THE ROLE OF NATURAL SALICYLATES IN FOOD INTOLERANCE

Transcription

Copyright © 1988 Anne Swain. For personal use only - may not be distributed. Further reproduction
prohibited without permission.
THE ROLE OF NATURAL SAL I CY LATES
IN FOOD I NTOLERANC E
by
A . R . Swa i n
A t hes i s submi tted for the degree of
DOCTOR OF PH I LOSOPHY
i n t he Un i vers i ty of Sydney .
PREFAC E
The work
descri bed
in
th i s
thes i s
was
i n i t i ated
in
order
i nvest i gate adverse react i on s to food i n sen s i t i ve i nd i v i dual s .
to
Al l
experi ments were personal l y carri ed out by the author between Apri l
1 977 and September 1 986 .
None of the materi al h as prev i ous l y been presented for the purpose of
obta i n i ng any other degree .
Anne . R . Swa i n,
B . Sc . , D i p . Nutr . & D i et .
February , 1 988 .
ABSTRACT
Our i ng
the
1 960 ' s
man i pul at i on
of
and
d i et
1 970' s
to
several
excl ude
authors
certa i n
reported
add i t i ves
and
t h at
natural
chemi cal substances l ed to apparent cl i n i cal benefi t i n a n umber of
cond i t i ons,
however ,
ava i l abl e d i ets were l arge l y emp i ri cal .
In
Apri 1 1 97 7 , the present study commenced w i th t h e devel opment o f an
el i mi n at i on d i et ,
recurren t
in
order
i d i opath i c
to
i nvest i gate the rol e
urt i c a r i a!ang i oedema .
Stabl e
of food
in
asymptomat i c
remi ssi on was fi rst establ i s hed on th i s basel i ne d i et ,
pri or to
chal l enge
gel at i ne .
wi th
test
substances
encapsul ated
in
Fol l owi ng compl et i on o f the chal l enge protoco l ,
mod i fi cat i on
based
on
i nd i v i dual
oral
c l ear
l ong - term d i etary
provocat i on
resul ts
was
adv i sed .
The i n i t i al cl i n i cal exper i ence i n 76 pat i ents i nd i cated t h at n atural
sal i cyl ates ( asp i ri n ) were one of the main groups of compounds wh i ch
coul d
prec i p i tate
recurrent
i d i opath i c
urt i cari a!
ang i oedema ,
h owever , the 1 i terature reveal ed that pub 1 i shed i nformat i on about
the i r presence
i n food was l i mi ted .
Consequentl y ,
a systemat i c
anal ysi s o f the total sal i cyl ate content of commonl y eaten foods was
undertaken
usi ng
th i n
l ayer
chromatography and
h i gh
performance
l i qu i d chromatography , after wh i ch the el i mi nat i on d i et was mod i fi ed
and ch arts were constructed wh i ch coul d be
used by sal i cyl ate
sensi t i ve i nd i v i dual s to control the total d a i l y dose of sal i cyl ate
consumed .
I t then became apparent that adverse react i on s to food may cause not
onl y symptoms i nvol v i ng the s ki n
ang i oedema ) ,
( recurrent i d i opath i c urt i cari al
but al so of the gastro i ntest i na1
tract and/or central nervou s system .
tract ,
resp i ratory
Cl i n i cal observat i on suggested
t h at i n these pat i ents a vari ety of other food add i t i ves and n atural
compounds mi ght be i mp1 i cated i n provo ki ng s ome of t he i r symptoms .
The chal l enge battery was therefore expanded and made doub l e - bl i nd to
al l ow for the exten s i ve and obj ect i ve i nvest i gat i on of al l pat i ents
present i ng wi th more subj ect i ve symptoms ( such as mi gra i ne , i rr i t abl e
bowel
and
vary i ng
neuropsych i atri c
manifestat i ons
i nves t i gated .
than
of
symptoms ) .
food
Over
3 000
i ntol erance
pat i ents
h ave
n ow
wi t h
been
Suscept i b i l i ty appears to be fami l i al , more wi despre ad
general l y
apprec i ated
and
there
is
strong
c i rcumstant i al
ev i dence to suggest that react i ons are pharmacol og i cal
( rather t h�n i mmunol og i cal ) .
i n nature
React i on s appear to be dose - re l ated ,
and s ens i t i ve pat i ents may exh i bi t wi t hdrawal and s upersen s i t i v i ty ,
as
wel l
as
tachyphyl axi s
and
tol erance
after
re i ntroduct i on .
Overal l , n atural sal i cyl ates are the s i ng1 e commonest s ubstance to
produce react i ons when tested by doubl e - bl i nd oral chal l enge .
pat i ents are sens i t i ve to mul t i pl e s u bstances
common l y ) , and t h e effects can be add i t i ve .
Most
( between 2 and
10
ABBREV IAT I ONS
ARS
Anne Ruth Swa i n
ASA
Asp i r i n
BDH
Bri t i s h Drug House
BFSTA
B i s (Tri methyl s i l yl ) Tri fl uoroacetami de
CaC1 2
Cal c i um C h l ori de
CNS
Central Nervous System
GABA
G amma-Ami n obutyr i c Ac i d
GlC - MS
Gas Chromatography-Mass Spectrometry system
HCl
Hydrochl or i c Ac i d
H P LC
H i gh Performance l i qu i d Chromatography
H 3 P04
Phosphori c Ac i d
I BS
I rri t abl e Bowel Syndrome
KHS04
Potas s i um B i sul phate
MgS04
Magne s i um Sul phate
MSG
Mono S od i um Gl utamate
N aHC03
Sod i um B i carbonate
NaOH
S od i um Hydroxi de
NH&MRC
Nat i onal Heal th and Med i cal Research Counc i l
NSW
New South Wal es
R I U/AO
Recurrent I d i opath i c Urt i cari a/Ang i oedema
RPAH
Royal Pri nce Al fred Hosp i tal
SO
Standard Dev i at i on
SE
Standard Error
S PSs-x
Stat i st i cal Packages for Soc i al Sc i ences , N umber 1 0
TBAP
Tetrabutyl ammon i um Phosphate
T LC
Th i n Layer Ch romatography
USA
Un i ted States of Ameri ca
ACKNOWLEDGEMENTS
The work descri bed i n thi s thes i s was carri ed out i n the Human
Nutr i t i on Un i t of the Un i vers i ty of Sydney and the Al l ergy C l i n i c at
Royal Pri nce Al fred Hosp i tal and under the superv i s i on of Professor
A . S . Truswel 1 and Dr . R . Lobl ay .
I am deepl y grateful to Professor A . S . Truswel l , Boden Profes sor of
Nutri t i on , Un i vers i ty of Sydney , for al l owi ng me the pri v i l ege of
work i ng i n h i s department on a project of my own choos i ng , for maki ng
the nece s sary equ i pment ava i l abl e for sal i cyl ate anal yses and for
g i v i ng me h i s enthus i as t i c support and hel pful adv i ce throughout the
study .
I record my warm grat i tude to Dr .
R . Loblay , Sen i or Lecturer i n
Immunol ogy , Un i vers i ty of Sydney for the i nsp i rat i on and unfl agg i ng
enthus i asm wh i ch he has d i spl ayed throughout the course of th i s study
and for h i s fri ends h i p , g u i dance and general
superv i s i on of the
cl i n i cal aspects of t h i s project . Th i s thes i s woul d not h ave been
poss i bl e wi thout such as s i stance .
I wi s h
to t h ank Professor A .
Basten ,
Department
of
I mmunol ogy ,
Un i vers i ty of Sydney , for h i s superv i s i on i n the i n i t i al stages of
the project and for h i s encouragement throughout .
I wi s h to than k Profes sor R . Cl ancy , Facul ty of Med i c i ne , Un i vers i ty
of Newcastl e , for i n i t i at i ng t h i s work and prov i d i ng the genes i s of
the i dea for th i s thes i s .
I am espec i al l y i ndebted to J . Rogers , M . Hos ki ng. and J . Bul l oc k for
the i r encouragement and support i n the organ i zat i on of the cl i n i cal
and d i etet i c aspects of th i s study .
I wi s h to expres s my s i ncere th anks to G . Boyd and J . McQueen for
t he i r fri end sh i p and i nval uabl e ass i stance i n t h e d i etet i c man agement
of the pat i ents of th i s study .
My as soc i at i on wi th the members of the Al l ergy C l i n i c at Royal Pri nce
Al fred Hosp i tal ensured that the cl i n i cal work of t h i s proj ect was
both st i mul at i ng and enj oyabl e .
I woul d l i ke to acknowl edge t h e
contri but i on o f :
Dr . S . Adel ste i n , Profes sor A . Basten , Professor R . C l ancy , Dr . P .
Gatenby , Dr .
P.
Hogan , Dr . C . Katerl ari s ,
Dr . S .
Kri 1 i s , Dr .
D.
l i ndsay , Dr . A . ll oyd , Dr . R . lovett , Dr . R . Prent i ce , Dr . Scopp a ,
Dr .
V.
Soutter ,
Dr .
S.
Van
Nunen ,
Dr .
A.
Wh i te ,
Profe s sor
A.
Wool coc k , Dr . K . Yan and Dr . I . Young .
S i sters K . C ameron , J . F i el d , M . McWade and N . N i chol a s .
I n add i t i on , I thank Dr . P . Bye , Dr . W . Bye , Dr . P . Corte , Dr . P .
G i anoutsos , Profes sor M . Jol l y , Dr . R . Kater , Dr . P . Seal e , Dr . W .
Se 1 by , and al l the many other general p ract i t i oners and phys i c i an s
who have referred pat i ents to the study .
A very spec i a1
than ks i s due to my co1 1 eagues
i n the D i etet i cs
Department at Royal Pri nce Al fred Hos p i tal for t he i r warm fri ends h i p ,
i ntere s t , part i c i pat i on i n experi ments and for the i r p at i ence and
good h umour
i n deal i ng wi th pat i ents '
tel ephone cal l s .
I
woul d
ment i on part i cul arl y :
D i et i t i ans : M . A1 l man , W . Bi rk, G . Boyd , H . Buck , J . Bul l oc k , K .
Burn s , A .
C arval ho ,
S . Cl ubb ,
P.
Crowe , M .
Evan s ,
Y.
Furby ,
D.
George , P . G i l hol me , M . Hos ki ng , D . John son , I . Madden , J . McQueen ,
M . M i l o s avl j ev i c , M . Q ' Connor , M . Pang , M . Perki n s , J . Ravens , G .
Rob i n son , J . Rogers , l . Rouse , H . V i dot , J . Wen h am , M . Westgarth and
J . Wyatt
D i et Ai des : M . F i tzpatri c k , S . Haki n , K. Hos t , J . Hunter , J . Karaus ,
D . Morgan , N . S i l ver and M . late .
I wou 1 d al so 1 i ke to thank my many 1 aboratory co 1 1 eagues from the
Human Nutri t i on Un i t , Un i vers i ty of Sydney , who were i nstrumental i n
my educat i on at the bench , hel pful i n d i scu s s i on and co 1 1 aborat i on
and s i gnal
i n warm fr i end sh i p and encouragement .
I woul d ment i on
p art i cul arl y :
J . Al 1 en ,
S . Ash ,
Dr .
J.
Darton- H i l 1 , S . Dutton , P .
lhorburn and Dr . D . Zador .
Brand , V .
lyon s ,
Cheri koff ,
P.
Cra i g ,
Dr .
I.
Dr . D . Robert s , S . Samman , A .
I am espec i al l y grateful to the secretari es D . Bart i mote , R . Dedman ,
B . Rose , M . Syl vada de Soza and J . Wh i tehead , for thei r pat i ence ,
cheerful ness i n answeri ng pat i ents ' cal l s , t he adv i ce they gave about
the l ayout of t h i s t hesi s and t he i r ski l l i n the expert typ i ng of the
d i et charts and l etters perta i n i ng to th i s study .
My than ks are due to Dr . I . Brown , Dr . R . Caterson , Dr . R . Day , Dr .
G . Graham , H .
Guppy , Professor L . J u h l i n ,
Dr . K . Murray , Dr .
F.
Wh i tfi el d and Dr . J . Woodh i l l for the i r advi ce when sett i ng up the
l aboratory methods , to the gl assbl ower M . Wi c k , Chemi stry Department ,
for
maki ng
t he
spec i al
l i qu i d
extractors
and
t he
L aboratory
Techn i c i ans, E . Peden and E . Tri fonoff for l �nd i ng extra equ i pment
when needed . Spec i a 1 t h an ks are due to S . Out ton for h i s t i re 1 ess
i n s t ruct i ons about new equ i pment and the devel opment of the fi n a 1
l aboratory
methods
and
to
M.
Smythe
for
his
confi rmat i on
of
sal i cyl ate i n the food extracts for the Journal of Ameri can D i etet i cs
Assoc i at i on .
I am al so grateful to Dr . K . Mel drum , Macquari e Un i versi ty for h i s
i nval uabl e adv i ce and Professor Berry ,
Commonweal th
I nst i tute
of
Heal th for h i s assi stance wi th the stat i st i cal anal ysi s of the d at a .
I woul d al so 1 i ke to thank R .
Pri nce
Al fred
Hosp i tal ,
for
Sout h , Computer Department ,
al ways
be i ng
ava i l able
to
Royal
answer
quest i ons and wr i t i ng a number of computer programmes for stat i st i cal
tests .
I wou l d l i ke to than k B .
Pri nee Al fred Hosp i tal ,
tabl es and R .
Hai nes , Aud i o V i sual
Department ,
Royal
for the preparat i on of t he di agrams and
Barber , M .
San key and the photographers for t h e i r
ass i stance i n the taki ng of photographs .
I woul d al so 1 i ke to t h an k B . Porter , Food Technol ogy Branch , New
South Wal es Department of Heal th , for h i s i nformat i ve
and hel pful
adv i ce about food add i t i ves and V i rg i n i a Ri chardson for as s i st i ng i n
the p repari ng of the test capsul es i n the i n i t i a 1 years of the
proj ect .
I n add i t i on , many t h an ks are due to al l those pat i ents and col l eagues
who part i c i pated i n the cl i n i cal tri al s , wi thout whose co - operat i on
th i s study wou l d not h ave been possi bl e .
F i n a l l y , I wi sh to t h an k my h usband , parents and fami l y for the; r
compl ete support and encouragement .
BIBLIOGRAPHY
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G i bson , A . R . and C l anc y, R . L. (1980) : Management of chron i c i d iopath i c urti c ar i a by the i dent i f i c ati on .
C l i n . A l lerg y, 1 0:699-704
A l len , D. H . , Van Nunen, S . , Lobl ay, R . , C l arke , L. and Swain , A.(1984) : Advers e react i ons to f oods .
Med. J. Aust . , ,g,:S37-S42
Swai n , A . , Truswe l l , A . S . and Lobl ay, R . H . (1984) : Adverse react i ons to f ood. Food Techno l . Aust . ,
�:467-471
Lobl ay, R . H . and Swai n , A . R . (1985) : Adverse react i ons to t artr az ine . Food Tech . Aust . , �:508-51 0 &
514 .
Lobl ay, R . H . and Swai n , A . R . (1985) : Food I n to lerance . Recent Adv . C l i n . N ut r . ,g,:169-1 77 .
Swai n , A . , Dut ton , S . and Trus wel l , A . S . (1985) : S al i c yl ates i n food . J.
Swai n . A . , Sou tter , V"
Am.
Diet . Assoc . , �:950-960
Lo bl ay, R . and Truswe l l , A . S . (1985) : S al i c yl ates , o l i goant i gen i c d iets and
behav i our. Lance t. 1:4 1 -42 .
Loblay, R .
H.
and Swai n , A . R . (1987 ) : Adverse food reac t i ons . In Food and Heal th - I ssues and
Di rect i ons . Eds . M . L. Wah l qu i s t, R .W. F . Ki ng. J.J. McNe i l and R . Sewe l l . J. Li bbey, London .
Gr ac ey. M . ,
I rw in ,
T. ,
Lobl ay, R . , Swai n , A .
and Truswe l l , A . S .
( i n press ) : Food Al lerg y and
I nto lerance . In Ro yal Aus tr al i an Col lege of General Pract i t i oners Nutr i t i on Educ at ion Program Handbook .
Ed . T . I rwi n. Dai r y Corpor ation of Austr al i a, S ydney.
Lobl ay, R . H . and Swai n, A . R .
( in press) : F ood I ntolerance .
In Di et i t i ans Assoc i at ion of Austral i a
Hand book Number S i x, Di et i t i an ' s Reference - Pr i nc i p l es of Di et ar y Management . Eds . J. H awker , D.
Ke l leher and Diet i t i ans Assoc i at ion of Austral i a Ther apeut i cs C ornni ttee . Diet i t i ans Assoc i at i on of
Austral i a, C an berr a.
Ab st ract s
Lob la y, R . and Swa i n , A. ( 1982 ) : Dietary add i t i ve s and urt i car ia . Proceedi ng s of Aus tral i an Soc i et y for
I mnuno log y.
Lobla y, R . H . and Swa i n , A. ( 1982 ) : The rol e of food sen si t i vi t y i n ben i gn mya li c e ncaphal omyeli t i s.
Proceedi ng s of XI Internat iona l Congress of Al lergology and C l i n ical I mmunol ogy.
Swa i n , A . ( 1982 ) : The theoret i ca l basi s for e l iminat i on and rotat i on d iets. P roceedings of Au stral ian
C l i n i ca l Eco log y.
Swa i n , A . , Dutton , S . and Tru swe l l , A . S .
( 1982 ) : Sa l ic yl ates in Austral i an foods. P r oceed i ngs of
Nutr i t i on Soc i et y, 1: 1 63
Van Nunen, S .A . , Swa i n , A . , Kr i l i s, S . , Ba sten , A . , Gatenby, P . A. and Lob l a y, R . H . ( 1982 ) : Di et ar y
modi f i cat i on i n chron i c "i d i opat h i c " u rt i car i a and/or ang i oedema . Proceed i n gs of XI
I nternat i ona 1
Congre ss of Al lergol og y and C l i n ical I mmunol og y.
Swa i n , A . R . , Lob la y, R . H . , Van Nunen , S . A . and Tru swe l l , A . S . ( 1983) : Food sen si t ivi t i e s i n chron i c
urt i cari a. P roceed i ngs' o f Au stra l i a n Assoc iat i on of Di et i t i an s.
Swa i n , A . ( 1 984 ) : Adverse react i on s to food . P roceed i ngs of t he Austral i an I n st i tute o f F ood Sc ience
and Techno log y.
Swa i n, A . and Lob l a y, R . ( 1984 ) : Adver se react i ons to food . Proc eed i ng s of AFST/CIA �: 467 -471 .
Swa i n , A . R . and Lob la y, R . H . ( 1984 ) : I ssue s i n food a l lerg y and i ntolerance . Proceed i ng s of the Fourth
Nat i ona l Conference of the Diet i t i an s Assoc i at ion of Au stra l i a.
Al l e n, D. A . , Van Nunen , C . , Lob l a y, R . , C larke , L. and Swa i n , A . ( 1985) : Adver se react i on s to foods.
Read i ngs in Pathol og y, M ac quar i e Patho logy Serv i ce s. pp . 45-51 .
Swa i n , A . S . ,
Lob lay, R . H . and Tru swe11, A . S . ( 1985) : Ur i nary sa 1 i c ylate response to low and h i gh
sa l i c ylate d i et s i n no rmal adu lt s. I nternat i onal Congre ss of Nutr i t i on ( B r i ghton , Uni ted Kingdom) Book
of abstract s p 188.
Lob l a y, R . H . and Swa in , A . R . (1986 ): Reac tio ns to factor s in foods. Med i c i ne : Its pa st , the presen t a nd
the future , Au stra l ia n Med ica l Assoc i a ti o n, Sou th Au stra l i a n Branc h.
Swa i n , A . , Loblay, R . and Adelste i n , S . (1986 ) : Die ta ry factors in t he management of cold urt icar i a .
Proceedi ng s of I nternat i onal Congress of Allergology and Cli n i ca l I mmunology .
Pa mphlet s and Educat i onal Ma ter i al
Swa i n , A . and Soutter , V. (1984) : "I s your ch i ld ' allerg ic ' to f ood". Australia ' s Parent and Chi ldren
Magaz i ne 12: 7 1 -7 2 .
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10: 5-6.
Loblay , R . H . and Swa in , A . R . (1986 ) : F ood Intolerance . The Au stralian Nutr i t i on Foundat i on I nc .
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Hea l t h. Kraft Food s L im i ted .
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CONTENTS
PAGE NO .
Chapter
1:
I ntroduct i on
1
Chapter
2:
Sal i cyl ate An al ysi s
8
Chapter
3:
D i etary I nvest i gat i on of Recurrent
59
I d i opath i c Urt i cari a
Chapter
4:
D i etary Man agement and Fol l ow-Up
101
Chapter
5:
Sal i cyl ate Pharmaco ki net i cs
1 24
Chapter
6:
Cl i n i cal Spectrum of Food I ntol erance
1 44
Chapter
7:
Fami l y Stud i es
201
Chapter
8:
Fol l ow-Up
211
Chapter
9:
H i stori cal Perspect i ve
219
Chapter
1 0:
Concl usi ons
239
References
Appendi ces
261
CHAPTER 1
I NTRODUCT I ON
1
Th i s study commenced at Royal Pri nce Al fred Hosp i tal ( RPAH ) i n Apr i l
1 977 , after Dr . R . L . C1 ancy ( Staff Immunol og i st ) became i nterested i n .
the poss i b1e rol e of d i etary substances i n the pathogenes i s of re
current i d i opath i c urt i cari a and ang i oedema ( R I U/AO ) .
Duri ng the
1 960 ' s and 1 970 ' s several authors h ad reported t h at a n umber of chem
i cal s pre sent i n food coul d prec i p i tate acute exacerbat i ons of R I U/AO
and t h at d i ets desi gned to exc1 ude these substances often i nduced
prol onged remi ssi on
( Wari n ,
Champ i on et al . , 1 969 ;
1 960 ;
Moore - Robi nson & War i n ,
J ames & Wari n , 1 970 ;
et al . , 1 972 ;
M i chae1 sson & J uh1i n , 1 973 ;
Doegl as , 1 975 ;
Thune & Granhol t , 1 975 ;
1 976 ;
Ros et al . , 1 976 ;
Lockey , 1 97 1 ;
1 967 ;
Juh1 i n
Wari n & Champ i on , 1 974 ;
Wari n , 1 976 ;
Sett i pane et al . , 1 976 ;
War i n & Smi th ,
Doeg l as , 1 9 77 ) .
The chemi cal s that were i mpl i cated i ncl uded the n atural l y occurri ng
sal i cyl ates i n food as wel l as art i fi c i al l y added preservat i ves and
col ouri ngs .
RI U/AO i s a common cond i tion general l y t reated symptomat i ca 1 1y wi th a
vari ety of ant i h i stami nes , the si de effects of wh i ch are o ften l i mi t
i n g factors .
As a resu1 t of t h e favourab1 e f i nd i ngs reported by
Wari n and Smi th ( 1 976) Dr . C1 ancy dec i ded to i nvest i gate d i etary
man agement as an al tern at i ve ,
Therapeut i c D i et i t i an )
d i et .
and approached Ms M .
Hoski ng ( Head
i n order to devel op a su i tabl e el i mi n at i on
At t h i s t i me the author was consul ted wh i l e worki ng as an
i ntern d i et i t i an i n the Dermatol ogy Ward at RPAH .
Under the gu i dance
of Ms M . Hoski ng and Ms J . Rogers ( Head Food Serv i ces Di et i t i an ) , and
after rev i ewi ng t he avai l abl e l i terature on d i et and R I U/AO , an el i m
i n at i on d i et was formul ated and the study commenced ( G i bson & Cl ancy ,
1978 ) .
2
Rev i ew o f L i terature Lead i ng UP to Th i s Study
I t h ad been known s i nce the turn o f the century that a s p i r i n i ngest
i on coul d prec i p i tate acute urt i cari a ( H i rschberg,
1 902 ) and more
recent 1 y Ca 1 n an ( 1 957, 1 964 ) noted t h at aspi ri n caul d al s o tri gger
recurrences i n many pat i ent s wi t h R I U/AO .
War i n ( 1 960 ) h ad report ed
that 22 o f 70 pat i ents wi t h R I U/AO devel oped exacerbat i on s after
admi n i strat i on of asp i ri n .
Subsequentl y, Moore - Ro b i n so n and War; n
(1967) reported an i nc i dence of 22% i n 228 pat i ent s and C h amp i on et
al .
( 1969 ) found t h at 21% o f 268 pat i ents wi t h R IU/AO reacted to
aspi r i n .
James and Wari n ( 1 970) gave test doses o f asp; r i n to 96
pat i ents wi t h R I U/AO i n a "s i ng1 e b 1 i nd " manner, and 3 7 o f t hese
devel oped an urt i car i al react i on to t h e chal l enge .
I n 1 959, 1 969 and 1 97 1 , Lockey reported the rol e o f azo dye s deri ved
from coal tar, part i cul arl y the yel l ow dye tartrazi n e, i n R I U/AO .
Juhl i n et al .
( 1 972) s howed that i n seven out o f e i ght a s p i r i n
sens i t i ve pat i ents s i mi l ar exacerbat i on s occurred wi t h t artraz i ne, as
wel l
as wi t h certa i n
benzoates u s ed as
preservat i ve s .
In
1 973
M i chael s son and Juh l i n reported 52 pat i ents who were chal l enged w i t h
asp i r i n,
s od i um benzoate,
4 - 0H benzo i c ac i d,
t artraz i ne, sunset yel l ow and new cocc i n e .
and three azo dyes
Of these, t h i rty fi ve
reacted to a s p i ri n, twenty seven to benzo i c ac i d compounds and twenty
seven to azo dyes .
Doegl as (1975 ) h ad performed s i mi l ar provocat i on
tests, and i n 23 pat i ents wi th R I U/AO known to react to a s p i r i n, 30%
reacted to t artraz i ne , 1 7% to sod i um benzoate and 1 5% to 40H benzo i c
ac i d .
U s i ng a battery of chal l enge tests Thune and Granhol t i n 1 975
and Wari n and Smi th , and Ros et al . in 1976 al s o i dent i fi ed a group
of R I U/AO pat i ents who reacted to sal i cyl ate ,
tartraz i ne,
sod i um
3
benzoate and 4 - 0H benzo i c aci d .
Sett i pane et al . ( 1 976 ) chal l enged
38 pat i ents wi th tartraz i ne i n whom there was an e i ght percent pos i t
i ve res pon se .
Several of the above authors had reported that d i ets des i gned to
excl ude
foods
conta i n i ng
sal i cyl ates
and/or
add i t i ve s
i nd uced
prol onged remi s s i on of urt i cari a i n those pat i ents who h ad s hown a
pos i t i ve respons e to oral chal l enge wi th these compounds ( M i c h ael s son
and J u h l i n , 1 973;
Doegl as , 1 975;
Ros et al . , 1 976;
Doegl as , 1 97 7 ) .
Wari n , 1 976;
War i n & Smi th , 1 976;
Seventy - fi ve percent of the pat
i ents stud i ed by War i n and Smi th ( 1 976 ) became e i ther asymptomat i c or
i mproved after be i ng on an appropri ate d i et for a two month per i od .
Th i s i mprovement was s i mi l ar to the resul ts obt a i ned by M i chael sson
and J u h l i n ( 1 973 ) and Doegl as ( 1 975 ) .
In 1 976 , Ros et al . found t h at
i n 59 pat i ents w i t h R I U/AO who reacted to chal l enge wi th sal i cyl ates ,
pre servat i ves and azo dyes , a d i et des i gned· to reduce cons umpt i on of
these i tems resul ted i n compl ete remi s s i on i n 24% and i mprovement i n
57% .
Des i gn of the El i mi nat i on D i et at RPAH
Our approac h to the i dent i fi cat i on of d i etary chemi cal s wh i ch contri
bute to the pathogenes i s of R I U/AO was s i mi l ar to that of War i n and
Smi th ( 1 976) .
An i mportant d i fference , however , was our attempt to
establ i s h a stabl e asymptomat i c remi s s i on pri or to chal lenge , u s i ng a
baseli ne d i et constructed to excl ude all the test sUbstances ( G i bson
& C l ancy , 1 978 ) .
Th i s approach had the dual advantage that p at i ents
4
wou l d be abl e to d i scont i nue ant i h i stami nes , wh i ch m i ght otherw i se
mas k chal l enge react i ons , as wel l as reduc i ng background symptoms
from s ubstances i ncl uded
i n a normal
produce fal se pos i t i ve resul ts .
d i et wh i ch m i ght otherw i se
The l ow response rate w i t h the
l actose p l acebo i n t h i s study emphas i zed the i mportance of remov i ng
th i s background "no i se" and contrasts w i th the exper i ence of other
workers ( M i chael s son & J u h l i n , 1 973;
Doegl as , 1 977 ) .
We began wi t h a d i et based ma i nl y on the el i mi nat i on d i et s of Rowe
( 1 944 ,
1 972 ) ,
Shel l ey
( 1 964 ) ,
Fe i ngol d
( 1 968)
and
War i n
( 1 976 )
des i gned to excl ude the common food "al l ergens" as wel l as s a l i cy
l ates , preservat i ves and azo -dyes , but cl i n i cal exper i ence w i t h our
fi rst two pat i ents s uggested that thi s i n format i on was i nadequate .
S i nce p i neappl e and pears were the onl y fru i ts al l owed , both pat i ents
cons umed large amounts of p i neappl e j u i ce and fres h p i neappl e , and
found t h at
th i s
appeared
to exacerbate t he i r symptoms .
A more
deta i l ed rev i ew of the l i terature reveal ed that , where ava i l abl e ,
anal yt i cal dat a on the content of s al i cyl ates and benzoates occurr
i ng natural l y i n foods was i ncompl ete , scattered , and s omet i mes con
trad i ctory (Tabl e 2 . 6 ) , and-much of the publ i s hed i nformat i on was not
rel evant to the Au stral i an d i et .
I t was therefore dec i ded to under
take a systemat i c anal ys i s of the total sal i cyl ate content of common
l y eaten foods under the superv i s i on of Profes sor A . S . Truswe l l i n
the Human Nutr i t i on Un i t , Un i vers i ty of Sydney .
Th i s wor k , descri bed
i n C hapter 2 , was compl eted i n 1 983 and l ed to a number of mod i fi c at
i ons of our ori g i nal el i mi n at i on d i et ( G i bson & Cl ancy , 1 978 ;
et al . , 1 984 ) .
Al l en
5
The Cl i n i cal Spectrum of Food I ntol erance
Dr . Cl ancy l eft RPAH i n 1 978 , and cl i n i cal eval uat i on of pat i ent s
undergo i ng d i etary el i mi n at i on and chal l enge test i ng cont i nued w i t h
Professor A . Basten , Drs . P . Gatenby , S . Kri 1 i s a n d S . Van Nunen .
The cl i n i cal features and res u l ts of i mmunol og i cal and other i nves t
i gat i ons i n the fi rst 76 pat i ents wi th R I U/AO were publ i shed i n 1 980
( Gi bson & Cl ancy) .
F I GURE 1 . 1
TOTAL PAT I ENTS S E EN AT THE ALLERGY CL I N I C 1 97 7 - 1 986
e"
Z
i=
z
w
UJ
w
a:
0UJ
�
z
w
i=
c
0LL
0
a:
w
CD
�
900
800
700
600
500
400
300
200
100
::J
z
toto0)
,...
o
co
to0)
,...
0)
to0)
,...
0
co
0)
,...
,...
co
0)
,...
YEAR
C\I
co
0)
,...
('I)
co
0)
,...
�
co
0)
,...
10
co
0)
,...
co
co
0)
,...
TOTAL PATIENTS PRESENTING
� PATIENTS WITH DISORDERS
� OTHER THAN RIUI AO
I n 1 980 Dr . R . H . Loblay j o i ned the RPAH All ergy Cl i n i c as Cli n i cal
6
I mmunol og i st .
By the fol lowi ng year i t was becom i ng i ncreas i ngl y
ev i dent to us , as wel l as others (Juhl i n , 1 98 1 ) , t h at pat i ents wi th
R I U/AO s omet i mes al so e �per i enced abdomi nal p a i n , d i arrhoea , h e ad
ache ,
res p i ratory and/or const i tut i onal
symptoms when
bl i nd chal l enge wi th var i ous food s u bstances .
undergo i ng
I t was found t h at
el i mi n at i on of the rel evant foods somet i me s res u l ted i n d ramati c
i mprovement i n chron i c symptoms of th i s ki nd , even when R I U/AO was
onl y a mi nor component of the c l i n i cal presentat i on .
S i nce 1 981
t here h as
been a gradual
c hange
i n the s pectrum of
pat i ents attend i ng the RPAH Al l ergy Cl i n i c ( F i gure 1 . 1 ) .
Th i s was
partl y due to the d i s semi nati on of the protocol to other h os p i tal s
and pract i t i oners who were t hen abl e to manage pat i en t s wi t h uncomp
l i c ated R I U/AO i n the s ame way , so t h at those referred to RPAH tended
to h ave more compl ex or unusual
cl i ni cal
p re sentat i on s .
Another
factor was the i ncreas i ng publ i c i nterest i n "food al l e rgy" wh i ch i n
the 1 ate 1 970' s and earl y 1 980' s was wi de 1 y promoted by fri nge and
a l ternat i ve pract i t i oners as be i ng respon s i ble for a vast array of
symptoms and d i seases ( Fe i ngol d , 1 975;
1 980;
C roo k , 1 984 ) .
A i rol a , 1 977;
Mackarness ,
By 1 982 the Al l ergy C l i n i c at RPAH h ad become
we 1 1 known for i ts i nterest i n food i ntol erance , and many p at i ents
were t herefore referred wi th a vari ety of cl i n i cal p robl ems , wh i ch
t h ey s u s pected mi ght be
attri butable to
d i etary factors .
These
i nc l uded mi gra i ne , i rri tabl e bowel syndrome ( I BS ) , asthma and eczema ,
as wel l as p at i ents who experi enced symptoms referabl e to mul t i pl e
organ systems ,
often together wi th vague con st i tut i onal
suggest i ve of p sychoneuros i s .
symptoms
Th i s 1 atter group of pat i ents was
7
des i gn ated as h av i ng "systemi c" symptoms .
A Paed i atri c i an , Dr . V .
Soutte r , al so began attend i ng the Cl i nic i n 1 981 , and a s i gn i fi c ant
n umber of "hyperact i ve
11
ch i 1 dren have undergone d i etary eva 1 uat i on
s i nce then .
Cl i n i cal observat i ons s uggested that i n pat i ents w i t h syndromes other
than R I U/AO mi l k , wheat , natural ami nes ( Han i ngton , 1 967 ) , monosod i um
gl utamate ( MS G ) ( Kwo k , 1 968;
Schaumberg et al . , 1 969 ) , and a vari ety
of other food add i t i ves mi ght al so be i mpl i cated i n provoki ng some of
these symptoms , and a more stri ngent el i mi n at i on d i et was des i gned
for the i nvest i gat i on of such pat i ents .
At the s ame t i me the range
of c h a 1 1 enge s ubstances was extended , and starch and s ucrose were
i ntroduced as pl acebo s i n pl ace of l actose , whi ch was somet i mes found
to
provoke
abdomi n al
symptoms .
S i nce many
of these
add i t i onal
symptoms were of a subj ect i ve nature the chal l enge protocol was made
"doubl e - bl i nd" , wi th n umbered chal l enge capsul es admi n i stered i n an
arb i tary order .
The cl i n i cal ch aracter i s t i cs , d i etary i nvest i gat i on
and management of pat i ents wi th these syndromes other than R I U/AO are
desc r i bed i n C hapter 6 .
I n the fi nal Ch apter the resul t s of the
pre v i ous chapters are di scus sed .
Observat i on s about the range of
food chemi cal s i mpl i cated , the symptoms provoked on c h al l enge and the
cl i n i cal behav i our of react i ons prov i ded val uabl e cl ues as to the
underl y i ng mechan i sms of adverse food react i ons .
CHAPTER 2
SAL I CYLATE ANALYS I S
8
I NTRODUCT I ON
Anal yses descri bed i n t h i s Ch apter were i n i t i ated because of l ac k of
ava i l abl e i n format i on on natural sal i cyl ates i n food , as outl i ned i n
Chapter 1 .
I n i t i al l y after contact i ng Juhl i n ( 1 978) i t was dec i ded
to fol l ow h i s prev i ous l y establ i shed methods us i ng Th i n Layer Chrom
atography ( TLC ) , but t h i s proved unsat i s factory .
After a careful
rev i ew of the 1 i terature a n umber of d i fferent extract i on methods
were tri ed , and wi t h s u i tabl e mod i fi cat i on s good chromatograp h s were
eventual l y obta i ned .
However ,
it
soon became obv i ous t h at th i s
method , even at best , cou l d not prov i de rel i abl e quant i tat i ve est i m
ates of sal i cyl ate concentrati on , and i t was therefore dec i ded to
change to H i gh Performance L i qu i d Chromatography ( HPLC ) .
At t h at
t i me H PLC h ad on l y been used for assayi ng asp i ri n i n ti s sues and body
fl u i ds , and benzoates added to foods as preservat i ves .
To measure
natural s al i cyl ates present i n food s at one or two orders of magn i
tude l ower concentrat i on s required a con s i derabl e amount of prel i mi n
ary work t o mod i fy exi st i ng methods .
MATER IALS AND METHODS
Devel opment of Extract i on Method
Prel i mi n ary work extract i ng acetyl sal i cyl i c ac i d , sod i um sal i cyl ate ,
sod i um benzoate and 4 - 0H benzoic ac i d for TLC based on Horw i tz ( 1 975 )
gave 1 i mi ted recover i es wh i ch were on 1 y qual i tat i ve and so further
devel opment was undertaken to en sure max i mal extract i on of natural l y
occurri ng sal i cylates i n foods and beverages .
These method s i nvol ved
var i ous techn i ques summari zed i n the foll owi ng t abl e (Tabl e 2 . 1 ) .
9
TABLE 2. 1
METHODS OF E XT RACTION IN VEST IGATED
Meth ods of
e xt ract i on
i nvest i gat ed
Refe re nces u sed
i n development
of e xt ract io n
method
3
2
1
4
5
benzo i c
acid
(Murphy &
Stutte r 1978)
Sep Pak
C 18 cart ridge
by Wate rs
50g
5g
5g
yes
yes
yes
s ali cyli c
benzo i c
sa1 i cyli c
ac i d
ac id
ac i d
( Ho rw i t z. 1975) ( Horw i t z. 1975) ( Gu ppy et aL.
1977-1978 )
Steps i n meth od :
1 . Amou nt of fo od
50g
1 509
methyle ne
dichlori de ( AR )
+ 2 N HCl (AR )
2. Reagents
added to food
3. Homoge ni ze f ood
yes
yes
4 . Re age nts
added t o f ood
59 C aC12( AR )
10% NaOH (AR )
st and 2 h ou rs
l5g NaCl(AR)
1 0 % NaOH (AR)
st and 2 hou rs
5. Cent 1fuge
yes
yes
no
no
yes
6 . F i lter ( pape r)
no
no
yes
yes
no
7 . Re agents added
25% HCl(AR )
25% HCl(AR )
8. Ext ract i on
Di ethyl ethe r
Di ethyl et he r
D i s t i lled H 2 O
Diethyl e the r
9 . Ide nt i f i c at i on
TLC
TLC
HPLC
HPL C
HPL C
HPLC
3ml 2% acet i c
ac i d (AR ) he ated
100C for 1 0 m i n.
Bml 2N HCl ( AR )
he ated 1 00C 1 h r
10
2 .1
FIGURE
EXTRACTION METHOD FOR HPLC
100g food
�
1 00ml 25% NaOH(AR)
�
2gm CaC12 (AR)
homog eni zed
t
Sample d i v i d ed equally
�
�
S amp l e +
5gm Sali cyli c ac i d ( AR)
�
Stood ov er ni ght
t
>
Sa mpl e
1 2 hours
Ac i d i f i ed w i th ION Hel (AR)
t
t
ether
P lac ed i n l i qu i d extract or
200ml Di ethy l
(A R) i n flas k
t
E xtract i on ov r f i v e hours
�
Eth er extract cool ed a nd
evaporat ed to dryness
�
Taken up i n 20ml 2% NaHC03( AR)
�
M i l li pore f i lt er ed
t
20ul i nject ed o nt o HPLC c olumn
The met h ods by Guppy et al .
( 1 977 - 1 978 )
and Horwi tz ( 1 975) gave
reasonabl e extract i on , however al l these methods devel oped emul s i on s
wh i ch were d i ffi cul t to cl ear , so a mod i fi ed Horwi tz ( 1 97 5 ) method
was devel oped wi th extract i on vi a a
2.2(b) , 2 . 2(c) ].
1
i qu i d extractor [F i gures 2 . 1 ,
Th i s mod i fi ed method used stronger sod i um hydroxi de
( NaOH ) i . e . 25% NaOH (AR ) overn i ght i n stead of 1 0% NaOH (AR) for two
11
hours with the aim of completing the hydrolysis of all salicylate
esters to free salicylate.
Then the acidification step was improved
using concentrated hydrochloric acid
2.0.
Finally,
extraction by
the
extraction
(HC1 ){AR)
procedure
a separating funnel giving
was
a
to bring
changed
50%
the pH
from
recovery
of
to
ether
added
standards to ether extraction via glass extractors over five hours
resulting in good recoveries of added standard salicylic acid due to
the lack of emulsion formation [Figures 2.2(b), 2.2{c)].
FIGURE 2.2(a)
EXTRACTION EQUIPMENT
Homogenization of each food
to extraction.
sample by commercial blender prior
12
F I GURE 2 . 2(b)
EXTRACT ION EQU I PMENT
L i qu i d extractor w i th condenser and round bottomed fl a s k
Food Extract Preoarat i on for An al ys i s
Foods and beverages p urch ased from 1 oca 1 stores or d onated by the
RPAH ki tchen for anal ys i s were anal ysed for s al i cyl ate by t he method
outl i ned i n F i gure 2 . 1 .
Sampl es we i g h i ng a hundred grams were homog
en i sed i n a commerc i al bl ende r , al ong wi th 1 00ml s 25% NaOH (AR) and
13
two grams of cal c i um chl ori de ( CaC1 2 ) (AR) [F i gure 2 . 2 ( a ) ].
Dupl i cate
s ampl e s correspond i ng to 50gm food or beverage were we i g hed out .
To
one s ampl e of each pai r , fi ve mi l l i grams of s al i cyl i c ac i d (AR) stan
dard was added .
Both s ampl es were al l owed to stand o vern i ght .
two homogenates were then ac i d i fi ed wi th ION HCl
pl aced i n separate 1 i qu i d extractors .
The
(AR) to pH<2 and
Two hundred mi 1 1 i 1 i t res o f
d i ethy1 ether (AR ) were pl aced i n a round bottomed SOOml fl a s k , al ong
wi th several gl ass bo i 1 i ng beads to avo i d bump i ng .
The f1 a s k was
t hen pl aced i n a heat i ng mantl e and connected to the l i qu i d extractor
and condenser .
2 . 2 ( c ) ].
Extract i on was carri ed out for fi ve hours [F i gure
The ether extract was then al l owed to cool and evaporate to
dryne s s i n the fume cupboard .
The s ampl e was then taken up i n 2 0m1
2% s od i um b i carbonate ( NaHC0 3 ) {AR ) and fi l tered through 0 . 45 m i cron
m i 1 1 i pore fi l ters pri or to anal ys i s by HPlC.
Devel opment of TlC Procedure for Sal i cyl ate Detect i on
S i l i ca gel TlC separat i on after hydrol ys i s and extract i on have been
reported to g i ve excel l ent separat i on of acetyl s al i cyl i c ac i d , s odi um
s al i cyl ate , s od i um benzoate and 4 - 0H benzo i c ac i d ( Juhl i n ,
Several sol vent systems were tri ed ( Bal dwi n et al . , 1 960 ;
Mori anz ,
1 960 ;
Bal dwi n et
Peere bo om & Beekes , 1 9 64 ;
et al . , 1 966 ;
al . ,
1 96 1 ;
1 96 3 ;
Gan s h i rt &
Cop i u s
Gos sel e & Srebrn i k- Fri szman , 1 966 ; P i nel l a
Kheman i & French , 1 969 ;
Tjan & Konter , 1 972 ;
Gans h i rt ,
1 978 ) .
C h i ang , 1 969 ;
Zwe i g & Sherma , 1 972 ;
Gos sel e , 1 97 1 ;
Juhl i n , 1 978) a s wel l as
v i sual i zat i on by a range of sta i ns ( Cop i us -Peereboom & Beeke s , 1 964 ;
Gosse 1 e & Srebrn i k - Fri szman ,
Juhl i n ,
bel ow .
1 978) .
The fi n al
1 966 ;
Ch i ang ,
1 969 ;
Gosse 1 e ,
1 97 1 ;
met hod used i s outl i ned i n F i gure 2 . 3
14
FIGURE 2 . 2(c)
EXTRACTION EQUIPMENT
Total
salicylate
obtained
from
each
food
sample
by
liquid
extraction
TLC of Food and Beverage Extracts
Forty grams of kieselgel type 60 (AR) by Merck was shaken for two to
three minutes with 80mls of distilled water to give a homogeneous
15
s u spen s i on , wh i ch was spread evenl y w i t h a De sag a appl i cator on fi ve
g l ass p l ates ( 20cms by 20cms ) t o a t h i ckness of 0 . 2 5mm .
The p l ates
were dri ed i n an oven at 1 00� for hal f an hour and a l l owed t o coo l i n
a des s i cator .
F i ve mi crol i tres of 0 . 0Ig/1 ethanol i c s o l u t i ons ( AR)
of acetyl sal i cyl i c ac i d ( AR) , sod i um sal i cyl ate (AR) , s od i um benzoate
(AR) and
4-0H
benzo i c ac i d ( AR) were appl i ed to each TLC pl ate by a
SGE m i crol i t re syr i nge .
S ampl e appl i cat i on t o dupl i cate p l ates was
made on a l i ne t h ree cent i metres from the l ower edge , and the s amp l e
was devel oped by t h e ascend i ng meth od .
I n order t o ens ure the equ i l
i brat i on of the vapour i n the ch amber , the i ns i de wa s 1 i n ed w i t h
fi 1 t e r paper so aked i n· t h e so 1 vent .
unt i l
The devel opment wa s cont i n ued
the sol ven t reached fi ve cen t i metres from t h e u pper edg e .
Dup l i cate p l ates were run i n the two mob i l e phases separat e l y under
normal cond i t i on s ( room temperature and a rel at i ve h um i d i ty between
3 5% and 70%) .
The dupl i cate pl ates were sprayed wi th one of two
sprays for i dent i fi cat i on of acetyl s al i cyl i c ac i d , s od i um s al i cylate ,
s od i um benzoate and
4-0H
benzo i c ac i d ( Fi g ure 2 . 3 ) .
Val i d at i on Of TlC Met h od
Mul t i p 1 e extract i on s of two foods , roast beef and m i 1 k , s hown to
cont a i n no acetyl s al i cyl i c ac i d , sod i um s al i cyl ate ,
o r sodi um benzoate were
met h od .
carri ed out
to
4-0H
val i date
benzo i c ac i d
the
extract i on
16
F I GURE 2 . 3
TLC OF FOOD AND BEVERAGE EXTRACTS
Food or beverage extract
t aken up i n 5ml ethanol (AR)
�
5 41 stand ards and s ampl e spotted onto
Ki ese1 ge1 type 60 (AR) 0 . 25mm dupl i cate pl ates ( Stahl , 1 969 )
/
Sol vent I ( 50 : 40 : 20 : 8 : 2 ) 1
~
Sol vent 11 { 1 : 1 : 1 ) 2
( l i g ht petrol eum (AR) :
{ n - hexane ( AR) :
carbon tetrachl or i de (AR) :
benzene (AR) :
c h l oroform ( AR) :
gl ac i al acet i c ac i d (AR)
form i c ac i d (AR) :
acet i c ac i d ( AR)
/
3% FeC1 3 3
�
0 . 05% Rhodami ne B 3
( AR )
(AR)
1.
Gos se 1 e , 1 9 7 1
2.
C h i ang , 1 969
3.
Cop i us - Peere boom & Beekes , 1 964
3% FeC1 3 3
(AR)
0 . 05% Rhodami n e 83
( AR )
17
FIGURE 2.4 (a)
TLC PLATES OF STANDARD COMPOUNDS ELUTED WITH ROAST BEEF EXTRACTS
1
2
3
4
1 . Aspirin
2. Sodium salicylate
3 . Roast beef + aspirin
4. Roast beef + sodium salicylate
5
5.
6.
7.
6
7
Roast beef
Roast beef + 4-0H benzoic
acid
4-0H benzoic acid
FIGURE 2. 4 (b)
TLC PLATES OF STANDARD COMPOUNDS ELUTED WITH MILK EXTRACTS
.
. .:
1
2
. 3
1. Aspirin
2. Sodium salicylate
3. Mi 1 k
4 . Milk + aspirin
: :
4
7
5 . Milk + sodium salicylate
6 . Milk + 4 -0H benzoic acid
7 . 4 -0H benzoic acid
18
Devel opment o f H PLC Proced ure for Sal i cyl ate Detect i o n
The H P L C meth od u s ed to anal yse the sal icyl ate content o f foods and
beverages was b a s ed on those reported by other workers for the q u a nt
itative a n a l ysis o f benzoic and s alicyl ic acid as n atural l y occurring
compounds
( Nel s o n ,
1 9 73 ;
Murphy & Stutte , 1 9 78 ;
h ardt , 1 980 ;
Smyl y et al . ,
1 976 ;
Das Gupt a ,
1 977 ;
J andera & Engel
Leuenberger et al . , 1 97 9 ;
Weh r , 1 980 ) acro s s a pH range from 4 . 5 to 7.4 .
H P l C Separatio n
Dupl icate food extracts one o f wh i ch w a s s piked , t h e o t h e r u n spiked
with standard s al icyl i c ac i d
a n a l ysis .
( AR ) were injected into a HPLC for
Th i s H PLC system con s i s ted o f a Var i an 5060 pumping system
w i t h Rheodyne 7 1 2 5 inj ect i on v a l ve .
The col umn was a Waters uBondpak
C 1 8 reverse p h a s e col umn , 3 00mm by 4 . 6mm , fi tted with a precol umn
packed w i t h Vydac RP P389 pac king mater i al .
The el uent was monit ored
w i t h a Varian Vari-Ch rom v ariabl e wavel e ngth detector with wavel ength
at 2 3 5 nm connected to a Varia n COS III comput ing integrator and
Housto n Omnis cribe recorder .
Opt imum separat io n occurred w i t h a sol vent of 3 00ml met hanol
c h rom ) ,
700ml
gl ass
d i stil l ed
water ,
1 0ml
tetra
( uni -
butyl ammonium
p h o s p h ate ( TBAP ) ( un ichrom) and 1 09 phosphoric acid ( H 3 P0 4 ) ( AR) made
to
pH
7.0
with
2 5%
NaOH
( AR ) .
The
s eparation
was
programmed
isocratic a l l y at amb i ent temperature with a fl ow p rogramme which
re s u l ted in a back pre s s ure o f 9 0 - 1 50 atmo sphere s .
The fl ow rate was
1 . Oml /mi n for seven m i n utes , i ncreas i ng to 2 . Oml /mi n over t h e n ext
t h ree m i n u t e s .
A wavel ength of 23 5nm was c h o s en because it g ave the
bes t re sol ut i on and s peci f i ci ty ( Leuenberger et al . , 1 97 9 ) .
19
F I GURE 2.5
HPLC EQUI PMENT
Spec i fi c i ty o f S a l i cyl ate I dent i fi ed by HPLC
Spec i f i c i ty o f t h e s a l i cyl ate pea k was c hec ked by two met h o d s . F i r s t ,
20 p h enol i c c ompounds c h em i c a l l y s i m i l ar t o s a l i cyl i c a c i d a n d wh i ch
mi ght occur
in
foods were c h romatographed
by H PLC .
S e c o nd ,
t he
s al i cyl ate pea ks from 1 1 foods were c o l l ected and an al y sed by a G a s
C h romatography-M a s s Spectrometry system
( GLC - MS ) ( Eg l i ngton e t al . ,
1968) by Mr M . Smythe i n t he C hemi s t ry Dep artmen t , Sydn ey U n i v e rs i ty.
The food s were two veget abl es ( ma i ze and rad i s h ) , two fru i t s ( red
c u rran t s and d a t e s ) , t h ree herbs o r spi ces ( cu rry , c um i n and ro se
mary ) , two s ugary food s ( h oney and l i co r i ce ) , one s ampl e o f w i ne and
one s ampl e o f tea .
20
Sampl e s of s od i um s al i cyl ate (AR) were run on t h e H PLC to determ i n e
reten t i on t i me s , t o opt i mi ze cond i t i on s for col l ect i ng t h e s a l i cyl ate
peak .
Pea ks from foods w i th reten t i on t i me s i dent i cal to t h e s al i cy
l at e standard were col l ected , ac i d i fi ed w i t h l m1 3M H C 1 ( AR ) extract
ed wi t h 1 0m1 d i ethyl ether ( AR ) , t h ree t i me s and was hed w i t h 1 0m1
d i s t i l l ed water ,
t h ree t i mes .
The ether sol ut i o n was drawn o ff ,
d r i ed over anhydrous magne s i um sul phate ( MgS04 ) and f i l tered t h rough
c otto n
woo l
i nto
a
l m1
" React i v i a1 "
( Reg i s ) . .
The
evaporated t o 1 0� 1 w i t h dry n i trogen under gentl e h e at .
vol ume
was
One h undred
m i cro1 i tres b i s ( tr i met hy1 s i 1 y1 ) t r i fl uoroacetam i de ( BFSTA)
( Reg i s )
was added i n a dry env i ronment and ref1 uxed gentl y for one hour .
The
s o l uti on was reduced to 1 04 1 under dry n i trogen and i nj ected i nto t h e
Gas C h romatograph ( GLC ) .
T h e col umn o f t he G LC , a Pye 1 04 , w a s g l a s s
2m by 6mm, p a c ked w i t h av 1 7 ( 3%) o n Chromos orb W ( 1 0 0/ 1 20 mes h ) .
Hel i um fl ow through the col umn was 30 ml /m i n .
The G LC was i nterfaced
( v i a an A E I gl a s s j et separator ) to an AE I MS- 3 0 mas s s pectrometer
operat i ng at 4KV w i th an i on i z at i on vol tage of 70ev .
The chromat o
g raph i c trace w a s produced by t h e total i on c urrent mon i tor of t h e
mas s s pectrometer r u n a t 20ev except when scan n i ng ( 1 0 second/decade )
when the i on i z i ng vol tage returns t o 70ev.
Cal cul at i on s o f Sal i cyl ate Content o f Foods An al ysed by H PLC
Pea k reten t i o n t i mes and peak are a ( McCoy et al . , 1 984 ) were mon i tor
ed
and
c omputed
automat i cal l y
by
the
i nteg rator ;
i n i t i al
peak
i de nt i fi cat i on was based on retent i on t i mes and c ompar i so n w i t h t he
s tandards a s wel l
as c o - chromatog rap hy w i t h t h e s t an d ard s .
S i nce
21
reten t i on t i me s a lone are not s u ffic i ent for po s i tiv e i de nt i f i c at i on ,
s ali cylate pea ks were collected and spectra of t h e c hromatograp h i c
p e a ks were also obta i ned .
Concentrat i on s of s a li cylate were deter
mined from the s lope o f the calibrat i on p lots i n wh i ch pea k area wa s
plotted ag a i n s t amount inj ected .
The detector re sponses were fo und
to be l i ne ar over the entire working range .
Res ul t s from t r ip li c ate or mul t i pl e extract i on s were used t o c ompute
the total s ali cylate per 1 00gm food s ample .
were calc ulated .
Extraction e ff i c i enc i e s
They vari ed with the c ompos i t i on o f the
food .
Fru i t s , vegetable s , condiments and beverages gave extractio n rate s of
g re ater t h an 85% , compared wit h cereals and p rote i n foo ds for wh i ch
t he e xtract i on rate was approx i mately 6 0% .
Vali dat i o n was carr i ed o u t by extract i ng s everal foods more t h an 1 0
t i me s a long wi th s amples spiked wit h s ali cyli c acid (AR) .
Several
food s were selected wh i ch v aried in phys i c a l attribut e s and wh i ch by
previ o us ana lys is h ad been found to contain s alicylate i n amounts
t h a' t were relat i ve ly low ( carrots and p umpki n ) , medium ( orange and
p i n eapple ) or h i gh (thyme ) . The foods h ad vari ed p hys i cal att ri butes .
The s al i cy late contents of the mu lt iple s ample s o f t he s e food s were
cal culated and t h en s u bj ected to statist i cal
an a l y s i s .
The mean ,
standard deviat i on ( SO ) and st and ard error ( S E ) for t h e s a li cy la te
content of e ach food was d etermin ed from wh i c h t h e 9 5% confi dence
i nterval was calc u lated ( Hays , 1 973 ;
Petrie , 1 978;
Sach s , 1984 ) .
22
The 9 5% confi dence i nterval for the mea n s a l i cyl ate content o f each
food , determ i n ed the normal range o f s al i cyl ate pre sent i n each food
i . e . t h e c h an c e of t h e mean n ot be i ng conta i n ed wi th i n th i s range
wou l d
be
at
mos t
fi ve
percent
( F i gure
A 9 5% confi dence
2 . 6) .
i nterv a 1 for a mean v a l ue i s the i n terva 1 from ( mean - 1 . 96S E ) to
( mean + 1 . 96SE ) where 1 . 96 , c orre spond i ng to a 9 5% confi dence l evel ,
; s cal l ed t h e c r i t i c a 1 v a l ue and was obta i n ed from tab1 e s for the
stand ard n o rmal d i stri b ut i on .
FI GURE 2 . 6
FORMULA FOR CALCULATION OF 95% CONFI DENCE INTERVAL
Mean
E
X
=
s al i cyl ate contents o f food s ampl es (x )
n umber o f extract i on s ( n )
S tanda rd dev i at i on o f the s ampl e
=
SO
Standard error ( es t i mated )
=
�
=
SE
=
� (x
- i} 2
n - 1
SO
Fn
9 5% Confi dence i nterval for t h e mean i s ( L,H) where :
L
=
x - 1 . 96 S E
H
=
x + 1 . 96SE
23
RES ULTS
S a l i cyl ate I dent i f i ed i n Food s by TLC
S ome 56 foods were extracted wi t h ether ( Tabl e 2 . 1 ) and ana l y s ed by
TLC ( F i g u re 2 . 3 ) .
Acety l s al i cyl i c a c i d a l o n e was found i n 1 4 o f t h e
food extract s , wh i l e b o t h acetyl s a l i cyl i c a c i d and s od i um s a l i cy l ate
were detected i n 23 of t h o s e food s exam i ned .
A furth e r 19 foods
cont a i n ed n o appre c i abl e amounts o f a cetyl s al i cy l i c ac i d or s odium
s al i cy l ate
( Tabl e
2 . 2) .
H owever a s ubsequent
s en s i t i ve
s p ec i f i c
meth od o f H PLC c omb i ned wi th an e ffi c i ent l i qu i d extract i on procedure
h a s s hown t h at e i ght o f these food s conta i ned apprec i a b l e s al i cy l ate .
The TlC meth od g ave l i m i ted res u l t s a s it was onl y a bl e to i dent i fy
but not quant i fy t h e pre sence o f acetyl s a l i cy l i c ac i d , s od i um s al i cy
l ate , 4 - 0H benzo i c ac i d and s od i um ben z o ate i n a food s ampl e .
I n t h e s e l ect i on o f foods a n al ysed by TLC , the re s u l t s s h owed a smal l
n umber wh i ch conta i ned onl y acetyl s a 1 i cyl i c ac i d , wh i 1 e most foods
conta i ned both acetyl s a l i cy l i c ac i d and s od i um s al i cy l ate i n vary i ng
amount s .
The pure acetyl s al i cyl i c
ac i d - s tanda rd a nd t h e
acetyl
s al i cy l i c ac i d pre s ent i n food extract s s howed d egrad at i on t o s a l i cy
l ate on the p l ate i f a del ay occurred between p l ate appl i cat i on and
e l u t i on .
Acetyl s a l i cyl i c ac i d. i s very u n stabl e i n aqueo u s s o l u t i o n s
bre a k i ng d own to s a l i cyl ate .
I t was therefo re d i ff i c u l t to q u ant i fy
accurate 1 y the spec ; fi c amounts o f acetyl sa 1 i cyl i c a c i d o r s od i um
s a l i cyl ate pre sent ; n e ach food ext ract so a H P LC met ho d was then
devel o ped to i nvest i gate th i s more tho ro ugh l y .
24
TABLE 2.2
SAL ICYLATE I DENTI F IED BY TLC
Food
A l nxmd
App l e
Banana
Beans
Beer
B l ack pepper
Bread
Caps i cun
Carrot
Choco l ate
C i der *
C i nnamon
C loves
Cocoa
Coconut
Coffee
Coke
Cucumber
Dates
Gin
Honey *
Lettuce
L i cori ce
Ma lt v i negar *
Mango
M i lk
M i nt
Mustard
Acety l sa 1 icyl i c
Ac i d
Sod i lll1
Sa l i cy late
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Food
Nutmeg
On i ons *
Orange ju i ce
Pars ley
Pawpaw
Peaches
Pears
Pears
Peas *
Pepperm i nt
P i neapp l e ju i ce
Potato
Pumpk i n *
Pumpk i n seeds *
Red w i ne
Roast beef
Sa lmon
Sherry
Su ltanas
Tea
Tomato paste
Tomato sauce
V i negar
Wh i skey
Wh i te grapes *
Wh i te w i ne
Zucch i n i
Acety l sa 1 i cy l i c
Ac i d
+
Sod i um
Sa l i cy l ate
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
* Sa l i cy late i dent i f i ed i n foods by HPLC ( i n sma l l amounts except honey wh ich was a d i fferent brand)
25
FIGURE 2.7
*
GRADED DOSES OF STANDARD COMPOUNDS
Figure 2.7(a) Graded Doses of Aspirin
1
2
3
4
*
5
6
Figure 2.7(b) Graded Doses of Sodium Salicylate
7
8
*
1
2
4
5
6
"1
8
26
FIGURE 2.7
GRADED DOSES OF STANDARD COMPOUNDS
Figure 2.7(c) Graded Doses of
2
1
*
4-0H
3
Benzoic Acid
4
5
*
6
7
8
10yg, 20yg, 30yg, 40yg,
Graded doses of standard compounds are
504g, l004g, 1504g, 20049
*
respectively.
Validation of Salicylate Identified by HPLC
Specificity of the salicylate was checked by comparision with several
phenolic
compounds
chemically
mi ght occur in foods .
(AR)
and had
All
20
simi1 ar
to
salicylic
acid
compounds were taken up in
and
2%
which
NaHC03
retention times different from the retention time of
salicylic acid.
27
FIGURE 2.8
HYDROLYSIS OF ASPIRIN TO SODIUM SALICYLATE
ON THE TLC PLATE PRIOR TO ELUTION
1
2
2
(A)
Aspirin (lane
(8)
1)
and sodium salicylate (lane
(C)
2) were plated at
various times after extraction.
(A) Aspirin peak undegraded
(8)
Partial degradation of aspirin peak
(C) Complete degradation of aspirin to salicylic acid
28
TABLE 2.3
RETENTION TIMES OF SEVERAL PHENOLIC COMPOUNDS
Retention Time
Compound
(minutes)
P-Amino benzene
2.46
Para amino benzoic acid
3.20
Phthalic acid
3.31
Salicylamide
3.32
Salicin
3.43
40H benzoic acid
3.46
Vanillic acid
3.51
Sulphosalicylic acid
4.68
Anthranilic acid
6.01
Gentisic acid
6.75
Acetylsalicylic acid
7.10
Benzoic acid
8.20
Catechol
8.23
Theophylline
8.34
Quercetin
11.30
Vanillin
11.72
Acetanilide
14.41
Phenol
14.81
Salicylic acid
16.81
Coumarin
18.88
Methyl salicylate
58.43
Solvent:
20%
methanol,
80%
glass
distilled
phosphoric acid, 0.0025 mmol TBAP pH 7.0
water,
0.01
mmol
29
FIGURE 2.9
STANDARD SALICYLATE AND BENZOATE PEAKS BY HPLC
®
10 -
"'"
®
"'"
'-"
9-
en
'-"
en
...
C»
�
Q.
C»
...
8-
�
Q.
en
C»
�
Q.
C»
�
7-
Q.
en
6-
5-
4-
3-
2-
t
injection
t
injection
The sal i cy1 ate peaks from 11 foods were co11 ected and Hr M.
Smythe
analysed them by GLC-MS in the Mass Spectrometry Unit of the School
of Chemistry at Sydney University.
All the peaks from the HPLC were
found to contain a significant amount of salicylate.
30
TABLE
2. 4
FOOD SALICYLATE ANALYS I S BY HPLC AND THEN GLC - MS
Foods Anal ysed by GLC - MS
Sal i cyl ate Pre sent
Sweetcorn
yes
Rad i s h
yes
Red currant s
yes
Dates
yes
Cu rry
yes
Cumi n
yes
Rosemary
yes
Cap i l l ano honey
yes
Barratt s l i cori ce
ye s
Red wi ne
yes
Darj eel i ng tea
yes
Extract i on Reprod uc i b i l i t y
Mul t i pl e e xtract i on s o f several
food s wi th l ow, med i um and h i gh
l evel s o f s a l i cyl ate were carri ed out to val i date the re s ul t s obta i n
ed .
The me an s al i cyl ate content o f each food was c a 1 c u l ated a 1 on9
wi th the s t and ard dev i at i on and t he s t and ard error .
31
TABLE 2 . 5
MULT I PLE EXTRACT IONS O F FOODS
Food
No of Extract i ons
5.0.
Mean
95X Confi dence Interva l
S.E
Potato
20
0
0
0
( O, 0)
Pumpk i n
36
0 . 12
0 . 01 6
0 . 113
(0 . 115,
0 . 125 )
Carrots
40
0 . 23
0 . 045
0 . 007
( 0 . 216,
0 . 244 )
P i neapp l e
28
2 . 10
0 . 246
0 . 04 7
( 2 . 009 ,
2 . 191 )
Orange
35
2 . 39
0 . 502
0 . 08 5
( 2 . 224 ,
2 . 556 )
Thyme
22
1 83
4 5 . 205
9 . 638
( 1 64 . 1 1 , 201 . 89 )
Tot al Sal i cyl ates i n Food
I t was found that mo st fru i ts contai ned con s i derabl e amounts o f
sal i cyl ate .
Mos t berry fru i t s are S i gn i fi cant sources of sal i cyl ate ,
wi th a range from O . 76mg/ l OOg for mul berri e s to 4 . 4mg/ l OOg for ras p
berri es .
Dr i ed
fru i t s
have
rel at i vel y h i g h
sal i cyl ate
content s
compared wi th the i r fre s h counterpart s becau s e o f the water removal
duri ng the dry i ng process .
Appl e s s h owed con s i derabl e var i at i on of
sal i cyl ate content between vari et i e s .
The s al i cyl ate content
of
c i trus fru i ts ranged wi del y from O . 1 8mg/ l OOg to 2 . 39mg/ l OOg .
Those
fru i t s l ow i n s al i cyl ate often have a l e s s p i quant fl avour .
Some
32
h e rb s and s p i ces were found t o conta i n very h i gh amounts per I OOg,
e . g . c urry powder, papri ka, thyme, garam masal a and rosemary .
Wi thi n
t h e beverage group, s a l i cyl ate content var i ed w i del y among t h e teas
and c offee s .
Tea s are an i mportant source o f s al i cyl ate i n t h e usual
d i et and s o 1 8 d i fferent brands and vari et i es were anal ysed .
conta i n ed more
t h an
I . gmg/ I OOml
c o n ta i n ed o nl y 0 . 3 7mg .
a s o l vent
c ommo nl y
t e a,
u sed
for extract i on
I OOml .
l i cori ce
h oneys conta i n s al i cyl ates .
Al l
o f c a ffe i ne .
Tabl e
and pepperm i n t
cand i e s
and
TOTAL SALI CYLATES I N FOODS
App le
State*
Sa l i cy late
m g/ 1 0 0 g
( th i s study )
Go l den de l i c i ous
Red de l i c ious
Granny smi t h
Jonathan
Ardmona
Mounta i n Ma i d
f
f
f
f
c
j
f
0 . 08
0 . 19
0 . 59
0 . 38
0 . 551
0 . 191
2 . 58
Ardmona
Letona
c
n
f
f
c
1 . 421
0 . 141
0 . 601
Type
Apr i cot
Avocado
Banana
B lackberry
John West
s ome
Cereal s, meat, fi s h and d a i ry products
TABLE 2 . 6
.E!.Y.i!
2.6
cont a i n l es s t h an 0 . 96 mg
cont a i n none o r n egl i g i bl e amount s .
Food
wh i ch
Sal i cyl ate i s s o l ubl e i n met hyl e n e c h l o r i de,
i nc l ude s data for n i ne coffee s .
s al i cyl ate per
except decaffe i n ated
Al l
01
1 . 86
References
65( . 004 )
65( . 004 )
94 « . 01 ) , 1 0
65( . 003)
94 « . 01 )
94 « . 01 )
65 ( . 005) , 64
54 , 57
Cont i nued
33
Food
Type
State*
Sa l i cy l ate
mg/100g
( th i s study)
B lueberry
Boysenberry
Cante lope
Cherry
Socan i n
John West
Rockmel on
sweet
c
c
f
f
2.76
2. 04
1 .50#
0.85
Cranberry
John West
More l lo Sour
S & W
Currants
b lackcurrant
c
c
c
s
fr
2. 78
0.30
1 . 64
1 . 44
3 . 06
fr
f
f
d
f
c
d
c
f
f
c
5.06
0 .21
3 . 73
4. 50#
0 . 18
0 . 25
0 . 64
2. 02
0 . 94
1 .88
0 . 16
0 . 88
0. 18
5.80
6 . 62#
7 .80
0.68#
red currant
Custard app le
Dates
Ca l -Date
F i gs
Guava
Grapes ·
S & W Kadota
Ca l amata str i ng
Gol d Reef
Red Ma l a i ta
S u l tana
S & W l ight seedl es s
Berr i Dark
San i tar i um L i ght
c urrants I . P . C
ra i s i ns A . D . F .A
s u l tana
Grapefru i t
Berr i
K iw i fru i t
Lemon
Loganberry
Loquat
Lychee
Mandari n
Mango
Mu l berry
Nectari ne
Orange
John West
Berr i
j
j
d
d
d
f
j
f
f
0 . 42
0 . 32
0 . 18#
c
f
c
f
f
f
f
f
4 . 40
0 . 26
0 . 30
0 . 56#
0. 11
0 . 76
0 . 49
2 . 39#
j
0 . 18#
References
42, 85
94 « .01 ) , 34
81 , 93
93
4,5
65 ( . 0005 ) , 1
2, 3 , 57 , 93
93
94 ( .019 )
1 0 , 59 , 73
57
66 ( . 004)
1 0 , 18 , 57 , 59
94 ( . 04 6 )
65 ( .01 )
83 , 8 ( - )
65 ( . 002 ) , 92
19 , 80 , 83 ,
8(-)
94 « .01 )
65 ( . 004 )
65 ( . 00 7 ) , 36
83 , 8 ( - )
36 ( . 003 ) , 19
94 « . 01 ) , 36
Cont i nued
34
Food
Type
State*
Sa l i cy late
mg/100g
( th i s study)
References
f
f
f
0 . 14#
O . OS#
0 . 58#
Letona
c
0 . 68#
Letona
Packham ( w i th sk i n )
Packham ( no sk i n )
W i l l i am ( w i th sk i n)
Letona Bart lett
n
f
f
f
c
0 . 10#
0 . 27#
01
0 . 31#
01
56 , 99
32
65 ( . 003) , 1 0
12 , 26 , 49
65 ( . 005)
94 ( . OS )
94 ( . 046)
f
f
c
0 . 18#
2 . 1 0#
1 . 36
0 . 1 61
Pas s i onfru i t
Pawpaw
Peach
Pear
Pers i nmon
P ineapp le
Gol den C i rc le
Go l den C i rc le
j
f
f
f
c
c
0 . 21
0 . 095
0 . 11
l . 16
6 . 87
Panegranate
Raspberr i es
f
f
0 . 07
5 . 14
Rhubarb
Strawberry
fr
f
f
3 . 88
0 . 13
1 . 36#
Tamar i l lo
Tange lo
Waterme lon
Youngberry
f
f
f
c
0 . 10
0 . 72
0 . 48#
3 . 06
f
f
0 . 70
0 . 14#
P lum
B lood ( red)
Ke l sey (green )
W i l son ( red )
S . P . C . dark red
Letona prunes
65 ( . 001 )
94 « . 01 )
94 ( < . 0 1 ) , 36
65 ( . 006)
36 ( . 008)
94 « . 0 1 )
65 ( . 003 ) , 81
65 ( . 034 )
94 ( . 061 )
65 ( . 003) , 1 0
54 , 57 , 59 , 67
65 ( . 004 ) , 1 0
18 , 54 , 55 , 57 ,
59 , 74 , 84
65 ( . 004)
8(-)
65 ( . 007 )
* key to abbrev i at i ons page
Vegetab les
A lfa l fa
Asparagus
16 , 1 7
94 « . 01 )
Cont i nued
35
State*
Sa l i cy late
mg/ lOOg
( th i s study)
Tri ang l e Spears
Sunsh i ne
b lackeye
Bor lott i
broad , v ic ia faba
brown
green French
c
c
d
d
f
d
f
0 . 321
0
0
0 . 08
0 . 73
0 . 002
0 . 1 11
l ima
mung
soya
soya gr i ts
d
d
d
d
f
f
c
f
f
f
0
0
0
0
0 . 06
0 . 181
0 . 321
0 . 65#
0 . 07
01
Type
Food
Asparagus
Bamboo shoots
Beans
Beansprouts
Beetroot
Gol den C i rc le
Brocco l i
Brusse l sprouts
Cabbage
green
References
62
94 ( . 01 5 )
65 ( . 008 )
94 « . 01 )
6 , 51 , 52 , 75
94 ( < . 01 ) , 82
65 ( . 007 )
66 ( . 001 )
94 ( < 01 ) , 7 0
•
red
Carrots
Cau l i f l ower
Ce l ery
Chi cory
Ch i ves
Choko
CuclJl1ber
Eggp l ant
End ive
Horseradi sh
Leek
Lent i 1
( Chayote )
(no pee l )
Ar i stocrat gherk i n
(with pee l )
( no pee l )
Eska l
brown
red
Lettuce
Marrow
Mushroom
( Cucurb ita pepo )
Okra
O l i ve
Champ i gnon
Zanae
b lack Kraft
green Kraft
On i on
P a r sn i p
f
f
f
f
f
f
f
f
c
f
f
f
c
f
d
d
f
f
f
c
c
c
c
f
f
0 . 081
0 . 231
0 . 1 61
01
1 . 02
0 . 03
0 . 01#
0 . 781
6 . 14#
0 . 881
0 . 301
1 . 90
0 . 18
0 . 08
0
0
01
0 . 17
0 . 24
1 . 26
0 . 59
0 . 341
1 . 291
0 . 161
0 . 45
94 ( . 035 ) , 82
S5 ( . 007 )
82
72 ( - )
72 ( - )
71
71
71
72 ( - )
70
72 ( - )
29
29
72 ( - )
Con t i nued
36
State*
Sa l l cylate
mg/ 1 00g
( th i s study )
chi ckpea
green
d
f
0
0 . 04#
green spl it pea
yel low sp l i t pea
green chi l l i
red chi l l i
ye l low-green ch i l l i
sweet . green
( cap i scum)
Arson sweet red
whi te (with pee l )
d
d
f
f
f
f
0
0 . 02
0 . 64#
1 . 20#
0 . 62#
1 . 20#
c
f
0. 15
0 . 121
f
f
f
f
f
fr
f
f
f
0#
0 . 1 2#
1 . 241
0 . 03
0 . 58
0 . 1 6#
0 . 63
0
0 . 131
c
0 . 261
65( . 073)
c
0 . 391
whi te
ye l low
f
f
f
0 . 50#
0 . 48#
0 . 13#
Letona
Gou lburn Va l ley
He i nz
Letona
Campbel l
Leggo
Tan P i per
He i nz
Kiora
P.M.U.
Founta i n
He i nz
I. X. L .
P.M.U.
