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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  degree at the  thesis in  University of  partial  fulfilment  of  of  department  granted  or  understood  his  or  her  representatives.  permission.  The University of British Columbia Vancouver, Canada  DE-6 (2/88)  an advanced  Library shall make it  this thesis for scholarly purposes may be by  for  agree that permission for extensive  It  publication of this thesis for financial gain shall not  Date  requirements  British Columbia, I agree that the  freely available for reference and study. I further copying  the  is  by the that  head of copying  my or  be allowed without my written  ABSTRACT  Urticaria physiological  and angioedema actions  urticaria  have  before  enters  as  it  fermented  these  the  circulation.  of  a histamine-reducing diet  angioedema control  intake.  reducing diet,  medication  intake,  angioedema  for  were c o m p l e t e d  dietary  (n=9)  group f o l l o w e d  to  starting  the  effect symptoms  of  the  a  histamine-  antihistamine  p r u r i t u s and  diet  and f o r  T h r e e day f o o d  The m e a n ' a n t i h i s t a m i n e  respect  intake  of  two weeks p r i o r  ii  to  the to  or  or a  the  group  symptom  treatment the  six  records  T h e r e were no s i g n i f i c a n t  study with  d u r i n g the  of  artificial  recorded  severity  intervention.  the  exacerbate  assess  group  The s u b j e c t s  two w e e k s .  throughout  butylated  and angioedema  a treatment  number o f w h e a l s ,  every  17±12 tablets  benzoates,  in  subjects with chronic u r t i c a r i a  two weeks p r i o r  weeks d u r i n g t h e  such  endogenous r e l e a s e  on u r t i c a r i a  the  histamine  and angioedema  c o n t r o l group e l i m i n a t e d diets.  from  with  dietary  s t u d y were t o  The t r e a t m e n t  and t h e  from t h e i r  variables.  the  Nineteen  (n=10).  sweeteners  differences  food c o l o u r ,  were r a n d o m i z e d t o  group  urticaria  by i n c r e a s i n g  The o b j e c t i v e s  and n u t r i e n t  degrade  b u t y l a t e d h y d r o x y a n i s o l e may  and angioedema  histamine.  primarily  Foods h i g h i n h i s t a m i n e ,  may e x a c e r b a t e  and  result  Some i n d i v i d u a l s  a b i l i t y to  individuals. Artificial  urticaria  was  histamine.  a decreased  foods,  hydroxytoluene  of  of  symptoms  diet  group and  12±13  tablets  during  intervention.  This  were s i g n i f i c a n t  the  first  difference  two weeks o f t h e was  g r o u p by t i m e  significant  interactions  dietary-  (p<0.05). (p<0.05)  calcium,  v i t a m i n C and v i t a m i n B 1 2 . O b s e r v a t i o n o f  indicate  that  total  fat,  and v i t a m i n C i n t a k e treatment  diet  increased  compared t o  medication. in  counselling  of  diet  d i d not  the  the  are  result  However,  need  for  essential  intervention.  iii  fat,  results decreased  the  control  i n an  diet.  improvement  dietary antihistamine  histamine-reducing diet  some n u t r i e n t s .  and f o l l o w - u p  the  consuming  consuming the  symptoms.  decreased  Adherence to  a reduced intake  i n subjects  subjects  and angioedema  i n t e r v e n t i o n may have  for  c a l c i u m and v i t a m i n B12 i n t a k e  The h i s t a m i n e - r e d u c i n g in urticaria  There  Therefore, components  may  result  dietary of  dietary  TABLE  OF  CONTENTS  ABSTRACT  i i  TABLE OF CONTENTS  iv  L I S T OF TABLES  viii  L I S T OF FIGURES  x  ACKNOWLEDGEMENT  x i  CHAPTER  1: INTRODUCTION  1  STUDY OBJECTIVES  3  NULL HYPOTHESES TESTED CHAPTER  ...  3  2: LITERATURE REVIEW  INTRODUCTION  4  TO LITERATURE REVIEW  4  PATHOLOGY OF URTICARIA AND ANGIOEDEMA  5  EFFECT OF DIET ON BODY HISTAMINE  9  Histamine  Poisoning  9  A l t e r e d Histamine Metabolism  i n U r t i c a r i a Subjects  11  Factors A f f e c t i n g Histamine Metabolism  15  Histamine  18  R e l e a s i n g Food and Food A d d i t i v e s . . . .  Micronutrient  Intake  21  Summary  22  PREVIOUS DIETARY MANIPULATION STUDIES I N CHRONIC URTICARIA AND ANG I OEDEMA 23 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  27  Diets  iv  OTHER CONDITIONS WHICH MAY BENEFIT DIET Atopic  FROM A  HISTAMINE-REDUCING  Disease  Migraine  28  Headaches  Gastrointestinal  28  Disturbances  29  BACKGROUND LITERATURE RELATED TO THE TREATMENT AND CONTROL DIETS  / Formation of  29  Histamine  i n Food  Conditions Necessary Amine C o n t e n t Natural  of  F o r m a t i o n o f Amines  Susceptible  and A r t i f i c i a l  Control Diet SIGNIFICANCE OF THE PRESENT  CHAPTER 3:  for  29 .  Food  29 31  Food C o n s t i t u e n t s  36  STUDY  38 39  METHODS  41  EXPERIMENTAL DESIGN  41  METHODS  42  Sample  size  42  Subject  Recruitment  43  Dietary  Intervention  45  Treatment Control Urticaria  Diet  45  Diet  46  and Angioedema A s s e s s m e n t S c a l e  47  T h r e e - D a y Food R e c o r d s Control  of  Subject  Appointments  Statistical  the  48  Confounding V a r i a b l e s  Analysis  50 51  .  52  Treatment  and C o n t r o l  Urticaria  and Angioedema  Nutrient Analysis Ethical  .  Group C o m p a r i s o n s Symptom S c a l e  .  . . .  52  .  53  .  .  54  Approval  56  v  CHAPTER 4: RESULTS  57  URTICARIA AND ANGIOEDEMA ASSESSMENT SCALE PRETEST  . . .  57  RECRUITMENT  57  SUBJECTS  59  COMPLIANCE TO STUDY PROTOCOL  60  S T A T I S T I C A L ANALYSIS  61  ' U r t i c a r i a and Angioedema Assessment S c a l e Antihistamine  ......  61  .  61  tablets  Wheals  63  Itchiness  64  Angioedema  65  Nutrient Analysis  68  Adequacy o f N u t r i e n t  Intake  S i g n i f i c a n t Changes i n N u t r i e n t  68 Intake  . . . .  68  CASE ANALYSIS OF TREATMENT GROUP SUBJECTS WITH IMPROVEMENT IN SYMPTOMS  77  C h a p t e r 5: DISCUSSION  81  MAJOR FINDINGS  81  COMPARISON TO C L I N I C A L FINDINGS  82  COMPARISON TO OTHER STUDIES  83  TREATMENT GROUP SUBJECTS WITH IMPROVEMENT I N SYMPTOMS  .  TREATMENT GROUP SUBJECTS WITHOUT IMPROVEMENT I N SYMPTOMS  85 86  NUTRITIONAL ADEQUACY OF THE HISTAMINE-REDUCING DIET  . .  87  LIMITATIONS OF THE STUDY  • .  90  THE V A L I D I T Y OF USING A CROSSOVER DESIGN TO EVALUATE THE EFFECT OF DIETARY MANIPULATION I N CHRONIC URTICARIA AND ANGIOEDEMA  94  FUTURE RESEARCH  95  C L I N I C A L A P P L I C A T I O N OF STUDY FINDINGS  97  REFERENCES  98  vi  APPENDICES  105  APPENDIX A :  RECRUITMENT POSTER  APPENDIX  B:  HISTAMINE-REDUCING  APPENDIX  C : CONTROL DIET  APPENDIX  D:  URTICARIA/ANGIOEDEMA DAILY ASSESSMENT  APPENDIX  E:  THREE-DAY FOOD RECORD  110  APPENDIX  F:  FOOD SOURCES OF SELECTED NUTRIENTS  Ill  APPENDIX  G: CONSENT FORM  APPENDIX  H: ETHICS APPROVAL FORM  APPENDIX  I:  J:  DIET  107 108 .  .  .  109  . . . . 1 1 2  REASONS GIVEN BY POTENTIAL SUBJECTS  PARTICIPATING APPENDIX  106  114 FOR NOT  IN THE STUDY  115  URTICARIA AND ANGIOEDEMA SYMPTOM ASSESSMENT  SCALES WHICH WERE NOT COMPLETED  116  APPENDIX  K:  STARTING AND ENDING DATES FOR EACH SUBJECT  APPENDIX  L : DIETARY NONCOMPLIANCE AND CONFOUNDING VARIABLE  CHANGES  .  117  118  APPENDIX M: WEIGHT CHANGE OVER THE STUDY PERIOD  vii  . . . .  121  L I S T  O F  T A B L E S  T a b l e 1: POSSIBLE CAUSES OF URTICARIA  9  T a b l e 2: SYMPTOMS OF HISTAMINE POISONING  10  T a b l e 3: HISTAMINE RELEASING FOODS  19  T a b l e 4: HISTAMINE RELEASE FROM THE WASHED LEUCOCYTES  OF 30  SUBJECTS ON EXPOSURE TO FOOD ADDITIVES OR A S P I R I N  ...  T a b l e 5: DIETARY MANIPULATION STUDIES I N CHRONIC U R T I C A R I A T a b l e 6: RESULTS OF FOOD ADDITIVE CHALLENGES  21 .  I N CHILDREN WITH  ANGIOEDEMA AND URTICARIA T a b l e 7: AMINES AND  26  THE AMINO A C I D PRECURSOR  31  T a b l e 8: NUMBER OF SUBJECTS INQUIRING ABOUT AND ENTERING  THE  STUDY  58  T a b l e 9: SUBJECT CHARACTERISTICS  60  T a b l e 10: TOTAL NUMBER OF ANTIHISTAMINE TABLETS TAKEN  . . . .  T a b l e 11: NUMBER OF DAYS ANTIHISTAMINE TABLETS WERE TAKEN  . .  T a b l e 12: TOTAL NUMBER OF ANTIHISTAMINE TABLETS TAKEN BEFORE CONTROL OR TREATMENT DIET OF THE DIET  24  (TIME 1) AND AFTER THE  62 62 THE  INITIATION  (TIME 2) . . .  63  T a b l e 13: TOTAL NUMBER OF WHEALS REPORTED  63  T a b l e 14: NUMBER OF DAYS WHEALS WERE REPORTED  64  T a b l e 15: TOTAL SEVERITY OF ITCHINESS SCORES  64  T a b l e 16: SEVERITY OF ITCHINESS OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA  65  T a b l e 17: NUMBER OF DAYS THAT ITCHINESS WAS  REPORTED  . . . .  T a b l e 18: TOTAL SEVERITY OF ANGIOEDEMA SCORES  65 66  T a b l e 19: NUMBER OF DAYS THAT ANGIOEDEMA WAS  REPORTED . . . .  T a b l e 20: ADJUSTED C R I T I C A L F AND CALCULATED  F FOR  66  EIGHT  URTICARIA AND ANGIOEDEMA VARIABLES  67  T a b l e 2 1 : MACRONUTRIENT INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT  viii  INTAKES  70  Table  22:  MINERAL INTAKE OF INDIVIDUALS WITH URTICARIA AND  ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT Table  23:  24:  INTAKES  25:  73  P AND F VALUES FOR NUTRIENTS  THAT SATISFY THE  ASSUMPTION OF SPHERICITY Table  26:  72  CALCIUM AND VITAMIN C INTAKE OF INDIVIDUALS WITH  URTICARIA AND ANGIOEDEMA Table  71  VITAMIN INTAKE OF INDIVIDUALS WITH URTICARIA AND  ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT Table  INTAKES  73  ADJUSTED CRITICAL F AND CALCULATED F FOR EIGHT  NUTRIENTS  THAT DID NOT SATISFY  THE ASSUMPTION  OF SPHERICITY 74  Table  27:  THE EFFECT OF THE TREATMENT DIET ON URTICARIA AND.  ANGIOEDEMA SYMPTOMS Table  28:  29:  30:  79  (SUBJECT  12)  79  THE EFFECT OF THE TREATMENT DIET ON URTICARIA AND  ANGIOEDEMA SYMPTOMS Table  11)  THE EFFECT OF THE TREATMENT DIET ON URTICARIA AND  ANGIOEDEMA SYMPTOMS Table  (SUBJECT  (SUBJECT  13)  80  THE EFFECT OF THE TREATMENT DIET ON URTICARIA AND  ANGIOEDEMA SYMPTOMS  (SUBJECT  ix  17)  80  LIST  OF  FIGURES  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 S I Z E 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  Figure  76  6: GROUP X TIME INTERACTION: V i t a m i n B12  F i g u r e 7: GROUP X TIME INTERACTION: V i t a m i n C  x  76  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  Urticaria  a f f e c t s 15 - 20 p e r c e n t  once i n t h e i r l i f e t i m e  (Lessof,  of the population at least  1 9 9 1 ) . The c o s m e t i c  associated pruritus of chronic u r t i c a r i a quality of l i f e  f o r those  burden and  and angioedema l i m i t t h 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 a n d c o n f u s i n g i n medical  p r a c t i c e , both f o r the c l i n i c i a n  Antihistamine medication chronic u r t i c a r i a medication  every  is a significant and  area  and t h e p a t i e n t .  i s the current treatment f o r  a n d a n g i o e d e m a . Many p a t i e n t s t a k e t h e day f o r t h e d u r a t i o n o f t h e d i s e a s e .  Drowsiness  side-effect of first-generation antihistamines,  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 a n d p r o d u c t i v i t y .  Second-generation, non-sedating, expensive.  Recent r e s e a r c h  antihistamines are very  suggests that c e r t a i n antihistamines  may p r o m o t e t u m o u r g r o w t h . The r e s e a r c h was c o n d u c t e d b e c a u s e t h e structure of antihistamines  i s s i m i l a r to a tamoxifen  w h i c h promotes tumour growth a t l o w d o s e s . (Claritin®), a s t e m i z o l e  analogue  Loratadine  (Hismanal®) a n d h y d r o x y z i n e  (Atarax®)  were shown t o p r o m o t e t u m o u r g r o w t h when i n j e c t e d i n t o (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  1  mice  r e s e a r c h and  Introduction epidemiological  studies  are required  t o determine 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 t h e human. antihistamine  medications are considered safe,  o f t h e i r u s e a p p e a r t o be g r e a t e r (Simons,  1994).  antihistamine  Currently and t h e b e n e f i t s  than the p o t e n t i a l r i s k s  However, some i n d i v i d u a l s do n o t want t o u s e  m e d i c a t i o n on a c o n t i n u o u s  I f d i e t a r y components cause  basis.  or contribute  t o u r t i c a r i a and  a n g i o e d e m a 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 a s a p o s s i b l e t r e a t m e n t . However, an i n a d e q u a t e  nutrient intake  a histamine-reducing diet.  isa  concern  associated with  purpose  o f t h e 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 t h e 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 intake.  2  Thus, t h e  and angioedema and n u t r i e n t  Introduction STUDY OBJECTIVES The s p e c i f i c o b j e c t i v e s o f t h e p r e s e n t 1.  study  were:  To e v a l u a t e the e f f e c t of a histamine-reducing 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 :  diet  1  in  a) t h e 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 w h e a l s a n d t h e s e v e r i t y o f u r t i c a r i a a n d angioedema b) t h e number o f d a y s 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 , a n d t h e number o f d a y s t h a t w h e a l s , p r u r i t u s a n d a n g i o e d e m a were r e p o r t e d 2.  To e v a l u a t e the nutrient intake.  effect  of  a  histamine-reducing  diet  on  NULL HYPOTHESES TESTED 1.  T h e r e w i l l be no d i f f e r e n c e b e t w e e n t h e t r e a t m e n t c o n t r o l groups w i t h r e s p e c t t o :  and  a) t h e 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 w h e a l s , t h e s e v e r i t y o f u r t i c a r i a a n d angioedema b) t h e number o f d a y s 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 a n d w h e a l s , p r u r i t u s a n d a n g i o e d e m a were reported 2.  T h e r e w i l l be no d i f f e r e n c e b e t w e e n t h e t r e a t m e n t 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 , b) c a l c i u m ,  p r o t e i n , carbohydrate  i r o n , magnesium,  and  and t o t a l f a t  phosphorus and z i n c  c) v i t a m i n s A, B l , B2, B3, B6, B12, C a n d f o l a c i n  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 , f o o d s t h a t may s t i m u l a t e e n d o g e n o u s h i s t a m i n e r e l e a s e a n d f o o d s w h i c h 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 . 1  3  Literature CHAPTER LITERATURE  INTRODUCTION TO Histamine  Review  2 REVIEW  LITERATURE REVIEW i s an i m p o r t a n t ' m e d i a t o r  a n g i o e d e m a , and  t h e p r e s e n t s t u d y was  of u r t i c a r i a  designed  and  to assess  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 w h i c h  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 w o u l d 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  section  literature  r e l e v a n t to the hypothesis i s reviewed.  s e c t i o n addresses of  angioedema. In t h i s  urticaria  and  The  first  t h e key r o l e o f b o d y h i s t a m i n e i n t h e angioedema. Next,  the s c i e n t i f i c  angioedema i s r e v i e w e d .  Finally,  the formation of  histamine i s discussed to provide a r a t i o n a l e reducing  pathology  evidence  s u p p o r t i n g t h e i n f l u e n c e o f d i e t on b o d y h i s t a m i n e and and  the  urticaria food  f o r the h i s t a m i n e -  diet.  PATHOLOGY OF URTICARIA AND Urticaria  ANGIOEDEMA  i s c h a r a c t e r i z e d by  erythema i n the dermis.  local p r u r i t i c hives  I n d i v i d u a l wheals  2  v a r y from  m i l l i m e t r e to s e v e r a l centimetres i n diameter  and may  A temporary r e d or p a l e r a i s e d area of the s k i n , a c c o m p a n i e d by s e v e r e i t c h i n g . 2  4  and  one be  found  often  on  Literature any p a r t o f t h e b o d y . The- w h e a l s  usually last  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 , edematous a r e a s t h a t i n v o l v e d e e p e r  Review  l e s s than four  but w i t h  larger  s w e l l i n g of the dermis  and  mucous membranes. A n g i o e d e m a u s u a l l y a f f e c t s t h e e y e l i d s ,  lips  and t o n g u e .  trunk  The  and arms may  a l s o be a f f e c t e d  Urticaria in  face, ears, chin,  genitalia,  (Holgate & Church,  and a n g i o e d e m a r e s u l t  al.,  1 9 9 0 ) . An  are seen a t the a f f e c t e d s i t e  (Natbony  e t a l . , 1983). Mast c e l l s These c e l l s  t h e b o d y , b u t a r e most a b u n d a n t a r o u n d l y m p h a t i c v e s s e l s and n e r v e s  mast c e l l s  (Burrall  o f 43  r e v e a l e d t e n times the normal  component o f t h e immune s y s t e m .  vessels,  microscope,  i n v e s t i g a t i o n of' t h e a f f e c t e d s i t e s  with chronic urticaria, mast c e l l s  1993).  from mast c e l l d e g r a n u l a t i o n  t h e d e r m i s o f t h e s k i n . U n d e r an e l e c t r o n  d e g r a n u l a t e d mast c e l l s  of  hands, f e e t ,  patients  number o f  a r e an  integral  are found  throughout  connective tissues, (White, 1990).  The  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  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  et  blood purpose  inflammatory 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 a r e r e s p o n s i b l e f o r t h e symptoms o f 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 f o r m e d 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 u p o n mast  degranulation. Subjects with chronic u r t i c a r i a significantly  cell  have a  i n c r e a s e d amount o f h i s t a m i n e i n t h e s k i n  5  within  (Smith et  Literature al.,  1 9 9 2 ) . T h i s may  result  f r o m an  Review  i n c r e a s e d number o f m a s t  c e l l s o r an i n c r e a s e d amount o f h i s t a m i n e  i n each mast c e l l  both.  are very  The  urticaria The in  biological and  e f f e c t s of histamine  angioedema  e f f e c t s of histamine t h e t i s s u e s . The  (Armenaka e t a l . , 1992;  important  White,  1  (HI)  in  1990).  are mediated through histamine  r e s u l t of histamine  or  receptors  receptor  stimulation includes increased vascular permeability, smooth m u s c l e 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 ,  pruritus, decreased  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 of vagal  increased l e v e l s of  r e f l e x e s and  g u a n o s i n e m o n o p h o s p h a t e . The  r e s u l t of histamine  2  cyclic  (H2)  receptor  stimulation includes gastric acid secretion, increased airway  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  m o n o p h o s p h a t e and H1/H2  receptor  f l u s h i n g and  e s o p h a g e a l c o n t r a c t i o n . The  Vasodilation,  p r u r i t u s and  tachycardia  the  v a s c u l a r changes, f l u i d  surrounding Prasad  urticaria  combined  (hypotension,  1990).  increased vascular permeability  the c e n t r a l f e a t u r e s of u r t i c a r i a these  (White,  adenosine  r e s u l t of  stimulation includes vasodilation  h e a d a c h e ) and  lower  and  a n g i o e d e m a . As  seeps from the b l o o d  tissues causing  are  a result  vessels  of  into  tissue swelling.  e t a l . (1967) f o u n d t h e b l o o d h i s t a m i n e  subjects i n active disease  levels  t o be. s i g n i f i c a n t l y  t h a n n o r m a l c o n t r o l s . O t h e r s t u d i e s , however, have not  6  of  higher  found a  Literature difference subjects little  i n plasma histamine  histamine,  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  even though t h i s  i s crucial  C o n c o m i t a n t symptoms may o c c u r arthralgia,  and  and c o n t r o l  (Murdoch e t a l . , 1987; P o l l o c k e t a l . , 1 9 9 1 ) . T h e r e i s  research  shortness  between u r t i c a r i a  Review  with urticaria,  such as headaches,  wheezing, nausea, v o m i t i n g ,  hoarseness,  abdominal  ( S o t e r , 1 9 9 1 ) . T h e s e symptoms may be  manifestations  o f excess plasma  systemic  than histamine  also contribute  a n d a n g i o e d e m a symptoms. A n t i h i s t a m i n e  does n o t 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  last  medication  longer  than the  t i m e t h a t c o u l d be a t t r i b u t e d t o t h e e f f e c t o f h i s t a m i n e (Holgate  & Church, 1993). P r o s t a g l a n d i n s ,  platelet-activating histamine  alone  kinins,  f a c t o r and major b a s i c p r o t e i n  t o produce u r t i c a r i a  pain  histamine.  Inflammatory mediators other to u r t i c a r i a  (Taylor,1986).  t h e s e n s a t i o n o f a lump i n t h e t h r o a t ,  of breath,  diarrhea  information  3  function with  a n d a n g i o e d e m a . The r e l a t i v e  importance o f each o f t h e inflammatory  m e d i a t o r s v a r i e s among  individuals. Mast c e l l s and  are degranulated  by a v a r i e t y o f  immunological  n o n - i m m u n o l o g i c a l f a c t o r s . A s a r e s u l t , many f a c t o r s h a v e  been i d e n t i f i e d i n t h e pathogenesis  of u r t i c a r i a  (Table  1). In  Major b a s i c p r o t e i n , a t o x i c product of e o s i n o p h i l degranulation, i s elevated i n the l e s i o n a l s k i n of subjects 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 ) . 