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The effect of dietary manipulation in chronic urticaria and angioedema King, Wendy Luina 1996

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THE EFFECT OF DIETARY MANIPULATION IN CHRONIC URTICARIA AND ANGIOEDEMA by Wendy Luina King BSc, The University of Alberta, 1990 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (School of Family and Nutritional Sciences) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA January 1996 © Wendy Luina King, 1996 ) In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. The University of British Columbia Vancouver, Canada Date DE-6 (2/88) ABSTRACT U r t i c a r i a and angioedema symptoms r e s u l t p r i m a r i l y from the p h y s i o l o g i c a l a c t i o n s o f h i s t a m i n e . Some i n d i v i d u a l s w i t h u r t i c a r i a have a d e c r e a s e d a b i l i t y to degrade d i e t a r y h i s t a m i n e b e f o r e i t e n t e r s the c i r c u l a t i o n . Foods h i g h i n h i s t a m i n e , such as fermented foods , may exacerbate u r t i c a r i a and angioedema i n these i n d i v i d u a l s . A r t i f i c i a l food c o l o u r , benzoates , b u t y l a t e d h y d r o x y t o l u e n e and b u t y l a t e d h y d r o x y a n i s o l e may exacerbate u r t i c a r i a and angioedema by i n c r e a s i n g endogenous r e l e a s e o f h i s t a m i n e . The o b j e c t i v e s o f the s tudy were to assess the e f f e c t o f a h i s t a m i n e - r e d u c i n g d i e t on u r t i c a r i a and angioedema symptoms and n u t r i e n t i n t a k e . N i n e t e e n s u b j e c t s w i t h c h r o n i c u r t i c a r i a or angioedema were randomized to a treatment group (n=9) or a c o n t r o l group (n=10). The treatment group f o l l o w e d a h i s t a m i n e -r e d u c i n g d i e t , and the c o n t r o l group e l i m i n a t e d a r t i f i c i a l sweeteners from t h e i r d i e t s . The s u b j e c t s r e c o r d e d a n t i h i s t a m i n e m e d i c a t i o n i n t a k e , number o f wheals , s e v e r i t y o f p r u r i t u s and angioedema f o r two weeks p r i o r to s t a r t i n g the d i e t and f o r s i x weeks d u r i n g the d i e t a r y i n t e r v e n t i o n . Three day food r e c o r d s were completed every two weeks. There were no s i g n i f i c a n t group d i f f e r e n c e s throughout the s tudy w i t h r e s p e c t to the symptom v a r i a b l e s . The m e a n ' a n t i h i s t a m i n e i n t a k e o f the treatment group was 1 7 ± 1 2 t a b l e t s d u r i n g the two weeks p r i o r to the d i e t and i i 1 2 ± 1 3 t a b l e t s d u r i n g the f i r s t two weeks o f the d ie tary-i n t e r v e n t i o n . T h i s d i f f e r e n c e was s i g n i f i c a n t (p<0.05). There were s i g n i f i c a n t group by t ime i n t e r a c t i o n s (p<0.05) f o r f a t , c a l c i u m , v i t a m i n C and v i t a m i n B12. O b s e r v a t i o n o f the r e s u l t s i n d i c a t e t h a t t o t a l f a t , c a l c i u m and v i t a m i n B12 i n t a k e d e c r e a s e d and v i t a m i n C i n t a k e i n c r e a s e d i n s u b j e c t s consuming the treatment d i e t compared to s u b j e c t s consuming the c o n t r o l d i e t . The h i s t a m i n e - r e d u c i n g d i e t d i d not r e s u l t i n an improvement i n u r t i c a r i a and angioedema symptoms. However, d i e t a r y i n t e r v e n t i o n may have d e c r e a s e d the need f o r a n t i h i s t a m i n e m e d i c a t i o n . Adherence to the h i s t a m i n e - r e d u c i n g d i e t may r e s u l t i n a reduced i n t a k e o f some n u t r i e n t s . T h e r e f o r e , d i e t a r y c o u n s e l l i n g and f o l l o w - u p are e s s e n t i a l components o f d i e t a r y i n t e r v e n t i o n . i i i T A B L E O F C O N T E N T S ABSTRACT i i TABLE OF CONTENTS i v LIST OF TABLES v i i i LIST OF FIGURES x ACKNOWLEDGEMENT x i CHAPTER 1: INTRODUCTION 1 STUDY OBJECTIVES 3 NULL HYPOTHESES TESTED . . . 3 CHAPTER 2: LITERATURE REVIEW 4 INTRODUCTION TO LITERATURE REVIEW 4 PATHOLOGY OF URTICARIA AND ANGIOEDEMA 5 EFFECT OF DIET ON BODY HISTAMINE 9 H i s t a m i n e P o i s o n i n g 9 A l t e r e d H i s t a m i n e M e t a b o l i s m i n U r t i c a r i a S u b j e c t s 11 F a c t o r s A f f e c t i n g H i s t a m i n e M e t a b o l i s m 15 H i s t a m i n e R e l e a s i n g Food and Food A d d i t i v e s . . . . 18 M i c r o n u t r i e n t I n t a k e 21 Summary 22 PREVIOUS DIETARY MANIPULATION STUDIES IN CHRONIC URTICARIA AND ANG I OEDEMA 2 3 U n c o n t r o l l e d F o o d - A d d i t i v e Free D i e t s 23 C o n t r o l l e d F o o d - A d d i t i v e Free D i e t s 25 Low H i s t a m i n e D i e t s 27 i v OTHER CONDITIONS WHICH MAY BENEFIT FROM A HISTAMINE-REDUCING DIET A t o p i c D i sease 28 M i g r a i n e Headaches 28 G a s t r o i n t e s t i n a l D i s t u r b a n c e s 29 BACKGROUND LITERATURE RELATED TO THE TREATMENT AND CONTROL DIETS / 29 Format ion o f H i s tamine i n Food 29 C o n d i t i o n s Necessary f o r Format ion o f Amines . 29 Amine Content o f S u s c e p t i b l e Food 31 N a t u r a l and A r t i f i c i a l Food C o n s t i t u e n t s 36 C o n t r o l D i e t 38 SIGNIFICANCE OF THE PRESENT STUDY 39 CHAPTER 3: METHODS 41 EXPERIMENTAL DESIGN 41 METHODS 42 Sample s i z e 42 S u b j e c t Recru i tment 43 D i e t a r y I n t e r v e n t i o n 45 Treatment D i e t 45 C o n t r o l D i e t 46 U r t i c a r i a and Angioedema Assessment S c a l e 47 Three-Day Food Records 48 C o n t r o l o f the Confounding V a r i a b l e s . 50 S u b j e c t Appointments 51 S t a t i s t i c a l A n a l y s i s . 52 Treatment and C o n t r o l Group Comparisons . . . 52 U r t i c a r i a and Angioedema Symptom S c a l e . . . . 53 N u t r i e n t A n a l y s i s 54 E t h i c a l A p p r o v a l 56 v CHAPTER 4: RESULTS 57 URTICARIA AND ANGIOEDEMA ASSESSMENT SCALE PRETEST . . . 57 RECRUITMENT 57 SUBJECTS 59 COMPLIANCE TO STUDY PROTOCOL 60 STATISTICAL ANALYSIS 61 ' U r t i c a r i a and Angioedema Assessment S c a l e . . . . . . 61 A n t i h i s t a m i n e t a b l e t s . 61 Wheals 63 I t c h i n e s s 64 Angioedema 65 N u t r i e n t A n a l y s i s 68 Adequacy o f N u t r i e n t I n t a k e 68 S i g n i f i c a n t Changes i n N u t r i e n t I n t a k e . . . . 68 CASE ANALYSIS OF TREATMENT GROUP SUBJECTS WITH IMPROVEMENT IN SYMPTOMS 77 Chapter 5: DISCUSSION 81 MAJOR FINDINGS 81 COMPARISON TO CLINICAL FINDINGS 82 COMPARISON TO OTHER STUDIES 8 3 TREATMENT GROUP SUBJECTS WITH IMPROVEMENT IN SYMPTOMS . 85 TREATMENT GROUP SUBJECTS WITHOUT IMPROVEMENT IN SYMPTOMS 8 6 NUTRITIONAL ADEQUACY OF THE HISTAMINE-REDUCING DIET . . 87 LIMITATIONS OF THE STUDY • . 90 THE VALIDITY OF USING A CROSSOVER DESIGN TO EVALUATE THE EFFECT OF DIETARY MANIPULATION IN CHRONIC URTICARIA AND ANGIOEDEMA 94 FUTURE RESEARCH 95 CLINICAL APPLICATION OF STUDY FINDINGS 97 REFERENCES 98 v i APPENDICES 105 APPENDIX A : RECRUITMENT POSTER 106 APPENDIX B: HISTAMINE-REDUCING DIET 107 APPENDIX C: CONTROL DIET 108 APPENDIX D: URTICARIA/ANGIOEDEMA DAILY ASSESSMENT . . . 109 APPENDIX E : THREE-DAY FOOD RECORD 110 APPENDIX F: FOOD SOURCES OF SELECTED NUTRIENTS I l l APPENDIX G: CONSENT FORM . . . . 1 1 2 APPENDIX H: ETHICS APPROVAL FORM 114 APPENDIX I : REASONS GIVEN BY POTENTIAL SUBJECTS FOR NOT PARTICIPATING IN THE STUDY 115 APPENDIX J : URTICARIA AND ANGIOEDEMA SYMPTOM ASSESSMENT SCALES WHICH WERE NOT COMPLETED 116 APPENDIX K: STARTING AND ENDING DATES FOR EACH SUBJECT . 117 APPENDIX L : DIETARY NONCOMPLIANCE AND CONFOUNDING VARIABLE CHANGES 118 APPENDIX M: WEIGHT CHANGE OVER THE STUDY PERIOD . . . . 121 v i i L I S T O F T A B L E S Table 1: POSSIBLE CAUSES OF URTICARIA 9 Table 2: SYMPTOMS OF HISTAMINE POISONING 10 Table 3: HISTAMINE RELEASING FOODS 19 Table 4: HISTAMINE RELEASE FROM THE WASHED LEUCOCYTES OF 30 SUBJECTS ON EXPOSURE TO FOOD ADDITIVES OR ASPIRIN . . . 21 Table 5: DIETARY MANIPULATION STUDIES IN CHRONIC URTICARIA . 24 Table 6: RESULTS OF FOOD ADDITIVE CHALLENGES IN CHILDREN WITH ANGIOEDEMA AND URTICARIA 2 6 Table 7: AMINES AND THE AMINO ACID PRECURSOR 31 Table 8: NUMBER OF SUBJECTS INQUIRING ABOUT AND ENTERING THE STUDY 58 Table 9: SUBJECT CHARACTERISTICS 60 Table 10: TOTAL NUMBER OF ANTIHISTAMINE TABLETS TAKEN . . . . 62 Table 11: NUMBER OF DAYS ANTIHISTAMINE TABLETS WERE TAKEN . . 62 Table 12: TOTAL NUMBER OF ANTIHISTAMINE TABLETS TAKEN BEFORE THE CONTROL OR TREATMENT DIET (TIME 1) AND AFTER THE INITIATION OF THE DIET (TIME 2) . . . 63 Table 13: TOTAL NUMBER OF WHEALS REPORTED 63 Table 14: NUMBER OF DAYS WHEALS WERE REPORTED 64 Table 15: TOTAL SEVERITY OF ITCHINESS SCORES 64 Table 16: SEVERITY OF ITCHINESS OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA 65 Table 17: NUMBER OF DAYS THAT ITCHINESS WAS REPORTED . . . . 65 Table 18: TOTAL SEVERITY OF ANGIOEDEMA SCORES 66 Table 19: NUMBER OF DAYS THAT ANGIOEDEMA WAS REPORTED . . . . 66 Table 20: ADJUSTED CRITICAL F AND CALCULATED F FOR EIGHT URTICARIA AND ANGIOEDEMA VARIABLES 67 Table 21: MACRONUTRIENT INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES 7 0 v i i i T a b l e 22: MINERAL INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES 71 T a b l e 23: VITAMIN INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES 72 T a b l e 24: CALCIUM AND VITAMIN C INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA 73 T a b l e 25: P AND F VALUES FOR NUTRIENTS THAT SATISFY THE ASSUMPTION OF SPHERICITY 73 T a b l e 26: ADJUSTED CRITICAL F AND CALCULATED F FOR EIGHT NUTRIENTS THAT DID NOT SATISFY THE ASSUMPTION OF SPHERICITY 74 T a b l e 27: THE EFFECT OF THE TREATMENT DIET ON URTICARIA AND. ANGIOEDEMA SYMPTOMS (SUBJECT 11) 79 T a b l e 28: THE EFFECT OF THE TREATMENT DIET ON URTICARIA AND ANGIOEDEMA SYMPTOMS (SUBJECT 12) 79 T a b l e 29: THE EFFECT OF THE TREATMENT DIET ON URTICARIA AND ANGIOEDEMA SYMPTOMS (SUBJECT 13) 80 T a b l e 30: THE EFFECT OF THE TREATMENT DIET ON URTICARIA AND ANGIOEDEMA SYMPTOMS (SUBJECT 17) 80 i x L I S T O F F I G U R E S F i g u r e 1: HISTAMINE METABOLISM 11 F i g u r e 2: FOOD-INDUCED HISTAMINOSIS 13 F i g u r e 3: SAMPLE SIZE CALCULATION 42 F i g u r e 4: GROUP X TIME INTERACTION: Fat 75 F i g u r e 5: GROUP X TIME INTERACTION: C a l c i u m 75 F i g u r e 6: GROUP X TIME INTERACTION: V i t a m i n B12 7 6 F i g u r e 7: GROUP X TIME INTERACTION: V i t a m i n C 7 6 x ACKNOWLEDGEMENT I would like to thank my supervisor, Dr. Linda McCargar, for her positive encouragement throughout the project. The members of my committee also deserve a special thank you. Dr. Janice Joneja spent many of her precious hours educating and guiding me in the area of food allergy management. Her time is much appreciated. Dr. Susan Barr offered insightful suggestions throughout each stage of the study. Without her help, the project would have been a much more difficult task. I thank my friends and family for their support during the last two and a half years. The term "boomerang children" has a new meaning to my parents. Finally, I would like to thank all of my subjects for their commitment to the study. xi Introduction CHAPTER 1 INTRODUCTION U r t i c a r i a a f f e c t s 15 - 20 p e r c e n t o f the p o p u l a t i o n a t l e a s t once i n t h e i r l i f e t i m e ( L e s s o f , 1991). The c o s m e t i c burden and a s s o c i a t e d p r u r i t u s o f c h r o n i c u r t i c a r i a and angioedema l i m i t t he q u a l i t y o f l i f e f o r t h o s e a f f e c t e d w i t h t h e c o n d i t i o n . The management o f t h i s c o n d i t i o n i s a f r u s t r a t i n g and c o n f u s i n g a r e a i n m e d i c a l p r a c t i c e , b o t h f o r the c l i n i c i a n and the p a t i e n t . A n t i h i s t a m i n e m e d i c a t i o n i s the c u r r e n t t r e a t m e n t f o r c h r o n i c u r t i c a r i a and angioedema. Many p a t i e n t s t a k e the m e d i c a t i o n e v e r y day f o r t h e d u r a t i o n o f the d i s e a s e . Drowsiness i s a s i g n i f i c a n t s i d e - e f f e c t o f f i r s t - g e n e r a t i o n a n t i h i s t a m i n e s , and t h i s may i n t e r f e r e w i t h p a t i e n t s a f e t y and p r o d u c t i v i t y . S e c o n d - g e n e r a t i o n , n o n - s e d a t i n g , a n t i h i s t a m i n e s a re v e r y e x p e n s i v e . Recent r e s e a r c h s u g g e s t s t h a t c e r t a i n a n t i h i s t a m i n e s may promote tumour growth. The r e s e a r c h was conducted because the s t r u c t u r e o f a n t i h i s t a m i n e s i s s i m i l a r t o a t a m o x i f e n analogue which promotes tumour growth a t low doses. L o r a t a d i n e (Claritin®), a s t e m i z o l e (Hismanal®) and h y d r o x y z i n e (Atarax®) were shown t o promote tumour growth when i n j e c t e d i n t o mice (Brandes e t a l . , 1994). F u r t h e r e x p e r i m e n t a l r e s e a r c h and 1 Introduction e p i d e m i o l o g i c a l s t u d i e s a re r e q u i r e d t o det e r m i n e the s i g n i f i c a n c e o f t h e s e f i n d i n g s i n the human. C u r r e n t l y a n t i h i s t a m i n e m e d i c a t i o n s a re c o n s i d e r e d s a f e , and the b e n e f i t s o f t h e i r use appear t o be g r e a t e r t h a n the p o t e n t i a l r i s k s (Simons, 1994). However, some i n d i v i d u a l s do not want t o use a n t i h i s t a m i n e m e d i c a t i o n on a c o n t i n u o u s b a s i s . I f d i e t a r y components cause o r c o n t r i b u t e t o u r t i c a r i a and angioedema symptoms, d i e t a r y i n t e r v e n t i o n must be c o n s i d e r e d as a p o s s i b l e t r e a t m e n t . However, an in a d e q u a t e n u t r i e n t i n t a k e i s a co n c e r n a s s o c i a t e d w i t h a h i s t a m i n e - r e d u c i n g d i e t . Thus, the purpose o f the p r e s e n t s t u d y was t o i n v e s t i g a t e the e f f e c t s o f a h i s t a m i n e - r e d u c i n g d i e t on u r t i c a r i a and angioedema and n u t r i e n t i n t a k e . 2 Introduction STUDY OBJECTIVES The s p e c i f i c o b j e c t i v e s o f the p r e s e n t s t u d y were: 1. To e v a l u a t e the e f f e c t o f a h i s t a m i n e - r e d u c i n g d i e t 1 i n c h r o n i c u r t i c a r i a and angioedema by m o n i t o r i n g : a) the a b s o l u t e number o f a n t i h i s t a m i n e t a b l e t s t a k e n , t h e number o f wheals and the s e v e r i t y o f u r t i c a r i a and angioedema b) t h e number o f days t h a t a n t i h i s t a m i n e t a b l e t s were t a k e n , and the number o f days t h a t wheals, p r u r i t u s and angioedema were r e p o r t e d 2. To e v a l u a t e the e f f e c t o f a h i s t a m i n e - r e d u c i n g d i e t on n u t r i e n t i n t a k e . NULL HYPOTHESES TESTED 1. There w i l l be no d i f f e r e n c e between the t r e a t m e n t and c o n t r o l groups w i t h r e s p e c t t o : a) the a b s o l u t e number o f a n t i h i s t a m i n e t a b l e t s t a k e n , the number o f wheals, the s e v e r i t y o f u r t i c a r i a and angioedema b) the number o f days t h a t a n t i h i s t a m i n e t a b l e t s were t a k e n and wheals, p r u r i t u s and angioedema were r e p o r t e d 2. There w i l l be no d i f f e r e n c e between the t r e a t m e n t and c o n t r o l groups w i t h r e s p e c t t o i n t a k e o f : a) k i l o c a l o r i e s , p r o t e i n , c a r b o h y d r a t e and t o t a l f a t b) c a l c i u m , i r o n , magnesium, phosphorus and z i n c c) v i t a m i n s A, B l , B2, B3, B6, B12, C and f o l a c i n 1 The h i s t a m i n e - r e d u c i n g d i e t e l i m i n a t e s f o o d a d d i t i v e s , foods t h a t may s t i m u l a t e endogenous h i s t a m i n e r e l e a s e and foods which have e l e v a t e d l e v e l s o f h i s t a m i n e . 3 Literature Review CHAPTER 2 LITERATURE REVIEW INTRODUCTION TO LITERATURE REVIEW H i s t a m i n e i s an i m p o r t a n t ' m e d i a t o r o f u r t i c a r i a and angioedema, and the p r e s e n t s t u d y was d e s i g n e d t o a s s e s s whether d e c r e a s i n g d i e t a r y h i s t a m i n e and .food a d d i t i v e s which may i n c r e a s e endogenous r e l e a s e o f h i s t a m i n e would a f f e c t the symptoms o f c h r o n i c u r t i c a r i a and angioedema. I n t h i s s e c t i o n the l i t e r a t u r e r e l e v a n t t o the h y p o t h e s i s i s r e v i e w e d . The f i r s t s e c t i o n a d d r e s s e s the key r o l e o f body h i s t a m i n e i n the p a t h o l o g y o f u r t i c a r i a and angioedema. Next, the s c i e n t i f i c e v i d e n c e s u p p o r t i n g the i n f l u e n c e o f d i e t on body h i s t a m i n e and u r t i c a r i a and angioedema i s r e v i e w e d . F i n a l l y , the f o r m a t i o n o f f o o d h i s t a m i n e i s d i s c u s s e d t o p r o v i d e a r a t i o n a l e f o r the h i s t a m i n e -r e d u c i n g d i e t . PATHOLOGY OF URTICARIA AND ANGIOEDEMA U r t i c a r i a i s c h a r a c t e r i z e d by l o c a l p r u r i t i c h i v e s and erythema i n the d e r m i s . I n d i v i d u a l w h e a l s 2 v a r y from one m i l l i m e t r e t o s e v e r a l c e n t i m e t r e s i n d i a m e t e r and may be found on 2 A temporary r e d o r p a l e r a i s e d a r e a o f the s k i n , o f t e n accompanied by s e v e r e i t c h i n g . 4 Literature Review any p a r t o f the body. The- wheals u s u a l l y l a s t l e s s t h a n f o u r h o u r s . Angioedema i s s i m i l a r t o u r t i c a r i a , b u t w i t h l a r g e r edematous area s t h a t i n v o l v e deeper s w e l l i n g o f the dermis and mucous membranes. Angioedema u s u a l l y a f f e c t s the e y e l i d s , l i p s and tongue. The f a c e , e a r s , c h i n , g e n i t a l i a , hands, f e e t , t r u n k and arms may a l s o be a f f e c t e d (Holgate & Church, 1993). U r t i c a r i a and angioedema r e s u l t from mast c e l l d e g r a n u l a t i o n i n the dermis o f the s k i n . Under an e l e c t r o n m i c r o s c o p e , d e g r a n u l a t e d mast c e l l s a re seen a t the a f f e c t e d s i t e ( B u r r a l l e t a l . , 1990). An i n v e s t i g a t i o n of' the a f f e c t e d s i t e s o f 43 p a t i e n t s w i t h c h r o n i c u r t i c a r i a , r e v e a l e d t e n t i m e s the normal number o f mast c e l l s (Natbony e t a l . , 1983). Mast c e l l s a re an i n t e g r a l component o f the immune system. These c e l l s a re found t h r o u g h o u t the body, but are most abundant around c o n n e c t i v e t i s s u e s , b l o o d v e s s e l s , l y m p h a t i c v e s s e l s and n e r v e s (White, 1990). The purpose o f mast c e l l s i s t o d e g r a n u l a t e and r e l e a s e p o w e r f u l i n f l a m m a t o r y c h e m i c a l s i n t o s u r r o u n d i n g t i s s u e s d u r i n g an immune system d e f e n c e . These i n f l a m m a t o r y c h e m i c a l s are r e s p o n s i b l e f o r the symptoms of u r t i c a r i a and angioedema. H i s t a m i n e , a b i o g e n i c amine, i s s t o r e d p r e formed w i t h i n mast c e l l s and i s r e l e a s e d i m m e d i a t e l y upon mast c e l l d e g r a n u l a t i o n . S u b j e c t s w i t h c h r o n i c u r t i c a r i a have a s i g n i f i c a n t l y i n c r e a s e d amount of h i s t a m i n e i n the s k i n (Smith e t 5 Literature Review a l . , 1992). T h i s may r e s u l t from an i n c r e a s e d number of mast c e l l s o r an i n c r e a s e d amount of h i s t a m i n e i n each mast c e l l o r b o t h . The b i o l o g i c a l e f f e c t s o f h i s t a m i n e are v e r y i m p o r t a n t i n u r t i c a r i a and angioedema (Armenaka et a l . , 1992; White, 1990). The e f f e c t s o f h i s t a m i n e are m e d i a t e d t h r o u g h h i s t a m i n e r e c e p t o r s i n the t i s s u e s . The r e s u l t o f h i s t a m i n e 1 (HI) r e c e p t o r s t i m u l a t i o n i n c l u d e s i n c r e a s e d v a s c u l a r p e r m e a b i l i t y , p r u r i t u s , smooth muscle c o n t r a c t i o n , p r o s t a g l a n d i n g e n e r a t i o n , d e c r e a s e d a t r i o v e n t r i c u l a r node c o n d u c t i o n time w i t h r e s u l t a n t t a c h y c a r d i a , a c t i v a t i o n o f v a g a l r e f l e x e s and i n c r e a s e d l e v e l s o f c y c l i c guanosine monophosphate. The r e s u l t o f h i s t a m i n e 2 (H2) r e c e p t o r s t i m u l a t i o n i n c l u d e s g a s t r i c a c i d s e c r e t i o n , i n c r e a s e d lower a i r w a y mucus s e c r e t i o n , i n c r e a s e d l e v e l s o f c y c l i c adenosine monophosphate and esophageal c o n t r a c t i o n . The r e s u l t o f combined H1/H2 r e c e p t o r s t i m u l a t i o n i n c l u d e s v a s o d i l a t i o n ( h y p o t e n s i o n , f l u s h i n g and headache) and t a c h y c a r d i a (White, 1990). V a s o d i l a t i o n , p r u r i t u s and i n c r e a s e d v a s c u l a r p e r m e a b i l i t y are the c e n t r a l f e a t u r e s o f u r t i c a r i a and angioedema. As a r e s u l t o f t h e s e v a s c u l a r changes, f l u i d seeps from the b l o o d v e s s e l s i n t o the s u r r o u n d i n g t i s s u e s c a u s i n g t i s s u e s w e l l i n g . P r a s a d e t a l . (1967) found the b l o o d h i s t a m i n e l e v e l s o f u r t i c a r i a s u b j e c t s i n a c t i v e d i s e a s e t o be. s i g n i f i c a n t l y h i g h e r than normal c o n t r o l s . Other s t u d i e s , however, have not found a 6 Literature Review d i f f e r e n c e i n plasma h i s t a m i n e between u r t i c a r i a and c o n t r o l s u b j e c t s (Murdoch e t a l . , 1987; P o l l o c k e t a l . , 1991). There i s l i t t l e r e s e a r c h i n v e s t i g a t i n g the c i r c u l a t i n g plasma l e v e l o f h i s t a m i n e , even though t h i s i s c r u c i a l i n f o r m a t i o n ( T a y l o r , 1 9 8 6 ) . Concomitant symptoms may o c c u r w i t h u r t i c a r i a , such as headaches, a r t h r a l g i a , the s e n s a t i o n o f a lump i n the t h r o a t , h o a r s e n e s s , s h o r t n e s s o f b r e a t h , wheezing, nausea, v o m i t i n g , abdominal p a i n and d i a r r h e a ( S o t e r , 1991). These symptoms may be s y s t e m i c m a n i f e s t a t i o n s o f excess plasma h i s t a m i n e . I n f l ammatory m e d i a t o r s o t h e r t h a n h i s t a m i n e a l s o c o n t r i b u t e t o u r t i c a r i a and angioedema symptoms. A n t i h i s t a m i n e m e d i c a t i o n does not c o m p l e t e l y r e l i e v e h i v e s , and h i v e s l a s t l o n g e r t h a n the time t h a t c o u l d be a t t r i b u t e d t o the e f f e c t o f h i s t a m i n e a l o n e (Holgate & Church, 1993). P r o s t a g l a n d i n s , k i n i n s , p l a t e l e t - a c t i v a t i n g f a c t o r and major b a s i c p r o t e i n 3 f u n c t i o n w i t h h i s t a m i n e t o produce u r t i c a r i a and angioedema. The r e l a t i v e i m portance o f each o f the i n f l a m m a t o r y m e d i a t o r s v a r i e s among i n d i v i d u a l s . Mast c e l l s a r e d e g r a n u l a t e d by a v a r i e t y o f i m m u n o l o g i c a l and n o n - i m m u n o l o g i c a l f a c t o r s . As a r e s u l t , many f a c t o r s have been i d e n t i f i e d i n the p a t h o g e n e s i s o f u r t i c a r i a (Table 1 ) . I n 3 M a j o r b a s i c p r o t e i n , a t o x i c p r o d u c t o f e o s i n o p h i l d e g r a n u l a t i o n , i s e l e v a t e d i n the l e s i o n a l s k i n o f s u b j e c t s w i t h c h r o n i c u r t i c a r i a (Armenaka & R o s e n s t r e i c h , 1 9 9 2). 