Rose l la
c
0 . 53#
0 . 1 01
O . le#
0 . 18#
0 . 57#
1 . 44#
0 . 43#
0 . 541
0 . 54#
0. 321
0 . 94#
2. 48#
1 . 06#
0 . 98#
2 . 1 51
65( . 082)
94 ( . 03)
65( . 004 )
65( . 004)
65( . 005) . 1 5
94 ( . 01 ) , 21 ,
38 . 44 . 63. 7 1
94 ( . 014)
36 (. 005- . 02 )
94 (. 01 6 ) . 21
Food
Peas
Peppers
P im i ento
Potato
Type
whi te ( no pee l )
Pumpk in
Rad i sh
Sha l l ots
Sp i nach
Squash
Swede
Sweet corn
red . sma l l
baby
Mounta i n Ma id
n i b lets
Mounta i n Ma id
creamed
Sweet potato
Tanato
j
j
j
p
p
p
sp
sp
sp
sc
sc
sc
sc
sc
References
65( . 002) , 7 1
94 « . 01 )
65( . 004 ) 13
71
•
65( . 006) . 14
23
94 « . 01 ) . 71
82
94 ( . 01 ) . 72
65( . 01 )
65( . 007 ) 21
•
65( . 008)
36 (. 003- . 05)
36 (. 19- . 24 )
65( . 005)
94 « . 01 - . 03 )
24 , 36
Cont i nued
37
F ood
Type
St ate*
S ali cylate
mg/100g
( th i s study)
f
f
f
0 . 1 61
0 . 841
1 . 041
powder
powder
leaves
powder
d
d
d
d
powder
powder
powder
powder
powder
flakes
powder
powder
whole
leaves
powder
powder
d
d
5. 20
22. 80
2. 52
3. 40
0 . 28
42. 60
7 . 70
2. 82
1 7 . 60
1 0 . 10
1 . 38
1 . 30
1 5. 201
5. 74
0 . 20
45. 00
218 . 00
6 . 90
94 . 40
0 . 80
1 2. 20
30 . 80
66 . 80
0 . 1 01
4 . 50
32. 20
0 . 711
9 . 401
55. 60
26 . 00
2. 401
66. 00
203 . 00
5. 70
0 . 081
6 . 201
1 . 101
Tur ni p
Wate rcress
Zucch1ni
Refere nces
71 (-)
* key to abbrev i at io ns page
Cond i ments
Allsp i ce
A ni seed
B ay leaf
Bas i l
, Bo nox '
C ane 1 la
C ardnon
C ar away
C aye nne
Celery
Chi li
C i nnamo n
Cloves
Cor i ander
CLI11 i n
Curry
Di 1 1
Fennel
Fenu greek.
F i ve sp ice
Gar am mas ala
Garli c
Gi nger
M ace
' Mann ite '
M i nt
M i xed herbs
Must ard
Nutmeg
Ore ga no
P apr i k a
P arsley
Pepper
powder
powde r
powder
powder
powder
bulbs
root
powder
S anit ar i um
cOO'l'OO n garden
leaves
powder
powder
powder
hot powder
sweet powder
leaves
black powder
whi te powder
d
d
d
d
d
d
d
f
d
d
f
d
d
d
d
d
f
f
d
p
f
d
d
d
d
d
d
f
d
d
1 1 , 60 , 61
28
1 0 , 27 , 41 , 59
25, 28
65( . 008) , 72
60
72, 82
Co nt i nued
38
Food
P im i ento
Rosemary
Saffron
Sage
Soy sauce
Tabasco Pepper
Tandor i
Tarragon
Turmer i c
Thyme
Van i l la
V inegar
Worcestersh i re
' Vegemi te '
Type
State*
powder
powder
powder
l eaves
d
d
d
d
McI l henny
powder
powder
powder
l eaves
essence
ma lt
whi te
sauce
Kraft
se
d
d
d
d
1
1
1
p
Sa l i cy late
mg/1 00g
( th i s study)
4 . 90
68 . 00
0
2 1 . 70
0
0 . 45
0
34 . 80
76 . 40
183 . 00
1 . 44
0
1 . 33
64 . 30
0 . 81#
References
39
Dr i nks
' Aktavi te '
Cerea l coffee
Bambu
Dande l i on
' Ecco '
' Natures Cuppa '
' Reform '
pw
0
pw
pw
pw
pw
pw
0 . 15
0 . 08
0
2 . 26
0 . 38
Coca-Co la
Coffee
0 . 25
Andron i cus Instant
Bushe l l s Instant
Bushe l l s Turk i sh
G ibsons I nstant
Harr i s Mocha Kenya
Harri s Instant I
Harr i s Instant I I
I nternat i ona l Roast
Maxwe l l House I nst
Moccona I nstant
Moccona Decaf
Nescafe I nstant
Nescafe Decaffe i nated
Pab lo i nstant
Robert T imms Inst
pw
pw
pw
pw
b
pw
pw
pw
pw
pw
pw
pw
pw
pw
0
0 . 21
0 . 19
0 . 12
0 . 45
0
0 . 10
0 . 96
0 . 84
0 . 64
0
0 . 59
0
0
0 . 16
10 , 59 , 86
76 ( - }
Con t i nued
39
Type
Food
State*
Sa l i cy late
mg/ 100g
References
( th i s study )
Herba l tea
' Mi lo
' Ova l t i ne '
Rose h ip syrup
Tea
caman i l le
fru it
peppenn i nt
rose h i p
r
De lrosa
Asco
B i l ly
Bunnese Green
Bushe l l s
Go lden Days Decaf
Harr i s
I nd i an Green
Peony Jasm i ne
O l d Ch i nese
Tet l ey
Twi n i ngs :
Earl Grey
Eng l i sh Breakfast
Darjee l i ng
I r i sh Breakfast
Lapsang Souchong
Lemon Scented
Orange Pekoe
Pr i nce of Wa les
b
b
b
b
0 . 06
0 . 36
1 . 10
0 . 40
pw
pw
0 . 01
0
1 . 17
6 . 40
2 . 48
2 . 97
4 . 78
0 . 37
4 . 00
2 . 97
1 . 90
1 . 90
5 . 57
1
b
le
le
b
b
b
le
le
le
b
b
b
b
b
b
b
22 , 30 , 3 5 . 37
40 , 47 , 53 , 58
68 , 69 , 79 , 87
89 , 90 , 91 , 95
1 02 , 1 03 , 104
3 . 00
3 . 00
4 . 24
3 . 89
2 . 40
7 . 34
2 . 75
2 . 97
Cerea ls
Arrowroot
Bar ley
Buckwheat
Ma i ze
M i l let
Oats
R ice
Rye
Wheat
powder
unpear l ed
gra i ns
mea l
gra i ns
hu l led gra i ns
mea l
brown gra ins
whi te gra i ns
ro l led
gra i ns
d
d
d
d
d
d
d
d
d
d
d
0
0
0
0 . 43
0
0
0
78
1 00
0#
46
0
0
52 , 67 , 76 ( - )
0#
Cont i nued
40
Food
Type
State*
Sa 1 i cy late
mg/ 100g
( th i s study )
References
N uts and Seeds
A lmonds
Braz i 1 nuts
Cashew nuts
Coconut
Hazel nuts
Macadamia nuts
Peanuts
Pecan nuts
P ine nuts
P istach io nuts
Poppyseed
Sesame seed
Sunf lower seed
Wa lnuts
Water chestnut
des s i cated
unshe l led
San itar i um butter
Socan i n
f
f
f
d
f
f
f
p
f
f
f
d
d
d
f
c
3 . 00
0 . 46
0 . 07
0 . 26
0 . 14
0 . 52
1 . 12
0 . 23
0 . 12
0 . 51
0 . 55
0
0 . 23
0 . 12
0 . 30
2. 92
d
d
0#
01
8
51 , 52
* key to abbrev iat i ons page
Sugars
Carob
Cocoa
Honey
syrup
Map le syrup
Sugar
Molasses
Go l den
powder
powder·
A l lowr i e
Ar i stocrat
Cap i l lano
Mudgee
' No Fr i l l s '
C . S .R .
Camp
whi te granu lated
C.S.R.
1
2. 50
3 . 70
1 0 . 14
3 90
1 1 . 24
0 . 101
0
0
0 . 22
.
d
58
Con fe ct i one ry
Caramel
L i cor i ce
Peppe rm i nts
Pasca 1 1 Cream
Barratts
G i ant
A l l ens S t rong M i nt
A l l en s ' Koo lm i nt '
L i f esavers
' M i nt i es '
A l l en s ' S teamro l l ers
d
d
d
d
d
d
d
d
0 . 12
9 . 78
7 . 96
0 77
7 . 58
0 . 86
1 . 78
2. 92
.
60
Con t i nued
41
Type
Food
State*
Sa l i cy late
mg / 100g
( th i s study )
References
Da i ry
Cheese
M i lk
Yogurt
b lue ve i n
Camembert
Cheddar
cottage
Mozare l la
tasty cheddar
fresh fu l lc ream
fu l lcream
f
f
f
f
f
f
0 . 05
0 . 01
0
0
0 . 02
0
01
f
0
f
f
f
f
f
f
f
f
f
f
c
f
f
c
0#
31
Meat . F i s h and Eggs
Beef
Chi cken
Egg
K idney
Lamb
L i ver
Oyster
Pork
P rawn
Sa lmon
Sca l l op
Tr i pe
Tuna
whi te
yo l k
L uncht ime P i nk
Seak i st
96
01
0
0
0
0#
0 . 05
0
0
0 . 04
0
0 . 02
0
0
96
A lcoho l ic Dr i nks
Beer
Reschs D i nner Ale
Tooheys Draught
Tooths Sheaf Stout
0 . 35
0 . 23
0 . 32
C i der
Bu lmer ' s Dry
Bu lmer ' s Sweet
L i lyda le Dry
Mercury Dry
0 . 17
0 . 19
0 . 17
0 . 16
45
Cont i n ued
42
Food
Type
State*
Sa l i cy l ate
References
mg/ 1 00g
( th i s study )
l iquers
P ort
S herry
Bened i ct i ne
9 . 04
Co i nt reau
0 . 66
Drambu i e
1 . 68
T i a Har i a
0 . 83
McW i l l i ams Roya l Reserve
1 . 40
Stonyfe l l Me l l ow
4 . 20
l i ndemans Roya l Reserve
sweet
M i l dara Supreme Dry
0 . 56
0 . 46
P en fo lds Roya l Reserve
sweet
Sp i r i ts
W i nes
0 . 49
brandy - Hennessy
0 . 40
g i n - G i l bey ' s
0
rLl11 - Bundaberg
0 . 76
rum - Capta i n Morgan
1 . 28
vodka - Sm i rnoff
0
wh i skey - Johnn i e Wa l ke r
.0
45
Buton Dry Vermouth
0 . 46
7 , 20 , 33 , 45
Ka i ser Stuh l Rose
0 . 37
97 , 98
l i n dema ns R i es l i ng
0 . 81
McW i l l i ams Dry Wh i t e W i ne
0 . 10
McW i l l i ams Cabernet
Sauv i g non
0 . 86
McW i l l i ams P r i vate B i n
C l aret
McW i l l i ams Reserve C l aret
0 . 90
0 . 35
Pen fo lds Tram i ner R i e s l i ng
B i n 202
*
0 . 81
Seav i ew Rh i ne R i es l i ng
0 . 89
Stonyfe l l Ma Chere
0 . 69
Ya l umba Champagne
1 . 02
key to abbrev i at i on s page
49
43
Legend for Tab le 6 .2 Total Sa l icyl ates i n Food
* b = bag , c = canned . d = dr ied, f = fresh , fr
j u i ce . 1 = l i qu i d . le = leaves . n = nectar. p
powder , sc = sauce , sp = soup .
=
•
frozen , j =
paste , pw =
Most trade names are those of products of var ious Austra l i an
compan i es . Some var i et ies of foods a lso are Austra l i an .
For coffee , m i l l i grams sa l i cy late per 1 00 m 1 made f rom 2 gm
powder in 1 00 m l water . For tea , m i l l i grams sa l i cy late per 1 00 ml
i nfus ion made from two standard tea bags ( 4 gm dry leaves ) .
*
,
Ed i b le port i ons
Mu lt i p le extract i ons
P ub l i shed stud i es on the sa l i cy late content of food are l i sted numer i ca l ly .
Va l ues obta ined when g i ven are recorded i n brackets i n mg/l00g and when no
sa l i cylate was ( - ) .
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13 .
14.
15.
16 .
17 .
18 .
19 .
20 .
21 .
22.
Andersson , J . , Bosv i k , R . and von Sydow. E . ( 1963 ) .
Andersson , J . and von Sydow, E . ( 1964 ) .
Andersson , J . and von SydoW , E . ( 1966) .
Anjou , K . and von Sydow, E . ( 1967 ) .
An jou , K . and von Sydow. E . ( 1969 ) .
Ara ; , S
Suzuk i . H . , Fuj imak i , M . and Sakura i , Y . ( 1966 ) .
Arch i naud . P . ( 1955) .
Ashoor . S . and Chu , F . S . ( 1980 ) .
Baardseth , P . and Russwurm, Jnr H . ( 1978 ) .
Be 1 1 anca , N . ( 1971 ) .
Benezet , L . and Brun . M . ( 1941 ) .
Broder i ck , J . J . ( 1966) .
Buttery, R . G . , Se i fert . R . M . , Guadagn i , D . G . and L ing , L . C .
( 1969 ) .
Buttery, R . G
Sei fert , R . M . and L ing, L . C . ( 1970) .
Buttery , R . G . , Se i fert , R . M Guadagn i , D . G . and L i ng . L . C .
( 1971 ) .
Buttery , R . G . and Kamm , J . A . ( 1980 ) .
Buttery , R . G . , Kamm. J . A . and L i ng , L . C . ( 1982) .
Cahours , ( 1 843 ) .
Ca lvarano , I . ( 1964) .
Chr i stensen , E . N . and Caput i , A . ( 1968 ) .
Chung . T -Y
Hayase , F . and Kato , H . ( 1983 ) .
C10ugh ley , J . B
E l l i s , R . T . , Pend l i ngton , S . and Humphrey , P .
( 1982) .
.
•
. •
.
•
. •
.
•
Cont i nued
44
References
23 .
24 .
25 .
26 .
27 .
28 .
29 .
30.
31 .
32 .
33 .
34 .
35.
36.
37 .
38 .
39 .
40.
41 .
42 .
43 .
44 .
45.
46.
47 .
48 .
49 .
50 .
51 .
52 .
53 .
54 .
55 .
56 .
57 .
58 .
59 .
60 .
61 .
62 .
63 .
64 .
65 .
66 .
67 .
68 .
69 .
Co leman , E . C . , Ho , C-T . and Chang , S . S . ( 1981 ) .
Daenens , P . and larve l l e , l . ( 1973 ) .
Deyama , T . and Hor i guchi , T . ( 1971 ) .
Do , J . E . , Sa lunkhe , D . K. and O lson , l . E . ( 1969 ) .
Dodge , F . D . ( 1918) .
E l -Deeb , S . R . , Karawya , M . S . , Wahba , S . K . and Ebe i d , F . M . ( 1962 ) .
Fede l i , E . and Jac i n i , G . ( 1970) .
Fernando , V . and Roberts , G . R . ( 1984 ) .
Ferrett i , A. and F lanagan , V . P . ( 1972 ) .
F l at h , R . A . and Forrey , R . R . ( 1977 ) .
Gent i l i n i , l . ( 1960) .
G i erschner , K . and Baumann , G . ( 1968 ) .
Gog i ya , V . T . ( 1965 ) .
Guppy, H . , Wh i tf ie ld , F . B . and Woodh i l l , J . ( 1977- 1978 ) .
Habu , T . , F l ath , R . A . , Mon , T . R . and Morton , J . F . ( 1985 ) .
Hayase , F . , Chung . T-Y . and Kato . H . ( 1984 ) .
Haymon . l . W . and Aurand , l . W . ( 1971 ) .
Hazar i ka , M . , Mahanta , P . K . and Takeo , T . ( 1984) .
He i de , R . ( 1972 ) .
H i rv i , T . and Honkanen , E . ( 1983 ) .
H i rv i , T . and Honkanen , E . ( 1985 ) .
Johnson , A . E . , Nursten , H . E . and W i l l i ams , A . A . ( 1971 ) .
Kahn , J . H . ( 1969 ) .
Kato , H . , Ohta , T . , Tsug i ta , T . and Hosaka , Y . ( 1983 ) .
Kawakami , M . and Yaman i sh i , T . ( 1983 ) .
Kemp , T . R . , Knavel , D . E . and Sto ltz , l . P . ( 197 1 ) .
l i eb ich , H . M . , Koen i g , W . A . and Bayer, E . ( 1970 ) .
Macleod , A . J . and Gonza l es de Trocon i s , N . ( 1982 ) .
Maga , J . A . and lorenz , K . ( 1974 ) .
Maga , J . A . ( 1978 ) .
Mahanta , P . K . , Hazar i ka , M . and Takeo , T . ( 1985 ) .
McGl umphy , J . H . ( 1951 ) .
M i nasyan , S . M . and Khodzhumyan , G . A . ( 1965 ) .
Murray , K . E . ( 1973 ) .
Nursten , H . E . and Wi l l i ams , A . A. ( 1976) .
Obata , Y . , Senba , Y . and Koshi ca , M . ( 1963 ) .
On i sh i , I . and Yamamoto , K . ( 1956) .
Pau l , A . E . ( 19 17 ) .
Porsch , F . , Farnow , H . and W i nk ler , H . ( 1965 ) .
Pr idham, J . B . and Young , M . ( 1964 ) .
Pyne , A . W . and W i ck , E . l . ( 1965) .
Ram , V . and V i r , D . ( 1984 ) .
Robertson , G . l . and Kenmode , W . J . ( 1 981 ) .
Robertson , G . l . ( 1983 ) .
Rubach , K . and Breyer , C . ( 1 981 ) .
Sa i jo , R . and Kuwabara , Y . ( 19 64 ) .
Sa i jo , R . and Kuwabara , Y . ( 1967 ) .
Cont i nued
45
References
70.
71 .
72 .
73 .
74 .
75.
76.
77 .
78 .
79 .
80 .
81 .
82 .
83 .
84 .
85 .
86 .
87 .
88 .
89 .
90.
91 .
92 .
93 .
94 .
95 .
96.
97 .
98 .
99 .
1 00 .
1 01 .
1 02 .
1 03 .
1 04 .
Schm ; dt l e i n , H . and Hernmann , K. ( 1975 ) .
Schm i dt l e i n , H . and Hernmann , K. ( 1975 ) .
Schm i dt le i n , H . and Herrmann , K . ( 1975 ) .
Schr ier, P . , Drawart , F . and Junker , A . ( 1 976 ) .
Se i de l , C . F . , Sch i nz , H . and Sto l l , M . ( 1958 ) .
Seo , A . and Morr , C . V . ( 1984 ) .
Shenman , H . C . ( 1910 ) .
Sh i nz , H . and Se i de l , C . F . ( 1957 ) .
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Stah l , W . H . ( 1 962 ) .
Stan ley, Wm. L . ( 1959 ) .
Stoehr , H . , Mose l , H-D . and He rnma nn , K . ( 1975 ) .
Stoehr , H . and Hernmann , K . ( 1975 ) .
Stoehr , H . and Hernmann , K . ( 1975 ) .
Stoehr , H . and Hernmann . K . ( 1975 ) .
Stoehr , H . and Hernmann . K . ( 1975) .
Stoffe l sma , J . , S i pna , G . , Kettenes , D . K . and Pypker , J . ( 1968 ) .
Takeo , T . ( 1 965 ) .
Takeo , T . ( 1983 ) .
Takeo , T . ( 1983 ) .
Takeo , T . ( 1 984 ) .
Takeo , T . ( 1984 ) .
TakeOka , G . R . , Guntert , M . , F lath , R . A . , Wurz , R . E . and Jenn i ngs ,
W. ( 1986 ) .
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Thornberg , W . ( 1 976) .
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T-F . ( 1984 )
Toth , L . and Potthast , K . ( 1983 ) .
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Von Fe l lenberg , T . and Krauze , S . ( 1932 ) .
W i nter , M . and K l ot i , R . ( 1972 ) .
Yaj ima , I . , Yana i , T . , Nakamura , M . , Sakak i bara , H . , Uch i da , H .
and Hayash i , K . ( 1983 )
Yamaguch i , K . and Sh i bamoto , T . ( 1980) .
Yamaguch i , K . and Sh ibamoto , T . ( 1 981 ) .
Yaman i sh i , T . , Kobayash i , A . , Sato , H . , Nakamura , H . , Osawa , K . ,
Uchi da , A . , Mor i , S . and Sa i jo , R . ( 1966 ) .
Yaman i sh i , T . ( 1978 ) .
Foods not ana lysed in thi s study but ana lysed i n the l i terature
Chestnut
Chokeberry
C 10udberry
Cottonseed o i l
Gooseberry
101
43
9
51
85
Ma lt
Muskme lon
Sapodi 1 1a fru i t
Speanmint
76 ( - )
48
50
60
46
Pee l o f Fru i t s and Vegetabl e s
T h e val ues o f s al i cyl ate i n food s var i ed i f the p e e l was i nc l uded i n
t h e an al y s e s .
The peel was found t o be a concentrated s ource o f
sal i cyl ate i n foo d s t h at were extracted both w i t h a n d w i t hout t he i r
peel
( Tabl e 2 . 7 ) .
I n add i t i on g herki n was s h own t o h ave a h i g h
sal i cyl ate content compared w i t h peel ed cucumbe r .
Th i s was due i n
part to t h e s a l i cyl ate content of the s ki n a s wel l a s t h e sal i cyl ate
present i n the v i negar and s p i ces u s ed i n p i c kl i ng .
Th i s fi nd i ng
proved i mportant i n the c l i n i cal context where p at i ents w i t h R I U/AO
were e at i ng pears as t h e o n l y fru i t al l owed o n t h e e l i mi n at i on d i et
( Ch apter 3 ) .
Such pat i e n t s o ften c o n s umed pears
in
c o n s i derab 1 e
quant i t i e s , and t ho s e who were s al i cyl ate s e n s i t i ve o ften d i d not
rem i t compl ete l y unt i l t h ey were i n st ructed t o e at o n l y peel ed pears .
TABL E 2 . 7
E FF ECT OF PEEL ON THE SAL I CY LATE CONTENT OF FOODS !
Food wi t h Peel
Foods
Granny smi t h appl e
0 . 59
Food w i t h n o Peel
0 . 55
0 . 78
Cucumber
Pot at o
0 . 12
0
Pe ar
0 . 27
0
Peanu t s
1 . 12
0 . 23
1.
Sal i cyl at e concentrat i on s are expre s sed a s mg/ 1 00g .
47
Compar i son of Fre s h , Canned and Ju i ced Food s
Fru i t j u i ce s conta i n onl y t h e 1 i qu i d fract i on o f fru i t , d i scard i ng
t he s ki n and fl e s h , res u l t i ng i n l ow l evel s for the j u i ce compared
wi t h t h e fru i t fl e s h ( Tabl e 2 . 8 ) .
However , t h i s t abl e was c omp i l ed
from fru i t s and j u i ce s wh i ch were deri ved from many s ources wh i ch
mean s t h at the resul t s expres sed are onl y an i nd i cat i on of t h e var
i at i on wh i ch can occur depend i ng on the source and vari ety o f fru i t
exami n ed .
From the tabl e , fru i t j u i ce h a s a l ower s al i cyl ate content
t h an i t s fre s h fru i t counterpart .
Howeve r , th i s i s m i s l e ad i ng i n a
cl i n i cal context because fru i t j u i ce i s u s ual l y consumed more o ften
and i n 1 arger amounts t h an fres h fru i t .
Consequent 1 y ,
s a l i cyl ate
sens i t i ve p at i ents h ave found that cons umpt i on of both fru i t and
fru i t j u i ce mus t be control l ed i n o rder to rema i n asymptomat i c .
TAB L E 2 . 8
COMPAR I SON OF FRESH , CAN N ED AND J U I C ED FOODS 1
Food
J u i ce 2
F re s h
C an n ed 2
Appl e
0 . 19
0 . 59
0 . 55
Orange
0 . 18
2 . 39
Wh i te grape
0 . 18
0 . 16
Red grape
0 . 88
1 . 88
0 . 94
P i neappl e
0 . 16
2 . 10
Apr i cot
0 . 14
2 . 58
1 . 36
1 . 42
Tomato
0 . 18
0 . 13
0 . 53
1 . Sal i cyl ate concentrat i on s are expres s ed as mg/ 1 00g .
2.
For s o u rce o f canned and j u i ce
see Tabl e 2 . 6
for
brands .
48
Concentrat i on of Sal i c yl ate i n Tomato Prod uct s
Concen trat i on o f the food wi th the l os s of water l ed to an i ncrease
in
s al i cy l ate
content .
Several
t omato
products
from
sources were an al ysed g i v i ng a range of val ues ( Tabl e 2 . 9 ) .
d i fferent
However ,
the re s u l t s s howed t h at concentrat i on o f a food w i t h t he l os s o f
water and the furt her concentrat i on o f fl avours wi t h the add i t i on o f
herbs and s p i ces l ed to a marked i ncrease i n s al i cyl ate content .
In
sen s - i t i ve p at i ent s t h i s concentrat i on o f foods can mean t h at very
smal l amounts o f a food i tem can l ead to a marked react i on .
TABLE 2 . 9
CONC ENTRAT I ON OF SAL I CYLATE I N TOMATO PRODUCTS 1
Tomato Product 2
Sal i cyl ate mg/ 1 00g
Tomato s auce
0 . 94 - 2 . 48
Tomato paste
0 . 43 - 1 . 44
Tomato s o up
0 . 3 2 - 0 . 54
T i nned t omato
0 . 53
Tomato j u i ce
0 . 1 0 - 0 . 18
Fresh t omato
0 . 13
1 . Sal i cyl ate concentrat i on s are expres s ed as mg/ 1 00g .
2 . For source of tomato products s ee Tabl e 2 . 6 for brands .
49
D I SCUSS I ON
Ext ract i on and An al ys i s
S al i cy1 ates were f i rst extracted from t h e bark o f t h e W i 1 1 ow tree
( Sa 1 i x ) i n the 1 820 ' s , al t hough the med i c i n a l propert i es of t h i s and
other pl ant s were known i n H i ppocrat i c t i me s ( Rev i ewed i n Gro s s &
Greenberg ,
1 948) .
Advances
i n organ i c chem i s try d u r i n g t h e
1 9t h
century e n a b 1 e d the French pharmac i st Lero ux ; n 1 82 9 t o ; sol a t e i n
the pure form sal i c i n , the act i ve i ngred i en t i n W i l l ow bark ( Leroux ,
1 830 ) .
I n 1 83 1 , s al i cyl al dehyde was d i st i l l ed from t h e fl owers of
Sp i rea U l mar i a by the Swi s s pharmac i st , Pagensteche r .
H e s u bsequent
ly transmi tted t h i s i nfo rmat i on to the German chem i st , Lowi g , who i n
1 83 5
produced
s al i cyl i c
( Tsch i rc h , 1 9 1 7 ) .
ac i d
by
ox i dat i on
of
s a l i cy l al d e hyde
I n 1838 , P i r i a al so o bt a i n ed s a l i cyl i c ac i d by
hydrol ys i s and ox i dat i on of s al i c i n .
In
the
1 840 ' s
and
1 850 ' s ,
fol l owi ng the i so l at i on of met hyl sal i cy1 ate from o i l o f w i nterg reen ,
sal i cyl i c ac i d was prepared by the act i on o f phosphorous perch l o r i de
on met hyl s a 1 ; cy1 ate by the French chem; st Cahours and the Scott i sh
chem i st Cooper .
I n the l ate 1 9th and e arl y 20th centur i e s sal i c i n was i ndent i fi ed i n
Popl ar and W i l l ow trees and i n the Bl ack Law ( Squ i bb , 1 87 5 ;
1 89 1 ;
J owett & Potter , 1 902 ;
1 92 5 ;
Lortat -Jaco b ,
1 94 5 ) .
trees
1 92 5 ;
S aj ous & S aj ou s , 1 9 1 6 - 1 93 2 ;
Evans et al . ,
1 945 ;
Bec k ,
G h os h ,
Iwamoto et al . ,
Methyl s al i cyl ate g l ycos i des were found i n B i rch and Beech
as
wel l
c hequerberry ,
as
in
Gaul t heri a
wi nterg reen ,
procumbers ,
G a u ltheri a h i s p i dul a ,
p a rt r i dge
wi 1 d
p a n sy ,
berry ,
mi 1 k
wort , bay tree , I nd i an l i cori ce , soap berry , o l i ve , madder , j asm i ne ,
50
myrt l e ,
l i nden ,
buckthorn ,
fol l ow i ng botan i cal
C upul i ferae
and
var i ous
orders :
Legum i n o s ae ,
Eryt hr i xyl eae
Stokv i s ,
1 899 ;
Lortat J aco b , 1 92 5 ;
&
S aj o u s ,
Autenre i t h ;
1951 ;
On i s h i
&
add i t i on ,
1 95 5 ,
yucca ,
been
found
cl over ,
181 8 ;
Ano n . ,
Wal ters ,
Cone , 1 903 ;
W i nters ,
1 92 0 ;
Sel f , 1 9 1 5 ;
Ghos h ,
1 92 5 ;
1 937 ;
Pri dh am & Young , 1 964 ;
Jul kunen -T i i tto , 1 985 ;
h ave
B i x i n e ae ,
Morel ,
I brah i m & Towers ,
1 95 6 ;
in
the
1 898 ;
H i l pert , 1 9 1 3 ;
Wal l ,
in
B i gel ow ,
Arny & F i schel i s ;
I brah i m , 1 964 ;
t h ey
tul i p ,
La
and
Ano n . , 1 882 ;
Ed i to r i al ,
Ta i l l eur , 1 90 2 ;
Yamamoto ,
Oarl i ng , 1 964 , 1 96 5 ;
hyac i nth ,
1 894 ;
Perutz , 1 930 ;
Tomaszews k i , 1 960 ;
In
Prebbl e ,
1 9 1 6 - 1 93 2 ;
1 928 ;
1 798 ;
Cahours , 1 843 ;
Pancoust & Pearson , 1 909 ;
1 904 , 1 907 ;
S aj o u s
1 89 5 ,
coffee ,
Euphorb i aceae ,
( Longmore ,
Proctor , 1 84 2 - 1 843 , 1 843 , 1 844 ;
1 888 ;
grasses ,
1 960 ;
Pearl &
Gaydou et al . , 1 986 ) .
the
woodruff ,
yel l ow b i rd ' s
nest ,
mar i gol d ,
meadowsweet ,
i pecacuan h a , m i gnonette , ammon i ac pl ant , Ameri ceae fami l y and pansy
'
( B i ge l ow , 1 8 1 8 ; Buchner , 1 854 ; W i c ke , 1 854 ; S qu i bb , 1875 ; Anon ,
1 888 ;
Gri ffi t h s ,
Lortat -J acob ,
1 92 5 ;
1 889 ;
B i nz ,
Perutz ,
1 897 ;
1 930 ;
Schl i mme ,
Desmou l i ere ,
1 943 ;
1 904 ;
Wood & Osol ,
1 943 ) .
Up to the e arl y 1 950 ' s the standard met h od for i dent i fi cat i on of
sal i cyl ates were col ori metr i c ( Gros s & Green berg , 1 948 ;
1984 ) .
W i t h the devel opment of TLC
Stahl et al . ,
195 2 )
it
1 95 6 ;
became
Stahl , 1 958 ,
poss i bl e
to
Ra i ns ford ,
( I zma i 1 ov & Schra i ber ,
1 938 ;
1 969 ) and GLC ( J ames & Mart i n ,
devel op
more
sen s it i ve
methods
of
detect i on , a n d t h i s was the i n i t i al approach adopted i n t h e present
study .
Q u ant i fi cat i on was attempted by den s i tomet ry , but t h i s proved
unre 1 ; ab 1 e s i nce t he read i ngs often d; d not refl ect the den s i ty of
51
spots a s est i mated by v i sual i n spect i on .
H PL C ( Jo h n s o n & Steven s on ,
1 977 ) , wh i ch was f i rst i nt roduced for anal ys i s o f s al i cyl ates i n
t i s s ue s and body fl u i ds i n t h e l ate 1 960 ' s ( Peng et a l . , 1 978 ) proved
to be a muc h more re 1 i a b 1 e and Quant i tat i v e met h od for a na l ys i s of
food extracts i n t h e present s tudy .
F I GURE 2 . 1 0
H I STOR I CAL EXTRACT I ON O F SAL ICYLATE FROM PLANTS ( COLL I ER, 1 96 3 )
Bark o f w i l l ow
( Sa l i x )
�
�
Extract i on
Mead owsweet fl ower
O i l o f w i n te rg reen
( Sp i rea )
( Ga u l t h e r i a )
�
�
D i s t i l l at i on
�
�
�
Ext ract i on
�
�
Sal i cyl al dehyde
Met hyl s al i cyl ate
Hydro l ys i s & oxi dat i on
Ox i dat i on
Hydro l YS i s
Synthes i s
Sal i cyl i c ac i d
Sal i c i n
�
-...
( Sp i rs aure )
�
�
Acetyl at i on
Acetyl sal i cyl i c ac i d
(As p i r i n )
Sod i um s a l i cyl ate
52
Extract i on methods h ave ch anged l i ttl e s i nce the e arl i est attempts by
European chemi sts i n the l ate 1 9th and earl y 20th centur i es ( Gros s &
Greenberg , 1 948 ;
Ra i n sford , 1 984 ) .
When the present study commenced
the s t andard method , as outl i ned i n the As soc i at i on of Anal yt i cal
Chemi sts Handboo k
( Horwi tz ,
1 975 ) ,
was to
s h a ke the
h omogen i zed
mater i al i n a separat i ng funnel so as to tran s fer sal i cyl ates from
the aqueous to the organ i c sol vent phase .
I t was s oon found t h at th i s
method was rather i neffi c i ent , requi ri ng l arge quant i t i es of food and
sol vent , and form i ng emul s i on s wh i ch were d i ffi cul t to separate .
A
more eff i c i ent method was therefore devel oped , where the h omogen i zed
food was f i rst hydrol ysed i n 2 5% NaOH overn i ght , fol l owed by ac i d i f
i cat i on to pH<2 . 0 .
Th i s re sul ted i n extens i ve pl ant t i s s ue break
down , wi t h al l bound s al i cyl ate esters be i ng freed from the cel l
structure ( Harbourne , 1 980 ;
Newby et al . , 1 980 ) .
The food s ampl e
was then extracted wi th l i qu i d extractors over 5 h ours wh i ch avo i ded
the format i on o f emu 1 s i on s and al l owed for more compl ete m i x i ng of
food and sol vent t h an i n prev i ous methods publ i s hed l ead i ng to a more
effi c i ent extract i on .
The resul ts o bt a i ned by th i s met hod y i el ded
con s i derabl y h i gher s al i cyl ate concentrat i on s t h an those reported i n
the l i terature , i . e about 1 0 t i me s h i gher for p i neappl e j u i ce but
more t h an 1 00 t i mes h i gher for p i neappl es (Tabl e 2 . 6 ) .
Th i s can be
expl a i ned part l y by the fact t hat e arl i er workers d i d not empl oy such
st ri ngent techn i ques as the effi c i ent 1 i qu id extract i on procedure ,
but more 1 i ke 1 y the h i g her 1 eve 1 s were due to the convers i on o f
conj ugated sal i cyl ates to 'free sal i cyl i c ac i d
sal i cyl ate
in
the
food s
was
measured
so t h at the total
( Harbourne ,
1 980 ) .
benzoates were successful l y extracted al ong wi t h total
(Tabl e 2 . 6 ) .
Total
sal i cyl ates
but as they were el uted cl ose to the sol vent front they
53
coul d n o t be accuratel y quant i f i ed .
v a l ues for total
benzo i c ac i d of
( Es t i mate s i n s ome foods g ave
1 00 t i me s the amount of t otal
s al i cyl ates ) .
D i st i but i on
S a 1 i cyl ates i n food were fi rst reported i n L ancet
(An o n . ,
1 903 ) .
They were i dent i fi ed i n smal l amounts i n t h e c ommo n fru i t s trawberry .
Subsequentl y ,
Desmo u1 i ere
( 1 90 4 ) ,
Paul
( 1917) ,
Dodge
( 1918)
and
Perutz ( 1 93 0 ) al so found s a l i cyl ates i n appl e , an i se , c herry , g rape ,
c i n n amo n , n u tmeg , orange , pepperm i nt , pl um , raspberry , s pe arm i n t , and
s i nce then there h ave been at l east 1 00 report s of t he i r p re sence i n
a v ar i ety o f fru i ts and vegetabl es , an i seed and a l mon d s ( Ta b l e 2 . 6 ) .
No prev i ous s tudy h a s , h owever , systemat i cal l y anal y s ed t h e s al i cy
l ate content of al l commonl y e aten foods , a n d s i n c e t h i s i nfo rmat i on
was found to be e s sent i al for the d i etary management o f pat i en t s w i th
I n al l ,
RI U/AO s uch an anal ys i s was undert a ke n by t h e author .
333
foods were extracted and anal ysed , and s i gn i f i cant s al i cyl ate concen
trat i on s were found i n a w i de vari ety o f fru i ts and vegeta bl e s , h erbs
and s p i ces , nuts , beverages , and m i scel l aneous pl ant - d e r i ved food s .
( a ) Fru i t s and Vege tabl e s
A range o f s a l i cyl ate val ues i n fru i ts a n d v egeta bl es was found t o be
dependent o n the s pec i es o f the pl ant , age i ng/r i pen i ng o f the fru i ts
or vegetabl e s and exten s i ve pro ce s s i ng ( co o k i ng , c an n i ng , freez i ng ) .
For
exampl e ,
s al i cyl ate
several
content s
vari et i e s
w i th
gol den
of
appl es
del i c i ous
exh i b i t
conta i n i ng
a
range
of
0 . 08mg/ 1 00g
c ompared w i t h red del i c i o u s w i th 0 . 1 9mg/ 1 00g and granny smi th s h av i ng
a val ue o f 0 . 59mg/ 1 00g .
Those vari et i e s wh i ch g ave a l es s ' p i qu ant
fl avour
be
were
fou nd
to
o ften
l ower
in
s al i cyl ate
conte n t .
54
S i mi lar ly , t h e s a li cylate content of frui ts and vegetable s was fo und
t o v ary w i t h r i pen i ng as t h i s proce s s leads to a change i n t h e
c h em i cal
compo s i t i on
and
t here fore
the
flavour
of
frui t
and
v egetable s .
He at ing by convent i on a l coo k i ng met h od s does not h ave an apprec i abl e
e ffec t o n the content o f ava i 1 a b 1 e s a licylate i n food .
comme rc i a 1
p roce s s i ng t h at res ult s
However ,
i n t h e e xte n s i ve brea kdown o f
p lant t i s s ue can re s ult i n an i ncre a s e o f ava i lable s al i cyl ate , for
examp l e
fres h
2. 10)
Th i s i s why the severe t rea tment w i t h s od i urn hyd ro x i de and
•
c orn
compared
w i t h proce s s ed
corn
prod ucts
( Table
hyd roc h lor i c ac i d used i n t h e extract i on met h od a ffected the f i bre
struct ure of t h e frui t s and vegetable s l ead i ng to a rel e a s e of bound
s al i cylat e .
Another
p hy s i ca l
c h aracter i st i c
wh i c h
h ad
an
i n fluence
on
the
s al i cy late content i n t he s ample we exam i ned was t h e pee l where the
concentrat i on o f s a li cylate i s h i g h er t han i n the frui t o r vegetable
fles h e . g . pot ato , pear , eggplant , peanut , apple ( Table 2 . 7 ) .
S i n ce
the peel i s t h e p hys i ca l b arr i er between t h e o ut s i de e nv i ronment and
th e fl e s h and s eed o f al l frui t s and vegetabl e s i t may be t h at t h e
h i g her s a li cylate content i s act i ng i n a protect i ve capac i ty .
At t h e
beg i nn i ng o f t h i s century i t w a s known t h at sali cyli c ac i d w a s a very
effect i ve ant i mi c ro b i a l agent and , i ndeed , i t was used a s a pre s erv
at i ve i n E urope unt i l report s o f adverse re act i on s led to i t s proh i b
i t i on i n t h e 1 9 50 ' s ( L uec k , 1 980 ) .
55
When fru i ts or veget abl es are crushed for j u i ce. the peel and fi bre
content are d i scarded wh i ch res u l ts i n a l oweri ng of the s al i cyl ate
content s upport i ng the not i on that sal i cyl ate i s bound i n the fru i t
or vegetabl e fi bre wh i ch i s d i scarded duri ng proce s s i ng (Tabl e 2 . 8 ) .
An average of four p i eces of fru i t i s needed to make one gl as s of
fru i t j u i ce
showi ng that con s i derabl e amounts
of s a l i cyl ate are
d i scarded i n the pul p after fru i t j u i ce manu facture .
Howeve r , the
ease of i ngest i on of vast quant i t i es of fru i t j u i ce compared wi th
p i eces of fresh fru i t often mean s i nd i v i dual s st i l l consume a l arge
quant i ty of sal i cyl ate i n the form of j u i ce .
Concentrat i on of sal i cy1 ate i n food s can be seen w i t h the range of
tomato products anal ysed .
Tomato s auce , soup , paste exh i bi t h i gh
1 eve 1 s of s al i cy1 ate compared wi th the fre s h t omato ( Tab 1 e 2 . 9 ) .
Th i s i s due to t he i r concentrat i on duri ng proces s i ng and t he add i t i on
o f s p i ces wh i ch even though t he i r u se i s i n sma l l amounts they can
s t i l l make a s i gn i fi cant contri but i on to d i etary sal i cyl ate .
( b ) Beverages
Beverages 1 i ke tea , coffee and the i r herbal or cereal counterparts
are al l h i gh sources of sal i cyl ate , be i ng deri ved from pl ant matter .
Cereal coffees are based on ch i cory and beetroot , wh i l e herbal teas
rel y for fl avour on var i ous herbs and n atural fl avours l i ke pepper
mi nt for t he i r con s i derabl e s al i cyl ate content .
Methyl ene d i ch 1 ori de i s a sol vent that was commonl y u sed i n t h e
decaffe i nat i on of coffees and teas .
read i l y
markedl y
sol ubl e
reduced
in
it.
Both caffe i ne a n d sal i cyl ate are
Consequentl y decaffe i n ated
sal i cyl ate
compared
w i th
coffee i s compl etel y devo i d of s al i cyl ate .
tea
and
tea
conta i ns
decaffe i n ated
56
Al cohol i c beverages exh i b i t a range of sal i cyl ate content depend i ng
on the raw products used i n the i r manufacture and t he i r proces s i ng .
Ferment at i on does not s i gn i fi cantly i ncrease the sal i cyl ate content
of beverages wi th grape j u i ce be i ng compa rab 1 e to wi ne and appl e
j u i ce comparabl e to c i der i n sal i cyl ate content .
Sp i ri ts l i ke vodka ,
wh i s key and g i n are very poor sources of s al i cyl ate because t he i r raw
i ngred i ents are l ow and d i st i l l at i on removes any sal i cyl ate present .
A 1 ternat i ve 1 y , 1 i quers are very h i gh sources of sal ; cyl ate d ue to
t he i r raw i ngred i ents e . g . Ti a Mari a ( chocol ate ) , Drambu i e ( herbs ) ,
Contreau ( orange peel ) and Bened i ct i ne ( herbs ) .
( c ) Prote i n Ri ch Foods (Meat , Poul try , F i sh , Eggs , Dai ry , Legumes )
Prote i n foods from both an i mal or vegetabl e ori g i n s were general l y
·
l ow sources o f s al i cyl ate . Al l dri ed l egumes analysed h ad l ess than
O . 08mg/ l OOg i n the dry state .
Beef, l amb , pork , ch i cken , oysters ,
fi sh
had
and
da i ry
products
al l
negl i g i bl e
s al i cyl ate
content .
L i ver was found to conta i n O . O Smg/ l OOg perhaps i nd i cat i ve of the
an i mal s ' food i ntake from pl ant sources .
( d ) Cereal s
Sal i cyl ate l evel s i n n i ne whol e gra i n cereal s were negl i g i bl e , wi th
the except i on of a yel l ow ma i ze meal wh i ch contri buted O . 43mg/ l OOg .
( e ) Sweets
Li ttl e research h ad been done prev i ously on the amount of sal i cyl ate
i n popul ar sweets and confect i onery .
However , Porsch et al . ( 1 96S )
and others h ave i dent i fi ed sal i cyl ate i n an i se and mi nt .
Therefore a
representat i ve number of 1 i cor i ces and peppermi nts were
al ong wi th some other popul ar sweet s .
anal ysed
57
Val ues for caramel s , cocoa and c arob were negl i g i bl e .
mi nts
conta i ned
vari abl e
s a l i cyl ate contents
amounts .
i n m i nt
It
wou l d
appear
cand i es come mos t l y from
fl avo r i n g s 1 i ke met hyl s al i cyl ate .
The peppert h at
h i gh
add i t i onal
M i n t sweets may a l s o b e u s ed i n
t h e manu facture of l i cori ces , to wh i ch an i se i s added for fl avour , a
h i gh s o u rce of s a l i cyl ate .
TABL E 2 . 1 0
SAL I CY LATE CONTENT OF CORN PRODUCTS
Corn Product
S a l i cyl ate Content
Ma i ze meal
0 . 43mg/ l 00g
Fre s h corn
0 . 1 3019/ l 00g
0 . 26mg/ l 00g
O . 39mg/ l 00g
Canned n i bl et s
C an n ed cre amed corn
Concl u s i o n s
I t was s u rpr i s i ng to fi nd , as a re s u l t of t h e analyses perfo rmed ,
t h at sal i cyl ates ( i nc l ud i ng asp i r i n ) are much more w i del y d i s t r i buted
t h an h i th erto s u s pected .
S i gn i fi cant 1 eve 1 s were pre sent i n most
fru i ts and vegetabl es , h erbs and s p i ce s , and pl a nt - de r i ved foods and
beverages , as wel l as i n unexpected foods s uch a s honey , Vegemi te ,
con fect i on e ry and a v ar i ety of nuts ( Tabl e 2 . 6 ) .
I n fru i t s and veg e
t abl es t he concentrat i on depended on t h e spec i e s ( and i n s ome cases
58
v a r i ety ) , age i ng , r i pe n i ng , p roces s i ng and preparat i on .
As s h own by
t h e TLC d at a ( F i g ure 2 . 8 ) as p i r i n i t sel f compr i se s a s i gn i fi cant , i f
n ot maj o r , p roport i on o f t h e total s a l i cyl ates p re s en t , a l t hough th i s
i s d i ff i c u l t t o q u an t i fy prec i sel y bec ause o f rap i d bre a k - down d u r i ng
extract i on and anal ys i s .
Sal i cyl ates were absent from an i mal - de r i ved
food s s uch as f i s h , me at s and d a i ry prod uct s , and from mos t gra i n s .
As w i l l
be d i s c u s sed
i n C hapter 1 0 ,
s al i cy l ates are product s of
s ec ondary p l ant met abol i sm , and al ong w i t h other benzo i c ac i d der i v
at i ves are probabl y synthe s i zed to a greater o r l es ser extent by most
p l a nt s , i nc l ud i ng those c ommon l y eaten as food s .
The s a l i cy l ate l evel s mea s u red i n the p resent s t udy a re h i g her t h an
those
reported
e l sewhere ,
p robabl y
due
extract i on proced u re and the use o f H PLC .
to
t he
more
effi c i ent
I t was prev i ou s l y t h ought
t h at the normal d i et con t a i n ed s uch smal l amo unts o f s al i cyl ate as to
be
c l i n i ca l l y
Samter ,
i rrel evant
( So ut h ,
1 976 ,
1976 ,
1 97 7 ,
1 97 9 ,
1 980 ;
1 9 7 7 ) , but cal c u l at i on s based o n t h e l evel s mea s ured here
i nd i cate t h at an average Au s t ral i an d i et cont a i n s of the o rder o f 1 0
t o 5 0 mg per d ay , and s ome i nd i v i du a l s may con s ume u p t o 1 00 mg per
d ay .
F u rt h e rmore , s al i cyl ate - cont a i n i ng food s al s o appear to be r i ch
s o u rces o f other benzo i c ac i d d e r i vat i ves , many o f wh i ch c ro s s - react
wi t h a s p i r i n i n s e n s i t i ve i nd i v i d u al s ( Ch apter 3 & C h apter 6 ) .
CHAPTER 3
D I ETARY I NVEST I GAT I ON O F RECURRENT I D I O PATH I C
URT I CAR I A/ANG I O EDEMA
59
I NTRODUCT I ON
Urt i c a r i a cau sed
by
nettl e s
and
i n sect
b i tes
was
recogn i zed
in
H i ppocrat i c t i me s , al thoug h i t s mode rn n ame was not c o i n ed u nt i l the
1 ate 1 8t h century .
It i s n ot cl ear exactl y whe n food s were fi rst
a s s oc i ated w i t h attac ks of R I U/AO , but ang i o edema c a u s ed by eggs was
d e s c r i bed by Donat i
i n the 1 6th century ( Sc h adewe l dt ,
1 98 1 ) ,
and
W i l s o n , i n the 1 8t h century , was s a i d t o h ave s omet i me s traced i t s
11
cause by
( Bateman ,
omi t t i n9
1813 ) .
fi rs t
one and then another art i cl e o f food
11
I n t h e 1 ate 1 9th and e arl y 20th century i t was
wi del y recogn i zed that food s , a s wel l a s d rug s , fevers , p hy s i cal and
emot i on a l factors coul d al l contri bute t o the aet i o l ogy of u rt i cari a ,
and by t h e 1 950 ' s al mos t every author wr i t i ng on the s u bj ect i ncl uded
a l ong l i s t of food s known to prec i p i tate symptoms ( War i n & Ch amp i o n ,
1 974 ) .
H owever ,
i t was not u nt i l
Lockey i mp l i cated t h e
azo - dye
tartraz i ne t h at more i nterest was t a ken i n ' i dent i fy i ng the rel evant
food c o n s t i tuents ( Loc key , 1 959 , 1 969 , 1 97 1 , 1 97 7 ) .
Asp i r i n a s a d rug was known t o be capabl e o f provo k i n g urt i ca r i a and
ang i oedema as earl y as 1 902 ( H i rsch berg , 1 902 ) , and a l though sal i cy
l ates were known t o be pre sent i n vari o u s pl ants a n d fru i ts ( Ch apter
2)
i t t o o k over 50 years before t herapeut i c d i et s were ; nt roduced
wi th t h e i de a of avo i d i ng exposure to n at u ral s al i cyl ate s ( Shel l ey ,
�,
1 964 ;
Fe i ngol d , 1 968 ;
1 974 ;
War i n ,
1 976 ) .
Loc key ;
1 971 ;
No i d e t al . , 1 974 ;
As outl i ned i n C h apter 1 ,
Ol i v i er ,
t h e s e p ro v i ded a
start i ng po i nt for the present s tudy , but i t was s oo n e v i dent t h at
knowl edge o f t h e d i st r i but i on o f n atural sal i cyl ates was i n adequate .
60
,I
s al i cyl ate s ,
s o t h at
a more e ffect i ve
e l i mi n at i on d i et coul d
be
i
1
'}
deve l oped .
,.�
1
Th i s c h apter descri bes t h e res u l t s o f d i etary i nv e s t i gat i on i n 1 , 349
p at i e n t s wi t h R I U/AO ,
j
·1
repres e n t i ng the l arges t s e r i e s reported to
d at e , u s i ng a standard e l i m i n at i on d i et and bl i nd c h a l l enge prot ocol
wh i c h was deve l o ped for use on an outpat i e n t bas is .
The stri ngency
o f s al i cyl ate excl u s i on , al ong w i t h c � o s e contact between pat i en t a nd
d i et i t i an , re s u l t ed i n excel l en t comp l i ance and a h i g h e r s ucces s rate
t h an general l y reported i n the l i terat ure .
Pat i en t s
Between Apr i 1
1 977 a n d September 1 986 ,
1 349 pat i en t s wi t h R I U/AO
p re sented to t h e Al l e rgy Cl i n i c at RPAH , refe rred general l y by t he i r
fam i l y doctor or a dermato l og i s t .
Pat i en t s were aged between one and
86 years ( F i gure 3 . 1 ) wi th R I U/ AO of s i x weeks to 60 years d u rati on
( F i gure 3 . 2 ) .
S i xty two percent were fema l e and 3 8% mal e ;
43 . 7%
presented w i t h u rt i c a r i a o n l y , 1 7 . 6% w i t h ang i oedema o n l y , and 38 . 7%
wi t h bot h u rt i cari a and ang i oedema .
The p at i e n t s w i th
II p hys i cal li
, prec i p i tants such a s col d , s u n exp o s u re or pre s s u re general l y a l s o
expe r i e nced " i d i op ath i c " attacks , a nd were i nvest i g ated and manag ed
al ong t h e s ame l i ne s a s other pat i ents w i t h R I U/AO .
'
61
FI GURE 3 . 1
H I STOGRAM OF THE AGES OF R I U/AO PAT I ENTS
200
(JJ
�
z
w
n = 801 patients
1 50
�
cC
a..
u.
0
1 00
a:
w
m
:::E
::)
z
50
10
20
30
40
50
60
70
80
90
AGE (YEARS)
C l i n i c al Eval u at i on
,
Each p at i ent was eval uated by a phys i c i an to excl ude underl y i ng
system i c d i sease before underg o i ng d i etary i nvest i gat i on ( G i bson
Cl ancy, 1 980) .
C l - estera s e
&
Rare pat i ents found to h ave u rt i c ar i a l vascul i t i s or
i n h i b i tor
defi c i ency
we re
man aged
w i th
appropr i ate
62
med i c a 1 therapy , and those wi t h atyp i c a 1 symptoms were referred to
the
dermato l og i s t
attend i ng
t he
cl i n i c
for
further
eval u at i on .
I nd i v i d u a l s w i t h a h i s tory o f a s t hma underwen t res p i ratory a s s e s s ment
befo re taki ng any c h a 1 1 enges , wh i ch were admi n i s te red under appro
p r i ate med i cal
s u perv i s i on ( depend i ng on t he i r degree o f bronc h i al
hype r - react i v i ty ) .
Pat i ent s
wi th
a
h i s t o ry
of
l aryngeal
oedema
and/or sys tem i c an aphyl ax i s were rou t i ne l y adm i t ted t o h o s p i ta l for
c h al l enge .
F I GURE 3 . 2
H I STOG RAM O F THE DURAT I ON OF R I U /AO
400
en
Iz
w
n
=
80 1
patients
( 67% of urticaria population )
300
i=
<
Q.
U.
0
200
a:
w
ca
�
::J
z
1 00
<
1
1 -5
5- 10 10 - 15 15-20
DURATION (YEARS)
> 20
63
Der i v at i on o f the El i mi n at i on D i et
As out 1 i n ed i n C h apter 1 ,
excl ude food
R I U/AO .
the e 1 i mi n at i on d i et was devel oped to
add i t i ve s and n atural
The Pure Food Act ( 1 908 ,
s a1 i cy1 ate s
i n p at i ents
wi th
1 93 7 ) and i ng red i en t l abel l i ng
( N a t i o n a 1 Heal t h and Med i ca 1 Research Counc i 1 , [ NH&MRC ] , 1 986 ) were
u s ed to determ i ne those foods conta i n i ng art i fi c i a 1 col ouri ngs and
pre s ervat i ves ( Br i gg s & Wahl qu i st , 1 985 ;
H a n s s en & Marsden , 1 986 ) .
I n the c a s e s where l abel l i ng was l i m i ted ,
ascert a i ned .
i ndustry pract i ce was
For exampl e , pasta ; s general l y col oured w i th carotene ,
a n atural vegetabl e extract but some brands may be col oured w i t h one
or more perm i t ted art i fi c i a 1
cl i n i cal
observat i on s
th at
col ours .
i ndustri al
I t soon became cl e a r from
pract i ce
did
not
al ways
correspond to t h e l egal requ i rements , and when s u s p i c i o n fel l upon a
part i cul ar product i nformat i on was obta i ned from the Food Technol og
i st concerned , or from Mr . B i l l Porter at the NSW Heal th C omm i s s i on .
I n the e arl y stages d a i ry products were exc1 uded because o f t he i r
pos s i bl e
contam i n at i on
w i th
pen i c i l l i n ,
and
bread
was
excl uded
because yeasts h ad been i mpl i cated as a cause o f R I U/AO by Hol t ;
( 1 966 & 1 967 ) and J ame s and War i n ( 1 9 7 1 ) .
By l ate 1 980· c l i n i cal
observat i on s i nd i cated the n eed for a rev i s i on o f the e l i mi n at i on
d i et .
D a i ry products , egg s , and unpre served bread rare l y i f ever
proved to be a s i gn i fi cant probl em for pat i ents once the correct
prec i p i tants were i dent i fi ed , and were therefo re re - i ntroduced i nto
the basel i ne d i et , maki ng i t much more pal atabl e .
At the beg i n n i ng
of 1 982 , and ag a i n i n e arl y 1 983 , l aboratory anal yses o f food sal i cy 1 ate content ( C h apter 2 ) re sul ted i n further mod i fi c a t i on s of the
d i et as s h own i n Tabl e 3 . 1 .
64
TABL E 3 . 1
MOD I F I CAT IONS OF THE E L I M I NAT I ON D I ET
T i me Peri ods *
Foods
I
11
III
Pear ski n
Pepper
+
+
+
+
+
+
Carrot s
+
+
Honey
+
Coffee ( certa i n brands )
+
*
=
+
i ncl uded ;
IV
+
+
-
=
excl uded
Ti me peri ods :
I.
Apri l 1 977 to January 1 979 .
11 .
January 1 979 to Janu ary 1 982 .
Ill.
January 1 982 to January 1 983 .
IV.
J anuary 1 983 to J anuary 1 986 .
The el i mi n at i on d i et wh i ch fi nal l y devel oped was a useful tool i n the
management of pat i ents wi th RI U/AO and contai ned adequ ate prote i n ,
fat and carbohydrate prov i ded that the d i etary recommendat i on s were
fo 1 1 owed ( NH&MRC , 1 986 ) .
However , the 1 eve 1 of ascorbi c ac i d was
part i cul arl y l ow because of the re stri cted range
of fru i t s
and
vegetabl es so the use of an unco1 oured , unf1 avoured mul t i v i t am i n was
adv i sed ( Myadec by Parke Dav i s , Mul t i v i t S i x by G1 axo , E1 ev i t RD I by
Roche ) .
65
Al l acetyl s al i cyl i c ac i d - based med i cat i on s ( D i s p i ri n , Al ka - se l tzer ,
As p i r i n and compound an al ges i cs ) were proh i b i ted .
Most fl avour i ng s
u sed i n toothpaste s , cough l ozenge s , fl avoured med i c at i o n s a n d syrups
conta i n s al i cyl ate and s o
Products
conta i n i ng
oi l
s u i t abl e al tern at i ve s were pre s cr i bed .
of wi n tergreen
( Decoru b ,
Deep
Heat ) ,
a
conce ntrated source o f methyl sal i cyl ate , were forb i dden a s were s ome
perfumes u sed to scent many to i l etr i e s because t h ey conta i n amyl and
ben zy l
sal i cyl ate
( More1 ,
1 95 1 ;
Bedou k i an ,
1 98 1 ;
Tod a et
al . ,
1 983 ) .
Medi cat i o n s wh i ch were al l owed i ncl uded uncol oured ant i h i stam i n e s and
other u n co l oured med i cat i on s w h i ch d i d not conta i n acetyl s a 1 i cyl i c
ac i d , met hyl sal i cyl ate or t he i r an al ogue s .
Wi t h other drug s ,
if
s u i tabl e wh i te med i c at i on s were not ava i l abl e and therapy coul d not
be i nterrupted ,
pat i ents were
i n stru cted to was h the
art i fi c i al
col our i n g o ff t h e s urface by rubb i ng gentl y under runn i ng water .
Capsul e s coul d be opened i f neces s ary ,
and t h e powdered content s
taken , d i scard i ng t h e col oured gel at i ne capsul e .
Pat i ent I n struct i on a bout the El i m i n at i on D i et
Fol l ow i ng con fi rmat i on o f a d i agnos i s o f R I U/AO e ach pat i ent was
i nterv i ewed by the d i et i t i an and a deta i l ed food h i story t a ke n .
At
th i s i nterv i ew t h e e l i mi n at i on d i et programme was d i scus s ed w i t h both
�t
the pat i ent and t h e person re spon s i b 1 e for prepa r i ng meal s .
�
author was re spon s i bl e for the proj ect and tra i n ed G abr i e l l e Boyd and
.r
The
Jenny McQueen to as s i st i n the di etet i c man agement of the R I U/AO
pati ents .
G abri el l e Boyd as s i sted from Apri l 1 983 to Febru ary 1 984
and Jenny McQueen from Apri l 1 984 to September 1 986 .
66
Pat i ents were gi ven i n format i on about t he food s ources of n atural
sa 1 i cyl ate ( Swa i n et al . ,
1 985 ) , benzoate ,
brewers yeas t and the
art i fi c i al col ours and preservat i ve s ( NH&MRC , 1 986 ) .
Th i s g ave e ach ·
pat i en t a perspect i ve as to the pos s i bl e d i etary prec i p i tan t s of
t he i r symptoms of R I U/AO .
The i mportance of compl i ance was stre s s ed ,
emphas i z i ng t h at onl y those foods l i sted were t o be eaten , a s d i etary
i nfract i on s coul d l ead t o recurrence of sympt oms and fal s e pos i t i ve
or confus i ng chal l enge resul ts .
Deta i l ed i nstruct i on s and expl anat
i ons were g i ven about wh i ch foods to eat and wh i ch foods to avo i d ,
al ong w i t h the reasons for each i n c 1 u s i o n and exc 1 u s i o n o f food on
t he d i et .
Pat i ents were warned t h at thei r atten t i on to deta i l was
cri t i cal to t he succe s s o f the programme .
Pract i cal adv i ce on s hopp i ng , food p reparat i on and h ow to vary the
d i et was g i ven , as wel l as a l i st of rec i pe s for preparat i on of
pal atabl e meal s .
The man agement of restr i ct i on s t o l i fe s tyl e were
al s o deal t w i t h .
Deta i l ed adv i ce was g i ven a bout l unches and s n ac ks ,
takeaway food , e at i ng out at restaurant s , d i nner part i e s and other
s oc i al occas i on s (wedd i ngs , part i es , sport i ng even t s ) al l o f wh i ch
prov i ded
pract i cal
i n format i on
compl i ance and confi dence .
wh i ch
was
cri t i cal
for
pat i ent
At the s ame t i me pat i ents were adv i s ed
about v i tam i n s uppl ements , med i cat i on s , cosmet i cs and t o i l et r i e s .
Frequent rev i ew of the pat i ents ' progres s over t h e tel ephone was
often nece s s ary for encouragement duri ng the earl y stage s of the
programme , cl ari fi cat i on of d i etary i nstruct i on s , pract i cal
adv i:ce
a bout day to day probl ems , and wh at to do about exacerbat i cn s o f
t he i r symptoms .
O n average e a c h pat i ent woul d ma ke contact w i th t h e
author a t 1 e a s t once p e r wee k over t he t i me t h at they were on the
el i mi n at i on d i et .
67
Pat i en t s who
exper i en ced marked
reduct i on or
compl ete rel i ef of
sympt oms for fi ve con s ecut i ve d ays a fter a m i n i mi um o f two wee ks o n
t h e e l i m i n at i on d i et tel ephoned the d i et i t i an for t he i r c h a l l enge
cap s u l e s ( see bel ow) wh i ch were sent by ma i l .
of
l aryngeal
chal l enges
oedema ,
a naphyl ax i s
i n g raded doses
or
Those w i t h a h i story
asthma
were
g i ven
under appropri ate med i c a l
t he i r
s uperv i s i on
(Append i x 5 ) .
I f t here was n o s i gn i fi cant i mpro vement after two wee ks , the d i et was
d i scus sed over the tel ephone to ens ure t h at the i n st ruct i on s h ad been
understood , and to check c omp 1 i ance .
Tho s e pat i ents who s h owed n o
i mpro vement a fter s i x weeks on t h e e l i mi n at i o n d i et were a s ked to
return for rev i ew by the phys i c i an .
I n s ome cases further restr i ct
i on o f wheat and m i l k p roducts was s ucce s s ful , but i n t h e maj o r i ty a
normal d i et was re s umed al ong w i th ant i h i stam i n e t herapy a s requ i red .
Pat i ents who coul d not compl y w i th t h e el i mi n at i on d i et for s oc i a l ,
fami l y or other rea s o n s d i d not u nderg o c h a l l enge , and were t re ated
symptomat i ca l l y .
·i
. 4
Chal l enges
The battery o f test s ubstances compri sed those c ompounds rep orted as
maj or prec i p i t an t s o f R I U/AO by War i n and Smi t h ( 1 9 7 6 ) and s od i um
metabi s u l ph i te wh i ch
i s wi del y u s ed
i n d r i n ks ,
l i qu i d
and mo i st
cons i stency foods and s ome d r i ed fru i t s ( NH&MRC , 1 986 ) .
C h al l enge
sets were i n i t i al l y prepared by the Pharmacy Department at RPAH a nd
1 ater by t h e author An ne Ruth Swa i n
(Append i x
3)
were
suppl i ed
by
Se ar1 e
(ARS ) .
( Aj ax
The test s ubstan ce s
chem i cal s )
a nd
SOH
68
( Br i t i s h Drug House chem i cal s )
capsu l e s
s uppl i ed
by
Parke
and encap s u l ated i n c l e ar g e l at i ne
Dav i s .
F i l l ed
separatel y i nto n umbered pl ast i c v i al s
capsu l e s
( Mel ewi s h ) .
were
p a c ked
Betwee n Apr i l
1 97 7 and J an uary 1 983 t he c h a 1 1 enge compounds were n umbered i n a
standard sequence , and t hereafter t hey were pac kaged i n an arbi tary
order wh i ch vari ed from one set to the n ext .
The c h al l enge c omp ound s
u sed h av e an i ndefi n i te s he l f- 1 i fe when s to red i n a cool d ry p l ace
and i t was there fore p o s s i bl e to prepare t hem i n batches of 200 sets
at a t i me .
The chal l enge set was upd ated at i nterval s a s s h own i n Tabl e 3 . 2 . The
i n i t i al c h al l enge set o f compounds based on War i n and Smi t h ( 1 97 6 )
was mod i fi ed to excl ude pen i c i l l i n after i t was found t hat t h i s was
not
detectabl e
in
Austral i an
d a i ry
prod uc t s
u n l i ke l y t o be of cl i n i cal s i gn i fi cance .
and
was
there fore
The c h a l l e n ge battery was
al s o expanded to i ncl ude s od i um sal i cyl ate and s od i um met a b i su1 p h i te .
Sod i um sal i cyl ate was added for c ompar i s on w i t h a s p i r i n , wh i l e sod i um
meta b i s u 1 p h i te was added as i t i s w i del y u s ed as a pre s ervat i ve i n
s i mi l ar foods to benzoate s .
uncol oured
chal l enge ,
I n i t i al l y t h e o n l y p l acebo was a s i ng l e
l actose ,
but
in
J a n uary
1 97 9
a
col oured
pl acebo , B c arotene , was added to t h e c h a l l enges as a control for the
yel l ow t artraz i ne cap s u l e .
In J an uary 1 982 t h e d o s e of t artraz i ne
was i ncreased from 1 0mg to 3 0mg , wh i ch i s equ i 1 avent to the amount of .
azo dye i n on e food i tem , for exampl e o n e I cey Pol e ( NH&MRC , 1 9 86 ) .
Twe l ve mont h s l ater t h e protocol was made d o u bl e bl i nd by n umberi ng
t h e chal l enges i n an arb i t ary sequence , and at t h e s ame t i me s tarch
was s ubst i t uted for the 1 actose pl acebo .
I n the 1 ate 1 983 i t was
n oted t h at a n ew batch of B carotene obta i n ed from a d i fferent
69
s uppl i er h ad
a very
s trong smel l
o f carrot s ;
thi s
appeared t o
c o i nc i de wi t h a s udden i ncrease i n the react i on rate to t h i s s econd
" pl acebo " ( Ta bl e 3 . 8 ) and i t was there fore omi tted from the c h a l l enge
battery i n May 1 984 .
TABL E 3 . 2
D EVELOPMENT O F THE CHA L L ENGE PROTOCOL
Dates
Mod i fi cat i o n s to C h al l enge Protocol *
J an uary 1 97 9
Add i t i on o f s od i um s al i cyl ate ( A&B d o s es ) , s od i um
meta b i sul ph i te , c arotene
J an u ary 1 98 1
Om i s sj on o f pen i c i l l i n
J a n uary 1 982
I nc re a se tartraz i ne dose t o 3 0mg
J a n uary 1 983
Random i zed s equen ce , doubl e bl i nd protocol
Subst i tut i on of st arch for l actose as a p l ace bo
S i ng l e dose ( 300mg ) for bot h asp i r i n and s od i um
s al i cyl ate
May
1 984
Omi s s i on of carotene
* From Apr i l 1 9 77 t o January 1 97 9 the chal l enge protocol c on s i s ted
of l actose , t artraz i ne , sod i um benzoate , 4 - 0H benzo i c ac i d ,
b rewers yeast , pen i c i l l i n , asp i r i n .
The c h a l l enge doses for the fo ur c h al l enge per i ods are s h own bel ow
( Tabl e 3 . 3 ) .
70
TABLE 3 . 3
CHALLENGE DOSE ( MG)
Cha l l enge Compounds
Lactose 2
B Carotene & lactose3
Tartraz i ne4
Sod i um benzoate
4 -0H be nzo i c ac id
Brewers yeast 5
Pen ic i l l i n 6
Acety l s a l i cyl i c ac i d7
Sod i um sa l i cy late 7
Sod i um metab i su lph i te 8
Starch & B carotene
1.
T ime per i ods :
I.
11.
I ll .
IV.
2.
3.
4.
5.
6.
7.
S.
9.
I
II
III
700
700
10
500
200
600
250
450
700
700
10
500
200
600
700
700
30
500
200
600
450
450
500
300
300
500
7 00
30
500
2 00
600
3 00
300
5 00
7 00
Apr i l 1 977 to January 1979 .
January 1 979 to January 1 982 .
Jan uary 1 982 to January 1 983 .
January 1 983 t o January 1 986 .
Lactose p lacebo rep laced by starch p l acebo .
B carotene p l acebo f i l l er changed from lactose to starch .
Cha l lenge f i na l ly om i tted because of contam i nated source .
Tartraz i ne dose i ncreased from lOmg to 30mg i n Jan ' 82 ,
equ i va l ent to one co l ou red food i tem .
B rewer ' s yeast was made by Cenov i s Hea l th Company Pty . Ltd .
Pen i c i l l i n de leted as not a s ign i f i cant amount i n m i l k .
Compa r i son between sod i um sa l icy l ate and acetyl sa l i cy l i c
ac i d , g i ven i n two doses 150mg f i rst , then 300mg two hours
l ater if no react i on . Changed to s i ng l e dose of 300mg i n
doub l e b l i nd set .
Add it i on of sod i um metab i su lph i te , a w i de ly used
preservat i ve .
S i ngle b l i nd cha l lenge order changed to double b l i nd Jan ' S3
onwards .
71
C h a l l e nge I n struct i o n s
C h al l enges were c ommenced a fter a t l east two wee ks o n t h e e l i mi n at i on
d i et , o n ce t here h ad been f i ve con secut i ve d ay s fre e o f symptoms .
N umbered caps u l e s were t a ke n i n t h e morn i ng h al f a n hour be fore or
two hours a fter bre a kfast ( fo r c h i l dren the c ap s u l e contents were
m i xed w i t h g o l den syrup i f t h ey were unabl e to swal l ow the c ap s u l e s ) .
Cha 1 1 enges were spaced by at 1 east
48
hours t o a l l ow for del ayed
react i on s , and any re s po n s e to chal l enge was fol l owed by a pause of a
furt he r t h re e symptom- free d ays befo re p roceed i ng to t he n ext chal l
enge , s i nce pat i ents o ften experi ence a temporary refractory per i od
d ur i n g
wh i ch
t h ey
are
unre sp on s i ve
to
further
c h al l e ng e .
Each
pat i e n t was prov i ded w i t h d i ary s heets and recorded i n deta i l t h e
t i me e a c h c h a l l e n g e was t a ken , a n d i f a react i on occurred t h e t i me o f
onset , type and severi ty o f sympt oms and t h e i r d urat i on .
Cha 1 1 enges were t a ken
at h ome except
i n pat i ents w i th
1 a ryngea 1
oedema and asthma for whom c h a l l e nges of acetyl s al i cy l i c ac i d , s od i um
metab i s u l p h i te and t artraz i ne were s uperv i s ed .
Pat i e n t s wi th very
m i l d a s t hma were s uperv i s ed by t he i r l ocal general pract i on e r .
Those
wi t h m i l d - moderate asthma were c h al l enged under s up e rv i s i on at the
Al l e rgy C l i n i c , pat i en t s w i t h s evere a s t hma and l aryng e al oedema were
admi tted ; nto h o s p ; tal
for c h a 1 1 enge w i th g raded d o s e s of acetyl
sal i cyl i c ac i d , s od i um meta b i s u l ph i te and t artraz i ne ( Append i x 5 ) .
72
Symptom D i ary
Pat i en t s were g i ven a d i ary and i n structed to kee p a d et a i l ed record
o f ( a ) al l food and beverages con s umed , ( b ) t h e type and d urat i on of
al l symptoms exper i enced , ( c ) det a i l s of al l food and c ap s u l e c h a l l
enges take n , and ( d ) the dose and type o f med i c at i o n s t a ke n when
n ece s s ary .
F I GURE 3 . 3
SAMPLE PAT I ENT SYMPTOM D I ARY
BREAKFAST
M I D MORN I NG
D I ETARY I NTAKE FOR :
DAY :
DATE :
2 Weetb i x
mi l k,
coffee
2 coffee
b i scu i ts
coffee
SYMPTOMS :
{ Type & Sever i ty }
h i ves on legs
and buttock s ,
swe 1 1 i ng around
eyes
MEDI CATI ONS AND/OR
CHALLENGES TAKEN :
( T ime taken , react i on
t ime and s)111ptans )
1 bo i l ed egg
2 bread
coffee
M I D AFTERNOON
coffee
TEA
EVENI NG
roast l amb
2 coffee
potato , lettuce b i scu i ts
c us tard , pear
coffee
h i ves on l egs
and buttocks
swe l l i ng around
eyes
none
D I ETARY I NTAKE FOR :
DAY :
DATE :
pear
2 toast
go l den syrup
coffee
SYMPTOMS :
( Type & Seve r i ty )
h i ves on legs
and b uttocks
eas i ng , swe l l i ng
s ubs i d i ng around
eyes
MED I CATI ONS AND/ OR
CHALLENGES TAKEN :
( T ime taken . react i on
t ime and symptans )
LUNCH
1 c h i cken
sandw i c h
pear
2 coffee
b i scu i ts
coffee
2 c hops
potatoes
pear
h i ves on legs
eas i ng , s l i ght
swe 1 1 i ng around
eyes
2 coffee
b i scu i ts
coffee
73
I n terpret a t i on o f Chal l enge React i on s
C h a l l enges were i n i t i al l y g i ven s i ng l e - bl i nd as a n umbered s equence ,
but by t h e end o f 1 98 2 both t he phys i c i an s and t h e d i et i t i an s h ad
become s o fami l i ar wi t h t h e st andard sequence t h at there was a d anger
of b i ased
i nterpretat i on wi t h
s ubtl e react i o n s .
Accord i ng l y ,
in
J an u ary 1 98 3 t h e protocol wa s made doubl e - bl i nd , wi t h t he c h a l l enge
s u bstances be i ng n umbered i n an arb i tary order for each pat i ent .
After c omp 1 et i on o f cha 1 1 enges pat i ents we re s een by the d i et i t i an
who rev i ewed t h e i r d i ary and recorded the re s u l t s .
The two other
d i et i t i an s , Gabri el l e Boyd and Jenny McQ ueen , were t ra i n ed for n i ne
to twe l ve mon t h s by the author i n order to e n s ure u n i formi ty of
i nterpretat i on .
recurrence
of
A c h a l l enge was con s i dered po s i t i ve i f there was a
u rt i cari a
and/or
ang i oedema w i th i n
react i on s were a l most al ways cl ear - c ut .
observed :
48
h ours ,
and
Th ree patterns were common l y
acute , i ntermed i ate and del ayed a s descri bed bel ow i n the
res u l ts s ect i on .
I f the res pon se to any c h a l l enge wa s uncert a i n i t wa s repeated as a
caps u l e or t h re e - d ay open food chal l enge (Append i x 6 ) .
Th i s meth od
al so prov i ded a check when chal l enges we re t a ke n too q u i c kl y i n
succes s i on d ue to the eagernes s o f the pat i ent to compl ete t h e tests .
Under
these
c i rcumstances
overl ap
of
c h a l l enges
c ou l d
l ead
to
con fus i o n a bo u t wh i ch one was respons i bl e for a part i c u l ar react i on ,
it:
or conve rs e l y a fal se negat i ve coul d be recorded i f the s ubsquent
chal l enge wa s t a ken duri ng t h e refractory peri od .
74
Fol l owi ng compl et i on of the prot ocol a mod i f i ed t herapeut i c d i et was
pre scri bed based on t h e f i nal assessment , and a fol l ow- up appo i ntment
made t o rev i ew progre s s s i x weeks l ater .
I n t h i s way c are was taken
t h at pat i ents were not over or under - restri cted because o f m i s l ead
i ng resul t s .
Long Term D i etary Management
After s i x wee ks , gradual 1 i bera1 i zat i on of the therapeut i c d i et by
food chem i cal groups was encouraged i n an attempt to i nduce tol erance
by ra i s i ng
t h e thres hol d
for tri ggeri n g
Pat i ents sens i t i ve to n atura 1
sympt oms
( Append i x
1 0) .
s al i cyl ates were t he n encouraged to
1 i beral i ze t he i r d i et by t a k i ng very smal l
amounts o f the foods
conta i n i ng moderate amoun t s of sal i cyl ate every th i rd day for two
weeks and then
i f there was n o adverse react i on
i ncreas i ng the
frequency to every second day for two wee ks and t hen t o every day .
