high-dose oral propranolol clearly differentiates between responders and nonresponders. Moreover, it appears that prior history of variceal bleeding and old age negatively influences the effect of propranolol.

Published
2000
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31. Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury

Author

Rajeshwar P. Mookerjee, L Noiret, Sambit Sen, R. Garcia-Martinez, and Rajiv Jalan

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Sympathetic nervous system, Cirrhosis, Renal function, Enzyme-Linked Immunosorbent Assay, urologic and male genital diseases, Thiobarbituric Acid Reactive Substances, Statistics, Nonparametric, Renal Circulation, Internal medicine, Malondialdehyde, von Willebrand Factor, medicine, Humans, Autoregulation, Decompensation, Endothelial dysfunction, Infusions, Intravenous, Serum Albumin, Respiratory Burst, Retrospective Studies, Hepatology, business.industry, Interleukin-6, Acute kidney injury, Hemodynamics, Acute Kidney Injury, Middle Aged, medicine.disease, Endocrinology, medicine.anatomical_structure, Renal blood flow, Cardiology, Female, business
Abstract

In cirrhotic patients with renal failure, renal blood flow autoregulation curve is shifted to the right, which is consequent upon sympathetic nervous system activation and endothelial dysfunction. Albumin infusion improves renal function in cirrhosis by mechanisms that are incompletely understood. We aimed to determine the effect of albumin infusion on systemic haemodynamics, renal blood flow, renal function and endothelial function in patients with acute decompensation of cirrhosis and acute kidney injury.Twelve patients with refractory ascites and 10 patients with acute decompensation of cirrhosis and acute kidney injury were studied. Both groups were treated with intravenous albumin infusion, 40-60 g/days over 3-4 days. Cardiac and renal haemodynamics were measured. Endothelial activation/dysfunction was assessed using von Willebrand factor and serum nitrite levels. F2α Isoprostanes, resting neutrophil burst and noradrenaline levels were quantified as markers of oxidative stress, endotoxemia and sympathetic activation respectively.Albumin infusion leads to a shift in the renal blood flow autoregulation curve towards normalization, which resulted in a significant increase in renal blood flow. Accordingly, improvement of renal function was observed. In parallel, a significant decrease in sympathetic activation, inflammation/oxidative stress and endothelial activation/dysfunction was documented. Improvement of renal blood flow correlated with improvement in endothelial activation (r = 0.741, P0.001).The data suggest that albumin infusion improves renal function in acutely decompensated cirrhotic patients with acute kidney injury by impacting on renal blood flow autoregulation. This is possibly achieved through endothelial stabilization and a reduction in the sympathetic tone, endotoxemia and oxidative stress.

Published
2013

32. Nitric oxide and L-arginine metabolism in a devascularized porcine model of acute liver failure

Author

Vikram Sharma, R Neil Dalton, Hans M.H. van-Eijk, Gabriella A. M. Ten Have, Nathan Davies, Lars M. Ytrebø, Sambit Sen, Arthur Revhaug, Rajiv Jalan, Charles Turner, Rajeshwar P. Mookerjee, Christopher F. Rose, Nicolaas E. P. Deutz, Surgery, and RS: NUTRIM - R2 - Gut-liver homeostasis

Subjects
Ornithine, medicine.medical_specialty, Arginine, Physiology, INTRACRANIAL-PRESSURE, Sus scrofa, PORTAL-DRAINED VISCERA, asymmetric dimethylarginine, arginine, Biology, Nitric Oxide, Nitric oxide, chemistry.chemical_compound, FULMINANT HEPATIC-FAILURE, Physiology (medical), Internal medicine, GUANYLATE-CYCLASE, medicine, Citrulline, Animals, COLLAGEN-SYNTHESIS, PLASMA AMINO-ACIDS, Hepatology, Portacaval Shunt, Surgical, digestive, oral, and skin physiology, arginase, Gastroenterology, ASYMMETRIC DIMETHYLARGININE ADMA, ALBUMIN DIALYSIS, Metabolism, Liver Failure, Acute, ENDOTHELIAL-CELLS, VASCULAR SMOOTH-MUSCLE, Arginase, Liver and Biliary Tract, Disease Models, Animal, Endocrinology, Liver, chemistry, Hyperdynamic circulation, Female, Asymmetric dimethylarginine
Abstract

In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23–30 kg) were randomized to sham ( N = 8) or hepatic devascularization ALF ( N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h ( P < 0.001), whereas citrulline and ornithine progressively increased in ALF ( P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis ( P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF ( P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.