7 Literature Review 75 % o f c h r o n i c u r t i c a r i a c a s e s , the i n c i t i n g agent remains unknown ( B u r r a l l e t a l . , 1990). D i e t may c o n t r i b u t e t o c h r o n i c u r t i c a r i a and angioedema symptoms i n some i n d i v i d u a l s . Table 1: POSSIBLE CAUSES OF URTICARIA Cause Examples P h y s i c a l S t i m u l i P r e s s u r e , change o f te m p e r a t u r e , s w e a t i n g , e x e r c i s e , s u n l i g h t Immune Changes B a c t e r i a l , v i r a l and p a r a s i t i c i n f e c t i o n s , a l l e r g i c d i s e a s e s , l u p u s erythematosus, m a s t o c y t o s i s , and u r t i c a r i a l v a s c u l i t i s Hormonal Changes Hormone replacement t h e r a p y , menarche, menopause, m e n s t r u a l c y c l e Drug i n g e s t i o n Morphine, c o d e i n e D i e t a r y B e nzoates, t a r t r a z i n e , s t r a w b e r r i e s P s y c h o l o g i c a l S t r e s s R e f e r e n c e s : B u r r a l l , 1990; L e s s o f , 1991; S o t e r , 1991; Armenaka & R o s e n s t r e i c h , 1992 EFFECT OF DIET ON BODY HISTAMINE H i s t a m i n e P o i s o n i n g H i s t a m i n e p o i s o n i n g r e s u l t s - f r o m the i n g e s t i o n o f food w i t h v e r y h i g h l e v e l s o f h i s t a m i n e . S p o i l e d f i s h and cheese are the p r i m a r y foods a s s o c i a t e d w i t h h i s t a m i n e p o i s o n i n g ( T a y l o r , 1986). A v a r i e t y o f symptoms d e v e l o p s e v e r a l minutes t o a few hours a f t e r the i m p l i c a t e d f o o d i s e a t e n (Table 2 ) . The symptoms u s u a l l y r e s o l v e a f t e r a few h o u r s . A. t o t a l o f 110 h i s t a m i n e 8 Literature JReviem-p o i s o n i n g o u t b r e a k s were r e p o r t e d i n the U n i t e d S t a t e s between 1968 and 1981 ( T a y l o r , 1986). Under a m e d i c a l l y s u p e r v i s e d r e s e a r c h s t u d y , h e a l t h y v o l u n t e e r s d e l i b e r a t e l y consumed s p o i l e d m a c k e r e l samples t o dete r m i n e the l e v e l o f fo o d h i s t a m i n e n e c e s s a r y t o produce h i s t a m i n e p o i s o n i n g . The amount o f h i s t a m i n e Table 2: SYMPTOMS OF HISTAMINE POISONING Body System Symptom Cutaneous Rash, u r t i c a r i a , edema, l o c a l i z e d i n f l a m m a t i o n G a s t r o i n t e s t i n a l Nausea, v o m i t i n g , d i a r r h e a , cramping Hemodynamic H y p o t e n s i o n N e u r o l o g i c a l Headaches, p a l p i t a t i o n s , f l u s h i n g , t i n g l i n g , b u r n i n g , i t c h i n g R e f e r e n c e : T a y l o r , 1986 i n each f o o d sample d i d not c o r r e l a t e w i t h the c l i n i c a l , r e a c t i o n s t o t he samples (Ijomah e t a l . , 1991). As fo o d samples s p o i l , h i s t a m i n e as w e l l as o t h e r amines i n c r e a s e i n the fo o d . These amines, such as c a d a v e r i n e , i n h i b i t t he enzymes which degrade h i s t a m i n e , a l l o w i n g plasma h i s t a m i n e l e v e l s t o r i s e ( B j e l d a n e s e t a l . , 1977). The l a c k o f c o r r e l a t i o n between the h i s t a m i n e i n foo d samples and the c l i n i c a l r e a c t i o n s may r e f l e c t v a r y i n g l e v e l s o f o t h e r amines i n the food samples. A d d i t i o n a l l y , t he 9 Literature Review e f f e c t i v e n e s s o f the enzymes which degrade h i s t a m i n e may d i f f e r among i n d i v i d u a l s r e s u l t i n g i n v a r y i n g s e n s i t i v i t y t o . d i e t a r y h i s t a m i n e ( L e s s o f , 1991). A l t e r e d H i s t a m i n e M e t a b o l i s m i n U r t i c a r i a S u b j e c t s H i s t a m i n e i s degraded by two enzymes, N - m e t h y l t r a n s f e r a s e and diamine o x i d a s e ( F i g u r e 1 ) . F i g u r e 1: HISTAMINE METABOLISM l-Histidme Dtcartxny**** /Masi calls.\ V Basophils / • (Small intestine A U w , Kidney, j Monocytes / N-Methyl Transferase \ Diamine OxfcWe (Small inlesiin* mucosa A Placenta. Liver. 1 Skin. Kidney. Thymus. J Eosinophil. Neutrophil / Ox klas« Conjugate Ftbose /v-Methyl Imid&20l8 Imidazole Af-Methyl Imidazole Acetic Acid Acate Acid Histamine Histamine Acenc Acid Riboside 42-47% 4-B% 2-3% 9-11% 16-23% FIG. 1. Synthesis and catabolism of histamine. Percentage recovery of histamine and its me-tabolites in the urine in the 12 hours after intradermal |"C|histamine in human males. (Modified from Douglas WW. Histamine and 5-hydroxytryst8mine [serotonin] and their autocords. In: Gilman AG, Goodman IS, Gilman A, eds. Toodman and Gilrrmn's The pharmacologic basis of therapeutics. 6th ed. New York: Macmillan Publishing, 1980:618.) (Figure 1: White M. The r o l e o f h i s t a m i n e i n a l l e r g i c d i s e a s e , J A l l e r g y C l i n Immunol 1990; 86, 4(2) :599-605. 10 Literature Review Diamine o x i d a s e (DAO) on the v i l l u s t i p o f the i n t e s t i n a l mucosa degrades i n t e s t i n a l h i s t a m i n e , p r e v e n t i n g the e n t r y o f l a r g e amounts o f h i s t a m i n e i n t o the p o r t a l c i r c u l a t i o n . Some u r t i c a r i a s u b j e c t s have s i g n i f i c a n t l y r educed DAO a c t i v i t y . L e s s o f e t a l . (1990) measured s m a l l bowel DAO a c t i v i t y u s i n g a p o s t - h e p a r i n plasma DAO c u r v e 4 and d i r e c t j e j u n a l b i o p s y . The u r t i c a r i a s u b j e c t s had a s i g n i f i c a n t l y d e c r e a s e d DAO a c t i v i t y compared t o the c o n t r o l s u b j e c t s (p<0.02). I n f o u r o f the f i v e u r t i c a r i a s u b j e c t s s t u d i e d , j e j u n a l DAO a c t i v i t y was l e s s than the l o w e s t c o n t r o l group response (n=10). N-methyl t r a n s f e r a s e and c i r c u l a t i n g d i amine o x i d a s e degrade plasma h i s t a m i n e . These enzymes may be d e f i c i e n t i n some s u b j e c t s w i t h u r t i c a r i a and angioedema. C o n t r o l and u r t i c a r i a s u b j e c t s r e c e i v e d i n t r a v e n o u s h i s t a m i n e i n f u s i o n s a t i n c r e a s i n g r a t e s u n t i l a c l i n i c a l e n d p o i n t , such as v a s o d i l a t i o n , f l u s h i n g o r headaches was reached. The h a l f l i f e o f plasma h i s t a m i n e was s i g n i f i c a n t l y g r e a t e r i n u r t i c a r i a s u b j e c t s t h a n c o n t r o l s u b j e c t s ( 6 . 2 ± 1.3 minutes compared t o 4.0 ± 0.7; p=0.02), and s i g n i f i c a n t l y l e s s h i s t a m i n e was r e q u i r e d t o r e a c h a c l i n i c a l e n d p o i n t i n the u r t i c a r i a s u b j e c t s ( P o l l o c k e t a l . , 1991). The wheal and f l a r e response t o i n t r a d e r m a l i n j e c t i o n o f h i s t a m i n e 4 I n t r a v e n o u s a d m i n i s t r a t i o n o f h e p a r i n r e s u l t s i n the r e l e a s e o f DAO from the v i l l u s t i p i n t o the c i r c u l a t i o n . DAO a c t i v i t y i n the plasma i s measured over t i m e . 11 Literature Review was shown t o be s i g n i f i c a n t l y l o n g e r i n u r t i c a r i a s u b j e c t s t h a n i n c o n t r o l s u b j e c t s (Maxwell e t a l . , 1990). These s t u d i e s suggest t h a t u r t i c a r i a s u b j e c t s have a compromised a b i l i t y t o remove h i s t a m i n e from the c i r c u l a t i o n . S a t t l e r & Lorenz (1990) proposed Food-Induced H i s t a m i n o s i s as a d i s t i n c t d i s e a s e concept ( F i g u r e 2 ) . J. Sattler and W. Lorenz Fig. 2. Scheme for the disease concept of enteral-induced histaminosis: histamine in the gastrointestinal tract (from food or upper GI bleeding) can only enter the circulation in case of DAO blockade (risk factor). Elevated plasma histamine leads to the wellknown disease presentation (Lorenz et al.. 1982) which is denominated here as histaminosis. This model is originally based on epidemiological terms (Fletcher et al., 1982) and was modified by Sattler and Lorenz (1987) for enteral-induced histaminosis F i g u r e 2: S a t t l e r J , Lorenz W. I n t e s t i n a l d i amine o x i d a s e and e n t e r a l . - i n d u c e d h i s t a m i n o s i s : s t u d i e s on t h r e e p r o g n o s t i c v a r i a b l e s i n an e p i d e m i o l o g i c a l , model. J N e u r a l . Transm. 1990; Suppl 32:291-314. F i g u r e 2: FOOD-INDUCED HISTAMINOSIS 12 Literature Review I n c r e a s e d h i s t a m i n e and DAO b l o c k i n g agents i n the i n t e s t i n a l lumen l e a d t o h i s t a m i n e a b s o r p t i o n , i n c r e a s e d plasma h i s t a m i n e and d i s e a s e p r e s e n t a t i o n . To demonstrate the f o o d - i n d u c e d h i s t a m i n o s i s concept, S a t t l e r e t a l . (1988) randomized p i g s t o r e c e i v e a DAO b l o c k e r or s a l i n e . The p i g s were g i v e n a 60 mg o r a l h i s t a m i n e dose. B l o o d h i s t a m i n e and c l i n i c a l symptoms i n c r e a s e d s i g n i f i c a n t l y i n the p i g s which r e c e i v e d the DAO b l o c k e r s , but d i d not i n c r e a s e i n t h e c o n t r o l p i g s (p<0.001). S i m i l a r r e s u l t s have been demonstrated i n sheep ( S j a a s t a d , 1967). Kanny et a l . (1993) a p p l i e d t h e s e c o n c e p t s t o human s u b j e c t s w i t h u r t i c a r i a . C o n t r o l and u r t i c a r i a s u b j e c t s were g i v e n 120 mg o f h i s t a m i n e t h r o u g h duodenal i n s t i l l a t i o n . The plasma h i s t a m i n e l e v e l s remained s t a b l e i n the c o n t r o l s u b j e c t s , and t h e y d i d not e x h i b i t symptoms o t h e r t h a n t r a n s i e n t f a c i a l f l u s h i n g . T h i r t y - t w o p e r c e n t o f the u r t i c a r i a s u b j e c t s d e v e l o p e d u r t i c a r i a w i t h i n one hour o f t h e h i s t a m i n e i n s t i l l a t i o n , and o v e r a l l , 64% o f t h e . u r t i c a r i a s u b j e c t s d e v e l o p e d u r t i c a r i a w i t h i n 12 hours of the h i s t a m i n e i n s t i l l a t i o n . The u r t i c a r i a s u b j e c t s e x h i b i t e d o t h e r symptoms, such as a c c e l e r a t e d h e a r t r a t e , drop i n b l o o d p r e s s u r e , f a c i a l f l u s h i n g , p r u r i t u s , headache, g a s t r o i n t e s t i n a l d i s t u r b a n c e ( b l o a t i n g , cramps, nausea or e p i g a s t r i c b u r n i n g ) , r h i n i t i s and c oughing. These symptoms may have r e s u l t e d from i n c r e a s e d plasma h i s t a m i n e . Plasma h i s t a m i n e was s i m i l a r between the groups a t 13 L i t e r a t u r e Review-time 0, but was s i g n i f i c a n t l y h i g h e r i n the u r t i c a r i a s u b j e c t s 5, 15 and 45 minutes a f t e r h i s t a m i n e i n s t i l l a t i o n . I t was c o n c l u d e d t h a t u r t i c a r i a s u b j e c t s have a d e f i c i e n c y o f h i s t a m i n e d e g r a d i n g enzymes, and t h i s r e s u l t e d i n i n c r e a s e d plasma h i s t a m i n e and c l i n i c a l symptoms. However, the u r t i c a r i a a t t a c k s may have been due t o the n a t u r a l o c c u r r e n c e o f the symptoms i n t h e s e s u b j e c t s and not the h i s t a m i n e i n s t i l l a t i o n . A s e p a r a t e u r t i c a r i a c o n t r o l group which r e c e i v e d a p l a c e b o t r e a t m e n t would a l l o w s t r o n g e r c o n c l u s i o n s t o be drawn from t h i s s t u d y . F a c t o r s A f f e c t i n g H i s t a m i n e M e t a b o l i s m The a c t i v i t y o f diamine o x i d a s e and N - m e t h y l t r a n s f e r a s e may be i n h i b i t e d by co n c o m i t a n t o r a l consumption o f food o r drug s . H i s t a m i n e p o i s o n i n g r e s u l t s from consumption o f h i s t a m i n e - r i c h food, such as s p o i l e d f i s h ; however, consumption o f h i s t a m i n e a l o n e does not produce h i s t a m i n e p o i s o n i n g ( T a y l o r , 1986). C a d a v e r i n e and p u t r e s c i n e a re amines t h a t i n c r e a s e i n s p o i l e d f o o d w i t h h i s t a m i n e . C a d a v e r i n e has been shown t o i n h i b i t t he a c t i v i t y o f diamine o x i d a s e in v i t r o ( T a y l o r & L i e b e r , 1978). B j e l d a n e s e t a l . (1977) s t u d i e d the a b i l i t y o f t h e s e amines t o p o t e n t i a t e h i s t a m i n e t o x i c i t y . O r a l a d m i n i s t r a t i o n o f 150 mg/kg of h i s t a m i n e d i d not cause m o r t a l i t y i n f i v e g u i n e a - p i g s . A d m i n i s t r a t i o n o f the same h i s t a m i n e dose w i t h 50 mg/kg o f 14 Literature Review c a d a v e r i n e r e s u l t e d i n the d e a t h o f 3 out o f 9 g u i n e a - p i g s . A 75 mg/kg c a d a v e r i n e dose r e s u l t e d i n the d e a t h o f 5 out o f 6 g u i n e a - p i g s . S i m u l t a n e o u s a d m i n i s t r a t i o n o f c a d a v e r i n e and h i s t a m i n e r e s u l t e d i n t h e g r e a t e s t m o r t a l i t y . A d m i n i s t r a t i o n o f p u t r e s c i n e d i d not r e s u l t i n d e a t h . S a t t l e r & Lorenz (1990) i n v e s t i g a t e d the in vitro p o t e n t i a l o f 486 drugs t o i n h i b i t p u r i f i e d i n t e s t i n a l DAO a c t i v i t y . N i n e t y - f o u r drugs i n h i b i t e d d iamine o x i d a s e . S e v e r a l cases o f h i s t a m i n e p o i s o n i n g have been a s s o c i a t e d w i t h isoniazid® which i s used i n the t r e a t m e n t o f t u b e r c u l o s i s (Uragoda & K o t t e g o d a , 1977). However, i n S a t t l e r & L o r e n z ' s study, isoniazid® was o n l y a weak i n h i b i t o r o f diamine o x i d a s e . F u r t h e r in vivo s t u d i e s are n e c e s s a r y t o c l a r i f y the r e l e v a n c e o f drugs and f o o d amines i n human h i s t a m i n e p o i s o n i n g . Diamine o x i d a s e i s l o c a t e d on the v i l l u s t i p o f the e n t e r o c y t e s . C o n d i t i o n s which damage the v i l l u s t i p may d e c r e a s e the a c t i v i t y o f diamine o x i d a s e . Rat i n t e s t i n a l mucosa was damaged by a p e r f u s i o n w i t h h yperosmolar sodium s u l p h a t e s o l u t i o n which r e s u l t e d i n a s i g n i f i c a n t d e c r e a s e i n mucosal and plasma DAO (p<0.005)(Luk e t a l . , 1980). C o e l i a c p a t i e n t s i n a c t i v e d i s e a s e e x h i b i t below normal p o s t h e p a r i n plasma DAO c u r v e s . The diamine o x i d a s e c u r v e s improved a f t e r 3 and 6 months on a g l u t e n -f r e e diet(p<0.001) (D'Agostino e t a l . , 1987). C o n d i t i o n s o r d i s e a s e s which damage the i n t e s t i n a l mucosa may d e c r e a s e DAO 15 Literature Review a c t i v i t y and a l l o w i n t e s t i n a l h i s t a m i n e t o be absorbed more r e a d i l y i n t o t h e c i r c u l a t i o n . T h e r e f o r e , the i n t e g r i t y o f t h e mucosa may be a r e l e v a n t f a c t o r i n the p r e s e n t a t i o n o f u r t i c a r i a and angioedema. Many f a c t o r s c o n t r i b u t e t o i n t e s t i n a l h i s t a m i n e . The i n t e s t i n a l f l o r a may have the a b i l i t y t o d e c a r b o x y l a t e h i s t i d i n e and t h e r e f o r e produce h i s t a m i n e . I r v i n e e t a l . (1959) demonstrated an i n c r e a s e i n u r i n a r y h i s t a m i n e , 2 t o 4 hours a f t e r meat consumption. A s i m i l a r i n c r e a s e was o b s e r v e d when o r a l h i s t i d i n e , which a p p r o x i m a t e d the h i s t i d i n e i n the meat meal, was a d m i n i s t e r e d . U r i n a r y h i s t a m i n e d i d not i n c r e a s e a f t e r a b r e a d and m i l k meal. T h i s s u g g e s t s t h a t the h i s t i d i n e i n the meat meal was r e s p o n s i b l e f o r the i n c r e a s e i n u r i n a r y h i s t a m i n e . A f t e r an a n t i b i o t i c was a d m i n i s t e r e d t o the s u b j e c t s , n e i t h e r the meat meal nor the h i s t i d i n e i n c r e a s e d u r i n a r y h i s t a m i n e . These r e s u l t s suggest t h a t i n t e s t i n a l f l o r a a r e n e c e s s a r y f o r h i s t a m i n e p r o d u c t i o n . The s t u d y was conducted on f o u r men and t h r e e dogs, and a s t a t i s t i c a l a n a l y s i s was not performed. There have been no w e l l - c o n t r o l l e d s t u d i e s t o s u p p o r t t h e s e f i n d i n g s . Mast c e l l s , w hich are numerous i n the i n t e s t i n a l w a l l , may c o n t r i b u t e t o i n t e s t i n a l h i s t a m i n e . B l o o d p a r t i c l e s r e m a i n i n g i n the gut a f t e r g a s t r o i n t e s t i n a l b l e e d i n g may a l s o c o n t r i b u t e t o i n t e s t i n a l h i s t a m i n e ( S a t t l e r & L o r e n z , 1990). C o n d i t i o n s which 16 Literature Review i n c r e a s e i n t e s t i n a l h i s t a m i n e may be r e l e v a n t t o the p r e s e n t a t i o n o f u r t i c a r i a and angioedema i f the i n t e s t i n a l h i s t a m i n e i s absorbed i n t o the c i r c u l a t i o n . I n summary, diamine o x i d a s e and N - m e t h y l t r a n s f e r a s e enzymes are d e f i c i e n t i n some s u b j e c t s w i t h u r t i c a r i a , a l l o w i n g i n t e s t i n a l h i s t a m i n e t o be absorbed i n t o the c i r c u l a t i o n and s l o w i n g d e g r a d a t i o n o f plasma h i s t a m i n e . These i n d i v i d u a l s may e x p e r i e n c e u r t i c a r i a a f t e r consumption o f h i s t a m i n e c o n t a i n i n g f o o d . F a c t o r s , such as amine and drug consumption, may f u r t h e r i n h i b i t t h e s e enzymes and worsen u r t i c a r i a . C h r o n i c u r t i c a r i a and angioedema may a l s o be e x a c e r b a t e d by i n c r e a s e d endogenous r e l e a s e o f h i s t a m i n e a f t e r consumption o f f o o d and f o o d a d d i t i v e s . H i s t a m i n e R e l e a s i n g Food and Food A d d i t i v e s C e r t a i n foods have been termed " h i s t a m i n e r e l e a s i n g f o o d s " , because t h e y e x a c e r b a t e f o o d a l l e r g y symptoms ( F i n n , 1987). However, r e s e a r c h s t u d i e s t o e v a l u a t e t h e s e c l a i m s have not been conducted ( O r t o l a n i , 1992). The " h i s t a m i n e r e l e a s i n g f o o d s " have c o n s t i t u e n t s which may account f o r the e x a c e r b a t i o n o f a l l e r g i c r e a c t i o n s (Table 3) . 17 Literature Review Table 3: HISTAMINE RELEASING FOODS FOOD CONSTITUENT P i n e a p p l e S a l i c y l a t e Strawberry- Benzoate Tomato S a l i c y l a t e F i s h H i s t a m i n e C h o c o l a t e Amines A l c o h o l Amines Egg w h i t e A l l e r g e n R e f e r e n c e s : Jacobsen, 1987 and Swain e t a l . , 1985 Twenty t o f o r t y p e r c e n t o f c h r o n i c u r t i c a r i a cases a re ag g r a v a t e d by a c e t y l s a l i c y l i c a c i d ( B u r r a l l e t a l . , 1990) t h r o u g h an unknown mechanism. A c e t y l s a l i c y l i c a c i d i n h i b i t s the c y c l o -oxygenase enzyme and a l t e r s p r o s t a g l a n d i n and l e u k o t r i e n e s p r o d u c t i o n from a r a c h i d o n i c a c i d . T h i s may be r e s p o n s i b l e f o r the e x a c e r b a t i o n o f u r t i c a r i a . S a l i c y l a t e s i n f o o d may have a s i m i l a r , b ut weaker, c y c l o - o x y g e n a s e e f f e c t (Stevenson, 1986). The s t r u c t u r e o f benz o a t e s i s s i m i l a r t o a c e t y l s a l i c y l i c a c i d ; t h e r e f o r e , benzoates may a l s o i n h i b i t t he c y c l o - o x y g e n a s e enzyme (Holgate & Chruch, 1993). The r o l e o f food a d d i t i v e s i n h i s t a m i n e r e l e a s e have been s t u d i e d in vitro and in vivo. Murdoch e t a l . (1987) i n c u b a t e d washed mast c e l l s and o t h e r l e u c o c y t e s o b t a i n e d from u r t i c a r i a and c o n t r o l s u b j e c t s i n a T r i s ACM b u f f e r . H i s t a m i n e r e l e a s e was 18 J Literature Review measured a f t e r a d d i t i o n o f v a r i o u s f o o d a d d i t i v e s t o the b u f f e r . The c o n c e n t r a t i o n s o f the food a d d i t i v e s i n the b u f f e r s were d e t e r m i n e d by an e s t i m a t e o f the plasma c o n c e n t r a t i o n a f t e r maximum d a i l y i n g e s t i o n o f the food a d d i t i v e s . A h i s t a m i n e r e l e a s e g r e a t e r t h a n the spontaneous r e l e a s e o f h i s t a m i n e i n t h e T r i s ACM b u f f e r a l o n e p l u s two s t a n d a r d d e v i a t i o n s was c o n s i d e r e d a p o s i t i v e r e s p o n s e . There was no s i g n i f i c a n t d i f f e r e n c e between the u r t i c a r i a and c o n t r o l s u b j e c t s (Table 4 ) . S i g n i f i c a n t h i s t a m i n e r e l e a s e o c c u r r e d i n a m i n o r i t y o f s u b j e c t s . I n a s e p a r a t e s t u d y , Murdoch, P o l l o c k & Naeem (1987) c h a l l e n g e d t e n h e a l t h y s u b j e c t s w i t h t a r t r a z i n e o r a p l a c e b o . There was a s i g n i f i c a n t r i s e i n plasma h i s t a m i n e a f t e r a 150 mg t a r t r a z i n e c h a l l e n g e ( p < 0 . 0 0 5 ) . There was no s i g n i f i c a n t r i s e i n plasma h i s t a m i n e a f t e r a c h a l l e n g e o f e i t h e r 5 o r 50 mg o f t a r t r a z i n e o r a p l a c e b o . These s t u d i e s suggest t h a t i n g e s t i o n o f t a r t r a z i n e and o t h e r f o o d a d d i t i v e s may r e s u l t i n endogenous h i s t a m i n e r e l e a s e i n some i n d i v i d u a l s . 