Antioxidants & Chronic Pancreatitis

232 Pages·2017·2.77 MB·English

Antioxidants & Chronic
Pancreatitis

A thesis submitted to The University of Manchester for the
degree of
Doctor of Medicine
in the
Faculty of Medical and Human Sciences

2016

Nehal Sureshkumar Shah

School of Medicine
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Index

No. PAGE

TABLE OF CONTENTS.............................................................................. 2

LIST OF FIGURE & LEGENDS.................................................................. 9

LIST OF TABLES....................................................................................... 11

ABBREVATIONS........................................................................................ 13

ABSTRACT................................................................................................. 16

DECLARATION.......................................................................................... 17

COPYRIGHT STATEMENT........................................................................ 18

DEDICATION.............................................................................................. 19

ACKNOWLEDGEMENTS........................................................................... 20

PRESENTATION TO LEARNED SOCIETIES............................................ 21

PUBLICATION FROM THIS WORK........................................................... 24

1 Introduction to Chronic Pancreatitis....................................................... 26

1 Introduction................................................................................................ 27

1.1 Epidemiology…………………………………………………………………... 27

1.2 Socio-economic impact in UK………………………………………………. 27

1.3 Pathogenesis……………………………………………………….................. 28

1.4 Genetic variations associated with chronic pancreatitis...................... 32

1.4.1 Trypsinogen mutations............................................................................ 32

1.4.2 Pancreatic secretory trypsin inhibitor mutations..................................... 32

1.4.3 Cystic fibrosis transmembrane conductance regulator gene.................. 32

1.5 Classification of chronic pancreatitis……………………………………… 34

1.6 Causes of Chronic Pancreatitis…………………………………………….. 35

1.6.1 Tropical Pancreatitis………………..……………………………………….. 35

1.7 Signs and Symptoms…………………………………………………………. 38
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1.7.1 Pain in chronic pancreatitis……………...…………………………………. 38

1.8 Diagnosis…...…………………………………………………………………... 40

1.8.1 Laboratory test................................................................................................ 40

1.8.2 Pancreatic function test.................................................................................. 40

1.8.3 Imaging Modality..............................................................................................
41

1.8.3.1 MRI/MRCP……………………………………………………………………….…… 41

1.8.4 Newer Modalities…………………………………………………………….……..
41

1.8.4.1 EUS/Elastography………………………………………………………….……….
41

1.8.4.2 Newer laboratory test……………………………………………………………...
42

1.9 Treatment…………….…………………………………………………………. 45

1.9.1 Medical………………………………………………........................................ 45

1.9.2 Endoscopic.................................................................................................... 48

1.9.3 Surgical……............................................……………………………….. 49

1.10 Summary................................................................................................... 56

1.11 Hypothesis................................................................................................. 57

1.12 Materials and methods.............................................................................. 57

1.12.1 Review of surgical treatment in surgery.......................................................... 57

1.12.2 Antioxidants overview...................................................................................... 57

1.12.3 Subjective assessment of quality of life in patients with chronic
Pancreatitis on antioxidant therapy............................................................... 57

1.12.4 Cytokines and antioxidants.............................................................................. 58

1.12.5 Randomised, double blind, placebo controlled trial of antioxidant
Therapy in chronic pancreatitis.................................................................
58

2 Variance in elective surgical treatment for Chronic Pancreatitis……… 59

2.1 Introduction……………………………………………………………………. 60

2.2 Patients and Methods...……………………………………………………… 61

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2.3 Results………………………………………………………………………...... 63