I f t here was st i l l n o adverse react i on t h e pat i ent was encouraged to
i ncrease the amount
react i on s .
as tol erated prov i ded there were n o adverse
In pat i ents wi th a mi 1 d degree of s e n s i t i v i ty i t was
s omet i mes poss i bl e to return eventual l y to a v i rtual l y normal d i et
w i thout rel apse .
Re - Chal l enge of R I U/AO Pat i ents
I n order to test the reproduc i b i l i ty o f the chal l eng e protocol , 1 42
pat i ents w i t h R I U/AO who h ad compl eted the el i mi n at i on d i et
chal l enge protocol
at
l east 1 2 months
before ,
and
were contacted by
tel ephone and as ked i f they woul d be prepared to repeat test i ng w i th
the cha 1 1 enges .
Those who agreed , prov i ded they h ad been free of
symptoms , were ma i l ed a second set of chal l enges wh i ch we re s ent out
75
i n b atches every t h ree to s i x mont h s between October 1 978 and May
1 98 1 .
The re - c h a l l e n ge c ompound s and t he i r d o s ag e s are as outl i n ed
i n Tabl e 3 . 4 .
Pat i ents were as ked to ma i nt a i n a s t r i ct excl u s i on
d i et d ur i n g t h e re - chal l enge peri od .
TAB L E 3 . 4
C HALL ENGE BATTERY FOR R E - C HAL L ENG E O F R I U/AO PAT I ENTS
C ha l l enge
Dos e
Asp i r i n & s od i um s a l i cyl ate
300mg & 3 00mg
S od i um benzoate & 4 - 0H benzo i c ac i d
500mg & 200mg
Sod i um met ab i s u l p h i te
500mg
Tartraz i ne
1 0mg
Brewers yeast
6 0 0mg
L acto s e
700mg
Record s a n d Stat i s t i cal An al ys i s
For each p at i ent underg o i ng d i etary i nvest i gat i o n a f i l e was created
compr i s i ng cl i n i cal
chal l enge
react i o n s .
det a i l s ,
d i etary
For
698
the
h i story ,
pat i ents
progre s s
wh o
n otes
underwent
and
bl i nd
chal l enges , re s ul t s were t abul ated i n s ummary form o n a s pread s heet
76
wh i ch was upd ated at reg u l ar i nterv a 1 s , and u s ed as the bas i s for
s ubsquent stat i st i c a 1
anal ys i s .
Oeta i 1 s o f d at e of p re sen t at i on ,
age , s ex , d urat i on and n ature o f symptoms ( urt i cari a , ang i oedema or
both ) , and chal l enge res u l ts were entered i nto a VAX 8600 computer ,
u s i ng fi 1 es created s o as to be comp at i b 1 e w i th the Stat i st i ca 1
Pac kage for Soc i al Sc i ence s , Vers i on ten ( S PSS - X ) .
Unl e s s otherw i se
st ated , t h i s program pac kage was u sed for al l stat i s t i cal anal yses .
( a ) 95% Conf i dence I nterval s
The proport i on ( p ) of pat i ents react i ng to each o f the c h a 1 1 e nge
compound s was t abul ated , and 9 5% con f i den ce i nterval s cal c u l ated as
fol l ows :
By t h e Cent ral L i mi t Theorem ( Sach s , 1 984 ) t h e n umber o f p at i ents
tested ( n=6 1 4 ) was s u ffi c i entl y l arge to j u st i fy a s s um i n g that the
proport i on i n e ach case was normal l y d i stri but ed .
( b ) McNemar ' s Test
Si nce e ach pat i ent was te sted wi th mul t ; p 1 e cha 1 1 enge s ubstance s ,
re act i on s tOJ
wh i ch
may n ot be compl etel y i ndependent , t he overa 1 1
re s u l t s for e ach compound compared w i t h p l acebo were analysed by
McNemar ' s test ( 1 947 ) .
Th i s test compares t h e frequency o f po s i t i ve
and negat i ve re act i on s to each chal l enge , w i t h t ho s e to t h e p l acebo ,
77
t he n u 1 1 hypoth e s i s b e i ng t h at t h e frequenc i e s d i ffer n o more t h an
expected by c h ance :
Pl acebo
+
Act i ve
+
a
b
C h al l enge
-
c
d
The freq ue n c i e s b and c are t h u s expected to h ave t h e s ame val ue as
O . S ( b+c ) ;
1
the more b and c dev i ate from t h i s expected v a l ue , the
ess confi d ence can be p l aced i n t h e stated n u l l
hypoth e s i s .
The
s i gn i f i c an ce of a d i fference betwee n these v a l ues was determ i n ed by
cal c u l at i ng
Ch i - square
by
McNemar ' s
formul a
and
con s u l t i n g
a
C h i - sq u are t abl e wh i l e a s s um i ng one degree o f freed om :
C h i - squ are
=
( b - c lZ
b+c+ l
S i n ce t h e n umber of p at i e n t s t e s te d was i n a l l i n s tances more t han
30 , the correct i on o f Bennett and Underwood ( 1 970 ) was not requ i red .
( c ) Bon Ferron i Correct i on
For a s i ng l e compa ri so n between act i ve and p l acebo c h a l l e ng e s a P
val ue
of
mu1 t i p 1 e
<0 . 05
wou l d
be
con s i d ered
s i gn i f i cant .
Howeve r ,
wi th
c h a 1 1 enges per p at i ent the probabi 1 i ty of ach i e v i ng th i s
val ue by c hance i nc re a s e s w i t h each compa r i s on , and t h e s i gn i fi cance
l eve l must be adj u s ted accord i ng l y .
The Bon F e rron i met h od sets a
78
s i gn i f i c an c e 1 eve 1
c ompari s on s .
o f P <0 . O S/N , where N refers t o the n umber of
In the present c a s e , N=7
ch�l l en ge s )
and
the
s i gn i fi cance
l evel
( s i n c e t he re a re 7 act i ve
requ i red
is
there fo re
P
<0 . 00 7 .
( d ) C h i - Square Test ( Co nt i ngency Tabl e )
S i n ce
the
e l i mi n at i on
d i et
and c h a l l enge
protocol
were mod i fi ed
d u r i n g t h e course o f t h e present st udy , t h e re s u l t s were a n a l ysed
s e p aratel y for e ach o f four t i me per i od s ( Tabl e 3 . 8) .
react i on
frequency for each
Changes i n
c h al l enge s u b s t an c e were a n a l y s ed
con struct i ng cont i ngency t ab l e s
to
compare
o b se rved
and
expected
val ues ( Sach s , 1 984 ) :
Observed val u e s
Expected val u e s
t ime per i ods
t ime per i ods
I
II
III
IV
tota l
+ ye
a
d
9
j
x
+ ve
- ye
b
e
h
k
y
- ye
tota l
c
f
II
III
IV
ex
z
fx
z
ix
z
lx
z
ey
z
fy
z
iy
z
ly
z
z
The C h i - s q u are val ue was t h en cal c u l ated a s fol l ows :
Ch i - s q u are
=
t ( o b s erved v a l ue - expected val u e ) 2
expected val u e
by
79
( e ) C h i -Square Te s t ( Goodne s s -Of- F i t )
I n those pat i ents who were re - c h al l e nged t h e res ul t s were tabul ated
accord i ng to whether each c h al l enge p roduced t h e s ame response o r a
d i fferent response o n
re -test i ng .
To determ i n e whether t h e s ampl e o f
7 7 p a t i e n t s w h o were re - c h a 1 1 enged was a representat i ve one , a 2*2
cont i ngency tabl e was con structed compari n g the i n i t i al res ul t s for
e ac h cha 1 1 enge i n the s ampl e ( " observed " ) w i t h those o f t h e whol e
R IU/AO group tested duri ng the s ame t i me per i od ( " expected " ) :
The
C h i - square
+ ve
- ve
observed
a
b
expected
c
d
goodne s s - o f- fi t
stat i st i c
was
then
determ i ned
as
fol l ows :
Ch i - square
•
� ( observed val ues - expected va1 ues ) 2
=
{ a- c ) 2 + ( b- d ) 2
c
expected v al ues
d
P val ues were deri ved from t abl e s o f t h e d i stri but i on of the C h i Square s t at i st i c , wi t h one d egree o f freedom .
For each pat i ent i n whom t h e c h a 1 1 enges were repeated , t h e res u l t s
were tabu1 ated accord i n g t o whether t h e response to e ac h c h a1 l enge
s U b s t an ce wa s pos i t i ve or negat i ve on
poss i bl e categori es :
both occas i on s ,
+/+ , +/ - , -/+ , and -/ - .
was t h at t h e cha 1 1 enge fi nd i ngs
wi th
four
The n u l l hypo t he s i s
i n each c a s e were d ue t o c h ance
,e'
80
a l on e .
in
Expected proport i on s were ca 1 cul ated from t h e known fi gures
R IU/AO pat i ents
as
a who l e ,
a s s um i ng
the
s ame
frequency of
p os i t i ve and negat i ve react i on s to occur at random i n both the fi rst
and second chal l enge seri e s .
The observed res u l t s were c ompared wi th
t h o s e " expected " by con st ruct i ng a 2*4 cont i ngency t abl e :
+/+
+/ -
-/+
+/+
observed
a
b
c
d
expected
e
f
g
h
and i n e ach case , C h i - square was cal cul ated a s fol l ows :
C h i - square
=
� ( ob s e rved - expected ) 2
expected
P val ues were deri ved from C h i - square t abl e s , w i t h t h re e degrees of
freedom .
( e ) Newman - Keu l s Test
To determ i n e whether there was a tendency for react i on s to c l u s ter
wi t h part i cul ar chal l enge compound s , the react i on frequ e nc i e s were
ranked and compari sons made between al l p a i rs u s i ng - th e c r i teri o n of
t h e l east s i gn i fi cant d i fference .
W i th mul t i pl e c omp a r i s on s ,
the
p robab i l i ty of fi nd i ng " s i gn i fi cant " d i ffe rences by c h an c e i nc re a s es ,
and the Newman - Keul s met h od was u s ed to avo i d d raw i n g erro n eo u s
concl u s i o n s ( Snedecor & Cochran e , 1 96 7 , p ages 233 - 23 7 ) .
!
The anal y s i s
was performed by Assoc i ate Pro fe s s o r R . Berry ( Commonwe a l t h I n s t i tute
o f Heal t h ,
Un i vers i ty of Sydney )
wri tten for the purpos e .
u s i ng
his
own
Fortran
p rogram
�j
e�
81
R ESU LTS
Of t h e 1 349 pat i ents ,
1 1 93 were prescri bed the el i mi n at i on d i et .
Remi s s i on o f symptoms was experi en ced by 698 pat i ents ( 58 . 5%) who
were s ubsequent l y cha 1 1 enged .
No
i mprovement was report ed i n 80
p at i ents ( 6 . 7%) and 4 1 5 . ( 3 4 . 8%) pat i ents d i d not pers i st w i t h t h e
e l i mi n at i on d i et ( Tabl e 3 . 5 ) .
The rema i n i ng 1 56 pat i ents were g i ven a " l ow c h em i cal d i et "
sal i cyl ate ,
l ow preservat i ve ,
l ow art i fi c i al
col our ,
( l ow
l ow brewer ' s
yeas t , ( Append i x 8 ) as i t was fel t t h at they wou l d be unabl e to cope
w i t h the very r i g i d d i etary re stri ct i ons and chal l enge procedure .
The l ow c h emi cal d i et res tri cted on l y t h e commonest food chem i cal
prec i p i t ants o f R I U/AO , resul t i ng i n a l es s r i g i d d i et .
Pat i ents who responded favourabl y to t h e e l i mi n at i on d i et general l y
became a symptomat i c w i t h i n one t o two wee ks .
The maj or i ty o f those
on reg u l ar an t i h i stam i nes were abl e to w i thdraw med i c at i on by t h e end
of t h e f i rst wee k wi thout exper i enc i ng an exacerbat i on , but s omet i mes
res i d u al
symptoms wou l d requ i re a few more d ays to s u bs i de .
The
chal l enges were on l y undertaken when the pat i ent h ad been free o f al l
symptoms , o ff al l ant i h i stam i nes , for at l e ast f i ve con secut i ve days ,
and a fter a m i n i mum o f two wee ks on the e l i mi n at i on d i et .
82
TAB L E 3 . 5
D I ETARY RESULTS O F R I U/AO PAT I ENTS ON THE E L I M I NATI ON D I ET
D i etary Resul t s
N umber o f Pat i en t s
Improvement
698
80
No i mprovement
F a i l ed t o compl ete
415
" Low chem i cal " d i et 1
1 56
Total
1.
1 349
" Low chem i cal " d i et
=
l ow s al i cyl ate , preservat i ve ,
art i fi c i al , col our , brewers yeast d i et .
Chal l enge Resul t s
Chal l enge react i on s general l y fol l owed t h ree pattern s :
h al f t o two hours , durat i on one to two hours ) ;
fi ve to e i ght hours , durat i on up to 24 hours ) ;
acute ( onset
i ntermed i ate ( on set
del ayed ( on s et 2 4 - 48
hours , d urat i on two or three days up to a wee k or more ) .
enge resul t s �re presen ted i n Tabl e 3 . 6 .
The chal l
The percen t age of pat i ents
react i ng to each of the act i ve cha 1 1 enge compounds c ompared wi th
p l acebo was anal ysed u s i ng McNemar ' s test , s i nce each i nd i v i dual was
s ubj ected
to
mul t i pl e
chal l enges .
Even
al l ow i ng
for
mul t i pl e
test i ng , us i ng the Bon Ferron i techn i que , the re s po n s e t o the e nt i re
set
of
chal l enges
compared
w i th
pl acebo
was
h i gh l y
s i gn i fi cant
83
( P < O . OOO l ) . I f a P - v a l u e of < 0 . 05 i s t a ken a s be i ng the s i gn i fi c ance
1 eve 1
for the n umber o f pat i ents react ; ng t o a
s ub s t an c e compared w i t h p l acebo ,
s ; n g l e c h a 1 1 enge
t he s i gn i fi c ance 1 e v e 1
for s even
s uc h compa r i s o n s i s P < 0 . 007 ( Bo n F e rron i techn i que , Mater i a 1 s and
Met hods ) .
TAB L E 3 . 6
TOTAL C HA L L E N G E RES PONS E O F PAT I ENTS W I TH R I U/AO
( T I M E P E R I ODS I , I I , I I I , I V COMB I NED l )
C h a l l enge Compounds
9 5%
P Val u e
Con f i dence
c ompa red
L i mi t s ( ± )
w i t h L actose
60 . 9
3.9
< . 000 1
Ace ty l s al i cyl i c ac i d
52 . 6
4.0
< . 000 1
S od i um s al i cy l a t e
41 . 4
3.9
< . 000 1
- Be n zo a t e s ( to t a l )
47 . 0
4.0
< . 00 0 1
S od i um benzoate
34 . 1
3.8
< . 00 0 1
40H benzo i c ac i d
32 . 9
3.7
< . 00 0 1
S od i um met ab i s u l p h i te
39 . 2
3.9
< . 000 1
Tart raz i ne
33 . 9
3.7
< . 00 0 1
Brewers yea s t
30 . 3
3.6
< . 000 1
6.8
2.0
% Po s i t i ve
Re s p o n s e
S a l i cy l a t e s ( total )
Lacto s e
1.
T i me per i ods I , I I , I I I , I V comb i n ed
=
Apr i l 1 9 7 7 to J an u ary 1 986
84
In o rder to determ i n e whether t here was a d i fferent p at t e rn of react
i v i ty i n pat i ents wi t h u rt i c a r i a al one vers u s t h o s e � i t h ang i oedema
t h e R I U/AO popul at i on was d i v i ded
i nt o t h re e s u b - g ro u p s
and
the
res ul t s t a b u l ated for e ac h separatel y ( Tabl e 3 . 7 ) .
TABL E 3 . 7
C HAL L ENG E RES PONS ES (%) I N PAT I ENTS PRESENT I NG W I TH
U RT I CAR I A , ANG I O EO EMA O R BOTH
Urt i c a r i a
Ang i oedema
U rt i c ar i a &
Al one
Al one
Ang i oedema
Acetyl s al i cyl i c ac i d
54 . 9
48 . 0
51 . 9
S od i um s al i cyl ate
45 . 1
35 . 6
38 . 0
S od i um benzoate
36 . 9
32 . 3
31 .7
4 - 0H benzo i c ac i d
36 . 0
2 7 .. 1
31 . 9
S od i um meta b i s ul p h i te
45 . 0
31 .3
35. 5
Tart raz i ne
37 . 8
30 . 5
31 .0
Brewers yea s t
32 . 7
29 . 3
28 . 0
6.6
9.1
6.4
C h a l l enge Compound s
Lacto s e
S i nce t h e re were s everal
s i gn i fi cant c h an g e s i n both t h e b a s e l i ne
e l i mi n at i on d i et i t s e l f ( Tabl e 3 . 1 ) and t h e c h a l l enge protocol ( Tabl e
3 . 2 ) , t h e res u l t s were al so t abul ated and a n al y sed s e parat e l y for
e ac h of t h e t i me i nterval s , as outl i n ed i n Tabl e 3 . 8 .
85
3.8
TABLE
PAT I ENTS R EACT I NG TO CHALLENGE I N DI FFER ENT T I ME PER I ODS
Cha l l enge Compounds
T ime Per i ods
I
A 1 1 s a l i cy l ates
59 . 9
51 . 9
39 . 3
46 . 6
33 . 2
31 .9
36. 0
51 . 6
51 . 6
Acety lsa l icyl i c ac i d
Sod i um sa l i cy late
A l l benzoates
31 . 9
20 . 9
23 . 1
Sod i um benzoate
40H
benzo i c ac i d
Sod i um metab i su lphi te
Tartraz ine
27 . 5
16 . 5
3 .3
Brewers yeast
Lactose
l
III
11
IV
71 . 6
54 . 7
56 . 5
54 . 6
38 . 1
43 . 3
45 . 3
46 . 9
41 . 7
7 .3
�9 . 1
28. 6
8.0
(%)
Starch
61 .3
52 . 8
34 . 8
51 . 4
39 . 8
33 . 7
40. 0
36. 7
33 . 5
6.0
12. 0
B Carotene I starch
Tot a l pat i ents
cha l l enged
93
24 1
97
1 83
137
577
311
475
1 . 47
2 . 39
3 . 21
2 . 58
Tot a l react i ons
to cha l lenges
Mean reac t i ons
per pat i en t
P va l ue
1.
< . 0005
< . 00 5
T ime per iods :
I.
11.
Ill .
IV.
Apr i l
1977 to Janua ry 1979 .
1979 to Janua ry 1982 .
Janua ry
Janua ry
January
1982
1983
to January
t o January
1 98 3 .
1 98 6 .
<.1
86
To
d e t e rm i n e
if
t h e re
was
a
s i gn i fi cant
d i ffe rence
between
the
react i o n rate s i n e ac h s uc ce s s i ve t i me p e r i od th e me a n s o f t h e n umbe r
of
react i o n s
T h e re w a s
a
per
p a.t i e n t
c omp a red
us i ng
h i g h 1 y s i g n i f i c ant
i n c re a s e
i n t h e me a n
fo l l ow i n g the c h a n g e s mad e i n J a n u ary
i n J a n u ary
Ch i square
we re
1 982
( Pe r i od I I I )
1 97 9
the
-
react i o n
t h e re fo re
s e n s i t i v i ty
to
s ug g e s t
t�e
rates
( Pe r i od I I ) and t h o s e mad e
I n each c a s e t h e re was an .i n c re a s e i n
.
the s t r i n g e n cy o f s al i cyl ate excl u s i on o n t h e b a s e l i n e d i e t ,
f i nd i ng s
te s t .
that
c h al l e n g e s
th i s
may
h ave
1 ed to a n
i n c re a s ed
Comp a r i s o n s
g e n e ral l y .
and the
b e tween
i nd i v i d u al c h a l l e n g e comp o u n d s ( C h i - s q u are t e s t ) s howed t h at the mo s t
s i gn i fi cant changes (P
was
i n cre a s e d )
and
<0 . 05 )
t o th e
occu rred wi t h t a rt raz i n e ( wh e n t h e d o s e
s al i cyl ate s ,
( corre s pond i ng t o t h e i n c re a s ed
1 983
b e n z o a t e s a n d brewe rs
s a l i cyl a t e
re s t r i c t i o n ) .
In
yeast
J a n u a ry
t h e c h a l l e n g e s we re a l t e red to a d o u bl e bl i nd p rotocol , and th i s
was accomp a n i ed
by a
fal l
i n t h e me an
h oweve r , r e a c h s t at i s t i c a l s i g n i fi c a n c e
react i o n rate wh i c h d i d
(0. 1>
P
>0 . 05 ) .
M E AN NUM B E R OF REAC T I ONS PER PAT I ENT
FIGURE 3. 4
5
4
mean number
of reactions 3
per patient
2
1
I
IT
m
time periods
not ,
87
C ro s s - React i v i ty between C h al l enge S u bstances
There appears t o be con fu s i on i n the l i terature a bo � t the deg ree to
wh i ch a s p i r i n and tartraz i ne may c ro s s - re ac t i n p at i e n t s w i t h R I U/AO
( Steve n s o n et al . , 1 986 ) �
I n o rder to d e f i n e t h i s more c l earl y , d ata
from t h e p resent s tudy was anal y s ed by con s truct i ng a s e r i e s of two
by two c on t i ngency tabl e s o f react i v i ty t o vari o u s p a i rs o f c h al l enge
.
c ompo u n d s .
C ro s s - react i v i ty
was
determ i n ed
by
c a l cul at i ng
the
pro b ab i l i ty o f react i ng to one c h al l enge , g i ven ei t h e r a p o s i t i ve or
negat i ve react i on to the other , a n d the d i fferences were a n al ysed by
a C h i - sq uare te s t ( Tabl e 3 . 9 ) .
Re sul t s are s h own for react i v i ty to
e ach compound accord i n� to whether p at i e n t s were c h al l enge - po s i t i ve
�
"
o r n eg a t i ve t o as p i r i n � l one , s od i um sal i cy l a t e al o n e , o r e i t he r/both
. sal i cyl ate/s (To p panel , Tabl e 3 . 9 ) and a l s o accord i ng to whether
p at i e n t s were pos i t i ve or n e g at i ve to s o d i um benzoat e al o n e , 4 -0H
benzo i c ac i d al one or e i t h e r/bot h benz,oate/ s ( Bottom panel , Tabl e
3 . 9) .
There w,e re h i g h l y s i gn i fi cant · correl at i o n s between a s p i r i n ,
s od i um s al i cyl ate and �oth benzoate s .
Ano t h er stri k i n g c orrel at i on
wa s between react i v i ty to s od i um met a b i s u l p h i te and both t h e s al i cy 1 ate a n d benzoate c h a 1; ' eng e s , " a f i nd i n g wh i c h h a s n o t p rev i o u s l y been
repo rted .
It i s i n terest i ng t o n ote , h owever , that c ro s s - re act i v i ty
between a s p i r i n and tartraz i ne d i d not reach s t at i s t i cal
cance ,
al t h o ug h tart raz i ne
re act i v i ty d i d c o rre l ate
s i gn i fi
s i gn i f i c antl y
w i th re s po n s e s to s od i um s al i cyl ate and b ot h benzoat e s .
Tab l e 3 . 9 Footnote :
*
P
val ues
s h own
as
<0 . 0000
ava i l abl e s t at i s t i cal tabl e s .
are
b e l ow
the
l i mi ts
g i ve n
in
CROSS-REACT I V I TY BETWEEN CHALLENGE SUBSTANCES (%)
TABLE 3 . 9
CHALLENGE COMPOUNDS
ASP I R I N
ANY SAL I CYLATE
SOD I UM SAL I CYLATE
+ve
- ye
x2
P « )
Asp i r i n
Sod i um sa l i cy l ate
Any sa l i cy l ate
59 . 7
22 . 1
68 . 4
. 0000
Sod i um benzoate
39 . 8
27. 5
10
1
4-0H benzo i c ac i d
39 . 9
24 . 4
16 . 1
.
+ve
-ye
x2
p « )
. 00 1 1
39 . 4
25 . 6
12 . 0
. 0005
. 0000
39 . 6
21 . 8
20. 4
. 0000
54 . 2
34 . 6
21 .8
. 0000
+ve
-ye
X2
73 . 6
34 . 8
68 . 4
. 00 00
. 00 1 5
45 . 8
31 . 0
10 . 6
. 0001
47 . 1
26 . 1
22 . 0
P « )
Any benzoate
Sod i um metab i su l ph i te
50 . 2
27 . 3
27 . 2
. 0000
57 . 1
26. 8
43 . 0
. 0000
50 . 0
21 . 4
40 . 0
. 0000
Ta rtraz i ne
37 . 0
33 . 4
30. 5
2.8
. 0965
44 . 3
29 . 3
11 . 0
. 00 09
36. 7
30 . 0
3.1
. 0798
26 . 0
3.9
. 0486
39 . 1
. 01 8 1
32 . 3
46 . 6
2.3
. 1 277
5. 2
2.0
. 1 528
10.4
28 . 6
6. 0
5.6
8.7
2.2
. 1398
9.0
4.0
4.0
. 0457
Brewers yeas t
Lactose
SOD I UM BENZOATE
CHALLENGE COMPOUNDS
ANY BENZOATE
4-0H BENZOI C AC I D
+ve
- ye
x2
p « )
+ve
- ye
x2
P « )
+ve
-ye
x2
P « )
Asp i r i n
61 . 2
47 . 5
10 . 1
. 00 1 5
63 . 9
46 . 2
16 . 1
. 0001
60. 7
44 . 7
15.3
. 0001
Sod i um s a l i cy l ate
50 . 6
35. 3
10 . 6
. 00 1 1
55 . 6
33 . 1
22 . 0
. 0000
50. 0
31 . 8
16. 1
. 0001
7 0 . 7 . 51 . 9
21 . 8
. 0000
Any sa l i cy late
Sod i um benzoate
4-0H benzo i c ac i d
59 . 0
19 . 5
93 . 7
. 0000
60 . 5
20 . 6
26 . 6
57 . 1
. 00 00
57 . 0
20 . 9
67 .
6
. 0000
25 . 1
26 . 3
38 . 0
. 00 0 0
45 .
0
23 . 6
30. 6
. 0000
7.2
. 0074
35. 3
25 . 4
6.8
. 0093
6. 1
0.8
. 38 4 7
8.4
5.4
1.6
. 2 083
93 . 7
. 0000
Any benzoate
Sod i um metab i su l ph i t e
Tart raz i ne
Brewers yeas t
Lactose
60 . 6
26 . 2
56 . 8
. 0000
46 . 8
26 . 6
24 . 4
38
. 0000
8
25. 5
11 .2
. 00 08
61 . 7
50 . 5
37 . 2
8.3
6.0
0.9
. 3 543
8.3
.
(X)
(X)
89
The quest i on t hen arose as to whether there m i ght be s u bgroups wi th i n
t h e R I U/AO pat i en t s i n whom part i cul ar chal l enge substan ce s h ave a
tendency to c l u s ter .
Th i s m i ght h ave i mportant i mp l i cat i ons
for
underst and i ng the mechan i sms by wh i ch certa i n chem i cal c ompounds , but
not others ,
cause urt i cari a 1
( Ch apter 1 0 ) .
react i on s i n pred i spos ed i nd i v i dual s
By ran ki ng the react i on frequen c i es w i th each of the
chal l enges , i t was pos s i bl e t o appl y the Newman - Keul s test to study
thi s
i s s ue .
Overal l ,
no s i gn i fi c ant c l u steri ng of react i on s was
found , al t houg h s al i cyl ates d i d stand out from the other sUbstances
as provo k i ng symptoms s i gn i fi cant 1 y more frequentl y t h an any other
s i ng l e substance or group o f substances ( data not s h own ) .
Re - Chal l enge of R I U/AO Pat i ents
In ord er to determ i ne the rel i ab i l i ty of the chal l enge protocol , 1 42
'
pat i ents p rev i ou s l y tested were sent a s econd chal l enge battery 1 2
mont h s l ater .
'
O f t hese 77 agreed t o undergo re - chal l enge
( Tabl e
3 . 10) .
F i fty p at i ents e i ther refu sed because they were fri ghtened of exper
i en c i ng a severe react i on ( s i x i nd i v i dual s ) , or i n i t i al l y agreed to
"\ .
p art i c i pate but t hen fa i 1 ed to take the second set of cha 1 1 enges .
S i n ce t h e 77 p at i ents who agreed coul d have been sel f - sel ected , the i r
i n i t i al c h al l enge re sul t s were compared to those of the R I U/AO group
as a whol e to determ i n e whether the re - ch a 1 1 enge pat; ents were a
representat i ve s ampl e .
the
only
s i gn i fi cantl y
Us i ng the Ch i - square goodne s s - of - fi t test ,
d i fferent
chal l enge
resul ts
were
wi th
sal i cyl ate s ( 4 2% on those agree i ng to re - ch al l enge vers us 5 2% i n the
whol e l arger group react i ng , re spect i vel y ;
0 . 0 1 < P < 0 . 05 ) .
90
TABL E 3 . 1 0
R E - CHALL EN G E OF 7 7 PAT I ENTS W ITH R I U/AO
C h al l enge Sets
Number o f Pat i en t s
Total chal l enge sets sent
1 42
Not t a ken
50
C hanged addres s
14
D i ed
1
Chal l enges t a ken
T h e respons e s
to
77
re � chal 1 enge
of
the
77
pat i ents
s t ud i ed
were
tabul ated together wi th t he i r react i on s to t h e i n i t i al battery and
c l as s i fi ed
as
" same "
( +/+
or
-/ - )
or
" d i fferent "
( +/ -
or
-/+)
responses ( Tabl e 3 . 1 1 ) .
Overal l , of t h e 462 re - chal l enge tes ts , 406 react i on s were t h e s ame
( 87 . 9%) and 56 were d i fferen t ( 1 2 . 1%) from t h e re s po n s e s recorded
after the fi rst set of chal l enge s .
The stat i st i cal anal ys i s of t h e se
f i gure s i s outl i ned i n deta i l i n the Mater i al s and Met h od s sect i on .
The res ul t s were h i gh l y s i gn i fi cant for al l c h a 1 1 enges ( P < 0 . 000 5 )
except w i t h metab i sul ph i te , where the n umbers test ed were smal l
pat i ents ) .
Furt hermore ,
( 29
when the d i scordant res u l ts are exam i n ed
c l osel y t here i s a stri ki ng tendency for i n i t i al l y pos i t i ve react i on s
to b e n egat i ve o n re - chal l enge , but n ot t h e reverse ( P <0 . 0005 by
91
McNemar ' s
tes t ) .
Th i s
i mpl i e s
res u l t s are more l i ke l y to be
t h at
the
a t rue
d i scord ant
re - c h al l enge
i nd i cat i on of a l os s
of
sens i t i v i ty rather t h an to a 1 ack o f re 1 i abi 1 i ty of the cha 1 1 enge
proced ure i t s e l f .
TAB L E
TO
RES PONS ES
3 . 11
RE -CHAL L EN G E
D i fferent Re spon se
Same Re sponse
C h al l enges
+/+
or
-/ -
+/ -
-/+
Sa1 i cy1 ates ( total )
58 ( 7 5%)
1 9 ( 2 5%)
0
Benzo ate s ( total )
68 ( 88%)
9 ( 1 2%)
0
Sod i um met abi s u 1 ph i te
73 ( 9 5%)
4 ( 5%)
0
T artraz i ne
67 ( 87%)
1 0 ( 1 3%)
0
Brewers ye ast
7 2 ( 94%)
5 ( 6%)
0
Lacto s e
77 ( 1 00%)
0 ( 0%)
0
Phys i cal Urt i cari as
Al t h ough p hys i ca l factors s uch as pressure were commonl y found to
exacerbate symptoms i n pat i ents w i t h R I U/AO ,
a few pat i ents
( 1%)
pre sented w i t h urt i cari a prec i pated onl y by p hys i cal st i mul i . Because
of
the
c l i n i cal
i nve st i g at i on .
overl ap
t hese
pat i ents
al so
underwen t
d i etary
92
Ten p at i e n t s w i t h col d urt i c a r i a were p l aced on t he e l i mi n at i on d i et
and were a s ked to perfo rm d a i l y i ce - cu be t e s t s ( at rotat i ng s i te s ) to
a s s e s s t h e i r col d - s e n s i t i vi ty .
Of t he s e , fou r became a symptomat i c
and underwen t b 1 i n d c h a 1 1 enge , four s h owed n o c h ange , and two were
u n su re of t h e o ut c ome .
Thre e o f t h e fou r d i et - s e n s i t i ve p at i e n t s
reacted t o s al i cyl ate c h al l enge ( by devel op i ng u rt i c a r i a i n respon s e
t o a c o l d s t i mu l u s ) and one reacted t o t artraz i ne .
Three p a t i e n t s w i t h i s o 1 ated dermograph i srn were a l s o p l aced o n t he
e l i mi n at i on d i et ,
and
two became
a symptomat i c .
One A of t he s e was
c h a 1 1 enged and re acted to e ryth ros i n e al one and t h i s pat i ent has
r ema i n ed free of sympt om s prov i ded she a vo i ds c o l o u red food s .
other
d i et - re s pon s i ve
p at i ent
was
a
s i x -year- o l d
g i rl
s uffered from a s t hm a and 1 i ved i n the far wes t o f NSW .
who
The
al so
She was
t h e re fore con s i d ered u n s u i t abl e for c h al l enge , but rema i n s wel l on a
d i et l ow i n s al i cy l ate s and add i t i ve s .
D I SCUSS I ON
Des p i te t h e publ i cat i on o f n umero u s s t ud i e s over t h e p a s t 2 0 years
( Tabl e 3 . 1 2 ) t he re a re st i l l w i d e d i vergences o f o p i n i on as to t he
rol e o f food i n p re c i p i t at i ng R I U/AO .
1 i te r at u re came from t h e USA ( Lac key ,
Beers , 1 96 7 , 1 968 ;
1 97 6 ;
Al t hough much o f the e arl y
1 95 9 ,
1 969 ,
Sett i pane & Pud u p u akkan , 1 97 5 ;
1 97 1 ;
Samter &
S e t t i pane e t a l . ,
Sett i p ane , 1 97 7 , 1 983 ) remarkabl y l i t t l e o f t h i s i n fo rmat i on
appears t o h ave h ad a ny i mp act on cl i n i cal pract i ce i n Nort h Ame r i ca
( Ma t h ew s , 1 980 ;
Smal l et al . , 1 982 ;
S aryan , 1 983 ;
Marg o l i s & N i s i ,
93
1 985 ) .
In Bri tai n and Europe , 1 arg e l y as a re s u l t o f the wor k o f
W ar i n a n d J u h l i n ( Tabl e 3 . 1 2 ) , t here h as b e e n i nc re a s i ng awaren e s s o f
t h e rol e o f s a l i cyl ates a n d food add i t i ve s i n R I U/AO ( BMJ Ed i to r i al ,
1 976 , 1 98 1 ;
Ormerod , 1 984 ) , a l t h ou g h t h e pract i ca l app l i cat i on o f
t h e s e f i nd i n g s i s s t i l l
v i ewed as que s t i on abl e ( Lancet Ed i tori al ,
1 98 1 ) .
I n Austra l i a , part l y a s a re s u l t o f the pre s en t s tudy , t here i s a
more g en eral
app rec i at i on of t h e rol e of d i et i n R I U/AO and ,
in
part i c u l ar , of t h e i mp ortance o f n atural l y occur i ng c ompounds a s wel l
as add i t i ve s ( Ro bert s -Thomp son et al . , 1 984 ;
1 986 ) .
Tru swel l , 1 985 ;
Wal l s ,
I n t h e ten years s i n ce t h e e l i mi n at i on d i et and c h al l enge
programme
was
f i rst
i ntroduced
at
RPAH
the
protocol
h as
been
requested by 575 g enera l pract i t i oners , spec i al i st s and d i et i t i an s ,
and i s i n u s e i n over 2 0 teach i ng h o s p i ta l s t h ro u g hout Au stral i a
( Tabl e 3 . 1 3 ) .
The s e f i g ure s are p ro babl y a refl ect i on of t h e fact t h at t he protocol
u sed at R PAH c an be read i l y appl i ed i n rout i ne cl i n i ca l pract i ce ,
g i v e n an understand i ng o f t h e
c ompo s i t i on of the c ommon food s .
bas i c pr i n c i pl e s and t h e chem i cal
In mo st p ubl i s h ed stud i es formal
d i etary i nvest i g at i on i s general l y reg arded a s on l y be i ng fea s i bl e i n
a re s earch i n st i tut i on , l e av i ng i nd i v i d u al pract i t i o ners to man age
t he i r p at i ents on an emp i r i cal b a s i s .
The protocol devel oped d u r i ng
t h e pre s en t s tudy i nv o l ves a s i ng l e outp at i en t v i s i t for con s u l t at i on
94
w i t h t h e p hys i c i an and expl an at i on of the el i mi n at i on d i et and c h al l
enge s by t h e d i et i t i an .
I n mo st cases t h e pat i ent i s then abl e to
carry out t h e . ent i re test i ng p roced u re at h ome , keep i ng i n regu J ar
tel ephone contact wi th the d i et i t i an ( and p hys i c i an when necess ary)
in
order
to
i n s truct i on s .
d i s c us s
any
uncerta i n i t i es
or
c o n fu s i on
about
the
After c ompl et i on of t h e c h al l enges ( us u al l y 4 - 6 weeks
l ater) pat i ents are as ked to ret u rn for fol l ow- up w i t h the i r d i ary
s h eet s ,
at wh i ch .t i me a s u i tabl y mod i fi ed l ong - term d i et can be
pre s cr i bed .
Comp 1 i ance w i t h t h i s protocol h a s been very g o od , w i t h 65% o f the
p at i ents ret u rn i ng for fol l ow - up .
Many factors con t r i buted to t h i s ,
i nc l ud i ng t h e prov i s i on o f cl e ar - cut i n s truct i on s a bo u t perm i s s i bl e
food s a s wel l as those to avo i d , the e ffect i venes s o f t h e e l i mi n at i on
d i et i t sel f i n rel i ev i ng symptoms o f R I U/AO and t h e a b i l i ty to c arry
out c h a l l enge test i ng o n an o ut - pat i ent bas i s . Re ady tel ephone acces s
t o t h e d i et i t i a n was al s o i mportant s i nce p at i ents o ften n eeded to
check whet her s ome unl i sted food was perm i s s i bl e , o r t o a s k adv i ce
about soc i al
occas i on s ,
rec i pe s ,
med i cat i on s
and
oth e r
p ract i cal
det a i l s .
Mod i fi cat i o n s to t h e basel i ne el i m i n at i o n d i et
i n 1 982 , w i t h t he
add i t i on o f bread , mi l k and eggs ( wh i ch we re on l y rarel y i mpl i cated ) ,
i mproved i ts pal at i b i 1 ty cons i d erab 1 y and made ad h e rence eas i e r for
p at i ents , al though there was n o not i ceabl e c h ange i n t h e compl i an ce
rate .
95
TABLE 3 . 1 2
PUBL I SHED D IETARY STUDI ES I N R I U/AO
o
Aut hor
Yea r
Lockey
War i n
Samter & Beers
Moore-Rob i nson & War i n
Lockey
James & War i n
Lockey
Juhl i n et a l .
M i chea l s son & Juh l i n
Thune & Granho l t
Ooeg las
Sett i pane et a l .
War i n & Sm i th
Ros et a 1 .
Doeg l a s
Kaaber
Fuj i ta et a l .
Neuman et a l .
M i kke l sen et a 1 .
August
Meynad ier et a l .
L i ndemayer & Schm i dt
Wutr i c h & Hack i Herrman
G i bson & C lancy
Va l verde et a l .
Wutr i c h & Fabro
Juh l i n
K i rkhof et a 1 .
Merk & Goerz
Hannukse l a
Ooeg las
Verschave et a l .
G i am & Rajan
Botey et a l .
A l len et a l .
Lob l ay & Swa i n
Supraman i am & Warner
1 948
1960
1967
1 967
1 969
1 97 0
1971
1972
1973
1 97 5
1 975
1 97 6
1 97 6
1976
1977
1 978
1978
1978
1978
1 97 9
1979
1979
1 980
1980
1 980
198 1
1981
1982
1983
1 983
1 983
1 983
1 983
1 984
1 984
1 986
1 986
D ietary Response
Cha l lenge Resu l ts
Number Contro l Tart- 4-0H
Sod i um Asp i r i n H i story Number Tota l Part ia l
of
raz i ne Benzo i c Benzoate
of
of
Pat i ents
Ac i d
Asp i r i n
P at i ents
4
70
40
228
6
96
4
8
52
1 00
23
38
1 08
75
65
57
30
61
86
24
90
81
65
3 06
330
1 00
25
137
271
100
30
8
0
22
100
71
37
21
30
8
13
67
0
0
0
5
23
11
23
46
19
21
26
0
5
86
40
6
17
29
42
10
23
5
59
11
59
3
23
3
23
22
25
29
18
34
22
25
29
18
34
54
6
11
8
6
11
8
22
23
6
18
15
24
1
10
4
11
14
6
6
30
35
26
35
55
9
17
55
9
67
34
26
0
41
79
+
6
+
29
1 00
49
100
41
4
10
50
1 00
33
32
26
36
4
8
16
1 00
27
38
38
75
18
23
44
+
86
6
50
63
34
75
57
67
30
22
98
90
45
80
20
23
12
55
65
2 58
51
75
61
31
15
22
57
41
44
29
14
81
12
24
10
18
67
36
9
826
43
7
2
36
1 00
61
62
2
73
33
826
43
70
93
96
TABLE 3 . 1 3
E L I M I NAT I ON D I ET PROTOCOL R EQU ESTS
Med i cal
Teac h i ng
Pract i t i oners
Hosp i tal s
NSW
2 43
11
90
I nt e rs t at e
1 13
10
86
32
7
11
Locat i on
Overseas
D i e t i t i an s
F i nd i ngs o f the Pre s en t Study
In
the
present
s tudy
58 . 5%
of
pat i en t s
present i ng
wi th
R I U/AO
expe r i enced remi s s i on of symptoms w i t h i n one to two wee ks o n the
e l i mi nat i on d i et .
up ,
Of t h e rema i nder , 3 4 . 8% d i d not ret urn for fol 1 0w
but when s ubsquent 1 y contacted by quest i onna i re a s i gn i fi cant
proport i on h ad i n fact cont i n ued to mod i fy t h e i r d i et i n o rder to
control symptoms ( Chapter 4 ) .
On l y 6 . 7% of p at i ents ret u rn ed for
fo 1 1 ow- up h ad not exper i enced any i mprovemen t
e 1 i mi n at i on d i et .
i n symptoms on t h e
I t i s cl ear , t herefore , t h at d i et i s a rel e vant
prec i p i tat i ng factor i n the g reat maj ori ty of p at i e n t s wi t h R I U/AO ,
and t h at i t i s t h e s i ng l e most i mportant factor i n nearl y 6 0% .
I n mos t s t ud i e s reported t o d ate d i etary res pon s e rates h av e on l y
been
documented
in
rel at i vel y
vari abl e re s u l ts ( Tabl e 3 . 1 2 ) .
smal l
numbers
of
p at i en t s ,
w i th
Al though mo st d i ets u s ed soug h t to
97
excl ude art i fi c i al preservat i ves and col ouri ngs , onl y Juhl i n ( 1 977 ,
1 980 , 1 98 1 , 1 985) , Thune and Gran ho1 t ( 1 97 5 ) , G i am and Raj an ( 1 983 )
and Botey et al .
i ntake ,
( 1 984 ) made any attempt to restri ct sal i cyl ate
and even here th i s was done i n a rather i ncomp 1 ete and
haphazard fas h i on .
Chal l enge protocol s al so vari ed great l y ( Tabl e 3 . 1 2 ) .
c arri ed out on a n ormal d i et ( Wari n 1 960 , 1 976 ;
Some were
Hannuksel a , 1 983 ) ,
and most others requ i red restri ct i on of add i t i ves onl y for peri ods of
3 d ays to one week before the cha 1 1 enges were commen ced (wi th the
except i on of Superaman i am and Warner , 1 986 ) .
I n the present study i t
was found that the stri ngency of sal i cyl ate excl us i on i n the basel i ne
d i et h ad a s i gn i fi cant i mpact on the react i on rate to the vari ous
chal l enge compounds , and th i s may i n part account for the h i gher
response rates documented .
wi th al l
I ncreased sen s i t i v i ty appears to occur
chal l enge compounds
(Tabl e 3 . 8)
and i s refl ected by an
i ncrease i n the mean n umber of react i on s per pat i ent ( Tabl e 3 . 8) .
Pos s i bl e reasons for th i s wi l l be d i scussed i n Ch apter 1 0 .
Two further d i fferences i n the ch a 1 1 enge protocol used here are of
rel evance .
F i rstl y ,
cl i n i cal
experi ence
i nd i cates
that
pat i ents
become more sens i t i ve to chal l enge over a two -week peri od of d i etary
restri ct i on ,
and a l owered react i on - threshol d may therefore
contri buted to the h i gh frequency of pos i t i ve chal l enges .
h ave
Secondl y ,
pat i ents are often found t o be i n a refractory state for u p t o 48
hours after a po s i t i ve react i on to a prev i ous chal l enge .
other stud i e s adm i n i stered chal l enges
at d a i l y
Al most al l
i nterval s wi thout
al l owi ng for a re fractory peri od , so that re act i on rates are l i kel y
to h ave been s i gn i fi cantl y under - e s t i mated .
98
The response to chal l enge i s known to be dos e -dependent (Wari n , 1 960;
Moore - Ro b i n son & Wari n , 1 967;
James & War i n , 1 970 ) and th i s effect
can be seen when the dose of tartraz i ne was changed from 1 0mg to 3 0mg
( per i ods 1 1 and I l l , Tabl e 3 . 8 ) .
A cumul at i ve effect can al so be
seen when the chal l enge sequence was changed from a fi xed order , w i th
asp i ri n and sod i um sal i cyl ate fol l owi ng sod i um benzoate and 4 - 0H
benzo i c ac i d , to a random order ( peri ods I I I and
IV,
Tabl e 3 . 8 ) .
Sal i cyl ates ( 2 -0H benzo i c ac i d der i vat i ves ) and benzoates are cl osel y
rel ated compounds wh i ch appear to frequentl y cros s - re act ( Tabl e 3 . 9 ) ,
and i t ; s therefore not supr; s i ng that consecut i ve cha 1 1 enges w ; t h
these compounds l eads to a n i ncreased react i on frequency .
React i ons to the chem i cal compounds were al so seen to be i nterrel ated
by cl u ster anal ys i s w i th a h i gh degree of cross react i v i ty between
4 -0H benzo i c ac i d , sod i um benzoate , tartraz i ne , asp i r i n and brewers
yeast .
These compounds
and thei r metabol i tes
al l
h ave
a
bas i c
structure wh i ch may account for the i r common act i on .
A h i gh degree of reproduc i bi 1 ty of the chal l enge re sul ts was ev i dent
from the o bservat i on that 88% of chal l enges produced the s ame resul t
when re - tested i n a subgroup of 77 of the R I U/AO pat i ents (Tabl e
3 . 11) .
I nterest i ngl y , i n those i nstances where re - test i n9 produced
d i scordant resul ts the pattern was i nvar i abl y +/ - rather t h an -/+
(Tabl e 3 . 1 1 ) , sugges t i ng a true l os s of react i v i ty rather t h an random
vari ab i l i ty .
Th i s ra i ses the i mportant quest i on of whether s uch
pat i ents may h ave experi enced e i ther " spontaneou s " o r d i et - i nduced
remi s s i on of sen s i t i v i ty .
From the ava i l abl e data i t i s not pos s i bl e
to determi ne i f t h i s was the case , al though at fol l ow- up there was no
s i gn i fi cant d i fference i n the degree o f d i etary re str i ct i on ma i nta i n
ed by these pat i ents ( Chapter 4 ) .
99
Phys i cal Urt i cari as
Urt i cari a p rec i pi tated by phys i ca 1 factors s uch ' as c o l d , pres s ure ,
exerc i se , s un l i gh t , etc .
i s general l y reg arded as a n o so l og i ca l l y
separate group o f d i sorders , i mpl y i ng d i fferences i n aet i ol ogy (War i n
&
C h amp i on , 1 974 ;
C h amp i on et al . , 1 986 ;
Czarnetz k i , 1 986 ) .
Among
these onl y dermograph i sm occurs common l y i n pat i ents w i t h R I U/AO and
i n the present study t h i s symptom was found to d i s appear and reappear
i n rel at i on to d i etary c h ange i n exactl y t he s ame way a s i n t he
p at i ent s w i t h the " i d i op at h i c " l es i ons .
Th i s o bservat i on prompted
d i etary i nvest i g at i on of a l l pat i ents seen at the al l ergy c l i n i c wi th
p hys i cal urt i cari as , and a l though the n umbers were rel at i ve l y smal l
i t i s c l ear t h at d i etary factors mod i fy the react i on to p hys i cal
st i mu l i
i n a s i gn i fi cant proport i on .
Pos s i bl e mec h an i sms of th i s
i nt eract i on wi l l be d i scus sed i n C h apter 1 0 .
New F i nd i ngs of Th i s St udy
Th i s study h a s contri buted to the further document i on that food
chemi cal s are very i mport ant prec i p i tants of R I U/AO and h as further
found that the i nc i dence of food i nduced R I U/AO prev i o u s l y reported
h a s p robabl y been u nder- es t i mated .
Th i s appears to h ave occurred
because mos t of the stud i e s on the prec i p i tants of R I U/AO h ave not
c on s i dered food as a prec i p i t ant and those who h ave , h ave not been
carr i ed
out
c h al l enge .
w i th
s uc h
stri ngent
d i etary
re stri ct i ons
pr i or
to
100
I n th i s study , the effect on R I U/AO of s od i um metabi s u l p h i te was al so
i nvest i g ated as i t i s one o f the mo st w i del y u s ed food p reservat i ves
today and prev i ou s l y i t s rol e i n R I U/AO h ad not been stud i ed .
Amongst the p hys i cal urt i c ar i as , col d u rt i cari a was found t o be the
one that was most s i gn ; f; cant l y affected by d i et .
Th i s e ffect was
stud i ed i n a smal l n umber o f pat i ents , i n whom the n at ural l y occurr
i ng sal i cyl ates i n food taken on a chron i c bas i s re sul ted i n exacerb
at i ng the e ffect of the pat i ents col d u rt i cari a .
The resu l t s o f th i s study i nd i cate t h at food may be a more i mportant
prec i p i tant
of
R I U/AO t h an
prevousl y thought .
Furthermore ,
the
resu l ts woul d seem to i nd i cate that food - re l ated R I U/AO may more
commonl y be due to the smal l mol ecul ar we i g ht s ubstances n at u ral l y
and art i f i c i al l y found i n food t h an t o food prot e i n s a s p re v i o u s 1 y
thought . Th i s has i mportant i mpl i cat i ons as t o the mec h an i sms beh i nd
the deve l opment o f R I U/AO . For t h i s re ason the st udy i s n ow i nvest i
g at i ng i n deta i 1 the effect o f ami nes ( tyram i ne and B p henyl ethyl
ami ne ) , mon o s od i urn g l utamate and sod i urn n i trate as p re c i p i tants o f
R I U/AO .
F rom Jan uary 1 986 the chal l enge battery was mod i fi ed s o t h at
the rel evance o f these compo unds i n the RI U/AO pat i ent s coul d 'be
; n vest i g ated thorough 1 y .
Up to September 1 986 ,
2 1 p at i ents
h ave
compl eted th i s chal l enge set and 4 4% h ave re acted to am i nes , 3 7% to
mon osod i um g l utamate and 63% to s od i um n i trate .
CHAPTER 4
D I ETARY MANAG EMENT AND FOL LOW - U P
10 1
I NT RODUCT I ON
F o l l ow i ng t h e i de nt i f i c at i on and e l i m i n at i on o f d i e t ary prec i p at i ng
factors i n p at i e n t s w i t h R I U/AO , i t wa s o ft e n o b s e rved t h at certa i n
i nc r i m i n at ed food s coul d be s afel y re - i n trodu ced where as ot h e rs wou l d
1 e ad to a rec urrence o f symptoms .
C l i n i c a 1 o b se rv at i on s s ugges t ed
t h at t h e food s mo s t l i ke l y t o prec i p i t at e recu rre n c e s o f u rt i c a r i a
were t h o s e cont a i n i ng t h e h i g h e s t concentrat i on s o f s a 1 i cyl ates , and
i n o rd e r t o c o n f i rm t h i s i mp re s s i o n i t was dec i ded to s urv ey pat i e n t s
who had comp l e t ed t h e e l i mi n at i on and c h al l enge p rogramme .
from a t o t a l o f 843
1 983 , 59 1 p a t i e n t s h ad comp l eted t h e p rotocol
pre s en t i ng
for
i nv es t i g at i o n .
I n i t i al l y
cont act t h e s e pat i e n t s by tel ephone ,
an
By J u l y
attempt
was
made
to
but t h i s p roved d i ff i c u l t i n
pract i ce , s o i t was d ec i d ed t o s end a s t an da rd q u e st i onn a i re to e ach
T h i s was fol l owed u p t h re e to fou r mon t h s l ater by a s econd
by ma i l .
ques t i on n a i re t o t h o s e p at i e n t s who h ad not rep l i ed .
From t h e repl i es i t d i d i ndeed appear t h at h i gh - s a l i cy l ate foods were
common l y i mp l i c at ed i n c a u s i ng rec u rrent symptoms .
F u rt h e rmore ,
it
h ad become c l i n i cal l y app arent t h at recurre n c e s s howed a c umul at i ve
dose - de pendence ,
several
d ays
wi th
symptoms
o f regu l ar
o ften
con s umpt i on
appear i n g
of
grad u a l l y
s u b - t h re s h o l d
a fter
amou n t s
of
asp i r i n from a v ar i ety o f food source s . I n order t o prov i de pract i ca l
g u i d e l i ne s
for d i etary man ageme n t
in
s uc h
p at i e n t s ,
a
c h art w a s
pre p ared l i s t i ng foods accord i ng t o s a l i cyl ate - content , taki ng i nto
account the q u an t i t i e s l i ke l y to be con s umed a s an averag e s e rv i ng
s i ze .
Th i s s ub s q u en t l y proved extreme l y u se fu l
i n h e l p i ng p at i ents
102
to
l i beral i ze
t he i r d i et max i mal l y w i t h o u t
devel op i ng
c umu l at i ve
e ffec t s , a s wel l as e n abl i ng t h em to i dent i fy t h e mo s t l i ke l y c auses
of acute rec urren c e s .
When t h e rep 1 i e s from t h e i n i t i a 1 q u e s t i o n n a i re were c o 1 1 ated and
t ab u l ated i t became apparent t h at at 1 e a s t t hree quarters o f the
pat i e n t s s urveyed were s t i l l ma i nt a i n i ng a res t r i cted d i et s i x months
to s i x years after i n i t i a l presentat i on .
Th i s was s urpr i s i ng s i nce
t h e remi s s i on rate ; n uncomp 1 ; cated u rt ; c a r ; a ; s s a ; d to be of the
o rder o f 50% w ; t h ; n t h e f; rst s ; x mon th s ,
a l t h o ug h a s ; g n i f; cant
m i n o r i ty may s t i l l be symptoma t i c after ten years ( Ch amp i on et al . ,
1 969 ) .
Con s equen tl y , t h e quest i o n o f o u tcome i n p at i e n t s who fa i l ed
t o c omp l ete t h e e l i mi n at i on and chal l enge p rogramme
30% o f the tot a 1 ) a� s o became of i nterest .
( ap p ro x i matel y
I t h ad prev i o u s 1 y been
a s s umed t h at t h e maj or i ty of t h o s e who d i d n o t retu rn for fol l ow- up
h ad not exper i en ced any i mprovement i n symptoms a ft e r an
i n i t i al
peri od o f d i etary res tr i ct i on ,
p l ac i ng t h em ; n a " d i e t - re s i s tent"
c at egory .
s e emed
In
these
cases
it
l i ke l y
t h at
other,
as
yet
u n i d en t i f i ed aet i 0 1 og i c a 1 factors were res po n s i b 1 e for t h e p re sence
o f cont i n u i ng symptoms .
s ome
p at i e n t s
h ad
found
Other pos s ; b i 1 i t i e s con s i d ered were t h at
the
d i etary
protocol
too
d i ff i c u l t
or
deman d i ng and preferred to cont i n ue symptomat i c d rug t re atment , or
t h at they h ad exper i enced spontaneo u s remi s s i on and no l onger need ed
to pursue d i e t ary i nv e s t i gat i on .
Thu s , i n November 1 985 , 304 s uch
p at i ents ( 23 . 5% of t h o s e seen up to t h at t i me )
were s urveyed by
q u es t i onna i re t o determ i n e wh at proport i on were s t i l l symptomat i c and
h ow many were s t i l l on a res t r i cted d i et .
103
MATER IALS AND M ETHODS
Durat i on of Symptoms
F rom t h e rep 1 i e s to the fi rst quest i o n n a i re the tot a 1 durat i o n o f
symptoms w a s e s t i mated i n al l pat i ents w h o were abl e to ret u rn t o an
u n re s t r i cted
d i et .
Th i s
was
c a l cul ated
by
add i ng
togeth e r
the
d urat i on o f symptoms at pre s en t at i on ( recorded i n t h e c a s e h i story
note s ) to t h e t i me t a ken to be abl e to ret urn to a normal
w i t hout recurrence o f symptoms .
d i et
The res u l t s were pl otted by a 1 i fe
t a b 1 e method , maki ng al l owance for those i n whom the d i sease was
s t i l l act i ve ( Ch amp i on et al . , 1 969 ) .
Confi dence l i m i t s ( 95%) were
cal c u l ated as descri bed i n Chapter 2 .
Que s t i on n a i res
The f i rst
des i gned to ' ascert a i n
quest i o n n a i re was
the
l ong - term
e ffec t i vene s s o f d i et ary man agemen t i n ' pat i ents who h ad comp l eted the
e 1 i m i n a t i o n and c h a 1 1 enge programme .
App en d i x 1 3 .
The forms used are s h own i n
Pat i ents were a s ked whether or not symptoms h ad recurr
e d s i n c e d i etary e l i mi n at i on a n d chal l enge test i ng .
not
recurred
res t r i c t i on s ;
t h ey
were
quest i on ed
i f symptoms
d et a i 1 s of t h e severi ty ,
about
t he i r
I f sympt oms h ad
current
d i etary
h ad recurred they were a s ked t o g i ve
d urat i on ,
re 1 at i o n s h i p to food ,
d i etary
c ompl i ance , d i etary i nd i scret i on s , curren t d i etary pract i ce s al ong
w i t h use of rel i ef med i c at i on s .
The second quest i on n a i re was mai l ed to t h o s e p at i e n t s who presented
t o t h e c l i n i c w i t h R I U/AO but d i d not compl ete t h e e 1 i mi n at i on and
c h al l e nge
test i ng
programme
( Append i x
14) .
Pat i ents
were
a sked
1 04
whether o r not t h ey h ad st arted the e 1 i m i n at i on d i et and i f i t had
been e ffec t i ve .
They were al so a s ked whether t h ey h ad return ed to a
" normal " d i et or whether they h ad con t i n ued d i et ary res t r i ct i on , and
i f so wh i ch food s they avo i ded .
Stat i st i cIl An al ys i s
Regre s s i on anal ys i s was performed on a VAX 8600 compu t e r u s i ng S PS S - X
o n the res ul ts o f those pat i e n t s w h o reported t h at t h ey were free of
symptoms
and
fol l ow i ng
an
unre s t r i cted
symptoms was compared w i t h t h e pat i ents
s al i cyl ate c h a l l enge and p resent i ng
I
d i et .
The
d urat i on
of
s ex , age , react i o n to the
symptoms o f u rt i c a r i a
a l one ,
ang i oedema al one or both t oget h e r .
The d eg re e of ongo i ng d i etary res t r i ct i on report ed i n t h e q u e s t i on
n a i re repl i es was exam i n ed i n rel at i on to ( a ) p re s en c e o r a b s e n ce o f
symptoms , a n d ( b) t h e re 1 a t i on s h i p or otherw i s e o f rec urre n c e s to
foods .
The Ch i - s quare con t i ngency test was u sed s i n c e t h e s e factors
are i ndependent vari abl e s .
Construct i on of Sal i cYl ate C h art s
T h e 1 e v e 1 s o f s al i cyl a t e found i n food presented i n C h a pter 2 were
u sed to const ruct c harts wh i ch coul d be u sed by p at i e n t s t o contro l
t h e total d a i l y d o s e o f sal i cyl ate con s umed .
Each food was ran ked by
t a k i ng i nt o account both i ts sal i cy l ate concentrat i on and t h e amount
t h at wou l d be commonl y eaten i n an average serv i ng .
g rouped
accord i ng
to whether
they wou l d
prov i de
Foods were t h u s
a
" negl i g i bl e " ,
" l ow " , IImod e rat e " , " h i gh " or li very h i gh " s a l i cyl ate d o s e p e r s e rve .
I
105
*
neg l i g i bl e
n o detectabl e s a l i cyl ate
l ow
<
moderate
0 . 1 - 0 . 5 mg sal i cyl ate per serve
h i gh
0 . 5 - 1 . 0 mg s a l i cyl ate per s erve
very h i gh
> 1 . 0 mg s a l i cyl ate per serve
ON E S E RV E :
Fru i t s :
0 . 1 mg s a l i cyl ate per serve
One i tem ( ap p l e , o r ange , etc . )
One s l i ce ( waterme l o n , roc kmel on ,
p i neappl e , etc . )
One cupful ( l S0g ) ( su l tanas ,
berri es , grape s , etc . )
Veget abl es :
Equ i val ent of o n e cupful ( l S0g )
Nuts :
One h al f cupful ( 80g )
Sweet s :
One tabl espoon
Herbs/s p i ces : One teaspoon
Dri n ks :
One gl a s s or cup ( l S0ml )
TABLE 4 . 1
SAL ICYLATE CHART
VEGETABLES
Neg l i g i b le
Low
Moderate
H ig h
Very H i gh
bamboo shoot
cabbage
ce lery
l ettuce .
potato ( pee l ed )
swede
brusse1 sprout
c h i ve
choko
green beans
green peas
l eek
mungbean spout
red cabbage
sha l l ot
asparagus
beetroot
brocco l i
carrot
cau l i f lower
marrow
mushroan
on i on
parsn i p
pumpk i n
sp inach
sweetcorn
sweet potato
turn i p
a lfa l fa sprout
broadbean
cucumber
eggp l ant
watercress
caps icun
champi gnon
ch i cory
endi ve
gherk i n
hot pepper
01 ive
rad i sh
tomato
products
zucchi n i
dr i ed beans
dr i ed peas
brown l ent i l s
red l ent i l s
Cont inued
106
FRUIT
Neg l igib le
Low
Moderate
H igh
Very High
banana
pear
(pee led )
go lden de 1 i c i ous
app le ( peel ed )
pawpaw
panegranate
custard app le
fig
lemon
loquat
mango
pear ( w i th pee l )
pers inmon
red de 1 i c i ous
appl e
rhurbarb
tamari 1 1 0
avocado
grapefru i t
granny sm ith
app l e
jonathan
app le
k iw i fru i t
lychee
manda r i n
mu l berry
nectar i ne
pas s i onfru i t
peach
tange lo
waterme lon
apr i cot
b lackberry
b lackcurrant
b l ueberry
boys en berry
cherry
cranberry
currant
date
grape
guava
loganberry
orange
p i neappl e
p hl1l
prune
ra i s in
raspberry
redcurrant
rock.me lon
strawberry
su ltana
youngberry
Low
Moderate
H igh
Very H i gh
a l l sp ice
bay l eaf
cardamon
carraway
c innamon
c loves
g i nger
nutmeg
pepper (b lack )
pepper (wh i te )
p im i ento
whi te v inegar
an i seed
cane l la
cayenne
cum i n
curry
di l l
f i ve sp i ce
garam masa la
mace
Marmite
mint
mixed herbs
mustard
oregano
papr ik.a
rosemary
sage
tarragon
turmer i c
Vegemi te
worster sauce
HERBS and SP ICES
Neg l i g i b le
gar l i c
ma l t v i negar
pars l ey
saffron
soy sauce
tandori
van i l la
Cont i nued
107
Neg l i g i b le
Low
Moderate
poppyseed
cashews
braz i 1
coconut
haze lnuts
macadami a
peanuts
pecans
p i nenuts
pi stachio
sesame seeds
sunf lower seeds
wa lnuts
Neg 1 i g i b le
Low
Moderate
carob
cocoa
map le syrup
whi te sugar
caramel s
go l den syrup
mo lasses
Negl i g i b le
Low
Moderate
tQEill
COFFEE
Harri s instant
Bushe l ls instant
Robert Tinms
i nstant
COFFEE
Harr i s Mocha
Internat i ona l
Roast instant
Moccona i nstant
Nescafe instant
ill
TEA
camani l le
roseh i p
ill
CEREAL COFFEE
dande l ion
Ecco
Bambu
CEREAL COFFEE
Reform
ALCOHOL
l iqueur
port
rum
w i ne
H i gh
Very H igh
a lmond
waterchestnut
SWEETS
H igh
Very H igh
honey
l icori ce
peppermi nts
BEVERAGE S
Andron i cus
Pab 10 i nstant
decaffe i nated
OTHER
Aktav i te
Mi l o
Ova lt i ne
ALCOHOL
gin
vodka
whi sky
decaffei nated
fru i t
�
coke
fru i t j u ice
rosehi p syrup
ALCOHOL
beer
brandy
c i der
sherry
H igh
Very H i gh
a l l brands
peppermi nt
CEREAL COFFEE
Nature ' s cuppa
108
As s e s smen t o f Nutri t i o n a l Adegu acy
I n pat i en t s o n a h i g h l y re s t r i cted d i et wh ere t h e re wa s con cern about
n u t r i t i o n al adequ acy a t h ree to fi ve day d i et h i s t o ry was recorded
and an a l ysed by comp u te r , us i ng t h e " Sod a " p rog ramme ( Vers i on 1 . 2 ,
R . J . Hart l ey ,
1 982 ;
Computer Model s ,
P . O . Box 280 ,
Ben t l ey ,
WA) . '
Th i s prov i des an e s t i mate o f prote i n , fat , c arbohyd rate , k i l oj oul es , .
v i t am i n A , t h i am i n , r i bofl av i n , n i ac i n , v i t am i n C , i ro n a nd cal ci um
i n t a ke .
RESULTS
Nat u ral H i story of R I U/AO
The tot al durat i on o f d i s ease wa s cal cul ated fo r t h o s e pat i en t s wi th
R I U/AO who were asymptomat i c and fo l l ow i ng a norma l d i et on fol l ow- up
and p l otted a s a l i fe tabl e ( F i gure 4 . 1 ( a ) ) , and fo r compar i s o n , the ,
data o f Ch amp i on � t al .
( 1 969 ) i s reproduced i n t h e F i g ure 4 . 1 ( b) .
Al t h ough the p roport i on o f pat i ents enteri ng rem i s s i on d u r i ng the '
f i rst fi ve ye ars was muc h l ower i n t h e pre s en t s tudy , t h e f i g u re s are
very comparabl e at ten and 20 years a fter o n s et .
Regre s s i on a n a l ys i s ,
was performed i n o rder t o l oo k fo r a correl at i on between durat i on of
d i se ase and age ,
pattern
s ex , res po n s e to s al i cyl ate ch al l enge or d i sease
( urt i cari a a l o n e ,
ang i oedema al one or both t og e t h er ) .
s i gn i fi cant re l at i on s h i p wa s fo und wi t h any of t h e s e parameters .
No
109
F I GU RE 4 . 1 ( a l
L I F E TAB L E PLOT OF R I U/AO PAT I ENTS I N PRES ENT STUDY
1 00
I_�.... .. _�
90
80
70
w
>
�
o
c
�
z
w
�
W
Q.
60
40
30
20
10
2
o
4
8
6
10
12
14
1 6 1 8 20 years
TOTAL DURATION
F I GURE 4 . 1 ( b )
L I FE TABLE PLOT OF R I U/AO PAT I ENTS ( CHAMP ION ET AL . , 1 969 )
A NGIO -O ED E M A
O N LY.
U R TICA R I A
AND
A NOIO- O E D E M A .
7'
�
...
C
!
...
\I
•
;:
1M
3M 6M
TOTAL
1
2
DUIlATION
(a)
5
10 2 0 YlAU
'0
25
1M
3M 6 M
TOTA L
1
2
S
DURATION
(b)
10 flAIt S
1 Nl
3M 6M 1
2
5
'O'AL DU. AT/ON
(e)
Flo . •.-ThfI expeeted �tap of pat.inntH active. with 95% confidence limit.... hy the total duraLi"n of di_ (11'Il _Ie\.
10
2 0 TEA.,
110
P at i ent s who Compl eted t h e E l i mi n at i o n D i et and C h al l enge Programme
Up to J u l y 1 983 , 843 p at i ents w i t h R I U/AO h ad pre s ented to t h e RPAH
Al l ergy C l i n i c .
Of t h e s e , 58 1 h ad comp l eted the e l i m i n at i on d i et and
c h a l l e ng e prog ramme , and duri ng 1 984 t he i r progre s s was eval u at ed by
a
tel ephone
Al togethe r ,
and ma i l ed
383
p at i ents
que s t i onn a i re ,
( 66%)
were
or
at
cl i n i c
s ucce s s fu l l y
attendances .
con t acted ,
the
rema i nder be i ng l os t to fol l ow- up due to ch ange o f addre s s , death or
fa i l ure to repl y ( Tabl e 4 . 2 ) .
From t h e quest i on n a i re rep l i es
i t was ev i dent t h at over h al f the
p at i e n t s s urveyed were st i l l symptomat i c , and o f t h e s e the maj ori ty
exper i e nced recurrences prec i p i t ated by food s ( Tabl e 4 . 3 ) .
a
s i gn i f i cant
d i fference
in
d i et ary
res tr i c t i on
p at i ent s i n remi s s i on and those w i th recurrences
s qu are test o f i ndependence ) ,
There was
p at tern
between
( P < 0 . 000 1 ,
and i n t h e 1 atter g roup there
Chi
was a
strong correl at i on between t h e degree o f d i et ary restr i ct i on and the
occurrence o f food - rel ated symptoms ( P <0 . 000 1 ) .
had
i den t i fi ed as caus i ng recurrence s . The food s reported are shown iq
Tabl e 4 . 4 ( mo s t commonl y i mpl i c ated ) and Tabl e 4 . 5 ( i mp l i cated b�
onl y one or two p at i ent s ) . I n al mo st every i n s t ance e ach food could
be i dent i fi ed as a s ource o f sal i cyl ates , col o urs or pres ervati ves J
often i n comb i n at i o n , and i n s ome c a s e s together w i t h ami nes and/o�
'4
MSG ( Ch apter 6) .
i
On the que s t i onn a i re p at i ents were as ked t o l i st foods they
�
.'
"
III
TABLE 4 . 2
RESPONSE TO FOLLOW UP OUES T I ON NA IRE OF RESPO NDERS
Pat i ents Surveyed
Number of Pat i ents
Number of pat i ents surveyed ( tota l )
581
Te l ephone
Quest i onna i re
C l i n i c rev i ew
Lost to fo l low-up ( Tota l )
141
222
20
198
Change of address
No rep ly
D i ed
1 54
42
2
TABLE 4 .3
MA I NTENANCE DI ETARY PRACTICES OF D IETARY RESPONDERS (%)
Outcome
at Fa l 1ow-Up
Number
of Pat i ents
Ma i ntenance D i et
Unrestr icted
Rem i s s i on
Part i a l
Restr ict i on
H i gh ly
Rest r i cted
138
41%
32%
27%
200
3%
24%
73%
45
78%
17%
4%
Recurrences :
Re l ated to food
Unrel ated to food
1 12
TABLE 4 . 4
COMMON PROVOK I NG FOODS
Chem i ca l
Foods
No . of
Content *
Pat i ents
s , a , m, (p)
43
Tomato
s , a , m,
Co l ours
c , (s •a ,m, p)
W i ne
Foods
Chem i ca l
No . of
Content *
Pat i ents
Sweets
(s,a,p,c)
6
30
Sa lads
s , (a)
6
23
Stone fru i t
s
6
Tomato sauce
s, a,m
6
Fru i ts &
Vegetab l es
s , (a ,m)
22
Nuts
s , a, (p)
6
Preservat i ve
p , ( s , a ,m , c )
20
Vegem i te
s,a,m
6
Lemonades
p , (c , s )
19
Seafood
( s , a ,m , p , c )
5
Tea
s
18
Zucc h i n i
s
4
I t a Han d i shes
s ,a,m
16
Dr i ed fru i t
s , (p)
4
Choco l ate
a, (s,c)
15
Honey
s
C i t rus
s
14
St rawberry
s
4
4
Beer
s,a
12
Mushroan
s,a,m
4
Sp i ces
s
12
Meat P i e
s , a , m, p , c
4
Fru i t ju i ce
s , (p)
11
Icecream
(s,a,p,c)
4
Sa 1 i cy lates
s
10
F i sh & ch i ps
a , p , ( c , s ,m )
4
Ch i nese d i shes
m, (s ,a,p)
8
Bread
(s ,p,c)
4
Cucumber
s
8
Xmas pudd i ng
s , a , (p,c)
4
P i neapp l e
s
7
Xmas cake
s,a, (p,c)
4
Rockme l on
s
3
Lemon
s,a
3
Tomato paste
s , a ,m
3
Coconut
s,a
3
Tw i st i es
s , a,m, c
3
P i ck l es
s , a , (m , p , c )
3
s , a , p, c
3
s,a,m
3
(p)
Cheese
5,
Preserved meat
p , a , (s ,m,c )
7
7
Restau rant mea l s
s , a , (m , p , c )
7
7
P i neap p l e
s,a
Cheese
a , (m , p , s , c )
7
App l e
s
7
Caps i cun
s
6
Curry
5,
* s • sa l i cy l ate , a
(a ,m , p , c )
=
6
F l avouredyogurt
Sp i c ey ch i cken
am i n e , m • g l utamate . p
=
preservat i ve , c
=
co lour
1 13
TAB L E 4 . 5
L ESS COMMON PROVOK I NG FOODS ( L E SS THAN 3 PAT I ENTS )
Foods
C hemi cal Content *
Food s
C h emi cal Content *
App l e p i e
s, (p,c)
Lebanese d i p
Avoc ad o
s,a
Mal t
Bl ackberr i e s
s,a
Mango
s
Beetroot
s
M i n t s auce
s , a, (p , c)
Brocco l i
s,m
McDon al d s meal s
s , a, {m, c , p)
Cheesecake
s , { a , c , p)
On i on
s
Ch i l l i
s
Pac ket gravy
s,a,m
Coffee
(s)
Peas
s
Cornfl akes
s
Pork
a
C arrot
s
Raspberr i es
s
Ch i c ken soup
s , a ,m,c
' Ri bena '
s,p
Dri ed beans
(p)
Rhubarb
s
Sard i nes
a
Egg
s ,m
Eggp l ant
s,a
Season i ngs
a, s ,m, (c)
F i sh paste
s , a , (m, c , p)
Smo ked sal mon
a, (p)
Frozen foods
( s , a,m, c , p)
Stock cubes
s , a,m, c
Fru i t buns
s , a, p, (c)
Taco shel l s
s , ( a , m , p , c)
Grapes
s, a,m
Tri pe
a
Herb s
s
V i negar
s,a
Jel l y
s , c, (a)
W ' cester s auce
s, a,m
* s
=
s al i cyl ate , a
c
=
col our
=
am i ne , m
=
gl utamate , p
=
pre servat i ve ,
1 14
From a total
of 200 pat i ents who reported that recurrences were
rel ated to food , 1 87 were abl e to recal l and l i st one or more foods
that they h ad i den t i fi ed as prec i p i tants o f R I U/AO .
A total of 489
foods were reported of wh i ch 465 ( 95%) corre l ated d i rect l y wi th the
pat i ents ' chal l enge responses (Tabl e 4 . 6 ) .
TABLE 4 . 6
FOOD RELATED RECURRENC ES COMPARED W ITH C HALLENGE RESULTS
Number of pat i ents report i ng food react i on s
1 87
Number o f food react i on s reported
489
Total food react i on s corres pond i ng to chal l enge react i on s
465
Sal i cyl ate
366
Preservat i ve
1 10
Tartraz i ne
>
56
39
Brewers yeast
Of these , 79% were attr i butabl e to sal i cyl ate and 24% to the preserv
at i ves
( benzo i c
ac i d
and
sod i um
metab i sul ph i te ) .
Some
reports
i mpl i cated cheese and chocol ate i n i nd i v i dual s sens i t i ve to s al i cy
l ates , preservat i ves and and/or tartraz i ne , but on c l o ser exam i n at i on
these referred to compo s i te products wh i ch al so conta i ned sal i cyl ates
and
add i t i ve s
" Cherry R i pe
11
(e.g.
proces sed
cheese ,
and "After O i nner" m i nts ) .
soft - centered
chocol ates ,
However , i n 24 i n stances ,
the foods i mpl i cated d i d not corres pond to chal l enge react i on s ( Tabl e
4 . 7) .