19 Literature Review Table 4: HISTAMINE RELEASE FROM THE SUBJECTS EXPOSED TO FOOD ADDITIVES WASHED LEUCOCYTES OF 30 OR ASPIRIN Ntuaber of Subjects with S i g n i f i c a n t Histamine Release Class Compound Healthy Subjects (Total 18) U r t i c a r i a Subjects (Total 12) Azo C o l o u r Amaranth 2 2 Azo C o l o u r Sunset Y e l l o w 1 1 Azo C o l o u r C a r m o i s i n e 3 2 Azo C o l o u r T a r t r a z i n e 3 1 Non-azo Colour Green S 0 1 Non-azo Colour Q u i n o l i n e Y e l l o w 1 0 Non-azo Colour I n d i g o Carmine 2 1 Natural colour A n n a t t o 1 1 A n t i o x i d a n t BHA 1 1 A n t i o x i d a n t BHT 4 1 Other Sodium Benzoate 3 3 Other A c e t y l s a l i c y l i c a c i d 2 3 Re f e r e n c e : Murdoch e t a l , 1987 BHA= butylated hydroxyanisole; BHT= butylated hydroxytoluene M i c r o n u t r i e n t I n t a k e J o h n s t o n e t a l . (1992) e v a l u a t e d the e f f e c t o f a s c o r b i c a c i d s u p p l e m e n t a t i o n on b l o o d h i s t a m i n e l e v e l s . B l o o d h i s t a m i n e was s i g n i f i c a n t l y lower d u r i n g 2 weeks o f d a i l y s u p p l e m e n t a t i o n w i t h 2000 mg o f a s c o r b i c a c i d t h a n d u r i n g two weeks w i t h a p l a c e b o 20 Literature Review (p<0.05). A s i g n i f i c a n t d i f f e r e n c e was not found d u r i n g two week o f s u p p l e m e n t a t i o n w i t h 500 mg o f a s c o r b i c a c i d . H i s t a m i n e m e t a b o l i s m i n the r a t may be i n f l u e n c e d by d i e t a r magnesium l e v e l s . I n response t o an e i g h t day magnesium r e s t r i c t e d d i e t , u r i n a r y h i s t a m i n e , h i s t a m i n e c o n t e n t o f some t i s s u e s and h i s t i d i n e d e c a r b o x y l a s e a c t i v i t y o f some t i s s u e s i n c r e a s e d (p<0.05). Duodenal DAO a c t i v i t y d e c r e a s e d . These changes i n d i c a t e an i n c r e a s e i n body h i s t a m i n e d u r i n g magnesium d e f i c i e n c y . The changes were r e v e r s e d a f t e r a two day magnesium r e f e e d i n g p e r i o d ( N i s h i o e t a l . , 1987). Summary H i s t a m i n e i s a s i g n i f i c a n t f a c t o r i n u r t i c a r i a and angioedema. D i e t a r y i n t a k e may a l t e r plasma h i s t a m i n e t h r o u g h exogenous or endogenous means. The h i s t a m i n e i n f o o d may be absorbed i n t o the c i r c u l a t i o n i f the i n t e g r i t y o f the h i s t a m i n e c a t a b o l i z i n g enzymes are compromised. C e r t a i n f o o d and f o o d a d d i t i v e s may i n d u c e endogenous r e l e a s e o f h i s t a m i n e . S e v e r a l s t u d i e s have e v a l u a t e d the e f f e c t o f d i e t a r y m a n i p u l a t i o n i n c h r o n i c u r t i c a r i a and angioedema. 21 Literature Review PREVIOUS DIETARY MANIPULATION STUDIES IN CHRONIC URTICARIA AND ANGIOEDEMA U n c o n t r o l l e d F o o d - A d d i t i v e Free D i e t s C l i n i c a l e v a l u a t i o n o f s e v e r a l f o o d a d d i t i v e - f r e e d i e t s have r e p o r t e d a p p r o x i m a t e l y 30 t o 90% complete o r p a r t i a l r e m i s s i o n o f u r t i c a r i a symptoms (Table 5 ) . The p o s i t i v e r e s p o n s e s may have been p a r t i a l l y due t o p l a c e b o e f f e c t o r spontaneous r e m i s s i o n o f symptoms. However, w i t h such a h i g h p e r c e n t a g e o f s u b j e c t s i m p r o v i n g i t i s l i k e l y t h a t the d i e t s were p a r t i a l l y r e s p o n s i b l e f o r t he symptom improvement. C h a l l e n g e s t u d i e s 5 have i m p l i c a t e d t a r t r a z i n e , s u n s e t y e l l o w , b e n z o a t e s , b u t y l a t e d h y d r o x y t o l u e n e (BHT) and b u t y l a t e d h y d r o x y a n i s o l e (BHA) as t h e most l i k e l y a d d i t i v e s t o e x a c e r b a t e u r t i c a r i a . 5 I n a c h a l l e n g e s t u d y , s u b j e c t s consume f o o d a d d i t i v e s and the c l i n i c a l response t o each a d d i t i v e i s m o n i t o r e d . 2 2 < — u o PH w C/5 H Q & H o l-H H -J & & z < H H o 3 I ill mm ta III mmwm o £ 55 • j ; or. Si m $ .2 p. os £ ' £ o 3 u a! lit J 3 i I i i a 111 mm I 00 in CO O oo O in in m vo CN CN CN o o in c o .tS on CD o CD 5 IT) ON cd o 3 "o o O vo ON 00 cn oo 00 in in ^ VO <-! on CD r/T <D o a CD on O on" CD on VO. ON on <U td o CD X) <u e ' N cd t-t; cd on OD JD '-a a o "{§ c 1 cd cn o IS4 3 on O 00 ON '"3 c o c cd O cd +^  4-» o IS* on O 0O as VO CN CN CN VO 00 m <N on CD on '5b — v_ T 3 O e w o -a cd 5 on O cd 3 S i CD ^5 • ° C § o -a u CD o 00 a) a) M -P M-l (« a -H e •H W 73 4J 0 <D O • H t-l i—I d) rH si a EH M <D 4-1 IH (0 4-1 w <U si -rH 4J 73 C 0 a g 0 •H 4-> CM rd C 0 •rH 4-> - H VD H a; to e >1 0 rrj T3 a 1 LT) M (0 c a o o u e • H o 4-> x; a 4-1 g M-l to o M-l n 0 C o c •rH 0 a •H W w 0 • H w 4-1 U 0) 4-1 g in tt) 3 MH rd o rd tt) tJi O rH ^ - l -g ^ 3 I tfl tt) V 0 4-1 & M-l o a o •rH (0 in -rH g tt) M M 0 c >1 rd 73 IT) 1 n rd rd 0) C O So 0 tt) C •H g rd 10 4-> S w O -H rH X! H rd tt) X! 4J 4-1 in C H g O rd X 4-1 tt) in - H —t - H 10 4) B si 10 g o 4-1 & c o - H 10 10 • H g tt) SH rH rd • H 4-> U rd ft M O tt) 4-> 1) rH o o o -P Ci 73 tt) 4-1 rd • H 4-1 C 4) M tt) M-l M-l 4-1 O C 10 rd a - H > o M 10 4-> u 0 -r-| X! 10 tt) Di rd 4-1 Ci d) o M 0) a D x; 23 Literature Review C o n t r o l l e d F o o d - A d d i t i v e Free D i e t s C o n t r o l l e d f o o d - a d d i t i v e c h a l l e n g e s t u d i e s have a l s o y i e l d e d i n c o n c l u s i v e r e s u l t s . F o r t y - t h r e e c h i l d r e n w i t h angioedema and/or u r t i c a r i a who showed improvement on an a d d i t i v e - f r e e d i e t , were c h a l l e n g e d w i t h v a r i o u s a d d i t i v e s o r a p l a c e b o i n a d o u b l e - b l i n d d e s i g n (Supramaniam, 1986). The c h a l l e n g e q u a n t i t i e s used were l e s s t h a n average d a i l y i n t a k e s . The p r i m a r y c r i t e r i o n f o r a p o s i t i v e r e a c t i o n was appearance o f u r t i c a r i a o r angioedema w i t h i n f o u r hours o f the c h a l l e n g e . Of the n i n e f o o d c o l o u r s and a d d i t i v e s c h a l l e n g e d , the most common compounds l e a d i n g t o e x a c e r b a t i o n o f u r t i c a r i a and angioedema were t a r t r a z i n e and suns e t y e l l o w (Table 6 ) . The r e s u l t s were r e p r o d u c e d i n s i x out o f s i x r e p e a t c h a l l e n g e s ; however, s t a t i s t i c a l a n a l y s i s was not completed. S i x t y - f i v e s u b j e c t s who had complete r e m i s s i o n o f u r t i c a r i a symptoms on an a d d i t i v e and d a i r y - f r e e d i e t were c h a l l e n g e d w i t h v a r i o u s f o o d a d d i t i v e s (Gibson and C l a n c y , 1980). Appearance o f u r t i c a r i a o r angioedema w i t h i n 24 hours o f the c h a l l e n g e was c o n s i d e r e d a p o s i t i v e r e s p o n s e . F i f t y - f o u r p e r c e n t o f the s u b j e c t s responded t o s a l i c y l a t e , 34 % responded t o benzoate and 26 % responded t o t a r t r a z i n e . There was no response t o the p l a c e b o . The c h a l l e n g e q u a n t i t i e s used were two t o t h r e e t i m e s g r e a t e r 24 Literature Review Table 6 : RESULTS OF FOOD ADDITIVE ANGIOEDEMA AND CHALLENGES IN URTICARIA CHILDREN WITH Food Additive Number Challenged Number Who Reacted (%) P l a c e b o ( l a c t o s e ) 43 1 (2%) T a r t r a z i n e 43 11 (26%) Sunset Y e l l o w 36 10 (28%) Amaranth 37 4 (11%) I n d i g o Carmine 19 3 (16%) C a r m o i s i n e 12 0 Sodium Benzoate 27 4 (15%) Monosodium Glutamate 36 3 (8%) Sodium M e t a b i s u l p h i t e 12 1 (8%) R e f e r e n c e : Supramaniam and Warner, 198 6 t h a n the q u a n t i t i e s used i n Supramaniam and Warner's s t u d y . T h i s may account f o r t h e i n c r e a s e d f r e q u e n c y o f r e a c t i o n s . Double-b l i n d c h a l l e n g e s w i t h 44 c h r o n i c u r t i c a r i a s u b j e c t s d i d not r e s u l t i n g r e a t e r r e a c t i o n s t o t a r t r a z i n e , sodium benzoate, b e n z o i c a c i d , BHT or BHA tha n t o the p l a c e b o (Hannuksela and L a h t i , 1986). Two i n d i v i d u a l s w i t h i d i o p a t h i c u r t i c a r i a who showed improvement on an a d d i t i v e - f r e e d i e t were c h a l l e n g e d w i t h f o o d a d d i t i v e s and a p l a c e b o i n a d o u b l e - b l i n d t r i a l (Goodman e t a l . , 1990). B o t h p a t i e n t s responded on t h r e e s e p a r a t e o c c a s i o n s t o BHA/BHT c h a l l e n g e s b ut not t o the p l a c e b o . N e i t h e r o f the p a t i e n t s responded t o t a r t r a z i n e o r b e n z o a t e s . One p a t i e n t 25 L i t e r a t u r e Review responded t o sodium s a l i c y l a t e . From t h e s e s t u d i e s i t i s c l e a r t h a t f o o d a d d i t i v e s l e a d t o an e x a c e r b a t i o n o f u r t i c a r i a and angioedema i n some i n d i v i d u a l s ; however, the p r e v a l e n c e o f t h e s e r e a c t i o n s i s u n c e r t a i n . Low H i s t a m i n e D i e t s Wantke e t a l . (1993) e v a l u a t e d the e f f e c t o f a low h i s t a m i n e d i e t . F o r t y - f i v e p a t i e n t s w i t h c h r o n i c headaches and f o o d and wine i n t o l e r a n c e ( f l u s h i n g , p r u r i t u s , r h i n i t i s , d i a r r h o e a and s h o r t n e s s o f b r e a t h , a f t e r consuming foo d o r wine) were f o l l o w e d o v er a f o u r week p e r i o d w h i l e consuming a low h i s t a m i n e d i e t . T h i r t y - t h r e e (73%) p a t i e n t s had more th a n a 50% d e c r e a s e i n f r e q u e n c y o f symptoms and/or drug use (p<0.01). S i x t y - s e v e n s u b j e c t s w i t h c h r o n i c u r t i c a r i a f o l l o w e d a low t y r a m i n e and low f o o d - a d d i t i v e d i e t . T h i s d i e t a l s o e l i m i n a t e d many, but not a l l , foods h i g h i n h i s t a m i n e . T h i r t y - s e v e n (55%) s u b j e c t s had complete or p a r t i a l r e m i s s i o n o f u r t i c a r i a symptoms. The s u b j e c t s who responded p o s i t i v e l y t o the d i e t p r e s e n t e d t o the s t u d y w i t h i n c r e a s e d f r e q u e n c y o f u r t i c a r i a a t t a c k s , s h o r t e r d u r a t i o n o f d i s e a s e , younger age, f a m i l y h i s t o r y o f atopy, f a m i l y h i s t o r y o f u r t i c a r i a and angioedema and p r e s e n c e o f g a s t r o i n t e s t i n a l d i s t u r b a n c e s (Verschave e t a l . , 1983 ). The d u r a t i o n o f the d i e t and the time p e r i o d s t h a t symptoms were 2 6 Literature Review e v a l u a t e d were not r e p o r t e d . R e m i s s i o n o f symptoms i s common i n c h r o n i c u r t i c a r i a . I f t h e p e r i o d o f time between the i n i t i a l and the f i n a l e v a l u a t i o n o f symptoms was l e n g t h y , the r e m i s s i o n o f symptoms may have been due t o the n a t u r a l p r o g r e s s i o n o f the d i s e a s e and not the t r e a t m e n t d i e t . Low h i s t a m i n e d i e t s appear t o b e n e f i t u r t i c a r i a , angioedema and o t h e r c o n d i t i o n s which a re media t e d by h i s t a m i n e . OTHER CONDITIONS WHICH MAY BENEFIT FROM A HISTAMINE-REDUCING DIET A t o p i c D i s e a s e A t o p i c d i s e a s e i s a d i s o r d e r caused by Immunoglobulin E mediated r e l e a s e o f i n f l a m m a t o r y m e d i a t o r s from mast c e l l s and b a s o p h i l s . The common m a n i f e s t a t i o n s o f atopy are r h i n i t i s , asthma, eczema and u r t i c a r i a . The p r e v a l e n c e o f a t o p i c d i s e a s e s i s not g r e a t e r i n c h r o n i c u r t i c a r i a s u b j e c t s (Soter,1991; Supramaniam & Warner, 1986) . A n t i h i s t a m i n e m e d i c a t i o n o f t e n c o n t r o l s the symptoms o f a l l e r g i c r h i n i t i s i n d i c a t i n g t h a t h i s t a m i n e i s the p r i m a r y m e d i a t o r . A h i s t a m i n e - r e d u c i n g d i e t may be e f f e c t i v e i n c o n t r o l l i n g a l l e r g i c r h i n i t i s . 27 Literature Review M i g r a i n e Headaches Wantke e t a l . ( 1 9 9 3 ) r e p o r t e d a s i g n i f i c a n t r e d u c t i o n i n headaches a f t e r f o u r weeks on a low h i s t a m i n e d i e t . Tyramine may be an i m p o r t a n t m e d i a t o r o f f o o d - i n d u c e d headaches (Vaughan & M a n s f i e l d , 1987). Many foods h i g h i n h i s t a m i n e are a l s o h i g h i n t y r a m i n e ( S t r a t t o n e t a l . , 1 9 9 1 ) . The h i s t a m i n e - r e d u c i n g d i e t may improve m i g r a i n e headaches. G a s t r o i n t e s t i n a l D i s t u r b a n c e s D e f e c t s i n i n t e s t i n a l f u n c t i o n , such as abdominal p a i n and d i a r r h e a are seen i n 40% o f p a t i e n t s w i t h c h r o n i c u r t i c a r i a ( M o n e r e t - V a u t r i n D, 1987; J u h l i n , 1981). H i s t a m i n e may mediate the p r o c e s s by which ex c e s s b i l e a c i d s i n the c o l o n cause d i a r r h e a . Excess b i l e a c i d s may r e s u l t i n d i a r r h e a by i n c r e a s i n g c h l o r i d e s e c r e t i o n from the e n t e r o c y t e s . In vivo, t h i s a c t i o n i s i n h i b i t e d by HI a n t a g o n i s t s ( a n t i h i s t a m i n e m e d i c a t i o n ) (Gelbmann e t a l , 1995). A h i s t a m i n e - r e d u c i n g d i e t may be e f f e c t i v e f o r some cases of d i a r r h e a caused by excess c o l o n i c b i l e a c i d s . BACKGROUND LITERATURE RELATED TO THE TREATMENT AND CONTROL DIETS The t r e a t m e n t d i e t w i l l e l i m i n a t e p o t e n t i a l h i s t a m i n e r e l e a s i n g f o o d , f o o d a d d i t i v e s and f o o d which i s h i g h i n h i s t a m i n e . 28 L i t e r a t u r e Review F o r m a t i o n o f H i s t a m i n e i n Food Conditions Necessary for the Formation of Amines H i s t a m i n e i s produced from the d e c a r b o x y l a t i o n o f h i s t i d i n e ( F i g u r e 1 ) . S e v e r a l m i c r o o r g a n i s m genera have h i s t i d i n e d e c a r b o x y l a s e a c t i v i t y ( T a y l o r , 1986). Free h i s t i d i n e , d e c a r b o x y l a s e - p r o d u c i n g m i c r o o r g a n i s m s and adequate c o n d i t i o n s f o r m i c r o b i o l o g i c a l growth are n e c e s s a r y f o r h i s t a m i n e f o r m a t i o n (Halasz e t a l . , 1994). The amount o f h i s t a m i n e formed i n foods v a r i e s c o n s i d e r a b l y . P r o t e i n a c e o u s foods t h a t are aged and fermented are l i k e l y t o have i n c r e a s e d h i s t a m i n e . Important genera w i t h d e c a r b o x y l a s e a c t i v i t y a re Escherichia, Salmonella, Clostridium, B a c i l l u s and L a c t o b a c i l l u s (Halasz e t a l . , 1994; T a y l o r , 1986). D e c a r b o x y l a s e a c t i v i t y v a r i e s between and w i t h i n s t r a i n s o f m i c r o o r g a n i s m s . F a c t o r s such as growth c o n d i t i o n s and growth-phase o f the m i c r o o r g a n i s m a f f e c t a c t i v i t y (Halasz e t a l . , 1994). M i c r o o r g a n i s m s may be p r e s e n t i n a f o o d t h r o u g h n a t u r a l o c c u r r e n c e , c o n t a m i n a t i o n o r as a s t a r t e r c u l t u r e f o r f e r m e n t a t i o n (Halasz e t a l . , 1994). Temperature, pH and s a l t c o n c e n t r a t i o n o f a f o o d i n f l u e n c e m i c r o o r g a n i s m growth and t h e r e f o r e amine f o r m a t i o n . Free amino a c i d s may o c c u r n a t u r a l l y i n f o o d o r r e s u l t from p r o t e o l y t i c a c t i v i t y (Halasz e t a l . , 1994). Scombroid o r m a c k e r e l f a m i l y f i s h t i s s u e s have i n c r e a s e d l e v e l s o f f r e e h i s t i d i n e , and 29 L i t e r a t u r e Review are t h e r e f o r e s u s c e p t i b l e t o h i s t a m i n e f o r m a t i o n ( t en B r i n k e t a l . , 1990). Other amines a r e produced by d e c a r b o x y l a t i o n o f t h e c o r r e s p o n d i n g amino a c i d s (Table 7 ) . The m i c r o o r g a n i s m s which d e c a r b o x y l a t e h i s t i d i n e , may, but do not n e c e s s a r i l y , Table 7: AMINES AND THE AMINO ACID PRECURSORS Amine Precursor amino aci d H i s t a m i n e H i s t i d i n e Tryptamine Tryptophan Tyramine T y r o s i n e Phenylethy1amine . P h e n y l a l a n i n e P u t r e s c i n e O r n i t h i n e C a d a v e r i n e L y s i n e R e f e r e n c e : t e n B r i n k e t a l , 1990 d e c a r b o x y l a t e o t h e r amino a c i d s . A l a r g e v a r i e t y o f mic r o o r g a n i s m s may be p r e s e n t d u r i n g f o o d p r o c e s s i n g ; t h e r e f o r e , the amine c o n t e n t w i l l a l s o be q u i t e v a r i a b l e ( t e n B r i n k , 1990). Amine Content of Susceptible Food Cheese: H i s t a m i n e l e v e l s v a r y e x t e n s i v e l y between and w i t h i n cheese v a r i e t i e s . L a c t o b a c i l l u s buchneri was i s o l a t e d from a b a t c h o f Swiss cheese t h a t was i m p l i c a t e d i n an ou t b r e a k o f 30 L i t e r a t u r e Review h i s t a m i n e p o i s o n i n g , and i t i s l i k e l y the most i m p o r t a n t h i s t a m i n e f o r m i n g m i c r o o r g a n i s m i n cheese ( S t r a t t o n e t a l . , 1991). However, h i s t i d i n e d e c a r b o x y l a s e a c t i v i t y i s l i m i t e d t o o n l y a few s t r a i n s o f L. buchneri. The a c t i v i t y o f h i s t i d i n e d e c a r b o x y l a s e s t r a i n s o f L. buchneri v a r i e s w i t h growth c o n d i t i o n s . A s t o r a g e t e m p e r a t u r e o f 21°C r e s u l t e d i n h i s t a m i n e l e v e l s o f 6.8 mmol/kg of.Gouda cheese. A s t o r a g e t e m p e r a t u r e o f 9°C r e s u l t e d i n h i s t a m i n e l e v e l s o f 2.2 mmol/kg of cheese. A s t o r a g e pH o f 5.39 r e s u l t e d i n t w i c e as much h i s t a m i n e f o r m a t i o n as a s t o r a g e pH o f 5.19. S t o r a g e a t 21°C and pH 5.39 r e s u l t e d i n h i s t a m i n e l e v e l s o f 9.4 mmol/kg o f cheese a f t e r 1 y ear o f r i p e n i n g ( J o o s t e n , 1988) . The h i s t i d i n e d e c a r b o x y l a s e a c t i v i t y o f L. buchneri i s not a f f e c t e d by heat t r e a t m e n t ( J o o s t e n , 1988). I f the m i l k used t o produce the cheese c o n t a i n s L. buchneri, p a s t e u r i z a t i o n w i l l not d e c r e a s e the r i s k o f h i s t a m i n e f o r m a t i o n . Most c o m m e r c i a l l y a v a i l a b l e s t a r t e r c u l t u r e s do not p o s s e s s h i s t i d i n e d e c a r b o x y l a s e a c t i v i t y ( t en B r i n k e t a l . , 1990). T h e r e f o r e , h i s t a m i n e f o r m a t i o n u s u a l l y r e s u l t s from c o n t a m i n a t i o n o f the m i l k w i t h a h i s t i d i n e d e c a r b o x y l a s e -p r o d u c i n g m i c r o o r g a n i s m . P u t r e s c i n e , t y r a m i n e , c a d a v e r i n e and o t h e r amines have a l s o been r e p o r t e d i n cheese. Cheese samples w i t h e l e v a t e d h i s t a m i n e 31 Literature Review o f t e n , but not always, have e l e v a t e d l e v e l s o f o t h e r amines ( S t r a t t o n e t a l . , 1991). Fish: H i s t a m i n e p o i s o n i n g from f i s h u s u a l l y i n v o l v e s scombroid f i s h due t o the l a r g e amount o f f r e e h i s t i d i n e i n the muscle t i s s u e s . Scombroid f i s h i n c l u d e s t u n a , b o n i t o , s k i p j a c k , a l b a c o r e and m a c k e r e l . Non-scombroid f i s h have o c c a s i o n a l l y been a s s o c i a t e d w i t h h i s t a m i n e p o i s o n i n g (Rohani e t a l . , 1985). F i s h i s c o n s i d e r e d t o x i c i f i t c o n t a i n s more th a n 100 mg o f h i s t a m i n e per 100 g o f f i s h . F i s h p r o d u c t s w i l l not be i m p o r t e d by Canada o r the U n i t e d S t a t e s i f t h e y c o n t a i n more th a n 10 mg o f h i s t a m i n e per 100 g o f f i s h . Random samples o f f o u r t y p e s o f scombroid f i s h were o b t a i n e d from a r e t a i l f i s h o u t l e t i n Serdang, S e l a n g o r (Rohani e t a l . , 1985). Three o f 56 samples: c o n t a i n e d 4.5 mg/lOOg, 10.9 mg/lOOg, and 18.6 mg/lOOg o f h i s t a m i n e . Ten d u p l i c a t e samples o f canned tuna and f o u r t e e n d u p l i c a t e samples o f canned m a c k e r e l p r o c e s s e d i n Serdang, S e l a n g o r f o r e x p o r t were a n a l y z e d f o r h i s t a m i n e c o n t e n t . Three canned tuna samples were found t o c o n t a i n 2.3 mg/lOOg, 9.4 mg/lOOg and 15.9 mg/lOOg o f h i s t a m i n e . H i s t a m i n e f o r m a t i o n o c c u r r e d due t o i n a d e q u a t e c o l d s t o r a g e p r i o r t o c a n n i n g . No m a c k e r e l samples c o n t a i n e d h i s t a m i n e . H i s t a m i n e l e v e l s as h i g h as 180 t o 500 mg/g o f f i s h have been r e p o r t e d (Malone & Metcalfe-, 1986) . Kim & B j e l d a n e s (1979) e v a l u a t e d 15 samples o f canned tuna i m p l i c a t e d i n an o u t b r e a k o f scombroid 32 Literature Review f i s h p o i s o n i n g and found the h i s t a m i n e , c a d a v e r i n e and p u t r e s c i n e c o n t e n t t o be h i g h e r t h a n 34 cans o f supermarket t u n a . The mean h i s t a m i n e c o n t e n t i n the 15 tuna samples was 116±6 mg/lOOg. Fermented f i s h p r o d u c t s and f i s h p a s t e o f t e n have i n c r e a s e d h i s t a m i n e c o n t e n t . Ten samples o f s a l t e d t e n g g i r i f i s h c o n t a i n e d between 3.5 mg/lOOg and 12.0 mg/lOOg o f h i s t a m i n e (Rohani e t a l . , 1985). S u g a r - s a l t e d h e r r i n g s t o r e d i n b a r r e l s were found t o have between 31 mg/lOOg and 101 mg/lOOg o f h i s t a m i n e . Canned h e r r i n g were found t o have h i s t a m i n e l e v e l s o f 0 - 18 mg/lOOg ( S t r a t t o n et a l . , 1991). Fermented beverages: A s u r v e y o f American and E n g l i s h wine r e p o r t e d a h i s t a m i n e range from n o n - d e t e c t a b l e t o 30 mg/L, w i t h r e d wines and s h e r r i e s g e n e r a l l y h a v i n g h i g h e r h i s t a m i n e c o n t e n t s ( S t r a t t o n e t a l . , 1991). E l e v a t e d l e v e l s o f c a d a v e r i n e and ty r a m i n e have a l s o been r e p o r t e d i n wine (Baucom e t a l . , 1986). Beer was r e p o r t e d t o have a h i s t a m i n e range o f 2.6 t o 20.0 mg/L ( S t r a t t o n e t a l . , 1991). H i s t a m i n e was not d e t e c t e d i n brandy, s c o t c h whiskey o r cognac (Granerus e t a l . , 1 9 6 9 ) . Meat and Meat Products: Zee e t a l . (1983) found low l e v e l s o f h i s t a m i n e , c a d a v e r i n e , p u t r e s c i n e and t y r a m i n e i n f r e s h pork and p r o c e s s e d meat. P r o c e s s i n g d e c r e a s e d the amine c o n t e n t o f f r e s h b e e f . Amine f o r m a t i o n can o c c u r d u r i n g s t o r a g e a t i n a p p r o p r i a t e time and te m p e r a t u r e . Sayem-El-Daher e t a l . (1984) 33 Literature Review a n a l y z e d 62 randomly chosen samples o f f r e s h ground b e e f . The h i s t a m i n e c o n t e n t ranged between 0.0 t o 21.7 mg/lOOg w i t h a mean l e v e l o f 0.57 mg/lOOg. There was a p o s i t i v e c o r r e l a t i o n between the l e v e l s o f p u t r e s c i n e , c a d a v e r i n e and t y r a m i n e and time and tempe r a t u r e o f s t o r a g e . Fermented meats have i n c r e a s e d h i s t a m i n e l e v e l s . The h i s t a m i n e c o n t e n