Published
2012

33. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: The RELIEF trial

Author

Rajiv Jalan, Steffen Mitzner, Beat Müllhaupt, Wim Laleman, Tilman Sauerbruch, Johann Ockenga, Sambit Sen, Martin Eefsen, Hartmut Schmidt, Antonio Gasbarrini, Tanja Brünnler, Ludwig Kramer, Julia Wendon, Alexander Wilmer, Rafael Bañares, Philippe Mathurin, Marco Pavesi, Vicente Arroyo, Albert Parés, Roger Williams, Manuel de la Mata, Agustín Albillos, Alexander Zipprich, Faouzi Saliba, Fin Stolze Larsen, Teresa Tenorio, Matthias M. Dollinger, Frederik Nevens, Sebastian Klammt, Publica, University of Zurich, and Bañares, Rafael

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, medicine.medical_treatment, Multiple Organ Failure, Settore MED/12 - GASTROENTEROLOGIA, Population, Alcoholic hepatitis, 610 Medicine & health, Peritonitis, Acute, Gastroenterology, End Stage Liver Disease, Liver disease, Spontaneous bacterial peritonitis, Renal Dialysis, Internal medicine, medicine, Humans, Prospective Studies, education, Hepatic encephalopathy, Dialysis, Serum Albumin, education.field_of_study, Hepatology, business.industry, liver failure, Settore MED/09 - MEDICINA INTERNA, Liver Failure, Acute, Middle Aged, medicine.disease, Surgery, Transplantation, Hospitalization, Logistic Models, Treatment Outcome, 10219 Clinic for Gastroenterology and Hepatology, Multivariate Analysis, Female, Sorption Detoxification, 2721 Hepatology, business
Abstract

Acute-on-chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n = 95) or to standard therapy (SMT) (n = 94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per-protocol (PP) analysis (PP population n = 156). Up to 10 6-8-hour MARS sessions were scheduled. The main endpoint was 28-day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28-day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44-1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P = 0.02) and bilirubin (P = 0.001) and a more frequent improvement in HE (from grade II-IV to grade 0-I; 62.5% versus 38.2%; P = 0.07) was observed in the MARS group. Severe adverse events were similar. Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE. (HEPATOLOGY 2013)

Published
2012

34. Extracorporeal albumin dialysis in acute-on-chronic liver failure: Will it stand the test of time?

Author

Sambit Sen, Roger Williams, and Rajiv Jalan

Subjects
medicine.medical_specialty, Hepatology, business.industry, medicine.medical_treatment, Bioartificial liver device, Albumin, medicine.disease, Extracorporeal, law.invention, Surgery, Fulminant hepatic failure, Chronic disease, Hepatorenal syndrome, law, Anesthesia, Medicine, Acute on chronic liver failure, business, Dialysis
Published
2002
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35. Biliary atresia and survival into adulthood without transplantation: a collaborative multicentre clinic review

Author

Teru Kumagi, Orlee Guttman, Vicky L. Ng, Sambit Sen, Eve A. Roberts, Yoichi Hiasa, Gideon M. Hirschfield, Les Lilly, Morikazu Onji, Kojiro Michitaka, Jenny Heathcote, Joost P.H. Drenth, Yuji Watanabe, William J.H. Griffiths, and George Therapondos

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Cholangiopancreatography, Magnetic Resonance, medicine.medical_treatment, Cholangitis, Sclerosing, Membrane transport and intracellular motility [NCMLS 5], Intrahepatic bile ducts, Portoenterostomy, Hepatic, Liver transplantation, Gastroenterology, Biliary disease, Biliary injury, Biliary atresia, Biliary Atresia, Internal medicine, Hypertension, Portal, medicine, Humans, Survivors, Molecular gastro-enterology and hepatology [IGMD 2], Ultrasonography, Cholestasis, Hepatology, business.industry, Jaundice, Middle Aged, medicine.disease, Surgery, Transplantation, Bile Ducts, Intrahepatic, Treatment Outcome, Portal hypertension, Female, medicine.symptom, business
Abstract

