CHRONIC PANCREATITIS: ELECTROPHILIC STRESS TEMPLATE Joan M Braganza DSc FRCP FRCPath DEVELOPMENT RATIONALISING GEOGRAPHY PETROCHEMICAL CONNECTION ACCOMMODATING GENE MUTATIONS MICRONUTRIENT THERAPY MAST CELL PATHOLOGY DISEASE PREVENTION CHRONIC PANCREATITIS: ELECTROPHILIC STRESS TEMPLATE By: Joan M Braganza DSc FRCP FRCPath University of Manchester Manchester, UK Published by: Pancreapedia: Exocrine Pancreas Knowledge Base In partnership with the University of Michigan Library Ann Arbor, MI 48109 and The American Pancreatic Association ISBN 978-1-60785-412-8 (e-book) This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License. To view a copy of this license, visit https://creativecommons.org/licenses/by- nc/4.0/ or send a letter to Creative Commons, PO Box 1866, Mountain View, California, 94042, USA. Publishers Preface This monograph presents a comprehensive review of the work of Professor Joan Braganza into the pathogenesis and treatment of chronic pancreatitis as a disease caused by oxidative and particularly electrophilic stress with an emphasis on environmental toxicants as one factor which is part of the balance of damaging and protective cellular forces in the pancreas, liver and other participating organs. This is the second monograph of this type and follows “The Hamster Pancreas” written by Parviz Pour. Both books are published in open access eBook form under a Creative Commons license and are available on the Pancreapedia site. Pancreapedia will from time to time publish eBooks that are more substantive than a review article and where the author prepares the text and secures copyright approval for figures or tables published previously. Publishing can be done at no or low cost to the author. Authors should obtain approval from the Editor before preparing detailed content. As was carried out for this book, the Pancreapedia Editor and staff carry out light copy editing and format the book with final approval by the author. Our books are assigned an ISBN number and can be cited as any other book. We thank the American Pancreatic Association for their support and especially thank Melissa Wu and Juliana Lam, two students from the University of Michigan School of Information who served as Content/Community Manager for the Pancreapedia and were responsible for taking the edited content and preparing the book you see here. John A. Williams Editor-in-Chief, Pancreapedia Table of Contents Glossary and Conversion factors vii Preface ix 1. Introduction 1 2. Chronic pancreatitis: 1980s 3 2.1. Frame of reference 3 2.2 The disease 5 2.3 Diagnosis 10 2.4 Treatment 13 2.5 Summary 14 3. Serendipity! 15 3.1 Boots versus GIH secretin 15 3.2 Studies on copper 17 3.3 Bilirubin hypersecretion 23 3.4 Introduction to free radical pathology 26 3.5 Overview and summary 34 4. Pancreatic Disease: Casualty of Hepatic ‘Detoxification’ Reactions? 35 4.1 Clues 35 4.2 Cytochromes P450 36 4.3 Hypothesis: Pancreatic disease is a casualty of liver ‘detoxification reactions’ 36 4.4 Testing the concept 37 5. Drug Metabolism and Ancillary Studies 38 5.1 Routine tests 39 5.2 Antipyrine, theophylline, debrisoquine 43 5.3 D-glucaric acid 51 5.4 Biliary fatty acids 53 5.5 Overview and summary 58 6. Hepatobiliary Aberrations: Reflux Link to Pancreatitis? 59 6.1 Liver histology 59 6.2 Endoscopic cholangiograms 63 6.3 Chronic pancreatitis-type artificial bile and experimental pancreatitis 66 6.4 Overview and summary 68 7. Probing the Defence Arc: Dietary Antioxidants 69 7.1 Versus intake in healthy controls 69 7.2 Versus intake in controls with epilepsy 72 7.3 Epilepsy plus chronic pancreatitis 75 7.4 Overview and summary 76 8. Occupational Volatile Chemicals 78 8.1 Pilot study 78 8.2 Case-referent study: chronic pancreatitis 81 8.3 Overview and summary 87 iv 9. Casualty of Pancreatic ‘Detoxificaton’ Reactions! 88 9.1 Futility of clinical bile diversion 88 9.2 Investigation of pancreatic CYP 91 9.3 Overview and summary 95 10. Taking Stock 97 10.1 Premises of 1983 confirmed 97 10.2 Modification of 1986 confirmed 97 10.3 Electrophilic stress: component clauses 98 10.4 Hepatisation of the pancreas 98 10.5 More questions 98 11. Free Radical Pathology of a Pancreatitis Attack 99 11.1 On secretory polarity 100 11.2 Free radicals as detonator 101 11.3 Methyl and thiol homeostasis 103 11.4 What role for trypsin? 107 11.5 What initiates inflammation? 