t o f 27 dry-sausage samples ranged between non-d e t e c t a b l e and 19.74 mg/lOOg o f d r y m a t t e r (Vanerkerckhove, (1990). Fermented Vegetables: Raw cabbage c o n t a i n s a v a r i e t y o f m i c r o o r g a n i s m s . The c o n t a m i n a t i o n o f s a u e r k r a u t p r o d u c t i o n depends on h a r v e s t t i m e , h y g i e n i c p r a c t i c e and p r o c e s s i n g t r e a t m e n t . In a s u r v e y o f 50 samples o f r e t a i l s a u e r k r a u t , the range o f h i s t a m i n e was 0.91 t o 13.0 mg/lOOg and the average h i s t a m i n e c o n t e n t was 5.06 mg/lOOg ( T a y l o r e t a l . , 1978). Fermented Soy Products: I n a s u r v e y o f o r i e n t a l f o o d s , t h e h i s t a m i n e l e v e l , o f t a m a r i was 2392 ug./g and one br a n d o f soy sauce was 220 ug/g (Chin e t a l . , 1989). Soy sauce made from b l a c k bean i s g e n e r a l l y h i g h e r i n h i s t a m i n e t h a n r e g u l a r soy sauce ( S t r a t t o n , 1991). Food p r o d u c t i o n and s t o r a g e methods which l i m i t amine f o r m a t i o n are e s s e n t i a l . Low temperature s t o r a g e i n h i b i t s t he growth o f m i c r o o r g a n i s m s . S t a r t e r c u l t u r e s used i n f o o d 34 Literature Review p r o d u c t i o n must be r e j e c t e d i f the m i c r o o r g a n i s m has d e c a r b o x y l a s e a c t i v i t y . Raw foods a re o f t e n c o n t a m i n a t e d w i t h m i c r o o r g a n i s m s ; t h e r e f o r e , h y g i e n i c p r a c t i c e i s e s s e n t i a l . Low temperature s t o r a g e and h y g i e n i c h a n d l i n g o f f o o d must be o b s e r v e d i n the f o o d i n d u s t r y and i n the home. The f o r m a t i o n o f amines i n f o o d depends on the p a r t i c u l a r m i c r o o r g a n i s m s i n the food , p r e s e n c e o f f r e e amino a c i d s and growth c o n d i t i o n s . L i t e r a t u r e v a l u e s o f amines i n s e l e c t e d foods are q u i e t v a r i a b l e (Zee e t a l . , 1983). The p h y s i o l o g i c a l e f f e c t o f f o o d borne amines w i l l depend on the l e v e l o f each amine i n the p a r t i c u l a r f o o d and the s e n s i t i v i t y o f the i n d i v i d u a l consuming the f o o d . N a t u r a l and A r t i f i c i a l Food C o n s t i t u e n t s Benzoates: B e n z o i c a c i d and sodium benzoate a re w i d e l y used as a n t i m y c o t i c and a n t i b a c t e r i a l p r e s e r v a t i v e s i n foods and beverag e s . B e n z o i c a c i d i s commonly added t o tomato p r o d u c t s , p r o c e s s e d f r u i t , m a r g a r i n e and meat p r o d u c t s . B e n z o y l p e r o x i d e i s used as a b l e a c h i n g , m a t u r i n g and dough c o n d i t i o n i n g agent f o r f l o u r . The presence o f benzoates must be d e c l a r e d on the i n g r e d i e n t l a b e l . A d d i t i o n a l l y , b e nzoates o c c u r n a t u r a l l y i n fo o d . L e v e l s o f n a t u r a l b enzoates a re h i g h e s t i n prunes, cinnamon, nutmeg, c l o v e s , t e a s , a n i s e and many b e r r i e s e s p e c i a l l y 35 L i t e r a t u r e Review-strawberries, r a s p b e r r i e s and c r a n b e r r i e s (Jacobsen, 1987; Heimuber & Herrmann, 1990). L e v e l s o f b e n z o a t e s v a r y c o n s i d e r a b l y w i t h growing c o n d i t i o n s (Heimuber & Herrmann, 1990). Food p r o d u c t s l a b e l l e d w i t h b e n z o i c a c i d , sodium benzoate, b e n z o y l p e r o x i d e and foods w i t h h i g h l e v e l s o f n a t u r a l l y o c c u r r i n g b e nzoates s h o u l d be e l i m i n a t e d from a h i s t a m i n e - r e d u c i n g d i e t . S a l i c y l a t e s : S a l i c y l a t e s o c c u r n a t u r a l l y i n a wide v a r i e t y o f f o o d . S a l i c y l a t e l e v e l s v a r y w i t h growing c o n d i t i o n s , f o o d v a r i e t y , s t a g e o f r i p e n e s s and p r o c e s s i n g . The most comprehensive i n v e s t i g a t i o n o f s a l i c y l a t e l e v e l s i n f o o d was completed by Swain et a l . (1985). The q u a n t i t y o f s a l i c y l a t e n e c e s s a r y t o provoke c l i n i c a l symptoms i s not known. Foods w i t h g r e a t e r than 5 mg p e r common p o r t i o n s i z e ( a r b i t r a r y l i m i t ) s h o u l d be e l i m i n a t e d from a h i s t a m i n e - r e d u c i n g d i e t . These foods i n c l u d e c u r r y powder, hot p a p r i k a , prunes and r a i s i n s (Swain e t a l . , 1985). BHA and BHT: BHA and BHT are used as a n t i o x i d a n t p r e s e r v a t i v e s i n f o o d such as f a t s and o i l s , b r e a k f a s t c e r e a l s and baked f o o d p r o d u c t s . The p r e s e n c e of BHA and BHT must be i d e c l a r e d on the i n g r e d i e n t l a b e l . A l l f o o d p r o d u c t s c o n t a i n i n g BHA and BHT s h o u l d be e l i m i n a t e d from a h i s t a m i n e - r e d u c i n g d i e t . Food p r o d u c t s w i t h BHA and BHT i n the package m a t e r i a l may be p e r m i t t e d . 36 L i t e r a t u r e Review A r t i f i c i a l food colours: A r t i f i c i a l c o l o u r s a re used t o improve the appearance o f p r e p a r e d f o o d . T a r t r a z i n e i s the food c o l o u r which i s most l i k e l y t o e x a c e r b a t e u r t i c a r i a . A r t i f i c i a l f o o d c o l o u r must be d e c l a r e d on the i n g r e d i e n t l a b e l ; however, s p e c i f i c c o l o u r s a re not n e c e s s a r i l y l a b e l l e d . T h e r e f o r e , f o o d p r o d u c t s l a b e l l e d as c o n t a i n i n g a r t i f i c i a l f o o d c o l o u r s h o u l d be e l i m i n a t e d from a h i s t a m i n e - r e d u c i n g d i e t . C o n t r o l D i e t For the purpose o f the p r e s e n t s t u d y a c o n t r o l d i e t was d e s i g n e d as one i n whi c h a r t i f i c i a l sweeteners were e l i m i n a t e d , because t h e y a re commonly b e l i e v e d t o e x a c e r b a t e u r t i c a r i a but have been shown t o not do so. K u l c z y c k i (1986) r e p o r t e d a s i n g l e case s t u d y o f u r t i c a r i a f o l l o w i n g a b l i n d e d c h a l l e n g e w i t h the a r t i f i c i a l sweetener aspartame® ( a s p a r t i c a c i d , p h e n y l a l a n i n e and m e t h a n o l ) . I n 1984, the American C e n t e r s f o r D i s e a s e C o n t r o l e v a l u a t e d 76 r e p o r t s o f a l l e r g i c o r d e r m a t o l o g i c symptoms r e s u l t i n g from aspartame® consumption. I t was c o n c l u d e d t h a t a c o n t r o l l e d r e s e a r c h s t u d y was n e c e s s a r y t o det e r m i n e t h e r e l e v a n c e o f aspartame® consumption i n a l l e r g i c and d e r m a t o l o g i c d i s e a s e p r e s e n t a t i o n . Geha e t a l . (1993) conducted a randomized, d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d , c r o s s o v e r c l i n i c a l s t u d y t o determine i f 37 Literature Review aspartame® consumption r e s u l t e d i n u r t i c a r i a . The s t u d y was conducted a t s i x h o s p i t a l s i n Canada and the U n i t e d S t a t e s . I n d i v i d u a l s who e x p e r i e n c e d u r t i c a r i a and/or angioedema w i t h i n 12 hours o f aspartame® consumption o r had r e s o l u t i o n o f symptoms when aspartame® was removed from the d i e t were i n v i t e d t o p a r t i c i p a t e i n the s t u d y . R e c r u i t m e n t l e t t e r s were m a i l e d t o 4700 a l l e r g i s t s i n Canada and the U n i t e d S t a t e s and 11 l o c a l a l l e r g y and dermatology s o c i e t i e s . One hundred and two i n d i v i d u a l s who had r e p o r t e d u r t i c a r i a and/or angioedema symptoms a f t e r consumption o f aspartame® t o the Nutrasweet Company, the p r o d u c e r s o f aspartame, were i n v i t e d t o p a r t i c i p a t e i n the s t u d y . One hundred and e l e v e n p o t e n t i a l c a n d i d a t e s c a l l e d a t o l l - f r e e number t h a t had been e s t a b l i s h e d f o r s u b j e c t r e c r u i t m e n t . Twenty-one s u b j e c t s e n t e r e d the s t u d y . F o r t y - f o u r s u b j e c t s d i d not meet the s t u d y c r i t e r i a , 32 d i d not w i s h t o p a r t i c i p a t e , 9 were l o s t t o f o l l o w - u p , 3 were a b l e t o consume aspartame® w i t h o u t problem, 1 was pregnant and 1 had p h y s i c a l u r t i c a r i a . The s u b j e c t s s t a y e d a t the s t u d y c e n t r e s f o r the f i v e days and were c h a l l e n g e d w i t h p l a c e b o , aspartame® and the c o n v e r s i o n p r o d u c t s o f aspartame® , a s p a r t y l p h e n y l a l a n i n e d i k e t o p i p e r a z i n e and ( 3-aspartame. S u b j e c t s w i t h a body weight g r e a t e r t h a n 40 kg r e c e i v e d 950 mg o f aspartame®. S u b j e c t who weighed l e s s t h a n 40 kg r e c e i v e d 475 mg o f aspartame®. The aspartame® dose was 5 t o 6 tim e s the average 38 L i t e r a t u r e Review amount cqnsumed. Subjects received either aspartame® or placebo on Day 2 or 4 i n random order. There was no s t a t i s t i c a l difference i n the incidence of po s i t i v e reactions between aspartame® and placebo. Even though several individuals have reported an exacerbation of u r t i c a r i a symptoms after aspartame® consumption, these claims have not been validated. SIGNIFICANCE OF THE PRESENT STUDY Diet may exacerbate u r t i c a r i a and angioedema by increasing histamine levels i n the body through exogenous or endogenous mechanisms. The control of u r t i c a r i a and angioedema through dietary manipulation would lead to a reduction i n medication use and an improvement i n the quality of l i f e for these patients. The effectiveness of dietary manipulation i n chronic u r t i c a r i a and angioedema should be evaluated i n a controlled study. 39 Methods C H A P T E R 3 M E T H O D S EXPERIMENTAL DESIGN The s t u d y was a randomized, p r o s p e c t i v e d e s i g n . S u b j e c t s w i t h c h r o n i c u r t i c a r i a and/or angioedema were r e c r u i t e d and randomized t o a t r e a t m e n t o r c o n t r o l d i e t . The t r e a t m e n t d i e t e l i m i n a t e d f o o d which was h i g h i n h i s t a m i n e and f o o d a d d i t i v e s w hich may i n c r e a s e endogenous r e l e a s e o f h i s t a m i n e . The c o n t r o l d i e t was based on Canada's Food Guide and e l i m i n a t e d a r t i f i c i a l sweeteners and sugar a l c o h o l s . The d i e t s were t o be f o l l o w e d f o r 56 days (8 weeks). Three-day f o o d r e c o r d s were a n a l y z e d e v e r y 14 days (2 weeks) t o ensure n u t r i t i o n a l adequacy and d i e t a r y c o m p l i a n c e . S u b j e c t s e v a l u a t e d t h e i r u r t i c a r i a and angioedema symptoms on a d a i l y b a s i s , as i n s t r u c t e d , b e g i n n i n g f o u r t e e n days p r i o r t o the s t a r t o f the d i e t and c o n t i n u i n g throughout the s t u d y p e r i o d . A n t i h i s t a m i n e m e d i c a t i o n i n t a k e , number o f wheals, s e v e r i t y o f p r u r i t u s and angioedema were r e c o r d e d . The d a t a were a n a l y z e d u s i n g a 2x2 (group x time) r e p e a t e d measures ANOVA. 40 Methods METHODS Sample s i z e A sample s i z e o f 15 t o 20 s u b j e c t s p e r group has been shown to be adequate f o r s t a t i s t i c a l s i g n i f i c a n c e i n a n t i h i s t a m i n e m e d i c a t i o n c l i n i c a l t r i a l s (Shareeah, 1992/ Sussman, 1991; B e r n s t e i n , 1988). The number o f a n t i h i s t a m i n e t a b l e t s t a k e n by the f i r s t t e n s u b j e c t s , d u r i n g the 14 days b e f o r e s t a r t i n g the d i e t , was used t o c a l c u l a t e sample s i z e (Cheney & Boushey, 1992). The mean number o f t a b l e t s t a k e n was 9.5 w i t h a s t a n d a r d d e v i a t i o n o f 7.2. A 50% change i n t h i s measure was c o n s i d e r e d m e a n i n g f u l ; t h e r e f o r e , a change o f 5 t a b l e t s . A t w o - t a i l e d t e s t was used; a was s e t a t 0.05 and (3 was s e t a t 0.02. F i g u r e 3: SAMPLE SIZE CALCULATION n= 2 n= (0.84 + 1.96) x 7.2 2 5 n= 16.25 o r 17 s u b j e c t s p e r group 41 Methods Thus, as shown i n F i g u r e 3, the r e q u i r e d sample s i z e was c a l c u l a t e d t o be 17 s u b j e c t s p e r group. S u b j e c t R e c r u i t m e n t R e c r u i t m e n t p o s t e r s were p l a c e d i n the w a i t i n g rooms a t f i v e m e d i c a l c l i n i c s and s i x pharmacies i n N o r t h Vancouver (Appendix A ) . The d e r m a t o l o g i s t s i n the lower m a i n l a n d were c o n t a c t e d by t e l e p h o n e , and the i n v e s t i g a t o r a t t e m p t e d t o make an appointment t o promote the s t u d y . A c c o r d i n g t o each d e r m a t o l o g i s t ' s response, a p e r s o n a l v i s i t was made, i n f o r m a t i o n was m a i l e d o r no f u r t h e r a c t i o n was t a k e n . The c h a i r p e r s o n o f the B r i t i s h Columbia A l l e r g y A s s o c i a t i o n was c o n t a c t e d by t e l e p h o n e and sent i n f o r m a t i o n about the s t u d y . The r e g i o n a l c o o r d i n a t o r o f the A l l e r g y Asthma I n f o r m a t i o n A s s o c i a t i o n and the n i n e a c t i v a t o r s i n the lower m a i n l a n d were c o n t a c t e d by t e l e p h o n e and sent w r i t t e n i n f o r m a t i o n about the s t u d y . The A l l e r g y Asthma I n f o r m a t i o n A s s o c i a t i o n a c t i v a t o r s p r o v i d e t e l e p h o n e s u p p o r t t o i n d i v i d u a l s w i t h a l l e r g i c d i s e a s e s . R e c r u i t m e n t n o t i c e s were p l a c e d i n the B r i t i s h Columbia D i e t i t i a n s ' and N u t r i t i o n i s t s ' A s s o c i a t i o n n e w s l e t t e r , B r i t i s h Columbia Pharmacy N e w s l e t t e r (the B u l l e t i n ) and Rogers Cable community c h a n n e l . R e c r u i t m e n t n o t i c e s were p l a c e d i n the 42 Methods Vancouver Sun o r the P r o v i n c e newspapers on January 21/22, A p r i l 22/23 and June 10/11, 1995. I n d i v i d u a l s were i n v i t e d t o p a r t i c i p a t e i f t h e y had u r t i c a r i a and/or angioedema symptoms f o r a t l e a s t s i x weeks and had g r e a t e r t h a n one e p i s o d e o f u r t i c a r i a and/or angioedema symptoms p e r week. S u b j e c t s were t o be n i n e t e e n y e a r s o f age o r o l d e r . Younger s u b j e c t s may be l e s s c o m p l i a n t t o d i e t t h e r a p y , and u r t i c a r i a i s most f r e q u e n t l y r e p o r t e d i n mi d d l e - a g e d women ( B u r r a l l , 1990; S o t e r , 1 9 9 1 ) . E x c l u s i o n c r i t e r i a i n c l u d e d t h o s e s u b j e c t s who were c h a n g i n g m e d i c a t i o n s t o c o n t r o l symptoms, were pregnant o r had u r t i c a r i a l v a s c u l i t i s , m a s t o c y t o s i s , dermatophyte i n f e c t i o n , Candida i n f e c t i o n , m o n o n u c l e o s i s , r h e u m a t o i d a r t h r i t i s o r l u p u s erythematosus. I n d i v i d u a l s were not e x c l u d e d i f t h e y were t a k i n g m e d i c a t i o n t h a t might e x a c e r b a t e u r t i c a r i a and angioedema. Many common drugs may e x a c e r b a t e t h i s d i s e a s e , and e x c l u d i n g a l l s u b j e c t s t a k i n g t h e s e drugs would have g r e a t l y l i m i t e d s u b j e c t r e c r u i t m e n t . The s u b j e c t s ' p h y s i c i a n s c o n f i r m e d the d i a g n o s i s and gave v e r b a l o r w r i t t e n consent f o r t h e i r p a t i e n t s ' p a r t i c i p a t i o n i n the s t u d y . 43 Methods D i e t a r y I n t e r v e n t i o n Treatment Diet (Appendix B ) The t r e a t m e n t d i e t e l i m i n a t e d f o o d which was p o t e n t i a l l y h i g h i n h i s t a m i n e and f o o d a d d i t i v e s which may i n c r e a s e endogenous r e l e a s e o f h i s t a m i n e . The foods t h a t were r e s t r i c t e d due t o p o t e n t i a l l y h i g h h i s t a m i n e c o n t e n t were: s p i n a c h , tomato and tomato p r o d u c t s , f i s h , p r o c e s s e d meat, l e f t o v e r meat, cheese p r o d u c t s , y o g h u r t , sour cream, fermented soy p r o d u c t s , fermented foods and a l c o h o l . S u b j e c t s were i n s t r u c t e d t o f o l l o w h y g i e n i c p r o c e d u r e s f o r f o o d s t o r a g e and p r e p a r a t i o n t o d e c r e a s e m i c r o b i o l o g i c a l growth and h i s t a m i n e f o r m a t i o n i n f o o d . Food p r o d u c t s c o n t a i n i n g t a r t r a z i n e , a r t i f i c i a l f o o d c o l o u r , b e n z o i c a c i d , sodium benzoate, b e n z o y l p e r o x i d e , b u t y l a t e d h y d r o x y a n i s o l e and b u t y l a t e d h y d r o x y t o l u e n e were a l s o e l i m i n a t e d because t h e s e a d d i t i v e s may i n c r e a s e endogenous r e l e a s e o f h i s t a m i n e . C r a n b e r r i e s , s t r a w b e r r y , r a s p b e r r y , prunes, cinnamon, a n i s e , c l o v e s and nutmeg were e l i m i n a t e d due t o p o t e n t i a l l y h i g h benzoate c o n t e n t . P i n e a p p l e , d a t e s , c u r r a n t s , r a i s i n s , p runes, c u r r y powder and hot p a p r i k a were e l i m i n a t e d due t o p o t e n t i a l l y h i g h s a l i c y l a t e c o n t e n t . S t r a w b e r r i e s , p i n e a p p l e , tomato and tomato p r o d u c t s , s e a f o o d , uncooked egg w h i t e , ' a n d c h o c o l a t e were e l i m i n a t e d due t o p o t e n t i a l " h i s t a m i n e r e l e a s i n g " p r o p e r t i e s o f t h e s e f o o d s . 44 Methods The r a t i o n a l e f o r the d i e t was d i s c u s s e d w i t h the treatment s u b j e c t s . S u b j e c t s were taught to r e a d i n g r e d i e n t l a b e l s . A w r i t t e n l i s t o f a c c e p t a b l e food p r o d u c t s was g i v e n to each s u b j e c t , and meal p l a n i n g sugges t ions were d i s c u s s e d . Control Diet (Appendix C) The c o n t r o l d i e t was d e s i g n e d to e l i m i n a t e food which would not i n f l u e n c e u r t i c a r i a and angioedema symptoms, but would appear to be a p l a u s i b l e t r e a t m e n t . The c o n t r o l s u b j e c t s f o l l o w e d a d i e t which was based on Canada's Food Guide and e l i m i n a t e d a s p a r t a m e ® , s p l e n d a ® , s u n e t t ® , s a c c h a r i n , cyc lamate , m a n n i t o l , x y l i t o l and s o r b i t o l . The c o n t r o l s u b j e c t s had d i e t i n s t r u c t i o n s i m i l a r to the treatment group. The importance o f a b a l a n c e d i n t a k e f o r p r o p e r immune system f u n c t i o n and h e a l t h was d i s c u s s e d as p a r t o f the r a t i o n a l e f o r the c o n t r o l d i e t . The s i n g l e documented case o f e x a c e r b a t i o n o f u r t i c a r i a a f t e r a b l i n d e d aspartame c h a l l e n g e was d i s c u s s e d ( K u l c z y c k i , 1986). S u b j e c t s were taught to read i n g r e d i e n t l a b e l s and f o l l o w Canada's Food G u i d e . A l t e r n a t i v e s to u n a c c e p t a b l e food p r o d u c t s were d i s c u s s e d . 45 Methods U r t i c a r i a and Angioedema Assessment S c a l e (Appendix D) A v a l i d a t e d measurement s c a l e f o r u r t i c a r i a and angioedema has not been d e v e l o p e d ( p e r s o n a l c o r r e s p o n d ence: Dr. Morton, MD and Dr.G.Sussman, MD). The s c a l e d e v e l o p e d f o r t h i s s t u d y was p r e t e s t e d w i t h u r t i c a r i a and angioedema p a t i e n t s . P r e v i o u s u r t i c a r i a and angioedema p a t i e n t s who had a t t e n d e d th e Vancouver H o s p i t a l A l l e r g y N u t r i t i o n C l i n i c were c o n t a c t e d by t e l e p h o n e and asked t o c r i t i q u e the u r t i c a r i a and angioedema symptom assessment s c a l e . The p a t i e n t s were asked t o suggest changes which would make the s c a l e e a s i e r t o complete and more r e f l e c t i v e o f the s e v e r i t y o f t h e i r symptoms. The assessment s c a l e was r e v i s e d based on t h e s e comments. The u r t i c a r i a and angioedema assessment s c a l e i n c l u d e d f o u r v a r i a b l e s . (1) A n t i h i s t a m i n e m e d i c a t i o n i n t a k e : The s u b j e c t s r e c o r d e d the number of t a b l e t s t a k e n each day. Drug e f f i c a c y and e f f e c t v a r i e s among p a t i e n t s ( J u h l i n , 1992); t h e r e f o r e , i t was n e c e s s a r y t h a t each p a t i e n t be c o n s i s t e n t w i t h r e s p e c t t o a n t i h i s t a m i n e m e d i c a t i o n b r a n d t h r o u g h o u t the s t u d y . The s p e c i f i c a n t i h i s t a m i n e s and the doses were r e c o r d e d each day t o i d e n t i f y changes i n t h i s v a r i a b l e . 46 Methods (2) Number of wheals: The s u b j e c t s r e c o r d e d the t o t a l number o f wheals each day, and t h e y s p e c i f i e d whether t h e y counted the wheals o r guessed. (3) S e v e r i t y o f i t c h i n e s s : The s u b j e c t s r e c o r d e d the o v e r a l l s e v e r i t y o f i t c h i n e s s each day on a s c a l e o f 0 t o 3, where the numbers r e p r e s e n t e d the f o l l o w i n g degrees o f s e v e r i t y : 0=symptoms absent; l=symptoms are p r e s e n t , but b a r e l y n o t i c a b l e ; 2=symptoms a r e d e f i n i t e l y n o t i c a b l e , b u t a r e t o l e r a b l e ; 3=symptoms are d e f i n i t e l y n o t i c a b l e , and are not t o l e r a b l e . (4) S e v e r i t y o f angioedema: The' s u b j e c t s r e c o r d e d the o v e r a l l s e v e r i t y o f angioedema each day on a s c a l e o f 0 t o 3, where the numbers r e p r e s e n t e d the f o l l o w i n g degrees o f s e v e r i t y : 0=symptoms absent; l=symptoms are p r e s e n t , but b a r e l y n o t i c a b l e ; 2=symptoms are d e f i n i t e l y n o t i c a b l e , but are t o l e r a b l e ; 3=symptoms are d e f i n i t e l y n o t i c a b l e , and are not t o l e r a b l e . The s u b j e c t s were i n s t r u c t e d t o complete t h e assessments a t the same time each day f o r the p r e v i o u s 24 h o u r s . C o n s i s t e n c y o f symptom assessment was s t r e s s e d t h r o u g h o u t the s t u d y . Three-Day Food Records (Appendix E) The purpose o f r e c o r d i n g d i e t a r y i n t a k e s was t o a s s e s s n u t r i e n t i n t a k e b e f o r e the d i e t s were i n i t i a t e d (Days -3 t o -5) and e v e r y two weeks a f t e r the d i e t s were i n i t i a t e d 47 Methods (Days 11,12,13, 25,26,27, 39,40,41, 53,54 and 5 5 ) . A d d i t i o n a l l y , the f o o d r e c o r d s were used t o p r o v i d e feedback t o the s u b j e c t s w i t h r e s p e c t t o d i e t a r y c o m p l i a n c e . Food r e c o r d s were chosen as the method t o e v a l u a t e d i e t a r y i n t a k e because d i e t a r y i n f o r m a t i o n was r e q u i r e d f o r s p e c i f i c days. The s u b j e c t s may not have been a b l e t o a c c u r a t e l y r e c a l l t h e i r d i e t a r y i n t a k e i f q u e s t i o n e d r e t r o s p e c t i v e l y . The s u b j e c t s were i n s t r u c t e d t o r e c o r d the type and q u a n t i t y o f a l l f o o d and beverages consumed and the p r e p a r a t i o n methods used. A w r i t t e n example of a meal r e c o r d e d a c c u r a t e l y was p r o v i d e d . The completed foo d r e c o r d s were r e v i e w e d f o r a c c u r a c y and d i e t a r y c o m p l i a n c e a t each appointment. The f o o d r e c o r d s were a n a l y z e d u s i n g the s o f t w a r e PC N u t r i c o m V e r s i o n 5.03 ( D e l t a N u t r i t i o n Systems; Vancouver, B.C.). The r e s u l t s o f the n u t r i t i o n a l a n a l y s e s were r e t u r n e d t o the s u b j e c t s a t the n e x t appointment. I f the a n a l y s e s i n d i c a t e d an i n a d e q u a t e i n t a k e , a handout e n t i t l e d Food Sources of S e l e c t e d N u t r i e n t s was p r o v i d e d and d i s c u s s e d w i t h the s u b j e c t (Appendix F ) . The handout l i s t s t he major foo d s o u r c e s o f each n u t r i e n t . 