Item does not contain fulltext BACKGROUND: Biliary atresia is a progressive biliary injury which occurs only in infants. AIMS: To review the experience of patients surviving into adulthood without the need for liver transplantation in childhood. METHODS: A multicentre review of patients with biliary atresia treated surgically who survived into adulthood without the need for transplantation. RESULTS: Twenty-two patients were identified across four centres. Median age at the last follow-up was 25 years (range: 18-46), and 21 patients had clinical features of portal hypertension. At last follow-up values of liver enzymes varied from normal to 15 x the upper limit of normal (ULN) for ALT (median 2.11 x ULN) and 9 x the ULN for ALP (median 2.02 x ULN). Six patients had a serum bilirubin > 50 mumol/l. Pruritus and jaundice were noted in 8 of 20 patients (40%) and 11 of 22 patients (50%) respectively. Thirteen patients (59.1%) were shown to have imaging features of sclerosing cholangitis, with strictures of intrahepatic bile duct(s) (IHBD), dilatation of IHBD (n = 8), or stone(s) within the IHBD (n = 5). A history of presumed bacterial cholangitis was present in 11 patients (50%). Successful pregnancies were recorded in three of fourteen female patients. Four patients underwent transplant between the ages of 20-27 years. Twenty-one patients (95.5%) were alive, including 18 (81.8%) with their native liver at the time of last follow-up. CONCLUSIONS: Some patients treated for biliary atresia will survive into adulthood with their native liver, but commonly with secondary biliary disease including cholangitis and portal hypertension. 01 maart 2012

Published
2011

36. Pulmonary complications in liver disease

Author

Sambit Sen and Graeme J.M. Alexander

Subjects
medicine.medical_specialty, Portopulmonary hypertension, business.industry, Hypertension, Pulmonary, Liver Diseases, General Medicine, Middle Aged, medicine.disease, Gastroenterology, Liver Transplantation, Liver disease, Internal medicine, Hypertension, Portal, medicine, Humans, Pulmonary vasculature, Hepatopulmonary syndrome, business, Epidemiologic Methods, Liver Failure, Aged, Hepatopulmonary Syndrome
Abstract

Pulmonary complications of liver disease are poorly understood and often identified late. Abnormalities of the pulmonary vasculature lead to two distinct complications, hepatopulmonary syndrome and portopulmonary hypertension, which differ in their clinical features and management. This article focuses on these two entities.

Published
2010

37. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality

Author

Nathan Davies, Sambit Sen, L Cheshire, Gert Matthes, Stephen J. Hodges, Vladimir Muravsky, Rajeshwar P. Mookerjee, Kerstin Schnurr, Roger Williams, and Rajiv Jalan

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Pathology, Cirrhosis, Gastroenterology, Liver disease, Spontaneous bacterial peritonitis, Ischemia, Renal Dialysis, Internal medicine, Fatty acid binding, Albumins, Malondialdehyde, medicine, Humans, Functional ability, F2-Isoprostanes, Binding Sites, Hepatology, business.industry, Albumin, Electron Spin Resonance Spectroscopy, Liver Failure, Acute, Middle Aged, medicine.disease, Human serum albumin, Oxidative Stress, Case-Control Studies, Female, business, medicine.drug
Abstract

Albumin concentration is diminished in patients with liver failure. Albumin infusion improves survival of cirrhotic patients with spontaneous bacterial peritonitis, and it is hypothesized that this may be due in part to its detoxifying capabilities. The aim of this study was to perform detailed quantitative and qualitative assessment of albumin function in patients with cirrhosis. Healthy controls and patients with acute deterioration of cirrhosis requiring hospital admission (n = 34) were included. Albumin function was assessed using affinity of the fatty acid binding sites using a spin label (16 doxyl-stearate) titration and electron paramagnetic resonance spectroscopy and ischemia-modified albumin (IMA) was measured. Twenty-two patients developed acute-on-chronic liver failure. Twelve were treated with the Molecular Adsorbents Recirculating System (MARS) and 10 with standard medical therapy. For each parameter measured, the patients' albumin had reduced functional ability, which worsened with disease severity. Fifteen patients died, and IMA, expressed as an albumin ratio (IMAR), was significantly higher in nonsurvivors compared with survivors (P < 0.001; area under the receiver operating curve = 0.8). No change in the patients' albumin function was observed following MARS therapy. A significant negative correlation between IMAR and the fatty acid binding coefficients for sites 1 and 2 (P < 0.001 for both) was observed, indicating possible sites of association on the protein. Conclusion: The results of this study suggests marked dysfunction of albumin function in advanced cirrhosis and provide further evidence for damage to the circulating albumin, which is not reversed by MARS therapy. IMAR correlates with disease severity and may have prognostic use in acute-on-chronic liver failure. (HEPATOLOGY 2009;50:555–564.)