3  7  with  Literature 75 % o f c h r o n i c u r t i c a r i a c a s e s , unknown  the i n c i t i n g agent  Review  remains  ( B u r r a l l e t a l . , 1 9 9 0 ) . D i e t may c o n t r i b u t e t o c h r o n i c  urticaria  a n d a n g i o e d e m a symptoms i n some  individuals.  Table 1: POSSIBLE CAUSES OF URTICARIA Cause  Examples  Physical Stimuli  Pressure, exercise,  Immune C h a n g e s  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 diseases, lupus 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 r e p l a c e m e n t t h e r a p y , 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,  Dietary  Benzoates, t a r t r a z i n e ,  change o f t e m p e r a t u r e , sunlight  sweating,  menarche,  codeine  Psychological Stress R e f e r e n c e s : B u r r a l l , 1990; L e s s o f , R o s e n s t r e i c h , 1992  strawberries  1991; S o t e r ,  1991; Armenaka &  EFFECT OF DIET ON BODY HISTAMINE Histamine  Poisoning  Histamine  poisoning  r e s u l t s - f r o m the i n g e s t i o n o f food  very high l e v e l s of histamine. primary  with  S p o i l e d f i s h and cheese a r e t h e  foods a s s o c i a t e d w i t h histamine  poisoning  (Taylor,  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 m i n u t e s t o a few h o u r s a f t e r the i m p l i c a t e d food i s eaten  (Table  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 8  2 ) . The symptoms o f 110  histamine  Literature poisoning outbreaks 1968  were r e p o r t e d i n t h e U n i t e d S t a t e s b e t w e e n  a n d 1981 ( T a y l o r , 1 9 8 6 ) . U n d e r a m e d i c a l l y  research study,  supervised  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  m a c k e r e l samples t o determine t h e l e v e l necessary  JReviem-  t o produce histamine  o f food  spoiled  histamine  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  R a s h , u r t i c a r i a , edema, l o c a l i z e d inflammation  Gastrointestinal  Nausea, v o m i t i n g , cramping  Hemodynamic  Hypotension  Neurological  Headaches, p a l p i t a t i o n s , flushing, t i n g l i n g , burning, itching  Reference:  diarrhea,  T a y l o r , 1986  in  each f o o d sample d i d n o t c o r r e l a t e w i t h t h e c l i n i c a l , r e a c t i o n s  to  t h e samples  histamine  (Ijomah e t a l . , 1991). As food samples  as w e l l as o t h e r amines i n c r e a s e i n t h e f o o d .  amines, such as c a d a v e r i n e , histamine, al.,  spoil, These  i n h i b i t t h e enzymes w h i c h d e g r a d e  a l l o w i n g plasma histamine  levels to rise  (Bjeldanes e t  1 9 7 7 ) . The l a c k o f c o r r e l a t i o n b e t w e e n t h e h i s t a m i n e i n  food samples and t h e 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  varying  l e v e l s o f o t h e r amines i n t h e food samples. A d d i t i o n a l l y , t h e  9  Literature effectiveness  o f t h e enzymes w h i c h  d e g r a d e 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 histamine  (Lessof,  and d i a m i n e  to.dietary  1991).  A l t e r e d Histamine Metabolism Histamine  Review  i nUrticaria  Subjects  i s d e g r a d e d b y two enzymes,  oxidase  N-methyltransferase  (Figure 1 ) .  F i g u r e 1: HISTAMINE METABOLISM  l-Histidme  /Masi calls.\ V Basophils /  Dtcartxny****  •  (  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 Imidazole Acate Acid  Af-Methyl Histamine  Histamine  Imidazole Acenc Acid  Imid&20l8 Acetic 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 metabolites 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 A G , Goodman IS, Gilman A, eds. Toodman and Gilrrmn's The pharmacologic basis of therapeutics. 6th ed. New York: Macmillan Publishing, 1980:618.)  (Figure 1: W h i t e 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 J A l l e r g y C l i n Immunol 1990; 86, 4(2) :599-605.  10  disease,  Literature Diamine oxidase  (DAO)  on t h e v i l l u s  t i p of the  Review  intestinal  mucosa d e g r a d e s 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 of  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 .  urticaria  s u b j e c t s have s i g n i f i c a n t l y  reduced  L e s s o f e t a l . (1990) m e a s u r e d s m a l l b o w e l DAO p o s t - h e p a r i n p l a s m a DAO urticaria  s u b j e c t s had  curve  direct  a significantly  compared t o the c o n t r o l urticaria  and  4  subjects  c o n t r o l group response  N - m e t h y l t r a n s f e r a s e and  and  until  a clinical  life  l e s s h i s t a m i n e was  flare  response  five  less  than  degrade  i n some s u b j e c t s subjects  flushing  of plasma histamine  s u b j e c t s than  m i n u t e s c o m p a r e d t o 4.0  i n the u r t i c a r i a  activity  oxidase  urticaria  half  greater i n u r t i c a r i a  w h e a l and  deficient  as v a s o d i l a t i o n ,  significantly  endpoint  be  diamine  such  reached.  significantly  The  i n f u s i o n s at i n c r e a s i n g rates  h e a d a c h e s was  s u b j e c t s ( 6 . 2 ± 1.3  The  DAO  a c t i v i t y was  a n g i o e d e m a . C o n t r o l and  endpoint,  jejunal biopsy.  decreased  circulating  received intravenous histamine  a c t i v i t y using a  (n=10).  p l a s m a h i s t a m i n e . T h e s e enzymes may with u r t i c a r i a  activity.  (p<0.02). I n f o u r o f t h e  s u b j e c t s s t u d i e d , j e j u n a l DAO  the lowest  DAO  Some  ± 0.7;  p=0.02),  of  The  histamine  Intravenous a d m i n i s t r a t i o n of 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 f r o m t h e v i l l u s t i p i n t o t h e 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 time. 11  and  clinical  ( P o l l o c k et a l . , 1991).  to intradermal i n j e c t i o n  4  was  control  required to reach a  subjects  or  Literature was  shown t o b e s i g n i f i c a n t l y  i n control subjects that u r t i c a r i a histamine  longer  i nurticaria  subjects  (Maxwell e t a l . , 1990). These s t u d i e s  s u b j e c t s have a compromised a b i l i t y  Review than suggest  t o remove  from t h e c i r c u l a t i o n .  Sattler as a d i s t i n c t  & Lorenz disease  (1990) p r o p o s e d F o o d - I n d u c e d concept  Histaminosis  (Figure 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 D A O 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 enteralinduced histaminosis  F i g u r e 2: S a t t l e r J , L o r e n z W. I n t e s t i n a l d i a m i n e o x i d a s e a n d 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 a n e p i d e m i o l o g i c a l , m o d e l . J N e u r a l . Transm. 1 9 9 0 ; S u p p l 32:291-314.  F i g u r e 2: FOOD-INDUCED HISTAMINOSIS  12  Literature Increased histamine  and  lumen l e a d t o h i s t a m i n e and  b l o c k i n g agents i n the  r e c e i v e a DAO  significantly not  Blood histamine  The  p i g s w e r e g i v e n a 60 mg  and  clinical  i n c r e a s e i n the c o n t r o l p i g s  have been d e m o n s t r a t e d i n sheep  concepts  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  percent  of the u r t i c a r i a  histamine  subjects developed  instillation,  instillation.  symptoms, s u c h facial  The  (bloating, coughing.  The  plasma  results  and  they d i d not  flushing.  Thirty-two  urticaria within  overall,  64%  of  pressure,  disturbance  cramps, nausea o r 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 have r e s u l t e d  h i s t a m i n e . P l a s m a h i s t a m i n e was  the  subjects e x h i b i t e d other  headache, g a s t r o i n t e s t i n a l  These symptoms may  and  from i n c r e a s e d plasma  s i m i l a r between the groups at  13  one  the  u r t i c a r i a w i t h i n 12 h o u r s o f urticaria  mg  histamine  as a c c e l e r a t e d h e a r t r a t e , d r o p i n b l o o d  flushing, pruritus,  but  t o human s u b j e c t s  s u b j e c t s , and  exhibit  . u r t i c a r i a subjects developed  blockers,  s u b j e c t s w e r e g i v e n 120  duodenal i n s t i l l a t i o n .  l e v e l s remained s t a b l e i n the c o n t r o l  hour of the histamine  oral  ( S j a a s t a d , 1967).  C o n t r o l and u r t i c a r i a  through  to  symptoms i n c r e a s e d  (p<0.001). S i m i l a r  Kanny e t a l . (1993) a p p l i e d t h e s e  of histamine  food-induced  i n t h e p i g s w h i c h r e c e i v e d t h e DAO  with urticaria.  histamine  S a t t l e r e t a l . (1988) r a n d o m i z e d p i g s  b l o c k e r or s a l i n e .  h i s t a m i n e dose.  intestinal  a b s o r p t i o n , i n c r e a s e d plasma  d i s e a s e p r e s e n t a t i o n . To d e m o n s t r a t e t h e  h i s t a m i n o s i s concept,  did  DAO  Review  Literature time  0, b u t was s i g n i f i c a n t l y  higher i n the u r t i c a r i a  Review-  s u b j e c t s 5,  15 a n d 45 m i n u t e s 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  concluded  that u r t i c a r i a  degrading  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  enzymes, a n d t h i s clinical due  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  symptoms. However, t h e u r t i c a r i a  to the n a t u r a l occurrence  o f t h e symptoms i n t h e s e  and n o t t h e h i s t a m i n e i n s t i l l a t i o n . group which  received a placebo  The be  a c t i v i t y o f diamine  inhibited  Histamine  by concomitant  poisoning results  subjects  A separate u r t i c a r i a  treatment  c o n c l u s i o n s t o be drawn f r o m t h i s  Factors A f f e c t i n g Histamine  a t t a c k s may h a v e b e e n  control  would a l l o w s t r o n g e r  study.  Metabolism 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 oral  may  consumption o f food o r drugs.  from consumption o f h i s t a m i n e - r i c h  f o o d , such as s p o i l e d f i s h ; however, c o n s u m p t i o n o f h i s t a m i n e a l o n e does n o t produce h i s t a m i n e p o i s o n i n g Cadaverine  (Taylor,  1986).  and p u t r e s c i n e a r e amines t h a t i n c r e a s e i n s p o i l e d  food w i t h histamine. Cadaverine a c t i v i t y o f diamine  h a s b e e n shown t o i n h i b i t t h e  o x i d a s e in v i t r o  (Taylor & Lieber,  1978).  B j e l d a n e s e t a l . (1977) s t u d i e d t h e a b i l i t y o f t h e s e a m i n e s t o potentiate histamine t o x i c i t y . of  O r a l a d m i n i s t r a t i o n o f 150 mg/kg  h i s t a m i n e d i d n o t cause m o r t a l i t y i n f i v e  guinea-pigs.  A d m i n i s t r a t i o n o f t h e same h i s t a m i n e d o s e 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 death of 3 out of 9 g u i n e a - p i g s . A mg/kg  75  c a d a v e r i n e dose r e s u l t e d i n t h e 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 histamine r e s u l t e d i n the greatest m o r t a l i t y . A d m i n i s t r a t i o n p u t r e s c i n e d i d not r e s u l t  i n death. S a t t l e r  i n v e s t i g a t e d t h e in  p o t e n t i a l o f 486 d r u g s t o  purified  vitro  i n t e s t i n a l DAO  & Lorenz  a c t i v i t y . N i n e t y - f o u r drugs  of  (1990) inhibit inhibited  diamine 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® w h i c h i s u s e d i n t h e t r e a t m e n t o f tuberculosis  ( U r a g o d a & K o t t e g o d a , 1 9 7 7 ) . However, i n S a t t l e r  L o r e n z ' s s t u d y , isoniazid® was o x i d a s e . F u r t h e r in  vivo  &  o n l y a weak i n h i b i t o r o f d i a m i n e  studies are necessary to c l a r i f y  the  r e l e v a n c e o f d r u g s and f o o d a m i n e s i n human h i s t a m i n e p o i s o n i n g . D i a m i n e o x i d a s e i s l o c a t e d on t h e v i l l u s  t i p of the  e n t e r o c y t e s . C o n d i t i o n s w h i c h damage t h e v i l l u s  t i p may  t h e a c t i v i t y o f d i a m i n e o x i d a s e . R a t i n t e s t i n a l mucosa  decrease was  damaged b y a p e r f u s i o n w i t h h y p e r o s m o l a r s o d i u m s u l p h a t e w h i c h 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 m u c o s a l and DAO  (p<0.005)(Luk  disease  et a l . ,  1980). C o e l i a c p a t i e n t s  free diet(p<0.001)  (D'Agostino et a l . ,  c u r v e s . The  3 and 6 months on a g l u t e n 1987). C o n d i t i o n s o r  d i s e a s e s w h i c h damage t h e i n t e s t i n a l mucosa may  15  plasma  i n active  e x h i b i t b e l o w n o r m a l p o s t h e p a r i n p l a s m a DAO  diamine oxidase curves improved a f t e r  solution  decrease  DAO  Literature activity  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  r e a d i l y into the c i r c u l a t i o n .  Review  t o be a b s o r b e d more  Therefore,  the i n t e g r i t y of the  mucosa may be a r e l e v a n t f a c t o r i n t h e 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 .  intestinal and  flora  The  may h a v e t h e a b i l i t y t o d e c a r b o x y l a t e  t h e r e f o r e produce histamine.  histidine  I r v i n e e t a l . (1959)  d e m o n s t r a t e d 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  after  meat c o n s u m p t i o n . 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 histidine,  which approximated the h i s t i d i n e  administered. and  Urinary histamine  i n t h e meat m e a l ,  d i d not increase a f t e r a bread  m i l k meal. This suggests t h a t the h i s t i d i n e  i n t h e meat m e a l  was r e s p o n s i b l e f o r t h e 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 n t i b i o t i c was a d m i n i s t e r e d meal n o r t h e h i s t i d i n e  production. and  A f t e r an  t o t h e s u b j e c t s , n e i t h e r t h e meat  increased urinary histamine.  suggest that i n t e s t i n a l  f l o r a are necessary  These  dogs,  a n a l y s i s was n o t p e r f o r m e d . T h e r e h a v e b e e n no  w e l l - c o n t r o l l e d s t u d i e s t o support Mast c e l l s ,  results  f o r histamine  The s t u d y was c o n d u c t e d on f o u r men a n d t h r e e  a statistical  was  these f i n d i n g s .  w h i c h a r e numerous i n t h e i n t e s t i n a l w a l l ,  contribute to i n t e s t i n a l histamine.  Blood  particles  may  remaining i n  t h e g u t 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 histamine  ( S a t t l e r & Lorenz,  16  1990). C o n d i t i o n s  which  Literature increase i n t e s t i n a l of  urticaria  absorbed In  and  i n t o the  h i s t a m i n e may  intestinal  r e l e v a n t to the p r e s e n t a t i o n  angioedema i f the i n t e s t i n a l  histamine i s  circulation.  summary, d i a m i n e  are d e f i c i e n t  be  Review  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  i n some s u b j e c t s w i t h u r t i c a r i a ,  h i s t a m i n e t o be  absorbed  enzymes  allowing  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 p l a s m a h i s t a m i n e . These i n d i v i d u a l s experience u r t i c a r i a food.  a f t e r consumption of histamine c o n t a i n i n g  F a c t o r s , s u c h as amine and d r u g c o n s u m p t i o n ,  inhibit  t h e s e enzymes and w o r s e n u r t i c a r i a .  a n g i o e d e m a may  may  a l s o be  exacerbated  by  may  further  Chronic u r t i c a r i a  and  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 c o n s u m p t i o n o f f o o d and  food  additives.  Histamine  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 because they exacerbate  f o o d a l l e r g y symptoms  (Finn,  foods",  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 h a v e n o t conducted  (Ortolani,  1992).  c o n s t i t u e n t s w h i c h may reactions  The  account  "histamine r e l e a s i n g foods"  f o r the e x a c e r b a t i o n of  ( T a b l e 3) .  17  been have  allergic  Literature  Review  Table 3: HISTAMINE RELEASING FOODS CONSTITUENT  FOOD Pineapple  Salicylate  Strawberry-  Benzoate  Tomato  Salicylate  Fish  Histamine  Chocolate  Amines  Alcohol  Amines  Egg w h i t e References: Jacobsen,  Allergen 1987 a n d S w a i n 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 aggravated by a c e t y l s a l i c y l i c a c i d  cases a r e  (Burrall et al.,  an unknown m e c h a n i s m . A c e t y l s a l i c y l i c  acid inhibits  1990) t h r o u g h the cyclo-  o x y g e n a s e enzyme a n d a l t e r s p r o s t a g l a n d i n a n d 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 . exacerbation of u r t i c a r i a . similar,  T h i s may b e r e s p o n s i b l e f o r t h e  Salicylates  b u t weaker, c y c l o - o x y g e n a s e  The s t r u c t u r e o f b e n z o a t e s t h e r e f o r e , benzoates (Holgate & Chruch,  i n f o o d may h a v e a  effect  (Stevenson,  i ssimilar to acetylsalicylic  may a l s o i n h i b i t  the cyclo-oxygenase  1986). acid; enzyme  1993).  The r o l e o f f o o d 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 h a v e b e e n s t u d i e d in  vitro  washed m a s t c e l l s  a n d in  vivo.  M u r d o c h e t a l . (1987) i n c u b a t e d  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  urticaria  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 food a d d i t i v e s t o t h e b u f f e r . The  c o n c e n t r a t i o n s o f t h e f o o d a d d i t i v e s i n t h e 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 t h e p l a s m a 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  histamine  r e l e a s e g r e a t e r than t h e spontaneous r e l e a s e o f h i s t a m i n e  i n the  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 response. the u r t i c a r i a histamine  T h e r e was no s i g n i f i c a n t d i f f e r e n c e b e t w e e n  and c o n t r o l  subjects  (Table 4 ) . S i g n i f i c a n t  release occurred i n a minority of subjects.  In a separate  s t u d y , M u r d o c h , P o l l o c k & Naeem  (1987)  challenged t e n healthy subjects with t a r t r a z i n e or a placebo. T h e r e was a s i g n i f i c a n t  rise  t a r t r a z i n e challenge(p<0.005). plasma h i s t a m i n e  i n plasma histamine  T h e r e was no s i g n i f i c a n t r i s e i n  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 or a placebo.  These s t u d i e s s u g g e s t 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 a n d 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 histamine  a f t e r a 150 mg  r e l e a s e i n some  individuals.  19  i n endogenous  Literature  Review  Table 4: HISTAMINE RELEASE FROM THE WASHED LEUCOCYTES OF 30 SUBJECTS EXPOSED TO FOOD ADDITIVES OR ASPIRIN Ntuaber o f S u b j e c t s w i t h S i g n i f i c a n t Histamine Release Class  Compound  Healthy Subjects ( T o t a l 18)  Urticaria Subjects ( T o t a l 12)  Azo  Colour  Amaranth  2  2  Azo  Colour  Sunset  1  1  Azo  Colour  Carmoisine  3  2  Azo  Colour  Tartrazine  3  1  Non-azo C o l o u r  Green S  0  1  Non-azo C o l o u r  Quinoline  1  0  Non-azo C o l o u r  Indigo Carmine  2  1  Natural colour  Annatto  1  1  Antioxidant  BHA  1  1  Antioxidant  BHT  4  1  Other  Sodium Benzoate  3  3  Other  Acetylsalicylic acid M u r d o c h e t a l , 1987  2  3  Reference:  Yellow  Yellow  BHA= b u t y l a t e d h y d r o x y a n i s o l e ; BHT= b u t y l a t e d  Micronutrient Johnston  Intake e t a l . (1992) e v a l u a t e d t h e e f f e c t o f a s c o r b i c a c i d  supplementation significantly  hydroxytoluene  o n 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  l o w e r d u r i n g 2 weeks o f d a i l y  supplementation  with  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 (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 n o t f o u n d of supplementation Histamine magnesium  restricted diet,  i n t h e r a t may  In response  be i n f l u e n c e d b y  t o an e i g h t d a y  urinary histamine, histamine  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 increased  d u r i n g two week  w i t h 500 mg o f a s c o r b i c a c i d .  metabolism  levels.  Review  (p<0.05). D u o d e n a l DAO  dietar  magnesium content  o f some  a c t i v i t y o f some t i s s u e s  a c t i v i t y decreased.  These  c h a n g e s i n d i c a t e an i n c r e a s e i n b o d y h i s t a m i n e d u r i n g  magnesium  deficiency.  magnesium  The c h a n g e s were r e v e r s e d a f t e r a two d a y  refeeding period  ( N i s h i o et a l . , 1987).  Summary Histamine  i s a significant  a n g i o e d e m a . D i e t a r y i n t a k e may  factor i n urticaria  a l t e r plasma histamine  e x o g e n o u s o r endogenous means. The h i s t a m i n e absorbed  and through  i n f o o d may  be  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 of the histamine  c a t a b o l i z i n g enzymes  a r e compromised. C e r t a i n f o o d and  a d d i t i v e s may  endogenous  induce  release of histamine.  