I n the l i ght of subsequent exper i ence ( Chapter 6 ) i t i s l i kely
that these pat i ents were al so sen s i t i ve to ami nes , MSG , n i trates and .
1 15
prop i on a t e and p o s s i bl y o t h e r s ub s t a n ce s , wh i ch were n o t rout i ne l y
i nc l uded i n t h e c h al l enge set for p at i e n t s w i t h R I U/AO .
TAB L E 4 . 7
FOOD R EACT I ONS TO COMPOUNDS NOT TESTED
Foods Reported
Compound
Foods Repo r te d
C ompound
C au s i ng React i on s
Res pon s i bl e
C a u s i ng Re act i on s
Respon s i bl e
Bacon
a,n
C h o co l ate
a, (s,p,c)
Bread
{ s , a,p}
Corned beef
a,p
Cheese
a , {m, p , c}
Ham
a,p
C h i c ken
(m, s , a)
Mus h rooms
a, s ,m
Ch i cken soup
(m, s , a , c , p)
Pork
a
Ch i nese meal s
(m, s , a)
Sard i n e s
a
* s
•
s a l i cyl ate , a
c
=
col our
=
ami n e , m
=
g l utamate , p
=
p re s e rvat i ve ,
Pat i ent s who F a i l ed to Como l e t e D i e t ary I nv e s t i gat i on Programme
From a total of 1 294 pat i e n t s pre s en t i ng w i t h R I U/AO to the RPAH
Al l ergy Cl i n i c up to November 1 985 , 304 fa i l ed to return for fol l ow
up .
In order to a scerta i n the outcome i n t h i s group , each pat i ent
was s ent a q u e s t i on n a i re by ma i l , and 1 1 9 rep l i e s were rece i ved .
the rema i nder , 73 h ad ch anged addre s s and 1 1 2 fa i l ed to repl y .
Of
1 16
Of those
1 1 9 who
rep l i ed to the quest i onn a i re
101
p at i ent s had
commenced the el i mi nat i on d i et , 4 1 of whom i mproved symptomat i c al l y
even though they d i d not cont i n ue t h ro ugh t h e chal l enge programme .
S i xty - one percent
of
the
pat i ents
report i ng
i mprovement
on
the
el i mi nat i on d i et s a i d they were st i l l re stri ct i ng the i r d i et to some
extent at the t i me o f the s urvey , compared wi th on l y 28% of the
60
pat i ents who fa i l ed t o show i mprovement ( P <0 . 00 1 by t h e Ch i - square
tes t ) .
By contrast , of the rema i n i ng 1 8 pat i ents who d i d not start
the el i mi n at i on d i et , on l y two pat i ents i nd i cated t h a t they were
restr i ct i ng the i r d i et when surveyed .
Overal l , amongst pat i ents who fa i l ed to comp l ete the el i mi n at i on and
chal l enge programme the quest i onn a i re respon se rate wa s 5 1% ( Tabl e
4 . 7)
•
From a compari son o f the rep 1 i es w i t h t h o se o f pat i ent s who
h ad compl eted the programme (Tabl e 4 . 2 ) i t was ev i dent t hat a s i mi l ar
spectrum o f foods was i nc r i m i nated by both groups
i n t r i ggeri ng
recurrent attacks of urt i c ari a ( Tabl e 4 . 8 ) .
Pat i ents who i mpl i cated " s ugar" were common l y re ferr i ng to sweet
food s when quest i oned spec i fi cal l y , most of wh i ch cont a i n sal i cyl ate
( i n the fl avour) , as wel l as preservat i ves and col o u r i ngs i n most
cases .
These p at i ents were al so as ked whether they h ad experi enced
rec urrent symptoms up to the t i me o f survey .
S i xty - fo u r ( 53 . 8%) of
those an sweri ng the quest i onn a i re (wi t h 30 pat i ents avo i d i ng certai n
foods ) were s t i l l symptomat i c , wh i l s t 55 h ad s uffered n o recurrence
( al thoug h 14 of these al so cont i nued to re st r i ct t he i r d i et ) .
1 17
TAB L E 4 . 8
COMMON P ROVOK I NG FOODS O F PAT I ENTS WHO D I D N OT COMP L ET E
E L I M I NAT I ON AND CHAL L EN G E PROGRAMME
Food
Chemi cal No of
Food
Chem i cal No o f
Conten t* Pat i ent s
Content* Pat i ents
" Pre serv at i ve s "
p
16
Dai ry product s
a, (p,c)
5
" Col ours "
c
13
Soft dri n ks
s,a,p,c
4
" Sal i cyl ates "
s
9
Orange
s,a
4
Fru i t
s,a,p
9
Red meat
a
4
Al coho l
s ,a,m,p
8
Not st ated
Sp i ces
s
6
Garl i c
( s , a , m)
3
" Sugar ll
( s , a, p , c) 6
Bread
p , ( s , c)
2
4
Art ; fi c i al fl avour ( s , a , m)
6
As p i ri n
s
2
Ant i ox i dant
p
5
Tomato
s , a,m
2
Vegetabl e s
s,a,m
5
On i on
s
2
Coffee
s
5
Strawberry
s
2
* s - sal i cyl ate , a
c
•
col our
=
ami ne , m
=
g l utamate , p
=
preserv at i ve ,
118
D I SCUSS I ON
There i s l i tt l e i n format i on i n the l i terature document i ng the natural
h i story of R I U/AO .
o f C h amp i on et al .
The l arge s t , and mo st w i del y c i ted seri e s i s that
( 1 969 )
i n wh i ch 5 5 4 pat i ent s were i dent i fi ed
ret rospect i vel y through hosp i t al record s , and s urveyed by ques t i on
n a i re .
F i gures from th i s study s howed that between 2 5% and 50%
of
pat i ent s h ad rem i tted w i th i n 6 month s of on set ( depend i ng on whether
they s uffered
from urt i cari a
al one ,
al one ,
ang i oedema
or
both ) ,
al thoug h a s i gn i fi cant m i nori ty h ad rema i ned symptomat i c for over ten
years .
( For compari son , the fi nd i ng s o f Champ i on et al . , 1 969 are '
reproduced i n F i gure 4 . 1 ( b » .
Earl i er stud i es o f Urbach and Gottl i eb
( 1 946 ) and Wari n ( 1 954 ) i n smal l er n umbers o f pat i ents quot ed even
h i gher f i gures for the remi s s i on rate
i n the fi rst s i x months ,
probab 1 y refl ect i ng the i n e 1 us i on of many cases o f acute urt i car; a
where symptoms subs i de wi th i n two to three wee ks i n about 90% of
pat i ents ( Czarnetzki , 1 986 , page 3 1 ) .
More recent l y L ev i ne ( 1 975)
made br i ef reference to h i s own earl i er ser i e s of 88 pat i ents wi th
chron i c urt i cari a , i n wh i ch two - t h i rds of those contacted were i n
remi s s i on three years o r more after presentat i on .
present study
The res u l t s o f the
i nd i cate a rather l ower remi s s i on
rate
than
that
descri bed by Champ i on et al . ( 1 969 ) , w i t h 50% o f our pat i ents s t i l l
exper i enc i ng symptoms more than e i gh t years after the on set , and 30%
wi th u rt i cari a st i l l act i ve after 20 years .
Th i s d i fference cou l d be
a res u l t o f pat i ent sel ect i on b i as toward s a more chron i c popul at i on
at the RPAH Al l ergy Cl i n i c , or due to the more thorough excl us i on of
pat i ents wi th acute urt i cari a i n a prospect i ve study s uc h as th i s .
119
An i mportant i s sue not addres sed adequate l y i n prev i ou s stud i e s i s
the rol e of avo i dance o f d i etary prec i p i tants i n the control
of
R I U/AO .
in
In
the present study pat i ents are defi ned as be i ng
" remi s s i on " i f t h ey are asymptomat i c , and rema i n s o on an unres tr i ct
e d d i et .
Many o f those surveyed here woul d h ave 1 e arned t o avo i d
spec i fi c foods known to t r i gger recurrences and wou l d not h ave been
c l as s i fi ed a s " act i ve " by C h amp i on et al . ( 1 969 ) , thus y i el d i ng more
favorab1 e fi gures for the remi s s i on rate .
Regres s i on anal ys i s s howed
n o s i gn i fi cant corre l at i on between durat i on o f symptoms and age , sex ,
asp i r i n (ASA) react i v i ty or pattern of symptoms ( urt i cari a al one ,
ang i o edema al o n e or both together) .
I t i s not pos s i bl e to determi ne
whether d i etary restri ct i on accel erates " remi s s i on "
(defi ned as a
l os s o f sens i t i v i ty to food and other tri gge r i ng factors ) wi thout
h av i ng stud i ed a control group on a normal d i et .
However , u s i ng the
data o f C h amp i on et al . ( 1 96 9 ) as h i stor i cal contro l s i t . does seem
t h at t h e s l ope of the l i fe - tabl e anal ys i s i s s i mi l ar to that observed
i n the pre s en t study ( F i gures 4 . 1 and 4 . 2 ) , i mp l y i ng t h at d i etary
restri ct i on i s l i ke l y to have prevented symptom recurrences , but not
nece s s ar i l y to h ave accel erated the l os s o f underl y i ng sens i t i v i ty .
The observat i on t h at amongs t the pat i ents surveyed here , recurrences
were food - re l ated i n the great maj ori ty , most of whom cont i nued to
restri ct t h e i r d i et ,
supports the cl i n i ca 1
va 1 ue o f the d i etary
e l i mi n at i on and c h al l enge protocol i n pat i en t s wi t h R I U/AO , as out
l i ned i n C h apter 3 .
Moreove r , the foods i mp l i cated general l y corres
ponded t o t h e c h al l enge responses i n i nd i v i dual p at i ents , al though i n
a few i nstances foods conta i n i ng ami nes , MSG , n i trates or prop i on ates
were i mp l i cated .
As outl i ned i n Ch apter 6 , some pat i ents w i th R IU/AO
are sen s i t i ve t o these substances when chal l enged , and t h ey are now
i nc l uded as part o f the rout i ne chal l enge battery .
1 20
The foods most common l y found to tri gger recurrences were those wh i ch
conta i ned sa1 i cy1 ates ( Tabl e 4 . 6 ) .
At fi rst s i gh t i t may s eem that
the amount o f sal i cyl ate pre sent n atural l y i n food s ( Ch apter 2 ) wou l d
be too smal l
to produce a s i gn i fi cant effect , even i n sens i t i ve
i nd i v i du al s , and that the dose used i n chal l enge tes t i ng (300 - 600 mg
of ASA)
does not accuratel y refl ect
a normal
d i etary s t i mu l u s .
However ,
the resul ts of the present study strong l y s uggest t h at
s al i cyl ate sens i t i v i ty as defi ned by react i on to a s i ngl e h i gh -dose
chal l enge
doe s
i ndeed
correl ate
cl osel y
tri ggered by s al i cyl ate conta i n i ng foods .
expl anat i on s for t h i s .
general l y
r i ch
in
wi th
cl i n i cal
symptoms
There are two poss i b 1 e
F i rstl y , foods that cont a i n s al i cyl ate are
other
cross - react i ng
compound s ,
part i cul arl y
benzo i c ac i d and i ts der i vat i ves ( i ndeed sa1 i cyl ates are themsel ves
2 -0H - benzoate
deri vat i ves ) ,
and
these
are
o ften
pre sent
at
concentrat i on s one or two orders of magn i tude greater than ASA al one
( Ch apter 1 0 ) .
marker
of
Thus , ASA cha 1 1 enge react i vi ty may be regarded as a
sen s i t i v i ty
to
a
range
of
c l osel y
rel ated
chem i cal
compounds wh i ch may be present i n mi l l i gram ( or g reater) amounts i n
certa i n foods .
Secondl y , even sma 1 1 amounts of s al i cyl ate s uch as
found i n an average Au stral i an d i et ( est i mated at be i ng of the order
of ten mi l l i gram per day ;
over a peri od of t i me .
of
Ch apter 2 ) may h ave cumul at i ve effects
I ndeed , i t has been found t h at ten to 2 5 mg
ASA d a i l y for one to two weeks can reproduce the acute i nh i b i tory
effects of standard doses on pl atel et funct i on ( We ks 1 er et al . , 1 985 ;
Patrono et al . , 1 985 ) .
S i nz i nger et al . ( 1 984) h a s s hown that as
1 i tt 1 e as one mi 1 1 i gram of ASA da i 1 y for seven wee ks can
s i gn i fi cant i n v i tro effect s .
h ave
1 21
At a c l i n i cal l ev e l s a l i cyl a t e - cont a i n i ng foods were q u i te o ft e n seen
to h av e c umul at i ve e ffect s
i n p a t i e n t s w i t h R I U/AO .
Th i s became
p art i c u l arl y obv i o u s once t h e c h art s were drawn up 1 i s t i ng
accord i ng t o s al i cyl ate content i n a n averag e s erv i n g .
foods
Aft e r the
comp l e t i on o f c h a l l e n g e t e s t i ng e ac h p at i e n t wh o reacted t o ASA was
p ro v i d ed w i t h t h e s e c h a rt s and g i v en i n s truct i on s to b eg i n g radual
1 i bera 1 i zat i on after a s i x -wee k p e r i od o f s t a b i 1 i z at i on on
ma i n t en ance d i et (Append i x 1 0 ) .
thei r
Th i s i nv o l ved t h e re - i n troduct i on o f
foods conta i n i ng l ow l ev e l s o f s al i cy l ate , i n i t i al l y i n smal l q u an t
i t i es a n d at i nfrequent i nterval s ;
i f n o symptoms app ea red , pat i e n t s
were i n s tructed t o i nc re a s e t h e amo u n t s e at e n a n d frequency , a n d t hen
t o mov e o n t o foo d s i n the " moderate " col umn ( Tabl e 4 . 1 ) .
In t h i s
way a p at i e n t was abl e , by t r i al - and - e rror to e stabl i sh a t h re s ho l d
dai l y dose ,
beyond wh i ch symptoms wo u l d reapp e ar .
recurrence was
i ns i d i o us rath e r t h an acut e ,
I n many c a s e s
and i t was there fore
often n ec e s s a ry t o return pat i e n t s to the basel i ne " s al i cyl ate - free "
d i et for a two o r t h re e wee k p e r i od , al l ow symptoms t o s u bs i de , and
then beg i n l i be ral i z i ng the d i et more grad u a l l y .
t h e dos e
of
s al i cy l ate
i ng es t ed w a s
furt h e r
The i mport ance of
i l l u strated
by
react i on s o f pat ; e n t s to d i fferent forms of t h e s ame food .
exampl e ,
s ome
the
For
i nd i v i du a l s cou l d s afe l y tol erate a s l i ce of fres h
tomato , b u t wou l d react t o t h e more concentrated s u b s t an c e s i n tom ato
sauce o r tomato paste ( i n wh i ch s al i cyl ate content i s o ften furth e r
i ncreased b y t h e add i t i on o f h erbs and s p i ces ) .
Us i ng t h i s approach , mos t p at i e n t s were abl e to ach i ev e a reasonabl e
degree o f v a r i ety i n t he i r d i et w i thout exper i e nc i ng a recurrence o f
c h ron i c symptoms .
The extent o f u l t i mate l i beral i zat i on o f t h e d i et
122
was general l y determ i n ed by each i nd i v i dual s ' dose - t h re s h o l d wh i ch
o ften ros e gradual l y wi th cont i nued expos.ure , so t h at s ome pat i ents
cou l d u l t i matel y tol erate a v i rtu al l y normal d i et wi thout a maj or
recurrence of symptoms .
I n most cases , h owever , pat i ents s t i l l found
i t n eces s ary to 1 i mi t the i r i ntake of foods wi t h t h e h i g h e s t concen
trat i on s of sal i cyl ate ( e . g .
wi ne , s p i ces , Vegem i t e , strawberri es ,
orange s , ston e fru i ts and p i neappl e ) .
Re - i ntroduct i on o f add i t i ve - conta i n i ng foods was o ften more d i ffi ·
cul t ,
pre s umabl y
s ubstances
bec ause
present
threshol d
l evel s
vegetabl e s .
in
of
the
proces sed
h i gher
concentrat i on s
of
these
food s ,
compared
the
s ub
fru i ts
and
of ASA occurr i n g n atural l y
Pat i ents
were
t herefore
in
wi t h
many
i n structed
to
read
l abel s
c a reful l y when s h o p p i n g , and to be part i cu l ar1 y caut i o u s w i th soft
dri n ks , fru i t j u i ce s , d r i ed fru i ts and other fru i t - ba s ed , l i q u i d and
mo i st
con s i stency
foods
( wh i ch
are
u s �a1 1 y
preserved
wi th
metabi su1 ph i te or benzoate ) .
Pract i ca l d i etet i c adv i ce was an i mportant a spect o f s ucce s s fu l l ong
term man agement i n food - sen s i t i ve pat i ents .
For examp l e , when eat i ng
out at restaurant s or d i nner-part i es adverse react i o n s coul d o ften be
prevented by avo i dance o f grav i e s , s auce s and sp i ces ,
as wel l
as
sal i cyl ate - ri ch vegetabl e s wh i ch often accompany meat d i s h e s , and by
the j ud i c i ous choi ce o f wi nes taken i n smal l amou nt s .
I f , for s oc i al
rea s on s , avo i dance was n ot pos s i bl e on cert a i n occas i on s , an anti
h i s tami ne taken after the meal wa s recommended t o prevent a s evere
react i on .
S i m i l arl y ,
t ravel l i ng pat i ents were adv i sed
to
contact
123
a i rl i ne s i n adv ance f o r prov i s i on o f s u i t ab l e me al s , a n d to d i s c u s s
t h e i r req u i rement s w i t h
h ot e l
a n d re st aurant
s t a ff
( wh e re
it
is
al mo st al ways po s s i bl e t o obt a i n s i mp l e , p l a i n ro a s t s and g r i l l s ) .
Pat i en t s were a l so adv i s ed to avo i d ASA- con t a i n i ng med i c at i on s and to
be c au t i o u s w i t h other non - stero i d al ant i - i n fl ammatory d ru g s wh i ch
may provo ke i d i o syncrat i c react i on s .
Tho s e s e n s i t i ve to t artraz i ne
were adv i s ed t o avo i d col o ured caps u l e s and t abl e t s whe re po s s i bl e ;
i f nece s s a ry caps u l e s c o u l d be opened and on l y t he i r contents taken ,
and t h e col o u red coat i ng o f tabl e t s coul d be removed by rubb i n g t h e
s urfac e g e n t l y under runn i ng wate r .
N u t r i t i onal s t at u s coul d somet i me s be comprom i sed i n pat i e n t s on a
h i gh l y re s t r i cted
d i et ,
pat i ents w i t h R I U/AD .
but
s uppl ements were
rare l y requ i red
in
I f any doubt ex i s ted , - a t h ree t � f i ve d ay d i et
h i story was recorded and anal ysed u s i ng ' t h e " Sod a " computer programme
( Ve rs i on 1 . 2 , R . J . Hart l ey , 1 982 ;
Bent l ey , Wes t ern Aus tral i a ) .
Compute r Mode l s ,
P . D . Box 280 ,
C HA PTER 5
SAL I C Y LAT E PHARMACOK I N ET I (S
124
I NTRODUCT I ON
As o u t 1 i ned i n C h apter 4 , fo 1 1 ow- up o f p a t i ents w i t h R I U/ AO s howed
t h at foods
symptom s .
were
frequent l y i n cr i m i n ated
as
a caus e
of rec u rren t
Furthermore , t here was a very good correl at i o n betwee n t h e
s a 1 i cyl a t e con tent o f t h e food s reported and t h e res u l t s o f b l i n d
c h al l enge w i t h
n at ural
ASA
in
i nd i v i du a l
p at i e n t s ,
s ugges t i ng
t h at
the
s al i cyl a t e s p re se n t i n a w i d e v a r i ety o f p l a n t foods are
i ndeed capabl e of produc i ng cl i n i ca 1 e ffec ts .
From the 1 aboratory
a n a 1 ys i s des c r i bed i n C h apter 2 i t w a s c a 1 c u l ated t h at an averag e
d a i 1 y d i et con t a i n s between ten mi 1 1 i g ram and 1 00 mg o f n at u r al
s a l i cy1 ate , but h ow much o f t h i s i s act u a 1 1 y a b s o rbed i s u n kn own .
I ndeed , t h e h a r s h treatme n t o f food s requ i red for e ffi c i e n t extract
i on ( Ch apter 2 ) s ugges t s that much o f t h e s a l i cyl ate pre s en t i n food
may be c h em i c a l l y bound ( e . g . as e s t ers ) o r p hys i c al l y sequeste red
( H arbo u rn e , 1 980 ;
Newby et al . , 1 980 ) , and t h e extent to wh i ch t h i s
may be rel e a s ed i n v i vo by the normal d i ge s t i v e proces se s i s as yet
u ncerta i n .
I t was t h e re fore dec i ded t o conduct a feed i ng s t udy ,
u s i ng n o rmal s ubj ect s , i n wh i ch u r i n ary excret ion o f s a l i cyl ates and
t he i r maj o r met abol i te s woul d be mea su red a s an i ndex o f the b i o
avai l ab i l i ty o f d i et ary s al i cyl ate .
Hav i ng
e s t abl i s h ed
t h a t d i etary
s al i cyl ates
are
i ndeed
absorbed
phys i o l og i c al l y , t h e quest i on aro s e as to why cert a i n i nd i v i dual s may
react i d i o syncrat i c al l y t o t h e s e s u bs t an ce s .
I t i s general l y agreed
t h at t h e mec h an i sm i s u n l i ke l y t o be attri butabl e t o i mmuno l og i c al
hyper s e n s i t i v i ty ( Ch apter 1 0 ) .
t herefore c o n s i dered :
(i )
Two other broad p os s i b i 1 ; t i es were
t h e pat i ents w i th
R I U/AO may h ave
an
125
a b n o rm a 1 i t y o f s al i cyl ate
ab sorpt i on ,
rnet ab o 1 i srn o r excret i on ,
( i i ) t h ey m ay h ave abn o rmal t arget - org a n re s po n s i ve n e s s .
test the
fi r s t
of
these
hypo t h e s e s
a
p h arrnaco k i n et i c
or
I n o rd e r to
s tu dy was
d e v i s ed t o compare s erum l ev e l s and u r i n ary excret i on o f s a 1 i cy 1 ates
and t he i r met a bo 1 i te s i n ASA - s en s i t i ve R I U/AO p at i e n t s and n o rmal
control s .
The res u l t s cl e ar l y i nd i cated t h at s al i cy l ate d i s p o s i t i on
i s normal i n s uc h i nd i v i d u a l s , at l ea s t w i t h res pect to t h e i r h and
l i ng of a s i ngl e h i gh d o s e , mak i ng i t l i ke l y t h at t he i r abno rmal i ty
l i e s i n t h e e n d - o rg an res p o n s e .
MATERIALS AND M ETHODS
Extract i on o f S a l i cyl ate i n U r i n e
The concentrat i on o f . total s al i cyl i c ac i d i n u r i n e w a s a s s ay e d by a
mod i fi cat i on o f t h e meth od by D ay et a l . ( 1 98 1 ) .
S amp l e s wer e ac i d
i fi ed a n d h e ated i n o rder t o bre a k d own a l l t h e maj o r meta bo 1 i te s of
a sp i r i n
( ge nt i s i c ac i d ,
s al i cy l u r i c ac i d ,
s al i cy l i c a c i d ,
s a 1 i cyl
phenol i c g l u c u ro n i de and s a1 i cyl acyl g l ucuro n i de ) t o s al i cy l a t e , for
wh i ch standard s were ava i l ab l e .
Dupl i cate o n e m i l l i l i t re a 1 i q u ot s of
uri n e were ac i d i fi ed w i t h o n e m i l l i l i tre o f I ON Hel ( AR ) , s e al ed i n a
o
g l a s s ampo u l e and h eated to 120C for two hours .
There a ft e r t h e ac i d-
i f i ed u r i n e s were extracted w i t h fi ve m i 1 1 i 1 i t re s o f d i e t hy l ether
(AR) by m i x i ng o n a vortex for 30 s econds and t h e e t he re a l extract
p i petted
i nt o
a
s t o rage
v i a1
and
temperatu re i n t h e fume c u p bo a rd .
m i l l i 1 i tre met h an o l
HPlC .
evaporated t o
d ry ne s s
at
room
The res i d u e wa s t a ke n u p i n one
( un i c h rom ) p r i o r to i nj ect i on o f 2041 o n t o the
.
1 26
F I GU R E 5 . 1
SAL I C Y LATE EXTRACT I ON I N U R I N E AND S E RU M
I ml Serum
Iml Uri ne
1ml Uri ne
+
+
+
1 ml I ON HCl
I ml S% KHS0 4
1 ml I ON HCl
+
�
Autocl ave 2hrs
�
at 1 20C.
/
Vortex and extract wi t h 1 0m1 d i ethyl ether (AR)
l
Ether extract
l
D i s so l ve i n Im1
l
D i scard aqueou s
meth anol ( un i chrom)
l
I nject 2 0 41 i nto H PLC
Method of Sal i cyl ate Extract i on from Serum
Sal i cyl i c ac i d i n pl asma was extracted by mod i fi c at i on s of t h e manual
method
o f Row1 and
and
Ri egel man
( 1967 )
as
thi s
g ave
the
l east ·
emul s i on format i on of the extract i on methods pub1 i sh ed t h at were
Lange & Bel l , 1 966 ;
tri ed ( Brod i e et al . , 1 944 ;
Bekersky et al . , 1 977 ;
1 974 ;
W ; 1 son ,
al . ,
1 979 ;
C aters on et al . , 1 978 ;
Peng et al . , 1 978 ;
1 978 ;
Cham et
Fraw1 ey , 1 982 ) .
al . ,
L ars s o n & Fuch s ,
1 980 ;
Cham et al . , 1 979 ;
S i oufi
&
Pomm i e r ,
Chras t ; l &
De Boer et
1 980 ;
Ou &
One m i 1 1 i 1 i t re of serum was p i petted i nt o a I Sm1
127
con i cal
centri fuge
t ube
cont a i n i ng
one
potas s i urn b i s u 1 ph ate ( KHS0 4 ) (AR) sol ut i on ,
m i l l i l i tre
fi ve
percent
(wh i ch acted as an ac i d
i fy i ng med i um and adj usted the pH to two ) extracted wi t h fi ve m i l l i
l i tre s d i ethy1
ether
(AR)
by vortex i ng
for 30
seconds
and
then
cen t r i fuged at 2 500 rpm i n an I EC centra refri g erated centr i fuge
mi n u s fi ve degrees cent i grade .
The ethereal
at
extract was p i petted
i nto a storage v i al and evaporated to dryne s s at room temperature i n
t h e fume cupboard .
The res i d u e was taken u p i n o n e m i 1 1 i 1 i tre of
met h anol ( un i c h rom) pri or to i nj ect i on of 20m1 i nto t h e H P LC .
H PLC Devel opmen t
I n order to conven i en t l y i nvest i g ate the d i spos i t i on o f s al i cyl i c
ac i d i n pl asma and uri n e a d i rect , spec i fi c and s en s i t i ve a s s ay
sought .
The vari ety of publ i s h ed a s s ay methods ( Brod i e et al . , 1944 ;
Schacter & Man u s ,
F i orese ,
was
1 963 ;
1 9 58 ;
Ch i ri gos & Uden fr i end ,
Row1 and & R i ege l man ,
1 967 ;
1 95 9 ;
Umberger &
Thomas e t al . ,
1 973 ; ,
Ranee et al . , 1 97 5 ) presented probl ems as to t he i r ease of operat i on ,
d i rectn e s s , spec i fi c i ty , a n d sen s i t i v i ty requ i red for t h e an al ys i s o f
a l arge n umber o f sampl e s .
H P LC prov i ded a met h od t h at woul d s i mul ·
taneou s l y perm i t the separat i on and quant i fi cat i on of acetyl s a l i cyl i c
ac i d metabol i tes from serum a n d uri n e ( Be kers ky et al . , 1 977 ;
et al . , 1 9 78 ;
al . , 1979 ;
1 982 ) .
Caterson et al . , 1 978 ;
C h am et al . , 1 980 ;
Peng et al . , 1 978 ;
Day et al . , 1 98 1 ;
8l ai r
C h am et
Ou & Fraw1 ey ,
The u s e o f a fl uoresce n t detector rather t h an u l tra v i ol et
detector max i mi z �d sen s i t i v i ty wh i l st m i n i mi z i ng t h e backg ro u nd
to b i ol og i cal i mpuri t i es ( Be kers ky et al . , 1 9 77 ;
due :
Bl a i r et al . , 1 978 ; ,
•
Day et al . , 1 986 , 1 987 ) .
Exten s i ve sampl e cl ean - up was e l i mi n ated by
t h i s met h od and en abl ed rap i d an al ys i s o f a l arge n umber o f s ampl es .
128
H PLC Separat i on
H P LC was c arr i ed out us i ng a Vari an 5060 pump i ng sy stem wi t h Rheodyn e
7 1 2 5 i nj ect i on val ve .
A sta i nl e s s steel col umn 1 2 5mm by 4 . 6mm , was
packed wi t h Spher i sorb Sum aDS packi ng fi tted w i t h a precol umn packed
wi t h Vydac RPP389 p ac k i ng materi al .
The e l uent was mon i tored wi t h a
Schoeffel FS 9 7 0 LC fl uorometer and a GM 970 monochromater operated at
3 1 5 nm for exc i t at i on and emi s s i on greater t h an 389nm ( Day et al . ,
1 986 ) .
The i socrat i c mob i l e phase used was a m i xture of meth anol :
water :
g l ac i al acet i c ac i d ( 20 : 80 : 1 . 6 ) ( Be kers ky e t al . , 1 977 ;
C aterson et al . , 1 978 ;
et a l . , 1 98 1 ;
l i tres
per
connected to
C h am et al . , 1 979 ;
Cham et al . , 1 980 ;
Day
Day et al . , 1 986 ) at a constant fl ow of two m i l l i
m i nute .
a Var i an
The
COS
fl uorescence
111
detector
comput i ng
sen s i t i v i ty
i ntegrator
was
and Houston
Omn i scr i be recorder .
Twen ty m i crol i tre s of extracted uri ne and serum s ampl es were i nj ected
onto the H PlC al ong wi t h standard s .
Retent i on t i mes and areas under
the peak were mon i tored and computed automat i cal l y by the i ntegrator .
I de n t i fi cat i o n was based on retent i on t i me and fl uorescence wave
l ength compared wi t h the standards , as wel l as by co - chromatography
wi t h t h e standards .
Di etary Study
( a ) Su bj ect s
Twenty n i ne heal t hy vol unteers from the D i etet i cs Departmen t and
I mmunol ogy Department , RPAH , and the Human Nutri t i on Un i t , Un i vers i ty
o f Sydney , g ave i n formed con sent to part i c i p at i o n i n t h e s tudy .
The
s ubjects were adul t s , aged 19 to 55 years , and cons i sted of 1 1 mal e s
129
a n d 1 8 femal es .
N o n e h ad been taki ng any med i c at i on for the prev i ous
two wee ks .
( b ) Study des i gn
Subj ects were al l owed to eat norma 1 1 y unt i 1 t h e even i ng be fo re the
any
t a ke
were
as ked not
to
an
overn i gh t
fast e ac h was
study beg an ,
but
med i cat i on s .
After
asp i r i n - co nt a i n i ng
s uppl i ed
wi th a
l ow- s al i cyl ate d i et for two d ays and then al l owed t o return to a
n o rmal d i et for two wee ks . At t h e end o f th i s t i me , a h i g h - sal i cy1 ate .
d i et was prov i ded for a further two days , fo 1 1 owed by a return to
normal d i et once aga i n .
At the beg i nn i ng of e ac h test d i et , s u bj ects '
were as ked to empty the i r b1 adde r before bre a kfast , and to co1 1 ect '
al l
uri n e pas sed over t h e next three days
Col l ect i on bottl e s were preserved wi t h t hymol
i nterfere wi t h s al i cy1 ate est i mat i on s .
i n 24 - h o u r a1 i quot s .
( BP ) wh i ch doe s not
At t h e end o f each 24 - hour .
co 1 1 ect i on , uri ne vol ume was measured and an a 1 i quat pl aced i n a ·
s pec i men j ar for storage at - 20C .
( c ) Food Preparat i on
A1 1 meal s were prepared by the author ( ARS ) and s upp 1 i ed to the
s ubj ects ( u su al l y ) i n the Metabol i c House .
S avoury food s , d e s se rts
and c a ke s were prepared , packaged and frozen i n advance ;
meat , eggs , ,
s al ads , fru i t , vegetabl e s , sandw i ches and t arts were fre sh l y prepared :
the day before . they were requ i red .
The h i g h - s al i cyl ate d i et was '
des i gned w i t h an emphas i s o n fru i ts , vegetabl e s and cond i ments known .
to be r i ch i n s a 1 i cy1 ate s ( Ch apter 2 ) , prov i d i ng a n e s t i mated 88 mg
per d ay , whereas the " l ow" s al i cyl ate d i et con s i sted o f food s w i th no .
detectabl e sal i cyl ate content ( Tabl e 5 . 1 ) .
130
TAB L E 5 . 1
D I ETARY I NTAKE ON LOW AND H I GH SAL I CY LATE D I ETS
H i gh Sal i cYl ate I ntake
Low Sal i cyl ate I ntake
mg/serve
mg/ serve
Weetb i x + mi l k + sugar
0
Orange j u i ce
1 . 00
Poached egg
0
Dr i ed fru i t + honey
8 . 55
Toast + butter + G . syrup
0
Toast + butter + honey
2 . 74
Andron i cu s coffee + m i l k
0
Tetl ey tea ( I bag )
2 . 79
Pl a i n oatmeal b i scu i t
0
Al mond + date sl i ce
5 . 37
Andron i cus coffee + mi l k
0
Tetl ey tea ( 1 bag )
2 . 79
Egg and l ettuce s andwi ch
0
Savoury meat l oa f
7 . 08
Pee l ed pear
0
Carrot + ra i s i n s al ad
2 . 69
Banana
0
Cherry al mond tart
6 . 06
2 . 79
0
1 00g sul tan as + ra i s i n s
7 . 21
Andron i cus coffee + mi l k
0
Tetl ey tea ( 1 bag )
2 . 79
Lamb chops
0
200ml orange j u i ce
1 . 00
Potato ch i ps
0
Curry + bo i l ed ri ce
16 .31
Lettuce
0
Al mond apri cot p i e
4 . 46
T i nned pears
0
Dri ed fru i t + honey
5 . 02
Baked r i ce custard
0
I cecream
0
Al mond + date s l i ce
5 . 37
Andron i cus coffee + m i l k
0
2 . 79
Total s al i cyl ate (mg ) /day
0
88 . 27
131
( d ) Stat i s t i cal An al ys i s
The 24 - hour uri n ary s al i cyl ate l evel s i n the per i od s o n the h i gh
and
l ow s al i cyl ate d i et were compared us i ng the P a i red Student ' s T-Test .
The d at a were p a i red for e ach o f the t h ree d ays and t h e d i fferences
were assumed to be normal l y d i stri buted .
Asp i ri n Chal l enge Study
( a ) Subj ects
Two g roups were stud i ed :
sal i cyl ate - sen s i t i ve pat i en t s w i t h R IU/AO
and normal control subj ect s .
Pat i ents w i t h R I U/AO were cho sen from
amon g those i nvest i g ated pri or to August 1 984 i n t h e Al l ergy Cl i n i c
;
'
i
I
at RPAH ;
al l h ad responded to the el i mi n at i on d i et and were s hown
be sal i cyl ate sens i t i ve on bl i nd chal l enge .
to
Pat i e n t s known to be
compl i an t and rel i abl e were contacted , and after expl an at i on of
protocol 23 i nd i v i du al s con sented to part i c i pate i n t h e study .
.
the
When ·
tested prev i ousl y , fi ve p at i e n t s h ad reacted to asp i r i n al one and
t he
rema i n i ng 1 8 h ad reacted to asp i r i n and between one and seven other
chal l enges .
N i ne mal e s ( 3 9%)
and 1 4 femal e s part i c i pated i n
study , t he i r age s rang i ng from 1 5 to 70 years ( med i an age 3 8 ) .
t he
The
I
durat i on of R I U/AO pri or to presentat i on ranged betwee n fou r wee ks
and 36 years ( med i an three years ) .
Con t rol s u bj ects were ten h eal t hy femal e vol u nteers w i t h n o h i story
of R I U/AO , from t h e Department of D i etet i c s and Metabo l i c Ward
RPAH .
at
Each was a s ked to absta i n from a sp i ri n - conta i n i ng med i cat i ons
and to fol l ow a l ow sal i cyl ate d i et for two wee ks before the s tudy
order to ens ure a n equ i v al ent
s u bj ects wi th R I U/AO .
sal i cyl ate
in
i ntake t o t h at o f the :
132
( b ) Study De s i gn
The l ow s al i cyl ate d i et fo l l owed by al l s u bj ect s was t h e s ame as t h at
u s ed for t h e man agemen t o f pat i ent s wi t h R I U/AO ( Ch apter 3 , Append i x
7) .
Aft e r an overn i g h t fas t t h e s u bj ects presen ted to t h e met abol i c
ward at RPAH .
On arr i val , e ac h was as ked to empty t he i r bl adde r for
a basel i ne ur i ne me a s urement , and a 2 1 - gauge i ndwel l i ng " butterfl y "
n eedl e was pl aced i n a s u i t abl e forearm ve i n .
The n eed l e was fl u s h ed
w i t h hepar i n i zed sal i ne to ma i nta i n patency , and before col l ect i on o f
e ac h s ampl e approx i matel y two m i l l i l i tre o f bl ood w a s asp i rated and
d i sc arded to c l ear the n eedl e .
Each s ubj ect was then g i ven one 3 00mg
s o l u bl e ASA t abl et d i s sol ved i n approx i matel y 200ml o f water ,
and
bl ood and u r i n e s ampl e s taken at the fol l ow i ng i nterv al s :
Bl ood :
0 , 3 , 6 , 1 0 , 1 5 , 20 , 2 5 , 30 , 40 , 50 , 6 0 , 7 5 , 90 , 1 05
m i n u te s , 2 h r , 2 . S h r , 3 h r , and t h en h ourl y u p t o 1 0 h r .
( Rowl and
et al . , 1 97 2 ) .
Uri n e :
hourl y for 1 0 h ours ( Graham et al . , 1 977 ) .
At
the end of
the d ay pat i e n t s and contro l s were g i ven a bottl e t o t a ke home and
a s ked to co l l ect u r i ne overn i gh t , e nd i ng t h e col l ect i on at 24
hours .
Bl ood s ampl e s of 1 0ml were al l owed to c l ot i n pl a i n pl ast i c tubes at
room temperature .
The bl ood was then centr i fuged at four degrees
o
cent i grad e , serum p i petted o ff and stored at - 20C unt i l a s s ayed .
The
u r i n e was col l ected i n SOOml gl a s s beakers , measured , and stored i n
ster i l e p l a st i c spe c i men j ars at - 2 �C unt i l as s ayed .
A
water i ntake
133
of 200ml / h r was ma i nt a i n ed for ten hours and a l i g h t bre a kfa s t , l un ch ,
and d i n n e r were al l owed at two h ours , f i v e h o u rs and ten h ours after
admi n i strat i on of the ASA .
RESU LTS
D i etarY Study
The tota l sal i cyl ate excret i on i n e ac h 24 - hour peri od on the l ow and
h i gh s al i cyl ate d i et was cal c u l ated and t abu l ated for
subj ects ( Tabl e 5 . 2 ) .
Two o f these ( W . B and
i nd i v i dual '
A . l . ) took part i n the .
l ow sal i cyl ate d i et per i od but were un abl e to comp l ete t h e s tudy as
t h ey were overseas at t h e t i me .
I n a furth e r t h ree p at i e n t s one or '
two u r i n e s amp l e s were d i scarded as t h e frozen al i quo t s th awed when
j
1
�
the freezer was acc i dentl y l e ft open .
�
j
�
1
1
For each d ay o f t h e l ow and h i g h s al i cyl ate d i et peri od , t h e mean ,
1
,j
1
s tandard d ev i at i on ( SO ) and standard e rror ( SE ) o f t h e total u r i nary
�
s al i cyl ate , was cal cul ated for t h e s u bj ects a s a grou p ( Tabl e 5 . 2 and
F i gure 5 . 2 ) .
The mean excret i on of s al i cyl ate on t h e " l ow " d i et :
decreased s i gn i f i c ant l y from a basel i ne o f 8 1 . 66 mg t o 3 7 . 47 mg over
the three days stud i ed ( P <0 . 002 ) .
Converse l y , on t h e " h i g h " d i et ,
i
mean sal i cyl ate excret i on i ncre a s ed from 96 . 3 2 mg to 1 1 4 . 34 mg ( P 'l
<0 . 002 ) .
Overal l , the d i fference between day one on the " l ow" and ,
" h i gh " d i et per i od was n ot s i gn i f i cant ( P <0 . 2 ) , but on d ays two and :
three t h e d i ffe rences i ncreased to 53 . 7 mg and 76 . 87 mg res p ec t i vel y
( P <0 . 00 1 ) .
134
TABLE 5 . 2
TOTAL SAL ICYLATE EXCRETED ( MG/24 HOUR UR I NE )
Subjects
Low Sa l i cy late
Day 1
Day 2
Day 3
B.R
S.H
J. H
H. B
T.G
Y.F
M.P
A. S
S.V
M.A
M.O
N.S
D.M
K. B
J.K
G. B
A. S
W.B
LD
P .W
M.D
G.T
P.D
S.S
S.D
V.C
D.T
R.L
A. T
28 . 80
137 . 18
42 . 62
71 . 60
1 19 . 56
76 . 09
147 . 60
35 . 50
130 . 13
107 . 60
89 . 33
60 . 9069 . 54
43 . 51
43 . 37
93 . 32
83 . 50
81 . 90
94 . 18
70 . 54
1 27 . 36
32 . 94
78 . 48
101 . 49
80 . 94
121 . 09
84 . 86
27 . 1 5
86 . 95
18 . 83
42 . 87
85 . 73
67 . 17
45. 40
72 . 75
41 . 73
25 . 52
53 . 27
68 . 37
4 . 48
54 . 00
33 . 41
37 . 54
23 . 13
76 . 84
51 . 71
53 . 07
46 . 12
27 . 83
67 . 50
22 . 09
59 . 15
92 . 13
43 . 01
63 . 84
80 . 85
28 . 14
27 . 48
2 . 41
22 . 58
69 . 56
7 1 . 47
49 . 48
72 . 28
48 . 33
Mean
81 . 66
48 . 76
S.E
6 . 26
4 . 03
28 . 48
55 . 91
2 . 66
55. 67
5 . 41
45 . 15
13 . 92
53 . 48
18 . 02
37 . 96
1 1 . 88
33 . 44
79 . 12
1 . 96
60 . 59
24 . 39
61 . 90
53 . 00
29 . 12
2 1 . 40
18 . 90
H i gh Sa 1 i cy late
Day 1
Day 2
Day 3
37 . 23
107 . 67
122 . 67
173 . 98
94 . 20
96 . 80
98 . 68
131 . 70
54 . 36
1 15 . 50
44 . 39
145 . 82
87 . 29
101 . 35
67 . 99
83 . 90
106 . 80
176 . 80
1 19 . 64 . 113 . 86
120 . 80
1 12 . 70
133 . 01
1 1 1 . 94
99 . 10
1 15 . 30
99 . 48
89 . 78
82 . 65
1 1 7 . 36
150 . 12
9 1 . 56
126 . 54
105 . 28
121 . 73
75 . 80
,1 25 . 96
132 . 12
87 . 84
59 . 49
78 . 68
79 . 20
1 03 . 66
144 . 20
96 . 25
85 . 05
135 . 12
102 . 61
9 5 . 47
81 . 27
1 14 . 96
49 . 21
1 1 2 . 30
122 . 40
133 . 89
38 . 76
149 . 04
43 . 38
109 . 40
92 . 04
1 17 . 4 1
64 . 50
88 . 46
100 . 44
65 . 9 5
136 . 99
98 . 78
74 . 96
37 . 47
96 . 32
1 02 . 46
1 14 . 34
4 . 49
7 . 23
4 . 13
6 . 39
184 . 00
1 18 . 99
60 . 20
96 . 60
80 . 60
148 . 40
122 . 90
148 . 95
124 . 53
90 . 30
v
m
�
Ij
,',
:1
�
:ii
'I
�:
ill
�
I!I
�,
135
F I G U RE
5 .' 2
TOTAL SAL I CYLATE E X C R ET I ON
""
U)
""
E
n = 29
CD
U)
+1
� c:
C\I
...... tU
CD
�
.s::.
C) �
E
E
�
U)
CD
:!::
110
(;
100
...
90
E
80
.c
tU
CD
"C
c:
tU
70
...
CD
60
>.
.2
1U
50
40
�
30
as
U)
�
as
c:
.�
�
®
120
0
20
10
1U
...
0
I-
1
2
3
DAYS
A . Uri nary sal i cyl ate of pat i ents on l ow sal i cyl ate d i et
B . Uri nary sal i cyl ate of pat i ents on h i gh s al i cyl ate d i et
Aspi ri n Chal l enge Study
I n order to determi ne whether pat i ents wi t h R I UjAO mi ght h ave an
abnormal i ty of ASA pharmo ki net i c s ,
23 sal i cyl ate - sen s i t i ve pati ent
and ten control s were g i ven a s i mpl e oral dose of 300 mg ASA , wh i l st
1 36
o n a l ow - s a l i cyl ate d i et , and t he i r bl ood and u r i n e c o l l ected over a
2 4 h ou r p e r i od .
The re s u l t s o f s erum s al i cyl ate l evel s are s h own i n
F i g ur e 5 . 3 , and u r i n ary excret i on i n F i gure 5 . 4 , i n e a c h c a s e w i t h
t h e c o n t ro l val u e s s up e r i mpo s ed over t h o s e o f t h e t e s t s ubj ects .
No
s i gn i f i c an t d i fferenc e s were seen i n e i t h e r s e rum o r u r i n ary s al i cy l at e l evel s a t e ac h t i me p o i nt , s ugge s t i ng t h at t h ere i s u n l i ke l y t o
b e any abnormal i ty i n t h e absorpt i on , metabol ; s rn o r excret i o n o f a
s i ng l e d o s e o f ASA i n p at i e n t s w i th R I U/AO .
F I GURE 5 . 3
SERUM SAL I CYLATE L EV E LS
-
e
•
•
+I
c:
•
•
E
p at i ents ( 2 8 )
CD
�
III
>
III
�
c o ntrol ( 1 0)
2
::)
Cl:
III
•
III
..
C
...
>
(,)
:::;
c
(I)
I
60
1 00
200
300
400
600
i
800
m i nu t e s
137
F I GURE 5 . 4
U R I NARY SAL I CYLATE EXCRET ION
300
,..
e
•
•
+c:
..
•
e
-
Cl
E
w
...
j
280
260
240
220
200
>-
1 80
Cl)
Cl)
<
1 �O
�<
I
a.
Cl)
<
�
�
...
w
a:
()
)c.
w
>-
a:
i
::)
1 40
patients (28)
1 20
controls · ( 1 0 )
100
80
60
40
20
'1
·2
3
4
5
6
7
8
9
10
24
hours
D I SCUSS ION
The absorpt i on , d i stri but i on and metabol i sm of ph armol og i cal l y admi n
i stered s al i cyl ates i s exceed i ng l y comp l ex ( rev i ewed by Ra i n s ford ,
1 984 , pp . 3 2 -66) .
exten s i vel y stud i ed :
�
Asp i ri n and sal i cyl l e ac i d have been the most ,�
they are weak ac i ds , and are rap i dl y absorbed
as the non - i on i zed forms at l ow pH i n the stomach .
appears i n the serum more rap i dl y ,
Sal i cyl i c ac i d '·
part 1 y because o f i ts h i gher ·r
part i t i on coeffi c i ent and stronger b i n d i ng to pl asma prote i n s , and
138
p art 1 y bec ause o f t h e del ay i n transport o f ASA d u e t o i t s i nter
act i on w i t h muc o s al esterases .
Pl asma 1 eve 1 s i ncre a s e w i t h f i rst
order k i n et i c s , reach i ng a peak between 20 m i n utes and 2 hours after
a s i ngl e oral d o s e , a l t hough there i s a h i gh degree o f i nter - s u bj ec t
v a r i a b i l i ty ( Rowl and e t al . , 1 972 ) .
More t h an 90% o f t h e s al i cyl ate
and 85% o f ASA i n p l asm a i s bound to a l bum i n ,
mod i fi ed by age , d i etary prote i n i nt a ke ,
pH ,
but t h i s can
pl a sma 1 i p i d s ,
be
d rug
t h erapy and d i sease s t ates ( i nc l ud i ng hypersens i t i v i ty ;
Storm van
Leeuwen ,
s i te s :
1 9 24 ) .
There are t hought to
be two
b i nd i ng
a
p r i mary one re s embl i ng t h at for tryptop h an and i t s d er i v at i ve s , and a
second ary s i te rather 1 i ke t h at occup i ed by l ong - ch a i n fatty ac i ds
and an i on i c azo - dye s .
a s wel l
1 97 1 ) .
S a1 i cyl ates may compet i t i ve l y d i s p l ace t h e s e ,
a s other bound drug s ,
hormones and met abo1 i tes
( Da v i son ,
Free and bound forms are i n dyn ami c equ i l i br i um and t h e free
concentrat i on
determ i nes
bot h
therapeut i c
and " adverse
e ffects
( Ra i n s ford , 1 984 ) .
As p i r i n
i s rap i dl y hydrol ysed to s al i cyl ate
by esterases
in
g astro i ntest i n a 1 tract , bl ood , l i ver , ki dney and other org an s .
the
More
t h a n 50% o f an ora 1 1 y adm i n i stered dose may be extracted and/or
metabol i zed o n
fi rst p a s s
t h rough
the
l i ver .
Met abol i sm
occurs
t h rough hydroxy1 at i on or conj ugat i on , s ummari zed i n F i g ure 5 . 5 .
capac i ty for format i on o f gl yc i n e -
and gl ucuron i de conj ugates
The
is
l i mi t ed , and c a n be compet i t i ve l y i nh i b i ted by other pheno1 s , wh i ch
m ay there fore be an i mportant factor i n determ i n i ng tox i co l og i c a 1
e ffec ts .
uri ne ;
Excret i on of al l met abo 1 i tes i s al mos t ent i re 1 y v i a the
s a 1 i cyl ate i t s e 1 f undergoes gl omeru1 ar fi 1 trat i on ,
p a s s i ve
proxi ma 1 reabs orpt i on and act i ve tubul ar s ecret i on , and the 1 atter
139
can be i nh i b i ted by compe t i ng ac i ds ( i ncl ud i ng benzoate metabol i tes ) . '
Reabsorpt i on
is
strongl y
pH -dependent
wi t h
cl e arance
i ncreas i n�
dramat i cal l y above uri ne pH l evel s o f 6 . 5 ( D av i son , 1 9 7 1 ) .
The ma i n p arameters govern ; ng sal i cyl ate pharmacok i net i c s are shown
i n F i g ure 5 . 6 .
Rate constants can be cal cul ated from math emat i cal
'
model s compr i s i ng two or more compartment s ( Rowl and et al . , 1972) ,
al though the s i t u at i on becomes very compl ex wi t h chron i c adm i n i strat
i on .
Thu s ,
the steady - st ate
p l ate au l evel s
ach i eved by regul ar
i ngest i on i ncrease more than proport i onatel y w i t h i ncreas i ng dose , as
does the t i me requ i red to reach the p l ateau ( Levy
t
1 968 ;
Levy l j
!
Tsuch i ya , 1 972 ) , probabl y due to s aturat i on of the p athway s respons - ;
'
i bl e for b i otran s format i on to sal i cyl uri c ac i d and s al i cyl phenol i c
gl ucuroni de ( Levy , 1 96 5 , 1 966 , 1 978 ) .
The d i sproport i onal i ty i s more marked wi t h respect to free than bound
s al i cyl ate
due
to
decreased
concentrat i on s ( Levy , 1 980 ) .
b i nd i ng
by
al bum i n
wi t h
i ncreas i ng
I n add i t i on to t h i s t here are marked
i nter- i nd i v i dual var i at i on s i n sal i cyl ate pharmaco k i n et i cs , w i th a
four- fol d range of areas under the concentrat i on - t i me curv e .
The degree to wh i ch sal i cyl ates i n foods are present a s free ASA and
sal i cyl i c aci d ,
versu s chemi cal l y bound e s ters or t h e phys i cal l y
sequestered compounds i s un known .
The feed i n g study descri bed i n
th i s C hapter was des i gned to exam i n e the bi oava i 1 ab i 1 i ty of di etary
sal i cy1 ates by measuri ng t he i r uri n ary excret i on p roducts on a h i gh
and l ow- s al i cyl ate d i et ( Swa i n et al . , 1 985 ) .
attempted
to
s al i cy1 ate s ,
exami ne
the
gastro i ntest i n al
No p rev i ou s study h as
absorpt i on
of
d i etary
a l though many stud i e s s ugge st t h at t h ey c an produce
1 40
s i gn i f i c a n t cl i n i cal
e ffects .
I ntere s t i ng l y ,
many p h armaco l og i s t s
h av e n o ted smal l b u t detectabl e l evel s i n t h e serum o f i nd i v i du a l s
n o t exp o s ed to any s al i cyl ate - cont a i n i ng med i c at i on s , and t h i s h as
u s u al l y been attri b uted to " bac kground n o i s e " i n t h e a s s ay sys tem
rath e r t h an to genu i ne a bs orpt i on from d i e t ary · s ou rces ( R . O .
D ay ,
p e rs o n a l commun i cat i on ) .
F I GU R E 5 . 5
SAL I CY LATE METABO L I SM
Asp i r i n
2
/
Gent i s i c ac i d
S a l i cyl i c ac i d
Sal i cyl uri c aci d
\
4
S a l i cyl phenol i c g l ucuro n i de
S al i cyl acyl g l ucuron i de
1.
2.
3.
Hydroxyl ati on ( he p at i c m i cro somal cytochrome P450 )
4.
G l ucuro n i c ac i d conj ugat i on ( gastro i ntest i na l tract , l i ve r ) *
Spo n t aneous , a s p i r i n esterases or prote i n acetyl at i on
G l yc i n e conj ugat i on ( l i ver , k i dney s ) *
( * capac i ty l i mi ted p roces s e s )
141
F I GURE 5 . 6
SAL I CY LATE B I OD I STR I BUT ION
Absorpt i on
�
BLOOD
Bound
Met abol i sm
( l i ver , k i dney )
t�
Free
Therapeut i c e ffects
Adverse react i on s
Tox i c i ty
Excre t i on
Basel i ne l evel s of total uri n ary s al i cyl ates i n the s u bj ects stud i ed .
h ere were approx i matel y 80 - 1 00 mg per d ay ( range 29 to 1 49 ;
Tabl e
5 . 2 ) , and a s s um i ng these to be steady - state v al ues they can be taken '
to refl ect the amount of s al i cyl ate absorbed per d ay from the gastro
i ntest i na l
tract .
Al thoug h the
bowel
m i crofl ora
are capabl e of
synthes i z i ng certa i n phenol i c substances t here i s no ev i dence that
they are c ap abl e of produc i ng s al i cyl ates .
I t i s therefore reason
ab 1 e to concl ude t h at the base 1 i ne excret i on i s equ i v a 1 ent to the
amount absorbed from the normal d a i l y d i et .
I n retros pect i t woul d
h ave been i nterest i ng to h ave t a ken a d i et h i story from the each o f
the subj ects before they entered the study i n order to e s t i mate the i r
d a i l y i nt a ke .
Nevert hel ess , the excret i on o f the group a s a whol e
142
corre s ponds to the cal cul ated s al i cyl ate content ( 1 0 - 1 00 mg ) o f an
average Austral i an
d i et
( Ch apter
2) ,
sugge s t i ng
t h at
the
great
maj ori ty i s i ndeed rel eased by the normal d i gest i ve proces s and i s
a v a i l abl e for absorpt i on .
Dur i ng t h e two d ays on a l ow sal i cyl ate d i et mean uri n ary excret i on
fel l progre s s i vel y to approx i mate l y h al f t h e basel i ne ;
s i mi l arl y , on
t h e h i gh s al i cyl ate d i et excret i on i ncre a s ed by al mos t 20 mg/24 hour
and h ad cl earl y not yet reached a pl ateau on day t hree .
Gi ven the
compl ex i t i e s o f sal i cyl ate pharmaco k i n et i cs i t may wel l h ave t a ken
several more d ays or even l onger , to reach a steady - s t at e i n each
case .
It t h erefore rema i n s for fut ure
stud i es to determ i n e t h e
extent to wh i ch s al i cyl a t e s c a n be comp l etel y el i mi n at ed from t he
body on a l ow s a l i cyl ate d i et ,
and t h e exten t t o wh i ch they may
accumu l ate on a sal i cyl ate - r i c h d i et .
I nter- i nd i v i dual v ari a b i l i ty i n sal i cyl ate ph armaco k i n et i cs i s wel l
docume nted , and can be qu i te marked , a s outl i ned above ( Levy , 1 980 ) .
I t was there fore o f i ntere s t i n t h e present study to a s k whether
p harmacogenet i c d i fferences m i ght be a s i gn i fi cant factor i n deter
m i n i ng the s u s cept i b i l i ty o f cert a i n i nd i v i du al s t o asp i ri n - i nduced
R I U/AO .
Th i s quest i on was appro ached by compari ng t h e p harmaco k i n et i cs o f ASA
i n s al i cyl ate - sen s i t i ve R I U/AO pat i ents wi t h t h at o f a normal control
grou p .
Al l
subj ect s fol l owed a l ow- s al i cyl ate d i et for a 2 wee k
peri od , at t h e end o f wh i ch t h ey g i ve a s i ngl e dose o f 300 m g o f ASA
oral l y ,
and s erum and uri n ary s a l i cyl ate l evel s were me a s ured at
143
appropri ate i nterv a 1 s over the next 24 hours .
As i n other stud i e s
s e rum l evel s pea ked at around 60 mi n utes and decl i ned exponen t i al l y
over t h e n ext 1 0 hours ;
uri n ary excret i on i ncreased progre s s i vely
over t h i s t i me , and rema i ned n ear pl ateau l evel s overn i g h t ( Grah am et
a l . , 1 977 ;
Levy , 1 978 ) .
No s i gn i fi cant d i fferences were seen i n the
R I U/AO pat i en t s compared wi th t h e control
F i gure 5 . 4 ) .
Th i s
metabol i sm
the
a l though
in
is
fi nd i ng makes
reason
for
it
u n l i ke l y
s al i cyl ate
v i ew o f t h e compl ex i t i e s
group
( F i g u re 5 . 3
t h at
abnormal
i nt o l erance
o f s a l i cyl ate
in
and
ASA
R I U/AO ,
accumul at i on ·
k i net i cs outl i ned above , pat i ents g i ven regu l ar ASA doses may h ave
s h own s i gn i fi cant d i fferences after several d ays .
Howe ve r , t h e fact
t h at 20 out o f t h e 26 R I U/AO s u bj ect s devel oped urt i c a r i a w i t h i n 36
hours o f t h e s i ng1 e ASA test dos e , wh i 1 st t h e i r serum and u r i n ary
sal i cyl ate l evel s were no d i fferent from contro l s , sugg e s t s t h at the
abnorma l i ty
is
more
l i ke l y
respon s i ven e s s ( Ch apter 1 0 ) .
to
l ie
at
the
l evel · of
end - organ
1
1 44
I NTRODUCT I ON
Al t ho ug h t h i s study was beg un wi th the i ntent i on o f defi n i ng t h e ro l e
o f d i e t i n R I U/AO ,
cl i n i c al
exper i ence i n the fi rst t h ree ye ars
i nd i cated t h at food react i on s coul d a l s o provo ke a n umber o f other
symptoms
( 1 98 1 ) ,
in
s u s cept i bl e
obs erved
t h at
i nd i v i du a l s .
s ome
I n i t i al l y we ,
l i ke
pat i ents presen t i n g w i t h
s u ffe red other concom i t ant symptoms ,
s uc h a s
Juhl i n
R I U/AO
h e ad ach e ,
a l so
abdomi n al
p a i n , rh i n i t i s or asthma , and t h at t h e s e symptoms coul d be provo ked
by spec i fi c chal l enges .
pop u l at i on ch anged
L ater , as the spectrum o f t h e Al l ergy C l i n i c
( C h apter
1)
it
became c l ear
t h at
these
n on
cutaneous man i fes t at i on s o f food i ntol erance coul d occur a s i sol ated
syndromes , or i n vari o u s comb i n at i on s .
Dur i n g t h i s t i me i t a l s o bec ame e v i dent t h at a n umber o f pat i ent s
e xperi en ced v ague con s t i t ut i o n al and/or n e uropsych i at r i c sympt oms i n
conj unct i on w i t h the i r s omat i c comp l a i n t s , and t h at t h e s e too coul d
s u bs i de
wi th
c h a l l en g e .
d i etary
restri ct i on
and
re appe ar
wi t h
s ub s equen t
The i ncreas i ng n umbers o f pat i ents present i ng w i t h sub
j ec t i ve symptoms
made i t i mperat i ve to u s e a doubl e - bl i nd c h al l enge
protocol wh i ch i ncl uded s u i t abl e pl acebos .
As a res u l t t h e chal l enge
battery devel oped fo r i nvest i g at i on o f R I U/AO wa s mod i f i ed i n 1 981 .
A n umbe r o f ot her s u bstances not prev i o u s l y tes ted i n urt i cari a , but
i mp l i cated
in
the
l i terat ure
as causes
o f vari ous
n o n - cut aneou s
adverse react i on s , were i n cl uded ( Tabl e 6 . 1 ) , al o ng w i t h a ch ange to
145
suc ros e
s t a r c h as
an d
n um bered
in
I n add i t i on , the c h al l enges were
p l a c e bo s .
a n ar b i t r ary
orde r wh i c h
v ar i e d
thu s m i n i mi z i ng obs e rve r b i as
n e xt ,
from one pat i ent to
a s s e s s i ng
wh e n
the
t he
c h a l l enge
r e a ct i on s .
S i nce
tha t
t i me
3 , 000 pat i ents
appr ox i ma t e l y
h a ve
attended
the :
Al l e rgy Cl i n i c fo r d i e t ary i n ves t i gat i o n of non - urt i ca ri al cond i t i ons :
i rr i t ab l e bo wel
i ncl udi ng m i g r a i n e ,
wel l
c erta i n
as
syndrome , asthma and eczema , as
sy n d r ome s
controv e r s i al
such
as
" hype ract i ve"
be h avi our d i st urbances i n ch i l dren and vague symptoms sugges t i ve of
psychoneuro s ; s i n
d i et ary
Th i s
ad u l ts .
i nve s t i g at i on
i n such
the re s ul t s o f
chapter outl i nes
pat i ents ,
and prov i de s a bro ad v i ew o f
the cl i n i cal spectrum of food i ntol erance w i th i n wh i ch R I U/AO may be
v i ewed as one amongst s everal i nter - re l ated synd romes .
MAT E R IALS
AND M ETHODS
Mod i fi c at i on of
E l i m i n at i o n
D i et
and
C h a l l enge Programme
T he e l i mi nati on d i et used for R I U/AO pat i ents ( Ch apter 3 ) was further ;
mod i fi ed
for
and
p at i ent s
syndrome ,
symptoms
re s t r i ct e d wi th the excl u s i on of wheat , and m i l k products
pre senti ng
apht hou s
wi th
ul cers ,
( A pp end i x 2 ) .
eczema ,
m i gra i ne ,
asthma ,
i rr i ta bl e
hyperact i v i ty
At the s ame t i me the range
and
0
bowel
systemi c
f cha 1 1 enge
compounds was e xtende d , and s tarch an d s ucro se were i nt roduced as
pl acebos ( Tab l e s 6 . 1 and 6 . 2 ) .
1 46
TAB L E 6 . 1
ADD I T I ONAL SUBSTANC ES I M P L I CATE D I N ADV ERS E R EACT I ON S TO FOOD
Food or S u b s t ance
L i terat ure
•
Mi l k
H arr i son et a l . , 1 976 ;
Ath e rton et a l . , 1 9 78 ;
B l ume n t h a l e t a l . , 1 98 1 ;
Wheat
Ferg u s o n , 1 976 ;
Eggs
Meara , 1 96 5 ;
1 982 ;
Franc i s , 1 982 ;
Dodge , 1 980 ;
Franc i s , 1 982 ;
Ath erto n et a l . , 1 978 ;
Franc i s ,
Ford & Tayl or , 1 98 2
MSG
Kwok , 1 968 ;
Sch aumberg et a l . , 1 96 9 ;
N i trate
Henderson & Ras k i n , 1 972 ;
Moneret - Vautr i n et
a l . , 1 980 ;
Ant i ox i d an t s
J u h l i n et a l . , 1 97 2 ;
Ami ne s
Bet h un e et a l . , 1 963 ;
Han i ngton , 1 980 ;
J u h l i n , 1 98 1 ;
Han i ngton , 1 96 7 ;
Moneret - Vautr i n e t al . , 1 979 ;
Kal i s h , 1 98 1 ;
Sorb i c ac i d
NH&MRC , 1 986
S od i um prop i on ate
NH&MRC , 1 986
E ryth ro s i ne
Augu s t i n e & Lev i t a n , 1 980 ;
147
TABL E 6 . 2
MOD I F I CAT I ON S TO CHALLEN G E S ET
Dates
Mod i fi cat i on s to C h al l eng e s
November 1 98 1
Doubl e bl i nd protoco l
Pl acebo s :
November 1 98 1
st arch
J an uary 1 982
sucro s e
November 1 98 1 - May . 1 984
B carotene ( 1 60a ) *
Mul t i pl e acetyl s al i cyl i c ac i d doses :
May 1 984 - J an u ary 1986
two doses o f acetyl s al i cy l i c ac i d
Pres ervat i ve s :
November 1 98 1 - J anuary 1 982
propyl g a l l ate ( 3 1 0 ) *
May 1 984
add i t i on o f :
s od i um pro p i o n ate ( 281 )*
November 1 98 1 - May 1 984
reduct i on o f :
sod i um n i t rate ( 2 5 1 )*,
sod i um n i tr i t e ( 25 0 ) *
Art i fi c i al col o urs :
May 1 984
add i t i on o f :
eryth ro s i n e ( 1 2 7 ) *
M i scel l aneous :
November 1 98 1 - May 1 984
bakers yeast
* Code n umber for add i t i ves i n food ( NH&MRC , 1 986 )
148
The c h a l l enge s et was made double - bl i nd w i t h two p l acebo s i n o rder
t h at the re s u l t s o bt a i n ed wou l d be as o bj ect i ve a s pos s i bl e .
The
dose e ffect wa s s t ud i ed w i t h t h e acetyl s al i cyl i c ac i d c h a l l e n g e where
s everal
doses
were
r andoml y
g i ven
to
p at i en t s .
S i mi l arl y
t h ree
col o ur c h a l l enges and a compo s i t e col o u r and pres e rv at i ve chal l e n g e
were g i ven to a random s e l ect i o n o f p at i e n t s s o t h at correl at i on s
c ou l d b e made .
Prop i on i c ac i d was added t o t h e set after a p i l ot
s tudy was perfo rmed a s i t i s a w i d e l y u se d p re s e rv at i ve i n ye as t
l eave n ed
b akery
i tems .
Several
c h a l l e ng e s were
omi tt ed :
b a kers
yea s t beca u s e i t was found to be den atured by b a k i n g , B carotene as
i t was fou n d t o b e cont am i n ated and pro pyl g a l l ate a s i t was an o i l
and d i ff i c u l t t o encap s u l ate .
The d o s e o f t h e chal l e n g e o f sod i um
n i trate and s od i um n i tr i t e was reduced a s s ome pat i en t s exp e r i enced
severe react i o n s .
Pat i e n t s were i n s tructed t o commen ce t h e ' c h al l enge p roced u re o f foo d
and c a p s u l e c h al l enges a fter at l east two wee ks o n t h e e l i mi n at i on
d i et w i t h
f i v e a sympt omat i c d ays .
Open c h a 1 1 enge s w i t h m i 1 k and
whe at ( as wel l a s egg s i n t h o s e w i t h eczema ) were t aken f i r s t , and
these foo ds were added t o the basel i ne e l i mi n at i on d i et i f t he re was
n o o bv i o u s
react i on .
pl aceb os were t h en
Doubl e
bl i nd c h em i cal
admi n i s tered ( Ap pend i x 4 ) .
chal l e n g e s
i nc l ud i ng
C h a 1 1 enge caps u l e s
were t a ke n i n t h e morn i ng h al f a n h o u r befo re o r two h o urs aft e r a
bre a kfas t ( fo r c h i l dren t h e c a p s u l e c o n t e n t s were m i xed w i t h g o l d e n
syrup o r m a s h e d p o t at o i f t h ey were u n abl e t o swal l ow t h e c ap s ul e s ) .
The c ap s u l e s were s p aced by at l ea s t 48 hours t o al l ow for del ayed
react i on s and a ny res p o n s e to chal l enge wa s fol l owed by a p a u s e o f a
149
furt her three
symp tom
free
days
before
proceed i ng
to
n ext
the
chal l enge , s i nce pat i en t s were often found to expe r i ence a temporary
refractory per i od dur i ng wh i ch they are unrespon s i ve .
S ome chal l -
enges were g i ven d i v i ded i nto "A" dose and a " B " dose , represen t i ng
a
smal l dose ( "A" ) and a 1 arger dose ( " B " ) o f t h e s ame or rel ated '
compound s .
The s e were taken on the s ame d ay , the smal l do s e ( "A" )
fi rst and i f there was no re act i on wi th i n two hours the second dose
( " 8" ) was taken .
However , i f a not i ceabl e re act i on occurred to dose
"A" the subsequent dose
"8"
was not taken .
I n some pat i ents , doubl e bl i nd c apsul e ch al l enge was not pract i cal or '
feas i bl e and i n these cases open food c h al l enge were carr i ed out .
Th i s ma i n l y occurred i n ( a ) very young ch i l dren who were un abl e to
1
1
J
1
who
swal l ow the cap s u l es or the powder , ( b ) pat i ents who were terri fi ed
by the thought of t a k i ng caps ul es or the i r e ffect or ( c ) p at i ents
l i ved out of town w i thout a cl ose general
superv i se the i r c h al l enges .
sel ected
food s
accord i ng
pract i t i oner who could
I
!
Open ch a 1 1 enges con s i sted o f s pec i al ly �
1
to chemi cal compos i t i on ( Append i x 6) . 1
Pat i ents were as ked to record the t i me , type and q u ant i ty o f food
taken , and i f a react i on occu rred t h e type a nd s ever i ty o f symptoms .
and
the i r
t i me
of
onset
and
durat i on . .
Wi th
a
po s i t i ve
food
cha1 l eng e ,
re - ch a1 1 enge was performed three t i mes to con fi rm the
react i on .
When a food chal l enge provo ked a react i on the pat i ent was ;
i n structed to wa i t unt i 1
symptoms had cl eared and then al l ow a
further three days before taki ng the next food c h a 1 1 enge �
If
symptoms occurred the next food c h al l enge was taken after 48 ho urs .
no
150
C l i n i c a l and D i etary Eval u at i o n
E a c h p at i ent was a s s e s s ed by a phys i c i an at t h e Al l ergy C l i n i c b e fore
embark i ng on d i etary i n v e s t i g at i o n and was a s s i g n ed to a cl i n i cal
c at eg o ry as s h own i n Tabl e 6 . 3
TAB L E 6 . 3
S PECTRUM O F PAT I ENTS S EEN AT TH E ALL ERGY C L I N I C
F ROM A PR I L 1 97 7 TO S E PTEMBER 1 986
Pr i mary D i agn o s i s
R I U/AO ( Ch apter 3 )
Number o f Pat i e n t s
1 349
Eczema
233
Ast hm a
251
I rr i tabl e bowel syndrome
3 58
46
Aph t h o u s ul cers
M i gr a i n e
237
Hyperac t i v i ty
301
System i c
809
Uncl a s s i fi ed
817
Eczema :
Al l
p at i e n t s h ad bee n pre y i o u s 1 y seen by a general
p aed i atri c i an
t o p i cal
and/or dermato l og i st ,
stero i ds
and mo s t h ad
and mo i sturi zers at s ome s t ag e .
pract i t i oner ,
been
pre s c r i bed
A d i agn o s i s o f
atop i c eczema w a s made o n cl i n i ca l g ro u nd s , based o n t h e h i story ,
151
typ i cal appearance and d i str i but i on o f ski n l es i on s , a fami l y h i sto�
of atopy , and i n some cases measurement of total and spec i fi c I g E . �
I f there was any doubt about the d i agnos i s pat i ents were seen by the
Al l ergy Cl i n i c dermatol og i st before d i etary i ntervent i on . I n add i t i on
to the standard el i mi n ati on d i et , the common food al l ergen s ( eggs ,
mi 1 k and wheat ) were al so rout i ne 1 y excl uded from the d i et i n the
pat i ent s wi th eczema i n i t i al l y .
Because of severe i nfl ammat i on and
excori ati on pat i ents general l y took 6 to 8 weeks to settl e , and i n
the meant i me were encouraged t o cont i nue
u s i ng top i cal
therapy .
Un 1 e s s there was a cl ear- cut h i story of spec i fi c food al l ergy each
pat i ent rout i nel y underwent open
egg ,
mi l k
and wheat chal l enge ;
food s tol erated wi thout any recurrence of symptoms were added to t he
basel i ne d i et before the admi n i strat i on
of doubl e - bl i nd
c hemi cal
chal l enges .
Any react i on s were treated top i cal l y i f necess ary , and
al l owed to
settl e comp� etel y before any further ch al l enges were
admi n i stered .
Asthma :
Regardl e s s of whether prev i ou s i nve st i gat i on h ad been carri ed out al l
pat i ents wi th a h i story of asthma underwent formal s p i rometry and
test i ng of bronch i al react i v i ty to h i stami ne .
Based on the dose of
h i stami ne req u i red to provoke a fal l i n F EV 1 . 0 of >20% , pat i en t s were
cl as s i fi ed as h av i ng mi l d , moderate or severe bronch i al hyperact i v i ty
( Van et al . , 1 983 ) . I f d i etary tri gger i ng factors were suspected by
the pat i ent and/or phys i c i an , pat i ents were pl aced on the e 1 i mi na
t i on d i et and asked to mon i tor d a i l y peak- fl ow rates and/or symptoms .
Improvement was asses sed accord i ng to both s ubj ect i ve and o bj ect i ve
parameters , i ncl ud i ng chest t i ghtnes s , exerc i se tol erance , n octurnal
wheez i ng , med i cat i on requ i rements , peak- fl ow rates and/or sp i rometry .
152
supe rv i sed accord i ng
C h a l l enge s were
to
hy perreact i v i ty a s me as u red at prese nta t i on :
i v i ty
t o h i s ta m i ne
s u p e rv i
of
s i on
.t h e i r
gener al
p r ac t i t i o ne r ,
a
of
re sp i ratory
h yperr e a ct i v i ty were
adm i tt ed
th e Al
p hy s i c i an ,
to
bro n c h i al
t h o s e w i th m i l d reac t
wer e c h al l en ged e i t h e r at the c l i n i c
hyp errea ct i vi ty were cha 1 1 eng ed i n
s up e rv i s i on
degree of
the
those
or
under t h e
wi t h
moderate
l ergy C l i n i c o r under t h e
and
ho s p i t al
those
for
wi th
chal l enge .
s e v e re
The
c h a l l enge p rot ocol for a s t h mat i cs wa s mod i fi e d t o al l ow for graded
do s ag � as outl i ne d i n Append i x 5 .
I rr i t ahl e Bow e l
Sy n drome ( 1 85 ) :
Ap rox i � te1 y
two th i rds of s uch p at i ents were referre d to t h e Al l ergy
Cl i n i c by a
g a s tro e n t e ro l og i s t ,
and mo s t
of t h e rema i n i ng p a t i ents
h a d p revi ousl y been i nves t i gated w i th a bari um meal and/ o r endoscopy .
The approach t o cl i n i cal eval uat i on at t h e Al l e rgy Cl i n i c correspond
ed to that
d e s cri
bed by Kru i s et a l
score was not as s i gned .
d i agnosi s a t
.
.
( 1 984 ) , al though a n umer i ca 1
I f t here was any uncert a i n ty about t h e
p r e s en t at i o n , p at i ents
were referred to a g a stroenter-
o l ogi st before undergo i ng d i etary i nvest i gat i on .
Mouth U l ceration :
Ap p rox i matel y two - th i rd s o f the pat i ents pre s ent i ng w i th " i d i opath i c "
aph t hous ul cerat i on were referred by Profes so r M . Jol l y , Departmen t
o f Oral Surgery , School of
Dent i s t ry ,
U n i ver s i ty of Sydney .
E ach
pat i ent was asses s ed by a p hy s i c i an at t h e Al l ergy Cl i n i c to excl ud e
u n d e r l yi ng organ i c d i se ase b efo re un derg o i n g d i etary i nvest i g at i o n .
On t h e e1 i mi n at i on d i et symp toms ofte n i mp rov ed mar ked l y w i th i n two
to s i x weeks , b ut i n severe c ases compl ete re s o l ut i on coul d t a ke u p
t o 1 2 we e ks .