Published
2009

39. Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure

Author

Geir I. Nedredal, Christopher F. Rose, Lars M. Ytrebø, Rajiv Jalan, Arthur Revhaug, Nathan Davies, Mireille Bélanger, Sambit Sen, Université de Montréal. Faculté de médecine. Centre de recherche du CHUM, and Université de Montréal. Faculté de médecine

Subjects
medicine.medical_specialty, Défaillance hépatique, Intracranial Pressure, Swine, Glutamine, Glutamic Acid, Biology, chemistry.chemical_compound, Ammonia, Internal medicine, Lactate dehydrogenase, medicine, Extracellular, Animals, Acide lactique, Lactic Acid, Pression intracrânienne, Intracranial pressure, Brain Chemistry, Ammoniac, Hepatology, Glutamate receptor, Metabolism, Liver Failure, Acute, Lactic acid, Disease Models, Animal, Endocrinology, Biochemistry, chemistry, Cerebral blood flow, Lactate, Female, Sorption Detoxification, Glutamate, Extracellular Space, Detoxification, Liver Failure
Abstract

We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using die molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by portacaval anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brain ammonia correlated with the percent change in ICP (r(2) = 0.511). Increases in brain lactate dehydrogenase activity and mitochondrial complex activity for complex IV were found in ALF compared with those in the sham, which was unaffected by MARS treatment. Brain oxygen consumption did not differ among the study groups. Conclusion: The observation that brain oxygen consumption and mitochondrial complex enzyme activity changed in parallel in both ALF- and MARS-treated animals indicates that the attenuation of increased extracellular brain ammonia (and extracellular brain glutamate) in the MARS-treated animals reduces energy demand and increases supply, resulting in attenuation of increased extracellular brain lactate. The mechanism of how MARS reduces extracellular brain ammonia. requires further investigation.

Published
2007

40. Increased gene and protein expression of the novel eNOS regulatory protein NOSTRIN and a variant in alcoholic hepatitis

Author

Marco Novelli, Werner Müller-Esterl, Anja Wiesenthal, Stephen J. Hodges, Roger Williams, Sambit Sen, Rajeshwar P. Mookerjee, Nathan Davies, Ann Icking, Rajiv Jalan, and Kirstin Schilling

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Alcoholic liver disease, Cirrhosis, Nitric Oxide Synthase Type III, Ubiquitin-Protein Ligases, Caveolin 1, Alcoholic hepatitis, Gene Expression, CHO Cells, Cricetulus, Enos, Internal medicine, Cell Line, Tumor, Cricetinae, Gene expression, medicine, Animals, Humans, Protein Isoforms, Tissue Distribution, RNA, Messenger, Endothelial dysfunction, Adaptor Proteins, Signal Transducing, Hepatitis, Hepatology, biology, Hepatitis, Alcoholic, Gastroenterology, Intracellular Signaling Peptides and Proteins, Genetic Variation, Middle Aged, medicine.disease, biology.organism_classification, Nitric oxide synthase, DNA-Binding Proteins, Endocrinology, Liver, biology.protein, Female, Carrier Proteins
Abstract

Background & Aims: Increased intrahepatic resistance in cirrhosis is associated with reduced endothelial NO synthase (eNOS) activity and exacerbated by superimposed inflammation. NOSTRIN induces intracellular translocation of eNOS and reduces NO generation. Our aims were to quantify and compare hepatic expression of eNOS, NOSTRIN, NOSIP, and caveolin-1 in alcoholic cirrhosis with or without superimposed alcoholic hepatitis and in normal livers. Methods: Biopsy specimens from 20 decompensated alcoholic cirrhotic patients with portal hypertension (10 with alcoholic hepatitis) and 6 normal livers were analyzed: real-time polymerase chain reaction for quantification of messenger RNA; Western blotting; and enzyme assays of eNOS in normal and diseased liver were performed. Localization and interaction of eNOS and NOSTRIN in liver was assessed by immunohistochemistry and co-immunoprecipitation. Results: eNOS mRNA was significantly increased and eNOS activity decreased in alcoholic hepatitis patients, despite no differences in eNOS protein expression among the patients. Patients with alcoholic hepatitis had significantly higher hepatic levels of NOSTRIN and caveolin-1 mRNA compared with cirrhosis alone or normal biopsy specimens. A NOSTRIN splice variant, not present in normal tissue, was detected on mRNA and protein levels in all alcoholic patients. Coimmunoprecipitation demonstrated association among NOSTRIN, eNOS, and caveolin-1. Conclusions: An increase in mRNA and protein of NOSTRIN and its shortened variant in alcoholic hepatitis may partly account for the paradox of increased mRNA levels and normal protein expression but decreased enzymatic activity of eNOS in diseased liver. Such intracellular regulators of NO production may be important in the development of increased intrahepatic resistance in alcoholic hepatitis patients.