food Several  s t u d i e s have e v a l u a t e d t h e 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 chronic u r t i c a r i a  and angioedema.  21  Literature  Review  PREVIOUS DIETARY MANIPULATION STUDIES I N CHRONIC URTICARIA AND ANGIOEDEMA Uncontrolled Food-Additive  Free  Diets  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 food a d d i t i v e - f r e e d i e t s have reported urticaria  approximately symptoms  been p a r t i a l l y  30 t o 90% c o m p l e t e o r p a r t i a l  (Table  remission of  5 ) . The p o s i t i v e r e s p o n s e s may h a v e  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 s u c h 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 improving for  i t i s l i k e l y t h a t t h e d i e t s were p a r t i a l l y  t h e symptom i m p r o v e m e n t . C h a l l e n g e  tartrazine, (BHT)  sunset  5  yellow, benzoates, b u t y l a t e d  and b u t y l a t e d h y d r o x y a n i s o l e  a d d i t i v e s t o exacerbate  have i m p l i c a t e d hydroxytoluene  (BHA) a s t h e m o s t l i k e l y  urticaria.  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 a n d c l i n i c a l response t o each a d d i t i v e i s monitored. 5  the  studies  responsible  22  mmwm o in  00  £  I  O  oo  M <D  VO  4-1 IH (0  •j;  or.  O in  CN CN  in  —  u  o PH  w C/5  ta  III  C 0 g  a 0  <U  73  rd C  •rH  4->  m  m  Si  $ .2 p. os £  CN  vo  a  VO  o 3 u a!  a  •H  M  >1 rrj  T3  1  a o  in  00 cn  00 ^  oo in  in  VO  <-!  e o  u W •H 73 4J 0 x; <D O 4-1 • H t-l M-l  00  m <N  Q  on  CD  & H  on '5b v_  on  o  JD  CD  l-H H  c o  -J  r/T <D  o  &  .tS  &  CD  z  on cd  o  3  H  H o  o  CD  Iii a  111  5  "o  o  a  CD X)  on  e  CD  <u  c  on"  CD  cd on  OD cd  o  cd  1 +^  o  on  IT)  vo  VO.  ON  ON  ON  cd  cn  O 4-»  o  IS  IS*  on  on  4  O  w  o  o  -a on  3  O  00 ON  O  0O  as  §  o -a  u  CD  73  tt)  4-1  0  •H  •H 4-1  rd C  4)  U 0)  M 0  c  00  rd 73  V  O ^ - l -  rH  IT) 0)  n  So tt)10 0  g ^ rd 3 I tfl tt) C  M tt) M-l M-l 4-1  O C  10  rd  1  C rd O  a -H  > o M  g  o  •H  g rd  4-1  &  10 4->  S  o  tt) 4-> 1) rH  Ci  W w  SCD i^5 C  M O  •H  tJi  •°  U rd ft  a  4-1  3  •H 4->  -P  c0  rd tt)  O  SH  o o o  g in w tt) 3 MH rd 4-1  5  cd  cd t-  t;  cd  g tt) M  >1  'N O  <  on <U td  '-a '"3 c a o o "{§ c  e  in -rH  to  •rH  —3 T O  (0  M-l 0  d)  EH  o  a g  n rH C si a o  tt) rd  M-l  4->  i—I o  g  rH  o (0 •rH  o  o o  0 4-1 &  LT) a  c  lit 3 i  e  -H  e  '£  J  H a;  a) a) to M -P M-l (« 0  CN  CN  -H  VD  CN  c o  -H 10 10 •H  •H 4->  0  H  3  -rH  CM  mm <  4-1  w si 4J  55  ill  CO  10 4->  u 0  w O -H rH X! H rd tt) X!  -r-| X! 10  4J 4-1  tt) Di rd in  4-1 Ci  C  d)  o  H g O rd X 4-1 10 tt) in  I  mm  M 0)  a  4) -H  23  — t  -H  B  D  si  x;  Literature Controlled Food-Additive Controlled  challenged design  Diets  food-additive challenge  inconclusive results. u r t i c a r i a who  Free  Forty-three  c h i l d r e n w i t h angioedema  with various a d d i t i v e s or a placebo  i n t a k e s . The p r i m a r y  w i t h i n four hours of the c h a l l e n g e . additives challenged,  yellow  of s i x repeat  i n a double-blind  criterion  for a  o r angioedema  Of t h e n i n e  food colours  and  t h e most common compounds l e a d i n g t o  of u r t i c a r i a (Table  were  q u a n t i t i e s u s e d were  r e a c t i o n was a p p e a r a n c e o f u r t i c a r i a  exacerbation  and/or  showed i m p r o v e m e n t on an a d d i t i v e - f r e e d i e t ,  l e s s than average d a i l y  sunset  s t u d i e s have a l s o y i e l d e d  (Supramaniam, 1 9 8 6 ) . The c h a l l e n g e  positive  Review  a n d a n g i o e d e m a were t a r t r a z i n e  and  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 o u 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 n o t  completed. Sixty-five  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 a n d d a i r y - f r e e d i e t were c h a l l e n g e d various  food 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 a n g i o e d e m a w i t h i n 24 h o u r s o f t h e c h a l l e n g e considered  a p o s i t i v e response. F i f t y - f o u r percent  subjects responded t o s a l i c y l a t e , 26 % r e s p o n d e d t o t a r t r a z i n e . placebo.  The c h a l l e n g e  with  was  of the  34 % r e s p o n d e d t o b e n z o a t e a n d  T h e r e was no r e s p o n s e t o t h e  q u a n t i t i e s u s e d were two t o t h r e e  greater  24  times  Literature  Review  Table 6 : RESULTS OF FOOD ADDITIVE CHALLENGES IN CHILDREN WITH ANGIOEDEMA AND URTICARIA Food A d d i t i v e  Number Challenged  Number Who Reacted (%)  Placebo  43  1  (2%)  Tartrazine  43  11  (26%)  Sunset  36  10  (28%)  Amaranth  37  4  (11%)  Indigo  19  3  (16%)  Carmoisine  12  0  Sodium Benzoate  27  4  (15%)  Monosodium G l u t a m a t e  36  3  (8%)  12 Sodium M e t a b i s u l p h i t e R e f e r e n c e : S u p r a m a n i a m a n d W a r n e r , 198 6  1  (8%)  (lactose)  Yellow  Carmine  t h a n t h e q u a n t i t i e s u s e d i n Supramaniam and Warner's s t u d y . may  account f o r t h e increased frequency  b l i n d challenges result benzoic Lahti,  o f r e a c t i o n s . Double-  w i t h 44 c h r o n i c u r t i c a r i a  subjects did not  i ngreater reactions to t a r t r a z i n e ,  sodium benzoate,  a c i d , BHT o r BHA t h a n t o t h e p l a c e b o  (Hannuksela and  1 9 8 6 ) . 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 i m p r o v e m e n t o n a n 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 food a d d i t i v e s and a placebo al.,  This  i na double-blind t r i 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  t o BHA/BHT c h a l l e n g e s  butnott o the placebo.  (Goodman e t occasions  Neither of the  p a t i e n t s r e s p o n d e d 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  with  Literature responded to sodium s a l i c y l a t e . that food  Review  From t h e s e s t u d i e s i t i s c l e a r  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  of u r t i c a r i a  a n g i o e d e m a i n some i n d i v i d u a l s ; h o w e v e r , t h e p r e v a l e n c e  and of  these  reactions i s uncertain.  Low  Histamine  Diets  Wantke e t a l . (1993) e v a l u a t e d diet.  the  e f f e c t o f a low  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 h e a d a c h e s and  wine i n t o l e r a n c e shortness  (flushing, pruritus, rhinitis,  of breath,  Thirty-three  (73%)  consuming a low  p a t i e n t s had  t y r a m i n e and many, b u t  low  not  s u b j e c t s had  food-additive diet. foods high  s u b j e c t s who  the  study  with  and followed  diet.  decrease i n  followed a  This d i e t also  i n histamine.  complete or p a r t i a l  The  diarrhoea  (p<0.01).  subjects with chronic u r t i c a r i a  all,  and  histamine  more t h a n a 50%  f r e q u e n c y o f symptoms a n d / o r d r u g use Sixty-seven  food  a f t e r consuming f o o d o r wine) were  o v e r a f o u r week p e r i o d w h i l e  histamine  remission  low  eliminated  Thirty-seven of u r t i c a r i a  (55%) symptoms.  responded p o s i t i v e l y to the d i e t presented increased  frequency of u r t i c a r i a  duration of disease,  y o u n g e r age,  h i s t o r y of u r t i c a r i a  and  d u r a t i o n o f t h e d i e t and  the  presence  time periods  family  of  ( V e r s c h a v e e t a l . , 1983  26  shorter  f a m i l y h i s t o r y of atopy,  a n g i o e d e m a and  gastrointestinal disturbances  attacks,  to  ).  The  t h a t symptoms were  Literature evaluated  were n o t 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  chronic u r t i c a r i a . the  I f t h e p e r i o d o f time between t h e i n i t i a l and  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 remission of  symptoms may h a v e b e e n due t o t h e n a t u r a l p r o g r e s s i o n disease  Review  and n o t t h e treatment  benefit urticaria,  diet.  Low h i s t a m i n e  angioedema and o t h e r  of the  d i e t s appear t o  c o n d i t i o n s which are  mediated by histamine.  OTHER CONDITIONS WHICH MAY BENEFIT Atopic  FROM A HISTAMINE-REDUCING  DIET  Disease  Atopic disease  i s a d i s o r d e r caused by Immunoglobulin E  mediated release o f inflammatory  m e d i a t o r s f r o m mast c e l l s a n d  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 a s t h m a , eczema a n d u r t i c a r i a . is not greater Supramaniam  mediator.  The p r e v a l e n c e  i n chronic u r t i c a r i a  subjects  of atopic  diseases  (Soter,1991;  & W a r n e r , 1986) .  Antihistamine medication allergic  of atopy are r h i n i t i s ,  o f t e n c o n t r o l s t h e symptoms o f  r h i n i t i s i n d i c a t i n g that histamine A histamine-reducing  i s the primary  d i e t may b e e f f e c t i v e i n  controlling allergic rhinitis.  27  Literature  Migraine  Headaches  Wantke e t a l . ( 1 9 9 3 )  reported a significant  reduction i n  headaches a f t e r  f o u r weeks on a l o w h i s t a m i n e d i e t .  be  mediator  an i m p o r t a n t  Mansfield, tyramine  of food-induced  headaches  1 9 8 7 ) . Many f o o d s h i g h i n h i s t a m i n e  ( S t r a t t o n e t a l . , 1 9 9 1 ) . The  improve m i g r a i n e  headaches.  Gastrointestinal  Disturbances  Defects  in intestinal  d i a r r h e a a r e s e e n i n 40% (Moneret-Vautrin  D,  1987;  d i a r r h e a . Excess  bile  1981). Histamine  result  treatment  r e l e a s i n g food,  diet w i l l  urticaria may  vivo,  mediate  this action is  (antihistamine medication)  excess  BACKGROUND LITERATURE RELATED TO The  and  i n d i a r r h e a by i n c r e a s i n g  e t a l , 1 9 9 5 ) . A h i s t a m i n e - r e d u c i n g d i e t may o f d i a r r h e a c a u s e d by  may  b i l e a c i d s i n the c o l o n cause  a c i d s may  antagonists  (Vaughan &  as a b d o m i n a l p a i n  c h l o r i d e s e c r e t i o n f r o m t h e e n t e r o c y t e s . In i n h i b i t e d b y HI  may  are a l s o h i g h i n  of p a t i e n t s w i t h chronic Juhlin,  Tyramine  histamine-reducing diet  f u n c t i o n , such  the p r o c e s s by w h i c h excess  cases  Review  be  effective  TREATMENT AND  eliminate potential  histamine.  28  f o r some  colonic bile acids.  THE  f o o d a d d i t i v e s and  (Gelbmann  CONTROL DIETS histamine  food which i s high i n  Literature  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  Histamine i s produced  Formation  of  Amines  from the d e c a r b o x y l a t i o n of  ( 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 decarboxylase a c t i v i t y  (Taylor,  1986).  decarboxylase-producing microorganisms for microbiological (Halasz et a l . ,  Free  histidine  histidine  histidine,  and a d e q u a t e  conditions  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  1 9 9 4 ) . The  amount o f h i s t a m i n e f o r m e d  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 a r e aged  and  f e r m e n t e d a r e 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 Escherichia,  Salmonella,  (Halasz et a l . ,  1994;  Clostridium, Taylor,  B a c i l l u s and  1986). D e c a r b o x y l a s e  are Lactobacillus activity  v a r i e s b e t w e e n 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 . as g r o w t h activity  c o n d i t i o n s and g r o w t h - p h a s e (Halasz et a l . ,  F a c t o r s such  of the microorganism  1 9 9 4 ) . 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 culture  f o r fermentation (Halasz et a l . ,  affect  starter  1994). Temperature,  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  pH  growth  and t h e r e f o r e amine f o r m a t i o n . F r e e amino a c i d s may proteolytic activity  occur n a t u r a l l y i n food or r e s u l t  (Halasz et a l . ,  1994). Scombroid  or mackerel  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 ,  29  from  and  Literature are t h e r e f o r e s u s c e p t i b l e t o histamine al.,  formation  Review  (ten Brink et  1990). Other amines a r e p r o d u c e d b y d e c a r b o x y l a t i o n o f t h e  corresponding  amino a c i d s  decarboxylate h i s t i d i n e ,  Table  ( T a b l e 7 ) . The m i c r o o r g a n i s m s  which  may, b u t do n o t n e c e s s a r i l y ,  7: AMINES AND THE AMINO A C I D PRECURSORS  Amine  P r e c u r s o r amino  Histamine  Histidine  Tryptamine  Tryptophan  Tyramine  Tyrosine  acid  . Phenylalanine  Phenylethy1amine  Ornithine  Putrescine  Lysine Cadaverine R e f e r e n c e : t e n B r i n k e t a l , 1990  decarboxylate microorganisms  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 may be p r e s e n t  t h e amine c o n t e n t w i l l  Amine Content  cheese v a r i e t i e s . batch o f Swiss  a l s o be q u i t e v a r i a b l e  of Susceptible  Cheese: H i s t a m i n e  during food processing; t h e r e f o r e , (ten Brink,  1990).  Food  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  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  c h e e s e t h a t was i m p l i c a t e d i n a n o u t b r e a k o f  30  Literature h i s t a m i n e p o i s o n i n g , and histamine  i t i s l i k e l y t h e most  forming microorganism  i n cheese  1 9 9 1 ) . However, h i s t i d i n e d e c a r b o x y l a s e o n l y a few  s t r a i n s o f L.  decarboxylase  buchneri.  s t r a i n s o f L. buchneri  c o n d i t i o n s . A storage temperature l e v e l s o f 6.8 9°C  o f 5.39  as a s t o r a g e pH histamine ripening  varies with  o f 21°C  histidine  growth  mmol/kg o f c h e e s e .  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  o f 5.19.  l e v e l s o f 9.4  i s not  Storage  a t 21°C  and pH  5.39  mmol/kg o f c h e e s e a f t e r  treatment  not decrease  Most c o m m e r c i a l l y  1990). Therefore, contamination  histamine  1 year  of activity  of  (Joosten, 1988). I f buchneri,  the r i s k of histamine  activity  A  formation  formation.  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  h i s t i d i n e decarboxylase  of  resulted in  h i s t i d i n e decarboxylase  a f f e c t e d by h e a t  pasteurization w i l l  producing  to  resulted i n histamine  t h e m i l k u s e d t o p r o d u c e t h e c h e e s e c o n t a i n s L.  possess  i s limited  a c t i v i t y of  l e v e l s o f 2.2  ( J o o s t e n , 1988) . The  L. buchneri  ( S t r a t t o n et a l . ,  mmol/kg o f . G o u d a c h e e s e . A s t o r a g e t e m p e r a t u r e  resulted i n histamine  s t o r a g e pH  important  activity  The  Review  not  (ten B r i n k et a l . ,  formation u s u a l l y results  of the m i l k w i t h a h i s t i d i n e  from  decarboxylase-  microorganism.  Putrescine,  tyramine,  cadaverine  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  31  histamine  Literature 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  Review amines  ( S t r a t t o n e t a l . , 1991). Fish: scombroid  Histamine  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  f i s h due t o t h e 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 tuna, 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 .  N o n - s c o m b r o i d f i s h have o c c a s i o n a l l y been  associated with histamine poisoning  (Rohani  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 t h a n per  100 g o f f i s h .  Fish products  will  e t a l . , 1985).  100 mg o f h i s t a m i n e  n o t be i m p o r t e d  o r t h e 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 t h a n per  b y Canada  10 mg o f h i s t a m i n e  100 g o f f i s h . Random s a m p l e s o f f o u r t y p e s o f s c o m b r o i d  were o b t a i n e d f r o m a r e t a i l f i s h o u t l e t (Rohani 10.9  i n Serdang,  fish  Selangor  e t a l . , 1 9 8 5 ) . T h r e e o f 56 samples: c o n t a i n e d 4.5 mg/lOOg,  mg/lOOg, a n d 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 mackerel for  Fish  processed  histamine  and f o u r t e e n d u p l i c a t e samples o f canned  i n Serdang, Selangor  content.  Three canned tuna  f o r e x p o r t were  analyzed  samples were found t o  c o n t a i n 2.3 mg/lOOg, 9.4 mg/lOOg a n d 15.9 mg/lOOg o f h i s t a m i n e . Histamine to  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  canning.  No m a c k e r e l  cold storage  samples c o n t a i n e d h i s t a m i n e .  prior  Histamine  l e v e l s a s h i g h a s 180 t o 500 mg/g o f f i s h h a v e b e e n r e p o r t e d (Malone & M e t c a l f e - , 1986) . K i m & B j e l d a n e s samples o f canned tuna  (1979) e v a l u a t e d 15  i m p l i c a t e d i n an o u t b r e a k  32  of  scombroid  Literature f i s h p o i s o n i n g and found content  t o be h i g h e r t h a n  histamine  content  the histamine,  content.  and p u t r e s c i n e  34 c a n s o f s u p e r m a r k e t t u n a . The mean  i n t h e 15 t u n a  Fermented f i s h p r o d u c t s histamine  cadaverine  Review  s a m p l e s was 116±6 mg/lOOg.  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  Ten s a m p l e s o f s a l t e d t e n g g i r i  b e t w e e n 3.5 mg/lOOg a n d 12.0 mg/lOOg o f h i s t a m i n e  fish  contained  (Rohani  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 b e t w e e n 31 mg/lOOg were found et  et a l . , t o have  a n d 101 mg/lOOg o f h i s t a m i n e . C a n n e d h e r r i n g  t o have h i s t a m i n e  l e v e l s o f 0 - 18 mg/lOOg  (Stratton  a l . , 1991). Fermented beverages: A s u r v e y o f A m e r i c a n a n d E n g l i s h w i n e  reported a histamine red  range from n o n - d e t e c t a b l e  t o 30 mg/L,  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  with  contents  ( 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 tyramine  have a l s o been r e p o r t e d i n wine  B e e r was r e p o r t e d t o h a v e a h i s t a m i n e  (Baucom e t a l . , 1 9 8 6 ) .  r a n g e o f 2.6 t o 20.0 mg/L  ( S t r a t t o n e t a l . , 1991). Histamine  was n o t d e t e c t e d i n b r a n d y ,  s c o t c h whiskey o r cognac  et al.,1969).  (Granerus  Meat and Meat Products: Zee e t a l . (1983) f o u n d of histamine,  cadaverine,  p u t r e s c i n e and t y r a m i n e  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  low l e v e l s  i n f r e s h pork  t h e 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 c a n 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 t e m p e r a t u r e .  33  S a y e m - E l - D a h e r e t a l . (1984)  Literature analyzed  Review  62 r a n d o m l y c h o s e n s a m p l e s o f f r e s h g r o u n d b e e f .  histamine  content  level of  0.57 mg/lOOg. T h e r e was a p o s i t i v e  r a n g e d b e t w e e n 0.0 t o 21.7 mg/lOOg w i t h a mean  the l e v e l s o f p u t r e s c i n e , cadaverine temperature  correlation  and t y r a m i n e  between  and time and  of storage.  Fermented meats have i n c r e a s e d h i s t a m i n e histamine  The  content  levels.  The  o f 27 d r y - s a u s a g e s a m p l e s r a n g e d b e t w e e n n o n -  d e t e c t a b l e a n d 19.74 mg/lOOg o f d r y m a t t e r  (Vanerkerckhove,  (1990). Fermented V e g e t a b l e s : Raw c a b b a g e c o n t a i n s a v a r i e t y o f microorganisms.  The c o n t a m i n a t i o n  of sauerkraut  production  d e p e n d s 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 a n d p r o c e s s i n g treatment.  I n a s u r v e y o f 50 s a m p l e s o f r e t a i l  sauerkraut, the  r a n g e o f h i s t a m i n e was 0.91 t o 13.0 mg/lOOg a n d t h e a v e r a g e histamine  c o n t e n t was 5.06 mg/lOOg  (Taylor et 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 histamine  l e v e l , o f t a m a r i was 2392 ug./g a n d one b r a n d  foods, t h e of soy  s a u c e was 220 u g / g ( C h i n e t a l . , 1 9 8 9 ) . S o y s a u c e made f r o m 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 sauce  (Stratton,  than r e g u l a r soy  1991).  Food p r o d u c t i o n and s t o r a g e methods w h i c h l i m i t formation are e s s e n t i a l . growth o f microorganisms.  Low t e m p e r a t u r e  storage  amine  i n h i b i t s the  S t a r t e r c u l t u r e s used i n food  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 t h e m i c r o o r g a n i s m h a s decarboxylase a c t i v i t y .  Raw f o o d s a r e o f t e n c o n t a m i n a t e d  microorganisms; therefore, hygienic p r a c t i c e  with  i s essential.  Low  t e m p e r a t u r e s t o r a g e a n d 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 t h e f o o d i n d u s t r y a n d i n t h e home. The  f o r m a t i o n o f amines i n f o o d depends on t h e p a r t i c u l a r  microorganisms growth are of the  i n t h e f o o d , p r e s e n c e o f f r e e amino a c i d s a n d  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  quiet variable food borne particular  consuming  (Zee e t a l . ,  amines w i l l  1 9 8 3 ) . The p h y s i o l o g i c a l  foods  effect  d e p e n d on t h e l e v e l o f e a c h amine i n  f o o d and t h e s e n s i t i v i t y o f t h e i n d i v i d u a l  the food.  