1 53
Mi gra i ne :
Pat i ents wi th mi gra i ne were most 1 y referred by the i r general pract· .
i t i oner
al though
approx i mate l y
one - th i rd
i nve st i gated and treated by a neurol og i st .
h ad
prev i ou s l y
been
D i agnost i c cri teri a and
grad i ng o f severi ty were as descri bed by Lance ( 1 986 ) .
Mo st pat i ents
s uffered from " common " m i gra i ne , wi t h or wi thout ep i sod i c " cl as s i cal "
mi gra i ne attacks , and i n general on l y those wi t h moderate o r seve"
head aches
occurri ng
more
than
twi ce
a
mot i v ated to warrant di etary i nvest i gat i on .
11
month
were
s u ff i c i ently
On the el i mi n at i on diet
s i gn i fi can t " i mprovement was cons i dered to h ave occurred i f there !
was ( a ) compl ete resol ut i on of head aches , ( b ) ces s at i on o f a n eed for
med i c at i on ,
or
(c)
a
reduct i on
in
severi ty
and/or
frequency of :
headaches by 50% or more .
" Hyperact i ve " C h i l dren :
Three hundred and one ch i l dren wi th beh av i our d i sturbances presented ·
to the Al l ergy Cl i n i c , often havi ng been d i agnosed as " hyperact i ve"
and general l y see k i ng d i etary i nvest i gat i on because o f sus pected food
react i on .
The probl ems as soc i ated wi th th i s as a d i agnost i c entity
are con s i dered i n deta i 1
bel ow ( see D i scu s s i on ) .
Each c h i 1 d was
screened by a paed i atri c i an , Dr . V . Soutter , at the Al l ergy . C l i n i c
before undergo ; n g d i etary assessment . The most common pre s entat i on
was of an over exc i tabl e ,
i rri tabl e ch i l d who c r i ed eas i l y and
exh i bi ted unpred i ctabl e mood swi ngs and/or s l eep d i s turbance s .
The
parents often descri bed the ch i l d as be i ng unre s pon s i ve to the usual
d i s c i p l i nary measure s when " out o f control " , and a s be i ng general ly
" d i ff i cul t to l i ve wi t h " .
ch i 1 dren were boys ,
As i n other seri e s , thre e - quarters of the
the average age be i ng seven years .
A 1 though
154
" so ft "
neurol og i cal
s i gn s
we re
somet i me s
present ,
none
of
the
c h i l dren h ad maj or abnormal i t i e s s u c h as e p i l epsy or men t al ret ard
at i on .
Al mo st al l fami l i e s h ad prev i ou s l y sought h e l p from one or
more o t h e r sources w i thout success ( for examp l e ch i l d p syc h o l og i st ,
paed i atr i c i an , p sych i at r i st , commun i ty h e a l t h cen tre or baby h e al t h
cl i n i c ) .
About h al f h ad prev i o u s l y t r i ed t h e Fe i ng o l d d i et , o ften
w i t h part i al benefi t , or somet i me s wi th i n i t i al i mp roveme n t fo l l owed
by rel a p s e .
I n general , a non - j udgemental att i t ude was adopted toward s parents '
bel i e fs concern i ng the i r c h i l d ' s behav i our .
U n l e s s contra i nd i c ated
( se e bel ow) , t h e e l i mi n at i on d i et was u sed as a screen i ng procedure
to s e l ect c h i l dren who were ( a ) more l i ke l y to be d i et - se n s i t i ve , and
( b) s u ff i c i en t l y comp l i an t to undergo dou b l e - bl i nd c h a l l enge t e s t i ng .
For several
reason s , p sychome t r i c t e s t s and behav i o u r rat i ngs were
not c arr i ed out .
Beh av i oural
c h anges were o ften comp l ex , v a r i abl e
and i nterm i ttent , and i t was fel t t h at t h o s e i n mo s t i nt i mate contact
wi t h the c h i l dren , n ame l y paren t s , were i n the be s t pos i t i on to make
a j udgemen t .
Futhermore ,
c h i l dren wi t h s i t u a t i o n al
as
pO i nted
out
by
We i s s
( 1 985 ,
1 986 )
hype ract i v i ty are o ften abl e to exert a
degree of vol untary control over t he i r b e h av i our d u r i ng t h e fi rst two
or t h ree encounters wi t h a p hy s i c i an , or at school , account i ng for
the fact that i n p rev i ou s s t ud i e s parent rat i ng s h av e not al ways
agreed w i th doctor and/or teacher rat i n g s .
F i n a1 1 y ,
p arent s were
o ften very s t re s sed by h av i ng to cope wi t h one or more di ffi cul t
ch i l dren ,
and good
comp l i an c e wou l d
ach i eve w i t h a comp l ex protoco l .
h ave
been more d i ffi c u l t
to
To e n s ure s c i ent i f i c v a l i d i ty o f
1 55
the
outcome ,
rel i ance
was
th erefore
p l aced
on
the
d o u b l e - bl i nd
p l acebo - contro l l ed c h al l enge protocol (wh i ch corres pond s to t h e g u i de
l i nes
s uggested
by
the
Nutri t i on
Foundat i on
Adv i sory
Comm i ttee
Report , 1 980 ) .
I n fami l i e s where the re was a poor mot h e r - c h i l d rel at i on s h i p formal
el i mi n at i on and chal l enge test i ng was not recommended .
C h i l dren who
exh i b i t ed
the
s o c i opat h i c
beh av i our
or
h o st i l i ty towards
mother,
mak i ng compl i ance u n l i kel y , were g i ven general adv i ce about avo i dance
of add i t i ve s
and pro b l em foods on an emp i r i cal
bas i s .
A s i mi l ar
approach was adopted i n c a s e s whe re i t was suspected t h at a stri ct
d i et m i g h t be u s ed by t h e mother as an i n st rumen t of ch i 1 d abuse
( Me adow , 1 977 ) .
C h i 1 dren w i t h
beh av i our d i st urbances who underwen t formal
d i etary
test i ng were pre s c r i bed t h e s ame e 1 i m i n at i on d i et as t h at u sed for
R I U/AO ( Append i x 1 ) u n l e s s t h ey s uffered g a s t ro i ntest i n al
symptoms ,
i n wh i ch c a s e wheat and m i l k were al so restri cted i n i t i al l y ( Appendix
2) .
c h i 1 dren ,
For
i n i t i al
a
i nterv i ew and
d i s c u s s i ng
i n deta i l
bi rthday p art i es ,
spec i a 1
approach
was
throughout the d i et ,
h ow to
wee kends at
cope
fri ends ,
cooki ng for t h e rest of the fami l y .
t he i r c h i l dren i n t h e school
wi th
requ i red
both
wi t h much
school
treat s ,
1 unche s ,
t i me
at the
spent
tuckshop,
t akeaway food and
Many parents c h o s e to chal l enge
h o l i days so t h at i t wou l d cause the
l ea s t d i srupt i on to t h e i r progre s s at school and so t h ey coul d best
mon i tor t he i r respon s e .
1 56
Ad u l t s w i th " system i c " symptoms :
Pat i e n t s were cl a s s i fi ed as h a v i ng " system i c " symptoms i f t h ere we re
two or more organ systems i nvol ved , and i f th ere were con s t i tut i onal
symptoms pre s e n t s uch as headache , mal a i s e , l et h argy and/or mya l g i a .
S i nce symptoms o f t h i s
k i nd are qu i te non - spec i f i c pat i e n t s were
carefu l l y screened to excl ude organ i c pathol ogy and overt p sych i at r i c
i l l ne s s .
Where i nd i cated on cl i n i cal ground s , approp r i ate l aboratory
t e s t s were carri ed out or psych i at r i c a s s e s sment wa s arranged .
The
c l i n i cal c h aracter i s t i c s o f t h i s h eterogeneous group o f pat i e n t s are
d e s c r i bed furth e r i n t h e res u l ts and d i scus s i on s ec t i on s bel ow .
Pat i en t Manageme n t
Fol l ow i n g con f i rmat i on o f a d i agnos i s o f eczema ,
a s t hma ,
i rr i tabl e
bowel syndrome , aphthous u l cers , m i g r a i ne , hyperact i v i ty o r system i c
symptoms by t h e phys i c i an each pat i ent was i n terv i ewed by a d i et i t i an
who outl i n ed t h e e l i m i nat i on d i et i n det a i l
( Ch apt�r 3 ) .
Pat i ents
were adv i sed t o t a ke an uncol oured mul t i v i tam i n and a cal c i um s u p p l e
e n t and were g i ven det a i l ed i n struct i on s about perm i s s abl e " over the
counter" med i c at i o n s .
I n t h e s e p at i e n t s frequent cont act and w i t h t h e d i e t i t i an over the
tel e p h o n e was
i n struct i on s
nece s s ary for encouragement ,
and
pract i cal
re i terat i o n o f di etary
adv i ce about day
to d ay
i s s ue s
wh i ch
res u l ted i n exce l l ent compl i ance ( Tabl e 6 . 4 ) .
Pat i en t s who
exper i enced
marked
reduct i on
or
comp l e t e
rel i ef
of
symptoms for f i ve con secut i ve days after a m i n i mi um o f two wee ks o n
157
t h e el i m i n at i on d i et tel ephoned t h e d i e t i t i an for t h e i r chal l enge
c a p s u l e s wh i ch were sent by ma i l .
For t h o s e pat i e n t s who pre s ented w i th a st hma ,
m i g ra i n e ,
i rri tabl e
bowel syndrome , hyperact i v i ty and system i c symptoms i n whom t h ere was
no i mprovement after s i x wee ks of str i c t d i et i ng on t h e el i mi nat i on
d i et , cont i n ued res tr i ct i on was not found to be h e l pful
as
pat i e n t s were i n s tructed by t h e d i et i t i an
and these
to h ow to gradual ly
res ume a normal d i et . They added foods back by c h em i ca 1 food groups
every t hree d ays
unt i 1
a ful l
d i et was reached .
A few pati ents
exp e r i enced an exacerbat i on of t h e i r symptoms wi th t he add i t i on of
s ome of t h e food group s .
Pat i e n t s wi th a p h t h o u s ul cers and eczema
o ften took l onger to resol ve ,
i n i t i al
s howi ng mi n i ma 1
i mp roveme n t
i n the
s i x wee ks wi th cont i n u i ng i mprovement over a further s i x
wee ks s o t h at marked
i mprovement h ad occurred a ft e r 1 2 wee ks , at
wh i ch t i me t h ey were ready to be c h a l l enged .
Fol l owi ng compl et i on o f t h e c h a l l enge protocol , re act i on s were noted
by the d i et i t i an and t h e doubl e b 1 i nd code was bro ken .
Long term
d i etary mod i fi c at i o n based on i nd i v i dual oral provocat i on re s u l ts was
adv i s ed ,
avo i d i ng
c h emi c al s .
After
onl y
those
s i x wee ks ,
foods
gradual
wh i ch
cont a i ned
l i beral i zat i on
i nc r i mi nated
of
foods �
c h em i cal group i ng was encouraged i n an attempt t o i nduce t o l erance
and
ra i se
the
encouraged to
t h re sh o l d
for t r i gger i ng
1 i bera 1 i ze t h e n atural
sympt oms .
compounds
Pat i en t s
were
to wh i c h t h ey had
s h own a sen s i t i v i ty i . e . n atural sal i cyl ates , am i n e s and mono sod i um
g l utamate by t a k i ng very smal l amo u n t s on an i n term i ttent bas i s and
t h en i ncrea s i ng t h e frequency and amo u n t s as t o l erated ( Append i ces
10, 1 1 , 12) .
158
S t at i s t i c a l Anal Ys i s
McNemar ' s test for correl ated pro port i on s as outl i ned i n deta i l
in
C h apter 3 was u s ed to comp are e ac h chemi cal c h al l enge re s p o n s e wi th
al l t h e other compounds g i ven so t h at any s i gn i f i cant corre l at i on s
between t h e chemi c a l s u b s t ances a n d p l acebos coul d be made f o r e ac h
syndrome .
The McNemar ' s t e s t was al so u s ed to determ i n e i f t h e d o s e e ffect o f a
smal l
and 1 arg e d o s e o f a s p i ri n g i ven to 239 p at i e n t s was of any
s i gn i f i c an c e . -
RESULTS
Of t h e 2 2 3 5 pat i en t s ,
1 93 0 were pre s cr i bed t h e el i m i n at i on d i et .
N i ne h undred and s eventy two p at i ents ( 50 . 4%) i mproved on t h i s d i et
and were c h al l eng ed w i t h t h e chemi cal ch al l enge s , 84 ( 4 . 3%) pat i ents
d i d not i mprov e .
E i g h t h u ndred and seventy four pat i e n t s ( 45 . 3%) d i d
not pers i st w i t h t h e e l i mi n at i on d i et ( Tabl e 6 . 4 ) .
A furt h e r 494 pat i en t s commenced a l e s s r i g i d " l ow chemi c a l d i et "
( l ow s a l i cyl ate ,
art i fi c i al
col our ,
l ow ami n e ,
l ow gl utamate ,
l ow brewers yea s t )
l ow pre s e rv at i ve ,
after med i ca l
and
l ow
d i etet i c
a s s e s sme n t s ugge s t ed t h at t h ey wou l d be u n 1 i ke 1 y t o cope w i t h t h e
very r i g i d d i etary res t r i c t i o n s a n d c h a l l enge procedure .
The l ow
chemi c al d i et re s t r i cted o n l y t h e commo n e s t food chemi c a l s t h at may
prec i p i t ate symptoms .
159
TABLE
6.4
TOTAL PAT I E NT S
Syndrome
Number of
N umber of
Pat i ents
Pat i ents
Respond i n g
Mod i f i ed
Fa i l ures
D i et
No Cha l l enges
Dropouts
Percentage
( No
Response
Fo l low-Up )
1349
698
156
80
415
58 . 5%
Eczema
234
80
37
9
107
40 . 5%
Asthma
251
65
1 04
4
78
44 . 2%
IBS
358
157
29
21
148
48 . 2%
46
23
15
2
6
74 . 2%
M i gra i ne
237
109
9
11
108
47 . 8%
Hyperact i v i t y
301
136
45
2
118
53 . 1%
System i c
809
403
62
35
309
53 . 9%
3584
1670
650
1 64
1 289
53 . 6%
Urt i car i a
Mouth u l ce rs
Tota l pat i ents
The pre s e n t i ng age of pat i ents ranged from a few wee k s to 86 ye ars of
age .
The spe ctrum of age s for e ach syndrome are s h own i n the s eri es
o f h i stograms i n F i gure 6 . 1 be l ow .
NO. Of PATENTS
o
�
t
8 8
8
0
()-6
�
t
g
0
g
�
t
8
8
0
6-10
10-16
16-20
20-26
26-30
35-CO
30-36
40-45
(J)
Ui
-f
m
�
46_60
60-66
61H1O
8CHS6
,
�
:0
>
Z
86-70
o
m
f
I
46_50
60-66
65-80
80-86
85-70
70-76
76-80
�
01
46_60
�
_
�
�
t
g
8 � �
g
�
-
�
»
�
60-66
66-80
5i
:j
80-85_
0
>
85-70
70-76
11
:
76-80_
li:
...
80-85_
86-80
�
>
N
0
G'>
,."
CJ
�
�
::0
......
......
......
::0
,."
C
�
�
�
CH
I
o
�
t
g
....
0
�
$
8
8
.
8
0
�
....
..
,
6-10
6-10
5-10
6-10
10-15
10-16
1 0- 1 6
10-16
15-20
16-20
1 6-20
16-20
20-26
20-26
20-26
20-26
26-30
26-30
26-30
25-30
30-36
35-CO
30-35
::
30-36
35-40
60-56
66-00
8(H6
85 -70
�
CO)
m
�
I
>
en
-f
f
>
::
�
60-66
61H1O
80-86
86-70
!
:0
�
�
>
�
<:
=i
<
§
::=:�
:J:
50-66
55-80
80-86
70-76
7 ��
�
t
'
10
z
g
1
8
o
."
8
�
1 1
;p
:j
,."
Z
�
(/)
�
35-40
85-70
0
11
:0
t
F
0
�
en
45-60
60-66
61H1O
80-86
J
N
�
I
�
N
�
>
."
OJ
G'>
C
Ol
.......
.......
Q)
0
16 1
The s ex rat i 0 among s t t h e ad u l ts s howed a preponderance o f fema l es
wh i ch was mo st str i k i ng i n t h o s e w i t h " system i c " sympt om s. ( Tabl e 6 . 5
and Tabl e 6 . 6 ) .
Whereas i n t h o s e pat i e n t s pre s en t i ng w i t h
act i v i ty " o n l y 27% were fema l e .
TABLE 6 . 5
SEX RAT I OS OF TOTAL PAT I E NTS PR ESENTED
P resent i ng Syndrome
Urt i car i a
Eczema
Asttlna
I rr itab le bowe l syndrome
Mouth u lcers
M i gra i ne
Hyperact i v i ty
" System i C "
Ma le ( %)
37
39
37
31
19
25
74
23
Fema l e ( % )
63
61
63
69
81
75
26
77
TABL E 6 . 6
SEX RATI OS OF PAT I ENTS WHO R ESPONDED TO D I ETAR Y EL I M I NAT ION
P resent i ng Syndrome
Urt icar i a
Eczema
Astrma
I rr i tab le bowe l syndrome
Mouth u lcers
M igra ine
Hyperact i v i ty
"System i C "
Ma l e (%)
38
31
35
31
18
30
73
26
Fema l e (%)
62
69
65
69
82
70
27
74
" hyper -
16 2
C h a l l enge Re s u l t s
Pat i e n t s who became a symptomat i c o r wh o ach i eved marked l y reduced
symptoms o n the e l i mi n at i on d i et we re ch a l l enged ( Tabl e 6 . 7 ) .
The
c h a l l enge battery was upda ted t h ro ug ho ut s o t h at i mport a n t c ompa r
i s o n s c o u 1 d be made betwee n syn d rome s w i t h re s p ec t t o co l ou r and
a sp i r i n d o s e . For t h i s rea s o n the tot a l n umber o f p at i e n t s c h a l l e n g ed
w i t h e ac h comp o u n d are p re s e nt ed by syndrome .
T h e fre q u e n cy o f po s i t i ve c h a l l e n g e react i on s i n t h e v a r i o u s p at i e n t s
g ro u p s i s s h own i n Tabl e 6 . 8 .
Of
t h e comp o u n d s t e s t ed t h e o n e mo s t
frequ e n t l y i ncri mi n at ed was s al i cyl ate b u t cro s s react i on s betwee n
many s U b s t an c e s was c ommon a n d i d i o syncra t i c .
T h e res po n s e s t o e ac h
chemi c a l c h a l l e n g e were comp ared w i t h t h e p l acebos s t arch and s ucro s e
u s i ng McNemar ' s t e s t for dependent v a r i abl e s ( Ch ap t e r 3 ) .
al l
A n d for
t h o s e c h a 1 1 e n g e s wh i c h we re t a ke n by t h e maj o r i ty o f p a t i e n t s
( s a l i cyl a t e ,
ami n e s ,
MSG ,
pre se rv a t i ve s ,
n i trate s ,
a n t i ox i d an t s ,
t artr az i n e and brewers y ea s t ) , t h e react i on r at e s were fou n d · t o be
s i gn i f i c an t l y d i fferent from the p l acebo s s ta rc h and s uc ro s e w i th
. 00 2 <
P
c a l c u l ated
< . 00001 .
l i s t i ng
The
res p o n s e
rate
those
p at i e n t s
onl y
to
a
who
c h al l e n g e
h ad
was
then
expe r i enced
a
rec u rren c e o f t he i r p re s e n t i ng sympt oms ( Tabl e 6 . 8 ) .
Al mos t al l p at i e n t s react to more t h an o n e s u b s t an c e , averag i ng from
2 . 1 i n t h o s e p re s e n t i ng wi th a p h t h o u s u l cers to 6 . 4 i n t h o s e wi t h
" sy s tem i c "
symptoms .
The
l atter
beh ave
cl i n i cal l y
as
the
mo s t
s en s i t i ve g ro u p o f p at i e n t s i n whom e v e n v e ry m i n o r d ev i at i on s from
t he i r pres c r i bed d i et c a n cau s e react i on s .
16 3
TABL E 6 . 7
TOTAL NUMBER OF PAT I ENTS CHALLENGE TESTED
Urt i ca r i a
Eczema
Astllna
I BS
Mouth
M i gra i ne
U lcers
Hyperact i ve
Systemic
Chi ldren
62
80
58
1 59
23
1 09
136
403
Sa 1 i cy l ate
57
58
61
1 52
4
1 04
92
394
Am i nes
55
56
23
1 56
3
1 02
98
380
MSG
57
45
41
147
4
95
82
370
P reservat i ve
61
71
45
148
22
1 07
131
378
Ant i ox idant
56
42
22
141
4
98
82
362
Prop i onate
27
27
13
88
2
34
42
1 29
N i trate
55
43
22
1 46
3
98
79
364
Tartraz i ne
60
70
61
1 50
22
1 06
125
379
E rythros i ne
23
24
7
86
2
35
44
121
Brewers yeast
57
67
41
137
21
1 03
117
359
G l uten
55
40
29
1 40
21
93
80
356
Lactose
56
55
42
1 25
22
1 02
105
3 53
Wheat
60
80
50
1 55
21
1 08
136
397
M i lk
60
79
52
1 51
22
1 08
135
394
Starch
56
50
27
1 44
21
1 04
84
3 69
Sucrose
54
41
28
1 24
3
98
81
364
Tota l Cases
Act i ve
P l acebo
16 4
TABL E 6 . 8
CHALL ENGE RESPONSES ( PRESENTI NG SYMPTOMS ONL Y ) (%)
Urt i car i a
Eczema
Asttma
I BS
Mouth
M i gra i ne
Hyperact i ve
System i c
Ch i l dren
U lcers
Act i ve
Sa l i cy l ate
48
51
42
62
74
51
68
63
Am i nes
29
50
30
39
0
52
36
55
MSG
33
31
32
48
0
54
39
57
Preservat i ve
25
44
40
39
18
51
51
57
Ant i ox i dant
29
19
27
38
0
33
33
46
Prop i onate
19
22
8
37
0
32
24
46
N i trate
38
40
41
47
. 0
58
44
55
Tartraz i ne
23
33
30
36
18
43
50
48
Erythros i ne
35
38
57
40
50
31
43
49
Brewers yeast
16
30
20
32
10
40
31
42
G l uten
2
15
3
16
0
7
1
14
Lactose
9
15
7
18
0
11
8
16
Wheat
3
16
o
17
o
5
2
15
M i lk
o
22
2
20
o
5
5
16
Starch
5
6
7
8
o
8
4
8
Sucrose
2
o
o
5
o
7
1
7
P l ac ebo
16 5
TABLE 6 . 9
CHAL LENGE RESPONSES (ANY S YMPTOMS ) (%)
Urt i car i a
Eczema
AsttJna
I BS
Mouth
M igra i ne
U lcers
Hyperact i ve
Systemic
Ch i l dren
Act i ve
Sa 1 i cy late
66
63
55
71
91
61
80
76
Am i nes
44
54
52
53
33
59
52
65
MSG
53
47
42
61
75
61
48
67
Preservat i ve
48
59
51
51
73
59
66
70
Ant i ox i dant
41
24
46
46
75
37
44
55
Prop i onate
30
33
23
44
0
41
38
55
N i trate
58
51
64
52
33
66
65
67
Tartraz i ne
38
44
46
46
46
49
59
59
Erythros 1 ne
35
58
71
47
50
37
57
60
Brewers yeast
25
42
29
45
29
42
41
49
G l uten
6
15
7
17
0
14
1
20
Lactose
16
18
10
22
5
14
10
21
Wheat
5
19
o
19
o
5
5
19
M i lk
5
28
6
21
o
7
10
24
Starch
7
8
7
1
10
11
6
10
Sucrose
7
o
4
5
o
7
4
7
P lacebo
166
F I GURE 6 . 2
NUMBER OF POS I T I V E REACT I ON S
80
et)
....
z
ViI
....
<
�
�
i
ECZEMA
URTICARIA
50
.0
n = 82
30
mean = • .38 :J:: 2.8
" = 80
mean = 3.18
30
20
20
10
10
o
1
I BS
2
± 2.1
3 • 5 8 7 a 8 10
MOUTH
ULCERS
50
" = 23
n =1 58
mean = 5.88 ± 2.8
mean = 2. 1 3 ± 1 .8
30
20
10
10
o
1
2 3 .
5 8 7 8 8 '0 1 "
2 13 1 . , 5 1 8
HYPERACTIVITY
MIGRAINE
n . 1H
" = '08
30
mean = •.20 ± 2.5
20
10
o 1
2 3 •
o
5 8 7 8 8 10 1 1 1 2
1
2 3 • 5 8 7 a 8 10 1 1
ASTHMA
SYSTEMIC
80
50
" = 85
n = .03
mean = 2.88 ± 2 .•
mean = 8.38 ± 3.1
30
20
20
10
10
o
1
2 3 . 5 8 7 a 8 10 1 " 2 '3 ' . , 5
o
1
2 3 .
5 e 7 a 8 10 1 1 1 2 1 3 1 . ' 5
16 7
The c l i n i c al
s pectrum of
acetyl s a l i cyl i c ac i d ,
ch al l enge react i o n s
am i nes , MSG ,
;s
p res ervat i ve s
i l l u s t rated
for
( s od i um ben zoate ,
40H benzo i c ac i d , sorb i c ac i d , sod i um met a b i s u l p h i te ) , ant i ox i dants
( BHT , BHA ) and n i t rat e s ( sod i um n i t rate ,
s od i um n i t r i t e ) .
In e ach
g ro u p o f p at i ent s the sympt oms p rovo ked are ma i n l y con f i n ed t o the
o rg an
sys tem i n vol ved at
p re s en t at i on ,
wi t h an
i dent i ca 1
p attern
be i ng seen when react i on s to any of t h e compou n d s are t � b u l ated i n
the
s ame
way .
popu l at i on
chem i c al s
When e ac h cl i n i ca l g ro u p i s compa red w i t h t he overal l
it
becomes
ev i dent
can
provoke
a
t h at
vari ety
of
each
of
the
symptoms ,
re l evant
depend i ng
food
on
the
p art i cul ar p attern o f t arget o rg an s u scept i b i l i ty i n e ac h i nd i v i du al .
TAB L E
6. 10
S YMPTOMS PROVOKED PER CHALL ENGE
CA) SAL I CYLATE CHALL ENGE
RESPONSE
(X)
SY N DR OME
Urt i car i a
Urt i ca r i a
Eczema
Asthna
�
0
2
Eczema
0
!1
Asthma
IBS
5
8
10
0
1
0
2
1
0
0
5(
15
28
�
9
�
12
5
13
M i gra i ne
16
12
8
13
2
9
10
9
11
0
5
4
2
0
Mya l g i a
10
43
I BS
Lethargy
3
2
1
60
CNS*
M i gra i ne Hyperact i v i ty System i c
6
63
11
5
5
6
2
0
33
21..
�
l§.
16 8
( B ) AM I N E CHAL LENGE
RESPONSE ( %)
Urt i car i a
Urt i ca r i a
Eczema
Asthma
IBS
M i gra i ne
CN S*
Lethargy
Mya l g i a
Eczema
Asthma
29
2.
0
0
7
9
9
4
4
50
2
4
11
2
4
2
Urt i car i a
Eczema
Asthma
33
0
0
11
12
9
4
2
2
31
4
7
11
11
2
0
4
0
�
4
9
9
9
9
SYNDROME
I BS
4
1
1
�
12
9
6
3
M i gra i ne Hyperact i v i ty Syst em i c
2
0
1
13
52
7
8
2
2
2
1
17
10
36
7
0
8
1
3
27
33
17
23
14
(C ) MSG CHALLENGE
RESPONSE (%)
Urt i cari a
Eczema
Asthma
I BS
M i gra i ne
CNS*
Lethargy
Mya l g i a
0
2
�
12
12
12
2
0
SYNDROME
I BS
7
1
3
47
14
7
12
3
M i gra i ne Hyperact i v ity Syst em i c
5
0
0
12
�
6
6
2
2
1
4
18
7
39
7
1
11
1
5
II
36
22
25
14
(D) PRESERVATIVES ( BENZOATES , SORBATE & METAB I SULPH I TE ) CHAL LENGE
RESPONSE ( %)
Urt i ca r i a
Eczema
Astt'ma
IBS
M i gra i ne
CNS*
Lethargy
Mya l g i a
Urt i car ia
Eczema
Asthma
II
7
44
0
3
7
7
0
0
2
0
0
3
10
18
7
5
2
�
11
9
4
2
0
SYNDROME
I BS
6
0
1
38
18
6
9
5
M i gra i ne Hyperact i v i ty Systemic
6
0
2
19
50
8
6
2
8
2
1
18
5
51
8
1
10
1
7
II
�
II
24
14
169
(E l ANTIOX I DANT ( BHA & BHT l CHALLENGE
RESPONSE (X)
Urt icar i a
Eczema
�
Urt i caria
Eczema
Asthma
rBS
M i gra i ne
CNS*
Lethargy
Mya l g i a
2
19
0
5
5
2
5
2
2
0
7
13
4
4
4
Asthma
SYNDROME
I BS
0
0
3
2
0
1
II
�
8
7
6
3
9
9
5
0
5
0
0
10
33
5
5
2
6
1
3
1
0
0
13
5
�
Z3
M
�
5
1
20
10
(Fl SODI UM NITRATEI N I TR ITE CHALLENGE
RESPONSE (X)
Urt icar i a
Eczema
Asthma
38
0
2
11
16
9
6
0
2
0
0
Urt i car i a
Eczema
Asthma
IBS
M i gra i ne
CNS*
Lethargy
Mya l g i a
�
£
23
14
23
5
9
M igra i ne Hyperact i v i ty System ic
5
0
2
28
3
1
0
II
2
7
14
9
5
0
SYNDROME
I BS
�
14
8
8
5
7
1
3
�
1
1
1
28
15
�
�
4
10
2
16
21
14
15
0
(�) TARTBAZI N� �HALLENGE
RESPONSE (%)
Urt i ca r i a
Eczema
Asthma
IBS
M i gra i ne
CNS*
Lethargy
Mya l g i a
*
CNS
•
Urt i cari a
Eczema
n
6
33
6
1
6
10
1
1
0
2
8
10
8
5
2
Centra l nervous system
SYNDROME
Asttma
I BS
5
2
�
8
10
2
5
2
7
0
1
36
10
6
5
3
2
0
2
11
�
7
7
2
5
2
1
18
5
�
8
0
7
1
2
II
29
18
21
13
1 70
T h e d o s e e ffec t o f a s p i r i n w a s stud i ed i n a t o t a l o f 2 3 0 p a t i en t s who
were r an doml y g i ven a c h a l l enge battery wh i ch c o nt a i n ed two s e p a r a t e
a s p i r i n c h al l e n ge s :
a h i g h d o s e ( 1 200mg ) and a l ow d o s e o f ( e i t he r
1 50 , 2 0 0 , 3 0 0 o r SOOmg ) .
Th e re s u l t s are s h own i n Tabl e 6 . 1 1 .
TAB L E 6 . 1 1
DOS E E F F ECT O F ASP I R I N
L ow d o s e Asp i r i n
1 20 0 mg Asp i r i n
Pos i t i ve
Negat i ve
P o s i t i ve
2 4 . 3%
33 . 5%
N eg at i ve
1 0 . 8%
3 1 . 4%
As the n umber o f p a t i ents g i ven e ac h d o s e w as smal l t h e groups were
comb i n ed i nt o smal l
vers u s l arge d o s e fo r s t at i st i c al
McNemar ' s t e s t fo r dependent g ro up s .
a dose
rel ated
e ffec t w ; th
a
T h e t e s t s h owed t h at t he i r was
s i gn i f i c a n t d i fference
r espon s e rate t o t h e l ow and h i g h d o s e s P < . 00 0 5 .
were
t he n
comp ared
on
the
b as i s
a n al ys i s by
of
t he i r
respon se to s al i cyl ate ( F i gures 6 . 3 and 6 . 4 ) .
betwee n
the
Pat i e n t s res u l t s
p o s i t i ve
or
n eg a t i ve
171
F I G URE
6.3
RES PONS E T O SAL I CY LATE AND OTH ER COMPOUNDS
MIGRAINE
URTICARIA
A MINE S
�.m
MSG
__
HYPE RACTIVITY
SYSTEMIC
PRESERVATIVE
ANTIOXIDANT
��I
PROPIONATE
��
NITRATE
TARTRAZINE
SUCROSE
10 20 10 40 10 80
1 0 20 1040 10 80
1 0 20 80 40 10 80
1 0 20 80 40 1080
1 0 20 80 40 10 80
,. RE SPONSE
D
�
F I GU R E
TOTAL
SALICYLATE-NEGATIVE
SALICYLATE -POSITIVE
6.4
NUMB E R O F R EACT I ONS TO C HA L L EN G E P E R PAT I ENT
SALICYLATE POSITIVE PATIENTS
SALICYLATE NEGATIVE
PATIENTS
90
80
rn
c
Q)
:;
CD
Cl.
mea n = 5.87
70
mean= 3.98
-
60
50
50
Q)
.a
40
40
z
30
30
20
20
10
10
0
-
...
E
�
1 2 3 4 5 6 7 8 9 1 0 11 12 13 14 15
1 2 3 4 5 6 7 8 9 10 11 12
Number of reactions per patient
n = 739 patients
n = 266 patients
172
Re - c h al l e n g e R e s po n s e t o C h a l l e ng e
N i n e t e e n p at i e n t s e l e c t ed t o r e p e at t h e e l i m i n at i on d i et and c h a l l
e n g e p r o c e d u re .
Overal l t h e repro d uc i b i l i ty w a s fou nd t o b e 7 7% w i t h
a r a n g e o f 2 5% t o 1 0 0% .
F I GURE 6 . 5
R E - CHA L L EN G E R E S PO NS E TO CHAL L EN G E S (%1
1 73
D ISCUSS I ON
A rev ; ew o f the recent 1 ; terature revea l s a good deal o f confus i on
and controversy surround i ng the subj ect o f adverse food react i on s ,
the h i stor i cal background o f wh i ch i s d i scu s s ed i n C h apter 9 .
Term-
. i no 1 ogy i s i tse 1 f an i mport ant source of confu s i on s i nce the word
" al l ergy "
is
o ften
us ed
i n approp i ate1 y
to
react i on , regard 1 ess of mechan i sm (Anders on ,
d es cri be
1 986 ) .
any
adverse
Some authors ,
s uch as May ( 1 986 ) , d i smi s s as �p5ychol og i ca1 o r erroneou s the as soc
i at i on o f food s w i th any l sympMotnSf oth er t h an t h o s e o f a c l as s i ca 1
al l erg i c react i on ( anap·nY,l axi"s ,- �urt i cari a , ang i oedema , as thma , eczema
and gastro i ntest i n al .�d�i sturbances ) , on the bas i s t h at i mmuno l og i cal
mec h an i sms h ave not been demonstrated .
1 9 78 ,
1 983 ;
S peer et a l . ,
between react i on s to acetyl
food
" al l ergen s " ,
but
1 98 1 ) ,
Oth ers , s uc h a s Speer ( Speer ,
h ave recog n i zed an a s s oc i at i on
s a l i cyl i c ac i d ,
,
add i t i ve s and vari ous
because most o f the p at i en t s
stud i ed were
atop i c , and symptoms such as a sthma and urt i cari a were commo n , Speer
if,
( 1 97 5 ) regards s uc h react i on s as al l erg i c man i festat i on s , desp i te the
cons i stent
fa i l ure o f mo st
i nvest i g ators to demo n s t rate
aspi ri n
spec i fi c I g E by s ki n pri ck or RAST test i ng ( Kr i 1 i s e t a1 , 1 98 1 ) .
Amongst
" orthodox"
authors ,
Moneret - Vautr i n
draws
the
c l eare s t
d i st i nct i on between true , i mmuno1 0g i ca1 1 y med i ated food a l l ergy , and
pharmaco l og i cal food i ntol erance or i d i osyncracy , med i at ed by "
known ,
suspected or un known p h armaco 1 og i c a 1
Vautri n ,
food
1 983 ) .
al l erg i es "
He refers to pharmacol og i cal
or
" pseudo - food
al l erg i es "
mech an i sms "
•
•
•
( Moneret
react i on s as II fa l s e
s i n ce
t h ey
s omet i me s
�
1 74
provo ke
urt i cari a
al l erg i c react i on s .
or
asthma ,
and
can
therefore
" masquerade "
as
Al though h i s v i ews are i n s ubstant i al agreement
w i th those pre s ented here , h i s cho i ce of term i nol ogy i s u n fort un ate
s i n ce i t i s l i ke l y to l e ave a casual reader w i th the i mp re s s i on th at
s uch react i on s are i mag i nary .
I n the d i scus s i on wh i ch fol l ows , each of the c l i n i ca1 synd romes i n
wh i c h food i nto l erance was i mp 1 i cated i n the p resen t study w i 1 1 be
con s i dered separatel y .
Space does not permi t an exhaust i ve rev i ew o f
t h e 1 i terature i n eac h are a , and therefore on l y the most rel evant
references wi l l be c i ted , al ong wi th sel ected rev i ew art i cl es .
A
h i stor i cal overv i ew w i l l be g i ven i n Chapter 9 .
"
Asthma
Asp i ri n i ntol e rance has . been recogn i zed as a t ri ggeri ng factor i n
u rt i car i a and asthma s i nce the turn of the century ( H i rschberg , 1 90 2 )
I
and wi th the except i on of Speer ( 1 98 1 ) most authors now v i ew th i s a s
a p h armacol og i cal i d i osyncracy ( Sett i pane , 1 983 ;
Van Arsde1 , 1 984 ;
i nc r i m iflated
as
Sl epi an et al . , 1 985 ) .
a
cause
of urt i cari a
Asad et al . , 1 984 ;
Tartraz i ne has al so been
and
asthma ,
fol l owi ng
the
o r i g i n a l anecdotal report s of Speer ( 1 9 58 ) and Loc key ( 1 959 ) nearl y
3 0 years ago .
S i nce then several stud i es h ave s uggested an assoc i at
i on between asp i r i n and tartraz i ne react i v i ty i n asthmat i cs ( Samter &
Beers , 1 96 7 , 1 968 ;
1 976 ;
Sett i pane & Padupakkam , 1 97 5 ;
Spector e t al . ,
1 979 ;
Weber et al . ,
Sten i u s & Lemo1 a ,
1 979 )
,
al t houg h t h i s
rel at i on sh i p h a s been quest i oned by others ( Steven son et al . , 1 986 ) .
175
More recentl y i t has become apparent that al l asthmat i cs are sen s
i t i ve t o t h e effects of i nh al ed 502 , a common atmospher i c pol l utan t ,
and a proport i on are sens i t i ve t o i ngested 50 2 i n t h e form o f meta- '
b i sul ph i te used as a preservat i ve ( Koen i g et al . , 1 980 ;
al . ,
1 980 ;
Freedman ,
Boushey , 1 982 ;
1 980 ;
Bake r et
5teven son and 5 i mon , 1 984 ;
al . ,
1 98 1 ;
5hepp ard et
rev i ewed by
and Bush et al . , 1 986 ) . "
I ngested metab i sul ph i te can rel ease S0 2 from the fl u i d phase i n the
oropharynx ,
rad i cal
and may al so c i rcul ate to the l ungs as the s u l ph i te
( H503 - ) .
I n those asthmat i cs sen s i t i ve to i ngested meta
b i sul ph i te , reduced t i ssue l evel s of sul ph i te ox i da s e may be p artl y ,
res pon s i bl e for i ncreased vul nerabi l i ty to 502 , al thoug h h e i ghtened
sens i t i v i ty of the chol i nerg i c bronchoconstri ctor mec han i sm h as al so
been postul ated ( 5teven son & 5 i mon , 1 984 ) .
F i nal l y , MSG has al so been reported as a cause of " Ch i nese rest aurant
asthma " i n a smal l n umber of pat i ents , al though t he i r react i v i ty to
other s u bstances has not as yet been documented , and the mec han i sm i s .
unknown (Al 1 en & Baker, 1 981 ) .
I n the present study 6 1 asthmat i c pat i ents underwen t s i ngl e b1 i nd
chal l enges w i th asp i r i n and tartraz i ne , and a proport i on were al so
cha 1 1 enged wi th other compounds i n the standard c h a 1 1 enge battery
( Tabl e 6 . 3 ) .
At the t i me of wri t i ng the chal l enges rout i ne l y admi n
i stered to asthmat i cs were asp i ri n , t artraz i ne , metab i s u 1 ph i te ( i n
sol ut i on ) , MSG and pl acebo ( Append i x 5 ) .
As a rul e , moderate to
severe asthmat i cs ( as defi ned cl i n i cal l y and by bronch i al res pon s i ve
ness to h i stam; ne ) were cha 1 1 enged under observat i on at RPAH ,
those w i th mi l d
asthma were s uperv i sed
by
t he i r
a nd
fami l y doctor .
176
Overal l , 42% of pat i ents reacted t o aspi ri n , 3 0% t o tartraz i ne , 40%
to metab i sul ph i te and 3 2% to
MSG
( Tabl e 6 . 8 ) .
I n twenty - four of
these i nd i v i d ual s (who were chal l enged under s uperv i s i on at RPAH ) and
a further e i ght pat i ents chal l enged i n hosp i tal s i nce September 1 986 ,
stri ct cri teri a were appl i ed i n record i ng a pos i t i ve react i on , i . e .
>20% fal l i n F EV l .
were :
- 1 3% .
I n these 3 2 pat i ents the preval ence o f react i on s
asp i ri n - 4 1% ;
met ab i sul ph i te - 47% ;
MSG - 26% ;
tartraz i ne
Seven pat i ents d i d not react to any of these four chal l enge
compounds , and onl y three reacted to both asp i ri n and t artraz i ne .
Asp i ri n sen s i t i v i ty h as been reported i n between fou r and 28% of
asthmat i c pat i ents general l y , and i n up to 78% of a h i gh l y sel ected
popul at i on wi th n asal pol yps ( rev i ewed by Sl ep i an et al . , 1 985 ) , but
i t i s d i ffi cul t to make d i rect compari son s wi t h the present study
because o f vari at i on s i n referral pattern s and sel ect i on cri teri a .
Neverthel e s s ,
it
is
poss i bl e to concl ude
that the" frequency of
a s p i r i n i ntol erance i s s i mi l ar to that descri bed i n other seri es , and
moreover , t h at al t hough i t i s qu i te common for i nd i v i dual s to react
to both a s p i ri n and tartraz i ne , the assoc i at i on i s no greater than
that expected by chance .
Thus , of the 2 5 pat i ents who reacted to
a s p i r i n , 1 0 reacted to tartraz i ne and 1 5 were neg at i ve , and of the 36
who d i d not react to aspi ri n , e i gh t reacted to t artraz i ne and 28 were
negat i ve .
Ch i - squared anal ys i s o f these fi gures shows no stat i st i c
al l y s i gn i fi cant assoc i at i on between aspi ri n and t artraz i ne react i on s
( P >0 . 2 ) .
S i mi l arl y , there was no s i gn i fi cant assoc i at i on between
aspi r i n and met ab i sul ph i te chal l enges ( P >0 . 3 ) , al thoug h nearl y h al f
the pat i ents react i ng to sul ph i te chal l enge al s o reacted to asp i ri n ,
contrary to the cl a i ms of Stevenson and S i mon ( 1 984 ) .
1 77
Eczema
Sch l o s s ( 1 9 1 5 ) was one o f the fi rst i nve s t i g ators to draw attenti on
to the rel at i on s h i p between food al l ergy and atop i c e czema , but the ·
i s s ue l ater bec ame con fu s ed by the fi nd i ng t h at s k i n t es t s wi t h foods
correl ated
poorl y
wi th
cl i n i cal
sens i t i v i ty .
Neverthel e s s ,
the
cl i n i cal i mport ance of d i et , at l east i n a proport i on of cases , has ,
been i ncreas i ng l y recogn i zed i n recent years (Atherton et al . , 1 978 ; ·
Juto et al . , 1 978 ;
Jol i e ,
( He i ner ,
1 984 ) .
1 981 ) ,
H i l l & lyn ch , 1 982 ;
E s t i mates
arid
Samp s on , 1 983 ;
of preval ence vary
i n h i gh l y sel ected
between
S ampson & .
0% and 25% ,
seri e s may be
up to 59% '
( Sampson & McC a s k i l l , 1 985 ) .
It
i s general l y agreed by al l
rev i ewers t h at
t h e mo s t
commonl y
i ncri m i n ated foods are egg s , m i l k , wheat , peanu t s and fi s h , and that ·
the mec h an i sm
Samp son ,
1 986 ) .
RAST , however ,
is
I g E -med i ated
(Atherton ,
1 98 1 ;
Rasmu s sen ,
1 984 ;
The d i agnost i c u seful n e s s o f s k i n p r i c k tests or ;
i s controvers i al .
Our approach to s ki n test i ng i s '
s i mi 1 ar to that of Sampson ( 1 986 ) :
a negat i ve re s u l t e ffect ; vel y
rul e s out i mmed i ate food hypersen s i t i v i ty , and i s therefore u s e ful i n
�
cases where the h i story i s equ i vocal , but because o f the h i gh frequ
ency of pos i t i ve s k i n tests i n pat i ents wi thout cl i n i ca l food s en s i t
i v i ty they h ave poor pred i ct i ve val ue .
Of 234 pat i ents wi th eczema s een at the RPAH Al l ergy Cl i n i c , 80 under .
went food and chemi cal chal l enge .
Tho se wi t h a c l ear h i s tory of egg
hypersen s i t i v i ty ( 20%) were not chal l enged wi th egg s ,
rema i nder n i ne percent reacted to open egg c h a 1 1 enge .
and of the
A 1 1 p at i ents
1
i
178
took open c h a 1 1 eng es wi t h mi 1 k and whe at , 2 2% and 1 6% re spect i v e l y
report i ng a fl are of the i r eczema .
I f egg s , m i l k and/or whe at were
tol erated these food s were re - i ntroduced i nto the e 1 i mi n at i on d i et
before commenc i ng doubl e - bl i nd chem i cal c h al l enges .
of
react i ons
to
sal i cyl ate s ,
ami nes ,
The preval ence
pre servat i ve s ,
and
other
substances i n the cha 1 1 enge battery , was very comparabl e to t h at
observed i n pat i ents wi th R I U/AO (Tabl e 6 . 8 ) , an observat i on wh i ch
h a s not prev i o us l y been reported .
underwen t chem i ca 1
cha 1 1 enge al l
I ndeed , o f the 80 pat i ents who
re acted to
at 1 e as t one
act i ve
subst ance , the average be i ng between three and fou r ( F i gure 6 . 2 ) .
One ten year ol d boy reacted on l y to l actose amongst the doubl e - bl i nd
c h al l enge s , and he al so �e acted to mi l k on open chal l enge .
i ng l y ,
amongst
p at i ents
react i ng
to mi l k ,
nearl y
I nterest
th ree -quarters
reacted to the doubl e - bl i nd l actos e chal l enge , ra i s i ng the pos s i b i l
i ty th at some of these may not be Ig E -med i ated .
S k i n test i ng wi th
l acto se shoul d hel p resol ve th i s quest i on i n the future .
The fi nd i ng s presented here s uggest that i n pat i e n t s wi t h atop i c
eczema ,
col og i cal
a
comb i n at i on
i d i osyncracy
proport i on of cases .
of
may
I g E -med i ated
be
food
i nvol ved
al l ergy
in
and
pathogene s i s
pharma
in
a
I ndeed , the pos s i b i l i ty exi sts t h at chem i cal
i ntol erance may be a prerequ i s i te for d i sease expre s s i on , and that a
h i gh
IgE
l evel ,
wi th
i ncreased mast
cel l
rel ea s a bi l i ty ,
is
the
pred i spos i ng factor wh i ch renders an i nd i v i dual prone to . deve1 o p i ng
eczema rather than urt i cari a ( Ch apter 1 0 ) .
179
M i gra i ne
Reports of a 1 i n k between certa i n foods and headache d ate back to
H i ppocrat i c t i mes .
W i th
hypersen s i t i v i ty duri ng
i ncre as i ng knowl edge a bout mech an i sms of ·
the fi rst hal f of the 20th
cent ury ,
and
fol l ow i ng the i ntroduct i on of s k i n test i ng , many authors arri ved at .
the concl u s i on that mi gra i n e was an al l erg i c d i sorde r .
I n these
stud i es s ki n test i ng , el i mi n at i on d i et s and/or chal l enges were used
for d i agn os i s ,
and the foods I mo s t commonl y i mp1 i cated were mi l k, ·
wheat and choco l ate ( rev i ewed by Monro , 1 982 ; 1 987 ) .
I n 1 967 H an i ngton fi rst publ i shed ev i dence that ph armacol og i cal 1y .
act i ve am; nes ; n certa i n foods cou1 d cause vascu1 ar head aches , and ·
s i nce that t i me there has been cont i nu i ng debate abou t the re 1 at i ve
i mportance of al l ergy versus chemi ca 1 i d i o syncracy i n the aet i olo9Y
of m i gra i ne ( rev i ewed by Han i ngton , 1 983 ) .
been d i sputed i n some stud i es
Stewart , 1 977 ;
The rol e of tyram i ne has '
( Moffett et al . ,
Shaw et al . , 1 978 ;
1 97 2 ;
Ze i gler &
Congden & Forsyth , 1 979 ;
Kohl en- j
1
berg , 1 982 ) and s upported by others ( Bonnet & Lepreux , 1 9 7 1 ; Ghose .1
J
�
Rev i ewi ng the s ubj ect , Ras kin
j
( 1 98 1 ) fi nds the ev i dence support i ng tyram i ne sen s i t i v i ty i n m i grai ne
l
et al . , 1 977 ;
G l over et al . , 1 983 ) .
to be " persuas i ve il .
Neverthel e s s , some authors cont i n ue to regard
food i nduced mi grai ne as an al l erg i c d i sorder ( Monro et al . , 1 980 ,
1 984 ;
Grant ,
1 979 ;
Wi 1 son
et
al . ,
1 980 ;
Egger et al . ,
1983 ;
Mans fi e1 d et al . , 1 985 ) , al though Merrett et al . ( 1 983 ) coul d fi nd no
correl at i on between total and spec i fi c I g E or I g G 4 i n pat i ents wi th
" d i etary " versus " non - d i etary " m i gra i ne .
1 80 -
I n the pres ent study 23 7 pat i ents w i th m i gra i ne were eva1 uated and
pl aced on
the el i mi n at i on d i et ,
head ache - free ,
or
reported
and of these
suff i c i ent
1 09 bec ame e i ther
subj ect i ve
warrant undergoi ng systemat i c cha 1 1 enge test i ng
i mprovement
(Tabl e 6 . 4 ) .
to
The
pattern of respon s i vene s s was str i ki ngl y s i mi l ar to t h at found i n
pat i ents wi th
the other cl i n i c al
Over h al f ( 52%)
syndromes
stud i ed
( Tabl e 6 . 8 ) .
of the pat i ents tested experi enced head ache when
c h al l enged wi th tyram i ne and phenyl ethyl ami ne , wh i ch al ong wi th the
h i gh
preval ence
of
sen s i t i v i ty to
MSG
( 54%)
and
n i trate
( 58%)
support s the fi nd i ngs of Han i ngton and others , as d i scus sed above .
I nterest i ngl y , 5 1% of our pat i ents al so reacted to sal i cyl ates ,
fi nd i ng wh i c h h a s not prev i ous l y been documented .
a
As wi th R I U/AO ,
eac h p at i ent exh i bi ted an i nd i v i dual pattern of react i on s , to between
one and 1 2 of the substances tested (mean=4 . 2 , SO=2 . 5 , F i gure 6 . 2 ) .
W i th h i nds i ght , the somewhat con fus i ng ' fi nd i ngs of prev i ou s stud i es
can now be reconc i 1 ed .
The wi de range of substances to wh i ch the
p at i ents wi th mi gra i ne react when cha 1 1 enged accounts for the fact
that such a d i vers i ty of foods , i ncl ud i ng many not normal l y con s i der
ed a s h i gh l y al l ergen i c , h ave been i mpl i cated .
al .
pork ,
( 1 980 )
fi s h ,
and Egger et al .
s hel l fi s h ,
( 1 983 )
orange ,
For examp l e , Monro et
i dent i fi ed cheese ,
tomato ,
col a ,
peanuts ,
mushrooms , corn , appl e , rhubarb , tea , coffee and w i ne .
conta i n ami nes
and/or s al i cy1 ates
(Append i ce s
chocol ate ,
10,
11) .
banana ,
These al l
The l ow
i nc i dence of react i on s to wheat and mi l k i n our pat i ents contrasts
tl
wi th the fi nd i ng s i n several of the stud i es rev i ewed by Monro ( 1 987 ) .
Th i s coul d be a res ul t of d i fferent referral pattern s and the pat i ent
se 1 ect i on methods , or due to other methodo l og i ca 1 d i fferences ( see
d i scus s i on of " hyperact i v i ty " bel ow , and Ch apter 1 0 ) .
1 81
I rr i tabl e Bowel Synd rome ( I BS )
Al though gastro i ntest i n al symptoms such as vomi t i ng , a bdomi n al pai n
and
d i arrhoea ,
h ave
been
recogn i zed
symptoms
of
acute
al l ergi c ·
react i on s to food s i nce the turn of the cen tury ( Po rt i e r & Ri chet , .
1 90 2 ) , t h e rol e of d i et i n chron i c or recurrent " funct i o n al " bowel ·
d i sorders i s much more controvers i al .
There i s an aston i sh i ng l y wi de ·
range of v i ews on the pa t hogenes i s of I SS ( Lancet Ed i tori a 1 , 1 975,
1 984 ) .
At one end of the spectrum , pat i ent s are s a i d to be anx i ous ,
dependent , hysteri cal
or otherw i se deranged ,
l argel y i mag i nary or gros s l y exaggerated
1 977 ) .
t he i r symptoms be i ng
( Al my ,
1 97 7 ;
F i el d i ng,
It has been suggested that s uch i nd i v i dual s may experi ence
m i nor symptoms , wh i ch are common amongst peop l e who regard t hemsel ves
as heal thy (Th ompson & Heaton , 1 980 ;
Dros sman et al . , 1 982 ) , but as
a resul t o f " l earned i l l ne s s beh av i our" i n ch i l dhood are more l i kel y
to seek med i cal atten t i on ( Mechan i c et a l . , 1 982 ;
1 982 ;
Ford ,
1 983 ;
Sandl er et a 1 ,
1 984 ) .
Wh i tehead e t al . ,
Others con s i der these
symptoms to be genu i ne , but produced by the respons e o f the gut to
stre s s fu l
l i fe
even t s ,
con s c i ous · or
con fl i ct , anxi ety or aggre s s i on
uncon s c i o u s
( rev i ewed by Ford ,
psycho l og i cal
1 986 ) .
At the
other end of the spectrum i s the v i ew t h at I BS i s an org an i c d i sorder
of gut funct i on resul t i ng e i ther from an i nt r i n s i c abnormal i ty of the
smooth muscl e or i ts n eurohumoral control mechan i sms ( Sn ape et al . ,
1 976 ) .
Cl a i ms t h at I SS can be c aused by food " al l ergy " date bac k to the
1 92 0 ' s , at wh i ch t i me the d isorder was known a s " mucous col i t i s "
( Du ke , 1 9 2 1 ;
Vaug h an , 1 92 2 ;
Rowe , 1 944 ) .
The i s sue h a s l ong been a
controvers i al one , prompt i ng I ngel fi nger et al .
( 1 949 ) to l ay down
1 82
spec i fi c cri teri a for the d i agnos i s of gastro i ntest i n al al l ergy :
(i)
demo n s trat i on that symptoms are caused by contact wi th a spec ; fi c
substance that i s i nnocuou s to the bul k of the popul at i on ,
(i i )
ev i dence o f an i mmune mechan i sm i n pathogenes i s , and ( i i i ) demon
strat i on of l es i on s or funct i onal ch anges i n the gut .
More recentl y
i t has been suggested that I BS may occu r , at l east i n a proport i on of
case s , on the bas i s of n o n - i mmunol og i cal food i ntol erance ( Bu i s seret
et al . , 1 978 ;
1 982 )
•
Cooper et al . , 1 980 ;
Ferguson , 1 982 ;
Al un Jones ,
Oesp i te th i s a number of authors have fa i 1 ed to apprec i ate
the d i st i nct i on between i mmunol og i cal hypersen s i t i v i ty and non - i mmune
mechan i sms , concl ud i ng that fa i l ure to confi rm an al l erg i c aet i ol ogy
exc l udes food a s a cause of symptoms i n I BS ( Bentl ey et al . , 1 983 ;
F arah et al . ,
1 985 ) .
The s hortcomi ngs o f such stud i e s h ave been
po i nted out by Al un Jones et al . ( 1 983 ) , and are d i scu s s ed i n deta i l
bel ow .
I n t h e present study 3 58 pat i ents w i t h IBS were eval u ated , 3 2 9 of
whom were pl aced on the standard el i mi n at i on d i et .
Of these 1 59
( 48%) reported compl ete l os s of symptoms or s i gn i fi cant i mprovement ,
and
u nderwen t
doubl e - bl i nd
chal l enge
( Tabl e
6. 1)
.
The
res u l ts
fol l owed the s ame pattern as i n other pat i ent group s , wi t h sal i cy1 ates most
common l y reproduc i ng
symptoms
( 62%) ,
fol l owed by MSG ,
n i trates , ami nes and food add i t i ve s ( Tabl e 6 . 8 ) .
The symptoms most
frequentl y provoked by ch al l enges were n ausea , mal a i se ,
p a i n , bl o at i ng and d i arrhoea .
I BS who
proved
to
abdomi nal
As wi th R I U/AO pat i ents , those wi th
be d i et - sen s i t i ve
s ucce s s fu l l y by l ong- term restri ct i on
cou l d general l y
be managed
of the i r d i etary i ntake of
foods con t a i n i ng the rel evant substances ( Ch apter 8 ) .
1 83
Mouth Ul cers
Recurrent aphthous ul cerat ; on i s a common cond i t i on wh lch may affect
up to 20% of the popu1 at i on , and i s ch aracteri zed by smal l pa i nful
Al though mouth ul cerati on:
l es i on s occurri ng s i ngul arl y or i n crops .
can occur
i n connect i ve
t i s s ue d i seases ,
bu l l ous
ski n
d i seases ,
Behcet ' s syndrome , i n fl ammatory bowel d i sease , defi c i ency states a��
cycl i c
neutropen i a ,
v ar i ety
of
factors
pred i spos i t i on ,
p sycho 1 og i ca 1
Chal l acombe ,
the
maj ori ty
h ave
been
of cases
i mp l i cated ,
endocri ne factors ,
factors
1 987 ) .
and
In
are
v i ral
i nc l ud i ng
i nfect i on s ,
soc ; o - economi c
recent years ,
" i d i op ath i c " .
status
atten t i o n
spec i fi c food al l erg i es or i ntol erances as
a
geneti c
auto i mmun ity, .
( rev i ewed
has
by .
sh i fted to
a cause o f recurrent
aphthous u l cerat i on , i ncl ud i ng gl uten ( Wal ker et al . , 1 980 ;
1 98 1 ;
Ai
Wray,
Wr i ght et al . , 1 986 ) , d a i ry products ( Thomas et al . , 1973 ;
Wri ght et al . , 1 986 ) , and a number o f mi sce1 l aneous foods ( H ay &
Reade , 1 984 ) .
A 1 though many of these authors h a ve s pecu 1 ated about
pos s i bl e i mmunol og i c al
mech an i sms ,
none h ave presen ted
ev i dence of a true al l erg i c bas ; s of th i s cond i t ; on .
any cl ear
Wray et al .
( 1 982 ) found that some pat i ents rel ease h i s tami ne from basoph i 1 s i n .
res pons e to s pec i fi c foods , but th i s d i d not corre1 ate wel l wi th "
cl i n i cal
fi nd i ngs .
Furthermore ,
even
though
chal l enges
provoked '
mouth u l cerat i on i n sel ected pat i ents , removal o f the rel evant foods '
from the d i et d i d not prevent recu rrences i n the l ong - term .
On
the
other hand , Wri ght et al . ( 1 986 ) found s i x pat i ents i n whom prol onged
and rel entl e s s mouth u l cerat i on responded dramat i cal l y to avo i dance
of gl uten , mi 1 k or azo - dyes ,
and who were wel l
peri od o f between one and four years .
over a fo 1 1 ow-up
.
Two oth er groups h ave al so
i ncri m ; n ated gl uten but none of the p at i ents stud i ed were found
to '
1 84
h av e any c l i n i c al or h i stol og i cal ev i dence o f coel i ac d i sease ( Wal ker
et a l . , 1 980 ;
Wray , 1 98 1 ) .
H ay and Re ade ( 1 984 ) fou n d fo u r pat i en t s
who s e mouth u l cerat i on re s o l ved o r i mproved mar kedl y w i t h a d i et
based o f t h e Rowe el i m i n at i on d i et s , and recurrences were v a r i o u s l y
pro v o ked by f i g s , cheese , tomato , v i negar , l emon , p i neappl e , mu stard ,
m i l k and wheat fl o u r .
Bec a u s e o f t h e observat i on o f a l atent peri od
of between ei ght and 72 h o u rs ,
t h e s e authors spec u l ate t h at t h e
mech an i sm may i nvol ve a del ayed ( Type I V ) hypersen s i t i v i ty res po n s e ,
but n o e v i dence was p resented tOr s upport t h i s .
I n t h e p re s e n t s tudy , 46 p at i e n t s were referred t o t h e RPAH Al l ergy
C l i n i c for a s s e s sment of p o s s i bl e food i ntol erance as a c o n t r i butory
facto r .
O f t h e s e , 3 1 were p l aced o n t h e s tand ard e l i mi n at i on d i et ,
and 1 5 were g i ven an emp i r i cal l y mod i fi ed d i et ( Tabl e 6 . 3 ) .
Twen ty
t h re e pat i ents ( 74%) bec ame symptom- free o n t h e el i mi n at i on d i et and
were systemat i cal l y c h a l l enged .
None of the p at i en t s tested reacted
to open food c h a l l enge wi t h wheat o r m i l k , o r to. doubl e - bl i nd chal l
enge w i t h g l uten , i n contrast to prev i o u s l y p ubl i s hed s t ud i e s ( Wal ker
e t a l . , 1 980 ;
Wray , 1 98 1 ;
Wri g h t e t al . , 1 986 ) .
H owever , al l 23
pat i e n t s reacted to one o r more of the chem i ca 1 c h a 1 1 enge s , by far
the c ommo n e s t be i ng sal i cyl ates ( Tabl e 6 . 8 ) .
Even t h o s e who fa i l ed
t o react t o a s i ng l e d o s e o f ASA o ften devel o ped recu rrences o f mouth
u l cerat i on
( somet i me s
t ogether
wi t h
urt i c ar i a )
when
sal i cyl ate
conta i n i ng foods were t a ken over a l onger per i o d o f t i me , s ugges t i ng
a c umul at i v e d o s e -dependent e ffect .
C h al l enges other t h an col o u r i n g s
and preserv at i ve s rarel y p rovo ked react i on s , but t h e n umbers t e sted
were too smal l t o draw any val i d concl u s i o n s ( Tabl e 6 . 8 ) .
1 85
I t i s i nteres t i ng to note t h at pat i ents w i th t h e mos t i ntract abl e ant
l ong- stand i ng mout h - u l cerat i on
( referred from t h e Dent a l
H o s p i tal )
general l y too k l onge s t to settl e o n t he el i mi n at i o n d i et , s omet i mes
requ i r i ng as l on g as three mon t h s .
ental ,
Th i s was u n l i ke l y to be c o i ncid- ,
s i n c e c h a l l enges regu 1 arl y provoked acute recurrences wi th<
u l cerat i on o ften l as t i ng for two wee ks or more i n s uc h c a s e s .
As an i nc i dental i s s ue , 1 1 p at i ent s referred from t h e Den t al Hosp it� �
bec a u s e o f burn i n g sen s at i on s ; n t h e mouth ( Lancet Ed i t o r ; a 1 , 1 978)
underwe n t d i etary i nvest i gat i o n .
!
On l y o n e appeared t o i mp rove , but
s h e reacted t o al l the c h a l l enges g i ven i nc l ud i n g t h e p l acebos (data :
not s h own ) .
Neuropsyc h i atri c Syndromes
By far t h e mos t h e ated' o f t h e many controvers i e s s u rrou nd i ng the
who 1 e subj ect of food i ntol erance revo l ves around t h e que s t ; on of ,
'
whether food react i on s can provo ke n euro p sych i at r i c symptom s .
The ··
h i stor i cal roots o f t h i s i s s u e ( see C h apter 9 ) d at e bac k more than 70
years when Hoobl er ( 1 9 1 6 ) ,
reported t h at u n u s u al
common i n al l e rg i c c h i l dren .
res t l e s s n e s s was ·
Later , Du ke ( 1 9 2 1 ) and S h an n o n ( 1 922) ,
c l a i med that food al l ergy coul d be res p on s i b l e for v a r i o u s " neuro· :
path i c " man i fes t at i on s such a s nervous n e s s , i rr i t a b i l i ty , wea kness , :
hypoten s i on , s l eep d i s turbance , hyperact i v i ty , beh av i o u r d i sorders , .:
mood i ne s s ,
1 9 50 ' s
poor concentrat i on
Speer
( 1 954 )
co i n ed
and
the
l earn i ng d i s ab i l i t i es .
term
" al l e rg i c
I n the
ten s i on - fat i gue
syndrome " to descri be wh at he and others bel i eved to be symptoms '
l
c haracteri s t i c o f an a 1 1 erg i c react i on i nvo 1 v i n g t h e b r a i n ( Wooton , :
186
1 93 4 ;
Turn bul l ,
Leon ard , 1966 ;
Speer , 1983 ) .
as
" Cl i n i c al
1 943 ;
Jones , 1 949 ;
Wol f , 1 9 7 1 ;
Dav i son ,
1 952 ;
C roo k ,
We i n berg & Tuch i nd a , 1 973 ;
1 963 ;
rev i ewed by
Me anwh i l e , another school of t hought ( now referred to
Ecol ogy " )
aro s e fol l ow i ng t h e earl i er work of Rowe
( 1 93 1 ) , cl a i mi ng t h at " n on - reag i n i c food al l ergy "
( Coca ,
1 94 2 ) or
"mas ked food al l ergy " ( Ri n ke l , Randol ph & Ze1 l er , 1 95 1 ) was respon s
i bl e for a wi de array o f vague , s u bj ect i ve symptoms .
Many orthodox al l erg i sts rej ect these cl a i ms , po i nt i ng out t h at they
are based on anecdotal cl i n i cal i mpre s s i o n s and unproven d i agnost i c
methods
( May ,
1 986 ) .
Neverthel e s s ,
i ntere s t from the med i a , the pub1 i c ,
they
attracted
w i despre ad
and cert a i n segments o f the
med i ca l pro fe s s i on d u r i ng the 1 970 ' s , d u e i n part to the publ i cat i on
o f two popul ar boo ks :
" Why your ch i l d i s hyperact i ve "
197 5 ) and " Not al l i n the mi nd " ( Mac kern es s , 1 976 ) .
( Fe i ngol d ,
The res u l ts o f
t h e pre sent study do i nd eed l end a degr�e of s upport to t h e s e cl a i ms ,
b u t as w i 1 1 be out 1 i ned bel ow ( and i n C h apter 9 ) t h e cone 1 u s i on s
drawn from the d a t a are n o t nece s s ari l y t h e s ame .
S i nce t h e cl i n i cal
probl ems encountered i n ch i l dren are somewhat d i fferent from those i n
adu l t s , t h e two areas w i l l "be d i scus s ed s eparatel y .
( a ) Hyperact i ve C h i l d ren
By 1 960 , an average of ten art i cl e s were appear i ng e ach year on the
ft
hyperact i ve ch i 1 d syndrome , " i ncreas i ng t o over 1 00 per year by
1 97 5 , and more than 2000 per year by 1 980 ( Ro s s & Ros s , 1 982 ) .
It
was f i rst descri bed by Hoffman ( 1 845 ) a s a syndrome con s i s t i ng o f
1 87
" hyperact i v i ty ,
i mp u l s i v i ty , d i s t rac t a b i l i ty and exc i t ab i l i ty " , and
h a s been g i ven many d i fferent
l abel s
s i nce t h at t i me ,
i ncl ud i ng
hyperki nes i s , m i n i ma l bra i n dys funct i on and Strau s s syndrome , and i s
c u rren t l y referred to i n t h e D i agno s t i c and Stat i s t i ca l
Manu a l of
Men t al D i s o rders ( DSM - I I I , 1 980 ) a s "Atten t i o n d e f i c i t d i sord e r , w i th
hyp eract i v i ty " .
The c l i n i cal p i cture of t h e " hyperact i ve " c h i l d i s
w i del y recogn i zed , and genera 1 1 y n o t d i sputed by i nv e s t i g ators and
c l i n i c i an s .
However there h as been a great deal o f debate a bo u t i ts
aet i o l o gy , and a bo u t the v al i d i ty and c l i n i ca l u seful n e s s of accord
i ng t h e s e symptoms t h e status o f a d i agn o s t i c e nt i ty
Greenh i l 1 , 1 979 ;
Rutter , 1 982 ) .
( Sh affer &
The mos t extreme v i ewpo i n t i s t h at
t h ere h a s been an u n h e al t hy co 1 1 u s i o n between p hy s i c i a n s , t e ac h ers
and drug compa n i es i n " med i c at i ng " d i ff i c u l t c h i l d re n who are n o rmal ,
but who may be react i ng to underst a ffed s c h o o l s o r poor h omes by
be i ng d i srupt i ve ( Sc h rag & D i vo ky , 1 975 ) .
A more rea s o n ed arg u ment
h as been put forward by Schechter ( l 982 ) , who bel i ev e s t h a t , e ven
though there may be a smal l n umber of g e n u i ne l y d i s t u rbed c h i l d ren
requ i ri ng med i cal atten t i on , e i ther on t h e bas i s of a n eurol og i cal
defi c i t ,
a devel opme n t al
del ay or a temperame n t a l
attr i bute ,
the
appare n t e p i dem i c of s o - c al l ed hyperact i v i ty h a s been exaggerated by
a n umbe r o f s oc i ol og i c al factors .
H e con s i ders t h e mo s t s i gn i fi cant
of t h e s e to be t h e breakdown of t h e trad i t i o na 1 extended fam i 1 y i n
the pos t -war era and t h e " med i c a l i zat i on " o f c h i l d - re ar i ng wh i ch took
p l ace after the pub 1 i c at i o n o f Benj ami n S poc k ' s boo k ( Commo n sen se
book o f baby and c h i l d c are by Spoc k , 1 945 ) .
1 88
U nt i l recen t l y t h e i s s ue of d i agn o s t i c and pred i ct i ve v a l i d i ty was
con fu sed by the
app aren tl y w i de l y d i ffe ri ng preva l ence of hype r
act i v i ty i n Br i t a i n ( 1/ I OO O ) compared w i t h t h e Un i t ed St at e s {where
between fi ve percent and 2 0% of schoo 1 - age ch i 1 d ren are sa i d to be
affected ( rev i ewed by L i pton et al . ,
1 979 ) .
It i s n ow recogn i zed
t h at t h e ' preval ence i s i n fact s i mi l ar i n bot h countr i e s , but t here
i s a tende n cy for B r i t i s h workers t o excl ude hyperact i ve - aggres s i ve
ch i l dren , and l abel them as h av i ng " conduct d i sorder " ( Tayl or , 1 986 ) .
Th i s probl em h a s been further compounded by confu s i ng perv a s i vel y and
s i t u at i o n a l l y hyperac t i ve ch i l d ren , w i t h the res u l t t h at p hys i c i an ' s ,
teacher ' s and parent ' s a s s e s sment s may be q u i te d i vergent ( d i scus s ed
i n deta i l by We i s s , 1 985 ) .
Th u s , desp i te cont i nu i ng debate , recent
s t ud i es s uggest that the hyperact i ve ch i l d syndrome h a s both concurr
ent and pred i ct i ve val i d i ty and may i ndeed be con s i dered a val i d
d i agn os t i c ent i ty ( We i s s , 1 985 , 1 98&;
I n 1 9 73 ,
L an cet Ed i tori a l , 1 986 ) .
Fe i ngo l d pre s en ted a p aper at a meet i ng o f the Ame r i can
Med i cal As soc i at i on c l a i m i ng ' t h at u p to 5 0% o f hyperact i ve c h i l dren
became wel l
or i mproved markedl y on a d i et free of add i t i ve s and
n atural s al i cyl ates ( Fe i ngol d , 1 973 ) .
i mag i n at i on ,
and fol l ow i ng the
Th i s i dea captured the publ i c
appearance o f h i s boo k
( Fe i ngol d ,
1 97 5 ) more t h an 1 00 parent sel f- h e l p o rg an i zat i on s s prang up i n the
USA , UK and Aus tral i a , advocat i ng t h e " Fe i ng o l d D i et " .
Duri ng the
n ext decade Fe i ngol d ' s c l a i ms generated enormo u s controversy .
The
i s s ue became strongl y pal i t i c i zed , ma i n l y bec au s e of the emphas i s
p l aced on
food
add i t i ve s ,
wi th
protagon i st s
cal l i ng
for
spec i al
.
189
l abel l i ng l aws and a ban on the use of foods conta i n i ng add i t i ves i n
school canteen s , wh i l e offi c i al statements den i ed any safety d i ffer
ence between natural
and art i fi c i al
( rev i ewed by
food substances
l i pton et al . , 1 979 ) .
The 1 i terature on d i et and hyperact i v i ty i s 1 arge ,
and h as been
exten s i vel y rev i ewed by several authors ( S i eben , 1 977 ;
l ayl or , 1 979 ;
l i pton et al . ,
1 979 ;
Ri bon & Josh i , 1 982 ;
Conners ,
Egger ,
1 980 ;
1 987 ) .
Di c kerson & Pepl e r ,
1 980 ;
The numerous cl i n i cal tri al s
des i gned to test Fe i ngo 1 d ' s hypothes i s fal l i nto three groups :
(i)
uncontrol l ed , open cl i n i cal tri al s of the add i t i ve - free d i et ;
(ii)
bl i nd cl i n i cal
tri al s of the d i et ;
( i i i ) doubl e - bl i nd chal l enge
experi ments wi th or wi thout cross - over of test and pl acebo d i ets .
general ,
open
tri al s
h ave
supported
Fe i ngol d ' s
cl a i ms ,
In
whereas
control l ed cl i n i cal tri al s have yi el ded much l es s i mpress i ve resul ts
( l i pton et al . ,
1 979 ) .
Up to
1 980 there were four open tri al s
report i ng benefi c i al effects of the Fe i ngol d d i et , bot h i n Austral i a
( Cook & Woodh i l l , 1 97 6 ) and the USA ( Sal zman , 1 976 ;
Harper et al . ,
1 978) .
Brenner , 1 977 ;
Several control l ed stud i es i nvol v i ng bl i nd
chal l enges wi th food col ours showed encourag i ng resul t s i n p i l ot
stud i es , but subsequentl y fa i l ed to confi rm the i r prel i mi n ary fi nd
i ng s ( Harl ey & Matthews , 1 977 , Harl ey et al . , 1 978 ;
1 978 ;
Levy et al . , 1 978 ;
al . , 1 978 ;
levy & Hobbes ,
Conners et al . , 1 976 , 1 978 ;
Mattes & G i ttel man -Kl e i n , 1 978 , 1 980 ) .
Goyette et
I n some seri es ,
desp i te the negati ve fi nd i ngs overal l , a smal l number o f ch i l dren
were i dent i fi ed i n whom chal l enge s appeared to provoke a con s i stent
adverse react i on compared to pl acebo ( Harl ey et al . , 1 978 ;
et al . , 1 978 ;
Rowe et al . , 1 979 ;
Ki n s bourne , 1 980 ) .
We i s s et al . , 1 980 ;
W i l l i ams
Swanson &
190
As
a resul t
of wi despread concern
Nutri t i on Foundat i on
a bout
Fe i ngol d ' s
i n the USA establ i shed
cl a i ms ,
a Nat i onal
the
Adv i sory
Commi ttee on Hyperki nes i s and Food Add i t i ves ch arged wi th the tas k of
enco urag i ng and eval uat i ng control l ed stud i es test i ng h i s hypothes i s .
I n i ts fi nal report ( 1 980 ) the Commi ttee concl uded that
tI
•
•
•
stud i es
al ready compl eted prov i de suffi c i ent ev i dence to refute the cl a i m
that art i f i c i a 1 food col ouri ngs , art i fi c i a 1 fl avouri ngs and sal i cyl
ates produce hyperact i vi ty and/or 1 earn i ng d i sabi 1 i ty " .
l ater
a
Nat i onal
I n sti tute
of
Heal th ,
Consen sus
Two years
Devel opment
Conference ( 1 982 ) reached general l y s i mi l ar concl us i on s , al though i t
was po i nted out that i n a smal l proport i on of ch i l dren the Fe i ngol d
d i et d i d appear to reduce hyperact i v i ty ,
and pub 1 i shed cha 1 1 enge
stud ies were cri t i c i zed for not hav i ng addressed the rol e of d i et
suffi centl y broadl y .