Published
2006

41. Systemic and regional hemodynamics in pigs with acute liver failure and the effect of albumin dialysis

Author

Nicolaas E. P. Deutz, Nathan Davies, Gabrie A. M. Ten Have, Christopher F. Rose, Geir I. Nedredal, Ole-Martin Fuskevaag, Sambit Sen, LM Ytrebo, Rajiv Jalan, Frits W. Prinzen, Arthur Revhaug, Roger Williams, Université de Montréal. Faculté de médecine. Centre de recherche du CHUM, Université de Montréal. Faculté de médecine, Algemene Heelkunde, Fysiologie, and RS: NUTRIM School of Nutrition and Translational Research in Metabolism

Subjects
medicine.medical_specialty, Mean arterial pressure, Swine, medicine.medical_treatment, Circulation hyperdynamique, Cardiac index, Renal function, Blood Pressure, Gastroenterology, Random Allocation, Catecholamines, Hepatorenal syndrome, Renal Dialysis, Albumins, Internal medicine, medicine, Animals, Nitrites, Dialysis, Analysis of Variance, Nitrates, business.industry, digestive, oral, and skin physiology, Hyperdynamic circulation, Syndrome hépatorénal, Liver Failure, Acute, medicine.disease, Dialyse albumine, Disease Models, Animal, medicine.anatomical_structure, Endocrinology, Albumin dialysis, Organes artificiels, Creatinine, Vascular resistance, Female, Vascular Resistance, business, Algorithms, Kidney disease, Artificial organs
Abstract

OBJECTIVE: Acute liver failure (ALF) is haemodynamically characterized by a hyperdynamic circulation. The aims of this study were to investigate the systemic and regional haemodynamics in ALF, to measure changes in nitric oxide metabolites (NOx) and to evaluate whether these haemodynamic disturbances could be attenuated with albumin dialysis. MATERIAL AND METHODS: Norwegian Landrace pigs (23-30 kg) were randomly allocated to groups as controls (sham-operation, n = 8), ALF (hepatic devascularization, n = 8) and ALF + albumin dialysis (n = 8). Albumin dialysis was started 2 h after ALF induction and continued for 4 h. Systemic and regional haemodynamics were monitored. Creatinine clearance, nitrite/nitrate and catecholamines were measured. A repeated measures ANOVA was used to analyse the data. RESULTS: In the ALF group, the cardiac index increased (PGT < 0.0001), while mean arterial pressure (PG = 0.02) and systemic vascular resistance decreased (PGT < 0.0001). Renal resistance (PG = 0.04) and hind-leg resistance (PGT = 0.003) decreased in ALF. There was no difference in jejunal blood flow between the groups. ALF pigs developed renal dysfunction with increased serum creatinine (PGT = 0.002) and decreased creatinine clearance (P = 0.02). Catecholamines were significantly higher in ALF, but NOx levels were not different. Albumin dialysis did not attenuate these haemodynamic or renal disturbances. CONCLUSIONS: The haemodynamic disturbances during the early phase of ALF are characterized by progressive systemic vasodilatation with no associated changes in metabolites of NO. Renal vascular resistance decreased and renal dysfunction developed independently of changes in renal blood flow. After 4 h of albumin dialysis there was no attenuation of the haemodynamic or renal disturbances.

Published
2006

42. The role of the Molecular Adsorbents Recirculating System (MARS) in the management of liver failure

Author

Sambit Sen and Rajiv Jalan

Subjects
medicine.medical_specialty, medicine.medical_treatment, 030232 urology & nephrology, Renal function, 030204 cardiovascular system & hematology, Pharmacology, Extracorporeal, 03 medical and health sciences, 0302 clinical medicine, Renal Dialysis, medicine, Humans, Radiology, Nuclear Medicine and imaging, Intensive care medicine, Hepatic encephalopathy, Dialysis, Serum Albumin, Advanced and Specialized Nursing, Kidney, business.industry, Albumin, Liver failure, General Medicine, medicine.disease, medicine.anatomical_structure, Sorption Detoxification, Cardiology and Cardiovascular Medicine, Systemic haemodynamics, business, Safety Research, Liver Failure
Abstract

Albumin-bound toxins accumulate in liver failure, and are believed to contribute to the development of the associated end-organ dysfunctions (kidney, circulation, brain). The scavenging functions of albumin are utilized in albumin dialysis for toxin removal. The Molecular Adsorbents Recirculating System (MARS) is an extracorporeal liver support device based on dialysis across an albumin-impregnated membrane, using 20% albumin as dialysate. Charcoal and anion exchange resin columns in the circuit help cleanse and regenerate the dialysate. Clinical studies over the last decade have demonstrated proven reduction in hyperbilirubinaemia, along with an improvement in hepatic encephalopathy, systemic haemodynamics and renal function in liver failure patients, as well as apparent improvement in survival. However, the specific mechanisms underlying these observed clinical changes are as yet unclear. The results of larger controlled clinical trials, as well as studies investigating the pathophysiological basis of its effect, are awaited.