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 a n d s o d i u m b e n z o a t e  a r e w i d e l y used  as a n t i m y c o t i c a n d 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 f o o d s a n d b e v e r a g e s . B e n z o i c a c i d i s commonly a d d e d t o t o m a t o p r o d u c t s , processed f r u i t ,  margarine  a n d 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  u s e d a s a b l e a c h i n g , m a t u r i n g a n d dough c o n d i t i o n i n g a g e n t f o r flour.  The p r e s e n c e o f b e n z o a t e s must be d e c l a r e d on t h e  ingredient label. Additionally,  benzoates occur n a t u r a l l y i n  food. Levels o f n a t u r a l benzoates c i n n a m o n , nutmeg, c l o v e s ,  teas,  are h i g h e s t i n prunes,  a n i s e a n d many b e r r i e s  35  especially  Literature strawberries,  r a s p b e r r i e s and  cranberries  (Jacobsen,  Review-  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  considerably  w i t h growing c o n d i t i o n s  Food  (Heimuber & H e r r m a n n , 1 9 9 0 ) .  products  l a b e l l e d with benzoic  peroxide  and  foods w i t h high  b e n z o a t e s s h o u l d be Salicylates:  Salicylate  variety,  stage  investigation  clinical  histamine-reducing  and  variety  growing c o n d i t i o n s ,  processing.  The  i n f o o d was  known. Foods w i t h  raisins  BHA  and  baked food products.  food  most c o m p r e h e n s i v e c o m p l e t e d by  Swain  to provoke  g r e a t e r t h a n 5 mg  ( a r b i t r a r y l i m i t ) s h o u l d be  per  e l i m i n a t e d from a hot  (Swain e t a l . , 1985).  BHT  a r e u s e d as  p r e s e r v a t i v e s i n f o o d s u c h as and  i n a wide  diet.  d i e t . These f o o d s i n c l u d e c u r r y powder,  p a p r i k a , p r u n e s and BHT:  occurring  q u a n t i t y of s a l i c y l a t e necessary  symptoms i s n o t  and  naturally  levels vary with  common p o r t i o n s i z e  BHA  occur  of s a l i c y l a t e l e v e l s The  benzoyl  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  of ripeness  et a l . (1985).  sodium benzoate,  l e v e l s of n a t u r a l l y  Salicylates  of food.  acid,  The  f a t s and  antioxidant  oils,  p r e s e n c e o f BHA  breakfast and  BHT  cereals  must  be  i  d e c l a r e d on  the  BHA  s h o u l d be  and  BHT  Food p r o d u c t s  i n g r e d i e n t l a b e l . A l l food products  w i t h BHA  containing  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 and  BHT  i n t h e p a c k a g e m a t e r i a l may  permitted.  36  diet. be  Literature Artificial improve  food c o l o u r s : A r t i f i c i a l  the appearance o f prepared  colour which  i s most l i k e l y  Review  c o l o u r s a r e used t o  food. T a r t r a z i n e i s the food  to exacerbate u r t i c a r i a .  f o o d c o l o u r must be d e c l a r e d o n t h e i n g r e d i e n t l a b e l ; s p e c i f i c colours are not necessarily l a b e l l e 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  Artificial however,  Therefore,  food  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 .  Control Diet For t h e purpose  o f t h e 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 a s one i n w h i c h  artificial  sweeteners  were e l i m i n a t e d ,  b e c a u s e t h e y a r e 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 b u t h a v e b e e n shown t o n o t do s o . Kulczycki  (1986) r e p o r t e d a s i n g l e c a s e  study of u r t i c a r i a  following a blinded challenge with the a r t i f i c i a l aspartame® the American  ( 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 ) . Centers  from  aspartame®  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 d e t e r m i n e consumption  I n 1984,  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 consumption.  sweetener  t h e r e l e v a n c e o f aspartame®  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) c o n d u c t e d placebo-controlled,  a randomized,  crossover c l i n i c a l  37  double-blind,  study t o determine i f  Literature aspartame® c o n s u m p t i o n 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  c o n d u c t e d a t s i x h o s p i t a l s i n Canada and t h e U n i t e d I n d i v i d u a l s who e x p e r i e n c e d  urticaria  Review was  States.  a n d / o r a n g i o e d e m a w i t h i n 12  h o u r s o f aspartame® c o n s u m p t i o n o r h a d r e s o l u t i o n o f symptoms when aspartame® was r e m o v e d f r o m t h e d i e t w e r e i n v i t e d t o participate allergists  i n the study.  Recruitment  l e t t e r s were m a i l e d  i n C a n a d a a n d t h e U n i t e d S t a t e s a n d 11 l o c a l  and  dermatology s o c i e t i e s .  had  reported u r t i c a r i a  t o 4700  allergy  One h u n d r e d a n d two i n d i v i d u a l s  a n d / o r a n g i o e d e m a symptoms  who  after  c o n s u m p t i o n o f aspartame® t o t h e N u t r a s w e e t Company, t h e producers  o f aspartame, were i n v i t e d t o p a r t i c i p a t e  One h u n d r e d a n d 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  i n the study.  called a toll-free  number t h a t h a d b e e n 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 . one  subjects entered  the  study  criteria,  to follow-up,  the study.  F o r t y - f o u r s u b j e c t s d i d n o t meet  32 d i d n o t w i s h  to participate,  placebo,  9 were  3 were a b l e t o consume aspartame® w i t h o u t  1 was p r e g n a n t a n d 1 h a d p h y s i c a l u r t i c a r i a . at the study  centres  The s u b j e c t s  products  stayed with  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. w i t h a body w e i g h t g r e a t e r t h a n  lost  problem,  f o r t h e f i v e days and were c h a l l e n g e d  aspartame® a n d t h e c o n v e r s i o n  aspartame®. S u b j e c t  Twenty-  Subjects  40 k g r e c e i v e d 950 mg o f  who w e i g h e d l e s s t h a n  40 k g r e c e i v e d 475 mg  o f aspartame®. The aspartame® d o s e was 5 t o 6 t i m e s  38  the average  Literature  Review  amount cqnsumed. Subjects r e c e i v e d e i t h e r aspartame® or placebo on Day 2 or 4 i n random o r d e r . There was no  statistical  d i f f e r e n c e i n the i n c i d e n c e of p o s i t i v e r e a c t i o n s between aspartame® and placebo. Even though s e v e r a l i n d i v i d u a l s have r e p o r t e d an e x a c e r b a t i o n of u r t i c a r i a  symptoms a f t e r aspartame®  consumption, these claims have not been v a l i d a t e d .  SIGNIFICANCE OF THE PRESENT STUDY D i e t may exacerbate u r t i c a r i a  and angioedema by i n c r e a s i n g  histamine l e v e l s i n the body through exogenous or endogenous mechanisms. The c o n t r o l of u r t i c a r i a  and angioedema through  d i e t a r y m a n i p u l a t i o n would l e a d to a r e d u c t i o n i n m e d i c a t i o n use and an improvement i n the q u a l i t y of l i f e  f o r these p a t i e n t s . The  e f f e c t i v e n e s s of 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 should be e v a l u a t e d i n a c o n t r o l l e d  39  study.  Methods  3  CHAPTER METHODS  EXPERIMENTAL DESIGN The  s t u d y was  a randomized, p r o s p e c t i v e design. Subjects  chronic u r t i c a r i a  a n d / o r a n g i o e d e m a were r e c r u i t e d  randomized to a treatment  or c o n t r o l d i e t .  e l i m i n a t e d f o o d w h i c h was  high i n histamine  w h i c h may d i e t was  days  and  and  treatment  b a s e d on C a n a d a ' s F o o d G u i d e and sugar  alcohols.  The  control  eliminated a r t i f i c i a l  d i e t s w e r e t o be  followed for  (8 w e e k s ) . T h r e e - d a y f o o d r e c o r d s w e r e a n a l y z e d  (2 weeks) t o e n s u r e n u t r i t i o n a l  compliance.  a d e q u a c y and  Subjects evaluated t h e i r u r t i c a r i a  symptoms on a d a i l y b a s i s , as i n s t r u c t e d , p r i o r t o t h e s t a r t o f t h e d i e t and  s e v e r i t y o f p r u r i t u s and a n a l y z e d u s i n g a 2x2  x time)  40  14  dietary  and  beginning  angioedema f o u r t e e n days the  i n t a k e , number o f w h e a l s ,  a n g i o e d e m a were r e c o r d e d .  (group  every  c o n t i n u i n g throughout  study p e r i o d . A n t i h i s t a m i n e medication  diet  food a d d i t i v e s  i n c r e a s e e n d o g e n o u s r e l e a s e o f h i s t a m i n e . The  s w e e t e n e r s and 56 d a y s  The  with  The  d a t a were  r e p e a t e d m e a s u r e s ANOVA.  Methods  METHODS Sample  size  A s a m p l e s i z e o f 15 t o 20 s u b j e c t s p e r g r o u p h a s b e e n shown to  be a d e q u a t e f o r s t a t i s t i c a l  medication  clinical  Bernstein,  1 9 8 8 ) . 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  trials  significance i n antihistamine  ( S h a r e e a h , 1992/ Sussman, 1 9 9 1 ;  f i r s t t e n s u b j e c t s , d u r i n g t h e 14 d a y s b e f o r e  diet,  was u s e d t o c a l c u l a t e s a m p l e s i z e  The mean number o f t a b l e t s t a k e n d e v i a t i o n o f 7.2. meaningful;  s t a r t i n g the  (Cheney & B o u s h e y ,  was 9.5 w i t h a  by  1992).  standard  A 50% c h a n g e i n t h i s m e a s u r e was  considered  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 u s e d ; a was s e t a t 0.05 a n d (3 was s e t a t 0.02.  F i g u r e 3: SAMPLE S I Z E CALCULATION  2 n=  2 n=  (0.84  + 1.96) x 7.2 5  n= 16.25 o r 17 s u b j e c t s p e r g r o u p  41  Methods  Thus, a s shown i n F i g u r e 3, t h e r e q u i r e d s a m p l e 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 g r o u p .  Subject  Recruitment  Recruitment medical c l i n i c s  p o s t e r s w e r e p l a c e d i n t h e w a i t i n g rooms a t f i v e and s i x pharmacies i n N o r t h Vancouver  A ) . The d e r m a t o l o g i s t s i n t h e l o w e r m a i n l a n d telephone,  and t h e i n v e s t i g a t o r attempted  (Appendix  were c o n t a c t e d by  t o make an a p p o i n t m e n t  to promote t h e study. 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 a personal v i s i t  response,  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 t h e B r i t i s h C o l u m b i a A s s o c i a t i o n was c o n t a c t e d b y t e l e p h o n e  Allergy  and sent i n f o r m a t i o n about  t h e 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 t h e A l l e r g y A s t h m a I n f o r m a t i o n A s s o c i a t i o n and t h e n i n e a c t i v a t o r s i n t h e lower mainland  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  a b o u t t h e s t u d y . The A l l e r g y A s t h m a 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 provide telephone diseases. Recruitment Dietitians'  support  to individuals with  allergic  n o t i c e s were p l a c e d i n t h e B r i t i s h  Columbia  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 ,  C o l u m b i a Pharmacy N e w s l e t t e r community c h a n n e l . R e c r u i t m e n t  (the B u l l e t i n )  British  and Rogers Cable  n o t i c e s were p l a c e d i n t h e  42  Methods  V a n c o u v e r Sun o r t h e P r o v i n c e n e w s p a p e r s o n J a n u a r y  21/22,  April  22/23 a n d J u n e 10/11, 1 9 9 5 . 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 urticaria had  i f they had  a n d / o r a n g i o e d e m a symptoms f o r a t l e a s t  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  s i x weeks a n d  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 . Y o u n g e r 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 and u r t i c a r i a (Burrall,  therapy,  i s most f r e q u e n t l y r e p o r t e d i n m i d d l e - a g e d  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  women  i n c l u d e d those  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, w e r e pregnant  o r had u r t i c a r i a l v a s c u l i t i s ,  infection,  m a s t o c y t o s i s , dermatophyte  Candida i n f e c t i o n , m o n o n u c l e o s i s ,  or lupus erythematosus.  rheumatoid  arthritis  I n d i v i d u a l s were n o t 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 m i g h t e x a c e r b a t e u r t i c a r i a a n d angioedema.  Many common d r u g s 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  greatly  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 t h e d i a g n o s i s a n d gave v e r b a l o r w r i t t e n c o n s e n t patients' participation  i n the study.  43  for their  Methods Dietary Intervention Treatment The  Diet  (Appendix  treatment  B)  d i e t e l i m i n a t e d f o o d w h i c h was  high i n histamine  and  f o o d a d d i t i v e s w h i c h may  e n d o g e n o u s r e l e a s e o f h i s t a m i n e . The due  to p o t e n t i a l l y high histamine  and  tomato p r o d u c t s ,  fish,  foods  potentially  increase  t h a t were  restricted  c o n t e n t were: s p i n a c h ,  processed  tomato  meat, l e f t o v e r meat,  products,  yoghurt,  s o u r cream, f e r m e n t e d  foods  alcohol.  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  and  procedures  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  m i c r o b i o l o g i c a l g r o w t h and products acid,  soy p r o d u c t s ,  cheese  histamine  containing tartrazine,  sodium benzoate,  formation i n food.  artificial  strawberry,  raspberry, prunes,  Pineapple, dates,  content.  tomato p r o d u c t s , e l i m i n a t e d due these  seafood,  "histamine  44  high  currants, raisins,  u n c o o k e d egg w h i t e , ' a n d  foods.  cinnamon, a n i s e ,  to p o t e n t i a l l y  Strawberries, pineapple,  to p o t e n t i a l  these  histamine.  c u r r y powder and h o t p a p r i k a w e r e e l i m i n a t e d due high s a l i c y l a t e  benzoic  were a l s o e l i m i n a t e d b e c a u s e  c l o v e s and nutmeg were e l i m i n a t e d due benzoate content.  Food  food c o l o u r ,  i n c r e a s e endogenous r e l e a s e o f  Cranberries,  decrease  benzoyl peroxide, butylated hydroxyanisole  and b u t y l a t e d h y d r o x y t o l u e n e a d d i t i v e s may  fermented  to  prunes,  potentially  tomato  and  c h o c o l a t e were  r e l e a s i n g " p r o p e r t i e s of  Methods The  rationale  subjects. written  Subjects  list  subject,  Control  diet  were t a u g h t  acceptable  was d i s c u s s e d to  w i t h the  read ingredient  f o o d p r o d u c t s was  and m e a l p l a n i n g s u g g e s t i o n s were  treatment  labels.  given to  A  each  discussed.  ( A p p e n d i x C)  Diet  The not  of  f o r the  control diet  influence  was d e s i g n e d  urticaria  t o be a p l a u s i b l e  to  and angioedema  treatment.  eliminate  food which would  symptoms,  but would appear  The c o n t r o l s u b j e c t s  followed a  diet  w h i c h was b a s e d on C a n a d a ' s Food G u i d e and e l i m i n a t e d aspartame®, xylitol  splenda®,  sunett®,  saccharin,  cyclamate,  mannitol,  and s o r b i t o l .  The  control subjects  treatment  group.  immune s y s t e m rationale  The i m p o r t a n c e o f  ingredient  f o r the  control diet.  (Kulczycki, labels  unacceptable  i n s t r u c t i o n s i m i l a r to a balanced intake  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  exacerbation of u r t i c a r i a discussed  had d i e t  after  1986).  The s i n g l e  for proper  as p a r t o f  documented c a s e  the of  a b l i n d e d aspartame c h a l l e n g e  Subjects  were  taught  and f o l l o w C a n a d a ' s F o o d G u i d e .  f o o d p r o d u c t s were  the  discussed.  45  to  was  read  Alternatives  to  Methods U r t i c a r i a and  Angioedema Assessment S c a l e  (Appendix  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 has  not  been developed  and  Dr.G.Sussman, MD).  (personal The  pretested  with u r t i c a r i a  urticaria  and  and  c o r r e s p o n d e n c e : Dr.  scale developed f o r t h i s angioedema p a t i e n t s .  a n g i o e d e m a p a t i e n t s who  had  asked to c r i t i q u e the u r t i c a r i a  make t h e  The  Morton, study  MD was  Previous  by  Vancouver  telephone  and  a n g i o e d e m a symptom a s s e s s m e n t  p a t i e n t s were a s k e d t o s u g g e s t c h a n g e s w h i c h w o u l d  s c a l e e a s i e r t o c o m p l e t e and  s e v e r i t y of t h e i r b a s e d on  and  angioedema  attended the  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  s c a l e . The  and  D)  symptoms. The  more r e f l e c t i v e o f  a s s e s s m e n t s c a l e was  the  revised  t h e s e comments. urticaria  and  angioedema assessment s c a l e i n c l u d e d  four  variables. (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  number o f t a b l e t s t a k e n e a c h day. among p a t i e n t s e a c h p a t i e n t be  (Juhlin,  m e d i c a t i o n brand throughout the antihistamines  and  the  D r u g e f f i c a c y and  1992); t h e r e f o r e ,  consistent with  subjects  respect  to  s t u d y . The  i t was  46  the  effect varies  necessary  that  antihistamine specific  d o s e s w e r e r e c o r d e d e a c h day  changes i n t h i s v a r i a b l e .  recorded  to  identify  Methods (2) Number o f w h e a l s :  The s u b j e c t s r e c o r d e d t h e t o t a l number o f  w h e a l s each day, and t h e y s p e c i f i e d whether t h e y c o u n t e d t h e 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 t h e 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 e a c h d a y on a s c a l e o f 0 t o 3, w h e r e t h e numbers r e p r e s e n t e d t h e f o l l o w i n g d e g r e e s o f s e v e r i t y : 0=symptoms a b s e n t ; l=symptoms a r e p r e s e n t , b u t b a r e l y  noticable;  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 a r e d e f i n i t e l y n o t i c a b l e , (4) S e v e r i t y o f a n g i o e d e m a : s e v e r i t y o f angioedema  and a r e n o t t o l e r a b l e .  The' s u b j e c t s r e c o r d e d t h e o v e r a l l  e a c h d a y on a s c a l e o f 0 t o 3, where t h e  numbers r e p r e s e n t e d t h e f o l l o w i n g d e g r e e s o f s e v e r i t y : a b s e n t ; l=symptoms a r e p r e s e n t , b u t b a r e l y n o t i c a b l e ; 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 ; definitely noticable,  0=symptoms 2=symptoms  3=symptoms a r e  and a r e n o t t o l e r a b l e .  The s u b j e c t s w e r e i n s t r u c t e d t o c o m p l e t e t h e a s s e s s m e n t s a t t h e same t i m e e a c h d a y f o r t h e 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 a s s e s s m e n t was s t r e s s e d t h r o u g h o u t t h e s t u d y .  Three-Day  Food R e c o r d s  ( A p p e n d i x E)  The p u r p o s e 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 nutrient  i n t a k e b e f o r e t h e d i e t s were i n i t i a t e d  and e v e r y two weeks a f t e r t h e d i e t s w e r e  47  (Days -3 t o -5)  initiated  Methods (Days 11,12,13, 25,26,27, 3 9 , 4 0 , 4 1 , 53,54 and the  food records  with respect  were u s e d t o p r o v i d e  feedback to the  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  the method t o e v a l u a t e was  55). A d d i t i o n a l l y , subjects  were c h o s e n  as  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  r e q u i r e d f o r s p e c i f i c d a y s . The  able to accurately r e c a l l  s u b j e c t s may  not have been  their dietary intake i f  questioned  retrospectively. 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 t h e  o f a l l f o o d and  b e v e r a g e s consumed and  type  and  quantity  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  accurately  was  provided. The  completed food records  were r e v i e w e d  d i e t a r y c o m p l i a n c e a t e a c h a p p o i n t m e n t . The analyzed  u s i n g the  software  analyses  were r e t u r n e d  appointment. I f the analyses  food records  PC N u t r i c o m V e r s i o n  N u t r i t i o n S y s t e m s ; V a n c o u v e r , B . C . ) . The nutritional  f o r accuracy  to the  i n d i c a t e d an  5.03  r e s u l t s of  d i s c u s s e d w i t h the  the major food  sources  subject  the  s u b j e c t s at the  48  next  inadequate intake, a  ( A p p e n d i x F ) . The  of each n u t r i e n t .  