Unt il recentl y the we i ght o f sc i ent i fi c ev i dence seemed to have
defi n i t i vel y refuted Fei ngo1 d ' s hypothes i s ( Kava1 e & Forness , 1 983 ) ,
but the controversy was reki ndl ed by a careful l y control l ed study
publ i shed
by
Egger
et
al .
( 1 985 ) .
S i xty
two
of
76
sel ected
ch i l dren wi th hyperact i v i ty i mproved obj ect i vel y when pl aced on an
" o l i goant i gen i c " d i et ,
and of these 28 compl eted a doubl e - bl i nd ,
c r os s over pl acebo -control l ed tri al i n wh i ch the suspected food s were
-
re - i nt roduced
.
The study showed a cl ear assoc i at i on between deter
; orat i on i n beh av i our and exposure to the suspect food ,
but not
pl acebo , wi th 45 d i fferent food s and add i t i ves be i ng i ncri mi n ated
overal l .
The authors i nterpreted these fi nd i ngs as · i nd i cat i ng that
al l erg i c mech an i sms rather than ph armacol og i cal i d i osyncrac i es were
i nvol ved , a v i ew wh i ch we have d i sputed on the bas i s of our own
fi nd i ngs ( Swa i n et al . , 1 985 ) .
191
Of the 30 1 chi l dren eval uated i n the present study , 4 S were g i ven a
modi fi ed d i et
wi thout
formal
test i ng
( for
the
reasons
outl i ned
above ) , and the rema i nder were g i ven i n struct i ons for fol l owi ng the
el i mi n at i on d i et .
One hundred and e i g hteen were l ost to fol l ow- up
(Tabl e 6 . 4 ) , two fa i l ed to i mprove , and 1 36 appeared to i mprove and
proceeded to dou bl e - bl i nd chal l enge tes t i ng .
Because of the subj ect·
i ve b i as i nherent i n parental eval uat i on , no fi rm concl us i ons can be
drawn from the reported benefi ts of d i etary el i mi nat i on .
However , i t
i s s i gn i f i cant that o f those c h a1 1 enged , al l but 4 c h i 1 dren were
j udged by the parents to h ave reacted to at l east one chal l enge
compound , and i n onl y 5 i n st ances was th i s a pl acebo ( P <0 . 0005)
( F i gure 6 . 2 and Tabl e 6 . 8) .
Somat i c symptoms such as headache ,
abdomi nal
occurred
pai n
or
urt i cari a
together
wi th
behavi oural
changes i n two th i rds of the ch i 1 dren tested , al t hough 73% o f the
ch i l dren were reported as man i fest i ng an i sol ated beh av i oural change
after at 1 east one of the act i ve cha 1 1 enge compounds , and in one
th i rd beh av i oural
react i ons .
ch ange was the onl y man i festat i on of chal l enge
I n al l , pos i t i ve �ha1 l enge react i on s were recorded on 522
occas i on s i n 1 36 ch i l dren .
Beh av i oural
symptoms occurred on 397
occas i on s , 247 of wh i ch ( 62%) were i n the absence of any accompanyi ng
phys i cal symptoms .
The commonest compound respons i bl e for pos i t i ve chal l enge react i on s
was asp i ri n , wh i ch was reported a s caus i ng behav i oural changes , wi th
or wi thout somat i c symptoms , i n 68% o f the ch i l dren tested (Tabl e
6 . 9) .
at i ves ,
Hal f the ch i l dren reacted to tartraz i ne and 5 1% to preservA
but i nterest i ngl y over one th i rd al s o reacted to ami nes
·
192
and/or MSG .
N o ch i 1 d reacted t o tartraz i n e al one .
R I U/AO p at i ents , those sen s i t i ve to as p i ri n h ad
a
As w i th the
h i gher probab i l i ty
o f react i ng to other substances ( F i gure 6 . 3 ) , but the pattern i n each
ch i l d was i nd i v i dual ( Lobl ay & Swa i n , 1 985 ) .
Our fi nd i ng s tend to support the ori g i nal hypothes i s put forward by
Fe i ngol d ( 1 9 7 5 ) , al thoug h the range of food substances i nvol ved i s
broader t h an he h ad suspected .
Cl earl y , therefore , i t i s not pos s
i bl e to dev i se a standard d i et s u i tabl e for al l hyperact i ve ch i l dren ,
- and i n th i s regard we are i n agreement wi th Egger et a l . ( 1 985 ) .
In
retros pect , some o f the reasons for the fa i l ure o f prev i ou s stud i es
to support F e i ngol ds ' cl a i ms can now be apprec i ated .
Of
cri t i cal
i mport ance i s the need for ri gorous e 1 i m i n at i on o f both sal i cyl ate
and ami ne cont a i n i ng foods from the basel i ne d i et i n order to reduce
the " bac kground noi se " of symptoms , as wel l as to l ower the dose
thresho l d for chal l enge react i ons .
A 'c areful read i ng o f publ i shed
stud i es i nd i cates that i n no case h a s th i s been done adequatel y , wi th
the pos s i bl e except i on of Egger et al . , where an "01 i goant i gen i c "
d i et was arri ved at emp i ri cal l y for each c h i l d .
Furthermore ,
as
po i n ted out by We i s s ( 1 986 ) and Egger ( 1 987 ) , some authors d i sgu i sed
the act i ve and pl acebo i ngred i ents i n choco l ate cook i es , apparentl y
wi thout real i z i ng that some ch i l dren may react to choco l ate ( Wi 1 1 i ams
et al . , 1 978 ;
Swan son & Ki nsbourn e , 1 980 ;
Other methodo l og i ca 1
Thorl ey , 1 983 ,
prob 1 ems i nc 1 ude the fact that
u sed i nadequate doses ( Swan son and Ki n s bourne , 1 980 ;
1 984 ) .
some stud i es
We i ss et al . ,
1 980 ) , and others d i d not i n sert - was hout peri ods between the test
peri ods ,
wi th
l i kel y carry- over effects
H arl ey et al . , 1 978 ;
(W i l l i ams
Swanson and Ki n sbourne , 1 980 ;
et a l . ,
1 978 ;
We i s s et al . ,
193
1 980 ;
Thorl ey , 1 984 ) .
F i n al l y , n o account was t a ken i n any study of
the poss i bl e c effects of MSG or n i trates , wh i ch i n our h and s provoked
react i on s i n 39% and 44% of the ch i l dren chal l enged , res pect i vel y .
Adyl ts wi th " Systemi c " Symotoms
Once the RPAH Al l ergy Cl ; n i c became known for i ts interest i n food
i ntol erance ,
the
proport i on
non -cut aneous d i s orders
of
pati ents
present i ng
i ncreased substanti al l y
w i th
v ar i ous
1 . 1) .
( F i gure
In
many cases symptoms were restri cted to a s i ngl e org an system , and
these h ave been d i scus sed i n det a i l above .
I n other cases , h owever ,
there were symptoms referabl e to mul t i pl e organ systems , and such
I
pat i ents were des i gnated a s h av i ng a " systemi c " syndrome .
s pec i fi c probl ems such as abdomi n al
s omet i me s
l ed
p at i ents
to
present
Al though
characteri st i c cl i n i ca 1 feature o f th i s group was the p re sence .of
mul t i pl e somat i c compl a i nts o f a " funct i onal " n ature , wh i ch are often
accompan i ed by v ague neuropsych i atri c symptoms .
commo n l y descri bed
as
" th i c k " i n the head ,
as soc i ated
wi th . poor
a
feel i ng of bei ng
The
" drugged " ,
l as s i tude ,
depres s i on .
1 atter were
" fuzzy "
l
1
or
concentrat i on ,
l os s
of
s hort - term
and
unexp l a i ned
bouts
of
memory,
fat i guab i li ty,
i rr i t a b i l i ty
or
Two - th i rds o f the pati ents were women , and the maj ori ty "
were i n t he i r th i rd or fourth decade ( F i gure 6 . 1 ) , w i t h an average
d urat i on of symptoms o f n i ne years .
One th i rd dated t h e on s et of
symptoms to a documented v i ral i nfect i on , o ften g l andul a r fever , from
#>
wh i ch t hey fel t they had never ful l y recovered , and i n t h i s g roup the
cl i n i cal
1
or an i n ab i l i ty to th i n k c l earl y , v a r i ously
i mp a i rment of cogn i t i ve t a s ks , bl urri n g of v i s i on ,
phys i cal
i
p a i n s , d i arrhoea o r headache 1
l
for i nves t i g at i on , the most �
p i cture correspond s to that descri bed as t h e post - v i ral
I
194
fat i gu e syndrome ( Behan et al . ,
1 985 ) .
I n some cases the on set
appeared to fo 1 1 ow a pregn ancy , adverse drug react i on , or a s udden
ch ange o f d i et , but i n others the onset was i n s i d i ou s or e p i sod i c ,
wi t.h n o obv i ous tri ggeri ng factor , o ften heral ded by a feel i n g of
be i ng " run down " .
Though many were under a degree of stres s i n the
home
env i ronment ,
and/or work
th i s
genera l l y
appeared
to
be
a
con s equence of try i ng to cope wi th the demands of d a i l y l i fe i n the
presence of chron i c i l l - heal th .
A 1 together ,
" systemi c
11
809 p at i ents were cl ass i fi ed at presentat i on as hav i ng
symptoms .
Of these , 6 2 were not con s i dered s u i tab 1 e for
formal test i ng , 3 5 reported no i mp rovement on the el i mi nat i on d i et
and d i d not undergo chal l enge , and 309 were l ost to fol l ow- up (Tabl e
6 . 4) .
The rema i n i ng 403 pat i ents e i ther became asymptomat i c o r were
substan t i al l y i mproved on the el i mi nat i on d i et , often for the fi rst
t i me i n many years .
Because of the subj ect i ve n ature of pat i ents '
sel f-eval uat i on i t i s i n approp i ate to attach much s i gn i fi cance to
th i s observat i on al one .
However , al most al l those pat i ents report i ng
s ubject i ve i mprovement on the el i m i nat i on d i et exper i enced a recurr
ence of symptoms i n response to one or more of the act i ve doub 1 e
bl i nd ch al l enges , whereas react i on s to pl acebo occurred i n l es s than
1 0% of pat i ents ( P <0 . 0005 , Tabl e 6 . 8 ) .
As i n the other pat i ent groups stud i ed , asp i r i n was the compound most
frequent l y respon s i bl e
for
provok i ng
symptoms ,
y i el d i ng , pos i t i ve
resul t s i n three - quarters o f those chal l enged · (Tabl e 6 . 8) i General l y ,
respons i veness t o al l act i ve chal l enge compounds was h i gher i n th i s
group t h an i n pat i ents wi th symptoms confi ned to a s i ng1 e organ
195
Psychol og i cal symptoms s uch as i rr i tab i l i ty , 'mood i ness or depres s i on ,
mental R fuzz i nes s " and l ack of concentrat i on were reported i n 63% of
pos i t i ve chal l enge react i on s , us ual l y i n conj unct i on wi th l ethargy ,
,�
mal a i se and myal g i a and other phys i cal symptoms .
On 1 0 1 occas i ons ,
62 pat i ents ( 1 5%) experi enced i sol ated mood ch anges wi th a chal l enge
i n the absence of any accompany i ng somat i c symptoms , but i n onl y four
i nstances d i d th i s occur fol l owi ng a pl acebo ( s ucrose i n al l four ,
none after st arch ) .
;j
1
t
,1
1 96
A rev i ew of the l i terature shows that " systemi c " react i on s to foods
i nvol vi ng neuropsych i atri c as wel l
as phys i ca 1
symptoms h ave been
descri bed often i n the past , al though we were not aware of th i s when
the present study began .
I ndeed , as Speer po i nted out when survey i ng
the l i terature i n h i s monograph ( 1 983 ) ,
". . .
the ten s i on - fat i gue
syndrome i s often d i scovered i ndependentl y -by those who h ave never
heard of i t " .
As outl i ned above , reports of th i s ki nd h ave general l y
been met wi th scept i c i sm by orthodox phYS i c i an s ( May , 1 986 ) , al though
i t i s not d i ffi cul t to see why th i s h as been the case .
To beg i n
wi th , many of the symptoms descri bed are typ i cal o f psychoneuro s i s ,
and are not recogn i zed features of cl a s s i cal al l erg i C react i on s .
Characteri sti cal l y l aboratory i nvest i gat i on s d o not show evi dence of
org an i c p athol ogy , and s uch pat i ents are frequentl y l abel l ed as be i ng
neuroti c or hypochrondri acal .
On top of th i s , the prej ud i ces of
orthodox phys i c i an s tend to be re i nforced by the over -enthus i ast i c
cl a i ms o f " cl i n i cal ecol og i sts " and other fri nge pract i t i oners whose
as sert i on s usual l y go far beyond the ava i l abl e ev i dence .
Ri gorous
test i ng proced ures are al most never empl oyed and sweep i ng general
i zat i ons are o ften made on the bas i s of anecdota l ev i dence ;
observat i on s
are
rarel y publ i shed
in
the
sc i ent i fi c
the i r
l i terature ,
u s ual l y appear i ng i n popu l ar books accompan i ed by mi sgu i ded or out
dated mech an i st i c expl anat i ons ( see , for exampl e , Mackarness , 1 976 ;
Itt:.
Rando l ph & Moss , 1 980 , 1 98 1 ) .
Such cl a i ms are often sei zed upon by
",
,
an uncri t i cal med i a anx i ous to sens at i onal i ie any perc i eved short
com i ngs of orthodox med i c i ne , and panderi ng to the popul ar bel i ef
that a corrupt al l i ance between government and i ndustry i s respon s
i b l e for adul terat i ng the food supp l y and env i ronment wi t h tox i c
substan ces .
197
Probab 1 y the most i mportant source o f confu s i on ,
h owever ,
i s the
fa i l ure by most i nvest i gators to apprec i ate the ph armaco l og i c al bas i s
o f t h e great maj o r i ty o f adverse food re act i on s , maki ng cl i n i cal
recogn i t i on d i ffi cul t .
As emph as i zed prev i o us l y ( Lobl ay & Swai n ,
1 986 ) , symptoms can be provoked by a vari ety o f chemi cal s u bstances ,
both natural and art i fi c i a 1
e ffect s o f these compounds
,
common to many d i fferen t food s .
are dose- re l ated ,
and
in
The
s u scept i bl e
peop l e t h ey exh i b i t pharmaco l og i cal propert i es such a s wi thdrawal ,
s upersen s i t i v i ty ,
tachyphyl axi s
and
tol erance .
Th u s , ," for
each
chemi cal the dose threshol d for tri gge ri ng symptoms vari e s depend i ng
o n the i nd i v i d u al ' s recent i ntake from a vari ety o f food s ources , so
that a part i cul ar food need not n ece s s ari l y produce t h e s ame react i on
on d i fferent occas i ons .
Th i s , together w i t h t h e fact t h at react i on s
may be del ayed by many h ours ( or even a d ay o r two ) , means that
pat i ents c an become ' eas i 1 y con fused o r m i staken about wh i ch foods
cause symptoms , i f i ndeed they are abl e to recogn i ze the rel at i o ns h i p
at al l .
S i mi l arl y , the phys i c i an may be mi s l ed by n egat i ve c h al l enge
tests w i t h i nd i v i dual foods wh i ch cont a i n o nl y smal l d o s e s of the
rel evant
chemi cal s ,
part i cul arl y
if
the
l atter
h ave
not
been
adequate l y e l i mi n ated from the d i et befo reh and .
These probl ems are wel l i l l ustrated i n t h e recent stud i es o f Pearson ,
R i x and Bentl ey ( Bentl ey et al . , 1 983 ;
al . , 1 984 ;
Pearson & Ri x , 1 987 ) .
Pearson et al . , 1 983 ;
Ri x et
C i t i ng the popul a r i ty o f a n umber
of boo ks wh i ch cl a i m t h at psychol og i cal as wel l as phys i cal symptoms
are commo nl y t h e resu1 t of " food al l ergy " , and expre s s i ng t h e i r own
scept i c i sm , these authors set out to exam i n e t h e val i d i ty o f such
cl a i ms .
They stud i ed 23 adul t outpat i ents who suspected food al l ergy
as a cause o f var i ous symptoms , and were o n l y abl e to con fi rm t h i s i n
.
198
four cases who d i d not man i fest psychol og i cal symptoms .
Cr i teri a for
con fi rmat i on of the d i agnos i s were a po s i t i ve i mmed i ate ski n test ,
prevent ; on of open cha 1 1 enge react i cns by pretreatment w; th oral
cromqg1 ycate , and the doubl e - bl i nd ch al l enge wi th encapsul ated dri ed
foods or foods d i sgu i sed i n a bl and "mi l k- shake " .
The protocol
used
in
these i nvest i gat i on s was des i gned onl y to
i dent i fy pat i ents wi th true , I g E-med i ated food al l ergy , and i s l i ke l y
t p h ave o verl ooked the occurrence o f g � n i une food i ntol erance due to
pharmacol og i cal i d i osyncrac i es .
To b eg i n wi th , a basel i ne d i et of
l amb , pears and ri ce i s d i ffi cul t to fol l ow for more than a week or
so , wh i ch we bel i eve to be i n suff i c i ent t i me for background symptoms
to sett l e i n most pat i ents wi th pharmacol og i cal food i ntol erance .
The authors do not spec i fy the durat i on of the i r basel i ne d i et , nor
do they i nd i cate wh i ch foods were · subse q uentl y re i ntroduced ,
the
t i mi ng and the amounts used for open ' chal l enges , or the cl i n i cal
responses of the pat i ents .
S i mi l arl y , there i s no i nd i cat i on of the
compos i t i on of the bl i nd chal l enges' and pl acebos , of the dos ages i n
wh i ch they were admi n i stered .
I n a repl y to the cri t i c i sms of Al un
Jones et al . ( 1 983 ) i t was stated that the dose was " up to 409 "
( Pearson et al . , 1 983 ) , but i t i s d i ffi cul t to i mag i ne th i s bei ng
pos s i bl e wi th encapsul ated chal l enges ;
d i sgu i s i ng the taste of the
foods themsel ves rai ses even more d i ffi cu 1 t i es , s i nce even n atural
fl avour- i ngs are l i kel y t o be ri ch i n sal i cyl ates and/or ami nes .
F i n al l y , the amounts u sed i n food chal l enges of th i s ki nd woul d often
be i nadequate to el i c i t an acute react i on i n our experi ence , al though
when eaten on a regul a r bas i s the i r cumul at i ve effects may resul t i n
the 1 ns i d i ous reappearance of symptoms a fter several days , or even
l onger .
Th i s i s l i kely to confound the i nterpretat i on of chal l enges
199
by produc i ng
pl acebo )
tes t i ng
both
fal se
react i on s .
protocol
neg at i ve
and
Such compl ex ; t i es
spec i fi cal l y de s i gned
fal se
pos i t i ve
h i g h 1 i g h t the
for the
( i ncl udi ng
n eed for
a
i nvest i gat i on of
pharmacol og i cal food i ntol e rance , even t hough pat i ent s t h emsel ves may
m i s taken l y c l a i m to be " al l erg i c " to spec i fi c food s .
I t i s ev i dent from t h e res u l t s presented here t h at even t hough R I U/AO
commonl y
occurs
i nto 1 erance ,
as
an
i sol ated
cl i n i cal
man i fe st at i on
of
food
i t can al so be regarded as formi ng part of a broad
cl i n i ca l spectrum i nvol v i ng several d i sorders wh i ch are not general ly
t h ought to be d i rectl y rel ated to one another .
i l l ustrated by the data shown i n Tabl e 6 . 8 .
syndromes
stud i ed ,
not
onl y
are
the
Th i s i s mos t c l early
I n eac h o f t h e c l i n i cal
s ame
c h a l l enge
substances
commo nl y i mpl i cated i n provoki ng a recurrence of symptoms , but the
frequency . w i th wh i ch · they do so i s al s o very s i mi l ar .
Thu s , as a
rul e , a sp i r i n i s the s i ngl e commonest chal l enge to produce a pos i t i ve
react i on i n al most every syndrome , fol l owed c l osel y by preservat i ves ,
ami nes , MSG and n i trates .
Other chal l enges such a s . col ouri ngs , ant i
oxi dant s , l actose and gl uten provoke react i on s l es s common l y , i n some
i nstances approac h i ng the pl acebo rate o f between 5 and 1 0% .
Thes e observat i on s are even more stri k i ng i f a l l symptoms provo ked by
each of the chal l enges are i nc l uded , rather then onl y t h o s e const i t
ut i ng t h e ma i n present i ng
compl a i nts
( Tabl e
6 . 9) .
I ndeed ,
many
pat i ents admi t to h av i ng h ad symptoms they t h ems e l ves d i d not connect
wi th t h e i r present i ng probl em when quest i oned i n i t i al l y ,
but the
rel at i on s h i p usual l y became qu i te obv i ous when a n umber o f d i v erse
symptoms wou l d occur together i n respons e to part i cul ar chal l enge s .
Categori z i ng pat i ents i nto spec i fi c syndrome groups was , t h erefore ,
200
not al ways compl etel y cl ear-cut .
As a ru l e , symptoms were j udged to
be s i gn i f i cant i f they h ad recentl y prompted con sul tat i on wi th a
doctor or other heal th profess i onal , or had i nterfered s i gn i fi cantl y
wi th the pat i ents ' day - to - day l i fe and/or work .
I n general , each pat i ent tended to react to chal l enges i n an i d i o
syncrat i c , though reproduc i b 1 e manner .
compounds
more
comb i n at i on
frequent l y
coul d
occur
i mportance of systemat i c
management .
provoked
in
Thus ,
reac t i ons ,
i nd i v i dual
even though certai n
any
cases ,
pe rmuta t i on
emph as i z i ng
or
the
i nvest i gat i on and i nd i v i dual i zed d i etary
Furthermore , when the react i ons to a part i cul ar chal l
enge compound were compared i n the vari ous pat i ent groups i t became
ev i dent that a s i ngl e substance such as asp i ri n cou l d provoke many
d i fferent symptoms , and that these were general l y the s ame as a the
pat i en t s '
present i ng compl � i nt
coul d
regarded not on l y as
be
(Tabl e 6 . 1 0 ) .
hav i ng
an
Thus ,
i nd i v i dual
each
pat i ent
cl uster of
chem i cal i d i osyncrac i es , but al so a spec i fi c pattern of target organ
s uscept i bi l i ty wh i ch may i nvol ve one or more organ systems .
From the pattern of cha 1 1 enge react i ons i t can al so be seen that
pat i ents wi th m i gra i ne , i rri tabl e bowel and " systemi c " symptoms were
a more sens i t i ve group than those wi th urt i cari a or asthma ( F i gure
I
6 . 2) , react i ng on average to a s i gn i fi cantl y greater number of chal l
enges wi th i n the test battery .
Those wi th systemi c symptoms were the
most sens i t i ve of al l , wi th a strong tendency to react adversel y to
mul t i p1 e drugs and other . env i ronmental substances as wel l ( Chapter
8) .
In these pat i ents asp i r i n - sen s i t i v i ty appears to be a goo�
marker of h e i ghtened reacti v i ty to other chal l enge sUbstances ( F i gure
6.3) .
CHAPTER
7
FAM I L Y STUD I ES
I
20 1
I NTRODUCT I ON
Once the ful l spectrum of cl i n i c al man i festat i on s of food i nt o l erance
was appre c i ated i t became apparent that a fam i l y h i story o f rel ated
sympt oms was common .
I n 1 982 a paed i atr i c i an , Dr . V . Soutte r , j o i ned
the Al l ergy Cl i n i c at RPAH , and i t was then pos s i bl e to t e s t symptom
at i c ch i l dren as wel l as the i r p arent s .
I n a t h ree -year peri od ( from
l ate 1 982 to September 1 985 ) 1 98 fami l i e s presented w i t h at l east one
c h i l d and one parent s u fferi ng from symptoms s uspected o f be i ng due
t o food i ntol erance .
In 1 26 fami l i es al l affected members underwent
d i etary e l i mi n a t i on and doubl e b l i nd c h al l enge test i ng , prov i d i ng an
opport un i ty t o determ i n e whether i d i o syncrat i c react i on s t o each
part i cul ar food s ubstance m i ght h ave a genet i c b as i s .
PAT I E NTS AND METHODS
Of t h e 1 98 fami 1 i es present i ng to the Al l ergy Cl i n i c , 72 were not
i nc l uded i n the present anal ys i s s i n ce at l east o n e member d i d not
compl ete t h e el i mi n at i on and chal l enge protocol .
The rema i n i ng 1 26
fami l i e s were made up of 3 50 i nd i v i dual s , as s ummari zed i n Tabl e 7 . 1 .
The d i stri but i on o f presen t i ng symptoms amongs t the 350 i nd i v i dual s
t es t ed i s s h own i n Tabl e 7 . 2 .
Because of the paed i atri c refe rral
pattern at t h e cl i n i c there was a sel ect i on b i as towards c h i l dren
pre s en t i ng w i th beh av i o ur d i sturbances ( 34% o f those under the age of
15) .
A maj o r i ty ( 50%) of parent s presented wi t h symptoms referrabl e
to two o r more org an systems , wi t h or wi t hout con st i tut i onal sympt oms
such as 1 ethargy and mal a i se , and were therefore c l a s s i fi ed i n the
202
" systemi c " group .
There was a strong tendency for s i mi l ar symptoms
to cl u ster wi th i n fami l i es , al though t h i s was not un i vers al (data not
s h own ) .
I n fami 1 i e s where two or more members were c l a s s i f i ed as
h av i ng " systemi c " man i festat i ons the dom i n an t symptoms o ften v ari ed
b etwee n i nd i v i dual s .
TAB L E 7 . 1
FAM I LY MEMBERS TESTED
Fam i l y Members Tested
Mother and 1 c h i l d
Mother and 2 c h i l dren
Mother and 3 or more c h i l dren
Father and 1 c h i l d
F ather and 2 or more c h i l dren
Both parents and 1 c h i l d ·
Number o f F am i l i e s
52
12
4
1
o
Both parents and 3 or more c h i l dren
6
11
5
Ne i t her parent and 2 c h i l dren
23
Bot h p aren t s and 2 ch i l dren
Ne i ther parent and 3 or more c h i l dren
*
6
Two fami l i es i ncl uded one grandch i l d and one fami l y i nc l uded two
grandch i l dren .
203
TABL E
7. 2
PRES ENT I NG SYMPTOMS
Syndrome
Number of Pat i ents
Ch i l dren
Parent s
4
11
Eczema
19
3
Asthma
7
4
Mouth u l cers
16
22
0
6
11
3
M i gra i n e
15
17
Hyperact i v i ty
77
7
Systemi c
66
62
226
1 24
U rt i cari a
Rh i n i t i s
I rr i tabl e bowel syndrome
TOTAL ( 3 50 )
C h al l enges
Dou bl e - bl i nd chal l enges were admi n i stered as outl i ned i n C h apter 6 .
C are was taken to ensure that each member o f a fami 1 y was g i ven
ch al l enges i n a d i fferent order so as to mi n i mi ze t h e l i ke l i hood of
t h em devel op i ng react i on s i n " sympathy " wi t h one another .
t i me of on set and durat i on of react i on s between
S i nce the ·
i nd i v i du al s was
204
extremel y vari abl e , chal l enges wi t h i n a fam i l y rap i dl y became out - of
step after two or three re act i o n s , furt her red u c i ng the l i ke l i hood of
t h e resul ts be i ng i nfl uenced by expectat i ons .
Stat i st i cal Anal ys i s
React i on s to each test s u bstance were tabul ated s ep aratel y for each
i nd i v i du a l .
To determi n e whether react i on s were random , o r whether
there was a s i gn i fi cant tendency for members o f the s ame fami 1 y to
react to
the
s ame
s ubstances ,
the
re s u l ts were
re - tabul ated
as
fol l ows .
I f every member tested wi th i n a fami l y reacted t o a p art -
i cul ar chal l enge compound , t h at fami l y was cl a s s i fi ed a s +/+ for that
compound ;
i f none o f the members tes ted s h owed any react i on , the
fam; 1 y was cl a s s i fi ed as -/ - for the compound ;
i f s ome members
reacted and others d i d not the outcome was c l a s s i fi ed a s d i scord ant
( +/ - ) for t h e c h al l enge i n quest i on .
e ach chal l enge compound .
Th i s proced u re was repeated for
The random c h ance o f any two o r more unre
l ated i nd i v i dual s h a v i ng +/+ , -/ - or +/ - react i on s to e a c h o f the
c h a 1 1 eng e s was determi ned from the frequency of react ; o n s i n the
overal l pat i en t popul at i on descri bed i n C h apter 6 , from whom the
fam; 1 i es were drawn , and expressed as b i nomi a 1 probab i 1 i t i e s .
The
n umber of fami 1 i es react i ng as +/+ , -/ - or +/ - for e ach c h a 1 1 enge
compound was then cal cul ated by mul t i pl y i ng t h e n umber of fami l i es i n
wh i ch al l members were tested w i t h that compound , by the rel evant
b i nom i al probab i 1 ty .
These were comp ared wi t h the n umber of fami l i es
observed i n each category ( +/+ , -/ - or +/ - ) for each compound , u s i ng
the C h i - squared goodnes s - offi t test ( Ch apter 3 ) .
1
I
j
1
I
'l
�
j
1
205
RESU LTS
The
expected
and
observed
react i on
patterns
for
eac h
substance are shown i n Tabl es 7 . 3 , 7 . 4 , 7 . 5 and 7 . 6 .
the n umber of fami l i es
tested w i t h
each
chal l enge
I n e ac h tabl e ,
c h al l enge
s ubstance
is
i nd i c ated , al ong wi th the observed number of fami l i es where none of
the members reacted (-/ - ) , al l members tested devel oped a react i on
( +/+) , or there were d i scordan t res u l ts wi th i n the fami l y ( +/ - ) .
For
compa r i son , the n umber of fami 1 i es " expected " i n each category i s
t abul ated a l ongs i de the observed res u l t s ,
together wi t h the C h i
s q ua re stat i s t i c and P- val ue .
Tabl e 7 . 3 s h ows the observed and expected pattern s wi t h each of the
c h al l enge s , pool i ng al l pos i t i ve react i on s regard l e s s o f the nature
of the
symptoms
provoked
in
eac h
case .
W i th
the except i on
of
prop i on ate , there was a s i gn i fi cant tendency for members of t h e s ame
fam i l y to react i n the s ame way to e ac h of the chal l enges .
S i nce the u s e of poo l ed data mi ght obscure a more s i gn i fi cant pattern
w i t h i n one or more sub-groups , the react i on s of, each i nd i v i du al were
re - tabul ated accord i ng to the part i c u l ar symptom compl ex provoked by
e ach c h a 1 1 enge ,
i ntest i na l ,
and
the most common of wh i ch were h eadache ,
neuropsych i atri c
symptoms .
The
l atter
gast ro
i ncl uded
l ethargy , cerebral symptoms s uch a s i mp a i rment of concentrat i on and
206
memory , hyperact i ve beh av i our , or ch anges i n mood s uc h as depre s s i on
and
i rr i tabi l i ty ,
wi t h
or
wi thout
concurrent
phys i cal
symptoms
( C h apter 6 ) .
Compari sons of observed and expected pattern s for e ac h of these,
u s i ng the C h i - squared goodnes s - offi t test , are s h own i n Tabl e s 7 . 4 ,
7 . 5 and 7 . 6 , respect i ve l y .
Al though asthma ,
rh i n i t i s , eczema and
urt i cari a al so occu rred i n some i nd i v i dua 1 s , t h e n umbers were too
smal l for val i d s t at i st i cal anal ys i s .
Among fami l y members who experi enced h e adache or g a s t ro i n t es t i nal
react i on s t here were onl y a few s i gn i fi c an t l y s hared p attern s , a
fi nd i ng wh i ch cou l d be due to chance g i ven t h e rel at i vel y smal l
n umber of i n d i v i dual s i n vo 1 ved .
However , amongst t h o s e who exper
i enced neuropsych i atri c symptoms there was a s t r i k i ng concordance of
react i on pattern wi th al l chal l enge compounds ( Tabl e 7 . 6 ) , s ugge s t i ng
t h at
thi s
sub-group
is
l argel y respon s i bl e
fi g ures s h own i n Tabl e 7 . 3 .
for
the
s i gn i fi cant
A cl oser exami n at i on o f t h e d at a i n
Tabl e 7 . 6 s h ows t hat t h e magn i tude o f the Ch i - square s t at i s t i c i s
a 1 mos t ent i re 1 y accounted for by the +/ + component o f t h e react i on
p attern w i t h eac h chal l enge .
Thu s , at l east w i t h respect to symptoms
i nvol v i ng the central nervo u s system , there appears to be a s i gn i fi
cant fami l i al tendency to react to the s ame test substance s .
207
TABLE 7 . 3
OBSERVED AND EXPECTED RESPONSE PATTERNS I N 1 26 FAM I L I E S
Cha l lenge
Asp i r i n
Am i ne
MSG
Preservat i ve
Ant i ox i dant
Prop i onate
N i trate
Tartraz i ne
Erythros 1 ne
Number of
farni l i es
tested
126
106
95
97
91
35
93
1 17
31
X2
Expected
Observed
-/ - +/+ +/ -
-/ -
+/+
+/ -
53
48
41
46
35
18
46
62
13
6.3
12 . 7
10. 5
9.7
19 . 1
8. 1
8.4
18 . 7
5.0
54 . 2
27 . 6
26 . 6
28 . 1
14 . 6
4.6
28 . 8
23 . 4
6.2
65 . 5
65 . 7
58 . 9
59 . 2
58 . 2
22 . 1
58 . 6
74 . 9
19 . 8
11
21
15
13
30
11
15
21
9
62
37
39
38
26
6
32
34
9
P va lue
7.0
13 . 4
13 . 2
7.6
24 . 4
2.2
8.3
7.3
6.8
<0 . 01
<0 . 005
<0 . 005
<0 . 01
<0 . 005
ns
<0 . 005
<0 . 005
<0 . 005
X2
P va l ue
TABLE 7 . 4
HEADACHE RESPONSE PATTERNS IN 126 FAMIL I ES
Cha l lenge
Asp i ri n
Amines
MSG
Preservat i ves
Ant i ox i dant
Prop i onate
N i trate
Tartraz i ne
Erythros i ne
Number of
farni 1 i es
tested
126
1 06
95
97
91
35
93
117
31
Expected
Observed
- / - +/+ +/ -
71
61
48
67
57
22
40
72
23
7
6
6
7
3
0
6
5
1
48
39
41
40
30
13
45
40
7
-/ -
60 . 2
49 . 9
43 . 6
55 . 2
51 . 3
22 . 5
36 . 6
65 . 8
19 . 1
+/+
4.8
4.0
4.0
4. 1
2.0
0. 5
5. 2
2.8
0. 5
+/ -
61 . 0
52 . 0
47 . 4
54 . 7
36 . 7
12 . 0
49 . 2
48 . 4
10. 5
5.7
6.7
2 .3
8.5
2.4
0.6
0.8
3 .8
2.6
<0 . 05
<0 . 01
ns
<0 . 01
ns
ns
ns
ns
ns
208
TABL E 7 . 5
GASTROI NTEST I NAL RESPONSE PATTERNS I N 126 FAM I L IES
Cha l lenge
Asp i r i n
Ami nes
' MSG
Preservat i ves
Ant i ox idant
Prop ionate
N i trate
Tartraz i ne
Erythros i ne
Nunber of
Pat i ents
Tested
-/ - +/+ +/ -
54
126
1 06
95
97
91
35
93
1 17
31
52
38
59
55
20
37
67
15
10
6
6
14
5
2
9
8
5
x2
Expected
Observed
61
47
51
41
30
13
46
42
11
- /-
+/+
+/ -
44 . 5
57 . 5
41 . 7
51 . 8
46. 6
17 . 6
34 . 1
65 . 8
14. 6
9.0
3.8
4.5
4.9
2.7
1.2
6.2
3.0
1.2
71 . 3
43 . 7
48 . 8
57 . 3
40 . 7
16 .3
51 . 7
50 . 2
15. 2
P va l ue
3.6
2. 1
0.9
22 . 5
6.2
1.6
2. 1
9.8
12 . 7
ns
ns
ns
< 0 . 005
< 0 . 05
ns
ns
<0 . 005
< 0 . 00 5
x2
P va l ue
TABLE 7 . 6
NEUROPSYCHIATR I C RESPONSE PATTERNS I N 1 2 6 FAM I L IES
Cha l l enge
Aspi r i n
Am ines
MSG
Preservat i ves
Ant i ox idant
Prop ionate
N i trate
Tartraz i ne
Erythros ine
Number of
Fami l i es
Tested
126
106
95
97
91
35
93
1 17
31
Expected
Observed
- / - +/+ +/ -
54
62
50
61
62
28
53
63
16
19
8
9
12
5
2
6
14
3
53
35
37
42
24
4
34
40
12
-/ -
+/+
+/ -
64 . 1
67 . 8
60 . 5
68 . 1
61 . 2
25 . 0
60 . 5
72 . 4
19 . 6
3 .9
1.5
1 .5
2.3
1.1
0.2
1 .2
1 .9
0.5
57 . 0
35 . 7
34 . 1
44 . 6
28 . 7
8.8
31 . 3
42 . 7
11 .0
60 . 3
29 . 5
39 . 6
41 . 8
14 . 6
19 . 2
18 . 6
77 . 4
14. 4
<0 . 0001
<0 . 0001
<0 . 0001
<0 . 0001
<0 . 0005
<0 . 0001
<0 . 0001
<0 . 0001
<0 . 0005
209
D I SCUSS I ON
The d a t a presented here ,
deri ved from ana 1 ys i s o f t h e c h a 1 1 enge
re act i on pattern s i n 1 26 fami l i es , prov i des e v i dence of a tendency
for c hemi cal i d i o syncras i es to exh i b i t a fam i l i al pattern .
Th i s i s
most marked wi t h n europsych i atri c symptoms ( Tabl e 7 . 6 ) , wh i ch ' may be
a res u l t of the fact t h at i n over h a l f of the fami l i e s were referred
for i nvest i gat i on of a ch i 1 d wi th beh av i oura 1 symptoms .
A 1 though
frequen t l y l abel l ed " hyperact i ve " , s uch c h i l dren often al so man i fest
ed systemi c symptoms such as l eth argy , mal a i s e , l i mb p a i n s , abdomi nal
p a i n , headaches and i rr i tabi l i ty .
The d i ffi cul t i es as soc i ated wi th
eval u at i ng s uch c h i l dren h ave al ready been d i scus sed (Ch apter 6 ) .
W i th s u bj ec t i ve symptoms o f t h i s k i nd t h e obv i ou s quest i on ari ses
whether s i mi l ar c h a l l enge react i on s wi t h i n
a
fami l y m i g h t be due to
p sycho l og i cal factors , s uch t h at c h i l dren , parents and/or s i bl i ng s
may h ave reacted " i n sympathy " wi th o n e another .
Th i s i s unl i kel y t o
h ave occurred , however , s i nce each fami l y member was g i ven a d i ffer
ent
set o f chal l enge c aps u l e s
in
wh i ch
the
order of t h e
test
compound s was random i zed , and s i nce the vari ab 1 e durat i on of t h e
chal l enge reacti ons usual l y resul ted i n t he chal l enges becom i ng o u t
o f s t e p w i th i n a fami l y .
Thu s , two members o f the s ame fami l y wou l d
rarel y , i f ever , h ave taken the s ame chal l enge on the s ame day .
210
T h u s t h e quest i on o f whet her " l earned i l l ne s s beh av i o u r " mi g h t resul t
i n fami 1 y members deve 1 o p i ng s i mi 1 ar symptoms
( Wh i tehead et al .
1 982 ) , reg ardl e s s of the tr i gger , i s more d i ffi c u l t to an swer .
,
How
ever , t h e fi nd i ng of s i gn i fi cant fami l i al cl uster i ng of react i v i ty
u s i ng a random i zed seri es of chal l enge tests s uggests t h at t h e spec
i fi c chemi cal i d i o syncrac i es are genet i cal l y determ i n ed , even t hough
the part i cul ar symptoms expres sed may i n some way h ave been psychol
og i cal l y cond i t i on ed .
I t i s wel l recogn i zed · t h at recurrent abdomi n a 1 p a i n , h e ad ache and
l i mb p a i n s , somet i me s referred to as " peri od i c " syndromes , a re common
i n c h i l dhood ,
and tend to c l u s ter i n " pa i nfu l
Cul l en & MacDon al d , 1 963 ;
Sch l e s s i nger , 1 933 ;
fami l i e s "
( Wyl i e &
Oster , 1 97 2 ;
Apl ey ,
I n t h e absence of organ i c pathol ogy s uc h sympt oms are often
·
a s s umed to be psychogen i c , al though t here i s ev i dence t h at t h i s may
1975) .
not be the case ( McGrath et al . , 1 983 ) .
Some authors h av e suggested
t h at such fami l i e s may h ave a " const i tut i onal l y l ow p a i n t h re s ho l d "
( Oster ,
1 972 ) .
The
rol e
of
food
i ntol erance
in
the
peri od i c
syndromes of ch i l dhood i s controvers i al ( Chapter 6 ) . Mos t author i t i es
con s i der t h i s to
be a rare cause (Ap l ey ,
1 97 5 ) ,
al t h ough
it
is
acknowl edged t h at pat i ents themse l ves frequen t l y i mp 1 i cate spec i fi c
foods ( Stone & Barbero , 1 97 0 ) .
" fami l i al
non - reag i n i c
food
Coca ( 1 953 ) noted t h e occurrence of
al l ergy "
d i agnost i c cri ter i a are o f doubtful
in
40
val i d i ty ,
fami l i e s ,
but
his
and h i s n ot i on of
" i d i obl apt i c " al l ergy h a s fal l en by the ways i de ( Ch apter 9 ) .
CHAPTER 8
FOL LOW - U P
21 1
I NTRODUCT I ON
From Ch apter 6 i t i s ev i dent that amongst pat i ents wi th a n umber of
apparentl y d i verse cl i n i c al syndromes there i s a h i gh preval ence of
food i ntol erance as j udged by the ab i l i ty of doubl e - bl i nd c h al l enges
to p rovo ke a recurrence 'of symptoms .
However , the cha 1 1 enge d ata
al one do not al l ow any concl us i on s to be drawn about the e ffect i ve
n e s s o f l ong - term d i etary man agement i n s u c h i nd i v i d u al s .
I n an
attempt to addres s t h i s i s sue , a retro s pect i ve fol l ow- up study of
pat i ents present i ng for d i etary i nvest i gat i on was carri ed out by
quest i on n a i re , the re sul ts o f "wh i ch are outl i ned i n t h i s chapte r .
Pat i ents s urveyed were those descri bed i n Ch apter 6 , fal l i ng i nto the
d i agnost i c groups l i sted i n Tabl e 8 . 1 .
Up to December 1 985 , a total
of 1 , 859 p at i ent s were eval u ated , 1 , 1 58 o f whom compl eted the stri ct
el i mi n at i on and chal l enge protocol .
Those who i mproved on the el i m
i nat i on d i et and subsquentl y compl eted the chal l enge protocol were
s urveyed separatel y from those who d i d not return for fol l ow- up
( Append i x 15 and Append i x 1 6 ) .
Pat i ents were as ked to i nd i cate the deg ree to wh i ch t he i r d i et was
s t i l l restri cted , and to rate the i r current s t ate of heal th compared
wi t h when the e l i mi n at i on d i et was fi rst prescri bed .
They were al so
asked wheth e r there were recurrences of symptoms , and i f so to i de n t
i fy s u spected tri ggeri ng factors .
212
TABL E 8 . 1
PAT I ENTS COMPL ET I NG EL I M I NAT I ON D I ET AND CHALL ENGE PROTOCOL
Presenti ng
Syndrome
Total No .
Present i ng
No . Ava i l abl e *
For Fol l ow-Up
191
1 14
1 40
1 07
121
309
14
1 95
244
696
1 56
13
111
1 63
46 1
1 43
12
99
Eczema
Asthma
213
I BS
Mouth ul cers
Mi grai ne
Hyperact i ve
Systemi c
*
No . Compl et i ng
Protocol
1 43
414
Pat i ents who had not changed the i r addre s s or d i ed .
TABL E 8 . 2
QU EST IONNA I RE REPL I ES (%l
Present i ng
Syndrome
Eczema
Asthma
I BS
Mi gra i ne
Hyperact i v i ty
Systemi c
Pat i ents Compl eti ng
Protocol
Pat i ents Not
Compl et i ng
51
40
66
43
40
38
69
37
46
37
67
42
213
Ten percent o f the pat i ents had ch anged addre s s , and coul d not be
contacted for fo 1 1 ow- up .
Of the rema i nder ,
comp 1 eted the cha 1 1 enges ,
rep 1 i ed to the quest i onna i res ,
53% of pat i ents who
and 3 9%
rep l i ed of those who were st arted on the el i mi n at i on d i et but fa i l ed
to ret urn for fo 1 1 ow- up and d i d not undergo doub 1 e - b 1 i nd cha 1 1 enge
( Tabl e 9 . 2 ) .
RESULTS
Overal l , of t h o s e who compl eted the e 1 i mi n at i on d i et and ch a 1 1 enge
protocol 76% cont i nued to ma i nta i n a restri cted d i et s i x month s to
fi ve years after i n i t i al
presentat i on
(Tabl e 8 . 3 ) .
The maj ori ty
( 81%) experi enced recurrences re1 ated to food s , and as i n pat i ents
w i th R I U/AO t h e foods
i dent i fi ed by each i nd i v i dual
corresponded
c l osel y to those i ncri mi n ated from the res u l ts of doubl e - bl i nd chal l
enge ( data not shown ) .
I n add i t i on , 3 5% of pat i ents noted that cert a i n smel l s al so prec i p
i tated symptoms , mos t often headache , nausea and mal a i se .
Stre s s was
fel t to be a tri ggeri ng factor by 1 0% of pat i ents , and other mi scel l
aneous factors ( e . g . i nfect i on , hormon al c h anges and exert i on ) were
i ncr i m; n ated by 3 1% .
Three -quarters regarded themse1 ves as be i ng
e i ther compl etel y wel l , or con s i derabl y better than when they had
fi rst presented for i nvest i gat i on .
214
TABLE 8 . 3
SYMPTOMS ON F I NAL D I ET AT FOLLOW-UP
Eczena
Asttvna
IBS
M i grai ne
Hyperact i ve
Systemic
Ch i 1dren
Number of pat i ents
55
48
95
68
66
278
Cont inu i ng restr ict i on (%)
73
73
84
77
77
75
Foods
95
79
71
79
86
82
Sme l ls
20
48
22
38
20
44
Stress
15
10
7
9
5
12
Other
40
38
26
41
21
29
Comp lete ly wel l
13
8
23
9
11
17
Much better
69
50
58
54
71
58
A 1 i tt le better
15
29
15
25
15
14
No change
4
10
3
7
3
8
Worse
0
2
1
2
0
4
Recurrences (%)
Symptoms at fo l low-up (%)
Al t hough t h e n umber of quest i on n a i re repl i es from t h o s e who fa i l ed to
compl ete the
el i mi nat i on and
chal l enge programme was
rather
l ow
( 39%) , i t was i nterest i ng to note that 63% h ad cont i n ued to restri ct
215
t he i r d i et ( Tabl e 8 . 4 ) .
The food s i ncri mi nated as tri ggeri ng recurr
ences i n th i s group were very s i mi l ar t o t h o s e i dent i fi ed by pat i ents
wh o h ad
compl eted the
chal l enge s .
Hal f th i s
group o f pat i ents
con s i dered themsel ves to be e i ther compl ete l y we 1 1 or much better
t h an t h ey h ad been at the t i me of present at i on , but a s i gn i fi cant
mi nori ty reported the i r symptoms as be i ng "no better " .
TABLE 8 . 4
NON STARTERS/COMPLETERS
Eczema
AsUma
M i gra i ne
I BS
Hyperact i ve
Systemic
Ch i 1dren
35
18
55
29
25
85
63
72
56
55
64
67
Coql 1ete 1y wel l
14
11
13
17
o
8
Much better
37
44
33
35
48
45
A 1 i tt le better
14
17
29
17
28
21
No better
29
22
18
24
24
22
6
6
7
7
24
4
No .
of pat i ents
Cont i n u i ng restr ict i on (%)
Symptoms at fo l low-up:
Worse
(%)
216
D I SCUSS I ON
At i n i t i al presentat i on pat i ents s us pected o f h av i ng foo d i ntol erance
were g i ven al l the nece s s ary i n struct i on for d i etary test i ng .
Those
who s e symptoms i mproved on the el i mi n at i on d i et were a s ked to contact
the d i et i t i an and were sent a set of doubl e - bl i nd c h al l enge capsu l es ,
wi th i n struct i on s to return for fol l ow- up once these were compl eted .
Overal l , of the 1 , 859 pat i ents commenced on the el i mi n at i on d i et 62%
s ucce s s ful l y compl eted the el i mi n at i on and c h al l enge p rotocol .
The
remai nder were l ost to fol l ow- up , and i t was i n i t i al l y a s s umed that
most o f these pat i ents had experi enced n o i mprovement on t h e e 1 i m
i nat i on d i et .
However , when s urveyed by quest i on n a i re i t was found
t h at of the 39% who rep 1 i ed a s i gn i fi cant pro port i on h ad i ndeed
restri cted t he i r d i et , al t hough thy d i d not proceed wi t h t h e c h al l
enge s .
The mos t common reason s for fa i l ure t o compl ete the protocol
had to do wi th the stri ngency and i nconven i ence of t h e e 1 i mi n at i on
d i et , but many o f these pat i ents h ad arr i ved at a mod i fi ed d i et by
tri al and error , based on the i n format i on rec i eved at t h e Al l ergy
Cl i n i c .
I t therefore seems reasonabl e to concl ude that the preval
ence of food i ntol erance among s t our p at i ents ,
as j udged by the
proport i on comp l et i ng the el i mi n at i on d i et and chal l enge p rogramme
( Chapter 6 , Tabl e 6 . 4 ) , i s l i kel y to be a con servat i ve e s t i mate .
The fact t h at the demand i ng n ature o f the el i mi nat i on d i et and
chal l enge protocol was s uc h t h at nearl y h a l f the pat i ents p re sent i ng
d ropped out mi ght be taken to i nd i cate t h at t h i s i s an u n s at i s factory
217
mean s o f d i et ary i nvest i g at i on .
I n general , however , i t was found
t h at those who were mo st h i gh l y mot i vated to comp l y wi th the program
were pat i ents wi th the mo st d i sabl i ng and chron i c symptoms , i n whom
t h e el i mi nat i on d i et had
re sul ted
in
substant i al
( and
somet i me s
A stri ngent i n i t i a 1 d i et can therefore be
dramat i c) i mprovement .
regarded as a useful
mean s of screen i ng out those pat i ents wi th
rel at i vel y mi l d symptoms who woul d be unl i ke l y to compl y wi th a
restri cted d i et i n the l ong - term , even i f some o f the i r symptoms were
found to be food - rel ated .
I t i s d i ffi cul t to accuratel y e s t i mate the l ong - term s ucce s s - rate of
d i et ary man agement , s i nce onl y sl i ghtl y more t h an h al f t h e pat i ents
s urveyed repl i ed to the quest i onn a i res .
The fi gures i n Tabl e 8 . 3 are
there fore l i kel y to be s i gn i fi cant l y b i ased toward s those pat i ents
who i mproved after di etary mod i fi cat i on .
Nevert h e 1 e s s , i t i s e v i,dent
t h at among st these i nd i v i dual s a maj o r i ty experi enced food,- rel ated
exacerbat i on s and h ad cont i nued to restri ct the i r d i et .
I n many
pat i ents other factors
change s ,
such
as
stro ng
smel l s ,
hormonal
stre s s and i nfect i on s were al s o i ncri mi n ated i n cau s i ng recurrences ,
emp h a s i z i ng t h at food i s not al ways the sol e tri gger i ng factor i n
such cases .
I ndeed ,
at a cl i n i cal
t h reshol d for adverse food
l evel
i t was noted t h at the
react i on s coul d
somet i mes
be
l owered
premens trua 1 1 y , duri ng an acute i nfect i on , or when a pat i ent was
under s evere emot i ona 1 stress .
Adverse react i on s to strong smel l s
and fumes usual l y con s i sted of head ache , n ausea and mal a i se , and were
more of a probl em when the d i et was h i gh l y restri cted ;
conversel y a s
2 18
the d i et w·a s 1 i bera 1 i zed such react i on s tended to become 1 e s s marked .
The most sen s i t i ve pat i ents ,
part i cul arl y those i n t h e " system i c "
group , often found i t i mpo ss i bl e to l i beral i ze the i r d i et s i gn i f i c
ant l y s i nce even mi nor l apses wou l d l ead to the recurrence o f d i s
abl i ng symptoms .
I n s uc h i nd i v i dual s s ucce s s fu l l on g - term man agement
o ften req u i red a mu1 t i d i sc i pl i n ary approac h ,
pa i d to d i etary , as wel l
t r i gger i ng factors .
wi t h atten t i on be i ng
as env i ronmenta 1 , p hys i ca 1 and emo t i ona 1
t
I n order to ma i nt a i n adequate nutri t i on pat i ents
were as ked to keep a check on the i r we i gh t and were al so prescri bed
appropri ate v i t ami n and mi neral suppl emen t s .
I f i nd i cated , d i etary
adequacy was formal l y asses sed by a s k i ng t he p at i en t s to keep a s -day
food d i ary .
( Verai on 1 . 2 ,
Th i s was anal ysed u s i ng the " Soda " computor programme
R . J . Hart l ey ,
1 982 ; Computer Model s ,
P.O.
Box 280 ,
Bentl ey , Western Austral i a ) , wh i ch prov i de s an est i mate o f t h e d a i l y
i ntake of al l macronutri en t s , v i tam i n s , cal c i um and i ron .
CHAPTER 9
H I STOR I CA L PERS PECT I VE
2 19
Al thoug h food i d i o syncrasy has been known s i nce H i ppocrat i c t i me s ,
modern i nterest i n the s ubj ect began around the turn of the century
wi t h the rap i d expan s i on i n knowl edge of i mmunol og i cal re act i on s to
tox i n s .
Progre s s s i nce t h at t i me c an be d i v i ded i nto three phase s :
( i ) a s c i ent i fi c phase duri ng the decade after the fi rst descri pt i on
o f anaphyl ax i s by Port i er and R i chet i n 1 90 2 , i n wh i ch mos t of the
bas i c al l erg i c p henomena were descri bed i n both an i mal s and man ;
( i i ) a cl i n i cal descri p t i ve peri od , spann i ng hal f a century , duri ng
wh i ch l i ttl e s c i ent i fi c progres s was made ;
and ( i i i ) a peri od of
renewed s c i ent i fi c i nterest beg i nn i ng wi th the i dent i fi c at i on of I g E
as
the
" re ag i n i c "
ant i body
( I s h i z a ka et al . , 1 966 ;
by
I s h i zaka
and
col l eagues
in
1 965
I s h i zaka & I s h i zaka , 1 967 ) .
Earl y S c i ent i fi c Stud i e s
The d i s covery of an aphy1 ax i s i s general l y attri buted to R i chet and
h i s a s s o c i ates Heri court and Port i er i n 1 90 2 , ari s i ng out of R i chet ' s
e arl i er s t ud i es on the toxi c or urt i cat i ng s ubstance of the Portugese
man - of-war .
I n i t i al l y , i t was bel i eved that anaphyl ax i s represented
the l os s o f protect i on from a tox i n , but i t was soon s h own t h at non
toxi c substances coul d produce s i mi l ar react i on s (Arthus , 1 903 ) , and
that s en s i t i zat i on res u l ted i n the format i on of an anaphyl actogen i c
substance wh i ch coul d be pas s i v e l y tran sferred w i t h s erum
1 90 7 ;
Fri edman , 1 909 ;
Doerr & Rus s , 1 90 9 ) .
coi ned the term " al l ergy " ,
(Otto ,
I n 1 906 Von P i rquet
al though at the t i me i t was st i l l not
cl e arl y apprec i ated t h at th i s was an i mmunol og i cal phenomenon .
The
s uggest i on that an aphyl ax i s and i mmun i ty were d i fferent man i fe s t at
i on s o f the same underl y i ng proces se s was fi rst made by Vaughan
2 20
( 1 90 7 ) after he d i scovered th at an i mal s coul d be sens i t i zed not onl y
t o bacteri al toxi n s , but al so prote i n s i n - horse serum and egg wh i te .
By 1 91 0 i t was recogn i zed that urt i cari a , ang i oedema and asthma i n
h uman s coul d occur as man i fe stat i on s o f anaphyl axi s , and h i s t ami ne
h ad been i dent i fi ed as the pri nci pal
med i ator ( Dal e and L a i d l aw ,
1910) .
Rosenau and Anderson
( 1 906 )
fi rst demo n s trated
t h e occurence
of
sens i t i zat i on v i a t h e gastro i ntest i nal tract , and the i dea that h uman
food i d i o syncras i es mi ght be al l erg i c react i on s was put forward s oon
after by Horw i tz ( 1 908 ) and Hut i nel ( 1 908 ) . Subsequent l y Doerr ( 1 909)
quoted the case o f a 1 3 year - o l d b oy wi t h 'urt i cari a and asthma t r i gg
ered by egg , and t h i s was fol l owed by s i mi l ar reports the fol l owi ng
year by Barb i er ( 1 9 1 0 )
French l i terature .
and Cast a i gne and Gourmand
( 19 1 0 )
in
the
Sch l o s s ( 1 9 1 2 ) , an Ameri can p aed i atr i c i an , des
cri bed al l ergy t o egg wh i te , oatmeal and n ut s , and drew atten t i on to
the occurrence of u rt i cari a , ang i oedema and eczema i n such case s .
He
al s o s h owed t h at serum from such p at i en t s coul d pas s i vel y tran s fer
sens i t i v i ty to g u i nea p i gs , and adapted the scarc i f i c at i on tech n i que
of Von P i rquet for use as a d i agnost i c tes t .
The phenomenon
of
desens i t i zat i on ,
termed
" an t i anaphyl ax i s " ,
was
observed by Rosenau and Anderson ( 1 906 ) and Otto ( 1 907 ) , as wel l as
by Ri ch et and others .
By 1 9 1 1 , Noon and Freeman h ad reported the
s ucce s s fu l use of t h i s procedure i n pat i ents wi th h ay fever ( Noon ,
1 9 1 1 ) , and soon after t h i s Schl o s s ( 1 9 1 2 ) reported t h e oral desen s
i t i zat i on of a boy wi th egg al l ergy .
221
Th u s , by t h e outbreak o f Worl d War I al l t h e bas i c phenomena as s oc
i ated w i t h al l erg i c re act i on s had been documented both i n experi
ment al an i mal s and h uman s .
The subsequent h i story o f food al l ergy i s
one o f i ncreas i ng confu s i on .
For nearl y hal f a century there was
l i ttl e furt her s c i ent i fi c progre s s i n the understand i ng of the bas i c
mechan i sms of al l erg i c react i on s , al though -muc h descri pt i ve work was
carr i ed out by pract i c i ng cl i n i c i an s .
C l i n i cal Descr i pt i ve Peri od
Tho s e i n cl i n i cal pract i ce were h ampered by t h e l ac k o f apprec i at i on
t h at symptoms such as asthma , urt i cari a and ang i oedema , wh i ch had by
then come to be regarded as typ i cal of al l erg i c react i on s , coul d al s o
be t r i ggered by n on - i mmunol og i cal mec h an i sms .
There w a s cl e arl y a
strong temptat i on amongst cl i n i c i an s to attr i bute al l adverse react
i on s to " al l ergy " , due n o doubt to the i r new- found abi l i ty to expl a i n
so many prev i ousl y mysteri o u s cl i n i cal
terms .
phenomen a i n i mmunol og i cal
Th i s i ncl uded react i on s to food s , so t h at a w i de vari ety of
as s oc i ated symptoms such as i nd i gest i on , col i t i s , mi gra i ne , Men i ere ' s
d i sease , can ker s ores and chron i c head col d s al so came to be regarded
as man i festat i ons of food al l ergy , as d i d chron i c fat i gue , " al l erg i c
toxaemi a " , and other i l l -defi ned con s t i tut i o n a 1 symptoms ( Hoob 1 e r ,
1916 ;
Shannon , 1 922 ;
Du ke , 1 923 ;
Rowe , 1 928) .
The ; nterpretat i on of s k i n tests was another maj o r probl em .
Many
authors con s i dered the frequent absence of cutaneous react i v i ty to
food extracts i n pat i en t s wi th cl i n i cal
symptoms to be a " fal s e
negat i ve il , d u e e i t h e r to fa i 1 ure of observers to pay attent ; on t o
del ayed pos i t i ve react i on s
( Vaughan ,
1927) ,
or t o the fact that
•
2 22
p at i ents were 1 i ke 1 y to be sens i t i ve to d i gested fragments rather
than the i ntact food a s used i n t h e tes t sol u t i ons ( Du ke , 1 923 ) .
i ntroduc t i on o f
( Cooke , 1 92 1 ) .
i ntradermal
test i ng
on l y added
to
the
The
confu s i on
Th i s method proved to be 1 0 - 1 00 t i me s more s en s i t
i ve than the trad i t i onal " scratch " test , resul t i ng i n fewer " fal se
negat i ve s " , but more " fal se pos i t i ve " react i on s .
I t i s i nterest i ng to observe that a n umber of e arl y al l erg i s t s began
wi th a sound sc i ent i fi c background of an i ma 1 experi mentat i on , but
extrapol at i on to h uman s o ften 1 ed t h em far from t h e path they h ad
ori g i nal l y embarked upon .
For examp l e , Coca began h i s career wi th
p as s i ve trans fer s t ud i es i n the gu i nea p i g ( Coca , 1 9 1 9 ) and was l ater
res pons i bl e for establ i sh i ng the standard met hod for prepari ng al l er�
gen extracts
( Coca 1 92 2 ) ,
and for co i n i ng the wi del y u s ed terms
" reag i n i c' ant i body " and " atopy " ( Coca and Grove , 1 9 2 5 ) .
S ubsequentl y , he publ i s hed a monograph descr i b i ng a cl i n i cal syndrome
of fami l i al non - reag i n i c food al l ergy , the symptoms o f wh i ch i ncl uded
headache , t i redne s s , i nd i gest i on , con st i p at i on , nervo u s n es s , eczema ,
d i zz i ne s s ,
neural g i a ,
canker
sores ,
heartburn ,
chron i c
rh i n i t i s ,
urt i cari a , hyperten s i on , ast hma , and a vari ety of other non - spec i fi c
symptoms .
He cal l ed th i s " i d i ob1 apt i c al l ergy " to d i st i n gu i sh i t
from reagi n i c al l ergy ( Coca , 1 942 ) , but fortunatel y the term never
g a i ned wi despread acceptance .
Another case i n pO i nt i s Ri chet ' s son , C h arl e s J r . , who started work
i ng i n h i s father ' s l aboratory and was among the fi rst to study the
experi mental i nduct i on of food al l ergy .
L ater however , h e , l i ke many
223
o f h i s contemporari es i n the 1 920 ' s , was l ed a s t r ay when confronted
wi t h pat i e n t s compl a i n ; ng of a w ; de v a r ; ety of s ubj ect i ve sympt oms
a s s oc i ated wi t h the i ngest i on of spec i fi c foods
1 930 ) .
( Rowe and Ri chet ,
R i chet S r . , who was Profes sor of Phys i o l ogy at t h e Un i vers i ty
o f Par i s , and was awarded the Nobel Pri ze i n 1 9 1 3 for the d i s covery
o f a na p hyl ax i s , ended h i s career i n o bv i ous frus t at i on , a s descr i bed
by Vaug h an ( 1 944 ) :
" He took up s tudy o f the occul t .
He v i s i ted med i ums .
versed i n the l ore of th e i r p rofe s s i on .
He became
I t i s s a i d t h at wh at he
wanted mo s t was to produce a spec i men of ' ectop l asm ' so t h at h e
m i g h t exam i ne i t under the m i croscope . Th i s , o f cours e , h e never
accompl i s hed . "
Dur i ng the 1 930 ' s there was much l i vel y debate amongst the cl i n i c al
al l e rg i s t s struggl i ng to comprehend t h e , v ari o u s types o f al l erg i c
d i s orders , p a rt i cul arl y those attri buted to food .
Al t h ough there h a s
bee n con s i derabl e cri t i c i sm o f cl i n i c i an s dur i ng t h i s e r a ( part i cul
arl y by M ay , 1 982 ) , i t mu s t be remembered that they were work i ng at a
t i m� when b as i c knowl edge of i mmunopathol og i cal mech an i sms was st i l l
rud i mentary ,
and
t here
were
no
rel i abl e
i de nt i fy i ng i mmunol og i cal react i on s .
l aboratory
meth od s
for
A good exampl e o f the d i ffi
cul t i es encountered i s t h at o f urt i cari a and ang i oedema .
The cl i n i c
al feature s h ad l ong been recogn i zed a s typ i cal of anaphyl ax i s , and
there was n o doubt i n the m i nds o f mos t t h at they were al l erg i c i n
ori gi n .
However ,
s ki n tests were found to be pos i t i ve i n o n l y a
mi n o r i ty o f cases , and a s po i nted out by Sch l o s s ( 1 920 ) , the rel at i on
s h i p o f t h e symptoms to spec i fi c al l e rg i es was i mpos s i bl e t o prove i n
224
pract i ce .
T h e degree of confu s i on caused by s u c h obs ervat i on s c a n be
apprec i ated by peru s i ng the tran scri pts o f debates wh i ch took pl ace
duri ng conferences at the t i me ( e . g . d i scu s s i on fol l ow i ng Bal yeat and
One popul ar hypothes i s to account for the occurrence
Rusten , 1 933 ) .
of " fal se negat i ve " ski n tests was t h at many p at i ent s m i g ht h ave
become sens i t i zed to the d i gest i ve fragments o f cert a i n foods w i th i n
t h e gastro i ntest i nal tract , or fol l owi ng absorpt i on i nt o t h e bl ood
stre am , s o t h at tests wi th the i nt act foods woul d often fa i l t o react
wi th the reag i n i c ant i bod i es .
some t i me s carr i ed
out
as
Based on t h i s i de a , exper i me n t s were
descri bed
in
the
fol l owi ng
pas s age
by
Bernton ( 1 933 ) :
" I h ave h ad the opportun i ty to st udy a p at i e n t who was s u bj ect
to g i ant h i ves of the most aggravated type .
I
tested thi s
p at i ent i ntracutaneous l y w i t h her whol e bl ood and w i th her bl ood
s erum erupt i on .
both of wh i ch were col l ected
at
the h e i gh t o f an
I al s o performed a s k i n test w i t h extracts o f her
stool s and of uri ne , wi th the hope of reproduc i ng whe a 1 s , but
w i th n egat i ve resul t s " .
Bas ed on s i mi l ar reason i ng ,
1 933 ) and
11
" autohemotherapy " ( Bal yeat and Rusten ,
autogeno u s uri ne therapy
desen s i t i z i ng tec h n i ques .
c om i c a l l y b i zarre ,
11
( Pl esch ,
1 947 ) were t r i ed as
Al though these procedu re s n ow seem al most
they were
based on
hypoth e s e s wh i ch
appeared
pl aus i bl e i n the i ntel l ectual cl i mate o f the t i me .
Another puzzl i ng exampl e was t h at of asp i ri n , wh i ch by �the 1 93 0 ' s was
recog n i zed as c apabl e of caus i ng acute urt i cari a , ang i oedema and/or
225
a s t hma .
Th e s e symptoms were wi del y regarded a s al l erg i c man i fest at
i on s d e s p i te t h e a l mo s t i nvari abl e fi nd i ng o f neg a t i ve s k i n tests
( Coo ke , 1 9 1 9 ;
Duke ,
1 923 ) , a m i sconcept i on wh i ch h a s pers i s ted to
the p re s e n t d ay , at l ea s t i n the m i nd s o f s ome authors ( Sp ee r , 1 983 ) .
Rev i ew i ng t h e s i t u at i on at t h at t i me , May ( 1 982 ) commen t s as fol l ows :
" By 1 93 0 t h e s t age was set for overwhel m i ng confu s i on :
u se fu l n e s s of s ki n tests h ad been di scounted ,
c l i n i cal
i mpre s s i o n s
a symptoma t i c and
was
symptomat i c
h i gh ,
the
confi dence
d i st i nct i on
s e n s i t i zat i on was
the
in
between
not g eneral l y
made , the pl acebo effect was not cons i dered i n e v a 1 u at ; o n o f
t h e rapeut i c
man i pu l at i on s ,
bas i c
i mmun o l og i c
knowl edge
was
l i mi t ed , and no one resorted to bl i nd c h a l l enge s to e l i mi n ate
b i a s and the power of the i mag i n at i on a s wel l a s the m i m i cry of
n eu ro s e s " .
I n h i s h i s t or i cal rev i ews , May ( 1 982 , 1 986 ) d e s c r i bes t h e emergence
o f two school s o f t h o ug h t duri ng the 1 940 ' s and 1 9 50 ' s .
dox "
school
were
sai d
to
h ave
adopted
a
r i goro u s l y
The " ortho
s c i ent i fi c
approac h , accept i ng a s gen i une on l y t h o s e re act i on s wh i c h cou1 d be
s h own to h ave an i mmuno l og i cal bas i s .
By contra st , t h e " unort h odox"
s chool , wh i ch evol ved i nto the C l i n i cal Ecol ogy movement , were s a i d
to rel y on u n s ubstant i ated c l i n i cal i mpres s i on s , and to attri bute a
w i de array of i l l -defi ned symptoms to " mu l t i p 1 e food
a l l e rg i es
11
•
Wh i l st May ' s c r i t i c i sm o f today ' s fr i ng e p ract i t i oners i s l arge l y
j us t i fi ed ( d i s c u s sed i n C h apter 6 ) , the h i stor i c al p i cture h e p a i nts
i s over- s i mpl i fi ed .
For exampl e , comment i ng on the art i cl e by Rowe
226
and Ri chet ( 1 930 ) he states :
.
" . . . . b earl ng
the
reputabl e
and
i l l ustr i o u s
n ame
of
R i chet
amounted to open i ng a Pandora ' s Box wh i ch h as not yet been
cl osed . "
Yet , a c areful read i ng of Rowe ' s l ater work ( Rowe and Rowe , 1 972)
s h ows t h at he h ad adopted a sound emp i ri cal approac h .
He tested , but
eventual l y rej ected , most of the b i zarre methods of i nves t i g at i on and
treatment proposed by s ome of h i s l es s cri t i cal col l eag ue s .
Furt her
more , he p i oneered the systemat i c u s e of el i mi n at i on d i et s , mos t of
wh i ch are st i l l i n u s e today ( Ch apter 3 ) .
He ul t i matel y concl uded
that i nd i v i d ual food c h al l enges were the o n l y rel i abl e means o f test
i ng , prov i ded symptoms h ad settl ed on a s u i tabl e e l i mi n a t i on d i et .
Meanwh i l e , many other " orthodox "
pract i t i oners o f t h e 1 93 0 ' s
and
1 940 ' s searched u n s ucce s s fu l l y for a more obj ect i ve mean s of d i agnos
'i ng food al l erg i es .
For exampl e , Vaug h an ( 1 939 ) , who wrote one of
the most author; tat i ve and wi de 1 y c i ted textbooks of the t i me on
al l ergy , regarded 1 e u kopaen i a as a c haracte r i st i c featu re of food
al l ergy and promoted the " l e u kopaen i c i ndex " as a d i agnost i c test .
Based on t h i s , Bl ack ( 1 956 ) devel oped a more rap i d i n v i tro test
wh i ch was l ater mod i fi ed by Bryan and Bryan ( 1 96 0 ) and popul ari zed as
the "cytotox i c food test " , wh i ch , desp i te ev i dence o f i ts unre1 i a
b i l i ty ( Van Metre , 1 983 ;
Anderson , 1 987 ) , rema i n s w i del y u s ed today .
S i mi l arl y , t h e " pu l se test " was devel oped by Coca ( 1 942 ) i n order to
d etect non - reag i n i c or " i d i obl apt i c " al l erg i e s
( see above ) .
Th i s
test has al so fal l en i nto d i srepute i n med i cal c i rcl e s , a l though i t
,
227
is
sti l l
advocated
by
many
al tern at i ve
pract i t i oners .
Another
method , st i l l popul ar amongst Cl i n i c al Ecol og i s ts , i s i n tracutaneou s
and/or s u bl i ngual " provocat i on - neutral i zat i on " test i ng , based o n t h e
s ki n - test end - po i nt t i trat i on method popul ari zed by H a n s e l a n d R i n kel
i n the 1 940 ' s
Pfe i ffer
and l ater mod i fi ed by Lee
( 1 964 ) .
As
( 1 96 1 ) ,
wi th �the other tests
and D i ckey and
descri bed
above ,
the
current v i ew i s t h at th i s techn i que has no val i d s c i ent i fi c bas i s
( Van Metre , 1 983 ;
Anderson , 1 987 ) .
Recent S c i ent i fi c Stud i e s and Current V i ews
Thu s , for nearl y h al f a century l i ttl e s c i ent i fi c progre s s was made
i n the unders t and i ng of al l erg i c d i sorders , creat i ng an i ntel l ectual
a
vo i d wh i ch was f i l l ed wi th
i ce s advanced by cl i n i cal
al l ergy i n general ,
and
vari ety of fanc i ful theor i e s and p ract
al l erg i st s .
food al l ergy
As a res u l t , the fi el d o f
i n p art i cul ar ,
c ame to b e
regarded a s " un s c i ent i fi c " by many orth6dox phys i c i an s . T h e s i tuat i on
bega n to c hange duri ng the 1 960 ' s , part i cul arl y after the d i scovery
t h at mas t cel l s were the sou rce of h i stami ne ( Ri l ey & West , 1 953 ) and
the i dent i fi cat i on of I g E a s the reag i n i c ant i body ( I s h i zaka et al . ,
1 96 6 ) .
Th i s opened the way for a det a i l ed understand i ng o f mast cel l
funct i o n and the
i dent i fi cat i on of a w i de array of
i n fl ammatory
med i ators , i n c l ud i ng the prostagl and i ns and 1 eukotri enes , and more
recent l y the central rol e o f T cel l s i n regu l at i on of I g E product i on
( rev i ewed by Goetzl & K ay
,
1 98 2 ;
I sh i za ka , .
1 984 ) .
At a c l i n i ca l
l evel , i t became poss i bl e to c l as s i fy hypersen s i t i v i ty react i on s o n a
more
rat i on a l
bas i s
( Coombs & Gel l ,
accord i ng
1 968 ) ,
to
the
underl y i ng
i mmunopathol ogy
more soph i st i c ated d i agnost i c tests
were
2 28
i ntroduced ( rev i ewed by Freed , 1 987 ) , and a range of powerful ph arma
col og i cal
d i sease .
age n t s
bec ame
ava i l abl e
for t h e
tre atmen t
of
al l ergjc.
As a con s equence there h as recen t l y been ren ewed i nterest
i n food a l l e rgy , as wi tnes s ed by the i n crea s.; ng vo 1 ume of 1 i terature
on t h e s ubj ect ( Croo k , 1 97 5 ;
Le s so f ,
1 983 ;
Metcal fe ,
1 985 ;
1 984 ;
May , 1 97 9 ;
Boc k , 1 980 ;
Denman , 1983 ;
Moneret Vautri n ,
1 983 ;
Anderson ,
1 984 ;
At ki ns &
L e s s o f e t al . ,
1 984 ;
Metcal fe ,
1 984 ;
Tru swe1 1 ,
Brostoff & C h a l 1 acombe , 1 987 ) .
I t h a s gradual l y become cl ear that react i on s to food may be of two
broad type s :
( i ) True al l e rg i c react i on s , w i th a demo n strabl e i mmunol og i cal
mech an i sm and c h aracter i s t i c cl i n i c a l features
( i i ) Non - i mmunol og i cal reac t i on s , wh i ch may h ave a met a bo l i c or
p harmaco l og i cal b as i s , and t h e symptoms o f wh i c h m ay o r may not
res embl e those o f the cl a s s i cal al l erg i c d i s o rder s .
The re appears to be a general con sen s u s about t h e n ature o f true food
a l l e rgy .
Th i s occurs p redom i n ant l y i n young c h i l d ren w i t h an atop i c
fami l y backg ro und a n d a h i story o f eczema .
Stapl e foods s u c h as
egg s , m i l k or wheat , and l es s c ommonl y pean u t s or f i s h are u s ual l y
respons i bl e , a nd i n many cases the al l e rg e n i c c ompone n t s h ave been
wel l c haracter i zed (Aas , 1 987 ;
Lange1 and & Aas , , 1 987 ) .
U n recog n i zed
food a l l ergy m ay be res pons i ble for c h ro n i c eczema ( Samp s o n , 1 983 ) ,
g a s t ro i n t e s t i n a l symptoms and asthma ( Le s s o f , 1 983 ) .
Acute react i ons
,i
229
c an c a u s e contact urt i car i a a n d ang i oedema aro und the l i p s a n d mouth ,
vom i ti ng , a bdom i n a l p a i n and d i arrhoea , and rare l y general i zed u rt i
c a r i a , wheez i ng and an aphyl ax i s .
Re act i on s o f t h i s k i nd are wel l
recog n i zed man i fe s t at i on s of food al l ergy and are u s u a l l y accomp an i ed
by pos i t i ve s k i n pr i ck tests w i t h t h e offen d i ng foods ( Le s s o f et al . ,
1 980 ;
M ay & Bock , 1 983 ) .