Published
2004

43. Contractile response of femoral arteries in pigs with acute liver failure

Author

Arthur Revhaug, Rajiv Jalan, Lars M. Ytrebø, Geir I. Nedredal, Sambit Sen, Sveinung Ekse, Ole-Martin Fuskevåg, Christopher F. Rose, Université de Montréal. Faculté de médecine. Centre de recherche du CHUM, and Université de Montréal. Faculté de médecine

Subjects
medicine.medical_specialty, Vascular smooth muscle, Cirrhosis, Swine, Hemodynamics, Portacaval shunt, Femoral artery, Sensitivity and Specificity, Muscle, Smooth, Vascular, Contractility, Random Allocation, Norepinephrine, Internal medicine, medicine.artery, Angiotensine-II, medicine, Animals, Phénomènes physiologiques cardiovasculaires, Probability, Hémodynamique, business.industry, Angiotensin II, Gastroenterology, Liver Failure, Acute, medicine.disease, Haemodynamic, Femoral Artery, Vasodilation, Disease Models, Animal, Vascular physiology, Endocrinology, Vasoconstriction, Heart Function Tests, Hyperdynamic circulation, Cardiology, Female, business, Norépinéphrine
Abstract

BACKGROUND: Acute liver failure (ALF) is characterized haemodynamically by a progressive hyperdynamic circulation. The pathophysiological mechanism is unknown, but impaired contractility of vascular smooth muscle may play an important role. The aim of this study was to evaluate the vascular response to stimulation with norepinephrine and angiotensin II in endothelium-denuded femoral artery rings. METHODS: Norwegian Landrace pigs weighing 27.1 +/- 0.5 kg (mean +/- sx (standard error of the mean)) were used. ALF was induced by performing a portacaval shunt followed by ligation of the hepatic arteries (n = 6). Sham-operated animals served as controls (n = 5). Cumulative isometric concentration contraction curves were obtained after in vitro stimulation of the femoral artery rings with either angiotensin II (10(-13) - 10(-5) mol/L) or norepinephrine (10(-13) - 10(-3) mol/L). RESULTS: Pigs suffering from ALF developed a hyperdynamic circulation with an increased cardiac index (P = 0.017) and decreased systemic vascular resistance index (P = 0.015). Studies of the hind leg revealed a decreased vascular resistance index and increased blood flow compared to sham-operated controls (P = 0.003 and P = 0.01, respectively). Angiotensin II caused a concentration-dependent contraction of the arterial segments, with no significant differences in vascular responses between the two groups. Maximum force generated did not differ (55 +/- 7 versus 56 +/- 7 mN, P = 0.95). Furthermore, there were no differences for norepinephrine in the cumulative concentration-response curves and the maximum contractile force was not significantly different (87 +/- 8 versus 93 +/- 16 mN, P = 0.55). CONCLUSIONS: This study documents for the first time that there are no signs of endothelium-independent peripheral vascular hyporesponsiveness to angiotensin II and norepinephrine in pigs with ALF.

Published
2004

44. New liver support devices in acute liver failure: a critical evaluation

Author

Sambit Sen and Roger Williams

Subjects
medicine.medical_specialty, Pathology, Extracorporeal Circulation, Hepatology, business.industry, Swine, medicine.medical_treatment, Extracorporeal circulation, Liver failure, Liver transplantation, Liver Failure, Acute, Liver, Artificial, law.invention, Transplantation, Randomized controlled trial, law, Etiology, medicine, Hepatocytes, Animals, Humans, Intensive care medicine, business, Dialysis, Liver support systems
Abstract

Acute liver failure remains a condition with substantial mortality in spite of the best available medical care. Liver transplantation is often not possible or delayed, and liver support systems can be used to maintain the patient during the crisis by bridging to transplantation or allowing recovery of the native liver. Bioartificial devices, using porcine or human hepatocytes, have yielded encouraging results on consciousness levels in a number of studies and have generally been found to be safe, although in one large controlled trial reported to date, benefit was restricted to certain subgroups. Artificial devices, like those based on albumin dialysis, are undoubtedly effective in removing protein-bound toxins, and uncontrolled evidence shows some survival benefit. The large multicenter controlled trials necessary for proving the value of these systems are difficult to design. They have to take into account the influence of transplantation, etiology, and other factors on outcome. Achieving a standard medical regime for these critically ill patients between different centers is also difficult.