48 Methods C o n t r o l o f Confounding V a r i a b l e s A v a r i e t y o f m e d i c a t i o n s have been s u s p e c t e d t o c o n t r i b u t e t o u r t i c a r i a and angioedema. A n t i - i n f l a m m a t o r y drugs, such as a c e t y l s a l i c y l i c a c i d , f e n o p r o f e n , i n d o m e t h a c i n , k e t o p r o f e n , mefenamic a c i d , naproxen, acetaminophen, p h e n y l b u t a z o n e , are commonly s u s p e c t e d . A n g i o t e n s i n c o n v e r t i n g enzyme i n h i b i t o r s have a l s o been s u s p e c t e d (Armenaka, 1992; H o l g a t e , 1993). I s o n i a z i d i n g e s t i o n has been shown t o p o t e n t i a t e h i s t a m i n e p o i s o n i n g , and i may be r e l e v a n t i n u r t i c a r i a and angioedema (Uragoda & K o t t e g o d a , 1977). From the l i t e r a t u r e , i t appears t h a t a v a r i e t y o f m e d i c a t i o n s may e x a c e r b a t e u r t i c a r i a and angioedema. T h e r e f o r e , c o n s i s t e n c y o f a l l m e d i c a t i o n s d u r i n g the r e s e a r c h s t u d y was s t r e s s e d . Any changes i n m e d i c a t i o n from b a s e l i n e were documented. Changes i n b a c t e r i a l , v i r a l o r p a r a s i t i c i n f e c t i o n s ; use o f soaps, creams, c o s m e t i c s o r l a u n d r y d e t e r g e n t s ; e n v i r o n m e n t a l a l l e r g e n s and s t r e s s may a f f e c t u r t i c a r i a and angioedema ( B u r r a l l , 1990; Armenaka, 1992). S u b j e c t s were i n s t r u c t e d t o keep t h e s e f a c t o r s c o n s i s t e n t and t o r e c o r d changes i n any o f t h e s e v a r i a b l e s on the assessment s c a l e . 49 Methods S u b j e c t Appointments The s u b j e c t appointments were conducted a t the Vancouver H o s p i t a l and H e a l t h S c i e n c e s C e n t r e , Heather P a v i l i o n o r a t the b u s i n e s s o f f i c e o f the i n v e s t i g a t o r , #9, 106 E a s t 14th S t r e e t , N o r t h Vancouver. E l i g i b l e s u b j e c t s were i n v i t e d t o an i n i t i a l i n t e r v i e w . The s t u d y was f u l l y e x p l a i n e d and the s u b j e c t s were asked t o r e a d and s i g n t h e , c o n s e n t form (Appendix G). S e l f - r e p o r t e d w e i g h t , h e i g h t and f r e q u e n c y o f g a s t r o i n t e s t i n a l d i s t u r b a n c e s , a t o p i c symptoms o r m i g r a i n e headaches were r e c o r d e d . A weight and h e i g h t s c a l e was not a v a i l a b l e a t t h e s t u d y s i t e . Study b o o k l e t s c o n t a i n i n g d a i l y u r t i c a r i a and angioedema assessment s c a l e s and b i - m o n t h l y t h r e e day f o o d r e c o r d forms were g i v e n t o the s u b j e c t s . The f o u r v a r i a b l e s on the u r t i c a r i a and angioedema assessment s c a l e were d i s c u s s e d . P r i o r t o b e g i n n i n g the d i e t a r y i n t e r v e n t i o n , s u b j e c t s r e t u r n e d f o r a f o l l o w - u p appointment. U r t i c a r i a and angioedema assessment s c a l e s and f o o d r e c o r d s were r e v i e w e d . The s u b j e c t s were randomized t o the c o n t r o l o r t r e a t m e n t d i e t . The f i r s t s u b j e c t chose one o f f o u r p i e c e s o f paper. The l e t t e r "o" ( c o n t r o l ) was w r i t t e n on two o f the pa p e r s , and the l e t t e r " r " (treatment) was w r i t t e n on t h e o t h e r two p a p e r s . The second s u b j e c t chose from the t h r e e r e m a i n i n g p i e c e s o f paper. A f t e r 50 Methods f o u r s u b j e c t s had been randomized, the p r o c e d u r e began a g a i n . The s u b j e c t s were i n s t r u c t e d on the a p p r o p r i a t e d i e t . The d i e t s began on Day 0 o f the s t u d y . F o l l o w - u p appointments were conducted e v e r y two weeks. The symptom assessment s c a l e s were r e v i e w e d , and any v a r i a b l e changes o r d i e t a r y problems over the p r e v i o u s two weeks were d i s c u s s e d . The c u r r e n t f o o d r e c o r d s were r e v i e w e d f o r a c c u r a c y and d i e t a r y c o m p l i a n c e . The n u t r i e n t a n a l y s e s o f the p r e v i o u s f o o d r e c o r d s were d i s c u s s e d . A f i n a l appointment was h e l d a f t e r the s t u d y had been completed. S e l f - r e p o r t e d w e i ght changes over the s t u d y were r e c o r d e d . A weight change o f 5% o r more was c o n s i d e r e d s i g n i f i c a n t . Changes i n g a s t r o i n t e s t i n a l d i s t r e s s , a t o p i c symptoms o r m i g r a i n e headaches were r e c o r d e d . S t a t i s t i c a l A n a l y s i s The SPSS f o r Windows R e l e a s e 6.0 (SPSS I n c . , Chicago, I l l i n o i s , 1993) was used t o p e r f o r m the s t a t i s t i c a l a n a l y s i s . The a c c e p t a b l e l e v e l o f s i g n i f i c a n c e was s e t a t p <0.05. Treatment and Control Group Comparisons The age o f the two groups was compared w i t h an independent samples t - t e s t . Gender d i s t r i b u t i o n was a n a l y z e d w i t h a Mann-51 Methods Whitney U t e s t . D u r a t i o n o f d i s e a s e was a n a l y z e d w i t h a W i l c o x o n Signed-Rank t e s t because the d a t a was not n o r m a l l y d i s t r i b u t e d . These v a r i a b l e s a r e compared i n most a n t i h i s t a m i n e c l i n i c a l t r i a l s (Sussman, 1991; B e l a i c h , 1990). U r t i c a r i a and Angioedema Assessment Scale The p l a n n e d time p e r i o d s were: Days -14 t o -1 (time 1 ) , 0 t o 13 (time 2 ) , 14 t o 27 (time 3 ) , 28 t o 41 (time 4) and 42 t o 55 (Time 5) . The t o t a l number o f a n t i h i s t a m i n e t a b l e t s and .wheals were c a l c u l a t e d f o r each time p e r i o d . When the s u b j e c t s e x p r e s s e d the number o f wheals as a range, the l o w e s t number o f wheals was used. For example, >100 was c o n s i d e r e d t o be 100 and 50 - 60 was c o n s i d e r e d t o be 50. The t o t a l i t c h i n e s s and angioedema s e v e r i t y s c o r e s were c a l c u l a t e d . I f d a t a was m i s s i n g on a p a r t i c u l a r day, the average o f t h e o t h e r days i n the time p e r i o d was used as t h e v a l u e f o r t h a t day. The t o t a l number o f days t h a t a n t i h i s t a m i n e t a b l e t s were t a k e n , and the number o f days t h a t wheals, i t c h i n e s s and angioedema symptoms were r e p o r t e d were c a l c u l a t e d f o r each time p e r i o d . The symptom v a r i a b l e s were a n a l y z e d w i t h a 2x2 (group x time) RM ANOVA ( w i t h r e p e t i t i o n on the time f a c t o r ) . The time 1 s c o r e s f o r each v a r i a b l e were compared w i t h an independent samples t - t e s t t o i d e n t i f y s i g n i f i c a n t b a s e l i n e d i f f e r e n c e s between the c o n t r o l and the t r e a t m e n t groups. For v a r i a b l e s w i t h 52 Methods a s i g n i f i c a n t d i f f e r e n c e , the d a t a were a l s o a n a l y z e d w i t h a 2x2 (group x time) RM ANCOVA ( w i t h r e p e t i t i o n on the time f a c t o r ) u s i n g the time 1 v a l u e as the c o v a r i a t e . The symptom d a t a d i d not s a t i s f y t he assumption o f s p h e r i c i t y . T h e r e f o r e , an a d j u s t e d c r i t i c a l F v a l u e was c a l c u l a t e d u s i n g the Huynh-Feldt e p s i l o n . The a d j u s t e d c r i t i c a l F v a l u e was compared t o the F v a l u e c a l c u l a t e d by SPSS t o determine s i g n i f i c a n t e f f e c t s and i n t e r a c t i o n s . The s i g n i f i c a n t time e f f e c t was f o l l o w e d by a comparison o f the combined means f o r each time p e r i o d w i t h a p a i r e d t - t e s t . To account f o r m u l t i p l e comparisons, a p<0.008 was c o n s i d e r e d s i g n i f i c a n t . I n a d d i t i o n t o the RM ANOVA which a s s e s s e d the change i n a n t i h i s t a m i n e i n t a k e over the e n t i r e s t u d y p e r i o d , a p a i r e d samples t - t e s t was used t o compare the number o f a n t i h i s t a m i n e t a b l e t s t a k e n by the t r e a t m e n t group d u r i n g time 1 and time 2. A s e p a r a t e comparison o f the c o n t r o l group was completed. T h i s was done because o f the assumption t h a t i f the t r e a t m e n t d i e t i s e f f e c t i v e , symptoms w i l l improve w i t h i n a few days o f the d i e t a r y i n t e r v e n t i o n . Nutrient Analysis The foo d r e c o r d s were a n a l y z e d f o r k i l o c a l o r i e s , p r o t e i n , c a r b o h y d r a t e , f a t , c a l c i u m , i r o n , magnesium, phosphorus, z i n c and 53 Methods v i t a m i n s A, B l , B2, B3, B6, B12, C and f o l a c i n . The mean and s t a n d a r d d e v i a t i o n f o r b o t h groups a t time 1, time 2, time 3 and time 4 were compared t o the 1990 Recommended N u t r i e n t I n t a k e s (RNI) f o r Canadians ( H e a l t h and W e l f a r e Canada, 1990). For each n u t r i e n t and each group, a w e i g h t e d RNI was c a l c u l a t e d based on the number o f male and female s u b j e c t s i n each group. A mean i n t a k e l e s s than 70% o f t h e w e i g h t e d RNI was c o n s i d e r e d a s i g n i f i c a n t d e f i c i e n c y . The n u t r i e n t d a t a were a n a l y z e d w i t h a 2x2 (group x time) RM ANOVA ( w i t h r e p e t i t i o n on the time f a c t o r ) . The time 1 v a l u e s were compared w i t h an independent samples t -t e s t t o i d e n t i f y s i g n i f i c a n t b a s e l i n e d i f f e r e n c e s between the c o n t r o l and the t r e a t m e n t groups. For n u t r i e n t s w i t h a s i g n i f i c a n t d i f f e r e n c e , the d a t a were a l s o a n a l y z e d w i t h a 2x2 (group x time) RM ANCOVA ( w i t h r e p e t i t i o n on the time f a c t o r ) u s i n g the time 1 v a l u e as the c o v a r i a t e . For the n u t r i e n t s t h a t d i d not s a t i s f y the assumption o f s p h e r i c i t y , an a d j u s t e d c r i t i c a l F v a l u e was c a l c u l a t e d u s i n g the Huynh-Feldt e p s i l o n . S i g n i f i c a n t group x time i n t e r a c t i o n s were f o l l o w e d by a comparison o f the c o n t r o l and t r e a t m e n t groups a t each time w i t h an independent samples t - t e s t s . To account f o r m u l t i p l e comparisons, a p<0.0125 was c o n s i d e r e d s i g n i f i c a n t . The s i g n i f i c a n t time e f f e c t s were f o l l o w e d by comparison o f the combined means a t each time p e r i o d w i t h a p a i r e d t - t e s t . To 54 Methods account f o r m u l t i p l e comparisons, a p<0.008 was c o n s i d e r e d s i g n i f i c a n t . E t h i c a l A p p r o v a l (Appendix H) T h i s s t u d y r e c e i v e d a p p r o v a l from the U n i v e r s i t y o f B r i t i s h Columbia C l i n i c a l S c r e e n i n g Committee f o r R e s e a r c h and Other S t u d i e s i n v o l v i n g Human S u b j e c t s . 55 Results C H A P T E R 4 R E S U L T S URTICARIA AND ANGIOEDEMA ASSESSMENT SCALE PRETEST Ten p r e v i o u s u r t i c a r i a and angioedema p a t i e n t s o f the Vancouver H o s p i t a l A l l e r g y N u t r i t i o n C l i n i c commented on the u r t i c a r i a and angioedema assessment s c a l e . Based on the comments, " p r u r i t u s " was changed t o " i t c h i n e s s " . Three p a t i e n t s were not a b l e t o count t h e i r wheals. T h i s was because t h e r e were too many wheals t o count a c c u r a t e l y o r the wheals tended t o j o i n t o g e t h e r and i t was d i f f i c u l t t o d i f f e r e n t i a t e between a s i n g l e wheal and a group o f wheals. Thus, a space t o i n d i c a t e i f the wheals had been counted o r guessed was i n c l u d e d i n the assessment s c a l e . RECRUITMENT There was no response t o the r e c r u i t m e n t p o s t e r s i n the m e d i c a l o f f i c e s and pharmacies. T h i r t y - e i g h t d e r m a t o l o g i s t s were c o n t a c t e d by t e l e p h o n e and appointments w i t h two d e r m a t o l o g i s t s were o b t a i n e d . I n f o r m a t i o n and r e c r u i t m e n t p o s t e r s were m a i l e d t o s e v e r a l d e r m a t o l o g i s t s . One d e r m a t o l o g i s t r e f e r r e d one p a t i e n t t o the s t u d y . The B r i t i s h Columbia A l l e r g y A s s o c i a t i o n a l l e r g i s t s d i d not s u p p o r t the s t u d y because i t was not s u p e r v i s e d by a 56 Results m e d i c a l d o c t o r . However, one member o f the B r i t i s h Columbia A l l e r g y A s s o c i a t i o n r e f e r r e d t h r e e p a t i e n t s t o the s t u d y . E i g h t y - t h r e e i n d i v i d u a l s i n q u i r e d about the s t u d y (Table 8 ) . The most common re a s o n f o r not e n t e r i n g the s t u d y was d i s t a n c e from the p o t e n t i a l s u b j e c t ' s r e s i d e n c e t o the s t u d y c e n t r e (Appendix I) • Table 8: NUMBER OF SUBJECTS INQUIRING ABOUT STUDY AND ENTERING THE RECRUITMENT EFFORT Total Inquires Subjects Entering Study Newspaper Ad: Jan 21/22 56 12 Newspaper Ad: A p r i l 22/23 7 3 Newspaper Ad: June 10/11 8 1 Referral to ANC 6 3 Pharmacy newsletter 3 1 AAIA r e f e r r a l 2 0 Community Channel Ad 1 0 BCDNA newsletter 0 0 Ad= Advertisement ANC= A l l e r g y N u t r i t i o n C l i n i c AAIA= A l l e r g y Asthma Information Association BCDNA=British Columbia D i e t i t i a n s ' and N u t r i t i o n i s t s ' Association 57 Results SUBJECTS Twenty s u b j e c t s s t a r t e d the s t u d y , but one s u b j e c t withdrew from the s t u d y on a p p r o x i m a t e l y Day 30. The s u b j e c t had not been c o m p l e t i n g the f o o d r e c o r d s c o n s i s t e n t l y , and she l a c k e d m o t i v a t i o n t o c o n t i n u e w i t h the s t u d y . A n o t h e r s u b j e c t withdrew from t h e s t u d y on Day 42, but t h e d a t a were c o n s i d e r e d i n t h e a n a l y s i s . O r i g i n a l l y , the s t u d y had been d e s i g n e d f o r 56 days o f f o l l o w - u p , however, t o r e t a i n t h i s s u b j e c t ' s d a t a the s t u d y was c o n s i d e r e d complete a t 42 days. A l l a n a l y s e s are based on d a t a up t o 42 days even though the remainder o f the s u b j e c t s c o n t i n u e d w i t h the s t u d y u n t i l day 56. Data from 19 s u b j e c t s and f o u r time p e r i o d s (Days -14 t o 41) were used f o r the s t a t i s t i c a l a n a l y s i s . The p r e - d e t e r m i n e d sample s i z e was not a c h i e v e d . There were 10 s u b j e c t s i n the c o n t r o l group and n i n e s u b j e c t s i n the t r e a t m e n t group. There were no s i g n i f i c a n t d i f f e r e n c e s i n age, d u r a t i o n o f d i s e a s e or gender between the two groups (Table 9 ) . Thus, the r e s u l t s from the t r e a t m e n t and c o n t r o l groups w i l l not be d i f f e r e n t i a t e d by gender. 58 Results Table 9: SUBJECT CHARACTERISTICS GROUP Age Gender Duration of (years) Disease (years) Treatment 42±21* 6 female 13 ± 18 <n=9) ' 3 male Control 46+16 8 female 3 ± 6 2 male * mean ± SD No s i g n i f i c a n t differences COMPLIANCE TO STUDY PROTOCOL S i x t e e n out o f 560 u r t i c a r i a and angioedema assessment s c a l e s were not completed i n the c o n t r o l group, and 3 out o f 504 assessment s c a l e s were not completed i n the t r e a t m e n t group (Appendix J ) . Three s u b j e c t s i n the c o n t r o l group d i d not s t a r t t he d i e t i m m e d i a t e l y a f t e r day -1. There were 7, 9 and 26 day d e l a y s between day -1 and day 0 (Appendix K ) . A l l f o o d r e c o r d s were completed. The c o n t r o l group r e p o r t e d d i e t a r y noncompliance on 5 out o f 42 0 days.. The t r e a t m e n t group r e p o r t e d d i e t a r y noncompliance on 11 out o f 378 days (Appendix L) . One s u b j e c t i n the c o n t r o l group e x p e r i e n c e d a weight g a i n o f 8% over her i n i t i a l body w e i g h t . There were no o t h e r weight changes g r e a t e r t h a n 5%. One o f the 10 c o n t r o l s u b j e c t s l o s t w e i g h t , and f i v e o f the n i n e t r e a t m e n t s u b j e c t s l o s t w e i g h t (Appendix M). 59 Results One s u b j e c t i n the c o n t r o l group r e p o r t e d a c o l d w i t h f e v e r on Days 32 - 38. Tylenol®, robitussin® AC cough syr u p and ceclor® were t a k e n throughout t h i s p e r i o d . The s u b j e c t took one a n t i h i s t a m i n e t a b l e t on Days 32 and 33 f o r s n e e z i n g and r h i n i t i s . The i l l n e s s and/or m e d i c a t i o n i n t a k e appeared t o s l i g h t l y e x a c e r b a t e the u r t i c a r i a symptoms d u r i n g t h i s p e r i o d . STATISTICAL ANALYSIS U r t i c a r i a and Angioedema Assessment S c a l e Antihistamine Tablets There was a t r e n d toward a s i g n i f i c a n t d e c r e a s e i n the number o f a n t i h i s t a m i n e t a b l e t s t a k e n over the f o u r time p e r i o d s i n the t r e a t m e n t group compared t o the c o n t r o l group ( s i g n i f i c a n t group x time i n t e r a c t i o n F = 3.46; c a l c u l a t e d F = 3.15) as shown i n T able 10 and 20. There were no s i g n i f i c a n t d i f f e r e n c e s between groups o r time p e r i o d s i n the number o f days t h a t a n t i h i s t a m i n e t a b l e t s were t a k e n as shown i n Table 11 and 20. Table 10: T O T A L N U M B E R O F ANTIHISTAMINE T A B L E T S T A K E N G R O U P lime 1 Time 2 Time 3 Time 4 Treatment 17.5±11.5* 11.5±13.0 11.0±13.0 11.5±14.0 Control 7.5±6.5 7.5±5.0 7.0±6.0 7.5±4.5 * mean ± SD No significant differences (see table 20 for F ratio) 60 Results Table 11: N U M B E R O F DAYS ANTIHISTAMINE T A B L E T S W E R E T A K E N G R O U P Time 1 Time 2 Time 3 Time 4 Treatment 12±3* 9+6 8±7 8±7 Control 7±5 7±5 7±6 6±4 * mean ± SD No significant differences (see table 20 for F ratio) The t r e a t m e n t group took s i g n i f i c a n t l y mor e a n t i h i s t a m i n e t a b l e t s and took a n t i h i s tamine t a b l e t s on more days d u r i n g time 1 than the c o n t r o l group. When time 1 was used as a c o v a r i a t e f o r the RM ANCOVA o f the number o f a n t i h i s t a m i n e t a b l e t s t a k e n and the number o f days t h a t a n t i h i s t a m i n e t a b l e t s were t a k e n , t h e r e were no s i g n i f i c a n t d i f f e r e n c e s between groups. The t r e a t m e n t s u b j e c t s took s i g n i f i c a n t l y fewer a n t i h i s t a m i n e t a b l e t s d u r i n g time 2 tha n time 1 (p=0.02). There were no d i f f e r e n c e s between time 1 and time 2 i n the c o n t r o l group (p=0.81) as shown i n Table 12. 61 Results Table 12: TOTAL NUMBER OF ANTIHISTAMINE TABLETS TAKEN BEFORE THE CONTROL OR TREATMENT DIET (TIME 1) AND AFTER THE INITIATION OF THE DIET (TIME 2) GROUP Total tablets taken Time 1 Time 2 Treatment 17.5±11.5* 11.5±13.0a Control 7.5±6.5 7.5±5.0 * mean ± SD a p<0.05 (Time 1 vs Time 2) No significant differences in the control group Wheals There were no s i g n i f i c a n t d i f f e r e n c e s between groups o r time p e r i o d s i n the t o t a l number o f wheals r e p o r t e d as shown i n Table 13 and 20, and t h e r e were no s i g n i f i c a n t d i f f e r e n c e s between groups o r time p e r i o d s i n the number o f days t h a t wheals were r e p o r t e d as shown i n Table 14 and 20. Table 13: TOTAL NUMBER OF WHEALS REPORTED GROUP Time 1 Time 2 Time 3 Time 4 Treatment 5491839* 225±410 298±602 191±230 Control 382±554 228±345 216±214 162±150 * mean ± SD No significant differences (see table 20 for F ratio) 62 Results Table 14: N U M B E R O F DAYS W H E A L S W E R E R E P O R T E D G R O U P Time 1 Time 2 Time 3 Time 4 Treatment 9±6* 8±7 8±6 9±7 Control 12±4 10±5 10±5 8±5 * mean ± SD No significant differences (see table 20 for F ratio) Itchiness Averaged over group, t h e r e was a s i g n i f i c a n t change over time f o r the s e v e r i t y o f i t c h i n e s s ( s i g n i f i c a n t time e f f e c t F=3.50, c a l c u l a t e d F=4.00); however, the f o l l o w - u p comparisons d i d not d e l i n e a t e d i f f e r e n c e s between the time p e r i o d s as shown i n t a b l e s 15, 16 and 20. O b s e r v a t i o n o f the r e s u l t s i n d i c a t e s t h a t i t c h i n e s s d e c r e a s e d a f t e r time 1. There were no s i g n i f i c a n t d i f f e r e n c e s between groups o r time p e r i o d s i n the number o f days t h a t i t c h i n e s s was r e p o r t e d as shown i n t a b l e 17 and 20. Table 15: T O T A L SEVERITY O F ITCHINESS S C O R E S 1 G R O l P Time 1 Time 2 Time 3 Time 4 Treatment 19±10* 12±9 12±9 13±11 a Control 25±10 21±10 25±10 20±12 * mean ± SD 1 Severity of itchiness scale: 0=symptoms absent; l=symptoms are present, but barely noticeable; 2=symptoms are definitely noticeable, but are tolerable; 3=symptoms are definitely noticeable, and are not tolerable. Over 14 days, a score of 0 would reflect absence of symptoms on all days. A score of 42 would reflect intolerable symptoms on all days. a time effect *p<0.05 (see table 20 for F ratio) (follow-up comparisons did not delineate differences between the time periods) 63 Results Table 16: SEVERITY O F ITCHINESS O F INDIVIDUALS W I T H URTICARIA A N D A N G I O E D E M A Time 1 Time 2 Time 3 Time 4 Severity of Itchiness 22 ± 10* 1 7 ± 10 1 9 ± 11 1 6 ± l l a * mean ± SD 1 Severity of itchiness scale: 0=symptoms absent; l=symptoms are present, but barely noticeable; 2=symptoms are definitely noticeable, but are tolerable; 3=symptoms are definitely noticeable, and are not tolerable. Over 14 days, a score of 0 would reflect absence of symptoms on all days. A score of 42 would reflect intolerable symptoms on all days. a time effect *p<0.05 (see table 20 for F ratio) (follow-up comparisons did not delineate differences between the time periods Table 17: N U M B E R O F DAYS T H A T ITCHINESS WAS R E P O R T E D 1 G R O U P Time 1 Time 2 Time 3 Time 4 Treatment 1 1 ± 5 * 9±5 9±5 9±6 Control 13-2 11±4 12±4 9±5 * mean ± SD 1 Severity of itchiness scale: 0=symptoms absent; l=symptoms are present, but barely noticeable; 2=symptoms are definitely noticeable, but are tolerable; 3=symptoms are definitely noticeable, and are not tolerable. Over 14 days, a score of 0 would reflect absence of symptoms on all days. A score of 42 would reflect intolerable symptoms on all days. No significant differences (see table 20 for F ratio) Angioedema There were no s i g n i f i c a n t d i f f e r e n c e s between groups o r time p e r i o d s i n the s e v e r i t y o f angioedema as shown i n Table 18 and 20. There were no s i g n i f i c a n t d i f f e r e n c e s between groups o r time p e r i o d s i n the number o f days angioedema was r e p o r t e d as shown i n Table 19 and 20. 