were  (Delta  h a n d o u t e n t i t l e d F o o d S o u r c e s o f S e l e c t e d N u t r i e n t s was and  and  handout  provided lists  Methods C o n t r o l of 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 to 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 d r u g s ,  a c e t y l s a l i c y l i c acid,  fenoprofen, indomethacin,  mefenamic a c i d , naproxen,  such  as  ketoprofen,  acetaminophen, phenylbutazone,  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 a l s o been s u s p e c t e d  (Armenaka, 1992; H o l g a t e ,  1993).  have  Isoniazid  i n g e s t i o n h a s b e e n 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 , a n d i  may be r e l e v a n t i n u r t i c a r i a 1977).  From t h e l i t e r a t u r e ,  m e d i c a t i o n s may  and angioedema i t appears  exacerbate u r t i c a r i a  (Uragoda  & Kottegoda,  that a variety of  and angioedema. T h e r e f o r e ,  consistency of a l l medications during the research study  was  s t r e s s e d . Any c h a n g e s i n m e d i c a t i o n f r o m b a s e l i n e were documented. Changes i n b a c t e r i a l , soaps,  viral  o r p a r a s i t i c i n f e c t i o n s ; use o f  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 ;  a l l e r g e n s and s t r e s s may (Burrall,  1990; A r m e n a k a ,  affect urticaria 1992).  environmental  and angioedema  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 c h a n g e s i n any o f t h e s e v a r i a b l e s on t h e a s s e s s m e n t s c a l e .  49  Methods Subject  Appointments  The s u b j e c t a p p o i n t m e n t s w e r e c o n d u c t e d  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 or at the  business  #9,  North  o f f i c e of the i n v e s t i g a t o r ,  14th S t r e e t ,  Vancouver. Eligible  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  s t u d y was f u l l y sign the,consent and  106 E a s t  frequency  or migraine  i n t e r v i e w . The  e x p l a i n e d and t h e s u b j e c t s were a s k e d form  (Appendix  t o r e a d and  G). S e l f - r e p o r t e d weight,  height  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  headaches were r e c o r d e d . A w e i g h t  was n o t a v a i l a b l e a t t h e s t u d y s i t e . daily urticaria  and h e i g h t  Study b o o k l e t s c o n t a i n i n g  and a n g i o e d e m a a s s e s s m e n t s c a l e s a n d  bi-monthly  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 t h e s u b j e c t s . v a r i a b l e s on t h e u r t i c a r i a  scale  The  four  and angioedema assessment s c a l e were  discussed. Prior to beginning  the d i e t a r y i n t e r v e n t i o n ,  subjects  r e t u r n e d f o r a f o l l o w - u p a p p o i n t m e n t . 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 r a n d o m i z e d t o t h e c o n t r o l o r t r e a t m e n t  The  diet.  s u b j e c t c h o s e one o f f o u r p i e c e s o f p a p e r . The l e t t e r ( c o n t r o l ) was w r i t t e n on two o f t h e p a p e r s , (treatment)  50  "o"  and t h e l e t t e r " r "  was w r i t t e n on t h e o t h e r two p a p e r s .  s u b j e c t chose from the t h r e e remaining  first  The  second  pieces of paper.  After  Methods f o u r s u b j e c t s had been randomized, The  s u b j e c t s w e r e i n s t r u c t e d on t h e a p p r o p r i a t e d i e t .  b e g a n on Day  0 of the  symptom a s s e s s m e n t  were c o n d u c t e d  e v e r y two  diets  weeks.  s c a l e s were r e v i e w e d , and any  changes o r d i e t a r y problems d i s c u s s e d . The  The  study.  Follow-up appointments The  the p r o c e d u r e began a g a i n .  variable  o v e r t h e p r e v i o u s two weeks w e r e  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 t h e 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 final completed.  appointment  was  h e l d a f t e r the s t u d y had  S e l f - r e p o r t e d weight  recorded. A weight significant.  been  c h a n g e s o v e r t h e s t u d y were  c h a n g e o f 5% o r more was  considered  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 ,  atopic  symptoms o r m i g r a i n e h e a d a c h e s were r e c o r d e d .  Statistical The Illinois,  Analysis  SPSS f o r Windows R e l e a s e 1993)  was  6.0  used to perform the s t a t i s t i c a l  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  Treatment The  and  Control  age  o f t h e two  samples t - t e s t .  (SPSS I n c . , C h i c a g o ,  Group  analysis.  The  s e t a t p <0.05.  Comparisons  groups  was  c o m p a r e d w i t h an  G e n d e r d i s t r i b u t i o n was  51  independent  a n a l y z e d w i t h a Mann-  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  S i g n e d - R a n k t e s t b e c a u s e t h e d a t a was n o t n o r m a l l y  Wilcoxon  distributed.  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 trials  (Sussman, 1 9 9 1 ; B e l a i c h , 1 9 9 0 ) .  U r t i c a r i a and Angioedema The  planned  Assessment  Scale  t i m e p e r i o d s w e r e : Days -14 t o -1 ( t i m e 1 ) , 0  t o 13 ( t i m e 2 ) , 14 t o 27 ( t i m e 3 ) , 28 t o 41 ( t i m e 4) a n d 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 a n d .wheals were c a l c u l a t e d  f o r e a c h t i m e p e r i o d . When t h e s u b j e c t s  t h e number o f w h e a l s a s a r a n g e ,  expressed  t h e l o w e s t number o f w h e a l s was  u s e d . F o r e x a m p l e , >100 was c o n s i d e r e d t o b e 100 a n d 50 - 60 was c o n s i d e r e d t o be 50. The t o t a l s c o r e s were c a l c u l a t e d .  i t c h i n e s s and angioedema  severity  I f d a t a was m i s s i n g o n a p a r t i c u l a r d a y ,  t h e a v e r a g e o f t h e o t h e r d a y s i n t h e t i m e p e r i o d was u s e d a s t h e value  f o r t h a t d a y . The t o t a l number o f d a y s 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  a n d t h e number o f d a y s t h a t w h e a l s ,  itchiness  a n g i o e d e m a symptoms w e r e r e p o r t e d w e r e c a l c u l a t e d f o r e a c h  t i m e 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 t i m e ) time  RM ANOVA ( w i t h r e p e t i t i o n o n t h e t i m e  f a c t o r ) . The  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 i n d e p e n d e n t  samples t - t e s t t o i d e n t i f y  significant baseline differences  between t h e c o n t r o l and t h e treatment  52  groups.  For v a r i a b l e s with  Methods a significant difference,  t h e 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 o n t h e t i m e  u s i n g t h e time  1 v a l u e a s t h e c o v a r i a t e . The symptom d a t a d i d n o t  s a t i s f y t h e assumption critical  of sphericity.  an a d j u s t e d  F v a l u e was c a l c u l a t e d u s i n g t h e H u y n h - F e l d t  The a d j u s t e d c r i t i c a l  interactions. comparison  significant  e f f e c t s and  The s i g n i f i c a n t t i m e e f f e c t was f o l l o w e d b y a  o f t h e c o m b i n e d means f o r e a c h t i m e p e r i o d w i t h a  paired t-test. considered  epsilon.  F v a l u e was c o m p a r e d t o t h e F v a l u e  c a l c u l a t e d b y SPSS t o d e t e r m i n e  In  Therefore,  factor)  To a c c o u n t  f o r m u l t i p l e comparisons,  a p<0.008 was  significant.  a d d i t i o n t o t h e RM ANOVA w h i c h  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  a s s e s s e d t h e change i n  study p e r i o d , a p a i r e d  s a m p l e s t - t e s t was u s e d t o compare t h e number o f a n t i h i s t a m i n e t a b l e t s taken by the treatment separate comparison  1 a n d t i m e 2. A  o f t h e c o n t r o l g r o u p was c o m p l e t e d .  done b e c a u s e o f t h e a s s u m p t i o n effective,  group d u r i n g time  symptoms w i l l  that i f the treatment  T h i s was  diet i s  improve w i t h i n a few days o f t h e d i e t a r y  intervention.  Nutrient  Analysis  The f o o d r e c o r d s w e r e a n a l y z e d f o r k i l o c a l o r i e s , carbohydrate,  protein,  f a t , c a l c i u m , i r o n , magnesium, p h o s p h o r u s , z i n c a n d  53  Methods v i t a m i n s A, B l , B2, B3, B6, B12, C a n d f o l a c i n . 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  The mean a n d  a t t i m e 1, t i m e 2, t i m e 3 a n d  t i m e 4 w e r e c o m p a r e d t o t h e 1990 Recommended N u t r i e n t (RNI)  f o r Canadians  Intakes  ( H e a l t h and W e l f a r e Canada, 1990). F o r 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 b a s e d on  t h e number o f m a l e a n d f e m a l e s u b j e c t s i n e a c h g r o u p . A mean i n t a k e l e s s t h a n 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 significant deficiency. 2x2  The n u t r i e n t d a t a w e r e a n a l y z e d w i t h a  ( g r o u p x t i m e ) RM ANOVA ( w i t h r e p e t i t i o n on t h e t i m e  The t i m e 1 v a l u e s were c o m p a r e d w i t h an i n d e p e n d e n t test to identify  factor).  samples t -  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 t h e  c o n t r o l and t h e t r e a t m e n t groups. F o r n u t r i e n t s w i t h a significant difference,  t h e d a t a w e r e a l s o a n a l y z e d w i t h a 2x2  ( g r o u p x t i m e ) RM ANCOVA ( w i t h r e p e t i t i o n on t h e t i m e u s i n g t h e t i m e 1 v a l u e as t h e c o v a r i a t e .  For the n u t r i e n t s  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 , critical  an i n d e p e n d e n t  significant  epsilon.  g r o u p x t i m e i n t e r a c t i o n s were f o l l o w e d b y a  comparison o f t h e c o n t r o l and t r e a t m e n t groups  comparisons,  that  an a d j u s t e d  F v a l u e was c a l c u l a t e d u s i n g t h e H u y n h - F e l d t  Significant  factor)  samples  t-tests.  To a c c o u n t  a t each time  for multiple  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  t i m e e f f e c t s were f o l l o w e d by c o m p a r i s o n o f t h e  c o m b i n e d means a t e a c h t i m e p e r i o d w i t h a p a i r e d  54  t-test.  To  with  Methods account  f o r m u l t i p l e comparisons,  a p<0.008 was  considered  significant.  E t h i c a l Approval  (Appendix  H)  This study 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 of 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  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  British  Other  Results CHAPTER  4  RESULTS  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  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 urticaria  and angioedema  patients of the commented o n t h e  a s s e s s m e n t s c a l e . B a s e d o n t h e comments,  " p r u r i t u s " was c h a n g e d t o " i t c h i n e s s " .  Three p a t i e n t s were n o t  a b l e t o c o u n t t h e i r w h e a l s . T h i s was b e c a u s e t h e r e w e r e t o o 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 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 g r o u p o f w h e a l s . Thus,  together  a s i n g l e wheal and  a space t o i n d i c a t e i f t h e wheals had  b e e n c o u n t e d o r g u e s s e d was i n c l u d e d i n t h e a s s e s s m e n t s c a l e .  RECRUITMENT T h e r e was no r e s p o n s e t o t h e r e c r u i t m e n t p o s t e r s medical  i n the  o f f i c e s and p h a r m a c i e s . 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  c o n t a c t e d by t e l e p h o n e and appointments were o b t a i n e d .  w i t h two d e r m a t o l o g i s t s  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  several dermatologists. to the study.  were  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  The B r i t i s h C o l u m b i a 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 n o t s u p p o r t t h e s t u d y b e c a u s e i t was n o t s u p e r v i s e d b y a  56  Results medical  d o c t o r . However, one member o f t h e 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 three p a t i e n t s t o the study. Eighty-three individuals most common r e a s o n the p o t e n t i a l  i n q u i r e d about t h e study  ( T a b l e 8 ) . The  f o r n o t e n t e r i n g t h e s t u d y was d i s t a n c e  subject's residence t o the study centre  from  (Appendix  I) •  Table 8: NUMBER OF SUBJECTS INQUIRING ABOUT AND ENTERING THE STUDY Total  RECRUITMENT EFFORT  Inquires  Subjects Entering Study  56  12  7  3  Newspaper Ad: June 10/11  8  1  R e f e r r a l t o ANC  6  3  Pharmacy n e w s l e t t e r  3  1  AAIA r e f e r r a l  2  0  Community Channel Ad  1  0  BCDNA n e w s l e t t e r  0  0  Newspaper Ad: Jan 21/22 Newspaper Ad: A p r i l  22/23  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 I n f o r m a t i o n A s s o c i a t i o n 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 '  57  Association  Results SUBJECTS Twenty s u b j e c t s s t a r t e d  t h e s t u d y , b u t one  f r o m t h e s t u d y on a p p r o x i m a t e l y Day  30.  The  completing the food r e c o r d s c o n s i s t e n t l y ,  s u b j e c t had not  and  m o t i v a t i o n to continue w i t h the study. Another f r o m t h e s t u d y on Day analysis.  42, b u t  subject withdrew  she  lacked  subject withdrew  t h e d a t a were c o n s i d e r e d i n t h e  O r i g i n a l l y , t h e s t u d y had been d e s i g n e d  f o r 56 d a y s 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 c o n s i d e r e d complete  w i t h the study u n t i l  The  (Days -14  day  t o 41)  pre-determined  56.  Data from  19 s u b j e c t s and  were u s e d f o r t h e s t a t i s t i c a l  s a m p l e s i z e was  s u b j e c t s i n the treatment  groups control  i n age,  up  of the s u b j e c t s continued  not  four  time  analysis.  achieved.  T h e r e were 10 s u b j e c t s i n t h e c o n t r o l  differences  was  a t 42 d a y s . A l l a n a l y s e s a r e b a s e d on d a t a  t o 42 d a y s e v e n t h o u g h t h e r e m a i n d e r  periods  been  g r o u p and  nine  g r o u p . T h e r e w e r e no s i g n i f i c a n t  d u r a t i o n of d i s e a s e or gender between the  ( T a b l e 9 ) . Thus, t h e r e s u l t s f r o m  the treatment  g r o u p s w i l l n o t be d i f f e r e n t i a t e d b y  58  gender.  and  two  Results Table 9: SUBJECT CHARACTERISTICS GROUP  Age (years)  Treatment <n=9)  42±21*  Control  46+16  Gender  Duration o f D i s e a s e (years)  6 female ' 3 male  13 ± 18 3 ± 6  8 female 2 male  * mean ± SD No s i g n i f i c a n t d i f f e r e n c e s  COMPLIANCE STUDY S i x t e eTO n o u t o fPROTOCOL 560 u r t i c a r i a  a n d angioedema  assessment  s c a l e s w e r e n o t c o m p l e t e d i n t h e c o n t r o l g r o u p , a n d 3 o u t o f 504 a s s e s s m e n t s c a l e s were n o t c o m p l e t e d i n t h e t r e a t m e n t g r o u p (Appendix J ) . Three s u b j e c t s i n t h e c o n t r o l group d i d n o t s t a r t t h e d i e t i m m e d i a t e l y a f t e r d a y - 1 . T h e r e w e r e 7, 9 a n d 26 d a y d e l a y s between All  d a y -1 a n d d a y 0 ( A p p e n d i x K ) . f o o d r e c o r d s w e r e c o m p l e t e d . The c o n t r o l g r o u p  reported  d i e t a r y n o n c o m p l i a n c e o n 5 o u t o f 42 0 days.. The t r e a t m e n t g r o u p r e p o r t e d d i e t a r y n o n c o m p l i a n c e o n 11 o u t o f 378 d a y s  (Appendix  L) . One s u b j e c t i n t h e c o n t r o l g r o u p e x p e r i e n c e d a w e i g h t of  8% o v e r h e r i n i t i a l  changes  gain  b o d y w e i g h t . T h e r e were no o t h e r w e i g h t  g r e a t e r t h a n 5%. One o f t h e 10 c o n t r o l s u b j e c t s  weight, and f i v e o f t h e nine treatment s u b j e c t s l o s t (Appendix M). 59  lost  weight  Results One s u b j e c t  i n t h e c o n t r o l group r e p o r t e d  a cold with  fever  on Days 32 - 3 8 . Tylenol®, robitussin® AC c o u g h s y r u p a n d ceclor® w e r e t a k e n t h r o u g h o u t t h i s p e r i o d . The s u b j e c t antihistamine The  t o o k one  t a b l e t o n Days 32 a n d 33 f o r s n e e z i n g  i l l n e s s and/or m e d i c a t i o n  and r h i n i t i s .  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 t h e u r t i c a r i a symptoms d u r i n g  this  period.  S T A T I S T I C A L ANALYSIS Urticaria Antihistamine  and Angioedema Assessment  Scale  Tablets  T h e r e was a t r e n d t o w a r d a s i g n i f i c a n t number o f a n t i h i s t a m i n e  decrease i n the  t a b l e t s taken over t h e four time  i n t h e t r e a t m e n t group compared t o t h e c o n t r o l group  periods  (significant  g r o u p x t i m e 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) a s shown i n T a b l e 10 a n d 2 0 . T h e r e w e r e no s i g n i f i c a n t groups o r time p e r i o d s  d i f f e r e n c e s between  i n t h e number o f d a y s t h a t  antihistamine  t a b l e t s were t a k e n a s shown i n T a b l e 11 a n d 2 0 .  Table 10: T O T A L N U M B E R 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 GROUP  lime 1  Time 3  Time 2  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 D A Y S A N T I H I S T A M I N E T A B L E T S W E R E T A K E N GROUP  Time 2  Time 1  Treatment  Control  Time 4  Time 3  12±3*  9+6  8±7  8±7  7±5  7±5  7±6  6±4  * mean ± SD No significant differences (see table 20 for F ratio)  The  treatment  g r o u p t o o k s i g n i f i c a n t l y mor e  t a b l e t s and took a n t i h i stamine than the c o n t r o l  t a b l e t s o n more d a y s d u r i n g  t h e number o f d a y s t h a t a n t i h i s t a m i n e  treatment subjects tablets during  t a b l e t s taken and  t a b l e t s were t a k e n ,  w e r e no s i g n i f i c a n t d i f f e r e n c e s b e t w e e n  antihistamine  time 1  g r o u p . When t i m e 1 was u s e d a s a c o v a r i a t e f o r  t h e RM ANCOVA o f t h e number o f a n t i h i s t a m i n e  The  antihistamine  there  groups.  took s i g n i f i c a n t l y  fewer  t i m e 2 t h a n t i m e 1 (p=0.02).  There  w e r e no d i f f e r e n c e s b e t w e e n t i m e 1 a n d t i m e 2 i n t h e c o n t r o l group  (p=0.81) a s shown i n T a b l e 1 2 .  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) Total tablets taken GROUP  Time 1  Time 2  Treatment  17.5±11.5*  11.5±13.0  Control  7.5±6.5  7.5±5.0  a  * mean ± SD p<0.05 (Time 1 vs Time 2) No significant differences in the control group a  Wheals T h e r e were no s i g n i f i c a n t periods  d i f f e r e n c e s between groups o r time  i n t h e t o t a l number o f w h e a l s r e p o r t e d a s shown i n T a b l e  13 a n d 20, a n d t h e r e w e r e no s i g n i f i c a n t groups o r time p e r i o d s  d i f f e r e n c e s between  i n t h e number o f d a y s t h a t w h e a l s w e r e  r e p o r t e d a s shown i n T a b l e 14 a n d 2 0 .  Table 13: TOTAL NUMBER OF WHEALS REPORTED GROUP  Time 1  Time 3  Time 2  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 D A Y S W H E A L S W E R E R E P O R T E D GROUP  Time 4  Time 3  Time 2  Time 1  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 c h a n g e  time f o r t h e 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 . 0 0 ) ; h o w e v e r , t h e f o l l o w - u p did not delineate in tables that  over  comparisons  d i f f e r e n c e s b e t w e e n t h e t i m e p e r i o d s a s shown  15, 16 a n d 2 0 . O b s e r v a t i o n o f t h e r e s u l t s  indicates  i t c h i n e s s d e c r e a s e d a f t e r t i m e 1. 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 b e t w e e n g r o u p s o r t i m e p e r i o d s i n t h e number o f d a y s that  i t c h i n e s s was r e p o r t e d a s shown i n t a b l e  17 a n d 2 0 .  Table 15: T O T A L S E V E R I T Y O F ITCHINESS S C O R E S GROl P  Time 1  Time 3  Time 2  1  Time 4  Treatment  19±10*  12±9  12±9  13±11  Control  25±10  21±10  25±10  20±12  a  * mean ± SD 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. time effect *p<0.05 (see table 20 for F ratio) (follow-up comparisons did not delineate differences between the time periods) 1  a  63  Results  Table 16: S E V E R I T Y O F I T C H I N E S S O F INDIVIDUALS W I T H U R T I C A R I A A N D ANGIOEDEMA  Severity of Itchiness  Time 1  Time 2  Time 3  Time 4  22 ± 10*  1 7 ± 10  1 9 ± 11  16± l l  a  * mean ± SD 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. time effect *p<0.05 (see table 20 for F ratio) (follow-up comparisons did not delineate differences between the time periods 1  a  Table 17: N U M B E R O F D A Y S T H A T I T C H I N E S S W A S R E P O R T E D GROUP  Time 1  Time 2  1  Time 4  Time 3  Treatment  11±5*  9±5  9±5  9±6  Control  13-2  11±4  12±4  9±5  * mean ± SD 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) 1  Angioedema T h e r e w e r e no s i g n i f i c a n t periods 20.  i n  the severity  o f angioedema  T h e r e w e r e no s i g n i f i c a n t  periods Table  differences  i n t h e number o f d a y s  between  a s shown i n T a b l e  differences  between  a n g i o e d e m a was  19 a n d 2 0 .  