2.3.3 Demographic profile……………………………………………..…………….......... 63

2.3.2 Description of Indication of surgery and QoL assessments……….…………. 63

2.3.3 Type of surgery………………………………………………………………………….63

2.3.4 Operative outcome….…………………………………………………........... 64

2.4 Discussion…………………………………………………………………....... 65

2.5 Literature update………………………………………………………………. 68

2.6 Tables and Legends……………………….................................................. 69

3 Anti-oxidants…………………………………………………………………… 75

3.1 Introduction…………………………………………………..………………… 76

3.2 Experimental models......................…………………………………………. 80

3.3 Antioxidants Pharmacology.……………………..………….………………

3.3.1 Mechanism of Action………...………………………………………………. 81

3.3.2 Other trial medications used in oxidative stress....................................... 81

3.3.3 Anti-oxidants in clinical trial………………….……………………………… 82

3.4 Methodology............................................................................................. 8 2

3.5 Results....................................................................................................... 85

3.5.1 Study design…….…………………………………………………………… 85

3.5.2 Demographic profile………………………………………………………….
85

3.5.3 Diagnostic criteria...................................................................................
85

3.5.4 Variation in Antioxidants.........................................................................
88

3.5.5 Biochemistry........................................................................................... 88

3.5.6 Outcome (analgesia, antioxidants, pain & Qol)........................................ 88

3.6 D i s c u s s i o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... 91

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4 Quality of Life in patients with Painful Chronic Pancreatitis on Anti-
oxidant therapy.……………………………………………………………….. 93

4.1 Introduction…………………………………………………………………… 94

4.2 Aim.............................................................................................................. 96

4.3 Material & Methods……………………………………………………………. 96

4.3.1 Study Design…………………………… …………………………………………... 96

4.3.2 Patients and treatment algorithm………………………………………………… 96

4.3.3. Administration of questionnaire………………………………………………….. 97

4.3.4 Disease duration-matched cohort………………………………………………...
97

4.3.5 Ethics approval …………………………………………..………………………….. 98

4.3.6 Statistical analysis…………………………………………………………..….…… 98

4.4 Results……………………………………………..……………………...................... 98

4.4.1 Entire cohort comparison (not matched)………………….…………………. 98

4.4.2 Entire cohort outcome……..………………………………………..………….. 98

4.4.3 Disease duration matched cohort outcome………………………….………
99

4.5
Discussion................................................................................................. 106

4.6
Flow chart (Qol Study)………………………………………………………... 109

5 Antioxidant therapy and Cytokines (AIMAK study)..……..………… 110

5.1 Introduction ………………………………………....................................... 1 1 1

5.1.1 Cytokines................................................................................................... 111

5.1.1.1 TNF-α...................................................................................................... 114

5.1.1.2 Il-1, IL-6, IL-8............................................................................................ 114

5.1.1.3 IL-18........................................................................................................ 114

5.1.1.4 IL-10........................................................................................................ 116

5.1.1.5 TGF-β1.................................................................................................... 116

5.1.1.6 IL-6………………….………………………………………………………… 116

5.2 Methods…………………………………………………………………………. 116
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5.2.1 Hypothesis………….……………………………………………………………….. 116

5.2.2 Study population………………………..………………………………………….. 116

5.2.3 Study design…..…....…………………………………………………………........ 117

5.2.4 Study setting……………..…………………………………………………………. 117

5.2.5 Inclusion/exclusion criteria..……………..…………….………......................... 117

5.2.6 Identification and selection of study sub-group........................................... 117

5.2.7 Standard Clinical Care …………………………………………………………..... 118

5.2.8 Withdrawal from the study.…………………...………………………………...... 118

5.2.9 Primary end point…..………………………………………………………………. 119

5.2.10 Sample size calculation.…………………………..…………………………........ 119

5.3 Ethics.......................................................................................................... 120

5.4.1 Interleukin Assay measurement.....…………………………………………….
121

5.4.2 Sample collection.....................……...…………………………………………………. 121

5.4.3 Specificity of the assay...........…………………………………………………………... 121

5.4.4 Interference...................................................................………………………… 121

5.4.5 Assay procedure............…………………………..…………………….………… 122

5.5 Statistical analysis.........………………………………………………………
123

5.6 Results.....................……………………………………………………….………...
123

5.6.1 Demographic profile......................……………………………………………..
123

5.6.2
Antioxidant profile…………………………………………………………….
123

5.6.3 Cytokine levels…………………......…………………………………………
124

5.7 Discussion................................................................................................. 133

5.8 AIMAK flow chart..…………………………………………………………….. 1 3 6

6 A Randomized Double-blind, Placebo-controlled trial of Anti-oxidant
therapy in painful chronic pancreatitis……………………....................... 137

6.1 Introduction ………………………………………....................................... 1 3 8

6.2 Methods…………………………………………………………………………. 141
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6.2.1 Hypothesis…….…………………………………………………………………….. 141