64 Results Table 18: T O T A L SEVERITY O F A N G I O E D E M A SCORES 1 G R O U P lime 1 Time 2 Time 3 Time 4 Treatment 11±12* 9±11 8±10 10±11 Control 13±13 11±9 13±12 11±12 * mean ± SD 1 Severity of angioedema scale: O=symptoms absent; l=symptoms are present, but barely noticeable; 2=symptoms are definitely noticeable, but are tolerable; 3=symptoms are definitely noticeable, and are not tolerable. Over 14 days, a score of 0 would reflect absence of symptoms on all days. A score of 42 would reflect intolerable symptoms on all days. No significant differences (see table 20 for F ratio) Table 19: N U M B E R O F DAYS T H A T A N G I O E D E M A WAS R E P O R T E D 1 G R O U P Time 1 Time 2 Time 3 Time 4 Treatment 6±6* 6±7 6±6 7±7 Control 6±6 6±5 7±6 5±6 * mean ± SD 1 Severity of angioedema scale: 0=symptoms absent; l=symptoms are present, but barely noticeable; 2=symptoms are definitely noticeable, but are tolerable; 3=symptoms are definitely noticeable, and are not tolerable. Over 14 days, a score of 0 would reflect absence of symptoms on all days. A score of 42 would reflect intolerable symptoms on all days. No significant differences (see table 20 for F ratio). 6 5 Results Table 20: ADJUSTED C R I T I C A L F 1 A N D C A L C U L A T E D F 2 F O R E I G H T URTICARIA A N D A N G I O E D E M A V A R I A B L E S Effect of Time Effect of Group Group x Time Interaction V A R I A B L E : Adjusted Critical F Calculated F Adjusted Critical F Calculated F Adjusted Critical F Calculated F Total antihistamine tablets taken 3.46 2.39 6.55 1.90 3.46 3.15 Number of days antihistamine tablets were taken 3.46 1.14 6.55 1.67 3.46 2.22 Total number of wheals reported 3.59 2.74 7.21 0.13 3.59 0.37 Number of days wheals were reported 3.40 1.80 6.20 0.32 3.40 1.79 Total severity of itchiness 3.50 4.00 6.55 4.65 3.50 1.44 Number of days itchiness was reported 3.40 2.95 6.20 0.82 3.40 1.09 Total se\crity of angioedema 3.59 1.08 6.72 0.24 3.59 0.67 Number of days angioedema was reported 3.46 0.21 6.2 0 3.46 1.13 'Critical F statistic after adjustment with Huynh-Feldt Epsilon for p <0.05 2 Calculated from SPSS 66 Results N u t r i e n t A n a l y s i s Adequacy of Nutrient Intake The n u t r i e n t i n t a k e o f the t r e a t m e n t group d i d not meet the w e i g h t e d RNI f o r : energy d u r i n g time 2, 3 and 4; c a l c i u m d u r i n g time 2, 3 and 4 and z i n c d u r i n g time 2 as shown i n t a b l e s 21 -22. There were no i n t a k e s t h a t were l e s s t h a n 70% o f the w e i g h t e d RNI. The n u t r i e n t i n t a k e o f the c o n t r o l group d i d not meet the w e i g h t e d RNI f o r : energy d u r i n g a l l f o u r time p e r i o d s ; c a l c i u m d u r i n g a l l f o u r time p e r i o d s ; i r o n d u r i n g time 2; magnesium d u r i n g time 2; z i n c d u r i n g time 1, 2 and 4 and f o l a t e d u r i n g time 4 as shown i n t a b l e s 21 - 23. There were no i n t a k e s t h a t were l e s s t h a n 70% o f the w e i g h t e d RNI. S i g n i f i c a n t Changes in Nutrient Intake The t r e a t m e n t group consumed s i g n i f i c a n t l y more c a r b o h y d r a t e t h a n the c o n t r o l group ( s i g n i f i c a n t group e f f e c t F=6.55, c a l c u l a t e d F=8.66) as shown i n t a b l e s 21 and 26. Averaged over group, t h e r e was a s i g n i f i c a n t change over time f o r c a l c i u m (p=0.03) and v i t a m i n C (p=0.04) as shown i n T a b l e s 22, 23 and 25. However, f o l l o w - u p comparisons d i d not d e l i n e a t e d i f f e r e n c e s between time p e r i o d s as shown i n Table 24. O b s e r v a t i o n o f the r e s u l t s i n d i c a t e s t h a t the c a l c i u m i n t a k e d e c r e a s e d a f t e r i n i t i a t i o n o f the d i e t . I n time p e r i o d 4, the c a l c i u m i n t a k e 67 Results i n c r e a s e d , but d i d not r e a c h the b a s e l i n e v a l u e . V i t a m i n C i n t a k e i n c r e a s e d a f t e r i n i t i a t i o n o f the d i e t . I n time p e r i o d 4, the v i t a m i n C i n t a k e d e c r e a s e d s l i g h t l y , b ut was s t i l l above the b a s e l i n e v a l u e . There was a d i f f e r e n t p a t t e r n o f change between groups when c o n s i d e r i n g time f o r f a t , c a l c i u m , v i t a m i n B12 and v i t a m i n C as shown i n T a b l e s 21, 22, 23, 25 and 26 and F i g u r e s 4-7. However, the c o n t r o l and t r e a t m e n t groups were not s i g n i f i c a n t l y d i f f e r e n t a t any time p e r i o d s . O b s e r v a t i o n o f the r e s u l t s i n d i c a t e s t h a t the c o n t r o l group's i n t a k e o f f a t , c a l c i u m and v i t a m i n C was c o n s i s t e n t o ver t i m e . I n the t r e a t m e n t group, f a t i n t a k e d e c r e a s e d a f t e r i n i t i a t i o n o f the' t r e a t m e n t d i e t and remained d e c r e a s e d f o r the remainder o f the s t u d y . The c a l c i u m i n t a k e i n i t i a l l y d e c r e a s e d a f t e r i n i t i a t i o n o f the t r e a t m e n t d i e t and i n c r e a s e d somewhat d u r i n g time 4, but was s t i l l below the b a s e l i n e v a l u e . The v i t a m i n C i n t a k e i n c r e a s e d a f t e r i n i t i a t i o n o f the t r e a t m e n t d i e t and remained i n c r e a s e d f o r the remainder o f the s t u d y . The v i t a m i n B12 i n t a k e i n c r e a s e d a f t e r , i n i t i a t i o n o f the c o n t r o l d i e t and d e c r e a s e d a f t e r i n i t i a t i o n o f the t r e a t m e n t d i e t . The t r e a t m e n t group consumed s i g n i f i c a n t l y more energy and c a r b o h y d r a t e (p<0.05) d u r i n g time p e r i o d 1 t h a n the c o n t r o l group. When time 1 was used as a c o v a r i a t e f o r the RM ANCOVA o f 68 Results k i l o c a l o r i e s and c a r b o h y d r a t e , t h e r e were no d i f f e r e n c e s between groups o r time p e r i o d s . Table 21: MACRONUTRIENT INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES1 NUTRIENT RNI Group Time 1 Time 2 Time 3 Time 4 H i & o c a l o r i e s 2230 Treatment 2310+626* 1738±440 19321383 19281215 2140 Control 16771453 1793±350 17111576 16691636 P r o t e i n 50 Treatment 83127 68125 69122 75118 < grams) •47 Control 78±24 75125 74131 74128 C»rbohy<irate none Treatment 308±108 247159 279148 279178 a (grams} none Control 205±61 2091 50 220172 206174 F a t none Treatment 86±33 58126 60116 63118 c (grams) none Control 61±29 70124 60131 62133 1 For each nutrient and each group, a weighted RNI was calculated based on the number of male and female subjects in each group. * mean ± SD a group effect (treatment vs control) *p<0.05 (see table 26 for F ratios) c group by time interaction *p<0.05 (see table 25 for P values) 69 Results Table 22: MINERAL INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES 1 NUTRIENT RNl Group Time 1 Time 2 Time 3 1 ime 4 Calcium 11 7 3 3 Treatment 955±408* 544±279 545±338 644±174 b - c (milligrams) 720 Control 682±307 687±278 674±317 680±325 Iron 12 Treatment 17±8 13±4 14±6 14±5 (milligrams) 12 Control 12±6 10±2 12±5 12±4 Magnesium 217 Treatment 295±136 265±87 . 291±122 295±63 (milligrams) 210 Control 259±73 207±30 237±67 220±65 Phosphorus 900 Treatment 1420±481 1059±385 1068±466 1218±217 (milligrams) 880 Control 1137±292 1083±226 1170±474 1160±373 Zinc 10 Treatment 10±5 9±4 10±4 10±3 (milligrams) 10 Control 9±3 8±3 10±5 9±3 1 For each nutrient and each group, a weighted RNI was calculated based on the number of male and female subjects in each group. * mean ± SD b time effect *p<0.05 (follow-up comparisons did not delineate differences between the time periods) (see table 25 for P values) c group by time interaction *p<0.01 (see table 25 for P values) 7 0 Results Table 23: VITAMIN INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES1 NUTRIENT RJNJ Group Time 1 Time 2 Time 3 Time 4 Folate 190 Treatment 253±107* 269±87 244±75 283±67 (micrograms) 184 Control 204±115 210±53 307±232 172±70 Niacin 16 Treatment 32±11 30±9 ,32±11 33±10 (NE) 15 Control 29±15 32±13 31±11 31±13 Rihoflai in 1.1 Treatment ' 1.9±0.8 1.5±0.5 1.4±0.5 1.5±0.4 (milligrams) 1.1 Control 1.4±0.5 1.4±0.4 1.4±0.5 1.4±0.6 Thiamin 0.9 Treatment 1.8±1.1 1.4±0.4 1.7±0.9 1.6±0.6 (milligrams) 0.9 Control 1.2±0.8 1.1±0.3 1.1±0.4 1.4±1.2 Vitamin A 867 Treatment 3654±2363 4335±2700 5385±5455 4604±3965 (RE) 840 Control 2451±1586 3590±2433 3859±2772 3459±3620 Vitamin B6 0.8 3 Treatment 1.7±0.8 1.7±0.7 1.9±0.9 2.2±0.7 (milligrams) 0.7 3 Control 1.6±0.7 1.6±0.6 1.6±0.5 1.5±0.6 Vitamin B12 2 Treatment 3.7±2.9 2.7±1.7 2.1±1.7 2.6±1.3-(micrograms) 2 Control 3.0±1.4 . 3.2±0.9 4.6±3.5 3.7±1.5 Vitamin C 37 Treatment 93±54 175±91 147±62 170±94^ (milligrams) 38 Control 105±96 103±85 126±70 90±69 1 For each nutrient and each group, a weighted RNI was calculated based on the number of male and female subjects in each group. 3 Based on a requirement of 0.015mg/gram dietary protein * mean ± SD b time effect *p<0.05 (follow-up comparisons did not delineate differences between the time periods) (see table 25 for P values) c group by time interaction *p<0.05 (see tables 25 and 26 for P values and F ratios) 71 Results Table 24: C A L C I U M AND VITAMIN C I N T A K E O F INDIVIDUALS W I T H URTICARIA AND A N G I O E D E M A NUTRIENT Time 1 Time 2 Time 3 Time 4 Calcium 831=383* 619±280 613±325 663±258 b Vitamin C 99±77 137±93 136±65 128±90 b * mean ± SD b time effect *p<0.05 (follow-up comparisons did not delineate differences between the time periods) Table 25: P AND F V A L U E S F O R NUTRIENTS T H A T SATISFY T H E ASSUMPTION O F SPHERICITY Effect of Time Effect of Group Group x Time Interaction NUTRIENT F value P value F value P value F value P value Protein 1.457 0.266 0.03 0.871 0.6 0.617 Fat 1.31 0.308 0.14 0.711 2.96 0.041 Calcium 3.85 0.032 0 0.99 4.59 0.006 Phosphorus 1.943 0.166 0.18 0.676 1.5 0.226 Rihofla\ in 1.877 0.177 1.16 0.296 1.63 0.195 Vitamin C 3.59 0.039 1.74 0.205 3.78 0.016 Vitamin A 0.964 0.435 1.05 0.321 ' 0.08 0.972 Vitamin B6 0.995 0.422 2.05 0.171 2.11 0.11 Zinc 0.853 0.487 0.47 0.5 0.19 0.903 72 Results Table 26: ADJUSTED C R I T I C A L F 1 A N D C A L C U L A T E D F 2 F O R E I G H T NUTRIENTS T H A T DH) N O T SATISFY T H E ASSUMPTION O F SPHERICITY Effect of Time Effect of Croup Group \ Time Interaction NUTRIENT Adjusted Critical F Calculated F Adjusted Critical F Calculated F Adjusted Critical F Calculated F Kilocalories 3.52 1.89 6.55 2.67 3.52 2.63 Carbohydrate 3.52 2.3 6.55 8.66 3.52 1.08 Folate 3.46 0.95 6.55 1.34 3.46 2.4 Iron 3.72 2.31 7.21 3.7 3.72 0.33 Magnesium 3.46 1.61 6.55 5.18 3.46 0.21 Niacin 3.46 0.17 6.2 0.04 3.46 0.55 Thiamin 3.46 0.87 6.2 3.45 3.46 0.38 Vitamin 12 3.46 0.08 6.2 1.45 3.46 3.83 1 Critical F statistic after adjustment with Huynh-Feldt Epsilon for p<0.05 2 Calculated by SPSS 73 Results Figure 4: GROUP X TIME INTERACTION Fat 100 An ou 60 _ _ 40 fl u Time 1 Time 2 Time 3 Time 4 Time Periods Legend — — — Treatment ——— • Control Figure 5: GROUP X TIME INTERACTION Calcium 1000 Time 1 Time 2 Time 3 Time Periods Time 4 Legend » Control 74 Results Figure 6: GROUP X TIME INTERACTION Vitamin B12 Time 1 Time 2 Time 3 Time 4 Time Periods Legend Treatment Control Figure 7: GROUP X TIME INTERACTION Vitamin C 200-i 1 1 1 1 1 oH 1 1 1 1 1 1 Time 1 Time 2 Time 3 Time 4 Time Periods Legend - Control 75 Results CASE ANALYSIS OF TREATMENT GROUP SUBJECTS WITH IMPROVEMENT IN SYMPTOMS S u b j e c t 11 (Table 27) e n t e r e d the s t u d y w i t h an 8 month h i s t o r y o f u r t i c a r i a and f a c i a l angioedema. The wheals and angioedema were c o n t r o l l e d by a n t i h i s t a m i n e m e d i c a t i o n and t o p i c a l c o r t i c o s t e r o i d . P r u r i t u s was the o n l y symptom r e m a i n i n g when the s u b j e c t e n t e r e d the s t u d y . The s u b j e c t had r e l i e f from p r u r i t u s on day 1 o f the t r e a t m e n t d i e t . M i l d p r u r i t u s was r e p o r t e d from day 9 t o the end o f the s t u d y . T h i r t e e n a n t i h i s t a m i n e t a b l e t s were t a k e n i n time 1, and two t a b l e t s were t a k e n i n time 2, 3 and 4. A d d i t i o n a l l y , t he s u b j e c t d i s c o n t i n u e d the-use o f a t o p i c a l c o r t i c o s t e r o i d on Day 0. The s u b j e c t had a l o n g h i s t o r y o f r h i n i t i s w hich improved on the h i s t a m i n e - r e d u c i n g d i e t . A t the end o f the stu d y , the s u b j e c t wrote, " v e r y i n t e r e s t i n g and s a t i s f a c t o r y r e s u l t s . " S u b j e c t 13 ( t a b l e 29) e n t e r e d the s t u d y w i t h a 20 year h i s t o r y o f u r t i c a r i a and o c c a s i o n a l f a c i a l angioedema. The symptoms began a t 6 y e a r s o f age and were i n r e m i s s i o n between 15 and 21 ye a r s o f age. The angioedema, wheals and i t c h i n g d i s a p p e a r e d on Day 4 o f the t r e a t m e n t d i e t . The symptoms were r e p o r t e d on Day 14, but o n l y l a s t e d a few hou r s . A n t i h i s t a m i n e t a b l e t s were d i s c o n t i n u e d on Day 4. On Day 2 the s u b j e c t wrote " I have much more energy - f e e l g r e a t " . The s u b j e c t had a l o n g h i s t o r y o f r h i n i t i s , b l o a t i n g and gas and m i g r a i n e headache w h i c h 76 Results improved on the h i s t a m i n e - r e d u c i n g d i e t . S u b j e c t 17 ( t a b l e 30). e n t e r e d the s t u d y w i t h a f i v e year h i s t o r y o f u r t i c a r i a w i t h o u t angioedema. A p a r t i a l r e d u c t i o n i n the number of a n t i h i s t a m i n e t a b l e t s , wheals and s e v e r i t y o f p r u r i t u s o c c u r r e d on Day 1 o f the h i s t a m i n e - r e d u c i n g d i e t . The number o f days t h a t symptoms o c c u r r e d and a n t i h i s t a m i n e t a b l e t s were t a k e n d i d not change, but the s e v e r i t y o f symptoms and the number o f a n t i h i s t a m i n e t a b l e t s t a k e n d e c r e a s e d . The s u b j e c t i n d i c a t e d t h a t she f e l t i n b e t t e r h e a l t h o v e r a l l on the h i s t a m i n e - r e d u c i n g d i e t . The s u b j e c t had a h i s t o r y o f gas, abdominal b l o a t i n g and c o n s t i p a t i o n . These symptoms improved on the h i s t a m i n e - r e d u c i n g d i e t . S u b j e c t 12 ( t a b l e 28) e n t e r e d the s t u d y w i t h a f i v e year h i s t o r y o f u r t i c a r i a and f a c i a l and body angioedema. The number o f wheals and the s e v e r i t y o f p r u r i t u s and angioedema appeared t o remain s t a b l e t hroughout the s t u d y , but the number o f a n t i h i s t a m i n e t a b l e t s t a k e n d e c r e a s e d . T h i r t e e n a n t i h i s t a m i n e t a b l e t s were t a k e n d u r i n g time 1, and f o u r t a b l e t s were t a k e n d u r i n g time 2, 3 and 4. 77 TS 7<? Discussion Chapter 5 DISCUSSION MAJOR FINDINGS The s t u d y was conducted t o e v a l u a t e the e f f e c t o f a h i s t a m i n e - r e d u c i n g d i e t i n c h r o n i c u r t i c a r i a and angioedema,.and t o e v a l u a t e the e f f e c t o f the d i e t on n u t r i e n t i n t a k e . The major f i n d i n g s were as f o l l o w s : A h i s t a m i n e - r e d u c i n g d i e t d i d not improve c h r o n i c u r t i c a r i a and angioedema. There were no d i f f e r e n c e s between groups over time i n the number o f a n t i h i s t a m i n e t a b l e t s t a k e n , the number of wheals, the s e v e r i t y o f u r t i c a r i a and angioedema, the number of days t h a t a n t i h i s t a m i n e t a b l e t s were t a k e n o r the number o f days wheals, p r u r i t u s o r angioedema were r e p o r t e d . However, the t r e a t m e n t group took s i g n i f i c a n t l y more a n t i h i s t a m i n e t a b l e t s d u r i n g the two weeks p r i o r t o the t r e a t m e n t d i e t t h a n d u r i n g the two weeks a f t e r the i n i t i a t i o n o f the t r e a t m e n t d i e t . Adherence t o the h i s t a m i n e - r e d u c i n g d i e t r e s u l t e d i n a d e c r e a s e d i n t a k e o f f a t , c a l c i u m and v i t a m i n B12 and an i n c r e a s e d i n t a k e o f v i t a m i n C. The t r e a t m e n t group met the w e i g h t e d RNI f o r energy and c a l c i u m d u r i n g time p e r i o d 1, but f a i l e d t o meet the recommendations f o r t h e s e n u t r i e n t s d u r i n g time p e r i o d s 2, 3 and 4. 80 Discussion The f o l l o w - u p comparisons f o r the s i g n i f i c a n t time e f f e c t s and group x time i n t e r a c t i o n s were not s i g n i f i c a n t . T h i s may have been due t o the s t r i c t a l e v e l s used f o r m u l t i p l e comparisons and the s m a l l sample s i z e . COMPARISON TO CLINICAL FINDINGS The h i s t a m i n e - r e d u c i n g d i e t has been used i n p a t i e n t c o u n s e l l i n g a t the A l l e r g y N u t r i t i o n C l i n i c a t the Vancouver H o s p i t a l and H e a l t h S c i e n c e s C e n t r e s i n c e October 1991. As o f January 1994, 16 p a t i e n t s w i t h u r t i c a r i a , angioedema o r p r u r i t u s have been i n s t r u c t e d t o f o l l o w the h i s t a m i n e - r e d u c i n g d i e t . The e f f e c t o f d i e t a r y i n t e r v e n t i o n on the d i s e a s e symptoms was e v a l u a t e d t h r o u g h f o l l o w - u p i n t e r v i e w n o t e s i n the p a t i e n t s ' c l i n i c a l c h a r t s . I f a f o l l o w - u p appointment was not h e l d , the i n v e s t i g a t o r c o n t a c t e d the p a t i e n t by t e l e p h o n e . Three p a t i e n t s c o u l d not be reached, and one p a t i e n t changed m e d i c a t i o n and d i e t a t the same t i m e . Four (33%) p a t i e n t s had a complete o r p a r t i a l r e m i s s i o n o f symptoms on the h i s t a m i n e - r e d u c i n g d i e t . The d i e t d i d not improve symptoms i n e i g h t (67%) p a t i e n t s . Of the n i n e t r e a t m e n t s u b j e c t s i n the p r e s e n t s t u d y , one (11%) s u b j e c t had complete r e m i s s i o n o f symptoms and d i s c o n t i n u e d a n t i h i s t a m i n e m e d i c a t i o n . One s u b j e c t (11%) had a de c r e a s e i n i t c h i n g (the o n l y symptom p r e s e n t d u r i n g time 1) and d i s c o n t i n u e d a n t i h i s t a m i n e m e d i c a t i o n and t o p i c a l c o r t i c o s t e r o i d . A n o t h e r 2 (22%) s u b j e c t s had p a r t i a l r e m i s s i o n o f symptoms and a r e d u c t i o n 81 Discussion i n a n t i h i s t a m i n e m e d i c a t i o n i n t a k e , and the r e m a i n i n g f i v e s u b j e c t s d i d not b e n e f i t from the h i s t a m i n e - r e d u c i n g d i e t . The c l i n i c a l f i n d i n g s from the A l l e r g y N u t r i t i o n C l i n i c a re s i m i l a r t o the t r e a t m e n t group f i n d i n g from the p r e s e n t s t u d y (33% v e r s u s 44% complete o r p a r t i a l r e m i s s i o n o f symptoms, r e s p e c t i v e l y ) . COMPARISON TO OTHER STUDIES The p r e s e n t s t u d y i s the o n l y d i e t a r y m a n i p u l a t i o n s t u d y i n c h r o n i c u r t i c a r i a and angioedema w i t h s t a t i s t i c a l a n a l y s e s o f a c o n t r o l and t r e a t m e n t d i e t . S e v e r a l s t u d i e s have e v a l u a t e d the e f f e c t o f f o o d - a d d i t i v e f r e e d i e t s i n open d e s i g n s . The r e s u l t s from the t r e a t m e n t group (n=9) w i l l be compared t o t h e s e s t u d i e s . The e f f e c t o f a f o o d - a d d i t i v e f r e e and l o w - t y r a m i n e d i e t i n . c h r o n i c u r t i c a r i a was e v a l u a t e d by V e r s c h a v e e t a l . (1983) . The d i e t e l i m i n a t e d f o o d a d d i t i v e s , a l c o h o l , stone f r u i t , oranges, n u t s , s t r a w b e r r i e s , tomatoes, peas, beans, s h e l l f i s h , bananas, p i n e a p p l e and o l d and fermented cheese. T h i s d i e t was s i m i l a r t o the h i s t a m i n e - r e d u c i n g d i e t . F i f t y - f i v e p e r c e n t (37/67) of the s u b j e c t s had complete o r p a r t i a l r e m i s s i o n o f symptoms w h i l e f o l l o w i n g the l o w - t y r a m i n e d i e t . These f i n d i n g s are s i m i l a r t o the 44% complete o r p a r t i a l r e m i s s i o n o f symptoms on the h i s t a m i n e - r e d u c i n g d i e t . The l e n g t h o f the d i e t o r the method and t i m i n g o f symptom e v a l u a t i o n were not d e s c r i b e d . T h i s b r i n g s the 82 Discussion r e s u l t s o f the lo w - t y r a m i n e d i e t i n t o q u e s t i o n , and impedes d e t a i l e d comparison between the two s t u d i e s . S e v e r a l f o o d - a d d i t i v e f r e e d i e t s have r e p o r t e d a range o f 32 to 90 % complete o r p a r t i a l r e m i s s i o n o f u r t i c a r i a symptoms (Table 5 ) . S i x o f the seven s t u d i e s r e v i e w e d , had 60% o r g r e a t e r complete o r p a r t i a l r e m i s s i o n o f symptoms. However, t h e s e s t u d i e s have s e v e r a l l i m i t a t i o n s . The method o f symptom assessment and l e n g t h o f the d i e t was not d e s c r i b e d . The time between the i n i t i a l and the f i n a l e v a l u a t i o n o f symptoms ranged from 6 months to 2 y e a r s . The l a r g e number o f s u b j e c t s f r e e from symptoms were l i k e l y due t o p l a c e b o e f f e c t and n a t u r a l r e m i s s i o n o f symptoms. However, the b e n e f i c i a l e f f e c t s may have been p a r t i a l l y due t o the t r e a t m e n t d i e t . Comparison