Published
2003

45. Albumin dialysis: a new therapeutic strategy for intoxication from protein-bound drugs

Author

Christopher F. Rose, Geir I. Nedredal, Arthur Revhaug, Rajiv Jalan, Roger Williams, Nathan Davies, Ole-Martin Fuskevaag, Sambit Sen, Lars M. Ytrebø, and Université de Montréal. Faculté de médecine. Département de médecine

Subjects
Resuscitation, Swine, medicine.medical_treatment, Midazolam, Serum albumin, Critical Care and Intensive Care Medicine, Fentanyl, Intensive care, medicine, Animals, Dialysis, Serum Albumin, biology, business.industry, Albumin, Orosomucoid, Liver Failure, Acute, Albumin dialysis, Charcoal, Anesthesia, biology.protein, Linear Models, Female, Sorption Detoxification, Adsorption, Hemodialysis, business, Anesthetics, Intravenous, medicine.drug, Protein Binding
Abstract

Objective: Although water-soluble drugs can be removed by haemofiltration/haemodialysis, morbidity and mortality from intoxication with protein-bound drugs remains high. The present study investigates whether albumin dialysis in the form of the Molecular Adsorbents Recirculating System (MARS) is effective in removal of protein-bound drugs. Design: Prospective animal study. Setting: Surgical research laboratory in a university hospital. Subjects: Seven female Norwegian Landrace pigs. Intervention: We studied whether midazolam (97% albuminbound) and fentanyl (85% alpha-1- acid glycoprotein-bound), administered as anaesthetics to pigs with induced acute liver failure, could be removed by MARS dialysis lasting for 4 h. Measurements: After 4 h of dialysis, total and free anaesthetic concentrations were measured in the blood and dialysate from different segments of the MARS circuit. Main results: Midazolam: total plasma concentrations fell by 47.1€2.1% (in 4 h) across the MARS filter (p

Published
2003

46. Liver failure: basis of benefit of therapy with the molecular adsorbents recirculating system

Author

Rajiv Jalan, Roger Williams, and Sambit Sen

Subjects
Kidney, Cirrhosis, business.industry, medicine.medical_treatment, Encephalopathy, Albumin, Bioartificial liver device, Renal function, Cell Biology, Pharmacology, medicine.disease, Biochemistry, law.invention, medicine.anatomical_structure, Hepatorenal syndrome, law, Albumins, medicine, Humans, Sorption Detoxification, business, Dialysis, Liver Failure, Serum Albumin
Abstract

Accumulation of albumin-bound toxins is known to occur in liver failure, and to variable extents is responsible for the associated end-organ dysfunctions (kidney, circulation, brain). The toxin-binding and scavenging functions of albumin are exploited in albumin dialysis for removal of these toxins. The extracorporeal liver support device known as molecular adsorbents recirculating system (MARS) is based on dialysis across an albumin-impregnated membrane, using 20% albumin as dialysate. Charcoal and anion exchange resin columns in the circuit help cleanse and regenerate the dialysate. Clinical studies over the last few years have demonstrated proven reduction in hyperbilirubinaemia, along with an improvement in encephalopathy, systemic haemodynamics and renal function in liver failure patients, as well as apparent improvement in survival. The results of larger controlled clinical trials, as well as studies investigating the pathophysiological basis of its effect, are awaited.

Published
2003

47. Treatment of phenytoin toxicity by the molecular adsorbents recirculating system (MARS)

Author

Rajeshwar P. Mookerjee, Sambit Sen, Philip N. Patsalos, Rajiv Jalan, Nathan Davies, Neville Ratnaraj, Roger Williams, and Chris E. Cooper

Subjects
Phenytoin, Male, medicine.medical_treatment, Pharmacology, medicine.disease_cause, Status Epilepticus, Renal Dialysis, Hemofiltration, medicine, Humans, Dialysis, Serum Albumin, business.industry, Albumin, Equipment Design, Middle Aged, Liver, Artificial, Anticonvulsant, Treatment Outcome, Neurology, Anesthesia, Toxicity, Kidney Failure, Chronic, Anticonvulsants, Neurology (clinical), Hemodialysis, Drug Overdose, business, Oxidative stress, medicine.drug, Protein Binding
Abstract

