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Post Hepatectomy Liver Failure: Risk Factors and Prediction of Post 1 Post Hepatectomy Liver Failure: Risk Factors and Prediction of Post-Operative Function using Novel Dynamic MRI David Alexander Longbotham Submitted in accordance with the requirements for the degree of Doctor of Medicine School of Medicine University of Leeds August 2019 2 The candidate confirms that the work submitted is their own, except where work which has formed part of jointly authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated below. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. List of included Publications (chapters 3-5) I. D Longbotham, A Young, G Nana, R Feltbower, E Hidalgo, G Toogood, JP Lodge, M Attia, KR Prasad (Pre-print) The impact of age on post-operative liver function following right hepatectomy: a retrospective, single centre experience HPB 2019 Jul 20 I was responsible for study design, data collection, data analysis and writing the manuscript. The contribution of the other authors was: KR Prasad conceptualised the study, G Nana assisted with data collection. A Young advised on data analysis, R Feltbower advised on the multivariable analysis, all authors advised and contributed to the manuscript. II. D Longbotham, S Sourbron, A Guthrie, E Hidalgo, R Prasad Measuring liver function with gadoxetic acid: Is a dual-input model needed in dynamic contrast enhanced liver MRI? (Oral presentation presented at IHPBA/ASGBI 2015) HPB April 16 Volume 18 S2 Page e697 I was responsible for study design, data collection, data analysis and writing the manuscript The contribution of the other authors was: S Sourbron initiated the study, S Sourbron contributed to study design and assisted with development of the MRI protocol with input from A Guthrie. S Sourbron advised on DGE-MRI analysis, all authors advised and contributed to the manuscript. 3 III. D Longbotham, D Wilson, A Guthrie, I Rowe, M Gilthorpe, E Hidalgo, M Attia, KR Prasad, S Sourbron Prediction of post-hepatectomy liver function with Dynamic Gadoxetate-Enhanced MRI: A pilot study in patients undergoing Colorectal Liver Metastasis Resection In submission (HPB), accepted for presentation at the International Society for Magnetic Resonance imaging in Medicine (ISMRM) annual meeting and exhibition, Sydney, Australia, April 2020 I was responsible for study design, data collection, data analysis and writing the manuscript The contribution of the other authors was S Sourbron, A Guthrie, E Hidalgo and KR Prasad initiated the study and advised with study design. D Wilson and S Sourbron developed the MRI protocol with input from A Guthrie. S Sourbron advised on DGE-MRI analysis, I Rowe and M Gilthorpe advised on data analysis and supported interpretation of results. All authors advised and contributed to the manuscript. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement The right of David Alexander Longbotham to be identified as Author of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. 4 Acknowledgements I wish to thank all my supervisors, Dr Steven Sourbron, Mr Raj Prasad and Mr Magdy Attia for their expert advice and support in the design and execution of this research degree, and to all my co-authors in the published manuscripts for their helpful advice and input. I also wish to thank the MRI department in St James’s University Hospital for their patience allowing me the opportunity to disrupt their lists with my research protocol patients, and the staff of the surgical department in Friarage Hospital, Northallerton for allowing me the grace of time to analyse the results of the results chapters and write the majority of this text. Finally I would mostly like to thank my fiancé Katie for putting up with me through all the time this thesis has been worked on for, I couldn’t have managed without her support. MD Supervisors University of Leeds/Scientific Supervisor: • Dr Steven Sourbron Clinical Supervisors: • Mr K Rajendra Prasad • Mr Magdy Attia 5 Abstract Liver surgery is an advancing specialty with improved outcomes in recent years(1). Liver resection is used with curative intent for both primary and metastatic cancer(2)(3)(4). Despite the rapid improvements and increasing range of surgical options, there remains a significant risk of developing Post-Hepatectomy Liver Failure (PHLF) – caused by inadequate remnant liver function after surgery(5)(6). This is a condition with high mortality and morbidity(7) and currently there are no specific treatments for it once it has developed(8). Its pathogenesis is complex and multifactorial(9)(10), and some risk factors, particularly ageing are uncertain as to their contributing significance. This thesis aimed to investigate risk factors for PHLF development and a imaging based measurement of liver function after major liver resection. This study identified patients over-75 years have a significantly increased risk of PHLF. Development of a method to predict post-operative function is needed to aid patient selection and reduce complications for those who undergo resection. Currently, volumetry is performed but this has proven inadequate, with some patients still developing PHLF despite adequate remnant volume(11). Other options such as Indocyanine Green(12) and Technetium-99m labelled Mebrofenin(13) are not readily available. One potential solution is Dynamic Gadoxetate Enhanced (DGE) MRI of the Liver, which has been developed to investigate liver function, with promising results for demonstrating liver heterogenicity in patients with parenchymal liver diseases(14). Oncological staging of the liver involves MRI to plan surgical resection, and DGE-MRI can be integrated into the diagnostic protocol easily with no additional burden to the patient. This thesis aimed to demonstrate if DGE-MRI functional estimates can predict post-operative liver function after resection of colorectal liver metastases. This study demonstrated that there was good correlation of DGE-MRI-function tests with post- operative hyperbilirubinaemia, a measure of hepatic dysfunction. This could be utilised in surgical planning to improve patient selection and outcomes. 6 List of Contents List of Tables ................................................................................................................................. 9 List of Figures .............................................................................................................................. 10 List of Abbreviations ................................................................................................................. 11 Chapter 1 – Introduction, Aims and Hypotheses ........................................................................ 14 1.1 Aims and Hypothesis ......................................................................................................... 15 Chapter 2 – Background ............................................................................................................. 18 2.1 Liver Surgery ...................................................................................................................... 18 2.1.1 History of Liver Surgery .............................................................................................. 18 2.1.2 Ancient history ............................................................................................................ 18 2.1.3 Renaissance .............................................................................................................. 19 2.1.4 Era of anaesthesia ..................................................................................................... 20 2.1.5 Blood loss control ....................................................................................................... 21 2.1.6 Modern developments and techniques ...................................................................... 23 2.1.7 Development of Liver Imaging ................................................................................... 26 2.1.8 Liver embryology, anatomy, and physiology .............................................................. 28 2.1.9 Anatomy ..................................................................................................................... 29 2.1.10 Microscopic Anatomy and Physiology ..................................................................... 33 2.1.11 Liver regeneration .................................................................................................... 35 2.1.12 Current indications for Liver Resection Surgery ...................................................... 36 2.1.13 Pathogenesis of Colorectal Liver Metastasis ........................................................... 37 2.1.14 Current pre-operative investigations for Liver Metastasis resection ........................ 38 2.1.15 Patient factors and fitness for surgery ..................................................................... 40 2.1.16 Liver resection technique and hemihepatectomy .................................................... 43 2.2 Complications of Surgery ................................................................................................... 45 2.2.1 Complications of Liver Surgery and Post Hepatectomy Liver Failure ....................... 45 2.2.2 Background liver disease and PHLF .........................................................................
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