between the f i n d i n g s from the p r e s e n t s t u d y and the f o o d - a d d i t i v e f r e e s t u d i e s i s d i f f i c u l t due t o the n o n s p e c i f i c methods and the s m a l l sample s i z e o f the p r e s e n t s t u d y . The h i g h e r p e r c e n t a g e s o f s u b j e c t s w i t h complete o r p a r t i a l r e m i s s i o n o f symptoms on the f o o d - a d d i t i v e f r e e d i e t s may have r e s u l t e d from the l o n g p e r i o d s o f time between i n i t i a l and f i n a l symptom assessment and p l a c e b o e f f e c t . TREATMENT GROUP SUBJECTS WITH IMPROVEMENT IN SYMPTOMS Four s u b j e c t s on the t r e a t m e n t d i e t (n=9) had an improvement i n u r t i c a r i a and angioedema symptoms (Tables 27-30). There were no f e a t u r e s which d i s t i n g u i s h e d the s u b j e c t s who improved on the 83 Discussion t r e a t m e n t d i e t from the s u b j e c t s who d i d not improve. A l a r g e r sample s i z e and d e t a i l e d c l i n i c a l e v a l u a t i o n by a d e r m a t o l o g i s t may have i d e n t i f i e d f e a t u r e s which d i s t i n g u i s h e d the two groups. S u b j e c t 11, 12 and 13 were c o n t a c t e d by t e l e p h o n e f i v e months a f t e r f i n i s h i n g the s t u d y . S u b j e c t 11 was f o l l o w i n g the t r e a t m e n t d i e t , and h i s symptoms were c o n t r o l l e d . S u b j e c t 12 was not f o l l o w i n g the treatment' d i e t because her symptoms had improved. S u b j e c t 13 was f o l l o w i n g the t r e a t m e n t d i e t , and her symptoms were c o n t r o l l e d . S u b j e c t 17 was c o n t a c t e d by t e l e p h o n e two months a f t e r f i n i s h i n g the s t u d y . She was not f o l l o w i n g the t r e a t m e n t d i e t because she d i d not have time t o p r e p a r e f o o d w i t h o u t p r e s e r v a t i v e s and found i t d i f f i c u l t t o e l i m i n a t e cheese arid tomatoes from her d i e t . The u r t i c a r i a and angioedema symptoms became worse when the t r e a t m e n t d i e t was d i s c o n t i n u e d . She took one h a l f o f an a n t i h i s t a m i n e t a b l e t p e r day when she was a d h e r i n g t o the h i s t a m i n e - r e d u c i n g d i e t . The s u b j e c t i n c r e a s e d her i n t a k e t o one t a b l e t p e r day a f t e r the d i e t was d i s c o n t i n u e d . TREATMENT GROUP SUBJECTS WITHOUT IMPROVEMENT IN SYMPTOMS Many f a c t o r s have been i d e n t i f i e d i n the p a t h o g e n e s i s o f c h r o n i c u r t i c a r i a and angioedema. D i e t may be the p r i m a r y cause o r a c o n t r i b u t i n g f a c t o r i n some i n d i v i d u a l s . The t r e a t m e n t d i e t i s based on the t h e o r y t h a t some i n d i v i d u a l s w i t h c h r o n i c 8 4 Discussion u r t i c a r i a and angioedema have reduced diamine o x i d a s e a c t i v i t y (DAO) i n the i n t e s t i n a l mucosa ( L e s s o f e t a l . , 1990). Plasma h i s t a m i n e and u r t i c a r i a symptoms may i n c r e a s e a f t e r consumption o f h i s t a m i n e r i c h f o o d s . A d d i t i o n a l l y , f o o d a d d i t i v e s may i n c r e a s e endogenous r e l e a s e o f h i s t a m i n e i n some i n d i v i d u a l s . The p o s t - h e p a r i n plasma DAO cur v e was d e c r e a s e d i n a sample o f n i n e s u b j e c t s w i t h u r t i c a r i a , i n d i c a t i n g an o v e r a l l d e c r e a s e i n i n t e s t i n a l mucosa DAO a c t i v i t y ( L e s s o f e t a l . , 1990). However, t h e r e was a l a r g e v a r i a t i o n among i n d i v i d u a l s . Two s u b j e c t s had a m i n i m a l DAO response, t h r e e s u b j e c t s had a 'low normal response, t h r e e s u b j e c t s had a normal response and one s u b j e c t had an above normal r e s p o n s e . I n t r a d u o d e n a l a d m i n i s t r a t i o n o f h i s t a m i n e d i d not a l t e r plasma h i s t a m i n e i n e i g h t c o n t r o l s u b j e c t s , and t h e r e was l i t t l e v a r i a t i o n i n plasma h i s t a m i n e w i t h i n the sample. The u r t i c a r i a group (n=25) had a s i g n i f i c a n t r i s e i n plasma h i s t a m i n e a f t e r i n t r a d u o d e n a l h i s t a m i n e a d m i n i s t r a t i o n . Moreover, t h e r e was a l a r g e v a r i a t i o n i n the plasma h i s t a m i n e l e v e l s . Based on t h e s e o b s e r v a t i o n s , the e f f e c t o f d i e t a r y h i s t a m i n e on u r t i c a r i a and angioedema would be e x p e c t e d t o d i f f e r among i n d i v i d u a l s . Plasma and u r i n a r y h i s t a m i n e i n c r e a s e i n some s u b j e c t s a f t e r o r a l a d m i n i s t r a t i o n o f f o o d a d d i t i v e s . Three s u b j e c t s who were asymptomatic on an a d d i t i v e - f r e e d i e t and had an e x a c e r b a t i o n o f u r t i c a r i a a f t e r a d o u b l e - b l i n d f o o d a d d i t i v e c h a l l e n g e were 85 Discussion e n r o l l e d i n a s t u d y t o measure b i o c h e m i c a l changes d u r i n g f o o d a d d i t i v e c h a l l e n g e . Plasma h i s t a m i n e and u r t i c a r i a symptoms i n c r e a s e d i n two o f the t h r e e s u b j e c t s . However, the s u b j e c t s ' r e sponses t o the c h a l l e n g e s d i f f e r e d d r a m a t i c a l l y . The a c t i v i t y o f DAO and the endogenous r e l e a s e o f h i s t a m i n e a f t e r f o o d a d d i t i v e consumption v a r i e s between i n d i v i d u a l s . As a r e s u l t , d i e t a r y m a n i p u l a t i o n w i l l not b e n e f i t a l l s u b j e c t s w i t h u r t i c a r i a and angioedema. NUTRITIONAL ADEQUACY OF THE HISTAMINE-REDUCING DIET Adherence t o the t r e a t m e n t d i e t was i n i t i a l l y d i f f i c u l t as the s u b j e c t s had t o change t h e i r e a t i n g p a t t e r n s i n o r d e r t o a b i d e by the d i e t a r y r e s t r i c t i o n s . The s u b j e c t s became accustomed t o the d i e t a r y r e s t r i c t i o n s and e s t a b l i s h e d new e a t i n g p a t t e r n s d u r i n g time 3 and 4. T h i s t r e n d c o n c u r s w i t h the o b s e r v a t i o n t h a t the n u t r i e n t i n t a k e s tended t o d e c r e a s e i n the t r e a t m e n t group d u r i n g time 2 but s u b s e q u e n t l y i n c r e a s e d d u r i n g time 3 and 4. F i v e o f the n i n e t r e a t m e n t s u b j e c t s had a m a r g i n a l w e i ght l o s s w h i l e o n l y one c o n t r o l s u b j e c t l o s t w e i g h t . F l u i d l o s s has been o b s e r v e d t o o c c u r when the h i s t a m i n e - r e d u c i n g d i e t i s f i r s t i n i t i a t e d ( p e r s o n a l c o r r espondence, Dr. J a n i c e J o n e j a ) . However, the w e i ght l o s s i n the t r e a t m e n t group was l i k e l y due t o an ' o energy r e s t r i c t i o n because s u b j e c t s appeared t o l o s e weight 86 Discussion g r a d u a l l y o ver the s t u d y r a t h e r than i m m e d i a t e l y p r e c e d i n g the i n i t i a t i o n o f the d i e t . The energy i n t a k e met the w e i g h t e d RNI o f the t r e a t m e n t group d u r i n g time 1, but f a i l e d t o do so d u r i n g time 2, 3 and 4. The energy i n t a k e o f the t r e a t m e n t group i n time p e r i o d 2 was 75% o f the energy i n t a k e i n time p e r i o d 1. A p p r o x i m a t e l y 45% o f t h i s d e c r e a s e was due t o a r e d u c t i o n i n f a t , 45% due t o a r e d u c t i o n i n c a r b o h y d r a t e and 10% due t o a r e d u c t i o n i n p r o t e i n . The energy i n t a k e i n c r e a s e d i n time p e r i o d s 3 and 4. For the e i g h t s u b j e c t s i n the t r e a t m e n t group who completed the e n t i r e 56 days o f the stu d y , the mean energy i n t a k e was 2150 k i l o c a l o r i e s / d a y (data not shown), which was s l i g h t l y l e s s t h a n the w e i g h t e d RNI (2230 k i l o c a l o r i e s / d a y ) f o r the t r e a t m e n t group. The d e c r e a s e d c a l o r i c i n t a k e was l i k e l y a temporary a d a p t a t i o n t o the d i e t a r y r e s t r i c t i o n s and d i d not appear t o put the t r e a t m e n t s u b j e c t s a t n u t r i t i o n a l r i s k . The c a l c i u m i n t a k e o f the t r e a t m e n t group met the w e i g h t e d RNI d u r i n g time p e r i o d 1, but f a i l e d t o do so d u r i n g time p e r i o d s 2, 3 and 4. For the e i g h t s u b j e c t s i n the t r e a t m e n t group who completed the e n t i r e 56 days o f the stu d y , the mean c a l c i u m i n t a k e was 731 mg/day (data not shown), which was s l i g h t l y l e s s t h a n the w e i g h t e d RNI (733 mg/day) f o r the t r e a t m e n t group. The d e c r e a s e d c a l c i u m i n t a k e was l i k e l y a temporary a d a p t a t i o n t o the 87 Discussion d i e t a r y r e s t r i c t i o n s and d i d not appear t o put the t r e a t m e n t s u b j e c t s a t n u t r i t i o n a l r i s k . There were no o t h e r n u t r i e n t i n t a k e s t h a t met the w e i g h t e d RNI of the t r e a t m e n t group d u r i n g time p e r i o d 1, but f a i l e d t o do so d u r i n g time 2, 3 and 4. The h i s t a m i n e - r e d u c i n g d i e t d i d not s i g n i f i c a n t l y l i m i t any n u t r i e n t s , and an adequate n u t r i e n t i n t a k e was a c h i e v e d w h i l e f o l l o w i n g the d i e t . N u t r i t i o n a l d e f i c i e n c y i s p o s s i b l e e s p e c i a l l y d u r i n g the i n i t i a l a d a p t a t i o n t o the d i e t ; t h e r e f o r e , d i e t a r y f o l l o w - u p and c o u n s e l l i n g i s an e s s e n t i a l component of d i e t a r y i n t e r v e n t i o n . The p o t e n t i a l b e n e f i t s o f the h i s t a m i n e - r e d u c i n g d i e t outweigh the p o s s i b i l i t y o f n u t r i t i o n a l d e f i c i e n c i e s . LIMITATIONS OF THE STUDY The l i m i t a t i o n s t o the s t u d y were the s m a l l sample s i z e , l a r g e w i t h i n - and b e t w e e n - s u b j e c t v a r i a t i o n , group d i f f e r e n c e s , l a c k o f a s t a n d a r d i z e d method t o a s s e s s u r t i c a r i a and angioedema, l a c k o f a b i o c h e m i c a l marker f o r plasma h i s t a m i n e , p o t e n t i a l f o r p l a c e b o e f f e c t and p o t e n t i a l f o r b i a s due t o a s i n g l e - b l i n d d e s i g n . P r i o r t o i n i t i a t i o n o f the s t u d y , a sample s i z e o f 34 s u b j e c t s was e s t i m a t e d t o be n e c e s s a r y f o r s t a t i s t i c a l s i g n i f i c a n c e . Due t o d i f f i c u l t y w i t h s u b j e c t r e c r u i t m e n t , d a t a 88 Discussion from 19 s u b j e c t s were used i n the s t a t i s t i c a l a n a l y s i s . S i g n i f i c a n t f i n d i n g s would not be a n t i c i p a t e d based on the s m a l l sample s i z e . The symptom d a t a f a i l e d the assumption o f s p h e r i c i t y i n d i c a t i n g t h a t t h e r e was a l o t o f v a r i a t i o n i n the d a t a . T h i s d e c r e a s e d the power of the s t u d y . The t r e a t m e n t group took s i g n i f i c a n t l y more a n t i h i s t a m i n e t a b l e t s and consumed more energy d u r i n g time 1 t h a n the c o n t r o l group. Even though not s t a t i s t i c a l l y s i g n i f i c a n t , the t r e a t m e n t group appeared t o have more wheals d u r i n g time 1 and e n t e r e d the s t u d y w i t h a l o n g e r d u r a t i o n o f d i s e a s e than the c o n t r o l group. The c o n t r o l and t r e a t m e n t groups may not have been comparable. I n the absence of a s t a n d a r d i z e d method t o a s s e s s the s e v e r i t y o f u r t i c a r i a and angioedema, an assessment s c a l e was d e v e l o p e d based on v a r i a b l e s t h a t were commonly e v a l u a t e d i n a n t i h i s t a m i n e m e d i c a t i o n c l i n i c a l t r i a l s . A n t i h i s t a m i n e m e d i c a t i o n i n t a k e was the most r e l i a b l e i n d i c a t o r because i t was an o b j e c t i v e v a r i a b l e and was congruent w i t h the r a t i o n a l e f o r the t r e a t m e n t d i e t . A n t i h i s t a m i n e m e d i c a t i o n i n t a k e was an i m p o r t a n t i n d i c a t o r f o r the s t u d y because the need t o t a k e t h i s m e d i c a t i o n l i k e l y r e f l e c t s i n c r e a s e d body h i s t a m i n e . However, t h e r e were c i r c u m s t a n c e s i n which a l t e r a t i o n o f a n t i h i s t a m i n e m e d i c a t i o n d i d 89 Discussion not r e f l e c t changes i n u r t i c a r i a and angioedema symptoms. A n t i h i s t a m i n e m e d i c a t i o n was a l s o t a k e n d u r i n g the s t u d y t o c o n t r o l r h i n i t i s . Some s u b j e c t s took a n t i h i s t a m i n e m e d i c a t i o n even though i t d i d not n o t i c e a b l y improve t h e i r symptoms. The a n t i h i s t a m i n e m e d i c a t i o n i n t a k e was v a r i a b l e i n t h e s e s u b j e c t s . The e f f e c t i v e n e s s o f a n t i h i s t a m i n e m e d i c a t i o n s may d e c r e a s e • w i t h use, and the i n d i v i d u a l may need t o change the type o f a n t i h i s t a m i n e o r i n c r e a s e the dose t o c o n t r o l symptoms. The s e v e r i t y o f p r u r i t u s was an i m p o r t a n t i n d i c a t o r f o r the st u d y because h i s t a m i n e i s s o l e l y r e s p o n s i b l e f o r p r u r i t u s . However, i t was a s u b j e c t i v e v a r i a b l e and t h i s d e c r e a s e d i t s r e l i a b i l i t y . H i s t a m i n e i s one o f many i n f l a m m a t o r y m e d i a t o r s t h a t produce wheals. The number o f wheals may not be a good i n d i c a t o r o f body h i s t a m i n e , and t h e r e f o r e , may not be a good i n d i c a t o r o f the e f f e c t i v e n e s s o f a h i s t a m i n e - r e d u c i n g d i e t . C o u n t i n g the number of wheals was d i f f i c u l t f o r most s u b j e c t s . The number o f wheals was a p p l i c a b l e t o 16 s u b j e c t s , and 11 s u b j e c t s guessed the number of wheals a t c e r t a i n t i m e s . The reasons g i v e n f o r g u e s s i n g were, t h a t t h e r e were too many wheals t o count, wheals were on body p a r t s t h a t c o u l d not be seen, and wheals were d i f f i c u l t t o d i s t i n g u i s h e s p e c i a l l y i f t h e y tended t o c o a l e s c e . The number o f wheals was a q u e s t i o n a b l e v a r i a b l e f o r use i n t h i s s t u d y . 9 0 Discussion H i s t a m i n e i s one o f many i n f l a m m a t o r y m e d i a t o r s t h a t produce angioedema. The s e v e r i t y r a t i n g o f t h i s v a r i a b l e was s u b j e c t i v e , and t h e r e f o r e , not r e l i a b l e . The s e v e r i t y o f angioedema was a q u e s t i o n a b l e v a r i a b l e f o r use i n t h i s s t u d y . A l t h o u g h the l a t t e r t h r e e measures are s u b j e c t i v e , c o n s i s t e n c y o f symptom assessment was s t r e s s e d t h r o u g h o u t the st u d y . T h e r e f o r e , the w i t h i n - s u b j e c t v a r i a t i o n s h o u l d have been m i n i m i z e d . S i g n i f i c a n t changes over time would have been d e t e c t e d . The a b i l i t y t o measure plasma h i s t a m i n e would have added an i m p o r t a n t v a r i a b l e i n t h i s s t u d y . S e v e r a l t e c h n i q u e s t o measure b l o o d h i s t a m i n e have been d e v e l o p e d . These i n c l u d e gas c h r o m a t o g r a p h i c - m a s s - s p e c t r o m e t r i c t e c h n i q u e , s i n g l e i s o t o p e assay, f l u o r o m e t r i c - f l u o r o e n z y m e assay, radioimmunoassay and h i g h performance l i q u i d chromatography. I n a European e x t e r n a l q u a l i t y c o n t r o l s t u d y , seven out o f t e n l a b o r a t o r i e s measuring samples w i t h known b l o o d h i s t a m i n e l e v e l s were a c c u r a t e and p r e c i s e . I n a c c u r a t e r e s u l t s were due t o human e r r o r r a t h e r than the method (Neugebauer e t a l . , 1990). D e s p i t e r e a s o n a b l e a c c u r a c y o f d e t e r m i n a t i o n , p r a c t i c a l a p p l i c a t i o n o f t h e s e methods may be l i m i t e d . Frequent f l u c t u a t i o n s i n plasma h i s t a m i n e make the i n t e r p r e t a t i o n o f plasma h i s t a m i n e l e v e l s d i f f i c u l t (Keyzer e t a l . , 1 9 8 4 ) . H i s t a m i n e has f i v e u r i n a r y m e t a b o l i t e s , o f which N-91 Discussion m e t h y l h i s t a m i n e and N - m e t h y l i m i d a z o l e a c e t i c a c i d are unique m e t a b o l i t e s . L e v e l s o f N - m e t h y l i m i d a z o l e a c e t i c a c i d are g r e a t l y i n f l u e n c e d by the amount of h i s t a m i n e i n the d i e t (Keyzer e t a l . , 1 9 8 4 ) . Measurement o f t h i s m e t a b o l i t e has not been c l e a r l y d e f i n e d t o make i t a v a l i d c l i n i c a l t e s t . F u r t h e r r e s e a r c h i s r e q u i r e d t o f i n d a v a l i d and r e l i a b l e marker f o r b l o o d h i s t a m i n e l e v e l s . P l a c e b o e f f e c t i s a p o t e n t i a l c o n c e r n i n t h e p r e s e n t s t u d y . S i g n i f i c a n t time e f f e c t s , w i t h a d e c r e a s e i n symptoms over t i m e , would have i n d i c a t e d a s t r o n g p l a c e b o e f f e c t . There was a s i g n i f i c a n t time e f f e c t f o r the s e v e r i t y o f i t c h i n e s s w hich d e c r e a s e d over time as shown i n t a b l e 16. The e f f e c t o f p l a c e b o was m i n i m i z e d by comparing the outcome of the h i s t a m i n e - r e d u c i n g and the c o n t r o l d i e t o v er t i m e . The r e s e a r c h e r c o n d u c t i n g the s t u d y and e d u c a t i n g the t r e a t m e n t and c o n t r o l s u b j e c t s was aware o f the d i f f e r e n c e between the d i e t s . A c o n s c i e n t i o u s e f f o r t t o t r e a t b o t h groups the same was made; however, the p o t e n t i a l f o r b i a s was p r e s e n t . 92 Discussion THE VALIDITY OF USING A CROSSOVER DESIGN TO EVALUATE THE EFFECT OF DIETARY MANIPULATION IN CHRONIC URTICARIA AND ANGIOEDEMA In a c r o s s o v e r d e s i g n the s u b j e c t s f o l l o w b o t h the t r e a t m e n t and the c o n t r o l d i e t i n a random o r d e r . Fewer s u b j e c t s are r e q u i r e d f o r a c r o s s o v e r d e s i g n because the w i t h i n - s u b j e c t v a r i a t i o n i s l e s s t h a n the b e t w e e n - s u b j e c t v a r i a t i o n (Monsen & Cheney, 1992; L o u i s e t a l . , 1984). In the p r e s e n t s t u d y , the s m a l l sample s i z e and l a r g e w i t h i n - and b e t w e e n - s u b j e c t v a r i a t i o n d e c r e a s e d the power o f the s t u d y . I f the s t u d y had been conducted as a c r o s s o v e r d e s i g n , s t a t i s t i c a l s i g n i f i c a n c e may have been found. However, the f i n d i n g s o f a c r o s s o v e r d e s i g n would not be v a l i d f o r t h r e e r e a s o n s . F i r s t , the s u b j e c t s must e n t e r the c o n t r o l d i e t and the t r e a t m e n t d i e t i n an i d e n t i c a l s t a t e . The symptoms o f c h r o n i c u r t i c a r i a and angioedema f l u c t u a t e o v e r t i m e , and the above assumption c o u l d not be guaranteed. Second, a c a r r y - o v e r e f f e c t from each d i e t p e r i o d may o c c u r . I f a s u b j e c t ' s symptoms were r e l i e v e d on the f i r s t d i e t , he would l i k e l y c o n t i n u e the d i e t a r y r e s t r i c t i o n d u r i n g the second d i e t p e r i o d . F i n a l l y , b l i n d i n g would be d i f f i c u l t w i t h a c r o s s o v e r d e s i g n . In the p r e s e n t s t u d y , the s u b j e c t s were g i v e n e i t h e r the t r e a t m e n t d i e t o r the c o n t r o l d i e t and d i d not compare the d i e t s u n t i l the s t u d y was complete. I f the d i e t s are compared, i t i s o b v i o u s t h a t the t r e a t m e n t d i e t i s much more r i g o r o u s than the c o n t r o l d i e t . '93 Discussion In a c r o s s o v e r d e s i g n , the s u b j e c t s may b e l i e v e t h a t the c o n t r o l d i e t i s not e f f e c t i v e . FUTURE RESEARCH The r e s u l t s o f t h i s s t u d y were n o t c o n c l u s i v e and f u r t h e r s t u d i e s are r e q u i r e d t o c l a r i f y the f i n d i n g s . I f d i e t a r y m a n i p u l a t i o n i s shown t o be e f f e c t i v e i n the management o f u r t i c a r i a and angioedema, a d d i t i o n a l r e s e a r c h w i l l be r e q u i r e d t o determine which a s p e c t s o f the d i e t were e f f e c t i v e and which s u b j e c t s are most l i k e l y t o b e n e f i t from a- h i s t a m i n e - r e d u c i n g d i e t . F i n a l l y , the f o o d h a n d l i n g c o n d i t i o n s which l e a d t o h i s t a m i n e f o r m a t i o n must be f u r t h e r i n v e s t i g a t e d . Food a d d i t i v e s and h i s t a m i n e - r i c h f o o d were e l i m i n a t e d i n the h i s t a m i n e - r e d u c i n g d i e t . I f the d i e t i s e f f e c t i v e i n u r t i c a r i a and angioedema, i t w i l l be i m p o r t a n t t o d e t e r m i n e w h i c h o f the r e s t r i c t i o n s are r e s p o n s i b l e f o r the b e n e f i c i a l e f f e c t . The a c t i v i t y o f DAO and the p a t t e r n o f h i s t a m i n e m e t a b o l i s m can be measured ( L e s s o f e t al.,1990 and Kanny et a l . , 1993, r e s p e c t i v e l y ) . I f u r t i c a r i a s u b j e c t s w i t h d e c r e a s e d DAO a c t i v i t y o r d e l a y e d h i s t a m i n e c a t a b o l i s m f o l l o w a h i s t a m i n e - r e d u c i n g d i e t , a l l s u b j e c t s s h o u l d improve. A s t u d y o f t h i s n a t u r e would t e s t the r a t i o n a l e o f the t r e a t m e n t d i e t . Moreover, the c o r r e l a t i o n between e f f e c t i v e n e s s o f the d i e t and the DAO a c t i v i t y c o u l d be 94 Discussion d e t e r m i n e d . Diamine o x i d a s e a c t i v i t y and/or i n d i c a t o r s o f h i s t a m i n e m e t a b o l i s m may be u s e f u l c l i n i c a l t e s t s t o dete r m i n e which s u b j e c t s may b e n e f i t from a h i s t a m i n e - r e d u c i n g d i e t . F u r t h e r r e s e a r c h i s r e q u i r e d t o determine the f o o d p r e p a r a t i o n c o n d i t i o n s t h a t l e a d t o h i s t a m i n e f o r m a t i o n . Presence o f h i s t i d i n e d e c a r b o x y l a s e - p r o d u c i n g m i c r o o r g a n i s m s , f r e e h i s t i d i n e and c o n d i t i o n s t h a t a l l o w f o r m i c r o b i o l o g i c a l growth r e s u l t i n h i s t a m i n e f o r m a t i o n . There i s e v i d e n c e t h a t poor hygi e n e i n the f i s h c a n n i n g i n d u s t r y may r e s u l t i n h i s t a m i n e f o r m a t i o n (Kim & B j e l d a n e s , 1978). However, t h e r e have not been any s t u d i e s t o determine the p r e v a l e n c e o f h i s t a m i n e f o r m a t i o n from poor hygiene i n o t h e r f o o d m a n u f a c t u r i n g i n d u s t r i e s , r e s t a u r a n t s and the home. E d u c a t i o n on h y g i e n i c f o o d h a n d l i n g may be n e c e s s a r y f o r h i s t a m i n e s e n s i t i v e i n d i v i d u a l s . CLINICAL APPLICATION OF STUDY FINDINGS C h r o n i c u r t i c a r i a and angioedema can be v e r y troublesome f o r those a f f l i c t e d w i t h t h i s c o n d i t i o n . P a t i e n t s a re o f t e n f r u s t r a t e d because the i n c i t i n g agent remains unknown i n 75 % o f cases ( B u r r a l l e t a l . , 1990). T h i s f r u s t r a t i o n was apparent i n the u r g e n t response t o the January 21 and 22, 1995 newspaper ad. Many s u b j e c t s s t a t e d t h a t t h e y would t r y a n y t h i n g t o a l l e v i a t e t h e i r s u f f e r i n g . A h i s t a m i n e - r e d u c i n g d i e t may improve symptoms 95 Discussion i n some s u b j e c t s w i t h c h r o n i c u r t i c a r i a . The symptoms w i l l improve w i t h i n two weeks, i f the d i e t i s e f f e c t i v e . The h i s t a m i n e - r e d u c i n g d i e t s h o u l d be c o n s i d e r e d f o r t r e a t m e n t o f c h r o n i c u r t i c a r i a and angioedema a t l e a s t f o r a t r i a l p e r i o d . The r e s u l t s o f the s t u d y and the d e t a i l s o f the d i e t , s h o u l d be d i s s e m i n a t e d t o h e a l t h c a r e p r o f e s s i o n a l s who p r o v i d e t r e a t m e n t f o r t h e s e p a t i e n t s . The r e s u l t s o f t h i s . s t u d y demonstrated t h a t the h i s t a m i n e -r e d u c i n g d i e t can a l s o r e s u l t i n a d e c r e a s e d i n t a k e o f energy and some n u t r i e n t s and subsequent weight l o s s i n some i n d i v i d u a l s . 