6.2.2 Study Design……………………………………...………………………………... 141

6.2.3 Setting…………..…………………………………………………………………… 141

6.2.4 Definition of Chronic pancreatitis and patient assessment protocols......
141

6.2.5 Inclusion criteria………………….……………………………………………….. 142

6.2.6 Exclusion criteria…….……………………………………………………………. 142

6.2.7 Justification for a placebo arm…………………………………….……………..
143

6.2.8 Randomisation and blinding ………………..……………….………………….. 1 4 3

6.2.9 Unblinding and withdrawal............................................................................. 143

6.2.10 Study medication............................................................................................. 143

6.2.11 Follow-up assessment........……………………………………………………… 144

6.2.12 Safety evaluation and reporting of adverse events...................................... 144

6.2.13 Primary outcome.............................................................................................. 145

6.2.14 Secondary outcome measures..................……………………………...……… 145

6.2.15 Stratification................…………………………………………………...………... 145

6.3 Statistical analysis............................................................................................ 145

6.3.1 Descriptive and analytic statistics................................................................................ 146

6.4 Ethical clearance......……...…………………………………………………. 146

6.5 Results………………………………………………………………....................................... 147

6.5.1 Base line comparability……………………………………………………………. 147

6.5.2 Response to treatment…………………………………………………………….. 147

6.5.2.1 Primary outcome measure …………..…………………………………………… 147

6.5.2.2 Secondary outcome measures…………………………………………………... 147

6.5.2.3 Need for supportive care……………………………………………………….. 148

6.5.2.4 Antioxidant levels….…………………………………………………………. 148

6.5.2.5 Haematological and biochemical levels………...……………………………… 148

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6.6 Post hoc analysis.........…………………………………………………………….. 149

6.7 Adverse events………………………………………………………………… 149

6.8 Discussion……………………………………………………………………… 150

6.9 Anticipate flow chart…..……………………………………………………………. 1 6 7

7 Integrated Discussion………….…………………………………………….. 168

8 References……………………………………………………………………… 176

9 Appendix.................................................................................................... 197

9.1 Case report form................................................................................................. 197

9.2 EORTC QLQ C-30 and PAN-28.......................................................................... 203

9.3 EQ-5D.................................................................................................................. 213

9.4 Adverse event..................................................................................................... 215

9.5 AIMAK form......................................................................................................... 216

9.6 Anticipate study –Composition of Trial Medication……………………………. 217

9.7 Anticipate study –Comparision: Age, Gender, Aeitology, Intervention......... 219

9.8 Information sheet…………………………………………………………………….. 221

9.9 Consent sheet………………………………………………………………….……… 229

9.10 G P letter………………………………………………………………………………… 231

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Figures & legends:

Figure Heading Page

Figure 1 Figure 1: Genetic model: Trypsin dependent pathological 33
pathway in development of CP
Figure 2 TIGAR-O Classification 36
Figure 3 Figure 3: Complex mechanism of peripheral sensitisation 39
Figure 4 Algorithm for diagnosis & work up of CP - Chapter 1 43
Figure 5 Stepwise approach for diagnosis of Chronic pancreatitis. 44
Figure 6 Illustrations of choice of surgery for chronic pancreatitis 50
Figure 7 Search Methodology –Chapter 2 62
Figure 8 Schematic presentation of increased avaibility of free 77
radical O - Chapter 3
2
Figure 9 Free O in pathogenesis of CP - Chapter 3 78
2
Figure 10 Schematic illustration of development of Pancreatitis and 91
progression to CP – Chapter 5
Figure 11 Cytokine Array - Chapter 5 129
Figure 12 Digital imaging, Carrier 1: Calibration Levels 1 – 9 - 130
Chapter 5
Figure 13 Carrier 2: Controls C1, C2, C3, Samples TG – 0 & 6 130
months, Study ID 1-3 - Chapter 5
Figure 14 Digital imaging, Carrier 3: TG – 0 & 6 months-study ID: 131
4-7. CG –0 months, Study ID: 8 - Chapter 5
Figure 15 Digital imaging, Carrier 4: Control group – 0 & 6 months, 131
Study ID 8-12 - Chapter 5
Figure 16 Digital imaging, Carrier 5: CG group – 0 & 6 months, 132
Study ID 13 & 14. Controls C2, C3–row 2, C1, C2, C3–
row 3 –Chapter 5
Figure 17 Consort Flow Chart: Anticipate-Trial – Chapter 6 160
Figure 18 Clinic VAS Pain Scores -Chapter 6 161
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Figure 19 Diary VAS Pain Scores –Chapter 6 162
Figure 20 Percentage of days free from pain by pain threshold - 163
Chapter 6

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