64  groups  groups  reported  o r time 18 a n d o r time  a s shown i n  Results Table 18: T O T A L S E V E R I T Y O F A N G I O E D E M A S C O R E S GROUP  lime 1  Time 2  Time 3  1  Time 4  Treatment  11±12*  9±11  8±10  10±11  Control  13±13  11±9  13±12  11±12  * mean ± SD 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) 1  Table 19: N U M B E R O F D A Y S T H A T A N G I O E D E M A W A S 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 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). 1  65  Results  Table 20: A D J U S T E D C R I T I C A L F A N D C A L C U L A T E D F 1  2  FOR EIGHT URTICARIA AND A N G I O E D E M A VARIABLES Effect of Group  Effect of Time  Group x Time Interaction  VARIABLE  : 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 Calculated from SPSS  2  66  Results Nutrient  Analysis  Adequacy  of Nutrient  Intake  The n u t r i e n t i n t a k e o f t h e t r e a t m e n t g r o u p w e i g h t e d RNI f o r : e n e r g y  during  t i m e 2, 3 and 4 and z i n c d u r i n g  d i d n o t meet t h e  t i m e 2, 3 a n d 4; c a l c i u m  during  t i m e 2 as shown i n t a b l e s 21 -  22. T h e r e w e r e no i n t a k e s t h a t were l e s s t h a n 70% o f t h e 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 t h e c o n t r o l g r o u p w e i g h t e d RNI f o r : e n e r g y  during  during  a l l four time p e r i o d s ;  during  t i m e 2; z i n c d u r i n g  d i d n o t meet t h e  a l l four time p e r i o d s ;  iron during  calcium  t i m e 2; magnesium  t i m e 1, 2 a n d 4 a n d 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. T h e r e w e r e no i n t a k e s t h a t w e r e l e s s t h a n 70% o f t h e w e i g h t e d R N I .  Significant  Changes  in Nutrient  The t r e a t m e n t g r o u p t h a n t h e c o n t r o l group  Intake  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  (significant  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. A v e r a g e d group,  over  t h e r e was a s i g n i f i c a n t c h a n g e o v e r t i m e f o r c a l c i u m  (p=0.03) a n d v i t a m i n C However, f o l l o w - u p  (p=0.04) as shown i n T a b l e s 22, 23 and 2 5 .  comparisons  between time p e r i o d s  d i d not d e l i n e a t e  differences  as shown i n T a b l e 24. O b s e r v a t i o n o f t h e  r e s u l t s i n d i c a t e s that the calcium i n i t i a t i o n of the d i e t .  intake decreased a f t e r  I n t i m e p e r i o d 4, t h e c a l c i u m 67  intake  Results increased, increased  but d i d not reach the baseline value. Vitamin after initiation  of the diet.  vitamin C intake decreased s l i g h t l y , baseline  C intake  I n t i m e p e r i o d 4, t h e  b u t was s t i l l  above t h e  value.  T h e r e was a d i f f e r e n t p a t t e r n o f c h a n g e b e t w e e n g r o u p s when c o n s i d e r i n g time f o r f a t , calcium,  v i t a m i n B12 a n d v i t a m i n C a s  shown i n T a b l e s 2 1 , 2 2 , 2 3 , 25 a n d 26 a n d F i g u r e s the c o n t r o l  a n d t r e a t m e n t g r o u p s were n o t s i g n i f i c a n t l y  at any time p e r i o d s . the c o n t r o l  Observation of the results  group's i n t a k e o f f a t , c a l c i u m  decreased a f t e r  initiation  fat intake and remained  o f t h e s t u d y . The c a l c i u m  initially  decreased a f t e r  initiation  increased  somewhat d u r i n g  t i m e 4, b u t was s t i l l  baseline value.  indicates that  o f the' t r e a t m e n t d i e t  decreased f o r the remainder  intake  o f t h e treatment d i e t and  The v i t a m i n C i n t a k e i n c r e a s e d  of t h e treatment d i e t and remained  different  a n d v i t a m i n C was  c o n s i s t e n t over t i m e . I n t h e treatment group,  increased  t h e 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 the c o n t r o l  4-7. However,  below t h e after  initiation  f o r t h e remainder o f after, i n i t i a t i o n of  d i e t and decreased a f t e r i n i t i a t i o n  of the treatment  diet. The  t r e a t m e n t g r o u p consumed s i g n i f i c a n t l y more e n e r g y a n d  carbohydrate  (p<0.05) d u r i n g  time p e r i o d  1 than the c o n t r o l  g r o u p . When t i m e 1 was u s e d a s a c o v a r i a t e f o r t h e 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 b e t w e e n groups o r time  periods.  Table 21: MACRONUTRIENT INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES 1  NUTRIENT  RNI  Group  Hi&ocalories  2230  Treatment  2140  Control  50  Protein < grams) C»rbohy<irate  (grams} Fat (grams)  Time 1  Time 2  Time 3  Time 4  2310+626*  1738±440  19321383  19281215  16771453  1793±350  17111576  16691636  Treatment  83127  68125  69122  75118  •47  Control  78±24  75125  74131  74128  none  Treatment  308±108  247159  279148  none  Control  205±61  2091 50  220172  none  Treatment  86±33  58126  60116  none  Control  61±29  70124  60131  279178  a  206174 63118  c  62133  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 group effect (treatment vs control) *p<0.05 (see table 26 for F ratios) group by time interaction *p<0.05 (see table 25 for P values) 1  a  c  69  Results  Table 22: MINERAL INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES NUTRIENT Calcium (milligrams)  RNl  11  7 3 3  Group Treatment  Time 1  Time 2  Time 3  1 ime 4  1  955±408*  544±279  545±338  644±174 -  682±307  687±278  674±317  680±325  b  720  Control  12  Treatment  17±8  13±4  14±6  14±5  12  Control  12±6  10±2  12±5  12±4  Magnesium (milligrams)  217  Treatment  295±136  265±87  . 291±122  295±63  210  Control  259±73  207±30  237±67  220±65  Phosphorus (milligrams)  900  Treatment  1420±481  1059±385  1068±466  1218±217  880  Control  1137±292  1083±226  1170±474  1160±373  Zinc (milligrams)  10  Treatment  10±5  9±4  10±4  10±3  10  Control  9±3  8±3  10±5  9±3  Iron  (milligrams)  c  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 time effect *p<0.05 (follow-up comparisons did not delineate differences between the time periods) (see table 25 for P values) group by time interaction *p<0.01 (see table 25 for P values) 1  b  c  70  Results  Table 23: VITAMIN INTAKE OF INDIVIDUALS WITH URTICARIA AND ANGIOEDEMA COMPARED TO THE RECOMMENDED NUTRIENT INTAKES NUTRIENT  RJNJ  Group  Folate (micrograms)  190  Treatment  184  Control  16  Time 1  Time 2  Time 3  1  Time 4  253±107*  269±87  244±75  283±67  204±115  210±53  307±232  172±70  Treatment  32±11  30±9  ,32±11  33±10  15  Control  29±15  32±13  31±11  31±13  Rihoflai in (milligrams)  1.1  Treatment  ' 1.9±0.8  1.5±0.5  1.4±0.5  1.5±0.4  1.1  Control  1.4±0.5  1.4±0.4  1.4±0.5  1.4±0.6  Thiamin (milligrams)  0.9  Treatment  1.8±1.1  1.4±0.4  1.7±0.9  1.6±0.6  0.9  Control  1.2±0.8  1.1±0.3  1.1±0.4  1.4±1.2  Vitamin A (RE)  867  Treatment  3654±2363  4335±2700  5385±5455  4604±3965  840  Control  2451±1586  3590±2433  3859±2772  3459±3620  Vitamin B6 (milligrams)  0.8  3  Treatment  1.7±0.8  1.7±0.7  1.9±0.9  2.2±0.7  0.7  3  Control  1.6±0.7  1.6±0.6  1.6±0.5  1.5±0.6  2.7±1.7  2.1±1.7  2.6±1.3-  3.2±0.9  4.6±3.5  3.7±1.5  Niacin (NE)  Vitamin B12 (micrograms)  2  Treatment  3.7±2.9  2  Control  3.0±1.4  Vitamin C (milligrams)  37  Treatment  93±54  175±91  147±62  170±94^  38  Control  105±96  103±85  126±70  90±69  .  For each nutrient and each group, a weighted RNI was calculated based on the number of male and female subjects in each group. Based on a requirement of 0.015mg/gram dietary protein * mean ± SD time effect *p<0.05 (follow-up comparisons did not delineate differences between the time periods) (see table 25 for P values) group by time interaction *p<0.05 (see tables 25 and 26 for P values and F ratios) 1  3  b  c  71  Results Table 24: C A L C I U M A N D V I T A M I N 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  Calcium Vitamin C  Time 2  Time 3  Time 4  831=383*  619±280  613±325  663±258  99±77  137±93  136±65  128±90  b  b  * mean ± SD time effect *p<0.05 (follow-up comparisons did not delineate differences between the time periods)  b  Table 25: P A N D F V A L U E S F O R N U T R I E N T S T H A T SATISFY T H E A S S U M P T I O N 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: A D J U S T E D C R I T I C A L F A N D C A L C U L A T E D F F O R E I G H T N U T R I E N T S T H A T DH) N O T SATISFY T H E A S S U M P T I O N O F SPHERICITY 1  Effect of Time  1 2  2  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  Critical F statistic after adjustment with Huynh-Feldt Epsilon for p<0.05 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 Legend » Control  74  Time 4  Results  Figure 6: G R O U P X TIME INTERACTION Vitamin B12  Time 2  Time 1  Time 3  Time 4  Time Periods Legend Treatment  Control  Figure 7: G R O U P X TIME INTERACTION Vitamin C 200-i  oH Time 1  1  1  1  1  1  1  1  1  Time 2  Time 3 Time Periods Legend -  75  Control  1  1  1 Time 4  Results CASE ANALYSIS OF TREATMENT GROUP SUBJECTS WITH IMPROVEMENT I N SYMPTOMS Subject  11 ( T a b l e 27) e n t e r e d  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 were c o n t r o l l e d  a n g i o e d e m a . The w h e a l s a n 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  topical corticosteroid. Pruritus when t h e s u b j e c t e n t e r e d  t h e s t u d y w i t h a n 8 month  was t h e o n l y symptom  the study.  The s u b j e c t h a d r e l i e f  pruritus  on day 1 o f t h e t r e a t m e n t  reported  from day 9 t o t h e end o f t h e study.  antihistamine tablets taken  were t a k e n  remaining  diet. Mild pruritus  was  Thirteen  i n t i m e 1, a n d two t a b l e t s  i n t i m e 2, 3 a n d 4. A d d i t i o n a l l y ,  from  the subject  were  discontinued  t h e - u s e o f a t o p i c a l c o r t i c o s t e r o i d o n Day 0. The s u b j e c t h a d a l o n g h i s t o r y o f r h i n i t i s w h i c h improved on t h e h i s t a m i n e - r e d u c i n g d i e t . A t t h e end o f t h e study, i n t e r e s t i n g and s a t i s f a c t o r y Subject  the subject wrote,  results."  13 ( t a b l e 29) e n t e r e d  t h e s t u d y w i t h a 20 y e a r  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 symptoms b e g a n a t 6 y e a r s and  21 y e a r s  disappeared  a n g i o e d e m a . The  o f age a n d were i n r e m i s s i o n b e t w e e n 15  o f a g e . The a n g i o e d e m a , w h e a l s a n d i t c h i n g on Day 4 o f t h e t r e a t m e n t  d i e t . The symptoms w e r e  r e p o r t e d on Day 14, b u t o n l y l a s t e d a few h o u r s . tablets  "very  Antihistamine  were d i s c o n t i n u e d o n Day 4. On Day 2 t h e s u b j e c t w r o t e " I  h a v e much more e n e r g y - f e e l g r e a t " . The s u b j e c t h a d a l o n g history  of 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  76  headache w h i c h  Results i m p r o v e d on t h e h i s t a m i n e - r e d u c i n g Subject  17  diet.  ( t a b l e 30). e n t e r e d  h i s t o r y of u r t i c a r i a without  the  angioedema. A p a r t i a l  t h e number o f a n t i h i s t a m i n e t a b l e t s , pruritus occurred  on Day  w h e a l s and  d i d not  change, but  the  s e v e r i t y of  felt  histamine-reducing  diet.  The  antihistamine tablets  d e c r e a s e d . The  i n b e t t e r h e a l t h o v e r a l l on The  diet.  s e v e r i t y o f symptoms and  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 i n d i c a t e d t h a t she  and  year  reduction i n  1 of the h i s t a m i n e - r e d u c i n g  number o f d a y s t h a t symptoms o c c u r r e d were t a k e n  study w i t h a f i v e  s u b j e c t had  subject the  a h i s t o r y of  gas,  a b d o m i n a l b l o a t i n g and  c o n s t i p a t i o n . T h e s e symptoms i m p r o v e d  the h i s t a m i n e - r e d u c i n g  diet.  Subject  12  ( t a b l e 28)  h i s t o r y of u r t i c a r i a o f w h e a l s and  the  and  entered  facial  a n t i h i s t a m i n e t a b l e t s taken  d u r i n g t i m e 2,  and  study w i t h a f i v e  b o d y a n g i o e d e m a . The  s e v e r i t y o f p r u r i t u s and  remain s t a b l e throughout the  t a b l e t s were t a k e n  the  study,  4.  77  and  on  year number  angioedema appeared  t h e number o f  decreased. Thirteen  d u r i n g t i m e 1,  3 and  but  the  antihistamine  f o u r t a b l e t s were  taken  to  TS  7<?  Discussion  Chapter 5 DISCUSSION  MAJOR FINDINGS The  s t u d y was  histamine-reducing to evaluate  conducted to evaluate diet  the  i n chronic u r t i c a r i a  e f f e c t of and  a  angioedema,.and  t h e e f f e c t o f t h e d i e t on n u t r i e n t i n t a k e . The  f i n d i n g s w e r e as  follows: A histamine-reducing  improve c h r o n i c u r t i c a r i a  and  diet did  angioedema. There were  major  not  no  d i f f e r e n c e s b e t w e e n g r o u p s o v e r t i m e i n t h e number o f a n t i h i s t a m i n e t a b l e t s taken, of u r t i c a r i a  and  t h e number o f w h e a l s , t h e s e v e r i t y  a n g i o e d e m a , t h e number o f d a y s  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  that  o r t h e number o f d a y s w h e a l s ,  p r u r i t u s o r angioedema were r e p o r t e d .  However, t h e  treatment  g r o u p t o o k 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 two  weeks p r i o r t o t h e  a f t e r the  treatment  d i e t than d u r i n g the  i n i t i a t i o n of the treatment  i n t a k e o f v i t a m i n C. e n e r g y and  The  treatment  diet resulted in a  v i t a m i n B12  g r o u p met  c a l c i u m d u r i n g t i m e p e r i o d 1, b u t  recommendations f o r these  and  an  80  increased  t h e w e i g h t e d RNI failed  t o meet  n u t r i e n t s during time periods  4.  weeks  diet.  Adherence to the h i s t a m i n e - r e d u c i n g 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  two  the  2,  for the  3  and  Discussion The f o l l o w - u p c o m p a r i s o n s f o r t h e s i g n i f i c a n t and  group x time  i n t e r a c t i o n s were n o t s i g n i f i c a n t .  b e e n due t o t h e s t r i c t and  t h e s m a l l sample  time  effects  T h i s may  have  a l e v e l s used f o r m u l t i p l e comparisons size.  COMPARISON TO C L I N I C A L FINDINGS The h i s t a m i n e - r e d u c i n g d i e t h a s b e e n u s e d i n p a t i e n t counselling at the A l l e r g y N u t r i t i o n C l i n i c 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 January  a t the Vancouver  s i n c e O c t o b e r 1991. As o f  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 t h e 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 t h e d i s e a s e symptoms was evaluated through clinical  follow-up i n t e r v i e w notes  i n the p a t i e n t s '  c h a r t s . I f a f o l l o w - u p a p p o i n t m e n t was n o t h e l d , t h e  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 telephone. c o u l d n o t be r e a c h e d , at  t h e same t i m e .  Four  Three p a t i e n t s  a n d one p a t i e n t c h a n g e d m e d i c a t i o n  (33%) p a t i e n t s h a d a c o m p l e t e o r p a r t i a l  r e m i s s i o n o f symptoms on t h e h i s t a m i n e - r e d u c i n g d i e t . did  n o t i m p r o v e symptoms i n e i g h t Of t h e n i n e t r e a t m e n t  (11%)  The  diet  (67%) p a t i e n t s .  subjects i n the present  study,  one  s u b j e c t h a d c o m p l e t e r e m i s s i o n o f symptoms a n d d i s c o n t i n u e d  antihistamine medication. itching  One s u b j e c t  ( t h e o n l y symptom p r e s e n t  antihistamine medication (22%)  and d i e t  (11%) h a d a d e c r e a s e i n  d u r i n g time  1) a n d d i s c o n t i n u e d  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  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 a n d a r e d u c t i o n 81  Discussion in  antihistamine medication  i n t a k e , and  the remaining  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 The  clinical  44%  diet.  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  s i m i l a r to the treatment (33% v e r s u s  five  group f i n d i n g  complete or p a r t i a l  from the p r e s e n t  are  study  r e m i s s i o n o f symptoms,  respectively).  COMPARISON TO The  OTHER STUDIES  present  study  chronic u r t i c a r i a c o n t r o l and  and  treatment  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 angioedema w i t h s t a t i s t i c a l diet.  The  group  (n=9)  w i l l be  The  a  the  results  compared t o t h e s e s t u d i e s . low-tyramine  diet  e v a l u a t e d b y V e r s c h a v e e t a l . (1983) .  d i e t e l i m i n a t e d food a d d i t i v e s , nuts,  i n open d e s i g n s .  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  c h r o n i c u r t i c a r i a was  analyses of  S e v e r a l s t u d i e s have e v a l u a t e d  e f f e c t of f o o d - a d d i t i v e f r e e d i e t s from the treatment  study i n  oranges,  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,  and  o l d and  fermented  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 s had  t h e 44%  diet.  complete or p a r t i a l  histamine-reducing diet.  The  c h e e s e . T h i s d i e t was  F i f t y - f i v e percent  complete or p a r t i a l  f o l l o w i n g the low-tyramine  stone  The  fruit,  pineapple  alcohol,  in.  similar  (37/67) o f  to  the  r e m i s s i o n o f symptoms w h i l e These f i n d i n g s a r e s i m i l a r  r e m i s s i o n o f symptoms on  to  the  l e n g t h o f the d i e t o r the method  t i m i n g o f symptom e v a l u a t i o n w e r e n o t d e s c r i b e d . T h i s b r i n g s  82  and the  Discussion r e s u l t s o f the low-tyramine d i e t  into question,  and impedes  d e t a i l e d c o m p a r i s o n b e t w e e n t h e two s t u d i e s . Several to  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  90 % c o m p l e t e o r p a r t i a l  (Table  remission of u r t i c a r i a  5 ) . S i x o f the seven s t u d i e s reviewed,  complete o r p a r t i a l  and t h e f i n a l  2 years.  e v a l u a t i o n o f symptoms r a n g e d f r o m 6 months f r e e f r o m symptoms w e r e  e f f e c t a n d n a t u r a l r e m i s s i o n o f symptoms.  However, t h e b e n e f i c i a l treatment  e f f e c t s may h a v e b e e n p a r t i a l l y due t o  diet.  Comparison between t h e f i n d i n g s from t h e p r e s e n t the  studies  The t i m e b e t w e e n t h e  The l a r g e number o f s u b j e c t s  l i k e l y due t o p l a c e b o  the  h a d 60% o r g r e a t e r  The m e t h o d o f symptom a s s e s s m e n t a n d  l e n g t h o f t h e d i e t was n o t d e s c r i b e d .  to  symptoms  r e m i s s i o n o f symptoms. However, t h e s e  have s e v e r a l l i m i t a t i o n s .  initial  a r a n g e o f 32  food-additive free studies i s d i f f i c u l t  study and  due t o t h e  n o n s p e c i f i c methods and t h e s m a l l sample s i z e o f t h e p r e s e n t study.  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 c o m p l e t e o r  partial  r e m i s s i o n o f symptoms o n t h e 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 t h e l o n g p e r i o d s final  o f time between i n i t i a l and  symptom a s s e s s m e n t a n d p l a c e b o  effect.  TREATMENT GROUP SUBJECTS WITH IMPROVEMENT I N SYMPTOMS Four s u b j e c t s on t h e t r e a t m e n t in no  urticaria  diet  a n d a n g i o e d e m a symptoms  (n=9) h a d a n i m p r o v e m e n t  (Tables  2 7 - 3 0 ) . T h e r e were  f e a t u r e s w h i c h d i s t i n g u i s h e d t h e s u b j e c t s who i m p r o v e d o n t h e 83  Discussion treatment  diet  f r o m t h e s u b j e c t s who  s a m p l e s i z e and may  detailed  months a f t e r treatment  f i n i s h i n g t h e s t u d y . S u b j e c t 11 was  two months a f t e r  following  the treatment  S u b j e c t 17 was  was  found  i t difficult  arid t o m a t o e s f r o m h e r d i e t . The  u r t i c a r i a and  became w o r s e when t h e t r e a t m e n t  d i e t was  d i e t , and  t o one  t a b l e t p e r day  was  her  telephone  following  the  food  to e l i m i n a t e cheese a n g i o e d e m a symptoms  d i s c o n t i n u e d . She  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  t o t h e h i s t a m i n e - r e d u c i n g d i e t . The  the  had  d i e t b e c a u s e she d i d n o t h a v e t i m e t o p r e p a r e  w i t h o u t p r e s e r v a t i v e s and  one  not  five  S u b j e c t 12  c o n t a c t e d by  f i n i s h i n g t h e s t u d y . She  groups.  following  t h e t r e a t m e n t ' d i e t b e c a u s e h e r symptoms  S u b j e c t 13 was  larger  t h e two  13 were c o n t a c t e d b y t e l e p h o n e  symptoms w e r e c o n t r o l l e d .  treatment  distinguished  d i e t , and h i s symptoms w e r e c o n t r o l l e d .  following  improved.  