Most c h i l dren w i th cl i n i cal food a l l ergy
are eventual l y abl e to tol erate the rel evant foods wi t hout a rec u rr
ence of symptoms , al though l i fe - l ong avo i dance of a part i cul ar food
i s s omet i me s nece s s ary (May , 1 982 ) .
present for the f i rst t i me
in
I t i s rare for an i nd i v i du a l to
adu l t l i fe wi t h symptomat i c
food
al l ergy .
An i mport ant unre s o l ved i s sue i s the quest i on o f why many ato p i c
i nd i v i du a l s
wi th
IgE
ant i bod i es
to
v a r i ous
foods
never
devel o p
sympt oms , y e t others - d o so read i l y , part i cul arl y i n earl y ch i l dhood .
C l e arl y , t h e pre s ence o f Ig E a n t i bod i e s al one i s i n suffi c i ent to
account for the presence o r absence of symptoms .
No dou bt ,
the
el u c i dat i on o f other factors i nvol ved i n t h e devel opment of cl i n i cal
symptoms ( and i n t h e s u bsequent dev e l opment of tol erance ) w i l l serve
t o c l ear up much of the confu s i on wh i ch h as bedev i l l ed th i s s u bj ect
s i nce s ki n t e s t i ng was i ntroduced i n the 1 920 ' s .
The s i tuat i on wi th n on - i mmunol og i cal
food react i on s
i s l es s wel l
understood , as refl ected by t h e i ncon s i stency i n term i n o l ogy used by
d i fferent authors .
The umbrel l a term " food i ntol erance " i s u sed to
descr i be a ny adverse food react i on , u sual l y excl ud i ng t h o se med i ated
i mmun o l og i cal l y and t h o s e o f p sych o l og i cal ori g i n .
Under t h i s broad
c ategory
pharmaco l og i cal ,
are
i nc l uded
i d i o syncrat i c ,
metabol i c ,
i rr i tant and tox i c react i on s , a s wel l a s symptoms produced by foods
230
wh i ch are s a i d to rel e a s e h i st ami n e and other chem i ca 1
1
Most c l as s i fi cat i o n s al s o i ncl ude a v ar i ety of 1
d i sorders i n wh i ch symptoms may be rel ated to �al s 1
( Barnetson & lessof,
Sampson ,
1 986 ) .
gastro i ntest i �al
med i ators
1 983 ;
les s o f et al . ,
1 984 ;
Anderson ,
1 986 ;
1
1
as a resul t o f abnormal fermentat i on of food res i dues , enzyme defi ci ences ( e . g . phenyl ketonur i a , gal actos aemi a and l actase defi c i ency) ,
and food po i son i ng wi t h bacteri al o r other tox i n s , chem i cal contami n -
1
j
;
'
ant s , o r mi cro - organ i sms .
Many o f these cond i t i ons are i ncl uded for
i
il
,
the s a ke o f compl etenes s , but , s i nce they rare l y pre s ent a s food j
'�
i ntol erance i n cl i n i cal pract i ce , can be i gnored for t h e p u rpose of
1
t he p resent d i scus s i on .
Terms
s uch
as
" i d i o syncrat i c " ,
" ph armaco l og i cal " ,
" i r r i tant "
and
" tox i c " are often used wi th a mechan i st i c connotat i on i n t h e l i terature , but are rare l y defi ned i n rel at i on to the underl y i ng patho
phys i 01 ogy , and the i r use tend s to be rather h aphazard .
There i s
general l y l i ttl e d i scus s i on o f the bas i s o f i nd i v i dual s u s cept i bi l i ty
beyond the l i s t i ng o f a few of the known enzyme defi c i en c i e s , and no
attempt to addre s s quest i on s s uch as the vari ab i l i ty of target organ
respon s i veness i n d i fferent i nd i v i d ual s ( Ch apter 1 0 ) .
More i mport
antl y , i t h as not prev i ous l y been recogn i zed t h at mo st pat i ents wi th
non - i mmuno l og i cal food i ntol erance tend to react i d i osyncrat i cal l y to
a range of subs t ances i n the d i et rather t h an h a v i ng an i sol ated
probl em w i th , for exampl e , a s p i r i n , MSG , met ab i sul ph i te , etc ( Ch apter
6) .
Present knowl edge i s st i l l
1 arge 1 y i n a descri pt i ve p h a s e , . and a
perusal o f c urrent l i terat ure reveal s t h at t here are al mos t a s many
v i ewpo i n t s a s t here are authori t i e s i n the fi el d .
Some authors st i l l
�
.�
i
I
j
231
bel ; eve t h at I g E -med i ated a 1 1 ergy i s t h e e x p 1 a n at ; o n of mos t food
react i on s
( Speer ,
1 983 ) ,
some
focus
ma i n l y
on
tox i c
react i on s
( J e l l i ffe & J el l i ffe , 1 982 ) , some t a ke a rather n arrow org an - based
perspect i ve
( Ch andra ,
1 984 ) ,
and others t a ke
a broader and more
Les soff , 1 983 ;
Brenema n , 1 987 ) , but
bal a nced po i nt of v i ew ( e . g .
adopt a s cept i ca l att i tude to unproven i de a s and pract i ce s .
The mos t
recent l y publ i s hed textboo k o n food al l ergy a n d i ntol erance , ed i ted
by Brostoff and Chal l acombe ( 1 987 ) , embrace s the ful l s pectrum of
o rt h odox and unorthodox v i ews from ma i n stre am i mmun o l ogy to the more
extreme fri ng e s of c l i n i cal ecol ogy .
Unorthodox V i ews
Amon g s t t h e v ar i ous unorthodox i deas about food al l ergy t h e mos t
w i despre ad
are
those advocated
by cl i n i cal
ecol og i st s ,
who
h ave
attracted i ncrea s i ng atten t i on from phys i c i an s , i ns urance c arr i ers ,
governme n t s ,
( Terr ,
1 98 7 ) .
med i ca l
the
s c tent i fi c commun i ty ,
t h e med i a
and the p u bl i c
I n the USA and Bri t a i n t h i s movement h a s pol ari zed
o p i n i on to t h e po i nt where rat i onal
pos s i bl e ( Chec k , 1 980 ) .
debate i s often not
Advocates bel i eve t h at ort hodox med i c i ne h a s
fa i l ed to recogn i ze a w i de range of env i ronmental l y i nduced i l l ne s s
( Mackarnes s , 1 976 , 1 980 ;
p hys i c i an s rej ect these
Randol ph & Mos s , 1 980 ) , whereas ort hodox
i deas
as
u n s ubstan t i ated ,
reg ard i ng
s uc h
p at i ents a s p art o f a " med i cal subcul ture " of mal i ngerers a n d other
wi s e
p sychol og i cal l y d i sturbed
i nd i v i du al s
( Brods ky ,
1 983 ) .
The
t heoret i cal and p ract i cal bas i s o f cl i n i cal ecol ogy h a s recent l y been
cri t i c i zed by t h e Ameri can Academy of Al l ergy and I mmunol ogy i n a
pos i t i on s t atement ( Anderson et al . , 1 986 ) , and i n C a n ad a i t was the
s u bj ec t of a recent Government i nqu i ry ( Th e Report o f the Ad Hoc
232
Comm i ttee on Env i ronmental Hyperact i v i ty D i sorders , Thompson et al . ,
1 985 ) .
The h i stori cal root s of the Cl i n i c al Ecol ogy movement can be traced
bac k to the 1 940 ' s when , as outl i ned abov e , t h e conceptual vacuum
wh i ch ex i sted was fi l l ed w i th theor i es wh i ch , thoug h p l aus i bl e at the
t i me , now seem n a i ve .
The mos t i n fl uent i al o f t h e s e was ori g i nal l y
put forward by Ri n ke l ( 1 944 ) who s uggested t h at cyc l i c fl uctuat i on i n
sen s i t i v i ty governs the cl i n i cal man i fes t at i o n s o f food al l ergy , and
that " mas k i ng " coul d occur w i t h food s eaten regul arl y .
Th i s concept
was t a ken up by Randol ph ( 1 950 ) who , together w i t h R i n ke l and Zel l er
( 1 95 1 ) , popul ari zed the i dea t h at "mas ked food al l ergy " coul d be
respon s i b 1 e for a w i de range of v ague ,
att r i buted to p sychoneuro s i s .
i l l - de f i ned symptoms often
L i ke Coca ( 1 942 ) , t h ey contrasted t h i s
wi t h t he reag i n i c, or " fi xed " food al l erg i es ,
i n wh i ch typ i cal l y
atop i c symptoms were regul arl y p rovoked by t h e s ame o ffend i ng foods .
Randol ph and h i s col l eagues devel oped an e l aborate hypothe s i s , based
part l y on Sel ye ' s t heory of phys i ol og i cal
adapt i on to stres s ,
in
wh i ch cycl i c food al l ergy represented al tern at i ng ad ap t i o n and mal
adapt i on to foods i n s uscept i bl e peopl e .
Th i s l ater formed the bas i s
of the C l i n i cal Ecol ogy movement ( D i c key , 1 976 ) , the foc u s o f wh i ch
has s i nce s h i fted
to the h armful
effect s o f tox i c envi ronmental
chem i cal s wh i ch are s a i d to produce a form of " i mmune defi c i ency" ,
resul t i ng
in
mul t i pl e
al l erg i es
to
foods
and
other
substances
( rev i ewed by Terr , 1 987 ) .
The i s sues i nvol ved i n the ongo i ng debate between ort hodox al l erg i sts
and c l i n i cal ecol og i st s are comp l ex , and h ave been d i scu s sed exte n s -
2 33
i vel y by others
Terr , 1 987 ) .
( May ,
1 982 ,
Thomp son et al . ,
1 985 ;
May ,
1 986 ;
The present st udy po i nts toward s the pos s i b i l i ty th at
i n some areas the truth may l i e somewhere i n the m i ddl e , al though as
po i nted out
i n C h apter 6 ,
the
i s sues are cl ouded by a l ac k of
s c i ent i fi c r i gour , sweep i ng general i zat i o n s and exaggerated cl a i ms by
t h o se who s ubscr i be to the cl i� i cal ecol ogy schoo l o f thought .
Commo n M i sconcept i on s
There are a n umber o f popul a r m i sconcept i on s worthy o f d i scuss i on
s i nce they are encountered so commonl y i n cl i n i cal pract i ce .
One i s
the i de a t h at many v ague symptoms wh i ch appear to be food rel ated are
due to " react i ve hyp og l ycaem i a " , resul t i ng from the i nt ake of sugar
( sucro s e )
and s ugar-conta i n i ng food s .
Th i s concept was fi rst put
forward i n the 1 940 ' s as a n expl a n at i on for var i o u s " psychosomat i c "
symptoms ( Port i s & Z i tman , 1 943 ;
res urfaced
repeatedl y
s i nee
" al tern at i ve " pract i t i oners .
then
Al exander & Port i s , 1 9 46 ) and h as
i n'
popul ar
books
and
amongst
There i s very 1 i ttl e ev i dence for the
exi stence of t h i s form o f hypogl ycaemi a as a cl i n i cal ent i ty ( Cah i l l
&
Soel dner , 1 974 ;
et al . , 1 97 6 ;
Yager & Young , 1 974 ;
Mer i mee , 1 977 ;
1 98 1 ;
leY - Ran & Anderson ,
1 98 2 ;
Hogan et al . , 1 983 ;
LeYc- Ran , 1 985 ;
Hofel dt et al . , 1 975 ;
John son et al , 1 980 ;
1 98 1 ;
Charl e s et al . ,
Ameri c an D i abetes
LeY - Ran , 1 983 ;
Bes t , 1 984 ;
Au stral i an D i abetes Soc i ety , 1 987 ;
Ford
As soc i at i on ,
Anderson &
Truswel l , 1 987 ) ,
al t h ough o n e recent study s uggests t h at there may be a smal l s u bgroup
of pat i e n t s i n whom exce s s i ve adrenal i ne rel ease after hypogl ycaemi a
correl ates w i t h post - prand i al symptoms ( Chal ew et al . , 1 984 ) .
Another m i sconcept i on currentl y i n vogue i s the n ot i o n t h at " cand i da
234
hypersen s i t i v i ty " i s re spon s i bl e for many o f t h e cl i n i ca l man i festat
i on s of food i ntol erance .
Fungal i n fect i on s h ave l on g been i ncri mi n
ated a s a cause o f a l l erg i c d i sease on an anecdot a l b as i s ( Vaughan &
Bl ack ,
1 954 ) ,
and
some authors h ave cl a i med t h at
a
rel at i ons h i p
ex i st s between C an d i da sens i t i v i ty a n d urt i cari a l react i on s to foods
conta i n i ng yeast
( Ho 1 t i ,
1 966 ;
J ames & Wari n ,
1 97 1 ) .
I n recent
years t h i s concept h a s been extended and el aborated i nto a compre
h en s i ve theory to account for the occurrence o f a n exten s i ve array of
p hys i cal and p sych o l og i cal symptoms .
It h as been w i del y publ i c i zed
both i n the med i c a l 1 i terature and the popul ar pre s s ( Tru s s , 1 978 ; .
Croo k , 1 980 ;
S a i fer & Bec ker , 1 987 ;
Kroker , 1 987 ) , and i s currently
embraced enthu s i ast i cal l y by many fri nge pract i t i oners .
,
I n the p resent study ,
" hypogl ycaem i a "
or
p at i ents who pre s en ted wi t h a d i agn o s i s o f
" cand i da
proved t o h ave pharmacol og i c al
systemat i ca l l y .
hypersens i t i v i ty "
food
a l mos t
i ntol erance when
i nvari abl y
i nves t i g ated
Bl o od sugar l evel s rare l y corre1 a ted w i t h symptoms
when measured , and symptoms occurr i ng duri ng a g l ucose tol erance test
were u s u al l y due to the col ouri ng and/or pre se rv at i ve present i n the
oral g l ucos e preparat i on s rout i ne l y u s ed because such pat i e n t s were
al most al ways abl e to con s ume sugar wi thout d i ffi c u l ty once t h e other
rel evant d i etary chem i cal s h ad been el i mi n ated .
starch were useful
general l y .
I ndeed , sucro s e and
pl acebos because they were so wel l
tol erated
Al though brewer ' s yeast con t r i buted t o sympt oms i n some
pat i ent s wi t h food i ntol erance ( ch apters 3 and 6 ) , we found n o ev i d
ence of t h e exten s i ve probl ems s u ppos ed l y d ue to yeast a s c l a i med by
many fri nge pract i t i oners .
2 35
Al t ho ug h m i sconcept i on s
about
food
a l l ergy a re
common
among
l ay
peopl e , a l tern at i ve pract i t i oners and med i c a l fr i nge groups , they may
al so
be
found
among
orthodox
perpetuated for s everal
11
decades ,
al l erg i s t s .
One ,
wh i ch
has
been
i s i l l u s trated by the tabl es of
food fami 1 i es " pub 1 i s hed i n many monograph s and textboo ks on the
s u bj ect ( Coca , 1 94 2 ;
1 984 ;
al . ,
1 987 ;
Bu i s t ,
Breneman ,
Rowe & Rowe , 1 972 ;
Ch andra ,
1 984 ;
1 98 7 ) .
1 984 ;
Speer , 1 978 ;
Workman et
Bro stoff & C h al l acombe ,
The i dea o f gro up i ng foods accord i ng to
t h � i r botan i cal fam i 1 i e s probabl y dates back to the e arl y work of
Sch 1 0 s s ( 1 9 2 0 ) , but i t was Vaughan ( 1 93 0 ) who fi rst i ntroduced th i s
as a systemat i c mean s of i dent i fy i ng foods l i kel y to s h ow al l ergen i c
cros s - re act i v i ty . Al thoug h based o n anecdotal e v i dence , t h i s approach
obv i o u s l y captured the i mag i n at i on of cl i n i c i an s who are accu stomed
to
t h i n k i ng
of
i n h a 1 ant
al l ergens
bot an i ca 1 t axonomi c groups .
s uch
as
pol l e n s · i n
terms
of
However , t h i s cl a s s i fi cat i on i s based
ma i n l y o n fl ower morphol ogy rath er than b i ochemi cal
rel at i o n s h i ps ,
and i s t herefore unl i kel y to be a useful means o f pred i ct i ng pharma
col og i cal cro s s - react i v i ty i n pati ents wi t h food i ntol erance .
In a
typ i ca l l i st of 5 2 food fam i l i es ( Co 1 1 i n s - W i 1 1 i ams & Levy , 1 984 ) , 40
i ncl ude at l east one member wh i ch conta i n s moderate or h i gh s al i cy
l at e l evel s , a n d 20 i ncl ude one or more ami n e - r i ch food s .
more the pattern i s qu i te haphazard wi t h i n fam i l i es .
Further
For exampl e ,
fi ve o f t h e s i x common members o f the potato fam i l y are s a1 i cyl ate
r i c h , potato i tse 1 f be i ng the sol e except i on , and two o f the s i x
( tomato and eggpl ant ) conta i n ami nes .
O f t h e ten members o f the
g ra i n fam i l y corn a l one conta i n s s al i cyl ate s ;
refi ned cane sug ar i s
free o f detect ab 1 e s al i cyl ate , but mol asses i s not .
I n the appl e
fam i l y , appl e and qu i nce are s a l i cy l ate - r i c h , �ut pears onl y conta i n
236
s i gn i fi c a nt amounts
in
the
s ki n .
Chemot axon omy
of
pl ants
is a
rap i dl y devel op i ng fi el d wh i ch may eventual l y prove to be rel evant
( S i ngl eton , 1 98 1 ) , al t houg h apart from the present s t udy t here i s as
yet i n suffi c i ent i n format i on on the chem i c al compo s i t i on of commonl y
eaten foods to be cl i n i cal l y u se ful .
From a pract i cal po i nt of v i ew , t h e m a i n u s e o f trad i t i onal
food
fami l i es appears to be for the des i gn o f rot at i on d i e t s for p at i ents
w i th mul t i pl e food " al l erg i es "
( Monro ,
1 987 ) ,
but a s po i n ted out
recentl y ( Le s so f et al . , 1 984 ) there i s l i tt l e o bj ect i ve ev i dence to ,
j ust i fy the use of t h i s appro ach .
Pat i ent s w i t h true food al l ergy
are al mo s t al ways cl i n i ca l l y s en s i t i ve to on l y one or two foods wh i ch
are e as i l y avo i ded , wher'e as those who react adverse l y to mul t i pl e
foods u su al l y prove t o h ave chem i cal i d i o syncras i es ( Ch apter 6 ) .
our experi ence rotat i on d i et s el i mi n ate add i t i ve s ,
and
may
In
al so
reduce t h e d a i 1 y i n t a-ke of n atural chem i c a 1 s by 1 i mi t i ng t h e range of
food cho i ce s ,
temporar i l y .
so t h at some p at i ents do
i ndeed
i mp rove ,
at l east
More sens i t i ve pat i ents , h owever , o ften do not res pond
and requ i re systemat i c control of n at ural
sal i cy1 ate , ami ne and/or
MSG i ntake , depend i ng on the i nd i v i dual ' s i d i o syncras i es .
Pract i s i ng al l erg i st s o ften al so h ave p art i cul ar prej ud i ces about the
d angers of a spec i fi c food .
For exampl e , i t i s c ommonpl ace for the
pat i ents to be prescri bed a m i l k- free or wheat - free d i et i n the m i s
taken bel i ef t h at these foods frequent l y produce " muc u s " o r g astro
i ntest i n al symptoms i n al l erg i c pat i ents .
Atop i c p at i e n t s o ften h ave
pos i t i ve s k i n tests to these food s , reg ardl e s s of whether t h ey cause
symptoms , and t h i s i s somet i mes t a ken as ev i dence o f a n " a l l ergy " ,
237
i nd i c at i ng t h at they shoul d b e el i mi n ated from t h e d i et .
I n a recent
rev i ew of food - i nduced mi gra i ne , Monro ( 1 987 ) focuses h e av i l y on mi l k
and wheat a s the cul pri ts , as do many o f the other authors she c i tes ,
and t h e s ame i s true o f Al un Jones and Hunter i n t he i r rev i ew o f food
i ntol erance i n the
i rri tabl e bowel
syndrome
( 1 987 ) .
I n our own
exper i ence , h owever , these food s are on l y respon s i bl e for provo ki ng
react i on s i n a mi nori ty o f p at i ents overal l
( Ch apter 6 ) , and even
then t h ey are rarel y the sol e probl em .
I t i s i ntere st i ng to specu l ate as to why pati ent s and pract i t i oners
h ave been so e as i l y l ed astray , whether i t be i n rel at i on to hypo
g l ycaem i a , yeast hypersen s i t i v i ty , or food " al l erg i e s " general l y .
is
o ften
suggested
factors ( May , 1 982 ;
th at
m i s attr i but i on
is
due
to
It
p sychol og i cal
Pearson and Ri x , 1 985 ) , but i n our expe r i ence
t h i s i s not u s u al l y the case .
W i t h the benefi t o f h i nd s i g h t i t can
read i l y be apprec i ated how th i s s i tuat i on comes about .
Mos t pat i ents
h ave very 1 i m i ted know1 edge o f food compos i t i on , and tend to bl ame
t h e mos t o bv i ous t h i ngs . For examp l e , p at i ents who bel i eve i n " hypo
g l ycaem i a " focu s on the sug ar i n chocol ates , l ol l i es , b i scu i t s , sweet
dessert s , c a ke s , fru i t , sweet dri n ks etc . , and t he i r a s s umpt i on s are
often re i n forced when el i mi n at i on of these food s resul t s i n cl i n i cal
i mprovement .
However , remov i ng these foods from the d a i l y d i et not
onl y red uces the i nt ake of s ug ar , but al so o f s al i cyl ate s , ami nes ,
preserv a t i ves
and
col ouri ngs ,
and
l i ke l y to be the rel evant ones .
these l atter
S i mi l arl y ,
ch anges
are more
an apparent l y s i mpl e
c hange such as the el i mi n at i on of bread on a wheat- free d i et can h ave
a profound effect on the i n take o f other foods suc h as honey , j ams ,
Vegem i te ,
cheese ,
tomato ,
proces sed
meat s
and
ant i ox i d ants
(in
2 38
marg ar i n e ) ,
al l
of
wh i c h
cont a i n
s i gn i f i cant
q u a nt i t i es
of the _
subs tances commonl y re s pon s i b l e fo r symptoms i n pat i e n t s wi th food l
i nto 1 erance .
Even more extens i v e ch anges occ ur wi t h mo s t "yeast-
�
Not only
,
free " d i et s c urren t l y recommended by fri nge pract i t i o ners .
are bread , ye ast extract s , beer and wi ne excl uded , but s o too are al l
food add i t i v e s ,
and al l
n at ural l y " ma u l dy "
foods s uch a s cheese ,
mus hrooms , many fru i t s and vegetab l es ( i n c l ud i ng proces s ed fru i ts aM
fru i t j u i ce s ) , mal t , v i n eg ar , s auce s , �i ckl es , s p i c e s , peanut s , tea ,
coffee and a 1 coh o 1 ,
foods .
The s e
s ugar ,
food s
are
sweet s and al l
i n cr i m i n ated
o t h e r h i gh carbohydrate
on
the
bas i s
t h at
they
s uppos ed l y encourage the g rowth o f yeas t i n t h e g a s tro i n t e s t i n al and
gen i touri n ary
trac ts
( C roo k ,
1 980 ;
Turn er
and
S i mo n s en ,
1 985 ) ,
al th oug h ev i dence o f cand i da overg rowth i s rare l y fou n d whe n sough t .
Pat i ents wi th symptomat i c food ; nto 1 erance o ften . ben e fi t ,
even i f
on l y tempo rar i l y , from a maj o r c h ange o f d i et o f t h e k i nd outl i ned
above .
C l i n i cal i mprovement c an be a dramat i c occurre n c e , s omet i mes
I
i
�
after many ye ars of c hro n i c i l l - heal t h where a l l other t h erapeut i c ,i
mea s ure s h ave fa i l ed , and both t h e pat i ent and t herap i s t c a n thus
become deep l y conv i nc ed t h at t he i r rat i onal e for d i etary change must
h av e been correct .
Th i s probabl y al s o acco u n t s
for s ome of the
swee p i ng cl a i ms of n aturopat h s and other a l tern at i ve p ract i t i oners
who dabbl e i n d i etary mod i fi cat i on a l t hough , as i n a ny other c l i n i cal
s i tuat i on , the therapeut i c re 1 at i on s h i p and p l acebo e ffect p l ay an
i mportant part as wel l .
I
1
CHAPTER 1 0
CONC LUS I ONS
239
As o u t l i n ed i n C h apter 1 , t h e present st udy beg an i n 1 97 7 w h e n i t was
d e c i ded to t e s t t h e hypo t he s i s t h at R I U/AO i s o ften c a u s ed by adverse
react i on s to food add i t i ve s and s al i cyl ates ( War i n & Smi t h , 1 976 ) .
The i n adequacy o f ava i l abl e data o n t h e occurrence o f d i etary sal i cy 1 ate s 1 ed t o t h e 1 aboratory anal y s i s o f a w i de range of commonl y
eaten foods ( Ch apter 2 ) , and t h i s i n fo rmat i on greatl y s i mp l i fi ed the
d i etary i nvest i gat i on and man agemen t o f pat i e n t s w i t h R I U/AO ( Ch apter
3 and C h apter 4 ) .
Once the i mportan c e of n at ural s a l i cyl ates was
recogn i zed , i t bec ame e a s i er to i dent i fy a n umber of other compounds ,
fou nd i n apparentl y u n re l ated food s , capabl e o f p rovo k i ng a s i mi l ar
range o f cl i n i ca 1 symptoms ( Ch apters 6 and 7 ) .
These obse rvat i on s
made i t p os s i bl e to g a i n a broader understandi ng o f t h e nature of
non - i mmuno l og i cal
food
react i on s ,
as
wel l
as
prov i d i ng a
u seful
concep t u al framework w i t h i n wh i ch the i nvest i gat i on and man agement of
i nd i v i du a l pat i ent s cou l d be rat i o n a l l y p l anned .
C l i n i cal Observat i on s
The maj o r i ty of pat i ents pre s ent i ng t o t h e R PAH Al l e rgy C l i n i c wi th
recogn i zed or unrecogn i zed adverse food react i on s were s h own to be
s en s i t i ve t o a range o f n at u ral and art i fi c i al food chem i cal s .
True
al l e rg i c react i on s to foods were s omet i mes a contr i butory factor ,
ma i n l y i n ch i l dre n w i t h eczema , but even i n the l atter g roup pharma
col og i cal i ntol e rance often appeared to be the more domi nant probl em .
Mos t pat i ents reacted i d i o syncrat i cal l y to several
compounds when
chal l enged d o u bl e - bl i nd , and t h e s e res u l t s general l y correl ated wel l
w i t h c l i n i cal
food react i on s .
Symptoms coul d
i nvol ve the
g a s t ro i nte s t i n a 1 t ract , res p i ratory tract , or nervous sys t em ,
s ki n ,
each
pat i en t man i fe st i ng an i nd i v i dual pattern o f target org an repon s i ve
nes s , i ndependent o f t h e chem i c al compounds i nvol ved .
240
I n approx i matel y 1 0% o f cases ,
probl em .
" s u persen s i t i v i ty " was a c l i n i cal
Such p at i ent s found that , a s t h ey rest r i cted t he i r d i et and
the i r dos e - respo n s e t h re s h ol d fel l , t h ey became sens i t i ve to foods
wh i ch were prev i ou s l y tol erated .
bel i eve t h at they h ad devel oped
Th i s somet i me s l ed pat i ents to
11
new al l erg i es " , wi thout real i z i n9
that the s ame component , found i n smal l er doses i n a vari ety of
foods , was respon s i bl e .
I n most i nd i v i du al s , t h i s proc e s s was re
versed when symptoms were control l ed and the d i et was systemat i cal ly
l i beral i zed .
However , the most sen s i t i ve pat i ents found i t necessary
to keep to a h i gh l y restri cted d i et i n o rder to ma i n t a i n wel l - be i ng .
Other , non - d i etary factors cou l d a 1 so b e a comp1 i cat i ng probl em i n
s uc h p at i ents ,
several
and d i etary man agement was
therapeut i c
mod a1 i t i es
req u i red ,
somet i mes o n l y one of
i ncl ud i n g
p syc h o l og i cal
support .
The cl i n i ca l behav i our o f these react i on s strong l y s u gges ted an under
l y i ng pharmacol og i cal mechan i sm .
Th u s ,
abrupt d i etary restr i ct i on
was o ften fo 1 1 owed by w; thdrawa 1 symptoms , and a fal l i n t h e dose
res pon se threshol d .
Acute react i on s
behaved
in
a d o s e -dependent
fas h i on , and cou l d be fol l owed by t achyphyl ax i s , i . e . a refractory
peri od , l as t i ng up to 48 hours .
Chron i c or recurrent symptoms were
often more i ns i d i ou s , and appeared to depend o n t h e cumul at i ve dose
i nge sted from a vari ety of food sources over several d ays , or over
two to three wee ks i n some cases .
Mos t of these p henome n a h av e al so
been documented by other i nvest i gators , i ncl ud i n g dose dependence ,
tachyphyl ax i s , tol erance , - and · wi t hdrawal reacti-on s { Pl e s kow et al . ,
1 982 ;
As ad et al . , 1 983 , 1 984 ;
Sl e p i an et al . , 1 985 } . Lowe r i n g of
the dose - thre s hol d wi th abs t i nence { s upersens i t i v i ty } , has not been
241
prev i ou s l y reported ,
however ,
probabl y because mo st o t h e r workers
h ave not excl uded s al i cyl ate - conta i n i ng
food s to the s ame extent
( Ch apter 2 ) .
The u s e o f a p h armacol og i cal " p arad i gm " made i t po s s i bl e to res o l ve
much of the con fl i ct i ng i n format i on i n the 1 i terature ,
prov i d i ng a val u abl e conceptual
d i etary man agement .
as wel l as
framework to a s s i st i n d ay - to -d ay
For exampl e ,
pat i ents o ften reported t h at
a
part i cu l ar food caused symptoms o n some occas i on s but not others . The
expl an at i on
depended o n :
became
cl ear once
i t was
apprec i ated t h at
react i on s
( i ) the c umul at i ve dose of the rel evant chemi cal s from
a v a r i ety of food source s ,
and ( i i ) the pat i ent ' s dose - threshol d ,
wh i ch may fl uctuate depend i ng o n wh i ch food s h ad been eaten recentl y .
A commo n l y
encountered
exampl e
o f th i s
was
the
ami n e - sen s i t i ve
pat i ent wi t h m i g ra i ne who h ad not i ced that chocol ate somet i me s , but
not a l ways , t r i ggered a head ac h e .
The d i agrams s hown i n F i gure s 1 0 . 1
and 1 0 . 2 were u sed to i l l ustrate to such p at i ents h ow a - comb i n at i on
of food s , � aten i n v ary i ng amounts and at v ary i ng i nterval s , coul d
determ i ne whether or not a react i on m i ght 1 i kel y to occur after a
" bo l u s " dose .
S i mi 1 arl y , c h art s s h owi ng the s al i cyl ate , ami n e and MSG content of
commonl y e aten
foods
( Append i ce s
10,
11,
12)
enabl ed
sens i t i ve
p at i ents to i ntroduce more vari ety i nto the i r d a i l y d i et , at the s ame
t i me en s ur i n g t h at they avo i ded the cumu l a t i ve e ffects wh i ch cou l d
l ead t o a rel apse of symptoms over several days or- wee ks .
2 42
F I GU R E
DOS E
10. 1
TH RE S H O L D
. ..•.....•••.. . . . .. .. . . ...... . . . . . . . . . . . . .• . . . . . . . . . . . . . . . . . . .. . . . . . . . . .•... . . . . . . . . . . . . .. . . . .... . . . . . . . . .
Toma to
Ch oco l a te
F I GURE
10. 2
Choco 1 a te
•••••• ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••
•••••••
• •••••••••••••• •••••••••••
T I ME
I nterpretat i on of Chal l enge Re s u l t s
The i nterpretat i on of pos i t i ve of chal l enge react i on s i n t h e present
study warrant s further d i scu s s i on .
Most of the c h a 1 1 enge d o s ages
were sel ected on the bas i s of those used i n prev i o u s l y publ i shed
243
s t ud i e s , t ak i ng i nto account the amounts l i kel y to be cons umed i n a
d ay o n an average d i et .
The doses used fo r met ab i sul p h i te and MSG
are two to three t i me s those wh i ch mi ght be con s umed under normal
c i rcumstances , and t h at o f as p i r i n i s approx i mat el y 1 0 - 20 t i mes the
average
dai ly
i nt a ke .
c h al l enges
represent
s ubstan ce s ,
and t h at
t e sted .
It
an
coul d
therefore
un phys i ol og i cal
some heal thy
be
arg ued
exposure
to
t h at
these
i nd i v i dual s may al s o
the
food
react
if
On the other h and , no s i ngl e chal l enge g i ven as a bol us dose
can accuratel y reproduce the cumul at i ve effect s o f l ong - term l ow-dose
s a l i cyl ate i ngest i on i n the d a i l y d i et o f a sen s i t i ve i nd i v i dual . I n
t h e cl i n i cal
rel i abl y
context ,
i dent i fy
the
the
o bj ect i ve o f chal l enge
foo d
substances
test i ng
respon s i bl e
for
is
to
provo k i ng ·
symptoms i n pat i ents sel ected because o f a favourabl e response to
d i etary el i mi n at i on .
I deal l y , normal control
s ubj ects s houl d h ave been i nc l uded i n the
present study i n order to e st i mate the sens i t i v i ty , spec i fi c i ty and
pred i ct i ve val ue o f the chal l enge tests i n the d i agnos i s o f food
i nto 1 e rance
( Gal en & Gamb i n o ,
1 97 5 ) .
However ,
the pract i ca 1
and
eth i cal d i ff i c u l t i e s assoc i ated wi t h pl ac i ng normal i nd i v i du 1 as o n a
h i gh l y restr i cted d i et for up to s i x wee ks precl uded th i s .
ava i l abl e
i nformat i on
" heal t hy "
rel at i ves
is
who
our
went
own
retros pect i ve
throug h
the
The o n l y
an al ys i s
el i mi n at i on
of
d i et
27
and
chal l enges i n o rder to prov i de moral support fo� t he i r c h i l dren who
were
undergo i ng
i nvest i gat i on .
Of
these ,
IS
h ad
no
react i on s
whatsoever whereas 1 2 devel oped symptoms i n response t o at l east one
act i ve chal l enge (data not s h own ) .
I ntere st i ngl y , each o f those who
reacted coul d i denti fy the symptoms as h av i ng occurred prev i ou sl y ,
244
even though they h ad not general l y been att ri buted to food , whereas
those
who
did
not
react
to
any
chal l enge
h ad
been
prev i ousl y
asymptomat i c .
Cl e arl y , th i s quest i on requ i res further anal ys i s , and s teps h ave been
t a ken to c arry out a pro spect i ve study of normal i nd i v i du al s .
eventual l y emerge
that
a
proport i on
of
a symptomat i c
I t may
peopl e
are
s u scept i bl e to the chal l enge doses empl oyed here , and t h at , as wi th
al l ergen s ki n pri c k tests , a pos i t i ve res u l t can on l y be i nterpreted
i n the appropri ate cl i n i cal context .
Neverthel e s s , i n the p resent
study chal l enge test i ng d i d appear to rel i ab l y i dent i fy the re l evant
foods
symptomat i c
pat i ents
as
j udged
by
the
fol l ow- up
resul ts
( Ch apters 4 and 7 ) .
Pos s i bl e Underl yi ng M e chan i sms
For the purposes of the present d i scu s s i on i t . i s u s eful to beg i n by
exami n i ng the 1 i terature deal i ng wi th two overl app i ng i s s ue s :
the
pathogene s i s o f R I U/AO , and the mechan i sm o f asp i r i n i ntol erance .
In
both c ases i t i s ev i dent t h at , des p i te a p l ethora o f i n fo rmat i on and
the exi stence o f many pl au s i bl e hypotheses , the n ature o f the u nder
l yi ng abnormal i t i es rema i n s un known .
I t i s wi de l y acknowl edged that the fi n al common p athway i n urt i cari a
i nvol ves the rel ease of h i s tami ne and other med i ators from s k i n mast
cel l s ( rev i ewed by Kapl an , 1 98 1 ; Czarn etz k i , 1 986 ) .
Mast cel l s may
rel ease med i ators i n response to i mmunol og i cal a s wel l as i n response
to n on - i mmunol og i cal st i mul i , as i l l u st rated i n F i g ure 1 0 . 3 .
It i s
now general l y recogn i zed that R I U/AO i s not an I g E med i ated react i on ,
245
by contrast w i th acute urt i cari a . Many mech an i sms h ave been propo sed ,
i ncl ud i ng
depos i t i on
act i v at i on
and
of
ki n i n
i mmune
compl exes ,
format i on
( rev i ewed
vascul i t i s ,
compl ement
by
1 98 3 ,
Les s o f ,
and
Czarnetz k i , 1 986 ) but none h as proved cap abl e of expl a i n i ng al l the
cl i n i cal
and l aboratory fi nd i ngs i n pat i ent s wi th R I U/AO .
In
a
recent rev i ew of the subj ect , Rosenstre i ch ( 1 986 ) po i nt s out t h at any hypothes i s concern i ng the pathogenes i s of chron i c urt i cari a must
account
for
three
observ at i ons :
(i)
the
presence
of
act i vated
T - 1 ymphocytes i n 1 es i on s , ( i i ) i ncreased dermal mast cel l h i stam i ne
rel ease wi th a vari ety of st i mul i , and ( i i i ) the decreased rel eas
ab i l i ty of peri pheral bl ood basoph i l s .
He argues that there i s
strong ev i dence to l i n k i ncreased mast cel l rel e as a b i l i ty to T- ce1 1
deri ved 1 ymphoki nes , but p o i nts out that the T - ce 1 1
i n fi 1 trate i s
i tse1 f 1 i kel y to be a 1 ate - phase react i on secondary to mast cel l
d egranul at i on , concl ud i ng t h at
ft
•
•
•
the maj or unresol ved quest i on i n
t h i s d i sease i s the n ature of the i nc i t i ng agent "
( Rosen stre i ch ,
1 986 ) .
The other rel evant i s sue , about wh i ch th ere h a s been a great deal of
recent specul at i on ,
i ntol erance .
concerns the underl y i ng mec h an i sm of asp i ri n
Urt i cari a , asthma and anaphyl ax i s due to asp i ri n h ave
been known s i nce the earl y part of the century ( H i rschberg , 1 902 ) and
were assumed to be al l erg i c phenomen a unt i l recentl y , ma i nl y on cl i n
i cal grounds ( Du ke , 1 923 ;
1 98 1 ) .
Vaug h an and Bl ack , 1 954 ;
Speer et al . ,
However , exten s i ve i nvest i gat i on has shown l i ttl e ev i dence of
an I g E med i ated · mech an i sm and most authors now con s i der as p i ri n
i ntol erance to be a non - i mmunol og i cal p henomenon ( rev i ewed by Spector
& F arr , 1 983 ;
Ra i n s ford , 1 984 ) .
246
F I GU R E 1 0 . 3
MAJOR TY P E S O F ST I MU L I WH I CH CAU S E MAST C E L L M ED I ATOR R E L EASE
Immunol ogj c al
Nox i oys St i mu l i
1 . Chem i cal s
�
,
and Drugs
2 . Phys i cal
St i mul i
/
3 . Hormone s
4 . Neurotran smi tters
I
Enh an ceme n t
cGMP
I nterferon
Acetyl chol i ne
Prostagl and i n F 2*
Med i ator Rel ease
*
Adapted from Czarnetzki , 1 986
1.
Al l erge n
S t i my1 1
·
247
( 1 984 ) ,
Stevenson
who
has
wr i tten
d i s c u s s e s fou r ma i n hypothe ses :
exten s i vel y
(1)
on
the
subj ect ,
cycl ooxygen ase bl oc kade w i th
d i vers i on of arach i don ate i n to the l i poxygenase p athway , ( 2 ) n on - I g E
med i ated mast cel l degran ul at i on , (3 ) exces s prod uct i on o f i n fl ammat
ory compl ement fragments , and ( 4 ) act i vat i on o f the contact system
wi th exces s ki n i n format i on .
mos t favo ured mechan i sm ,
The fi rst of these i s curren t l y the
partl y because o f the known effect s
a s p i r i n on arach i don i c ac i d met abol i sm ( Vane , 1 9 7 1 ;
1 97 1 ;
of
Smi th & W i l l i s ,
Ferre i ra et al . , 1 9 7 1 ) , and part l y bec au se of the cro s s react �
i v i ty w i th
other
non - steri odal
1 98 1 ;
( Lancet Ed i to r i al ,
Spector et al . ,
Szezekl i k & Grygl ews ki , 1 983 ;
Ra i n s ford , 1 984 ;
ant i - i n fl ammatory d rug s
1 98 1 ;
Szeze kl i k ,
As ad et al . , 1 983 , 1 984 ;
Steven son , 1 984 ;
( NSA I O ' s )
1 983 ;
rev i ewed by
Sl ep i an et al . , 1 985 ) .
One i nterest i ng aspect of asp i r i n i d i osyncrasy i s the observat i on
t h at reg u l ar i ngest i on can l ead to desen s i t i z at i on wh i ch wanes after
ces s at i on of expo sure ( W i d al et al . ,
Pl e s kow et a l . , 1 982 ;
al . ,
1 984 ;
1 982 ,
1 922 ;
Z ei s s & Lockey , 1 976 ;
As ad et al , 1 983 ; rev i ewed by Stevenson et
Sl ep i an
et
al . ,
1 985 ) .
Pos s i bl e
expl anat i on s
i nc l ude : ( 1 ) s aturat i on of aspi ri n bi nd i ng s i tes , ( 2 ) depl et i on of
med i ators , ( 3 ) i ncreased cl earance and/or degradat i on of med i ators ,
( 4 ) tachyphyl ax i s t o med i ators , ( 5 ) feedbac k ; n h i b i t i o n o f med i ator
rel ease ,
Present
bronch i al
1 985 ) .
or
(6)
ev i dence
a
non - spec i fi c decrease
s uggests
react i v i ty
are
t h at
unl i kel y
med i ator
in
a i rway
depl et i on
expl an at i on s
i rri tabi l i ty .
and
( Sl e p i an
reduced
et
al . ,
248
De s p i te t h e attract i on o f t h e i de a t h at a s p i r i n i d i o sync r a sy i s due
to an abnormal i ty of arach i don i c ac i d met abo 1 i srn t h e re are a n umber
of
i n co n s i s t e nc i e s
and
anoma 1 i e s
to
be
found
in
the
1 i t erature ,
l e ad i ng a t l e a s t two rev i ewers t o con c l ude t h at t h e re i s c u rren t l y no
s at i s factory expl an at i on for t h e underl y i ng mec h an i sm of a s t hma and/
or
urt i c a r i a
Steven son
in
s uc h
pat i e n t s
& Lewi s , 1 987 ) .
One
1 984 ;
( Steven s o n ,
1 984 ;
VanArsde1 ,
i mport ant probl em i s t h e o b s e rvat i on .
that t artraz i ne and benzoate appe ar t o cro s s - re act w i th asp i r i n , yet
ne i ther are known to
et al . ,
1 979 ) .
i nte rfere w i t h p ro s t ag l and i n synt he s i s
To t h i s may be added t h e
( Gerber
f i nd i ng from t h e present
s tudy t h at a range o f other substances may a l so provo ke react i on s i n
as p i r i n- s e n s i t i ve p at i en t s , i nc l ud i ng sod i um s al i cyl ate , am i n e s , MSG ,
and
a
arg u ed
number
t h at
of
food
d i fferent
add i t i ve s
mec h an i sms
syndrome s ( Sett i pa n e e t a l . ,
in
1 974 ;
3 and 6 ) .
o perate
in
It
m i ght
d i fferent
Steven s o n et a l . ,
be
c l i n i cal
1 982 ) , b u t l i ke
( 1 984 ) we h ave found i t d i ff i cul t to draw c l ear d i v i d i ng
As ad et al .
l i nes
( Ch apters
i nd i v i du a l
p at i en t s ,
s ugge st i ng
a
common
underl y i ng
abno rmal i ty .
I n con s i der ing a1 ternat i ve hypo t h e s e s
i t may be h e 1 p fu 1
to
exam i ne
the known pharmaco l og i c a l act i on s o f t h e var i o u s comp ound s c ap abl e of
provok i ng adv e r s e re act i on s .
The act i on s o f s od i um s al i cyl ate h ave
been the s ubj ect of s ome debat e ,
but i t n ow s eems c l e a r t h at t h i s i s
due to d i fference s between i n v i t ro and i n v i vo f i nd i n g s
Vane ,
1 983 ;
Ra i n s ford ,
of p ro s t ag 1 and i n
s a l i cyl ate
after
1 984 ) .
product i on
absorpt i on
( H i gg s and
As p i r i n i s a much s t ronger i n h i b i tor
in
v i t ro ,
but
is
( Ch apter
4) ,
and
r ap i d l y converted
in
v i vo
these
to
two
2 49
compounds h av e s i mi l ar ant i - i n fl ammatory propert i e s .
S al i cyl ate may
al s o p ar ad ox i c a l l y i ncre a s e t h e format i on of pro s t ag l a nd i n s by act i ng
a s a free rad i cal s cavenger , part l y over- r i d i ng t h e e ffect s o f i n h i b
i t i o n o f cycl ooxyg e n a s e ( Ra i n s ford , 1 984 ) .
Free rad i c a l s caveng i n g
coul d a l s o account for react i on s to benzo i c ac i d and other phenol i c
c ompounds wh i ch h ave n o d i rect e ffect o n prostag l and i n metabol i sm
( Ra i n sford , 1 984 ) .
I ntere s t i ngl y , a rol e for free rad i cal s has been
s ugge sted i n a sp i r i n i nt o l erance ( Moneret - Vautr i n and Mart i n , 1 98 5 ) ,
al t h ough t h e e v i dence was r at h e r i nd i rect .
Another pos s i b i l i ty 1 s
t h a t s al i cyl ates and other l i poph i l i c phenol s may act by u n c ou p l i ng
ox i da t i v e
phosphoryl a t i on
(Wai n i o ,
1 970 ) .
I nd eed ,
before
the
d i scovery of prostagl and i n s i n the earl y 1 970 ' s th i s was con s i dered
one of the most i mp o rta n t act i on s of aspi ri n ( Ra i n sford , 1 984 ) .
Another i mport a n t group o f c ompounds to con s i der are food add i t i ves ,
i n part i c u l ar t h e col ouri n g s and pre serv at i ves , wh i c h often cro s s
react wi th asp i r i n i n s en s i t i ve p at i e n t s .
L i ttl e i s known o f the
prec i se mode of a ct i on o f mos t preservat i ve s , but t h ey are tho ug h t to
i nh 1 bi t mi crobi a 1 enzyme systems , i n c 1 ud i n g t h o s e respon s i b 1 e for
bas i c me t a b o 1 i sm and for synthes i s of prote i n s , n uc l e i c a c i ds and
cel l
wal l
con s t i tuents
( Luec k ,
1 9 80 ) .
It
is
ac knowl edged
that
s i m i l ar enzyme sys tems may be i nh i b i ted i n h um an s , al though factors
s uch as absorpt i on , d i str i but i on , met abol i sm and excret i on are l i kel y
to l ower the effect i ve t i ssue concentrat i on o f t he s e substances far
be l ow those requ i red to i nh i b i t m i crob i a 1 growth i n foods �
Many
mech an i sms h ave been proposed to account for the adverse effect s of
tartraz i ne ,
but
the
e v i dence
so
far
avai l abl e
is
i nconcl u s i ve
·
( rev i ewed
i n det a i l
by Hesser ,
250
1 984 ;
Murdoch e t al . ,
1 987a , b) .
Tartrazi ne i tsel f i s not structu ral l y rel ated to sa1 i cy1 ates (wh i ch
are 2 -0H benzo i c ac i d deri vat i ves ) or to the commo n l y u s ed preserv
at i ves , but i ts maj or metabo1 i te , sul p h an i l i c ac i d , i s an ana l ogue of
para- am i nobenzo i c ac i d ( PABA) .
I ndeed , the fam i l y o f s u l phonami de
drugs was d i scovered acc i dent l y through tests o f azo dye s ( Sc h re i ber,
1 985 ) , rai s i ng the pos s i bi l i ty that ant i mi crob i al act i v i ty m i g ht be
a
common property o f compounds wh i ch are prone to t r i gger adverse
react i on s .
I t i s i nteres t i ng to note that eryth ro s i ne has been found
to al ter gut mi crofl ora , even though i ts pri n c i pal u s e i s as a food
col our ( Drs . R . Adams and K . Hurray , CS I RO D i v i s i on o f Food Research ,
personal commun i cat i on ) .
ant i mi cro b i al
act i v i ty ,
The sal i cyl ates are al s o known to possess (
and
were
u sed
as
pres ervat i ve s
in
some
countri es unt i l the 1 950 ' s ( luec k , 1 980 ) .
A maj or d i ffi cul ty wi t h the vari ous mechan i sms descri bed above i s the
probl em of h ow to account for the vari abl e pattern of i nd i vi dual
i d i o syncras i es and target org an suscept i b i l i ty seen i n pat i ents wi th
food i ntol erance .
One pos s i b i l i ty i s t h at d i fferen ces i n absorpt i on ,
met abol i sm and/or excret i on o f part i cul ar compounds coul d determi ne
the i nd i v i dual ' s i d i osyncras i es ( Gl over et al . , 1 983 ) , w i th the fi nal
common pathway be i ng v i a a non - spec i fi c mech an i sm .
The occurrence of
desens i t i zat i on m i ght then be seen as a refl ect i on of substrate
dependent
enzyme
( Guenger i ch , 1 984 ) .
i nduct i on
in
the
rel evant
met abol i c
pathways
However , the absence o f any s i gn i fi cant d i ffer
ence i n sal i cyl ate pharmacoki net i c s between a s p i r i n - s en s i t i ve R IU/AO
�
pat i ents and control s argues aga i n st th i s as the pr i nc i pal abnormal i ty ( Ch apter 5 ) .
251
A n Al tern at i ve Work i ng Hypo t h e s i s
As o u t l i n ed above , n o s i ng l e hyp o t h e s i s h a s t h u s far s at i s factor i l y
expl a i ned t h e prote an cl i n i c al
man i fe s t at i on s o f food i n tol erance ,
t h e rel at i on s h i p between a s p i r i n and v ar i o u s o t h e r s ubstances capabl e
o f provo k i ng
c o l og i c � 1
i d i o syncrat i c re act i on s ,
p h e n omen a .
However ,
an
and t h e
a s s oc i ated
i mportant c l u e may 1 i e
p h a rma
in
the
f i nd i ng o f a h i gh i nc i dence o f react i v i ty t o b i ogen i c ami ne s and MSG
amo n gs t our p at i ents
( Ch apter 6 ) .
ni zed a s ant i m i cro b i a 1 s ,
The s e s u bstances are not recog
i n h i b i tors o f pro s t ag l and i n product i on o r
uncoupl i ng age n t s i n o x i dat i ve p h o s ph o ryl at i on , a n d a r e more l i ke l y
to
act v i a n e u rogen i c mec h an i sms .
The b i ogen i c ami n e s h ave wel l
recogn i zed n e u ro - humoral act i o n s ( Jones , 1 983 ) , and g l u t amate i s an
exc i tatory neurotran smi tter i n the central n ervo u s sys t em ( CNS ) ( F i 1 er
e t al . , 1 97 9 ;
F ag g , 1 985 ) , s uggest i ng t h e po s s i bi l i ty o f an unde r
l y i ng n eu roph armacol og i cal
abno rmal i ty i nvol v i ng regu l atory neuro
pept i des ( lo b 1 ay & Swa i n , 1 986 ) .
As d i scu s sed a l re ady , R I U/AO i s c h aracteri zed by abnormal dermal mast
cel l rel ea s a b i l i ty w i t h a vari ety o f s t i mu l i , for re ason s wh i ch are
not underst o od ( Ro se n s t re i ch , 1 986 ) .
is
via
refl ex ,
pept i de rg i c n erve
One p athway of med i ator rel ease
fi bre s wh i ch
are
i nvol ved
i n the
axon
f i rst descri bed by S i r Thoma s Lewi s i n 1 93 7 ( rev i ewed by
Lembec k , 1 983 ;
Foreman & J o rd an , 1 983 ) .
The affe re n t C - type nerve
f i bres i n t h i s pathway med i ate p a in and i tc h , t h e whea1
and fl are
res po ns e , and t h e vascul ar re s po n s e to co1 � , and i n recent years h ave
c ome t o be regarded a s the med i a tors of " ne u rogen i c ; n fl ammat ; on "
( Hart s c h u h e t al . ,
1 983 ;
Foreman & J o rd an ,
1 984 ;
Payan et al . ,
2 52
1 984 ;
Pernow , 1 985 ) .
They compr i se s everal p o p u l at i on s o f n eurons
conta i n i ng - su b s t an c e P,
n e u roten s i n
( Lembec k ,
s omat o s t at i n ,
1 983 ;
CCK- 8 ,
bombes i n ,
Hart sc h u h et a l . ,
1 983 ) ,
V I P and/or
and
recent
ev i dence s h ows t h at s ome fi bres term i n ate i n d i rect cont act wi th
cutaneous mas t cel l s ( Profe s sor S . Ho 1 g ate , personal c ommuni cat i on ) .
Pri mary i nvol veme n t o f per i pheral n e rv e s i n · R I U/AO i s al s o s uggested
by the s i ze and d i s t r i but i on o f t h e l es i on s , t h e occas i on al occur
rence of prodoma 1
t i ng1 ; n g ,
and t h e i ntere s t i ng o b s e rv at i o n that
ang i oedema of the 1 i p o ften does
( Cz arnetzk i ,
1 986 ;
and
not s pread
unpubl i sh ed
mechan i sm i nvol v i ng abnormal
beyond t he m i d1 i ne
personal
o b s e rv at i on s ) .
A
sen s i t i v i ty o f t h e axon refl ex cou l d
a 1 s o accou n t for the tendency i n s ome p a t i e n t s for u rt i c a r i a to be
t r i ggered by p hys i cal factors s u c h a s col d , s u n s h i ne , v i brat i on and
exerc i se , as wel l as t h e common obse rv at i on t h at l oc al p re s su re or
scratch i ng c an i nduce l e s i on s .
S i mi l arl y , i t h a s recent l y been s ugge sted t h at a s t hma c an be regarded
as a d i sord e r o f t h e axon refl ex ( Barn e s , 1 986 ) and t h a t n e u rogen i c
i nfl ammat i on may p l ay a n
i mp o rt ant rol e
in
bronch i al hyperreact i v i ty ( Barn e s , 1 987a , b ) .
thought
to
be t r i ggere d
p r i mar i l y by
the
p a t h og en es i s
of
M i grai n e al s o i s now
n eu ro nal
mech an i sm s
( Rose ,
1 983 ) , wi th vascul ar d i l atat i on occur i ng s econdary to rel e a s e o f V I P
and s u bstance P ( Mo s kowi t z , 1 984 ;
G o ad s by & Macdonal d , 1 985 ) .
In
i rr i t abl e bowel syndrome , too , i t h as been s h own t h at motor control
mechan i sm s are defect i ve ( Kumar & W i ngate , 1 985 ) , ra i s i ng t h e poss
i bi l i ty o f an abnormal i ty- i n the structure o r funct i on of the enteri c
nervous system i n s u c h p at i e n t s ( Cal am et al . , 1 983 ;
Makh1 0 u f , 1 985 ;
Cervero & S h ar key ,
A n e u ropharma
1 985 ;
Furn e s s & C o s t a ,
1 987 ) .
col og i cal abnormal i ty c an al s o read i l y be env i s aged i n c h i l d re n wi th
253
food - re l a t ed beh av i our di st urbances
Swa n s on
& K i n s bourn e ,
L ev i tan , 1 980 ;
1 980 ;
( Sh ayw i tz et al . ,
We i s s
et
Kapl i t a & Tr i ggl e , 1 982 ;
al . ,
1 980 ;
1 977 ,
1 978 ;
August i ne
&
G u al t i eri & H i cks , 1 985 ) ,
a s wel l a s i n adu l t s wi t h i l l - defi n ed n e u ropsych i atri c man i fes t at i on s
( Ch apter 6 ) .
W i t h the exi s tence of ten cl a s s i cal neurot ran smi tters , and the ever
i ncreas i ng n umber o f newl y d i scovered reg u l atory neuropept i de s , each
act i ng on mul t i pl e receptors , there i s ampl e scope to env i s age a wi de
range of i nd i v i du a l
i d i o syncras i e s to s ubstances wh i ch may act as
agon i st s or antagon i sts at mul t i pl e s i te s ( Kri eger & Mart i n , 1 98 1 ;
Pol a k and Bl oom , 1 983 ;
Al tman , 1 985 ;
Schm i tt , 1 984 ;
S nyder , 1 986 ) .
Bl oom , 1 985 ;
Qu i ri on , 1 985 ;
Phenome n a s u c h a s w i thdrawal effects ,
desens i t i zat i o n and s upersens i t i v i ty coul d then be i nterpreted as
man i festat i on s
of l i g and - i nduced
( I versen & I versen ,
Hol l enberg , 1 985b ;
wel l - recogn i zed
1 98 1 ;
modu l at i on
Creese & .S i bl ey ,
occurrence
G - prote i n s
s u persen s i t i v i ty
1 985a ;
u nder
is
and
the
the
these
reverse
( Ho l l enberg ,
1 985a ;
funct i on
Fl em i ng ,
c i rcumstances ,
mes senger
of these
1 98 1 ;
Des en s i t i z at i on i s a
i nvol v i ng
and/or t he i r uncoupl i ng
second
S i b 1 ey & Lefkowi tz , 1 985 ;
" cros s - t al k "
198 1 ;
S i bl ey & Lefkowi t z , 1 985 ) .
d own - regul at i on of receptor n umbers
regu l atory
o f receptor
system ,
proces s e s
whereas
( Hol l enberg ,
Dun 1 ap e t al . , 1 987 ) .
S i bl ey & Lefkow i tz ,
from
Receptor
1 985 )
coul d
al so account for the apparent cro s s - react i v i ty of a wi de range of
apparen tl y unre l ated substances , as wel l
as for· t h e phenomenon of
cro s s -d e s e n s i t i z at i on between a s p i ri n , other NSA I D ' s and tartraz i ne
( Pl e s kow et al . , 1 982 ;
L umry et al . ,
rev i ewed by Sl ep i an et al . , 1 985 ) .
1 98 3 ;
M i chel et al . , 1 984 ;
2 54
The Bas i s o f I nd i v i d u a l S u s cept i b i l i ty
As yet noth i ng i s known o f the i nd i v i d u al v a r i ab i l i ty o f neu ron al
receptor structure or contro l mec h an i sm s . However , g i ven t h e e n ormous
range o f v a r i at i on i n the h uman genome , amo u nt i ng to approx i mately
one base ch ange per 1 00 n ucl eot i de s ( Lancet Ed i to r i al . , 1 987 ) , i t i s
1 i kel y t h at pol ymorp h i sms wi 1 1 eventual l y be found i n eac h receptor
system .
I f these occur , for exampl e , at a l l o steri c s i t e s wh i ch can
b i nd chemi c al s o f the k i nd d i scu s s ed h ere ( Ch angeux
&
Reva h , 1 987 ) ,
t h i s wou l d res u l t i n genet i c al l y determ i ned v a r i at i on s i n sen s i t i v i ty
to the l i g and i n quest i on .
Vari ab i l i ty o f t h i s
k i nd
i n t i s sue
spec i fi c receptors m i ght t h en expl a i n t h e pattern of t arget organ
s u scept i b i l i ty seen i n i nd i v i d ual p at i en t s ( Ch apter 6 ) .
Metabo l i c vari at i o n s , are a l s o l i kel y to mod i fy t h e expre s s i on of food
i ntol erance i n some i nd i v i dual s .
s ome pat i ents
For examp l e , i t h a s been s hown that
wi th d i et - rel ated m i g ra i n e h ave
l ower t h an
n ormal
l evel s of the enzyme phenol - s u l p hotran s feras e wh i ch i s respon s i bl e
for conj ugat i ng tyrami ne and other rel ated phenol s ( Gl over et al . ,
1 983 ;
I s h i kawa et al . , 1 986 ;
G i bb et al . , 1 987 ) .
I n women hormonal
factors s uc h a s pregnancy , men arche , menopau s e , oral con tracept i ves
or the men strual cycl e c an. i n fl uence t h e cl i n i ca l expre s s i on of food
i nto 1 erance ( C h apter 6 ) , and i t i s tempt i ng to s pecu l ate t h at t h i s
may be due to t h e effects o f s tero i d hormones on neuroreg u l a tory
mech an i sm s ( Mc Ewen
&
Pfaff , 1 985 ) .
255
"
I d i o s Yncras i e s , S i de - e ffec t s and Tox i c i ty
B e fo re concl ud i ng t h i s d i s c u s s i on ,
t ox i c
i t i s re l e v an t to con s i der t h e
s i de - e ffects o f sal i cyl ates ,
and t he i r rel at i o n s h i p to t h e
i d i o syncras i e s documented i n t h e pre s e n t s t udy .
c h ro n i c
s al i cy l ate
d i arrhoe a ,
sys t em
tox i c i ty
bl u rred v i s i on ,
( CN S )
symptoms
res t l e s s n es s ,
h e ad ac h e ,
t i nn i t u s ,
s uc h
exc i teme n t ,
i ncl ude
as
v e rt i go ,
l as s i t ud e ,
tremo r ,
Typ i c al symptoms o f
nausea ,
vomi t i ng ,
and central
d rows i ne s s ,
progres s i ng
in
n ervous
c o n fus i on ,
s evere
cases
to
h al l u c i n at i on s , del i ri um , convul s i on s , and e v e n t u a l l y depre s s i on and
c oma ( Ra i n s fo rd , 1 984 ;
Ko1 l er & C o h e n , 1 97 9 ) .
s al i cy1 ate s i de e ffect s a r e not wel l
T h e mech an i sm ( s ) o f
understood .
S ome
symptoms ,
i nc l ud i ng many o f t h o s e i nvol v i ng t h e CNS , are d u e t o t h e d i rect
e ffect s of s al i cyl ates on n eu ro n al fun ct ion ( rev i ewed by Ra i n s fo rd ,
Known
1 984 ) .
mec h an i sms
ami n o bu tyr i c ac i d ( GABA ) ,
Cohen ,
1 986 ) ,
p e rmeab i l i ty
conduct i on
i ncl ude
redu ced
synt h es i s
of
g amma -
an i nh i b i tory n e'urotran sm i tter ( Ko l l er &
i ncre a s ed seroton i n p roduct i on , and al t ered membrane
to
and
K+
Cl -
and
syn apt i c
e ffec t s of s al i cyl ates
i on s ,
act i v i ty
al s o occur
re s u l t i ng
in
( Ra i n s fo rd ,
at
i mp a i red
1 984 ) .
t herapeut i c dose s ,
i mp u l se
The
and
CNS
are
res p on s i bl e for t h e i r anal g es i c and ant i pyret i c propert i e s i ndepend
e n t o f any ant i - i n fl ammatory act i on .
Al t h o u g h s al i cyl ate i nt ox i c at i o n i s u s u al l y a s s oc i ated w i t h chron i c
h i gh -dose
i ng e s t i o n ,
it
is
kn own t h at
t he re
i nd i v i d u a l v ar i a t i on ( Sm i t h & Smi t h , 1 966 ) .
is
a w i de range of
I ndeed , t h e d i fferences
between " to x i c i ty " , " s i de - e ffect s " and " i d i o syncrasy " may s i mpl y be
one of degree , depend i ng on c umu l at i v e d o s ag e and a mul t i tude of
2 56
genet i c and envi ronmental factors wh i ch determ i n e i nd i v i du al res pons
i veness { Vesel l & Penno , 1 98 3 ;
Kl aas sen , 1 985 } .
The res u l t s o f the
present s tudy s uggest t h at s i mi l ar symptoms may occur at muc h l ower
d o s e s t h an h i therto sus pected i n a smal l proport i on o f t h e popul at
i on , pre s umabl y compri s i ng i nd i v i dual s who are at the t a i l - end o f the
normal d i s t r i but i o n curve ( Ar i ens & S i mon s , 1 982 ) .
Food I ntol erance - A B i o l og i cal Perspect i ve
I t i s o f s ome i ntere s t to con s i der the ori g i n s o f d i etary s al i cy
l ates , and to spec u l ate about the b i o l og i cal
s i gn i fi cance of the
tendency for
to
s ome
h uman s
to react
advers el y
such
compounds .
S a 1 i cyl ates , al ong w i t h several thous and other phenol i c and rel ated
compound s ,
are secondary metabol i te s syn t h e s i zed v i a t h e S h i ki mi c
ac i d pathway i n pl ant s ( S i ng l eton , 1 98 1 ;
Tors sel l , 1 983 ) and h ave
been a source of med i c i n al agents probabl y throughout h uman h i story.
The funct i on s o f phenol s i n pl ants h ave been a l ong - s t and i ng puzzl e ,
but i t i s now general l y thought t h at t h e i r pri n c i pal
rol e i s an
ecol og i cal one , i . e . control l i ng the b i o l ogy o f other spec i e s i n the
env i ronment ( Torssel 1 , 1 983 ) .
Secondary met abol i tes are i nv o l ved i n
protect i on from m i cro - org an i sms ,
tox i c e ffects ,
heal i ng
as wel l
mec h an i sms ,
env i ronment .
as
and
I ns ect s ,
and
and predators
i n t h e reproduct i v e cyc l e ,
i nteract i on
w i th
h erb i vorous an i mal s ,
vari o u s mean s of ad aptat i on
detox i fi c at i on
i n sects
excret i on
other
vi a
rep a i r and
pl a n t s
and man ,
& J a koby ,
in
the
h ave evol ved
to these tox i c s ubstances ,
( C al dwel 1
the i r
i ncl ud i n9
1 983 ) ,
t i s s ue
spec i fi c res i stance ( Cohen , 1 986 ) , and beh a v i oural mec h a n i sms ( Logue ,
1 986 ;
rev i ewed by Swa i n T . ,
S 1 at k i n , 1 983 ) .
1 978 ;
S i ngl eton ,
1 98 1 ;
Futuyma &
257
E a c h o f t h e general types o f n at ural phenol s c a n b e s u bd i v i d ed i n to
t h o s e of c ommo n , uncommo n , or bot an i cal l y rare occurrence .
Mo st of
the pheno 1 s n oted for tox i c i ty or phys i 0 1 og i c a 1 potency i n an i ma 1 s
are n ot onl y extreme l y l i m i ted i n botan i c al d i stri b ut i on , but are
al s o u n i que
or
h i gh l y
unusual
in
t he i r c h em i c a l
structure when
compared wi t h commo n p l ant phenol s ( S i ng l eton & Kratzer , 1 973 ) .
By
contrast , s al i cyl ates and ben zo ates may be reg arded as bota n i cal l y
commo n , and o f rel at i ve l y l ow tox i c i ty .
I t s h o u l d be remembered ,
h owever , t h at tox i c i ty i s dependent n ot o n l y o n the pharmaco l og i cal
propert i es
of
a
part i cul ar
fore i gn
substance ,
but
al s o
cumul at i v e d o s e a n d t h e s us cept i b i l i ty o f the i nd i v i dual
S i mo n s , 1 982 ;
on . the
( Ar i e n s &
Al bert , 1 987 ) .
The total amo u n t s o f common d i etary phenol s c an ran g e from n e arl y
zero i n refi n ed , pl ant -deri ved foods l i ke t abl e s ug ar , to 20% or s o
o f t h e d ry we i g h t o f t h e d i et o f some herb i vorous an i mal s ( S i ng l eton ,
1 98 1 ) .
When g i ven a free c ho i ce ,
an i mal s i n general , and man i n
part i cu l ar , sel ect food pl ant p art s wi t h a l ow phenol content .
P art
i cu l arl y w i t h agr i cul t ure , man h as not o n l y sel ected and mod i fi ed by
breed ; n9 t h e pl a n t s h e cul t i vates for food , but ; n a g re at p art of
the mos t fert i l e l an d h e h a s compl etel y changed the env i ronment i n
terms o f t h e d i vers i ty o f i nd i v i du al pl ant spec i e s and the res ul tant
occurrence o f vari ous phenol s .
We t here fo re may h ave a warped and
l i m i ted v i ew o f the p o s s i bl e r i s k o f pl ant tox i n s .
an i mal s were
i ntroduced
When dome s t i c ated
by Europeans to the un fami l i ar fl ora
in
Au s t ral i a , about one p l ant spec i as i n twen ty was found capabl e o f
caus i ng d e a t h ( C ul ven or , 1 9 70 ) .
The rat i o i s a l i tt l e more favorabl e
258
i n n at i ve North Ameri can or Afr i can fl ora , but al l owi ng for unrecog
n i zed , s l ow-devel op i ng , or subacute toxi c i ty , i t i s cl ear that many
p l ants are l i kel y to be h armful .
W i th the app arent except i on of the
gras ses and gra i n s of the G ram; neae , few pl ants al l ow predat i on by
an i mal s wi thout offer; ng some form of act i ve res i st ance ,
thorn s or tox i n s ( Cul venor , 1 97 0 ) .
such as
Fru i t may be s ac r i fi ced to an
ani mal i n return for seed d i s pers a l , but often the s eeds themsel ves
may be tox i c or may at l east res i st d i ge st i on .
Wh i 1 st p l ants h ave evol ved tox i n s to hel p protect them from pests ,
p aras i te s ,
d i sease org an i sms ,
or predators ,
an i mal s and man have
ev i dentl y evol ved and surv i ved by " l earn i ng " to avo i d or wi thstand
these toxi n s ( Swa i n T . , 1 978) .
One o f the mos t i mport ant mechani sms
of avo i dance i s the sen s i ng o f nox i o u s substan ce s by sme l l and taste ,
and the cond i t i on i ng o f avers i ve behav i our by foods wh i ch provoke
unpl e a sant react i on s ( Ri 1 ey & Tuc k , 1 985 ;
Logue , 1 986 ) .
The pharm
acol og i cal and neurol og i cal bas i s of beh av i oural avers i on are only
_
beg i nn i ng to be unravel l ed , and are l i ke l y to be exceed i ng l y compl ex
( Braveman & Bron s te i n , 1 98 5 ) .
erance ,
" avers i on "
is
I n the context o f c l i n i cal food i ntol
a term somet i mes
appl i ed to
psychol og i cal
react i ons i n wh i ch the p at i ent mi stakenl y attri butes symptoms to a
part i cul ar food , wh i ch -i s then avo i ded ( Le s sof et al . , 1 984 ) .
though
cond i t i oned
avers i on
can
to
some
extent
be
Al
mod i fi ed by
psychol og i cal and soc i al factors ( Logue , 1 986 ) , i t i s e s sent i al l y
a
phys i ol og i cal phenomenon wh i ch shoul d be c l earl y d i st i ng u i s hed from
phob i a s and del u s i on s - rel at i ng to food s .
The strongest avers i ve
st i mu l i are those wh i ch provoke n aus ea , vomi-t i ng or other gastro-
i ntest i nal symptoms v i a the eNS ( Ki efer , 1 985 ) , whereas symptoms such
'
259
a s urt i c a r i a or mou t h ul cerat i o n appear to be 1 e s s pote n t ( Gr i 1 1 ,
1 98 5 ) .
T h e ex i stence i n t h e h uman popul at i on o f po1 ymorp h i sms
c e ntral
and
p er i p h eral
certa i n
i nd i v i du a l s
n o c i cept i ve
to v ar i o u s
mec h an i sm s ,
food
and
and c hemi cal
may be a s i gn i fi cant evol ut i o n ary adv a n t ag e .
i nvol v i ng
pred i spo s i ng
i d i o syncras i es ,
For examp l e , i n t i me s
o f fam i n e or droug h t , or whe n expl ori ng n ew h a b i t at s , a p o p u l at i on o f
h un t e r - g at herers wou l d be more 1 i ke 1 y to adapt to n ew food s ources
cont a i n i ng potent i al l y tox i c s u b s tanc e s .
I t i s a l s o tempt i ng to
s pecul a t e t h at t h e h i g he r frequency o f adverse food react i on s amongst
femal e s o f rep roduct i ve age ( Ch apter 6 ;
Young et a l . , 1 987 ) may be
of s i mi l ar b i o l og i cal s i gn i fi cance .
Many food phenol s are known to
be
po s s i bl y
teratogen i c
( S i ngl eton ,
( Ra i n s ford , 1 984 ;
1 98 1 ) ,
i nc l ud i ng
s al i cyl ate s
Z i er1 er & Rothman , 1 98 5 ) . I t seems rea s o n abl e t o
s uppos e t h at women w h o a r e more s e n s i t,i ve t o s uch compound s wou l d be
more 1 i kel y
to
avo i d t h em ,
and
t h u s m i g h t enj oy a
reproduct i ve
advantag e ( Lobl ay & Swa i n , 1 986 ) .
Concl u s i on
Much rema i n s t o be l e arned about t h e c l i n i ca l feature s a s wel l as the
underl y i ng mechan i sms of food i nt o l e ranc e .
The maj or f i n d i ng s o f the
present s tudy h av e been recogn i t i on o f the w i d e s pread d i stri but i on of
n at ural s a1 i cyl ate s i n common food s , the c l i n i ca l spectrum of adverse
react i on s
in
s al i cyl ate - s e n s i t i ve
c ro s s - react i v i ty between
a wi de
p at i en t s ,
range of
and . the
n atural
i d i o syncrat i c
and
art ; fi c i a 1
260
1
j
1
s U b s t ances i n the d i et . These fi nd i ngs l ed to the s u cc e s s ful d evel op·
ment o f a systemat i c and re 1 i ab 1 e method for the ro u t i n e i nvest i gati on and management o f food - sen s i t i ve pat i ents , s u i tabl e for use in
'�
.�
�
)
1
outpat i ent cl i n i cs or pri v ate pract i ce .
The fi nd i ng s h ave al s o ra i sed many que s t i on s for fut u re study . For
examp 1 e , how common ; s unrecogn i zed food ; nto lerance ; n the general
c ommun i ty?
Wh i ch pat i ents requ i re formal
i nvest i gat i on ?
How many
normal , asymptomat i c i nd i v i dual s wou l d be l i ke l y to react t o some of
the chal l enges used here?
Wh i ch
other food s ubstan ce s ,
not yet
stud i ed m i ght al so be contri but i ng to symptoms i n s ome p at i ents?
What
is
the
d i agnost i c use?
most
appropr i ate
chal l enge
protocol
for
routi ne
How effect i ve i s l ong - term d i etary mod i fi c at i on i n
control l i ng symptoms ? Wh at rol e d o psychol og i cal factors pl ay i n
,
p at i ent s ubgroups such a s those wi th mi gra i ne , i rr i t abl e bowel ,
hyperact i v i ty or neuropsyc h i atri c man i fe s t at i on s ?
cro s s - over
underway ,
cl i n i cal
tri al
in
adul t s
wi t h
A
m i g ra i ne
doubl e - bl i nd
is
al ready
and a det a i 1 ed study o f · hyperact i ve ch i 1 dren i s i n the
pl ann i ng stages to an swer some of these quest i on s .
El uc i dat i on of underl yi ng mech an i sms i s l i kel y t o be more d i ffi cul t ,
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However , as d i scus sed
above , carefu l c l i n i cal i nvest i gat i on can prov i de val uabl e c l ues for
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D . , VlASOPOULOS , T . P . and S I RASANI AN , R . P . ( 1982 ) : Food a l lergens and basophi l h i stam i ne re lease
in recurrent aphthous stanat i t i s . Ora l Surg . , ,§,! : 388-395 .
RYAN , F . P . , WI LL I NGHAM , S . E . , HOLT , S . , PAGE , A . C . , HI NDLE , M . O . and FRANKLI N , C . D . ( 1986 ) :
WR IGHT . A . ,
Food a llergy
or
into lerance
in
severe
FABRO ,
(1981 ) :
recurrent aphthous u lcerat i on of
the mouth .
B.
M.
J. ,
l ebensmitte 1 -add i t i va- i nto1 eranz
be ;
W : 1231-1238 .
WUTR ICH .
B.
urt i car i a .
and
L.
Acetyl sa l i cyl aure-
und
asthna bronch i a 1e und chron i scher rh i noparh ie . Schwe i z . Med . Wochensc hr . , 1 1 1 : 1445- 1450 .
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and HACKI-HERRMANN , D .
( 198 0 ) : Zur at i o 1 og ie der urt i car i a . E i ne retrospekt i ve studie
anhand van 3 1 6 konsekut i ven fa l len . Ze itschr i ft fur Hautkrankhe i ten � : 1 02 - 1 1 1 .
WYLL I E . W . G . and
D i s . , �: 1.
SCHLES I NGER , B . ( 1933 ) : The per i od i c group of d i sorders i n ch i ldhood . B r i t . J . Chi ld.
.
319
YAGER ,
J.
and YOUNG , R . T .
( 1974) : Non-hypog l ycaem i a i s a n ep i dem i c cond i t i on . N . Eng l . J . Med . ,
29 : 907 -908 .
YAJ l MA , I . , YANA I , T . , NAKAMURA , M . , SAKAK I BARA , H . , UCH I OA , H . and HAYASHI , K . ( 1983 ) : Vo lat i le f lavor
compounds of bo i l ed buckwheat f l ou r . Agr i c . B i o 1 . Chem . , 47 : 729-738 .