109 11.6 Acute / RAP link to chronic pancreatitis 110 11.7 Overview and summary 112 12. Rationalising Disease Geography 113 12.1 Chennai, South India: 1988 113 12.2 Soweto, South Africa: 1993 119 12.3 Overview and summary 126 13. Accommodating gene mutations 129 13.1 Received wisdom 129 13.2 Against a central role for trypsin in HP 130 13.3 On CFTR mutations 131 13.4 Miscellaneous 135 13.5 Tweak to template 136 13.6 Conclusion 136 14. Towards an Animal Model Based on CYP Induction 137 14.1 Drug metabolism studies 138 14.2 Secretory studies 139 14.3 Histology studies 142 14.4 Overview and summary 144 15. Antioxidant Therapy for Relapsing Pancreatitis: Exploratory 147 15.1 Idiopathic relapsing pancreatitis 147 15.2 Metabolic predisposition 151 15.3 Overview and summary 154 16. Clinical Trials of AOT: Manchester and Beyond 157 16.1 RCTS: Manchester late 1980s 157 16.2 Subsequent trials 166 16.3 Pancreatic extracts: micronutrient therapy by proxy 170 16.4 Value of long-term treatment 171 16.5 Why does the prescription work? 175 16.6 Overview and summary 176 v 17. Towards First-Line Treatment for Acute Pancreatitis 177 17.1 Anecdotal clinical experience: positive impact of N-acetylcysteine 177 17.2 Allograft pancreatitis: protection by S-adenosylmethionine 178 17.3 Clinical trial of SAM plus NAC for first 24 hours 181 17.4 Why treatment failure: micronutrient lack / persisting oxidative stress? 183 17.5 Why treatment failure: fibrinolysis precedes hypercoagulability 190 17.6 Overview and summary 197 18. More on Micronutrient Lack and Pancreatitis Risk 198 18.1 Gallstones 198 18.2 Ischaemic heart disease 207 18.3 Raynaud’s phenomenon 209 18.4 Overview and summary 211 19. Electrophilic Stress and Pancreatitis: 2016 216 19.1 Stresses and stressors 216 19.2 Electrophilic stress template for chronic pancreatitis 217 19.3 Electrophilic stress and fatal acute pancreatitis 224 19.4 Summary 228 20. Coda 229 References 231 vi Glossary & Conversion factors Abbreviation Form represented α1PI alpha 1 proteinase inhibitor α2M alpha 2 macroglobulin AMP adenosine monophosphate AOT antioxidant therapy βNF beta naphthoflavone BDBF brain- derived neurotrophic factor BT PABA N-benzoyl L-tyrosyl para-amino benzoic acid BSP bromosulphthalein C18:2 linoleic acid Ca++ ionised calcium CAPAP carboxypeptide activartion peptide CCK cholecystokinin-pancreozymin CDE choline-deficient ethionine-supplemented diet CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator CGRP calcitonin gene related peptide CH3 methyl groups CHRU Crick Harper Raper Unit of Boots secretin CI confidence interval Cl clearance of probe CRP C-reactive protein CT computed tomography CU Clinical unit of highly purified or synthetic secretin CV coefficient of variation CYP cytochromes P450 DC diene conjugation DGA D glucaric acid ER endoplasmic reticulum ERCP endoscopic retrograde choalngiopancreatography FLLD familial lipoprotein lipase deficiency FRA free radical activity FROP free radical oxidation products GIH highly purified secretin from the Gastrointestinal hormone laboratory G-protein guanine nucleotide-binding protein Gs / Gi proteins stimulatory / inhibitory variant G-proteins GSH glutathione in bioactive reduced form GSSG glutathione in reversibly oxidised form after binding to peroxides GST glutathione-S-transferases GST-B ligandin HO haem oxygenase HOCl hypochlorous acid H2O2 hydrogen peroxide H2S hydrogen sulphide HPLC high performance liquid chromatography HPN haemorrhagic pancreatic necrosis / necrotising pancreatitis 9,11 LA’ specific DC isomer of linoleic acid MODS multiple organ dysfunction syndrome %MRLA % molar ratio of specific DC isomer to parent linoleic acid %MRVC % molar ratio of oxidised forms to total vitamin C MTA mean trypsin acitivity in meal test NAC N-acetylcysteine vii NGF nerve growth factor NO• nitric oxide radical NSAID non-steroidal anti- inflammatory drug O2 molecular oxygen -• O2 superoxide anion free radical OH• hydroxyl free radical PAH polycyclic aromatic hydrocarbons PMN polymorphonuclear cells / neutrophils PTA peak trypsin activity after pancreozymin PUFA polyunsaturated fatty acids RAP recurrent/relapsing acute pancreatitis RCT randomised controlled trial RER rough endoplasmic reticulum ROS reactive oxygen species RNI recommended nutrient intake RNS reactive nitrogen species RP Raynauds phenomenon RXS reactive xenobiotic species SAPE sentinel acute pancreatitis event SD standard deviation SE standard error SER smooth endoplasmic reticulum SH thiol / sulphydryl groups SIRS systemic inflammatory response syndrome SOD superoxide dismutase ` SP test secretin pancreozymin test SPINK1 specific pancreatic trypsin inhibitor Kazal type 1 S-S disulphide linkages T1/2 half-life of probe TAP trypsinogen activation peptide TBARS thiobarbituric acid reactive substances TNF-α tumour necrosis factor alpha TGF-β1 tumour necrosis factor beta 1 TRPV1 transient receptor vallinoid 1 UPR unfolded protein response UVF ultraviolet fluorescence V volume of distribution vWf von Willibrand factor antigen VF visible fluorescence ZG zymogen granules Conversion factors serum/plasma metric units factor