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J Food P r o t 1983; 46 (12) :1044-1049. 103 APPENDICES 104 APPENDIX B: HISTAMINE-REDUCING DIET DIETARY GUIDELINES FRUIT/VEGE TABLE • C r a n b e r r i e s 1 • S t r a w b e r r i e s 1 , 4 • P i n e a p p l e 2 , 4 • R a s p b e r r y 1 , 2 • D a t e s 2 • S p i n a c h 5 • Tomato and tomato p r o d u c t s • Prunes 1' 2 4,5 • C u r r a n t s 2 • R a i s i n s 2 ME AT/ALTE RNATE S • any se a f o o d ( s h e l l f i s h , f i n f i s h w hich i s canned, f r e s h , f r o z e n ) 4 , 5 • uncooked egg w h i t e (egg nog, some m i l k s h a k e s ) 4 • p r o c e s s e d meat (luncheon meat, sausage, w i e n e r ) 5 • l e f t o v e r meat, EAT f r e s h p r e p a r e d meat o n l y MILK/MILK PRODUCTS • cheese p r o d u c t s ( b l o c k , p r o c e s s e d , s l i c e s ) 5 • y o g h u r t 5 • sour cream FOOD ADDITIVES • r e a d a l l f o o d l a b e l s c a r e f u l l y , do not eat fo o d which c o n t a i n s : t a r t r a z i n e , a r t i f i c i a l f o o d c o l o r , b e n z o i c a c i d , sodium benzoate, b e n z o y l p e r o x i d e , BHT, BHA3 • many m e d i c a t i o n s , v i t a m i n p i l l s e t c . c o n t a i n t h e s e a d d i t i v e s ; ask your p h a r a m a c i s t 3 SEASONING • cinnamon 1 • c l o v e s 1 • hot p a p r i k a 2 • a n i s e 1 • c u r r y powder 2 • nutmeg 1 MISCELLANEOUS . • fermented soy p r o d u c t s (soy sauce, m i s o ) 5 • fermented f o o d ( s a u e r k r a u t ) 5 • t e a ( h e r b a l o r r e g u l a r ) 1 • c h o c o l a t e 4 • a l c o h o l (beer, wine, h a r d l i q u o r ) 4 , 5 May not be reproduced without permission from Dr. J a n i c e Joneja 1 Benzoates (Jacobsen, 1987;Heimhuber, 1990) 2 S a l i c y l a t e s (Swain,1985) 3 Food A d d i t i v e s 4 Histamine r e l e a s i n g food (Finn, 1987) 5 Histamine r i c h food ( S t r a t t o n et a l . , 1991; ten Bri n k et a l . , 1990) 106 APPENDIX C: CONTROL DIET DIETARY GUIDELINES Please DO NOT eat or d r i n k any o f the f o l l o w i n g a r t i f i c i a l sweeteners or sugar a l c o h o l s d u r i n g the r e s e a r c h s t u d y . • A s p a r t a m e ® • S p l e n d a ® • S a c c h a r i n • Cyclamate • M a n n i t o l • X y l i t o l • S o r b i t o l These sweeteners are added to food and may be found i n : FRUIT • canned f r u i t • f r u i t d r i n k MEAT/ALTERNATE S • peanut b u t t e r MILK/MILK PRODUCTS • yoghurt • i c e cream DESSERTS/SWEETS • p o p s i c l e s • c h o c o l a t e b a r s • cand ie s • soda pop • pudding • hot c h o c o l a t e • cake • syrup Many commercia l d e s s e r t s c o n t a i n a r t i f i c i a l sweeteners . MEDICATION • cough syrup • Neo C i t r a n ™ • cough lozenge MISCELLANEOUS • barbeque sauce • ketchup • chewing gum • c o l d and hot c e r e a l READ THE LABELS CAREFULLY A r t i f i c i a l sweeteners may be purchased i n a l i q u i d or a g r a n u l a t e d form. The brand names are E q u a l , S u c a r y l , Sugar Twin, Sweet n ' Low and S p l e n d a . P lease do not consume these p r o d u c t s . 107 A P P E N D I X D : U R T I C A R I A / A N G I O E D E M A D A I L Y A S S E S S M E N T V c x > « S » < x ) <x5 ^ s s > w > «SS» O O «SS> <3B Day of Study: Date: Name P l e a s e complete the assessment a t the same time each day. Complete the assessment f o r the previous 24 hours. [1) Number o f a n t i h i s t a m i n e t a b l e t s t a k e n : Name o f t a b l e t : Dose o f t a b l e t : mg (2) T o t a l number o f wheals ( h i v e s ) : D i d you count your wheals o r guess? (3) S e v e r i t y o f i t c h i n e s s : P l e a s e check one. symptoms absent symptoms are p r e s e n t , but b a r e l y n o t i c a b l e symptoms are d e f i n i t e l y n o t i c a b l e , but are t o l e r a b l e symptoms are d e f i n i t e l y n o t i c a b l e , and are not t o l e r a b l e (4) S e v e r i t y o f angioedema: P l e a s e check one. symptoms absent symptoms are p r e s e n t , but b a r e l y n o t i c a b l e symptoms are d e f i n i t e l y n o t i c a b l e , but are t o l e r a b l e symptoms are d e f i n i t e l y n o t i c a b l e , and a r e not t o l e r a b l e (5) Comments: (6) Changes i n m e d i c a t i o n s ( i n c l u d i n g hormonal t h e r a p y ) , creams, l a u n d r y d e t e r g e n t , s t r e s s , l i f e s t y l e and o t h e r f a c t o r s which a f f e c t your symptoms or dietary problems: 108 A P P E N D I X E : T H R E E D A Y FOOD R E C O R D Day of Study: 1 Date Name: P l e a s e l i s t e v e r y t h i n g you eat and d r i n k from 12:00 am t o 11:59 pm. I n c l u d e any m e d i c a t i o n , v i t a m i n s o r supplements. P l e a s e be s p e c i f i c . I n d i c a t e how the f o o d was p r e p a r e d , b r a n d names, and q u a n t i t i e s . TIME Example 8:00am FOOD QUANTITY F r i e d eggs 2 M a r g a r i n e 2 teaspoon Whole wheat t o a s t 1 s l i c e Jam 1 t s p TIME FOOD QUANTITY 109 Appendix F: Food Sources of Selected Nutrients Meat, Fish, Poultry Milk and Milk Fruits and Breads and Miscellaneous Nutrient and Alternates Products Vegetables Cereals Vitamin A Eggs, fish, liver Fortified milk and margarine, butter E>ark green and yellow vegetables, sweet potato, tomato Fish liver oils Vitamin Bi (Thiamin) Meats, dried peas, legumes Whole grains, enriched flour and cereals Nutritional yeast, wheat germ Vitamin B2 (Riboflavin) Meats, especially organ meats, legumes Milk, cheese, yogurt, cottage cheese Green vegetables Whole grains, enriched flour and cereals Niacin Meats, especially organ meats, poultry, fish, peanuts, legumes Com Whole grains, enriched flour and cereals Nutritional yeast Vitamin B6 (Pyridoxine) Meats, especially organ meats, eggs, fish, legumes Green leafy vegetables, banana, carrot, potato Whole grains Nutritional yeast, wheat germ Vitamin B12 Meats, especially organ meats, eggs, fish, shellfish Cheese, yogurt Vitamin C (Ascorbic Acid) Fruits, especially' citrus fruits and juices, strawberries, cabbage, tomato, potato Vitamin D Eggs, liver Fortified milk and Fish liver oils margarine, butter Vitamin E Eggs, nuts, liver, legumes Milk, butter Green leafy vegetables Whole grains, fortified cereals Vegetable oils, wheat germ Vitamin K Liver, egg yolk Butter, cheese Green leafy vegetables, potato Wheat, oats Vegetable oils Folic acid Organ meats, nuts, legumes Green leafy vegetables, asparagus, banana, strawberries Whole grains Nutritional yeast Pantothenic acid Eggs, organ meats, peanuts, walnuts Fresh vegetables Whole grains, rice bran Nutritional yeast Calcium Oysters, scallops, salmon and sardines with bones, tofu All Green leafy vegetables, broccoli, dates Blackstrap molasses Iron Meats, liver, eggs, shellfish, nuts, sardines, legumes Broccoli, peas, spinach, prunes, raisins Bran, enriched cereals Blackstrap molasses, wheat germ Magnesium Nuts, legumes Peas Whole grain Potassium Meats Milk Fruits, especially orange juice, bananas, dried fruits, potato Zinc Meat, liver, eggs, shellfish Cheese Green leafy vegetables, orange, prunes, strawberries Whole grains Chocolate syrup Sources: American Dietetic Association. Manual of Clinical Dietetics. Chicago: A D A 1988 Health and Welfare Canada. Action Towards Healthy Eating: Canada's Guidelines for Healthy Eating and Recommended Strategies for Implemen-tation. Ottawa: Supply and Services Canada, 1990. Ontario Dietetic Association and Ontario Hospital Association. Nutr-tional Care Manual 6th ed. Don Mills: Ontario Hospital Association, 1989. ii This appendix was written by : Cathy Hauchecome, R.D. University Hospital Vancouver N. 0 BCDNA Manual of Nutritional Care Any i n f o r m a t i o n r e s u l t i n g from t h i s r e s e a r c h s t u d y w i l l be kept s t r i c t l y c o n f i d e n t i a l . A l l documents w i l l be i d e n t i f i e d o n l y by code number and kept i n a l o c k e d f i l e c a b i n e t . The s u b j e c t s w i l l not be i d e n t i f e d by name i n any r e p o r t s o f t h e completed s t u d y . Your p a r t i c i p a t i o n i n t h i s s t u d y i s s t r i c t l y v o l u n t a r y . You are f r e e t o withdraw from the s t u d y a t anytime w i t h o u t consequence t o c o n t i n u e d m e d i c a l c a r e . Thank you f o r your i n t e r e s t i n t h i s s t u d y . I f you have any q u e s t i o n s o r comments, p l e a s e c o n t a c t Wendy K i n g a t 875-5002. I f you have any concerns about your t r e a t m e n t o r r i g h t s as a r e s e a r c h s u b j e c t , c o n t a c t the D i r e c t o r o f Res e a r c h S e r v i c e s a t the U n i v e r s i t y o f B r i t i s h Columbia, Dr. R i c h a r d S p r a t l e y a t 822-9252. I consent, t o p a r t i c i p a t e i n the " E f f e c t o f D i e t a r y M a n i p u l a t i o n i n C h r o n i c U r t i c a r i a / A n d i o e d e m a " Study, and have r e c e i v e d a copy o f t h i s consent form. S u b j e c t S i g n a t u r e Date Witness S i g n a t u r e Date I n v e s t i g a t o r ' s S i g n a t u r e Date Page 2 o f 2 112 APPENDIX I: REASONS GIVEN BY POTENTIAL SUBJECTS FOR NOT PARTICIPATING IN THE STUDY Reason Number D i s t a n c e 22 Unknown • 12 I n s u f f i c i e n t time t o p a r t i c i p a t e 7 Symptoms l e s s f r e q u e n t t h a n once p e r week 5 Symptoms were not u r t i c a r i a / a n g i o e d e m a 4 S u b j e c t began st u d y , but s t r e s s f u l p e r i o d d u r i n g Time 2 P e r i o d #1 S u b j e c t r e p o r t e d symptoms were too s e v e r e 2 S u b j e c t began st u d y , but r e p o r t e d pregnancy d u r i n g Time 1 P e r i o d #1 S u b j e c t began s t u d y , but changed m e d i c a t i o n / h e a l t h 1 d u r i n g Time P e r i o d #1 Does not want t o f o l l o w a d i e t 1 C u r r e n t l y f o l l o w i n g a d i e t f o r u r t i c a r i a 1 Does not t h i n k d i e t w i l l h e l p symptoms 1 Pregnant 1 Under 19 y e a r s o f age 1 P h y s i c i a n d i d not approve 1 TOTAL 62 114 APPENDIX J : URTICARIA AND ANGIOEDEMA SYMPTOM ASSESSMENT SCALES WHICH WERE NOT COMPLETED S u b j e c t #4 ( C o n t r o l Group) A n t i h i s t a m i n e M e d i c a t i o n I n t a k e : Day 27 Number o f Wheals: Day 9 S e v e r i t y o f I t c h i n e s s : Day 9 S e v e r i t y o f Angioedema: Day 9 S u b j e c t #5 ( C o n t r o l Group) Number o f Wheals: Day 11 S u b j e c t #6 ( C o n t r o l Group) Number o f Wheals: Day 38 S e v e r i t y o f I t c h i n e s s : Day 3. S e v e r i t y o f Angioedema: Days 2, 10 S u b j e c t #7 ( C o n t r o l Group) A n t i h i s t a m i n e M e d i c a t i o n I n t a k e : Day -3 S e v e r i t y o f Angioedema: Day 34 S u b j e c t #8 ( C o n t r o l Group) Number o f Wheals: Day -1 S e v e r i t y o f I t c h i n e s s : Days 22, 24 S e v e r i t y o f Angioedema: Days 22, 24 S u b j e c t #11 (Treatment Group) Number o f Wheals: Day 25 S u b j e c t #14 (Treatment Group) Number o f Wheals: Day 23 S u b j e c t #15 (Treatment Group) Number o f Wheals: Days 7 115 APPENDIX K: STARTING AND ENDING DATES FOR EACH SUBJECT Subject Group Day -14 (1995) Day 56 (1995) 1 C 02/12 04/22 2 C 01/05 03/17 3 c 01/10 • 03/20 4 c 02/05 04/23 a 5 c 02/14 04/24 6 c 02/01 04/11 7 c 01/28 04/17 a 8 c 02/13 05/18 b 9 c 05/19 07/28 10 C 05/12 07/21 11 T 02/01 04/11° 12 T 02/17 04/27 13 T 02/05 04/15 14 T 01/26 04/05 15 T 02/5 04/17 d 16 T 02/03 04/13 17 T 06/03 08/15 18 T 06/23 09/05 19 T 03/10 05/18 aDay 0 was d e l a y e d because t h e r e was a d e l a y i n o b t a i n i n g the p h y s i c i a n s ' a p p r o v a l s . b S u b j e c t completed time 1 and went t o H a w a i i . She s t a r t e d the c o n t r o l d i e t when she r e t u r n e d from H a w a i i . c S u b j e c t d i d not complete an assessment on 02/12, 03/28 and 03/30. d S u b j e c t withdrew from the s t u d y on Day 42. Note: Only d a t a up t o Day 42 were used i n the s t a t i s t i c a l a n a l y s i s . 116 A P P E N D I X L : D I E T A R Y N O N C O M P L I A N C E AND CONFOUNDING V A R I A B L E C H A N G E S S u b j e c t #1 ( C o n t r o l Group) 1. S u b j e c t r e p o r t e d a c o l d w i t h f e v e r on Days 32 through 38. 2. S u b j e c t took one reactine® ( a n t i h i s t a m i n e ) on Day 32 and 33 f o r s n e e z i n g and r h i n o r r h e a . 3. S u b j e c t took tylenol® (650mg) on Days 34 through 37 and tylenol® (325mg) on Day 38. 4. S u b j e c t took robitussin® AC (cough syrup) (40ml) Days 37 th r o u g h 41. 5. S u b j e c t took ceclor® ( a n t i b i o t i c ) (750 mg) on Days 38 th r o u g h 43. The c o l d o r the m e d i c a t i o n appeared t o s l i g h t l y e x a c e r b a t e the u r t i c a r i a symptoms d u r i n g t h i s p e r i o d . S u b j e c t #2 ( C o n t r o l Group) 1. S u b j e c t drank a d i e t coke® on Days 3, 9, 10 and 29. S u b j e c t #3 ( C o n t r o l Group) 1. S u b j e c t took tylenol® (lOOOmg) on Days -3, 0 and 1. The change d i d not appear t o a f f e c t the u r t i c a r i a symptoms. 2. S u b j e c t r e p o r t e d c o n g e s t e d s i n u s symptoms throughout the st u d y . 3. S u b j e c t used habitol® ( n i c o t i n e patch) on Days 2 t h r o u g h 19. The change d i d not appear t o a f f e c t the u r t i c a r i a symptoms. 4. S u b j e c t changed t o Cheers® c o l o r g a u r d l a u n d r y d e t e r g e n t on Day 30. The change d i d not appear t o a f f e c t the u r t i c a r i a symptoms. S u b j e c t #4 ( C o n t r o l Group) 1. S u b j e c t r e p o r t e d s e a s o n a l r h i n i t i s on Days 38 t h r o u g h t o the end o f the s t u d y ! S u b j e c t took a chlor-tripolon® ( s u b j e c t ' s u s u a l a n t i h i s t a m i n e m e d i c a t i o n ) (8 mg) e v e r y o t h e r day thro u g h o u t t h i s p e r i o d . S u b j e c t #5 ( C o n t r o l Group) 1. S u b j e c t r e p o r t e d s i n u s c o n g e s t i o n p e r i o d i c a l l y throughout the s t u d y . 2. S u b j e c t took benylin®-D-E E x t r a , V i t a m i n C (500 mg) and H2 b l o c k e r ( h i s t a m i n e r e c e p t o r 2) on Day -7. The change d i d not appear t o a f f e c t the u r t i c a r i a o r angioedema symptoms. 3. S u b j e c t a t e a r t i f i c i a l sweetener on Day 1. S u b j e c t #6 ( C o n t r o l Group) 1. S u b j e c t i n d i c a t e d an i n t e n t i o n t o withdraw from the s t u d y on Day 31 because o f the amount o f time a t t e n d i n g appointments and because her d o c t o r thought the u r t i c a r i a was a s i d e e f f e c t o f dyazide® m e d i c a t i o n . The s u b j e c t l i v e d one hour from Vancouver H o s p i t a l . On Day 35, the s u b j e c t i n d i c a t e d a d e s i r e t o remain i n 117 the s t u d y because d i s c o n t i n u a t i o n o f dyazide® d i d not improve the symptoms. The s u b j e c t had been c o m p l i a n t w i t h the c o n t r o l d i e t and had been r e c o r d i n g symptoms c o n t i n u o u s l y . S u b j e c t #7 ( C o n t r o l Group) 1. S u b j e c t took aspirin® (650 mg) on Day 10. The change d i d not appear t o a f f e c t the u r t i c a r i a o r angioedema symptoms. S u b j e c t #8 ( C o n t r o l Group) 1. S u b j e c t changed deodorant on Day -11. The change d i d not appear t o a f f e c t the u r t i c a r i a symptoms. S u b j e c t #9 ( C o n t r o l Group) 1. S u b j e c t used reactine® al o n e everyday u n t i l Day 14. S u b j e c t used reactine® and benadryl® on Day 15, and benadryl® al o n e on Day 16. S u b j e c t used reactine® al o n e from Days 17 th r o u g h 22, and benadryl® a l o n e Days 23 and 24. Day 25 reactine® was used. S u b j e c t used atarax® al o n e Days 26 th r o u g h 30. Reactine® a l o n e was used Days 31 and 32, and atarax® and reactine® on Day 33. Reactine® al o n e was used everyday u n t i l t he end o f the s t u d y . The s u b j e c t ' s symptoms were not c o n t r o l l e d by m e d i c a t i o n , and the a n t i h i s t a m i n e m e d i c a t i o n s d i d not have a s i g n i f i c a n t impact on symptoms. T h e r e f o r e , changes i n m e d i c a t i o n do not r e f l e c t changes i n d i s e a s e s e v e r i t y . 2. S u b j e c t took 0, 1 o r 2 t a b l e t s o f prednisone® (5mg) c o n s i s t e n t l y t h r o u g h o u t the s t u d y . 3. S u b j e c t took a c a l c i u m supplement on Day 1 and throughout the remainder o f the s t u d y . 4. S u b j e c t took V i t a m i n C (500mg) on Day 18. S u b j e c t #10 ( C o n t r o l Group) 1. S u b j e c t d o u b l e d premarin® (hormone replacement therapy) the day b e f o r e Day -14 and m a i n t a i n e d the doub l e d dose throughout the s t u d y p e r i o d . Premarin® o f t e n e x a c e r b a t e s u r t i c a r i a ( p e r s o n a l correspondence J a n i c e J o n e j a , Ph.D.). However, the i n c r e a s e d premarin® d i d not appear t o e x a c e r b a t e the s u b j e c t ' s symptoms. S u b j e c t #11 (Treatment Group) 1. S u b j e c t d i s c o n t i n u e d V i t a m i n s C, E and B complex and l e t h i c i n supplements b e f o r e Day-14. 2. S u b j e c t used sarna® HC 1% ( t o p i c a l c o r t i c o s t e r o i d ) t o c o n t r o l u r t i c a r i a symptoms on Days -14 t o 0. He d i s c o n t i n u e d the cream on Day 1. 3. S u b j e c t drank one can o f pepsi® on Day 11. S u b j e c t #12 (Treatment Group) 1. S u b j e c t used an new soap s t a r t i n g Day -9. The change d i d not appear t o a f f e c t the u r t i c a r i a o r angioedema symptoms. 2. S u b j e c t r e p o r t e d f l u symptoms on Days 11 th r o u g h 15. The change d i d not appear t o a f f e c t the u r t i c a r i a o r angioedema symptoms. 3. S u b j e c t a t e one p i e c e o f l e f t o v e r meat on Day 21. 118 S u b j e c t #14 (Treatment Group) 1. S u b j e c t took tylenol® (325 mg) on Days -14, -13, -12, -10, -8, -3, 1, 7, 9, 10, 11, 12, 14, 18, 36, 37, 38, 39 and 41. E l e v e n t a b l e t s were t a k e n i n time 1. T h i r t e e n t a b l e t s were t a k e n i n time 2. Two t a b l e t s were t a k e n i n time 3. F i v e t a b l e t s were t a k e n i n time 4. The change d i d not appear t o a f f e c t the u r t i c a r i a o r angioedema symptoms. 2. S u b j e c t r e p o r t e d a y e a s t i n f e c t i o n on Days 2, 3 and 4. The change d i d not appear t o a f f e c t the u r t i c a r i a o r angioedema symptoms. 3. S u b j e c t used diflucan® ( a n t i f u n g a l agent)(150mg) on Day 4. The change d i d not appear t o a f f e c t the u r t i c a r i a o r angioedema symptoms. S u b j e c t #15 (Treatment Group) 1. S u b j e c t r e p o r t e d c o l d symptoms Days 19 t h r o u g h 34. 2. S u b j e c t took novalhistine® DM ( a n t i t u s s i v e , decongestant) (45ml) Days 21 and 22. 3. S u b j e c t took bradosol® cough l o z e n g e s (3 loze n g e s ) Day 21. 4. S u b j e c t took Halls® cough l o z e n g e s (3 loze n g e s ) Day 23. 5. S u b j e c t took Tylenol® c o l d (1300 mg) Days 24 and 25, Tylenol® c o l d (975 mg) Days 26 and 27, Tylenol® c o l d (650 mg) Day 28 and Tylenol® c o l d (325 mg) Day 29. 6. S u b j e c t took Tylenol® (325 mg) Days 31 and 32. N e i t h e r the c o l d nor the m e d i c a t i o n appeared t o a f f e c t the u r t i c a r i a o r angioedema symptoms. 7. S u b j e c t took V i t a m i n E (600 I U ) Days 1,2 and 3. 8. S u b j e c t drank t e a on Day 1 and 39, a t e s m a l l amount o f c h o c o l a t e brownie on Day 3, 1 g l a s s o f r e d wine on Day 5, H cup chopped tomato 'on Day 6, 1 s l i c e o f p i z z a on Day 9, wine, tomato, t e a , s p i n a c h and cheese on Day 16, s m a l l amount o f yoghurt on Day 31 and Sprite® on Day 36. 9. S u b j e c t withdrew from the s t u d y on Day 42 because o f d i f f i c u l t y f o l l o w i n g d i e t . S u b j e c t #17 1. S u b j e c t a t e 1 t a b l e s p o o n o f Parmesan cheese on Day 7. 2. S u b j e c t a t e marshmallows on Days 9 and 10. S u b j e c t #18 1. S u b j e c t drank one can o f gingerale® on Day 26. 2. S u b j e c t a t e one s e r v i n g o f cheese on Days 39 and 40. 119 APPENDIX M: WEIGHT CHANGE OVER THE STUDY PERIOD 3 Subject Group I n i t i a l Weight (Day -14) (kg) Fi n a l Weight (Day 56) (kg) Percent Weight change I n i t i a l Body Mass Index (Day -14) 1 C 75 72 b -4% 24 2 C 66 66 0% 23 3 c 71 77 c 8% 25 4 c 64 64 0% 25 5 c 93 95 2% 29 € c 58 58 0% 24 7 c 68 68 0% 24 8 c 58 58 0% 21 9 c 63 64 2% 26 10 c 98 102 d 4% 34 11 T 87 85 -2% 29 12 T 91 ' 88 -3% 36 13 T 55 54 -2% 21 14 T 75 75 0% 26 15 T 62 . 62 0% 24 16 T 130 130 0%- 35 17 T 75 73 -3% 29 18 T 82 79 -4% 30 19 T 55 55 0% ' 21 a Based on s e l f reported weight and height b Subject was i l l and l o s t weight. c Subject stopped smoking one month before s t a r t i n g the study. The subject believes t h i s may have contributed to the weight gain. d Subject increased premarin® before Day -14. The subject believes t h i s may have contributed to the weight gain. 120 

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