Summary: Purpose: Toxicity is common in patients of epilepsy treated with phenytoin (PHT), requiring careful drug level monitoring and supportive care. Specific treatment options are limited, although charcoal haemofiltration has been used previously. We attempted to demonstrate that severe PHT toxicity can be treated successfully with the Molecular Adsorbents Recirculating System (MARS). The mechanism of drug removal by the system also was studied. Methods: A 45-year-old patient of status epilepticus with acute renal failure and severe PHT toxicity, associated with cardiac arrhythmias, hepatotoxicity, and altered sensorium, was treated with the MARS, a blood-purification system based on albumin dialysis, and including a charcoal filter, for 11.5 h. Serum PHT levels and blood levels of oxygen-based free radicals (by electron paramagnetic resonance spectroscopy) were measured before and after treatment. Results: Serum total and free PHT levels declined sharply (32 to 11 μM and 9.8 to 2.0 μM, respectively), with clinical improvement and a 65% reduction in measured oxidative stress. The mechanism of drug removal, deduced by measuring PHT in the dialysate collected from different segments of the MARS circuit, was by clearance from blood into the albumin dialysate, and ultimately removal by the charcoal filter. Conclusions: The observed removal of PHT by MARS, along with the clinical improvement of the patient and reduction of the associated oxidative stress after treatment, indicates that MARS offers a promising option in PHT toxicity.

Published
2003

48. Molecular Adsorbents Recirculating System (MARS) for acute decompensation of chronic liver disease: an early clinical experience

Author

Dharmesh Kapoor, A. Alisa, Roger Williams, Sambit Sen, Rajiv Jalan, and Christian Steiner

Subjects
medicine.medical_specialty, Cirrhosis, business.industry, medicine.medical_treatment, Encephalopathy, Bioartificial liver device, Liver transplantation, medicine.disease, Chronic liver disease, Gastroenterology, Liver regeneration, law.invention, law, Internal medicine, Immunology, medicine, Decompensation, business, Hepatic encephalopathy
Abstract

Patients with acute-on-chronic liver failure (ACLF) have a high mortality.1, 2, 3, 4, 5, 6, 7 Most are unsuitable for liver transplantation (OLT) and the current management is essentially supportive. The availability of an effective form of liver support, either to either bridge to OLT (in those eligible) or to buy time for liver regeneration and spontaneous recovery, would represent a major advance. Of the various types of liver support, some (bio-artificial) include hepatocytes,8,9 while others are based on detoxification using membranes and adsorbents. Such liver support devices have been mainly tried in patients with acute liver failure (ALF) and encephalopathy, and only rarely in patients with ACLF.

Published
2003
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49. Terlipressin-induced vasoconstriction reversed with N-acetylcysteine: a case for combined use in hepatorenal syndrome?

Author

Rajeshwar P. Mookerjee, Sambit Sen, and Rajiv Jalan

Subjects
medicine.medical_specialty, Cirrhosis, Hepatorenal Syndrome, Combined use, Lypressin, Gastroenterology, Acetylcysteine, Pharmacotherapy, Hepatorenal syndrome, Internal medicine, Medicine, Humans, Vasoconstrictor Agents, Hepatology, business.industry, medicine.disease, Vasoconstriction, Drug Therapy, Combination, medicine.symptom, business, Terlipressin, medicine.drug
Published
2002

50. Hemodynamic effect of spironolactone in liver cirrhosis and propranolol-resistant portal hypertension

Author

Sambit, Sen, Binay K, De, Pranab K, Biswas, Jayanta, Biswas, Debasish, Das, and Ajit K, Maity

Subjects
Adult, Liver Cirrhosis, Male, Adrenergic beta-Antagonists, Spironolactone, Esophageal and Gastric Varices, Propranolol, Portal System, Hypertension, Portal, Humans, Drug Therapy, Combination, Female, Diuretics, Gastrointestinal Hemorrhage
Abstract

In a proportion of patients with liver cirrhosis, portal pressure does not decrease adequately with propranolol. These patients may benefit from another drug that may reduce portal pressure. We evaluated the role of spironolactone, alone or with propranolol, in such patients.Patients with cirrhosis, with or without ascites, with esophageal varices and with hepatic venous pressure gradient exceeding 12 mmHg, which did not show a 20% reduction after an 80-mg oral dose of propranolol, were studied. They were allocated to receive spironolactone 100 mg orally once daily either alone (group 1, n=10) or with propranolol 40 mg orally twice daily (group 2, n=10), for 7 days, after which the hemodynamic study was repeated.Hepatic venous pressure gradient decreased in those receiving spironolactone and propranolol (p=0.007); 5 patients in group 1 and 7 in group 2 showed a reduction in hepatic venous pressure gradient by more than 20%. However, the reduction produced by spironolactone alone (20.5 [31.3]%) was not significantly different from that produced by combination therapy (30.3 [25.9]%; p=0.46).Spironolactone in combination with propranolol achieves adequate reduction (or = 20%) in hepatic venous pressure gradient in propranolol-resistant portal hypertension in patients with liver cirrhosis. Spironolactone alone was also effective in some patients.

Published
2002

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