12 and  A  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  have i d e n t i f i e d f e a t u r e s w h i c h S u b j e c t 11,  not  clinical  d i d not improve.  took  adhering  s u b j e c t i n c r e a s e d her i n t a k e  a f t e r t h e d i e t was  discontinued.  TREATMENT GROUP SUBJECTS WITHOUT IMPROVEMENT I N 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  c h r o n i c u r t i c a r i a and or  a contributing  a n g i o e d e m a . D i e t may  factor  be  the primary  i n some i n d i v i d u a l s . The  cause  treatment  i s b a s e d on t h e 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  84  of  diet  Discussion urticaria  and angioedema have reduced  (DAO) i n t h e i n t e s t i n a l mucosa histamine  and u r t i c a r i a  of histamine  rich  diamine  (Lessof e t a l . ,  foods. 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 some  DAO r e s p o n s e ,  Intraduodenal  a l t e r plasma histamine  was l i t t l e urticaria after  response,  a n d one s u b j e c t h a d an a b o v e  administration of histamine d i d  i n eight control  s u b j e c t s , and t h e r e  v a r i a t i o n i n p l a s m a h i s t a m i n e w i t h i n t h e s a m p l e . The group  (n=25) h a d a s i g n i f i c a n t  intraduodenal histamine  observations,  rise  histamine  l e v e l s . B a s e d on t h e s e  the effect of dietary histamine  a n g i o e d e m a w o u l d be e x p e c t e d  i n plasma  a d m i n i s t r a t i o n . M o r e o v e r , 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 histamine  to d i f f e r  Plasma and u r i n a r y h i s t a m i n e oral  decrease  Two s u b j e c t s h a d a  t h r e e s u b j e c t s h a d a 'low n o r m a l  three s u b j e c t s had a normal response normal response.  i n a sample  ( L e s s o f e t a l . , 1 9 9 0 ) . 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 .  not  individuals.  i n d i c a t i n g an o v e r a l l  i n i n t e s t i n a l mucosa DAO a c t i v i t y  minimal  Plasma  consumption  p o s t - h e p a r i n p l a s m a DAO c u r v e was d e c r e a s e d  of nine subjects w i t h u r t i c a r i a ,  activity  1990).  symptoms may i n c r e a s e a f t e r  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  oxidase  among  on u r t i c a r i a a n d individuals.  i n c r e a s e i n some s u b j e c t s  a d m i n i s t r a t i o n of food a d d i t i v e s .  after  T h r e e s u b j e c t s who w e r e  a s y m p t o m a t i c on an a d d i t i v e - f r e e d i e t a n d h a d an e x a c e r b a t i o n o f urticaria  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 study  t o measure b i o c h e m i c a l  additive challenge. i n c r e a s e d i n two  Plasma h i s t a m i n e  of the  three  responses to the c h a l l e n g e s The after  a c t i v i t y o f DAO  symptoms  s u b j e c t s . However, t h e  subjects'  differed dramatically.  and  dietary manipulation  urticaria  and  the endogenous r e l e a s e o f  histamine  Adherence to the s u b j e c t s had by  will  not b e n e f i t a l l s u b j e c t s  THE  with  HISTAMINE-REDUCING DIET  treatment  d i e t was  the d i e t a r y r e s t r i c t i o n s .  d u r i n g t i m e 3 and  initially  t o change t h e i r e a t i n g p a t t e r n s  to the d i e t a r y r e s t r i c t i o n s 4.  and  The  difficult  i n order  d u r i n g time 2 but  to  e s t a b l i s h e d new  eating  patterns  This t r e n d concurs w i t h the o b s e r v a t i o n  subsequently  F i v e of the nine l o s s w h i l e o n l y one  as  s u b j e c t s became a c c u s t o m e d  the n u t r i e n t i n t a k e s tended to decrease i n the treatment  treatment  group  i n c r e a s e d d u r i n g t i m e 3 and s u b j e c t s had  a marginal  that  4.  weight  c o n t r o l subject l o s t weight. F l u i d l o s s  been o b s e r v e d to occur initiated  a  angioedema.  NUTRITIONAL ADEQUACY OF  abide  urticaria  food  f o o d a d d i t i v e c o n s u m p t i o n v a r i e s b e t w e e n i n d i v i d u a l s . As  result,  the  and  changes d u r i n g  when t h e h i s t a m i n e - r e d u c i n g  ( p e r s o n a l c o r r e s p o n d e n c e , Dr.  the weight l o s s i n the treatment  diet  Janice Joneja).  g r o u p was  l i k e l y due  is  has first  However,  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 to l o s e weight  86  Discussion g r a d u a l l y over the study r a t h e r than immediately preceding the i n i t i a t i o n of the diet. the t r e a t m e n t group  The e n e r g y  during  t i m e 2, 3 a n d 4. The e n e r g y  i n t a k e met t h e w e i g h t e d RNI o f  t i m e 1, b u t f a i l e d  t o do s o d u r i n g  i n t a k e o f t h e t r e a t m e n t group  p e r i o d 2 was 7 5 % o f t h e e n e r g y  i n time  i n t a k e i n t i m e p e r i o d 1.  A p p r o x i m a t e l y 4 5 % 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 nf 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 a n d 10% due t o a  reduction  in protein.  intake increased  3 a n d 4.  The e n e r g y  For t h e e i g h t s u b j e c t s entire  i n t h e t r e a t m e n t group  56 d a y s o f t h e s t u d y , t h e mean e n e r g y  kilocalories/day  decreased c a l o r i c  The RNI 2,  at n u t r i t i o n a l calcium  during  less  than  f o r the treatment  and d i d n o t appear  group.  adaptation to  t o put the treatment  risk.  i n t a k e o f t h e t r e a t m e n t g r o u p met t h e w e i g h t e d  t i m e p e r i o d 1, b u t f a i l e d  3 a n d 4. F o r t h e e i g h t s u b j e c t s  completed  i n t a k e was 2150  i n t a k e was l i k e l y a t e m p o r a r y  the d i e t a r y r e s t r i c t i o n s subjects  who c o m p l e t e d t h e  ( d a t a n o t s h o w n ) , w h i c h was s l i g h t l y  t h e 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 ) The  i n time periods  t o do s o d u r i n g  i n t h e t r e a t m e n t group  t h e e n t i r e 56 d a y s o f t h e s t u d y , t h e mean  i n t a k e was 731 mg/day  time  periods who  calcium  ( d a t a n o t s h o w n ) , w h i c h was s l i g h t l y  t h a n t h e w e i g h t e d RNI (733 mg/day) f o r t h e t r e a t m e n t g r o u p . decreased calcium  i n t a k e was l i k e l y  87  a temporary  adaptation  less The to the  Discussion dietary restrictions  and  subjects at n u t r i t i o n a l T h e r e w e r e no RNI  The  2,  and  the  treatment  risk. the  g r o u p d u r i n g t i m e p e r i o d 1, b u t  3 and  weighted  failed  to  do  4.  histamine-reducing  nutrients,  appear to put  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  of the treatment  so d u r i n g t i m e  d i d not  d i e t d i d not  significantly  an a d e q u a t e n u t r i e n t i n t a k e was  achieved  limit  any  while  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 to the d i e t ;  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  intervention.  The  therefore, dietary component o f d i e t a r y  p o t e n t i a l b e n e f i t s of the  d i e t outweigh the p o s s i b i l i t y of n u t r i t i o n a l  LIMITATIONS OF The  THE  histamine-reducing deficiencies.  STUDY  l i m i t a t i o n s t o t h e s t u d y were t h e s m a l l s a m p l e  l a r g e w i t h i n - and  between-subject v a r i a t i o n ,  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  group d i f f e r e n c e s ,  urticaria  l a c k of 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 , placebo  e f f e c t and p o t e n t i a l  f o r b i a s due  size,  to a  and  angioedema,  potential  for  single-blind  design. P r i o r to i n i t i a t i o n of the s u b j e c t s was  estimated  s i g n i f i c a n c e . Due  t o be  study,  necessary  a sample s i z e of for  34  statistical  to d i f f i c u l t y with subject recruitment,  88  data  Discussion f r o m 19  s u b j e c t s were u s e d i n the  Significant sample  f i n d i n g s w o u l d n o t be  statistical  analysis.  a n t i c i p a t e d b a s e d on t h e  size.  The  symptom d a t a  f a i l e d the assumption of  i n d i c a t i n g t h a t t h e r e was  The  treatment  t a b l e t s and  sphericity  a l o t of v a r i a t i o n i n the data.  d e c r e a s e d t h e power o f t h e  antihistamine  consumed more e n e r g y d u r i n g t i m e 1 t h a n t h e c o n t r o l statistically  significant,  the  g r o u p a p p e a r e d t o h a v e more w h e a l s d u r i n g t i m e 1 and study with a longer d u r a t i o n of disease c o n t r o l and  treatment  g r o u p s may  treatment entered  s e v e r i t y of u r t i c a r i a  and  not have been comparable. the  a n g i o e d e m a , an a s s e s s m e n t s c a l e  d e v e l o p e d b a s e d on v a r i a b l e s t h a t w e r e commonly e v a l u a t e d antihistamine medication i n t a k e was  was  the  reflects  in  Antihistamine  i n d i c a t o r because i t  was  congruent w i t h the r a t i o n a l e f o r  i n t a k e was  study because the need to take i n c r e a s e d body h i s t a m i n e .  circumstances  was  diet.  Antihistamine medication for  trials.  t h e most r e l i a b l e  an o b j e c t i v e v a r i a b l e and the treatment  clinical  the  than the c o n t r o l group.  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  medication  This  study.  g r o u p t o o k s i g n i f i c a n t l y more  group. Even though not  The  small  an i m p o r t a n t  indicator  t h i s medication  However, t h e r e  likely  were  i n which a l t e r a t i o n of a n t i h i s t a m i n e medication  89  did  Discussion not  r e f l e c t changes  i nurticaria  Antihistamine medication control rhinitis.  and angioedema  was a l s o t a k e n  symptoms.  during the study t o  Some s u b j e c t s t o o k a n t i h i s t a m i n e  medication  e v e n t h o u g h i t d i d n o t n o t i c e a b l y i m p r o v e t h e i r symptoms. The antihistamine medication  i n t a k e was v a r i a b l e i n t h e s e  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 use,  a n d t h e i n d i v i d u a l may n e e d t o change  may  subjects.  decrease•with  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 t h e d o s e 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 a n i m p o r t a n t  study because histamine  i n d i c a t o r f o r the  i s solely responsible for pruritus.  However, i t was a s u b j e c t i v e v a r i a b l e a n d t h i s d e c r e a s e d i t s reliability. Histamine  i s one o f many i n f l a m m a t o r y  mediators that  produce  w h e a l s . The number o f w h e a l s may n o t be a good i n d i c a t o r o f b o d y histamine,  a n d t h e r e f o r e , may n o t be a good i n d i c a t o r o f t h e  effectiveness of a histamine-reducing o f w h e a l s was d i f f i c u l t was  diet.  Counting  t h e number  f o r most s u b j e c t s . The number o f w h e a l s  a p p l i c a b l e t o 16 s u b j e c t s , a n d 11 s u b j e c t s g u e s s e d t h e number  of wheals a t c e r t a i n times.  The r e a s o n s g i v e n  f o rguessing  were,  t h a t t h e r e w e r e t o o many w h e a l s t o c o u n t , w h e a l s w e r e on b o d y p a r t s t h a t c o u l d n o t be s e e n , a n d w h e a l s w e r e 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 they w h e a l s was a q u e s t i o n a b l e  tended t o coalesce.  v a r i a b l e f o r use i n t h i s  90  The number o f study.  Discussion Histamine  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  a n g i o e d e m a . 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  therefore, not r e l i a b l e .  questionable variable Although  The s e v e r i t y o f a n g i o e d e m a was a  f o r use i n t h i s  the l a t t e r  study.  t h r e e measures a r e s u b j e c t i v e ,  c o n s i s t e n c y o f symptom a s s e s s m e n t was s t r e s s e d t h r o u g h o u t t h e study. Therefore, minimized.  t h e 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  Significant  changes over time would have been  detected. The  ability  t o measure p l a s m a h i s t a m i n e w o u l d have added an  important v a r i a b l e i n t h i s  study. Several techniques  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 . chromatographic-mass-spectrometric assay,  t o measure  These i n c l u d e gas  technique,  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,  single  isotope  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 study,  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 w e r e a c c u r a t e a n d p r e c i s e . I n a c c u r a t e r e s u l t s w e r e due t o human e r r o r r a t h e r t h a n t h e m e t h o d (Neugebauer e t a l . ,  1990).  determination, p r a c t i c a l limited.  Frequent  Despite reasonable  accuracy of  a p p l i c a t i o n o f t h e s e m e t h o d s may be  fluctuations  i n p l a s m a h i s t a m i n e make t h e  i n t e r p r e t a t i o n o f plasma histamine l e v e l s d i f f i c u l t al.,1984). Histamine  (Keyzer e t  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  91  N-  Discussion methylhistamine  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  m e t a b o l i t e s . Levels of N-methylimidazole influenced  a c e t i c a c i d are  by t h e amount o f h i s t a m i n e i n t h e d i e t  a l . , 1 9 8 4 ) . M e a s u r e m e n t o f t h i s m e t a b o l i t e has 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 required  t o f i n d a v a l i d and  unique greatly  (Keyzer  et  not been c l e a r l y  test. Further research i s  r e l i a b l e marker f o r b l o o d  histamine  levels. Placebo  e f f e c t i s a p o t e n t i a l concern  S i g n i f i c a n t time e f f e c t s , w i t h a decrease would have i n d i c a t e d  a strong placebo  s i g n i f i c a n t time e f f e c t decreased  i n the present  study.  i n symptoms o v e r  time,  e f f e c t . T h e r e was  f o r the s e v e r i t y of i t c h i n e s s  o v e r t i m e as shown i n t a b l e  16.  The  a  which  e f f e c t of  placebo  was  m i n i m i z e d b y c o m p a r i n g t h e outcome o f t h e 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 The  treatment  d i e t over  time.  r e s e a r c h e r c o n d u c t i n g t h e s t u d y and and  control  s u b j e c t s was  educating  aware o f t h e  difference  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 t h e same was  made; h o w e v e r , t h e p o t e n t i a l  92  the  for bias  was  groups present.  Discussion THE V A L I D I T Y 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 both and  the c o n t r o l  the  d i e t i n a random o r d e r . Fewer s u b j e c t s  treatment are  r e q u i r e d f o r a c r o s s o v e r design 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 than the between-subject Cheney, 1992;  L o u i s et a l . , 1984). In the p r e s e n t  s m a l l s a m p l e s i z e and decreased  variation  large within-  t h e power o f t h e s t u d y .  as a c r o s s o v e r d e s i g n ,  study,  and b e t w e e n - s u b j e c t  I f the s t u d y had  statistical  (Monsen & the variation  been  s i g n i f i c a n c e may  conducted  have been  found. However, t h e valid  findings  f o r three reasons.  control  d i e t and  of a c r o s s o v e r design would not  First,  the treatment  t h e s u b j e c t s must e n t e r d i e t i n an i d e n t i c a l  symptoms o f c h r o n i c u r t i c a r i a and and  guaranteed.  c a r r y - o v e r e f f e c t f r o m e a c h d i e t p e r i o d may  continue the d i e t a r y Finally,  study,  first  difficult  d i e t and  s t u d y was  I f the d i e t s  the treatment  occur.  d i e t , he w o u l d  Second,  The time,  a  If a subject's likely  with a crossover design.  the s u b j e c t s were g i v e n e i t h e r t h e  d i e t or the c o n t r o l complete.  state.  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 .  b l i n d i n g w o u l d be  the present  the  angioedema f l u c t u a t e over  t h e a b o v e a s s u m p t i o n c o u l d n o t be  symptoms were r e l i e v e d on t h e  be  d i d not  treatment  compare t h e d i e t s u n t i l  are compared, i t i s o b v i o u s  d i e t i s much more r i g o r o u s t h a n t h e c o n t r o l '93  In  the that  diet.  Discussion I n a c r o s s o v e r d e s i g n , t h e s u b j e c t s may diet  i s not  b e l i e v e t h a t the  control  effective.  FUTURE RESEARCH The  r e s u l t s of t h i s  s t u d y w e r e 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 to c l a r i f y m a n i p u l a t i o n i s shown t o be  the  findings.  effective  angioedema, a d d i t i o n a l  If dietary  i n t h e management o f  urticaria  and  determine  w h i c h a s p e c t s o f t h e d i e t were e f f e c t i v e  s u b j e c t s a r e most l i k e l y diet.  Finally,  histamine  the  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  of the r e s t r i c t i o n s  all  and  If urticaria  and  in  to determine  the p a t t e r n of histamine  (Lessof et al.,1990  or delayed histamine  important  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  a c t i v i t y o f DAO  respectively).  I f the d i e t i s e f f e c t i v e  a n g i o e d e m a , i t w i l l be  c a n be m e a s u r e d  which  further investigated.  the h i s t a m i n e - r e d u c i n g d i e t .  The  and  r e q u i r e d to  t o b e n e f i t f r o m a- h i s t a m i n e - r e d u c i n g  f o r m a t i o n must be  and  be  food h a n d l i n g c o n d i t i o n s which l e a d to  F o o d a d d i t i v e s and  urticaria  research w i l l  which  effect. metabolism  Kanny e t a l . , 1993,  subjects w i t h decreased  DAO  activity  catabolism follow a histamine-reducing  s u b j e c t s should improve. A study of t h i s nature would  the r a t i o n a l e of the treatment  d i e t . Moreover, the  b e t w e e n e f f e c t i v e n e s s o f t h e d i e t and  94  t h e DAO  diet, test  correlation  a c t i v i t y could  be  Discussion determined.  Diamine o x i d a s e  histamine metabolism  a c t i v i t y and/or i n d i c a t o r s o f  may be u s e f u l c l i n i c a l  tests to  w h i c h s u b j e c t s may b e n e f i t f r o m a h i s t a m i n e - r e d u c i n g Further research i s r e q u i r e d t o determine preparation conditions that lead to histamine of h i s t i d i n e decarboxylase-producing  determine diet.  the food formation.  microorganisms,  Presence  free  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 result  i n histamine  hygiene  i n the f i s h canning  formation any  f o r m a t i o n . There i s evidence  (Kim & B j e l d a n e s ,  s t u d i e s t o determine  from poor hygiene  i n d u s t r y may r e s u l t  t h a t poor i n histamine  1 9 7 8 ) . However, t h e r e h a v e n o t b e e n  the prevalence  of histamine  i n other food manufacturing  formation  industries,  r e s t a u r a n t s a n d t h e home. E d u c a t i o n o n 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 rhistamine  sensitive  individuals.  C L I N I C A L A P P L I C A T I O N OF STUDY FINDINGS Chronic u r t i c a r i a those  a n d a n g i o e d e m a c a n be v e r y t r o u b l e s o m e f o r  a f f l i c t e d with this condition. Patients are often  f r u s t r a t e d because t h e i n c i t i n g cases  (Burrall et a l . ,  the urgent  response  a g e n t r e m a i n s unknown i n 75 % o f  1 9 9 0 ) . T h i s f r u s t r a t i o n was a p p a r e n t i n  t o the January  21 a n d 2 2 , 1995 n e w s p a p e r a d .  Many s u b j e c t s s t a t e d t h a t t h e y w o u l d t r y a n y t h i n g t o a l l e v i a t e their  suffering.  A h i s t a m i n e - r e d u c i n g d i e t may i m p r o v e symptoms  95  Discussion i n some s u b j e c t s  with chronic  urticaria.  The symptoms  will  i m p r o v e w i t h i n two w e e k s , i f t h e d i e t i s e f f e c t i v e . The histamine-reducing chronic  urticaria  d i e t should  be c o n s i d e r e d  f o r treatment of  and angioedema a t l e a s t f o r a t r i a l  r e s u l t s o f t h e s t u d y and t h e d e t a i l s o f t h e d i e t , disseminated  t o h e a l t h care  period.  should  p r o f e s s i o n a l s who p r o v i d e  The  be  treatment  for these p a t i e n t s . The reducing  r e s u l t s of t h i s . s t u d y demonstrated that the histamined 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 a n d s u b s e q u e n t w e i g h t l o s s i n some i n d i v i d u a l s . I t is  imperative  provided  t h a t d i e t a r y c o u n s e l l i n g and adequate f o l l o w - u p  f o rpatients wishing  t o modify t h e i r d i e t s .  96  be  REFERENCES  A r m e n a k a M, R o s e n s t r e i c h D. The p a t h o p h y s i o l o g y urticaria. 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I n v i t r o s t i m u l a t i o n o f lymphocytes i n p a t i e n t s with- c h r o n i c u r t i c a r i a i n d u c e d by a d d i t i v e s and f o o d . C l i n A l l e r g y 1980; 10:691-698. 102  V a n d e k e r c k h o v e P. 42:283-285.  Amines i n d r y sausage.  J Food S c i 1977;  V a u g h a n T, M a n s f i e l d L. A d v e r s e r e a c t i o n s t o b e n z o a t e s a n d p a r a b e n s . I n : M e t c a l f e D, Sampson H, Simon R ( e d s ) , F o o d A l l e r g y : A d v e r s e R e a c t i o n s t o Foods and Food A d d i t i v e s . Oxford, B l a c k w e l l S c i e n t i f i c P u b l i c a t i o n s , 1987:355-369. V e r s c h a v e A, S t e v e n s E, D e g r e e f H. Pseudo-allergen-free chronic u r t i c a r i a . D e r m a t o l o g i c a 1983; 167:256-259. W h i t e 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 C l i n Immunol 1990; 86, 4 (2) :599-605.  disease.  diet i n  J Allergy  Zee J , S i m a r d R, L ' H e u r e u x L. E v a l u a t i o n o f a n a l y t i c a l methods f o r d e t e r m i n a t i o n o f b i o g e n i c a m i n e s i n f r e s h and p r o c e s s e d meat. J Food P r o t 1983; 46 (12) :1044-1049.  103  APPENDICES  104  APPENDIX B: HISTAMINE-REDUCING DIET DIETARY GUIDELINES FRUIT/VEGE TABLE • Cranberries • Strawberries • Pineapple • Raspberry • Dates • Currants • Raisins 1  1 , 4  • • •  2 , 4  1 , 2  2  Spinach Tomato a n d t o m a t o Prunes ' 5  1  p r o d u c t s4,5  2  2  2  ME AT/ALTE RNATE S • any s e a f o o d ( s h e l l f i s h , f i n f i s h w h i c h i s canned, frozen) • u n c o o k e d e g g w h i t e (egg n o g , some m i l k s h a k e s ) • p r o c e s s e d meat ( l u n c h e o n meat, s a u s a g e , w i e n e r ) • 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  fresh,  4 , 5  4  5  MILK/MILK PRODUCTS • cheese products • yoghurt • sour cream  (block, processed,  slices)  5  5  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 n o t e a t f o o d contains: t a r t r a z i n e , a r t i f i c i a l food c o l o r , benzoic s o d i u m b e n z o a t e , b e n z o y l p e r o x i d e , BHT, BHA • 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 ; a s k your p h a r a m a c i s t 3  3  SEASONING • cinnamon • anise  • cloves • c u r r y powder  1  1  1  2  • hotpaprika • nutmeg 1  MISCELLANEOUS . • fermented soy p r o d u c t s (soy sauce, • fermented food ( s a u e r k r a u t ) • t e a (herbal or regular) • chocolate • a l c o h o l (beer, wine, h a r d l i q u o r ) 5  1  4  4 , 5  May n o t be r e p r o d u c e d w i t h o u t p e r m i s s i o n from Dr. J a n i c e J o n e j a 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 H i s t a m i n e r e l e a s i n g f o o d ( F i n n , 1987) 5 H i s t a m i n e r i c h f o o d ( S t r a t t o n e t a l . , 1991; t e n B r i n k e t a l . , 1990)  106  miso)  5  2  which acid,  APPENDIX C: CONTROL DIET DIETARY GUIDELINES P l e a s e DO NOT eat sweeteners or sugar • • • • • • •  or drink any o f the following artificial 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 .  Aspartame® Splenda® Saccharin Cyclamate Mannitol Xylitol Sorbitol  These  sweeteners  are  added t o  f o o d and may be  found i n :  FRUIT • •  canned f r u i t f r u i t drink  MEAT/ALTERNATE S •  peanut  butter  MILK/MILK PRODUCTS • •  yoghurt i c e cream  DESSERTS/SWEETS • popsicles • soda pop • cake Many c o m m e r c i a l  • • •  chocolate bars pudding syrup desserts contain  • •  candies hot chocolate  artificial  sweeteners.  MEDICATION • • •  cough s y r u p Neo C i t r a n ™ cough l o z e n g e  MISCELLANEOUS • • • •  barbeque sauce ketchup c h e w i n g gum c o l d and h o t c e r e a l  READ THE LABELS CAREFULLY A r t i f i c i a l sweeteners may be p u r c h a s e d i n a l i q u i d o r a g r a n u l a t e d f o r m . The b r a n d names a r e E q u a l , S u c a r y l , S u g a r T w i n , Sweet n ' Low and S p l e n d a . P l e a s e do n o t consume t h e s e p r o d u c t s .  107  APPENDIX  V  cx>  Day of Study:  D:  «S»  URTICARIA/ANGIOEDEMA  <x)  ^ss>  <x5  Date:  w >  DAILY  «SS»  ASSESSMENT  O O  «SS>  <3B  Name  P l e a s e c o m p l e t e t h e a s s e s s m e n t a t t h e same t i m e e a c h d a y . C o m p l e t e t h e a s s e s s m e n t f o r t h e p r e v i o u s 24 hours. [1) Number o f a n t i h i s t a m i n e Name o f t a b l e t : Dose o f t a b l e t : (2)  tablets  taken:  mg  T o t a l number o f w h e a l s ( h i v e s ) : D i d you count your wheals o r  guess?  (3)  Severity symptoms symptoms symptoms symptoms  o f i t c h i n e s s : P l e a s e check one. absent are present, but barely noticable are d e f i n i t e l y noticable, but are t o l e r a b l e a r e d e f i n i t e l y n o t i c a b l e , and a r e n o t 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 a b s e n t symptoms a r e p r e s e n t , b u t b a r e l y n o t i c a b l e 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 symptoms a r e d e f i n i t e l y n o t i c a b l e , a n d a r e n o t 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 h o r m o n a l t h e r a p y ) , c r e a m s , 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 w h i c h a f f e c t y o u r symptoms o r d i e t a r y problems:  108  APPENDIX  Day o f Study:  1  E:  THREE  Date  D A Y FOOD  RECORD  Name:  P l e a s e l i s t e v e r y t h i n g y o u e a t a n d d r i n k f r o m 12:00 am t o 11:59 pm. I n c l u d e a n y m e d i c a t i o n , v i t a m i n s o r s u p p l e m e n t s . P l e a s e be s p e c i f i c . I n d i c a t e how t h e f o o d was p r e p a r e d , b r a n d names, a n d quantities. TIME  Example 8:00am  TIME  FOOD  QUANTITY  F r i e d eggs Margarine Whole wheat t o a s t Jam FOOD  2 2 teaspoon 1 slice 1 tsp QUANTITY  109  Appendix F: Food Sources of Selected Nutrients Nutrient Vitamin A  Meat, Fish, Poultry Milk and Milk and Alternates Products Eggs, fish, liver Fortified milk and margarine, butter  Vitamin B i (Thiamin)  Meats, dried peas, legumes  Vitamin B2 (Riboflavin)  Meats, especially organ meats, legumes Meats, especially organ meats, poultry, fish, peanuts, legumes Meats, especially organ meats, eggs, fish, legumes Meats, especially organ meats, eggs, fish, shellfish  Niacin  Vitamin B6 (Pyridoxine) Vitamin B12  Milk, cheese, yogurt, cottage cheese  Green leafy vegetables, banana, carrot, potato  Eggs, liver  Vitamin E  Eggs, nuts, liver, legumes Liver, egg yolk  Fortified milk and margarine, butter Milk, butter Butter, cheese  Folic acid  Organ meats, nuts, legumes  Pantothenic acid  Eggs, organ meats, peanuts, walnuts Oysters, scallops, All salmon and sardines with bones, tofu Meats, liver, eggs, shellfish, nuts, sardines, legumes Nuts, legumes Milk Meats  Iron  Magnesium Potassium  Zinc  Fish liver oils  Nutritional yeast, wheat germ  Nutritional yeast  Nutritional yeast, wheat germ  Fruits, especially' citrus fruits and juices, strawberries, cabbage, tomato, potato  Vitamin D  Calcium  Whole grains  Miscellaneous  Cheese, yogurt  Vitamin C (Ascorbic Acid)  Vitamin K  Breads and Fruits and Vegetables Cereals E>ark green and yellow vegetables, sweet potato, tomato Whole grains, enriched flour and cereals Green vegetables Whole grains, enriched flour and cereals Whole grains, Com enriched flour and cereals  Meat, liver, eggs, shellfish  Fish liver oils Green leafy vegetables Green leafy vegetables, potato Green leafy vegetables, asparagus, banana, strawberries Fresh vegetables Green leafy vegetables, broccoli, dates Broccoli, peas, spinach, prunes, raisins Peas Fruits, especially orange juice, bananas, dried fruits, potato Green leafy vegetables, orange, prunes, strawberries  Cheese  Sources: American Dietetic Association. Manual of Clinical Dietetics. Chicago: A D A 1988 This Health and Welfare Canada. Action Towards Healthy Eating: Canada's Guidelines for Healthy Eating and Recommended Strategies for Implementation. Ottawa: Supply and Services Canada, 1990. Ontario Dietetic Association and Ontario Hospital Association. Nutrtional Care Manual 6th ed. Don Mills: Ontario Hospital Association, 1989.  ii  Whole grains, fortified cereals Wheat, oats  Vegetable oils, wheat germ Vegetable oils  Whole grains  Nutritional yeast  Whole grains, rice bran  Nutritional yeast Blackstrap molasses  Bran, enriched cereals  Blackstrap molasses, wheat germ  Whole grain  Whole grains  Chocolate syrup  appendix was written by : Cathy Hauchecome, R.D. N. University Hospital Vancouver  0 BCDNA Manual of Nutritional Care  A n y i n f o r m a t i o n r e s u l t i n g f r o m t h i s r e s e a r c h s t u d y w i l l be k e p t s t r i c t l y c o n f i d e n t i a l . A l l d o c u m e n t s w i l l be i d e n t i f i e d o n l y b y c o d e number a n d k e p t 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 n o t be i d e n t i f e d b y name i n a n y r e p o r t s o f t h e c o m p l e t e d 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 a r e f r e e t o withdraw from t h e study a t anytime w i t h o u t consequence t o continued medical care. Thank y o u f o r y o u r 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 8 7 5 - 5 0 0 2 . I f you have any c o n c e r n s a b o u t y o u r t r e a t m e n t o r r i g h t s a s a r e s e a r c h subject, contact the Director of Research Services at the U n i v e r s i t y o f B r i t i s h C o l u m b i a , 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 t h e " 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.  Subject  Signature  Date  Witness  Signature  Date  Investigator's  Date  Signature  Page 2 o f 2  112  APPENDIX I:  REASONS GIVEN BY POTENTIAL SUBJECTS FOR NOT PARTICIPATING IN THE STUDY  Reason  Number  Distance  22  Unknown  •  Insufficient Symptoms l e s s  time to p a r t i c i p a t e f r e q u e n t t h a n o n c e p e r week  12 7 5  Symptoms were n o t 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 b e g a n s t u d y , b u t s t r e s s f u l p e r i o d d u r i n g Time P e r i o d #1  2  Subject  2  r e p o r t e d symptoms w e r e t o o s e v e r e  S u b j e c t b e g a n s t u d y , b u t r e p o r t e d p r e g n a n c y d u r i n g Time P e r i o d #1  1  S u b j e c t began study, b u t changed m e d i c a t i o n / h e a l t h d u r i n g Time P e r i o d #1  1  Does n o t want t o f o l l o w a d i e t  1  Currently following a diet  1  Does n o t t h i n k d i e t w i l l  for urticaria  h e l p symptoms  1  Pregnant  1  U n d e r 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 :  U R T I C A R I A AND ANGIOEDEMA SYMPTOM ASSESSMENT S C A L E S 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 W h e a l s : 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 A n g i o e d e m a : Day 9 S u b j e c t #5 ( C o n t r o l Group) Number o f W h e a l s : Day 11 S u b j e c t #6 ( C o n t r o l Group) Number o f W h e a l s : 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 A n g i o e d e m a : 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 A n g i o e d e m a : Day 34 S u b j e c t #8 ( C o n t r o l Group) Number o f W h e a l s : 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 A n g i o e d e m a : Days 22, 24 S u b j e c t #11 ( T r e a t m e n t Group) Number o f W h e a l s : Day 25 S u b j e c t #14 ( T r e a t m e n t Group) Number o f W h e a l s : Day 23 S u b j e c t #15 ( T r e a t m e n t Group) Number o f W h e a l s : Days 7  115  APPENDIX K: STARTING AND ENDING DATES FOR EACH SUBJECT  Subject  a  b  c  d  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  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  16  T  02/03  04/13  17  T  06/03  08/15  18  T  06/23  09/05  a  d  05/18 T 03/10 19 D a y 0 was d e l a y e d b e c a u s e t h e r e was a d e l a y i n o b t a i n i n g t h e physicians' approvals. S u b j e c t c o m p l e t e d t i m e 1 a n d went t o H a w a i i . She s t a r t e d t h e c o n t r o l d i e t when s h e r e t u r n e d f r o m H a w a i i . S u b j e c t d i d n o t c o m p l e t e an a s s e s s m e n t o n 02/12, 03/28 a n d 03/30. S u b j e c t w i t h d r e w f r o m t h e s t u d y on Day 42.  N o t e : O n l y d a t a up t o Day 42 were u s e d i n t h e s t a t i s t i c a l analysis.  116  APPENDIX  L:  DIETARY  N O N C O M P L I A N C E AND  VARIABLE  CONFOUNDING  CHANGES  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 o n Days 32 t h r o u g h 38. 2. S u b j e c t t o o k one reactine® ( a n t i h i s t a m i n e ) on Day 32 a n d 33 f o r s n e e z i n g a n d r h i n o r r h e a . 3. S u b j e c t t o o k tylenol® (650mg) on Days 34 t h r o u g h 37 a n d tylenol® (325mg) o n Day 38. 4. S u b j e c t t o o k robitussin® AC (cough s y r u p ) (40ml) Days 37 through 41. 5. S u b j e c t t o o k ceclor® ( a n t i b i o t i c ) (750 mg) o n Days 38 t h r o u g h 4 3 . The c o l d or the medication appeared t o s l i g h t l y e x a c e r b a t e t h e 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 d r a n k a d i e t coke® o n Days 3, 9, 10 a n d 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 t o o k tylenol® (lOOOmg) on Days - 3 , 0 a n d 1. The change d i d n o t a p p e a r t o a f f e c t t h e 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 t h r o u g h o u t t h e study. 3. S u b j e c t u s e d habitol® ( n i c o t i n e p a t c h ) o n Days 2 t h r o u g h 19. The c h a n g e d i d n o t a p p e a r t o a f f e c t t h e u r t i c a r i a symptoms. 4. S u b j e c t c h a n g e d 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 c h a n g e d i d n o t a p p e a r t o a f f e c t t h e 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 o n Days 38 t h r o u g h t o t h e e n d o f t h e s t u d y ! S u b j e c t t o o k 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 d a y t h r o u g h o u t this period. Subject  #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 t h r o u g h o u t the study. 2. S u b j e c t t o o k benylin®-D-E E x t r a , V i t a m i n C (500 mg) a n d 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) o n Day - 7 . The c h a n g e d i d n o t a p p e a r t o a f f e c t t h e u r t i c a r i a o r a n g i o e d e m a symptoms. 3. S u b j e c t a t e a r t i f i c i a l s w e e t e n e r o n 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 w i t h d r a w f r o m t h e s t u d y on Day 31 b e c a u s e o f t h e amount o f t i m e a t t e n d i n g a p p o i n t m e n t s and b e c a u s e h e r d o c t o r t h o u g h t t h e 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 h o u r f r o m V a n c o u v e r H o s p i t a l . On Day 35, t h e 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 r e m a i n i n 117  t h e s t u d y b e c a u s e d i s c o n t i n u a t i o n o f dyazide® d i d n o t i m p r o v e t h e symptoms. The s u b j e c t h a d b e e n c o m p l i a n t w i t h t h e c o n t r o l d i e t and h a d b e e n 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 t o o k aspirin® (650 mg) on Day 10. The change d i d n o t a p p e a r t o a f f e c t t h e u r t i c a r i a o r a n g i o e d e m a 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 c h a n g e d d e o d o r a n t o n Day - 1 1 . The change d i d n o t a p p e a r t o a f f e c t t h e 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 u s e d reactine® a l o n e e v e r y d a y u n t i l Day 14. S u b j e c t u s e d reactine® a n d benadryl® on Day 15, a n d benadryl® a l o n e o n Day 16. S u b j e c t u s e d reactine® a l o n e f r o m Days 17 t h r o u g h 22, a n d benadryl® a l o n e Days 23 a n d 24. Day 25 reactine® was u s e d . S u b j e c t u s e d atarax® a l o n e Days 26 t h r o u g h 30. Reactine® a l o n e was u s e d Days 31 a n d 32, a n d atarax® a n d reactine® o n Day 33. Reactine® a l o n e was u s e d e v e r y d a y u n t i l t h e end o f t h e s t u d y . The s u b j e c t ' s symptoms were n o t c o n t r o l l e d b y m e d i c a t i o n , and t h e 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 n o t have a s i g n i f i c a n t i m p a c t on symptoms. T h e r e f o r e , c h a n g e s i n m e d i c a t i o n do n o t r e f l e c t c h a n g e s 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 t o o k 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 throughout the study. 3. S u b j e c t t o o k a c a l c i u m s u p p l e m e n t o n Day 1 a n d t h r o u g h o u t the remainder o f the study. 4. S u b j e c t t o o k V i t a m i n C (500mg) o n 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 r e p l a c e m e n t therapy) t h e d a y b e f o r e Day -14 a n d m a i n t a i n e d t h e d o u b l e d d o s e t h r o u g h o u t t h e 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 , P h . D . ) . However, t h e i n c r e a s e d premarin® d i d n o t a p p e a r t o e x a c e r b a t e t h e s u b j e c t ' s symptoms. S u b j e c t #11 ( T r e a t m e n t 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 a n d B c o m p l e x a n d l e t h i c i n s u p p l e m e n t s b e f o r e Day-14. 2. S u b j e c t u s e d 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 t h e c r e a m on Day 1. 3. S u b j e c t d r a n k one c a n o f pepsi® o n Day 1 1 . S u b j e c t #12 ( T r e a t m e n t Group) 1. S u b j e c t u s e d an new s o a p s t a r t i n g Day - 9 . The change d i d n o t a p p e a r t o a f f e c t t h e u r t i c a r i a o r a n g i o e d e m a symptoms. 2. S u b j e c t r e p o r t e d f l u symptoms on Days 11 t h r o u g h 15. The change d i d n o t appear t o a f f e c t t h e 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 2 1 . 118  S u b j e c t #14 ( T r e a t m e n t Group) 1. S u b j e c t t o o k tylenol® (325 mg) o n Days -14, - 1 3 , - 1 2 , 10, - 8 , - 3 , 1, 7, 9, 10, 11, 12, 14, 18, 36, 37, 38, 39 a n d 4 1 . E l e v e n t a b l e t s were t a k e n i n t i m e 1. T h i r t e e n t a b l e t s w e r e t a k e n i n t i m e 2. Two t a b l e t s were t a k e n i n t i m e 3. F i v e t a b l e t s w e r e t a k e n i n t i m e 4. The c h a n g e d i d n o t a p p e a r t o a f f e c t t h e u r t i c a r i a o r a n g i o e d e m a 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 o n Days 2, 3 a n d 4. The c h a n g e d i d n o t a p p e a r t o a f f e c t t h e u r t i c a r i a o r a n g i o e d e m a symptoms. 3. S u b j e c t u s e d diflucan® ( a n t i f u n g a l a g e n t ) ( 1 5 0 m g ) o n Day 4. The c h a n g e d i d n o t a p p e a r t o a f f e c t t h e u r t i c a r i a o r a n g i o e d e m a symptoms. S u b j e c t #15 ( T r e a t m e n t 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 t o o k novalhistine® DM ( a n t i t u s s i v e , d e c o n g e s t a n t ) (45ml) Days 21 a n d 2 2 . 3. S u b j e c t t o o k bradosol® c o u g h l o z e n g e s (3 l o z e n g e s ) Day 21. 4. S u b j e c t t o o k Halls® c o u g h l o z e n g e s (3 l o z e n g e s ) Day 2 3 . 5. S u b j e c t t o o k Tylenol® c o l d (1300 mg) Days 24 a n d 2 5 , Tylenol® c o l d (975 mg) Days 26 a n d 27, Tylenol® c o l d (650 mg) Day 28 a n d Tylenol® c o l d (325 mg) Day 2 9 . 6. S u b j e c t t o o k Tylenol® (325 mg) Days 31 a n d 32. N e i t h e r the c o l d nor the medication appeared t o a f f e c t the u r t i c a r i a o r a n g i o e d e m a symptoms. 7. S u b j e c t t o o k V i t a m i n E (600 I U ) Days 1,2 a n d 3. 8. S u b j e c t d r a n k t e a o n Day 1 a n d 39, a t e s m a l l amount o f c h o c o l a t e b r o w n i e o n Day 3, 1 g l a s s o f r e d w i n e on Day 5, H c u p c h o p p e d t o m a t o 'on Day 6, 1 s l i c e o f p i z z a o n Day 9, w i n e , t o m a t o , t e a , s p i n a c h a n d c h e e s e on Day 16, s m a l l amount o f y o g h u r t on Day 31 a n d Sprite® on Day 36. 9. S u b j e c t w i t h d r e w f r o m t h e s t u d y o n Day 42 b e c a u s e o f d i f f i c u l t y following diet. 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 P a r m e s a n c h e e s e o n Day 7. 2. S u b j e c t a t e m a r s h m a l l o w s on Days 9 a n d 10. S u b j e c t #18 1. S u b j e c t d r a n k one c a n o f gingerale® o n Day 26. 2. S u b j e c t a t e one s e r v i n g o f c h e e s e o n Days 39 a n d 40.  119  APPENDIX  M: WEIGHT CHANGE OVER THE STUDY  Subject  Group  Initial Weight (Day -14) (kg)  1  C  75  72  2  C  3  Final Weight (Day 56) (kg)  PERIOD  3  Percent Weight change  I n i t i a l Body Mass Index (Day -14)  b  -4%  24  66  66  0%  23  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  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  d  0% '  21  Based on s e l f r e p o r t e d weight and h e i g h t S u b j e c t was i l l and l o s t weight. S u b j e c t stopped smoking one month b e f o r e s t a r t i n g the study. The s u b j e c t b e l i e v e s t h i s may have c o n t r i b u t e d t o the weight g a i n . Subject i n c r e a s e d premarin® b e f o r e Day -14. The s u b j e c t b e l i e v e s t h i s may have c o n t r i b u t e d t o the weight g a i n . a  b  c  d  120  

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