YAMAGUCH I , K . and SH I BAMOTO , T . ( 1980 ) : Vo lat i le const i tuents of the chestnut f l ower . J . Agr i c . Food
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YAHAGUCH I , K . and
S H I BAMOTO , T . ( 1981 ) : Vo lat i le const i tuents of green tea , Gyckuro ( Came l l i a s i nens i s
L . var yabuk i t a ) . J . Agr i c . Food Chem . , 29 : 3 66-370 .
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S . , WAKABAYASH I ,
S . and MAK I TA , M .
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ITANO , H . , KATAOKA , H . and MAK ITA, M .
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A P P END I C ES
A P P END I C ES
App e nd i x
1.
E l i mi n at i o n D i et 1
App e n d i x
2.
E l i m i n at i o n D i e t 1 1
Append i x
3.
U rt i c a r i a C h al l e n g e Bat t e ry
Append i x
4.
Sys t em i c C h al l e n g e B a t t e ry
Append i x
5.
A s t hm a C h a l l e n g e Pro t o c o l
App end i x
6.
F o o d C h a l l e ng e Prot oc o l
App e n d i x
7.
L ow S a l i cyl a t e D i e t
App e n d i x
8.
L ow S a l i cyl a t e , Pre s e rv at i ve , Art i f i c i al C o l o ur i ng ,
Brewe r ' s Y e a s t D i e t
App e nd i x
9.
L ow S a l i cyl a t e , Am i n e , Mon o s od i um G l u t amat e ,
Pre s e rv at i ve , Art i f i c i al C o l o u r i ng , Brewer ' s Ye a s t D i et
App e n d i x
10.
S al i cyl a t e C h art
Append i x
11 .
Ami ne C h art
App e nd i x
12.
MSG C h art
Append i x
13 .
F o l l ow - u p que s t i on n a i re for R I U/AO p at i e n t s
w h o compl e t ed t h e p ro t o c o l
App e n d i x
14 .
Fo l l ow - u p q u e s t i on n a i re for R I U/AO p at i e n t s who d i d not
compl e t e t h e el i m i n at i on d i e t and c h al l enge prot o c o l
Append i x
15.
F o l l ow- u p que s t i on n a i re fo r p at i e n t s wh o c omp l eted
the p ro t o c o l
Append i x
16.
F o l l ow - up que s t i o n n a i re for p at i e n t s wh o d i d n o t
c omp l e t e t h e e l i m i n a t i on d i e t a n d c h a l l e n g e p ro t o c o l
APPEND I X 1
EL I M I NAT ION D I ET I
D I ETIT IAN :
TELEPHONE :
_________
The a i m of th i s d i et i s to exc l ude certa in add i t i ves and natura l chem i ca l s from your da i ly food intake .
These i nc lude : natura l sal i cylates , ami nes , brewers yeast , monosod i um g l utamate ( MSG) , ant i ox i dants ,
preservat i ves and co lour i ngs . Once exc l uded , de l i berate re i ntroduct ion of each of these substances
( "cha l l enge" ) can he lp i dent i fy the cause of your prob lem .
D I ET RULES :
1.
2.
3.
Use on ly those foods a l lowed
Do nQ! use any foods not l i sted
Avo i d a l l non-essent i a l med i cat i ons
D I ET NOTES :
W i thdrawa l s�ptoms may start to occur dur i ng the f i rs t two weeks on the e l imi nat i on d iet . Some or a l l
of your symptoms may i ncrease temporar i ly , but these w i thdrawa l symptoms usua l ly d i sappear w i t h i n a few
days to two weeks .
CHALLENGE RULES :
1.
Commen ce cha l lenges after a mi n imum of two weeks on the e l iminat i on d iet , and on ly after at least
f ive days free of symptoms . If , after s ix weeks , there i s no improvenent , contact your d i et i t i an
and doctor .
2.
Cha l lenge w i t h chem i ca l capsu les as out l i ned .
a.
Cha l l enge capsu les shou ld be taken i n the morn i ng ( 1/2 hour before , or two hours after
breakfast )
Reac t i ons may occur anyt ime up to 48 hours after tak i ng a chal lenge caps u l e .
b.
If you do deve lop symptoms dur i ng th i s t ime . wa i t unt i l they have gone comp l ete ly, and then a
c.
further three days free of s�ptoms , before go ing on to the next cha l lenge .
I f you do not deve lop any react i on w i t h i n 48 hours , go on to the next cha l lenge .
d.
P lease read carefu l l y
EL I M I NAT ION D I ET
1.
The d i et shou ld be fol lowed for at least two weeks or unt i l symptoms sett l e , whi ch may take up to
s ix to e ight weeks . ** Once you ach ieve a per i od of five days in a row free of symptoms , you are
to be cha l lenged w i th each of the chem i ca ls wh ich common ly cause symptoms . If symptoms are st i l l
present after s ix weeks , contact your d i et i t i an or doctor .
2.
On the chart prov i ded , keep a detai led record of :
a)
b)
c)
3.
foods eaten throughout t he day
symptoms - type and how l ong they last
cha l lenges and/or medi cat i ons taken
Any non-essent i a l med icat i on shou ld cease at least f i ve days before start i ng the c ha l l enges
( consu l t your doctor i f uncerta i n ) . Shou ld you have a headache dur i ng t he cha l lenge per i od ,
Panado l and/or code i ne preparat i ons may b e used .
ALL ASP IR I N-CONTA I N I NG DRUGS SHOULD BE AVOI DED
Co l oured capsu les ( e . g . ant i b i ot ic s ) can be opened and empt i ed i nto c lear ge lat ine
capsu les wh ich can be bought from most pharmac i es .
Co l oured tab l et s can be gent ly rubbed under a runn i ng tap to remove the co l oured
coat i ng .
Use on ly recommended v i tami n preparat i ons
**
In some i nd iv idua ls , improvement may be gradua l over four to s i x weeks . but i f there i s no change
i n symptoms after s ix to e i ght weeks of str i ct d i et i ng , cont i nued restri ct i on i s un l i ke ly to be
he l pfu l and the d i et i t i an shou ld be contacted for i nstruct i ons on how to resume a norma l d i et .
V I TAMI NS & M I NERALS
It i s recommended that pat ients on the e l imi nat i on d iet shou ld take a v i tami n and mi nera l supplement as
the d i et conta ins marg i na l amounts of some v i tami ns and m i nera l s . Care shou ld be taken to ensure that
these supp l ements do not conta i n preservat i ves , co lours or f lavours as these w i l l i nterfere w i th the
cha l lenge resu lts .
Some preparat i ons to avo i d are those whi ch conta i n
PABA = Para am i no benz o i c ac i d , o r ABA
co loured capsu les
syrups
a l fa lfa
ke lp
rosehi ps
A.
B.
C.
D.
E.
F.
=
Ami no benzo i c ac i d .
It i s suggested that one of the fo l l ow i ng mu lt i v i tam i n suppl ements be used
A.
B.
E 1 ev i t RDI ( Roche )
any mu lt i v i tami n i n a caps u l e : take t he powder on ly - d i scard
the p l ast i c co loured capsu le coat i ng , e . g . Myadec ( Parke
Dav ; s )
CHALLENGES
1.
Take the cha l lenge caps u l es i n the morn i ng ha lf an hour before or two hours after a mea l , and note
any effects over the fo l low i ng two days ( a del ayed react ion may beg i n up to 48 hours after tak ing
the cha l lenge capsu le ) . On the sheets prov ided record the t ime each cha l lenge was taken and , if a
react i on occurs , record the t ime i t began , type and sever i ty of symptoms and how long they lasted .
If the react i on i s severe , contact your d i et i t i an or doctor .
2.
Sane cha l lenges may be 1 abe l led "A" and "B" ( e . g . 3A , 38) , represent i ng a sma 1 1 dose ( "A" ) and a
larger dose ( "B" ) of the same ( or s im i l ar ) chem i ca l s . These shou l d b e taken o n the same day. the
sma 1 1 dose ( "A" ) f i rst . I f there i s no react i on w i th i n two hours , take the second dose ( "B" ) .
However , if a not iceable react i on occurs to dose "A" , dose "B" shou ld not be taken .
3.
React ions t o a cha l lenge usua l ly beg i n w i th i n a few hours , but may take u p to 4 8 hours to deve lop.
If a react i on occurs wUh i n two days of tak i ng a cha l lenge , wa i t unt i l the S)1Tlptoms have
d i sappeared comp l etely and then a l low a further three days w i thout symptoms before go i ng on to the
next cha l lenge the fo l low i ng day. as i l lustrated in the examp le bel ow
Days
1
Cha 1 1 enge
3
S)1TIptoms
++
2
3
4
5
6
7
4A
4B
+
o
o
o
o
8
5
o
o
Three fu l l days free
of symptoms before
next cha 1 1enge .
IN SOME I NDIVI DUALS :
1.
W i thdrawa l Symptoms may occur dur i ng the f i rst week or two on the e l imi nat i on d i et . Some or al l
of your symptoms may i ncrease for a short t ime , but these usua l ly d i sappear w i th i n two weeks .
Cal l your d i et i t i an or doctor i f symptoms pers i st .
2.
� may become more not i ceab le and can br i ng on symptoms . The c ommo nest prob lems are petro leum
products ( petro l , gas , o i l , kerosene ) , pa i nts . perfumes , c i garette smoke , pressure-pack products
and strong sme l l i ng c l ean i ng agents . Try to avo i d these fumes as much as poss i b l e dur i ng the
e l iminat i on and cha l lenge per i od . Once you i nc l ude other foods in your d i et at the end of the
test i ng per i od , sme l l s and fumes shou ld become less of a prob lem.
FOOD L I S T AND MEDICATI ONS
FOODS ALLOWED
FOODS TO AVO I D
Beef , lamb , vea l and pou ltry ( no sk i n or fat )
ch icken sausages by Summercross Sma l lgoods
Corned beef , ham. bacon , pork , offa l , sausages
f i sh and seafood , we l l browned meat .
Eggs
Co ld pressed saff l ower or sunf lower o i l
( NO ANTI OX IDANTS ) , butter and cream
Other o i l s and 01 1 s whi ch conta i n ant i ox i dants .
Margar i ne , cheese and yoghurt .
VEGETABLES
Iceberg lettuce ( i ns ide leaves on ly)
Old wh i te potatoes ( no sk i n )
Country Sty l e p l a i n potato cri sps by L ips
Pars l ey (fresh , spr i nk le through food on ly)
Pears - fres h , very ripe and th i ck ly pee led
Pears - canned i n syrup not
nectar or ju i ce
Al l other lettuce
New potatoes , Pont i ac ( red) potatoes
Other commerc i a l potato cri sps and chips
A l l other vegetab les
Unr i pe pears , Gou l burn Va l ley and SPC canned pears
in j u i ce or nectar , a l l other fru i t i nc l ud i ng
dr i ed fru i t
CEREALS
Other cerea l s , bread and b i scu i ts
Any p l a i n unpreserved breads , ro l l s , muff i ns or
crumpets . P l a i n homemade or commerc i a l b i scu its
sponge , p i ke lets , pancakes , scones , pastry , etc .
Brown r i ce cakes , San-Esu p l a i n r i ce crackers
Wh ite r i ce , r i ce f lour , r i ce nood l es , r i ce
venmi ce l l i , unco loured pasta ( spaghett i , macaron i ) ,
tap i oca and sago .
Al l wheat f l ours ( wholemea l , wh i te , se lf ra i s i ng ,
p l a i n ) , F i e l ders cornf lour , Parsons cornf l our ,
Kream cornf l ou r . Arrowroot f lour , potato f lour .
R i ce Bubbl es , Ro l l ed R ice, Hea lther i e R i ce F lakes ,
Weetbi x , A l l Bran , V ita Br i t s , Bran F l akes , Puffed
Wheat , Weet i es , Weetf 1 akes , Unprocessed bran .
Cont inued
FOqOS ALLOWED
FooOS TO AYDID
Wh i t e suga r , brown sugar , Go lden syrup
Honey , raw sugar , a rt if i c i a l sweeteners .
COND IMENTS
Sa l t , c i tr i c ac i d , fresh pars l ey ( sp i nk 1 e on ly) ,
Homemade french dres s i ng ( co ld pressed o i l and
c i tri c ac i d to taste )
Herbs and spi ces
V inegar
COOKI NG AIDS
B i carbonate of soda , Cream of tartar , Bak i ng
Powder ( McKenz ies and R i te-D i et )
Ge lat i ne { bo i l before use}
Other cook i ng a i ds
BEVERAGES
Decaffe i nated i n stant and bean coffee , water .
soda wat er , mi nera l water , homemade lemonade
( two cups sugar d i sso lved in one cup of wate r ,
add c i tr i c ac i d t o taste ; d i l ute w i t h soda water ,
mi nera l water or tap water ) , home made pear ju i ce
( b l end a can of pears and syrup , then add water
or m i nera l water to taste ) . M i l k ( homogen i sed ,
evaporated , condensed , UHT , sk im , H i l o , Shape ) .
Tea , herba l tea , cerea l coffee , any choco l ate
f lavoured dr i nk s , fru i t j u i ces and commer c i a l pear
j u i ce , soft dri nk s and a l cohol
MED I CAT IONS
Panado l , Panade i ne , Code i ne - on ly when necessary A l l med i cat i on nQt prescr i bed by your doctor e . g .
Asp i r i n , D i sp r i n , A lka Se l tzer , V i ncent s .
A l l med i cat i ons whi ch conta i n f lavour i ng or
Ant i h i stami nes - on ly when necessary
co l our i ng . Cough lozenges and syrups .
O i l of Wi ntergreen e . g . Dencoru b , Deep Heat , Tiger
Sav lon ant isept i c cream
Ba lm, musc l e ba lms etc .
TOI LETR I ES
A mixture of sa l t and soda , ord i nary sa l t ,
F loran HA o r Sou l Patt i n son ' s unf l avoured
toothpaste a nd Sensodyne may be used as
toothpaste subst i t utes .
Nona l lergen i c or l ight ly perfumed cosmet i c s ,
to i let r i es and mo i stur i sers can be used w i th
w i th caut i on ( e . g . Sun l i ght , Neutrogena) .
Aeroso l s and pressure pack products shou l d be
avo i ded
Toothpaste - avo i d f lavoured toothpaste .
Perfumes and st rongly perfumed cosmet i c s , toi l etr ies
and mo i stur i sers are to be avo i ded e . g . Avon
SAMP LE MENU
BREAKFAST
R i ce Bub b l es , mi lk and sugar
Bo i l ed egg
Toast ( unpreserved bread ) and butter and Go lden Syrup
Decaffe i nated coffee
Sandw ich made w i th unpreserved bread
and f i l l i ngs of co l d roast meat , ch i cken , egg and l ettuce
Fresh pear ( no sk i n )
G l ass of m i lk
Gr i l l ed steak
mashed potatoes and l ettuce
Baked custard and t i nned pears in syrup
BETWEEN MEALS
Decaffe i nated coffee , m i lk or m i nera l water ,
Homemade p l a i n cake or p l a i n b i sc u i ts ,
Arnott ' s water b i scu its or Th i n Capta i n wi th butter ,
D I ET AND CHALL ENGE SUMMARY
D i et Comme n ced :
CHALLENGE RESULTS
Caps u l e Cha l lenges
React i on
( yes/no )
1
2
3
4
5
6
7
8
9
10
11
12
13
14
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
. .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
· .
APPEND I X 2
EL I M I NAT I ON D I ET 1 1
D I ET IT I AN :
________
TELEPHONE :
________
The a i m of th i s d i et i s to exc lude certa i n add i t ives and natura l chemi ca ls from your da i ly food intake .
These i nc lude : natura l sa l i cylates , am i nes , yeast , monosod i um g lutamate (MSG ) , ant i ox idants ,
preservat i ves and col ouri ngs . Once exc l uded , de l i berate re i ntroduct i on of each of these substances
( " cha l lengen ) can he lp i dent i fy the cause of your prob lem .
DI ET RULES :
1.
2.
3.
Use on ly those foods a l lowed
D o ng! use any foods not l i sted
Avo i d a l l non-essent i a l med i cat i ons
D I ET NOTES :
W i thdrawa l symptoms may start to occur dur i ng the f i rst two weeks on the e l imi nat i on d iet . Some or al l
of your symptoms may i ncrease temporar i ly, but these w i thdrawa l symptoms usua l ly d i sappear w i t h i n a few
days t o two weeks .
CHALLENGE RULES :
1.
Commen ce cha l lenges after a m i n imum of two weeks on the e l imi nat i on d i et , and on ly after at least
f ive days free of symptoms . If , after s ix weeks , there i s no improvement , contact your d i et i t ian
and doctor .
2.
Cha l l enge w i th wheat as out l i ned .
3.
Cha l lenge w i th m i lk a s out l i ned .
4.
Cha l lenge w i th chem i ca l capsu les a s out l i ned .
Cha l lenge capsu les shou ld be taken i n the morn ing ( 1/2 hour before , or two hours after
breakfast )
b.
React i ons may occur anyt ime up to 48 hours after tak i ng a cha l lenge capsu l e .
If you do deve lop symptoms dur i ng th i s t ime , wa i t unt i l they have gone comp l etely, and then a
c.
further three days free of symotoms , before go ing on to the next cha l lenge .
I f you do not deve lop any react i on w i th i n 48 hours , go on to the next cha l lenge .
d.
a.
EL IMINAT ION D I ET
1.
2.
3.
The d i et shou ld be fol lowed for at least two weeks or unt i l symptoms sett l e , whi ch may take up to
s ix to e ight weeks . ** Once you ach i eve a per i od of f i ve days 1 n a row free of symptoms , you are
to be c ha l l enged w i th wheat and m i lk and then each of the chem i ca ls whi ch common ly cause symptoms .
I f symptoms are sti l l present after s ix weeks , contact your d i et i t i an or doctor .
O n t he chart prov i ded , keep a deta i led record of a )
b)
c)
foods eaten throughout the day
symptoms - type and how long they last
cha l lenges and/or medi cat i ons taken
Any non-essent i a l med i cat i on shou ld cease a t least f i ve days before start i ng the cha l lenges
( consu l t your doctor i f uncerta i n ) . Shou ld you have a headache dur i ng the cha l lenge peri od ,
Panado l and/or code i ne preparat i ons may b e used .
ALL ASP I R I N-CONTAI N I NG DRUGS SHOULD BE AVOIDED
Co loured capsu l es ( e . g . ant i b i ot i cs ) can be opened and empt i ed i nto c lear ge lat i ne capsu les
wh ich can be bought from most pharmac i es .
Co loured tab lets can be gent ly rubbed under a runn i ng tap to remove the co loured coat i ng'.
Use on ly recommended v itam i n preparat i ons
**
In some i nd iv idua l s , improvement may be gradua l over fOur to s i x weeks , but i f there i s no change
i n symptoms after s i x to e i ght weeks of st rict d i et i ng , cont i nued restrict i on i s un l i ke ly to be
he l pfu l and the d i et i t i an shou ld be. contacted for i nstruct i ons on how to resume a norma l d i et .
VITAMI NS & MINERALS
It is recommended that pat i ents on the e l imi nat i on d i et shou ld take a v i tami n and mi nera l supplement as
the d i et conta ins marg i na l amounts of some v i tamins and m i nera l s . Care shou l d be taken to ensure that
these supp l ements do not conta in preservat i ves . co lours or f lavours as these w i l l i nterfere w i th the
cha l lenge resu lts .
Some preparat i ons to avo id are those whi ch conta i n
A.
B.
C.
D.
E.
F.
PABA = Para ami no benzo ic ac i d , or ABA = Am i no benzo i c ac i d .
coloured capsu les
syrups
a lfa lfa
kel p
roseh ips
It is suggested that one of the fo l lowing mu lt iv i tam i n supp l ements be used
A.
B.
E lev i t RD I (Roc he )
any mu l t i v i tami n i n a capsu le
take the powder on ly - d i scard the p l ast i C co loured capsu le coat i ng ,
e . g . Myadec ( Parke Dav i s )
and one of t he fol low i ng calc i um supp l ements be used :
A.
B.
C.
DCP 340 Powder ( Parke Dav i s )
Sandoca l 1000 ( Sandoz )
Oyster She l l (V itag low)
CHALLENGES
1.
Take the cha l lenge capsu l es i n the morn i ng ha lf an hour before or two hours after a mea l , and note
any effects over the fol lowing two days ( a de layed react i on may beg i n up to 48 hours after tak ing
the cha l lenge capsu le) . On the sheets prov i ded record the time each cha l lenge was taken and, i f a
react i on occurs , record the t ime i t began , type and sever ity of symptoms and how long they lasted .
If the react i on i s severe , contact your d i et i t i an or doctor .
2.
Sane cha l lenges may be labe l led "A" and "B" ( e . g . 3A , 3B) , represent i ng a sma l l dose ( "A" ) and a
l arger dose ( "B" ) of the same ( or s im i lar ) chem i ca 1 s . These shou 1d be taken on the same day , the
sma l l dose ( "An) f i rst . If there i s no react i on w i t h i n two hours , take the second dose ( "B") .
However , i f a not i ceab l e react i on occurs to dose "A" , dose "8" shou ld not be taken .
3.
React i ons t o a cha l lenge usua l ly beg i n w i th in a few hours , but may take u p to 4 8 hours to devel op .
I f a react i on occurs w i th i n two days of tak i ng a cha l lenge , wa i t unt i l the symptoms have
d isappeared comp l etely and then a l low a further three days wi thout symptoms before go ing on to the
next cha l lenge the fo l lowing day , as i l lustrated in the examp le be low
Days
1
Cha 1 1enge
3
Symptoms
++
2
3
4
5
6
7
4A
4B
+
0
0
0
Three fu l l days free
of symptoms before
next cha l lenge .
0
8
5
0
0
I N SOME I NDI V I DUALS :
1.
W i thdrawa l Symptoms may occur dur i ng the f i rst week or two on the e l i m i nat i on d i et . Some or a l l
of your symptans may i nc rease for a short t ime , but these usua l ly d i sappear w i th i n two weeks .
Ca l l your d i et i t i an or doctor i f symptoms pers i st .
2.
� may becane more not iceab l e and can br i ng on symptoms . The commonest prob lems are petro l eum
products ( petro l , gas , o i l , kerosene ) , pa i nts , perfumes , c i garette smoke , pressure-pack products
and strong smel l i ng c lean i ng agents . Try to avo i d these fumes as rrlIch as poss i b l e dur i ng the
e l iminat i on and cha l lenge per i od . Once you i nc lude other foods in your d i et at the end of the
test i ng per i od , sme l l s and fumes shou ld becane less of a prob lem.
FOOD L IST AND MED I CATI ONS
FOODS ALLOWED
FOODS TO AVOI D
Beef , lamb , vea l and pou ltry ( no sk i n or fat )
ch i cken sausages by Summercross Sma l 1goods
Corned beef , ham, bacon , pork , offa l , sausages
f i sh and seafood , we l l browned meat .
Eggs
Co l d pressed saffl ower and sunflower o i l
( NO ANTIOXIDANTS )
Other o i l s and o i ls whi ch conta i n ant i ox i dants .
Butter, Margari ne , cheese and yoghurt .
VEGETABLES
Iceberg l ettuce ( i ns i de leaves on ly)
Old wh i te potatoes ( no sk i n )
Country Styl e p l a i n potato cri sps by L i ps
Pars ley (fresh , spr i nk le through food on ly)
Pears - fresh , very ripe and t h i ck ly pee led
Pears - canned i n syrup D21
nectar or ju ice
A l l other l ettuce
New potatoes , Pont i ac ( red) potatoes
Other comme rc i a l potato c r i sps and ch i ps
A l l other vegetab les
Unr i pe pears , Gou l burn Va l ley and SPC canned pears
in j u i ce or nectar , A l l other fru i t i nc l ud i ng
dr i ed fru i t
CEREALS
Other cerea ls , bread and b i scu i ts
Wh i te r ice , r i ce f l our , r i ce nood l es , r i ce
vermice l l i , tap i oca and sago .
F i el ders cornf l our , Parsons cornflou r , Kream
corn f l ou r . Arrowroot f lour , potato f l our .
Brown r i ce cakes . San-Esu p l a i n r i ce crackers .
R i ce Bub b l es , Ro l led R ice, Hea lther i e R i ce F lakes ,
Cont inued
FOODS alLOWED
FOODS TO AVO I D
Wh ite suga r , brown sugar , Go lden syrup
Honey , raw sugar, art i f i c i a l sweeteners .
CONO I MENTS
Sa l t , c i tr ic ac i d , fresh pars ley ( sp i nk le on ly) ,
Homemade french dress i ng ( co ld pressed o i l and
c i tr i c ac i d to taste)
Herbs and sp i ces
V i negar
COOKI NG AI DS
B i carbonate of soda , Cream of tartar , Bak i ng
Powder ( McKenz ies and R i te-D i et )
Ge lat i ne ( bo i l before use )
Other cook i ng a ids
BEVERAGES
Decaffe i nated i nstant and bean coffee , water ,
soda water , m inera l water , homemade lemonade
(two cups sugar d i sso l ved in one cup of water ,
add c i tr i c ac i d to taste ; di l ute with soda water ,
mi nera l water or tap water ) , home made pear ju i ce
( b lend a can of pears and syrup , then add water
or m i neral water to taste) .
Tea , herba l tea , cerea l coffee , any choco late
f lavoured dri nks , fru i t j u i ces and commerc i a l pear
j u i ce , soft dr i nks and a l coho l
MED I CAT I ONS
Panado 1 , Panadei ne , Code i ne - on ly when necessary A l l med icat i on not . prescr i bed by your doctor e . g .
Asp i r in , D i spr i n , A lka Se ltzer, V incents .
A
l l med i cat ions wh i ch conta i n f lavour i ng or
Ant i h i stami nes
on l y when necessary
co l ou r i ng . Cough lozenges and syrups .
O i l of W i ntergreen e . g . Dencorub , Deep Heat , Tiger
Sav l on ant i sept i c cream
Ba lm, musc l e ba lms etc .
TO ILETRI ES
A m i xture of sa l t and soda , ord i nary sa l t ,
F 10ran HA or Sou l Patt inson ' s unf lavoured
toothpaste and Sensodyne may be used a s
toothpaste s ubst itutes .
Nona l lergen i c or l i ght l y perfumed cosmet i cs ,
to i l etri es and mo i stur i sers can be used w i th
w i th caut i on ( e . g . Sun l i ght . Neutrogena) .
Aeroso l s and pressure pack products shou l d be
avo ided
Toothpaste - avo i d f l avoured toothpaste .
Perfumes and stongl y perfumed cosmet i cs , to i letries
and mo i stur i sers are to be avoi ded e . g . Avon
SAMPLE MENU
BREAKFAST
R i ce Bubb les and t i nned pears and syrup
Bo i led egg
R i ce cake and Go lden Syrup
Decaffe inated coffee
Co ld s l i ced ch icken
Lettuce
R i ce cakes
Fresh pear ( no sk i n )
M i nera 1 water
Gr i l led steak
Bo i led potatoes and saute lettuce
T i nned pears in syrup
BETWEEN MEALS
Decaffei nated coffee , homemade pear ju ice, minera l water ,
R i ce cakes and go lden syrup , fresh pears (NO SKI N ) .
D IET AND CHALLENGE SUMMARY
D i et Coomenced :
A.
1.
Food Cha l lenges
Wheat Cha l lenge - S i x to 24 Arnotts Water Crackers or one to three cups of wh i te pasta throughout
the day for three days . If there i s a react i on to the wheat cha l lenge , stop eat i ng the crackers
or pasta imnediate 1y , , wa it unt i 1 a 1 1 symptoms have gone and a further three days free from
s�ptoms before cont i nu i ng on to the next cha l lenge . .
I f there i s no react i on , inc l ude in the e l iminat i on d i et immed i ately the fo l lowi ng foods :
Any p la in , unpreserved breads , ro l l s muff i ns or crumpets ; homemade pastry ;
Weetb i x , A l l bran , V i ta Br i ts , Bran F lakes , Puffed Wheat , Weet i es , Weetflakes ;
Unco10ured pasta ( spaghett i , macaron i ) ;
A l l wheat f lours (wh i te . wholemea l , self ra i s ing . p l a in ) ;
P la i n homemade or coomerc i a 1 b i scu i ts , sponge , p i ke lets , pancakes , scones etc .
NOTE :
2.
LEAVE 48 HOURS BETWEEN THE WHEAT CHALLENGE AND THE M ILK CHALLENGE .
M i lk cha l lenge
1-3 glasses per day for three days . I f there i s a react i on , stop drink ing the
mi lk immed i ately, wa i t unt i l a l l symptoms have gone and and further three days free from symptoms
before go i ng on to the next cha l l enge .
-
I f there i s no react i on , i nc l ude in the e l imi nat i on d iet the fo l lOWing foods
A l l p l a i n mi l k ( UHT , condensed , powdered and evaporated ) ; a l l cream ; a l l butter .
� . �aps u ll Cha l lenges
Q!t.I
1
2
3
4
5
6
7
8
9
10
11
12
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Rea�t i on
(yes/no)
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APPENDIX
3
URT ICAR IA CHALLENGE BATTERY
l.
Asp i r i n
Sod i um sa l icylate
Sod i um benzoate
40H benzoic ac id
Sodi um metab i su l ph i te
Tartraz i ne
Brewer ' s yeast
Starch
2.
3.
4.
5.
6.
7.
8.
*
*
*
*
*
*
300
300
500
200
500
30
500
700
mg
mg
mg
mg
mg
mg
mg
mg
Cha l lenge capsu les every 2nd day
React ion w i th i n 48 hours
A l low for refractory period after pos i t ive response to cha l lenge .
I f asthmat i c , asp i r i n , metab i su lph i te and tartraz i ne taken under med i ca l superv i s i on .
For chi ldren 0 - 2 years , on ly 1/4 of the dose of the metab i su lph i te cha l lenge are to be taken .
For chi ldren 2 - 7 years , on ly 1/2 of · the dose of the metab i s u l ph i te cha l lenge are to be taken .
APPENDIX 4
SYSTEMIC CHALLENGE BATTERY
lA .
B.
2A .
A.
A.
B.
3.
4.
5.
6.
7.
8.
9.
10.
11.
1 2A .
B.
13 .
14.
*
*
*
*
*
*
*
*
Asp i rin
Asp i r i n
Sod i um benzoate
Sorb i c ac i d
40H benz o i c ac i d
Sod i um metab i su lph i �e
Sod i um n i trate
Sod i um n i t r i te
Buty lated hydroxy to luene
Buty lated hydroxy an isole
Sod i um propi onate
Tartraz i ne
Erythros i ne
B Pheny lethy lami ne HCL
Tyrami ne HCL
Monosod i um g lutamate
Monosod i um g lutamate
Gluten
Lactose
Starch
Starch
Sucrose
Brewers yeast
600
600
500
200
200
500
25
25
50
50
500
30
30
4
140
2.5
2.5
1.5
500
500
500
LO
700
mg
mg
mg
mg
mg
mg
mg
mg
mg
mg
mg
mg
mg
mg
mg
g
g
g
mg
mg
mg
g
mg
Food cha l lenge wi th m i lk and wheat .
Food cha l lenge wi th egg i n eczema pat i ents on ly .
Cha l lenge capsu les every 2nd day
React i on w i th i n 48 hours
A l low for refractory per i od after pos i t i ve response to cha l lenge .
I f asthmat i c , asp i r i n , metab i su lph i te , MSG , tartraz i ne taken under medi ca l superv i s i on and
erythro s i ne not to be taken .
For chi ldren 0 - 2 years , on ly 1/4 of t he dose of asp i r i n , metabi su lph i te and MSG cha l l enges are
to be taken .
For chi ldren 2 - 7 years , on ly 1/2 of the dose of asp i r i n , metab i su lph i te and MSG cha l l enges are
to be taken .
APPENDIX 5
ASTHMA CHALLENGE PROTOCOL
Assessment
Al l pat i ents w i th a h i story of asthma shou ld have the i r bronch i a l react i v ity measured by hi stamine
provocat i on before commenc i ng di etary i nvest i gat i on .
Superv i s i on of cha l l enge tests i s arranged
accord ing to the fol low i ng cri ter i a :
1.
Cha l l enge i n hospital :
* pat i ents with severe bronc h i a l hyper-react iv ity,
* pat i ents with a h i story of asthma provoked by asp i r i n , non stero ida l ant i inflamma tory
drugs (NSAID ' s ) , MSG , metab i su l ph i te or spec i f i c foods ,
* pat i ents with a h i story of laryngea l oedema or anaphylacto id react i ons .
2.
Cha l lenge i n outpat i ents :
* pat ients w i th moderate bronch i a l hyper-react i v i ty .
3.
Cha l lenge under superv i s i on of genera l pract i t i oner :
* pat i ents with mi ld bronc h i a l hyper-react iv ity,
* pat i ents with a past h i story of asthma .
Before tak i ng any cha l lenges , pat i ents shou ld have been on the e l iminat i on d iet for at l east two weeks ,
and shou ld be hav i ng opt imal bronchod i lator therapy accord ing to t he i r c l i n i ca l state .
Mon i tori ng
A base l i ne spi rometry read i ng shou ld be taken before each chal lenge and measurements repeated at 30
mi nute i nterva l s for four hours .
In severe asthmat ics , l ung func t i on shou ld be mon i tored at
appropri ate i nterva l s for 24 hours after each cha l lenge .
Cha l lenges
Cha l lenges shou ld be taken at 48 hour interva l s , ha lf an hour before breakfast .
as s ign i fi cant i f there i s a fa l l of 20% or more in FEV fo l l ow i ng a cha l lenge .
A react i on i s regarded
Treatment of react i ons
Appropri ate resusc i tat ion equ ipment shou ld be ava i lab l e . Asthma provoked by a cha l lenge shou ld be
treated prompt ly w i th appropr iate bronchod i lators . For pat ients with severe asthma , laryngea l oedema
or anaphylacto i d react i ons , an I V cannu la shou ld be in p lace and loaded syr i nges conta i n i ng adrena l i ne
and an ant ih i stami ne , prepared before cha l lenges are taken .
CHALLENGE DOSE SCHEDULE FOR PATI ENTS IN HOSP ITAL AND OUTPATI ENTS
A.
Metab i su lph i te
D i sso lve one capsu le conta i n i ng 500 mg of metabi su l ph i te i n 250 m l ( i . e . 2 mg/ml ) of 0 . 5% c it r i c
ac i d and admi n i ster i n d i v i ded doses as i nd icated be low . Each dose i s d i luted t o a f i na l vo l ume
of 30 m l by add i t i on of c itric ac id .
Dose 1 :
Dose 2 :
Dose 3 :
1 0 mg ; i f no react i on after 30 mi nutes then g ive
20 mg ; if no react i on after a further 30 mi nutes g i ve
50 mg .
B.
Tartraz i ne
G i ven i n a s i ng le dose as a 3 0 mg capsu le .
C.
Monosod i um G l utamate
G iven i n d i v i ded doses as capsu les , each conta i n i ng 0 . 5 g :
1 . 0 g ( 2 capsules ) ; i f no react i on after one hour then g i ve
Dose 1 :
Dose 2 :
1 .0 g
D.
Asp ; r i n
G i ven i n d i v i ded doses removed from 2 capsu les conta i n i ng 3 0 0 mg each (or b y break i ng 300 mg
tab lets ) . Asp i r i n may be taken as the powder or d i sso l ved i n water . Moderate/ severe asthmat i cs ,
and pat i ents w i th l aryngea l oedema o r anaphy lacto i d react i ons sho u l d beg i n w i th 2 5 1119 , but mi ld
asthmat ics can beg i n w i th 75 1119 :
Dose
Dose
Dose
Dose
1:
2:
3:
4:
25 1119 ; if no react i on after one hour then g i ve
50 1119 ; if no react i on after a further hour
7 5 1119 ; i f no reac t i on after a further hour
1 50 mg .
I f there ; s n o react i on to dose 4 after two hours , and the h i story i s susp i c i ous , a further
cha l lenge may be g i ven i f the pat i ent i s under hosp i t a l superv i s i on :
Dose 5 :
300 mg .
CHALLENGE DOSE SCHEDULE FOR PATI E NTS WITH GENERAL PRACTI T I ONER
Dear Doctor ,
Your pat i ent i s undergo ing i nvest i gat i on for food i nto l erance . Th i s i nvo l ves adherence to
str i ct e l imi nat i on d i et fo l lowed by cha l lenges w i th i nd i v i dua l food chem i ca l s .
a
Occas i ona l ly i n pat i ents w i th bronch i a l hyper-reac t i v i ty certa i n cha l lenges can prec i p itate
trans i ent asthma w i t h i n 1 - 2 hours of ingest i on . A l though the r i sk i s remot e , I wou l d be gratefu l if
you cou l d superv i se the fo l low ing four re l evant cha l lenges at your surgery
sa l i cyl ates
MSG
preservat i ves
tartraz i ne
Each cha l lenge s hou ld be taken as fo l lows
- 1/4 of the cha l lenge* every hour , and rema i n at the doctor ' s surgery for 2 hours after the l ast dose
- I f you deve l op a react i on at any stage , do not take any further doses of t hat cha l lenge
- If you deve lop asthma , use your usua l med i cat i ons
*Example :
I f the cha l lenge cons i sts of:
1 capsu l e ( do se B on ly)
2 capsu les ( dose A and B)
4 capsu les ( dose A and B )
10 capsu les ( dose A and B )
take
take
take
take
1/4 capsu l e every hou r .
1 / 2 capsu l e every hour .
1 capsu l e every hou r .
2 1/2 capsu les every hour .
Th i s w i l l requ i re the ava i labi l i ty of means to mon i tor a i rway funct i on and to adm i n i ster
bronchod i lator by aeroso ls and for I . V . as requ i red .
I f you requ i re further informat i on p l ease contact me or Dr . Yan at Roya l Pr i nce A lfred Hosp i ta l .
Yours s i ncere ly,
Robert H . Lob l ay ,
M S B S , PhD . FRACP
A l l ergy C l i n ic - R . P . A . H .
APPE N D I X 6
FOOD CHALL ENGE PROTOCOL
1.
2.
Record i n the d i a ry supp l i ed the fo l low i ng i nfonmat i on
Foods & dr i nk s
Cha l l enges
Symptoms
-
at each mea l and as snack s ;
foods used , quant i t i es . t imes
-
phys i ca l or behav i ou ra l
Other
-
e . g . part i es � out i ng s , i nfect i ons , exposure to strong sme l l s . domest i c
arguments , med i cat i on s , etc .
Cha l l enges may be commenced after a m i n i mum of two weeks on t he e l i m i nat ion d i et and once there
have been at l east f i ve days in a row free of symptoms .
3.
Each chemi ca 1 ; s tested by eat i ng the foods 1 i sted for three consecut i ve days as a "cha l lenge" .
The amounts of food/beverage l i sted for each cha l l enge shou l d be spread over the ent i re day .
React i ons may occur w i t h i n ha l f an hour , but are often de l ayed by severa l hours or even a day or
more .
4.
I f n o symptoms occur dur i ng a cha l lenge o r w i t h i n the fo l low i ng 48 hour s , cont i nue w i th the next
food cha l l enge .
5.
I f t he c ha l l enge provokes a react i on , stop the food cha l lenge , wa i t unt i l symptoms have c l ea red
and then a l l ow a further three days before tak i ng the next cha l lenge .
React i ons w i l l be no worse than prev i ou s l y exper i enced .
6.
I f any response i s doubtfu l , repeat the c ha l lenge two o r three t imes to conf i nm a react i on .
7.
Once the c ha l l enges
are comp l eted contact you r d i et i t i an for
further
i nstruct i on s .
Foods
be l on g i ng to those chem i ca l g roup i ngs whi ch d i d not appear to cause react i ons w i l l be re i ntroduced
i nto the d i et .
If you rema i n we l l over t he next four to s ix week s ,
sma l l amounts of foods
c onta i n i ng the prob l em chemica l s w i l l then be tr i ed , us i ng the sa l i cy late and/or am i ne charts .
FOOD C HALLENGE S
FOOD CHAL LE NGES
FOOD CHEM I CAL
app l es , apr i cots , asparagus , beetroot , caps i cum , carrot ,
SAL I CYLATE
M I N I MUM DOS E PER DAY
6 serves
*
corn , cucumber , herb s , honey , mango , on i on , pepperm i nt ,
pumpk i n , rockme l on , sp i ces , st rawberr i es , sweet potato ,
tea , waterme lon , zucch i n i .
bananas
1 20 grams
120 grams
3 bananas
MSG
soy sauce (m i x i nto fr i ed r i ce or meatba l l s )
4 tab l espoons
PRESERVATI VE S
p l a i n lemonade ( preserved - check labe l )
1 l i t re
N I TRATE
ham , or bacon , or corned beef
4 s l i ce s ( 1 20 gram)
ANT I OX I DANTS
margar i ne ( ant i ox i dant s added - check labe l )
10 teaspoon s ( 50 gram)
preserved bread (ant i -mou l d i n h i b i to r or preservat ive
4 s l i ces
b l ock cheese ( tasty or cheddar )
AM I NES
choc o l ate ( p la i n , mi lk o r dark )
PROP IONATE
added - check labe 1 )
COLOUR I NGS
*
1 serve
•
co loured I cy Pole ( I f no react ion to sa l i cy l ate)
one
g& musk st i cks
8 st i ck s
1 app l e , 2-3 apr i cots , 6-8 asparagus spears , 3-4 s l i ces beetroot , 1/2- 1 caps i c um ,
1 carrot , 1 cob corn , 1/2-1 cucumber , 1 teaspoon o f herbs , 1 t ab lespoon o f honey ,
1 mango , 1 on i on , 1/2 packet of pepperm i nt L i fesavers , 1 cup pumpk i n , 1/4- 1/2
rockme lon , 1 teaspoon sp i ces , 1/2- 1 cup st rawberr i es , 1 cup sweet potato , 1 cup tea ,
1 s l i ce watenme l on , 1 zucc h i n i
APPEN D I X 7
LOW SAL ICYLATE D I ET
D I ET I T IAN :
TELEPHONE :
_______
________
The a i m of t h i s d i et i s to keep the i ntake of sa l i cy lates , to a mi n imum.
SAL I CYLATES occur natura l ly i n many fru i ts and vegetab les , herbs and spi ces , and are frequent ly used i n
art i f i c i a l f lavour i ngs , perfumes , toothpaste and med i cat i ons ( aspi r i n ) .
GU I DEL I NES
1.
2.
3.
Use only foods l i sted as "a l l owed" .
Avo i d foods conta i n i ng fru i t or m i nt f lavours . Check a l l package l abe l s .
Be carefu l w i th med i cat i ons , to i l etr i es , pressure pack sprays and househo ld c lean i ng agents .
1.
I t i s necessary to carefu l ly check every food package or carton for ment i on of fru i t or m i nt
f lavour i ngs .
2.
T he sa l icy l ate content of the d i et may be l i bera l i sed after four to s ix weeks . Fo l low the
gu i de l i nes in the accanpany i ng "Sa l i cylate Chart" for i ntroduc i ng the moderate sa l i cy l ate foods
i nto the d i et .
FOOD L I ST AND MED ICATI ONS
FOODS ALLOWED
FOODS TO AVO I D
BEVERAGES
Decaffe i nated coffee , m i lk , cocoa , m i l o , ma lt
m i nera l wate r , ton i c water , soda water , water
unpreserved lemonade , wh i sky , g i n and vodka
Tea , fru i t ju i ces , commerc i a l soft dr i nks and
cord i a l s , c ider , w i ne , l i queurs and beer
Any p l a i n breads , ro l l s , muff i ns or crumpets
Pastry
Breads wh i c h conta i n dr i ed fru i ts
A l l f l ou rs except corn based f lours ,
p l a i n pasta ( e . g . spaghett i , macaron i )
Cornmea l , po l enta .
Canned baked beans and spaghett i , Gravox
CEREALS
A l l cerea l s except corn , comme rc i a l breakfast
cerea l s wh i c h do not conta i n fru i t or corn
Breakfast cerea l s whi ch conta i n dri ed fru i t or corn
e . g . mues l i , Su ltana Bran , Froot Loops
Cont i n ued
FOODS ALLOWED .
1
1
FOODS TO AVO I D
1
1
1
B I SC U I TS
P l a i n home made and comme rc i a l b i scu i ts ( us i ng
a l lowed i ngred i ents )
Home made o r commerc i a l b i scu i t s wh ich conta i n
fru i t , sp ices o r m i nt
P l a i n home made cakes and sponges ( us i ng a l lowed
i ngred i ent s )
Home made and commerc i a l cakes wh i c h conta i n fru it ,
spi ces o r m i nt
Beef , lamb , vea l , pork , m i nce , pou ltry
rabb it , ham, corned beef and bacon
Meats conta i n ing herbs and s pi ces e . g . sausages ,
sausage m i nce , sausage ro l l s , meat p i es , frankfurts .
devon , sa lami , processed ch i cken , meat paste .
seasoned ch i cken
Fres h , frozen or canned f i sh and seafood
Eggs , custard powder
DA IRY FOODS
Butter , a l l cream, a l l p 1a i n m i lks i nc l ud i ng UHT ,
.
condensed , powdered and evaporated . P l a i n and
van i l la yoghurt , a l l cheese
Ice cream
home made or comme rc i a l van i l la
chocol at e , pawpaw or banana f lavours
-
Butter , dr i pp i ng , margar i ne and o i l s ( saff lower
Fru i t f lavoured m i l ks
F ru i t yoghurt s
Co l oured or f lavoured i ce cream i ceb 10cks and and
ge l ato
A l l other 0 1 1 s , Copha , comme rc i a l sa l ad dreSS i ngs
and sunf lower ) , homemade sa l ad dress i ngs
Pears , Golden De l i c i ous app l es ( 1 per day on ly) ,
Paw Paw, Bananas . Fru i t can be fresh , frozen or
canned in syrup or water . P i ck r i pe fru i t and do
not eat sk i n
A 1 1 other fru i t
Dr i ed fru i t s ( i nc ludi ng pears )
Canned fru i ts i n natura l ju i ce or nectar ( i nc ludi ng
pears )
Cont inued
FOODS ALLOWED
FOODS TO AVOI D
VEGETABLE S
Wh i t e potato ( no sk i n ) , beans ( Frenc h , str i ng ) ,
brusse l sprout s , cabbage , ce l ery , ch i ves , choko ,
lettuc e , l eeks , pars ley , peas , Hung bean sprouts ,
swed e , s ha l l ot s , gar l i c , dri ed l egumes
A l l other vegetab les i nc l ud ing broad beans , Pont i ac
( red) potatoe s , New potato
Home made soups fran a 1 1 owed i ngredi ents
Comme rc i a l stock cube s , soups , grav i es and sauces
DESSER TS
Home made desserts from a l l owed i ngred i ents e . g .
steamed pudd i ngs , van i l la junket , egg custard
Comme rc i a l desserts
LOLL I E S AND CHOCOLATES
Wh i te je l ly bean s , wh i te marshme 1 1 ows ,
p l a i n toffees ( Ca 1 lard & Bowser) , mi lk choco late
dark chaco l ate and carob .
L iquo r i ce , chew i ng gum, c omme rc i a l , m i n t or fru i t
f lavoured l o l l i es and c hoco lates
NUTS AND C H I PS
Cashews ( raw , dry roasted)
p l a i n po tato c r i sp s , hot potato ch i ps
Other nuts
Snack foods and f lavoured potato c r i sps
JAMS . SUGARS AND SWE ETS
Go lden Syrup , ma l t , pear j am ( home-made)
suga r (wh i te , brown , i c i ng and castor)
Honey , a l l other jams , conserves and je l l i es
( i nc l ud ing l emon butter )
CONDI MENTS
Pars l ey , gar l i c , s al t , soy sauce , van i l la
Herbs , sp i ces , m i nt , mu stard, p i ck l es , v i nega r ,
tomato paste , tomato sauce etc . , meat pastes , f i sh
pastes , f lavour i ng syrups , and essences , Bonox ,
Marm i te , Pran i te , Vegemi te
TO I LETER IES
USE :
AVO I D :
Unscented soaps , s hampoos and cond i t i oners where poss i b l e and unf lavoured toothpaste .
Contact w i th perfumes , scented deodorants and cosmet i c s pressure pack sprays , househo l d
c l ean i ng agents , c i garette smoke a n d other strong sme l l s .
MEDI CATI ONS
USE :
Paracetamo l tab lets ( Panado l , Parapa i n , Panadejne) for pai n re l i ef .
E l ev i t RDI adu lt v i tam i n tab lets ( opt i ona l ) .
AVO I D :
A l l asp i r i n conta i n i ng med icat i ons , and co loured , f l avoured o r preserved med i cat i ons . Read
the labe ls carefu l ly . Most syrups and l i qu i d preparat i ons , l ozenges , l axat i ve s and antac i ds
are unsu i tab l e , as are mentho l , euca lytus , O i l of Wi ntergreen , v i tam i n s conta i n i ng
f l avour i ngs , herba l preparat i ons .
BALANC I NG YOUR D IET
Copyr i ght 1982 , Austra l ian
Nutr i t i on Foundat i on
FOOD
Bread and other cerea l foods
SERVES PER DAY
SERV I NG S I ZE
1 s l i ce bread
At least 4 serv es
1 potato
1(2 cup vegetab les
At l east 3 serves of vegetab les and 1 pear
( or an occas i ona l Go l den De l i c i ou s App le)
3/4 c up breakfast cerea l
1/2 cup cooked r i ce
Vegetab l es & Fru i t
1 p i ece fru it
M i lk & Cheese
Heat and Meat Subst i tutes
1 00 m l s m i lk
60g fresh cottage cheese
100 m l s p l a i n yoghurt
At l east 6 serves
1 20g cooked meat
At l east 2 serves
2 eggs
3/4 cup cooked lent i l s
Butter , margar i n e and o i l
1 teaspoon
3 - 5 serv i ngs
1.
Try to vary the foods and rec i pes you use from day to day
a bu i ld up of sa l i cy l ates .
2.
I f you are unab l e to fo l low these , gu i de l i nes because o f add i t i ona l restr ict i ons ( e . g . da iry
products or wheat ) , then the def i c i t must be made up from other food sources . An exper i enced
d i et i t i an can check your tota l energy i ntake � ( k i l ojou l es ) , as wel l as mak i ng you meet your
requ i rements for prote i n . v itam ins . m i nera l s and other essent i a l nutr i ents .
and week to week .
Th i s wi l l he l p avoid
FOOD FACTS - D . Br iggs and M . Wah l qv ist . Pengu i n Books . ( genera l nutr i t i o n ) .
EAT I NG MATTERS - D . Br i ggs and M . Wah l qv i st . Methuen Haynes . ( food add i t i ves ) .
COMMONSENSE COOKERY BOOK - N . S . W . Pub l i c Schoo l Cookery Teachers ' Assoc i at ion . Angus and Robertson .
( p l a i n rec i pes ) .
APP E N D I X 8
LOW SAL I CYLATE/LOW PRESERVAT I VES/LOW ART I F I C IAL COLOUR I N G/LOW BREWER S YEAST D I ET
D I ET I T I AN :
TELEPHONE :
_______
_______
The a im of th i s d i et i s to keep the i ntake of s a l icylates , preservat i ve s , art i f i c i a l co lours and
brewers ' yeast to a mi n imum .
SAL I CYLATES occur natura l ly in many fru i ts and vegetab les , herbs and s p i ces , and are frequent l y used i n
art i f i c i a l f lavour i ngs , perfumes , toothpas te and med i cat i ons ( asp i r i n ) .
BREWERS ' YEAST i s present in Vegem i t e , P rom i te , Marm i te , some w i nes and beers .
PRESERVATI VE S are added to food t o pro l ong s he 1 f 1 i fe . For examp l e , benzoates are used i n fru i t
j u i ces ; sorbate or s u l phur d i ox i de i n dr i ed fru i ts , fru i t sa lads and sausage m i nce ; n i tr i tes i n
processed meat s ; p ropi onate i n yeast products ; and ant i ox i dants i n o i l s and margar i nes .
COLOUR I NGS s uc h as tartraz i n e , erythros i ne and s unset ye l l ow are commo n l y used i n commerc i a l foods .
GU I DE L I NES
1.
2.
3.
U se on 1 y foods 1 1 sted a s "a 1 1 owed" .
Avo i d foods conta i n i ng add i t i ve s or f lavours , except for van i l la . Check a l l package l abe l s .
Be carefu l w i th med i cat i ons , to i letr i es , pressure pack sprays and househo l d c lean i ng agents .
1.
I t i s necessary to carefu l ly check every food package or carton for ment i on of art i f ic ia l
f lavour i ngs , colou rs and preservat i ves . Use the accompany i ng "Food Add i t i ves" l i st to i dent i fy
s pec i f i c add i t i ves and the i r correspond i ng code numbers .
2.
The sa l i cy late content of t he d iet may be l i bera l i sed after four t o s i x weeks .
Fo l low the
g u i de l i ne s i n the accompanyi ng "Sa l i cy l ate C hart " for i ntroduc i ng the moderate sa l i cy l ate foods
i nt o the d i et .
FOOD L I ST AND MED I CAT I ONS
FOODS ALLOWED
FOODS TO AVOI D
BEVERAGES
Decaffei nated coffee , m i l k , cocoa , m i 1 0 , ma l t
m i ne ra l water , ton i c water , soda water , water
un preserved lemonade , wh i sky , g i n and vodka
Tea , fru i t ju i ces , commerc i a l soft dr i nks and
cord i a l s . c ider , w i ne , l i queurs and beer
Any p l a i n breads , ro l l s , muff i ns or crumpets
Homemade pastry
Breads wh ich conta i n dr i ed fru i ts
Co l ou red and preserved pastry
Cont i n ued
FOODS ALLOWED
FOODS TO AVOI D
Al l f l ou rs except corn based f lours ,
unco l oured pasta ( e . g . spaghett i , macaron i )
Cornmea 1 , po lenta .
CEREALS
A l l cerea l s except corn , comme rc i a l breakfast
cerea l s wh ic h do not conta i n fru i t , corn or
co lour i ng
Breakfast cerea l s whi ch conta i n dr i ed fru i t , corn
or co lour i ng e . g . mues l i , S u l tana Bran , Froot Loops
BI SCUITS
P la i n home made and comme rc i a l b i scu i ts ( us i ng
a l lowed i ngred i ents )
Home made or commerc i a l b i scu i ts wh i c h conta i n
fru i t , sp i ces , m i nt and co l ouri ng
P la i n home made cakes and sponges ( us i ng a l lowed
i ngred i ents )
Home made and comme r c i a l cakes wh i c h conta i n fru it ,
spi ces , m i nt and co lour ing
Beef , lamb , vea l , pork , m i nce , pou ltry ( no sk i n )
rabb i t
Meats conta i n i ng preservat i ves , herbs and sp i ces
e . g . sausage mi nce , sausage ro l l s , meat p i es ,
frankfurt s , sausages , devon , sa lam i , processed
chi cken , meat paste , seasoned chi cken
Fres h , frozen or canned f i sh and seafood
Co l oured or preserved f i sh e . g . f i sh f i ngers
Eggs
Custard powder , custard m i x
DAIRY FOODS
Butter , a l l cream, a l l p la i n m i lks i nc l ud i ng
UHT , condensed , powdered and evaporated
P l a i n and van i l la yoghurt
I ce cream
home made or comme rc i a l van i l la
chocol ate, pawpaw or banana f l avours
Cheese
-
Art if i c i a l "cream" i n comme rc i a l cakes
F lavoured mi 1 ks
Other f lavoured and fru i t yogurts
Co l oured or f lavoured i ce cream , i ceb 1ocks , ge l ato
Cheese wh ich conta i ns preservat i ves or co l our i ng e . 9
cheese s l ices and spreads , tubs o f cottage cheese
Cont inued
FOODS ALLOWED
FOODS TO AVO I D
Butter , dr i pp i ng , margar i ne and o i ls ( saff lower
and sunf lower) ( no ant i ox i dants ) , homemade sa lad
dres s i ngs
A l l other o i l s , Copha , comme r c i a l sa l ad dress i ngs
Pears , Go l den De l i c i ous app l es ( 1 per day on ly ) ,
Paw Paw, Bananas . Fru i t can be fresh , frozen or
canned in syrup or water . P i ck r i pe fru i t and do
not eat sk i n
A 1 1 other fru it
Dr i ed fru its ( i nc lud i ng pears )
Canned fru i ts i n natura l j u i ce or nectar ( i nc l ud i ng
pears )
VEGETABLES
Wh ite potato ( no sk i n ) , beans (Frenc h , str i ng ) ,
brusse l sprouts , cabbage , ce lery , ch i ves , choko ,
lettuce , l eeks , pars ley, pea s , Mung bean sprouts .
swede , sha l l ots , gar l i c . Dr i ed legumes e . g . sp l i t
peas , lent i l s , soybeans , c h i ck peas
A l l other vegetab les i nc l ud i ng broad bean s , Pont i ac
( red) potatoes , New potatoes
Home made soups from a 1 1 owed i ngred i ents
Comme rc ia l stock cubes , soups , grav ies and sauces
DESSER TS
Home made desserts from a l lowed i ngred i ents e . g .
Canne rc ia l desserts
LOLL I E S AND CHOCOLATES
Wh i te je l ly bean s , wh i te marshma l lows ,
P l a i n toffees (Ca l lard & Bowser) , carob
P l a i n chocol ate
L iquor i ce , chew i ng gum, commerc ia l , m int or fru i t
f lavoured l o l l i es and choco lates
NUTS AND CHI PS
Cashews ( raw , dry roasted)
Other nut s , snack foods , potato c r i sps and
commerc i a l hot potato c h i ps
Cont i nued
FOODS alLoyED
FOODS TQ AVOI D
JAMS . SUGARS AND SWEETS
Go lden Syrup , ma It , pear jam ( home-made)
Sugar (wh i te , brown , i c i ng and castor)
Honey , a l l other jams , conserves and je l l i es
( inc l ud i ng lemon butter )
COND IMENTS
Pars l ey, gar l i c , sa l t , soy sauce , van i l la
Herbs , sp ices , m i nt , mu stard , p ick l es , v i nega r ,
tomato paste , tomato sauce etc . , meat pastes , f i sh
pastes , f lavour i ng syrups , and essences , Bonox,
Marmi te , Prom i t e , Veg�ite
TO I LETER I E S
USE :
Unscented soaps , shampoos and cond i t i oners where pos s i b le and unf l avoured toothpaste .
AVO I D :
Contact wi th perfumes , scented deodorants and cosmet ics pressure pack sprays , househo l d
c lean i ng agents , c igarette smoke and other strong sme l l s .
MED I CATIONS
USE :
Paracetamo l tab l ets ( Panado 1 , Parapa i n , Panade i ne ) for pa i n re l i ef .
E lev i t R D I adu l t v itam i n tab lets ( opt i ona l ) .
Wh i te med i cat i ons where poss i b l e . Co lour i ng c�n be washed off the surface of tab lets by
rubb i ng gent ly under runn i ng water . Co loured capsu les can be opened and the powdered contents
taken in a spoonfu l of Go l den Syru p .
AVO I D :
A l l asp i r i n conta i n i ng med i cat i ons , and co loured , f lavoured or preserved med i cat i ons . Read
the labe ls carefu l ly . Most syrups and l iqu i d preparat i ons , lozenges , l axat i ves and antac ids
are unsu itab le , as are mentho l , euca lytus , O i l of W i ntergreen , v itam i n s conta i n i ng PABA ,
co lour i ngs or f l avou r i ng s , herba l preparat i ons .
1.
Try to vary the foods and rec i pes you use from day to day
a bu i ld up o f sa l icyl ates .
and week to week .
Th i s w i l l he l p avoi d
2.
I f you are unab l e to fo l low these g u i de l i nes because of add i t i ona l restr ict i on s ( e . g . da i ry
products or wheat ) , then the def i c i t must be made up from other food sources . An experi enced
d iet i t i an can check your tota l energy i ntake ( k i l ojou les ) , as we l l as mak i ng you meet your
requ i rements for prote i n , v itam i n s , m inera l s and other essent i a l nutr i ents .
FOOD FACTS - D . Br i ggs and M . Wah l qv i st . Pengu i n Books . ( genera l nutr i t i on ) .
EATI NG HATTERS - D . Br i ggs and M . Wah l qv i st . Methuen Haynes . ( food add i t i ves ) .
COMMONSENSE COOKERY BOOK - N . S .W . Pub l i c Schoo l Cookery Teachers ' Assoc i at ion . Angus and Robertson .
BALANC I NG YOUR D IET
Copyr ight 1982 , Austra l i an
Nutri t i on Foundat i on
SERVES PER DAY
SERV I NG S I ZE
FOOD
1 s l i ce bread
3/4 cup breakfast cerea l
At least 4 serves
Vegetabl es & Fru i t
1 potato
1/2 cup vegetab les
1 p i ece fru i t
At least 3 serves of vegetab l es and 1 pear
( or an occas i ona l Go lden De l i c i ous Appl e )
M i lk & Cheese
100 m1s mi l k
60g fresh cottage cheese
1 00 m l s p la in yoghurt
At least 6 serves
Meat and Meat Subst i tutes
120g cooked meat
2 eggs
At least 2 serves
Butter , margar ine and o i l
3 - 5 serv i ngs
1 teaspoon
FOOD ADDIT IVES
Addi t i ve code numbers wh ich MAY cause
Benzo i c Ac ids
210 ,
Co lours
1 02 ,
Prop i on i c Ac ids
281 ,
Sorb i c Ac i ds
.
200 ,
Su lphi tes
. .
220 ,
N i trates
.
2 51 ,
N i tr i tes
249 ,
Ant i -oxi dants
. 310 ,
. . . . . . . .
. . . • . .
. .
. . . . . . . . . . . .
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. . . . . . . . . . . . . . . . . .
.
.
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.. . . . . . . . . . . . . .
.
. .
.
.
. .
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.
.
. . . .
. . . . . . . .
. . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
.
adverse react i ons
21 1 , 2 1 2 , 213
107 , 1 1 0 , 122 , 1 23 , 124, 1 27 , 132 , 133 , 142 , 1 51 , 155 , 160b
282 , 283
201 , 202 , 203
221 , 222 , 223 , 224
252
250
3 1 1 , 312 , 320 , 321
Add i t i ve code numbers UNLI KELY to cause adverse
Ant i -cak i ng agents
536 , 551 , 554
B l each i ng agents
925 , 926
Emu l s i f i ers
.
3 22 , 433 , 435 ,
Food ac i ds and sa lts .
260 , 261 , 2 62 ,
332 , 333 , 334 ,
G l utamates ( inc l ud i ng HSG)
620 , 62 1 , 622 ,
M i nera l Sa lts
1 70 , 339 , 340 ,
.
1 00 , 101 , 1 20 ,
Natura l Co lours
Prope l lants
. .
290
Sweeteners
420 , 42 1 , 422
Th i cken i ng agents . . . . . . . . . . . . . . .
Vegetab l e gums
400 , 401 , 402 ,
416 , 440 , 464
V i tam i ns
101 , 160
M i scel laneous . . . . . . . . . . . . . . . . . . . . 1 53 , 353 , 355 ,
631 , 900 , 901 ,
• . . . . . .
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.
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.
. .
react i ons
. . .
. .
. . . . . .
436
263 ,
335 ,
623
341 ,
140 ,
2 70 , 296 , 297 , 300, 3 25 , 326, 327 , 330 , 331 ,
336 , 350 , 351 , 352 , 354 , 380
450 , 500 , 501 , 503 , 504 , 508 , 509 , 529
1 50 , 153 , 160a , 1 61 , 162 , 1 63 , 172
. . . . . . . . . . . .
.
.
.
. .
. . . . . . . .
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.
403 , 404 , 405 , 406 , 407 , 410 , 412 , 413 , 414 , 415 ,
460 , 481 , 482 , 541 , 553 , 558 , 559 , 575 , 578 , 627 ,
903 , 904 , 905 , 920 .
APP E N D I X
9
Copyright © 1988 Anne Swain. For personal use only - may not be distributed. Further reproduction prohibited without
permission. LOW SAL I CYLATE/LOW PRE SERVAT I VES/LOW ART I F I C IAL COLOUR I NG/LOW MSG/ LOW AM I N E/LOW BR EWE R S YEAST D I ET
D I ET I T IAN :
_______
TELE PHON E :
...._
...
_____
The a im of th i s d iet i s to keep the intake of sa l i cylates , ami nes , preservat i ves , art i f i c ia l co l ours ,
monosod i um g lutamate and brewers ' yeast to a min imum .
SAL I CYLATES occur natura l ly in many fru i ts and vegetab les , herbs and sp i ces , and are frequent ly used i n
art i f i c i a l f lavour i ngs , perfumes , toothpaste and med icat i ons (asp i ri n ) .
AM I NES occur natura l ly in such foods as chocolate , cheese , wine, beer, l iver , yeast extracts , dr i ed and
sa lted f i sh, bananas , avocados , broadbeans , tomatoes and fermented products .
MONOSODI UM GLUTAMATE occurs natura l ly i n most sauces , tomato products , mushrooms , strong cheeses , yeast
extracts , meat extracts , stock cubes and w i nes ; it can a lso be added as a flavour enhancer i n most
soups , sauces , Chi nese food and snack foods .
BREWERS ' YEAST i s present in Vegemite, Promite , Marmi te, some w i nes and beers .
PRESERVATIVES are added to food to pro l ong she lf l ife . For examp l e , benzoates are used in fru i t
ju ices ; sorbate or sulphur d iox i de i n dr i ed fru i ts , fru i t sa lads and sausage mince ; n i tr i tes i n
processed meats ; propi onate i n yeast products ; and ant i ox i dants i n o i l s and margar ines .
COLOUR I NGS such as tartraz i ne , erythros i ne and sunset ye l low are commo n l y used in commerc i a l foods .
GU I DEL I NES
1.
2.
3.
Use on ly foods l i sted as "a l lowed" .
Avo i d foods conta i n i ng add i t i ves or f lavours , except ,for van i l la . Check a l l package labe l s .
B e carefu l w i th med i cat i ons , to i let r i es , pressure pack sprays and househo ld c lean i ng agents .
1.
I t i s necessary to carefu l ly check every food package or carton for ment i on of art i f i c ia 1
f lavour i ngs , MSG , hydrolysed vegetable prote i n , co lours and preservat ives . Use the accompany ing
"Food Add i t i ves" l i st to ident i fy spec i f i c add i t i ves and the i r correspond i ng code numbers .
2.
The sa l i cy late content of the d iet may be l i bera l i sed after four to s ix weeks . Fol l ow the
gu i de li nes i n the accompanyi ng "Sa 1 i cy late Chart" for i ntroduc ing the moderate sa l i cylate foods
i nto the d i et .
3.
S im i l ar ly , after estab l i s h i ng your sal icylate thresho ld , the "Am i ne Chart" can be used to
l i bera l i se the am i ne content of the d iet .
4.
Try to vary the foods and rec ipes you use from day to day and week t o week .
a bu i ld up of sa l icyl ates .
5.
I f you are unabl e to fo l low these gu i de l i nes because o f add i t i ona l restr i ct i ons (e . g . da i ry
products or wheat ) . then the def i c i t must be made up fran other food source s . An experi enced
d i et i t i an can check your tota l energy i ntake (k i l ojou les) , as wel l as mak i ng you meet your
requ i rements for prote i n , v i tam i ns , minera l s and other essent i a l nutr i ents .
Thi s w i l l he lp avo i d
FOOD FACTS - D . Br i ggs and M . Wahlqv i st . Pengu i n Books . ( genera l nutr i t i on ) .
EATI NG MATTERS - D . Br i ggs and M . Wah l qv i st . Methuen Haynes . (food add i t i ves ) .
COMMONSENSE COOKERY BOOK - N . S .W . Pub l ic Schoo l Cookery Teachers ' Assoc i at ion . Angus and Robertson .
FOOD L I ST AND MEDICAT IONS
FOODS ALLOWED
FOODS T O AVO I D
BEVERAGES
Decaffei nated coffee . m i lk . ma lt , m i nera l water
ton i c water , soda water , water . unpreserved
lemonade . wh i sky , g i n and vodka
Tea , fru i t ju ices , commerc i a l soft dr i nks and
cord i a l s , c i der , w i ne , l i queurs , beer , cocoa
Any p l a i n breads , ro l l s . muff i ns or crumpets
Homemade pastry
Breads wh i c h conta i n dr i ed fru i ts
Co l oured and preserved pastry
Al l f l ours except corn based f lours ,
unco loured pasta ( e . g . spaghett i , macaron i )
Cornmea 1 , po 1 enta .
CEREALS
Al l cerea l s except corn , comme rc i a l breakfast
cerea l s wh i ch do not conta i n fru i t , corn , cocoa
or co l ouri ng
Breakfast cerea l s wh i ch conta i n dri ed fru i t , corn ,
cocoa or co lour i ng e . g . mues l i , S u l tana Bran , Froot
Loops , Coco Pops
B I SCUITS
P l a i n home made and commerc i a l b i scu its ( us i ng
a l lowed i ngred i ent s )
Home made or comme rc i a l b i scu i t s wh ich conta i n
fru i t , sp i ces , mi nt , co lour i ng , cocoa , MSG or
savoury f lavour i ng
P l a i n home made cakes and sponges ( us i ng a l lowed
i ngred i ent s )
Home made and commerc i a l cakes wh i c h conta i n fru i t ,
s p i ces , m i nt , c oc oa and c o l ou r i ng
Beef . l amb , vea l , rabb i t . pou l try ( no sk i n )
Pork and meats conta i n i ng preservat i ves , herbs and
sp i ces e . g . sausage m i nce , sausage ro l l s , meat p i es ,
frankfurt s , sausages , devon , sa lami , processed
c h i cken , meat paste , seasoned c h i cken
F I SH
Fresh f i sh and seafood
Frozen , canned , col oured or preserved f i sh
Cont inued
FOODS ALLOWED
FOODS TO AVO I D
Eggs
Custard powder, custard m i x
DAIRY FOODS
Butter , a l l cream, a l l p la i n m i lks i nc ludi ng
UHT , condensed , powdered and evaporated
P la i n and van i l la yoghurt
Ice cream home made or comme rc i a l van i l la
Fresh cottage cheese , cream cheese and r icotta
Art if i c i a l "cream" in comme rc i a l cakes
F lavoured mi lks
Other f lavoured and fru i t yogurts
Co loured or f lavoured i ce cream , i ceb locks , ge lato
A l l other cheeses
Butter , dr i pp i ng , margarine and o i l s ( saff lower
and sunf lower) (no ant i ox idants ) , homemade sa lad
dres s i ngs
A l l other o i l s , Copha , commerc i a l sa lad dress ings
Pears , Go lden De l i c i ous app les ( 1 per day on ly) ,
Fru i t can be fresh , frozen or canned i n syrup or
water . P ick r i pe fru i t and do not eat sk i n
A 1 1 other fru i t
Dr i ed fru its ( i nc ludi ng pears )
'
Canned fru i ts in natura l ju i ce or nectar ( i nc luding
pears )
-
VEGETABLES
Wh i te potato ( no sk i n) , beans ( French, str ing) ,
A l l other vegetab l es i nc l ud i ng broad beans , Pont i ac
brus se l sprout s , cabbage , ce lery , ch i ves , choko ,
( red) potatoes , New potato
lettuce, l eeks , pars ley, peas , Hung bean sprouts ,
swede , sha l l ot s , gar l i c . Dri ed l egumes e . g . sp l i t
peas , l ent i l s , soybeans , c h i ck peas
Home made soups from a l l owed i ngred i ents
Comme rc i a l stock cubes , soups , grav i es and sauces
DESSERTS
Home made desserts from a l lowed ingred ients -e . g .
Comme rc i a l desserts
LOLL I ES AND CHOCOLATES
Wh i te je l ly beans , wh i te marshme l lows ,
p l a i n toffees (Ca l lard & Bowser) , carob
L i quor i ce , chew i ng gum, comme rc i a l , m i nt or fru i t
f lavoured lol l i es and choco lates
Cont inued
FOODS AlL O'dED
.
FOODS TO AVOI P
NUTS AND CHI PS
Cashews ( raw)
Other nuts , snack foods , potato c r i sps and
comme rc i a l hot potato c h i ps
JAMS . SUGARS AND SWEETS
Go 1 den Syrup , rna It , pear j am ( home-made )
Sugar ( wh i te , brown , i c i ng and castor)
Honey , a l l other jams , conserves and je l l i �s
( i nc l ud i ng lemon butter )
CONDIMENTS
Pars ley , gar l i c , sa l t , van i l la
Herbs , sp i ces , m i nt , mustard , p i ck l es , v i negar,
tomato paste , tomato sauce etc . , meat pastes , f ish
pastes , f lavour ing syrups , and essences , Bonox ,
Marm i te , Prom it e , Vegem i t e
TO I L ET EB I ES
USE :
Un scented soaps , s hampoos and cond i t ioners where poss i b l e and unf l avoured toothpaste .
AVO I D :
Contact w i th perfumes , scented deodorants and cosmet i c s pressure pack sprays , househo l d
c lean i ng agents , c igarette smoke and other strong sme l l s .
MEDI CATIONS
USE :
Paracetamo l tab lets ( Panado l , Parapa i n , Panade i ne ) for pa i n re l i ef .
E lev i t B D I adu lt v i tam i n tab lets ( opt i ona l ) .
Wh i te med icat ions where poss i b l e . Co lour i ng can be washed off the surface of tab lets by
rubb i ng gent ly under runn i ng water . Co loured capsu les can be opened and the powdered contents
taken i n a spoonfu l of Go l den Syrup .
AVOI D :
Al l asp i r i n conta i n i ng med i cat i ons , and co loured , f lavoured or preserved med i cat i ons . Read
the labe l s carefu l ly . Most syrups and l iqu i d preparat i ons , l ozenges , laxat i ves and antac ids
are unsu i tab le , as are mentho l , euca lytus , O i l of W i ntergreen , v i t am i ns conta i n i ng PABA,
co lour i ngs or f l avou r i ngs , herba l preparat i ons .
BALANC I NG YOUR D I ET
Copyr i ght 1982 , Austra l i an
Nutr i t i on Foundat ion
SERV I NG S I ZE
FOOD
SERVES PER DAY
1 s l i ce bread
3/4 cup breakfast cerea l
At least 4 serves
Vegetab l es & Fru i t
1 potato
1/2 cup vegetab les
1 p i ece fru i t
At least 3 serves of vegetab l es and 1 pear
( or an occas i ona l Gol den De l i c i ous App le)
M i l k & Cheese
1 00 m l s m i l k
60g fresh cottage c heese
1 00 m l s p la i n yoghurt
At l east 6 serves
Meat and Meat Subst i tutes
1 20g cooked meat
2 eggs
At l east 2 serves
1 teaspoon
Butter , margar i ne and o i l
3 - 5 serv i ngs
FOOD ADD ITIVES
Add i t i ve code numbers wh ich MAY cause
Benzoi c Ac ids . .
..
.
210 ,
Co lours
. .
. . 1 02 ,
Prop i on i c Ac ids
.
. . . 281 ,
Sorb i c Ac i ds
.
200 ,
Su lphi tes . . . .
. .
220 ,
N i t rates
.
. . . . 251 ,
N i tr i tes
. ..
.
249 ,
Ant i -ox i dants
.
. .
. 310,
G l utamates ( i nc l ud i ng M5G)
620 ,
.
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adverse react i on s :
21 1 , 212 , 213
107 , 1 1 0 , 122 , 1 23 , 124 , 1 27 , 132 , 133 , 142 , 151 , 155 , 1 60b
282 , 283
201 , 202 , 203
221 , 222 . 223 , 224
252
250
31 1 . 3 1 2 , 320 , 321
621 , 622 , 623
Add i t i ve code numbers UNLI KELY to cause adverse react i on s
Ant i -cak i ng agents
.
536 , 551 , 554
B l each i ng agents
. 925 , 926
Emu l s i f i ers . .
. .. .
322 , 433 , 435 , 436
Food ac i ds and sa lts . . . .
. 2 60 , 261 , 262 , 263 , 270 , 296 , 297 , 300 , 325 , 326 , 327 , 330 , 331 ,
332 , 333 , 334 , 335 , 336 , 350 , 351 , 352 , 3 54 , 380
M i nera l Sa lts
. . .
.
. 1 70 , 339 , 340 , 34 1 , 450 , 500 , 501 , 503 , 504 , 508 , 509 , 529
Natura l Co lours . .
. .
1 00 , 101 , 120 , 140 , 1 50 , 1 53 , 1 60a , 1 61 , 162 , 1 63 , 172
Prope l lants
.
. . 290
Sweeteners
.
.
.
420 , 421 , 422
Th ic ken i ng agents . . . . . . . . . . . . . . . . -Vegetab l e glll1s .
. . . 400 , 401 , 402 , 403 , 404 , 405 , 406 , 407 , 410 , 4 12 , 413 , 414 , 415 ,
4 1 6 , 440 , 464
V i tamins
101 , 160
M i scel l aneous . .
.
1 53 , 353 , 3 55 , 460 , 481 , 482 , 541 , 553 , 558 , 559 , 575 , 578 , 627 ,
631 , 900 , 901 , 903 , 9 04 , 905 , 920
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APPENDIX
10
GU I DEL I NES FOR THE USE OF THE SAL I CYLATE CHART
SAL ICYLATE CONTENT
AMOUNT USUAL LY TOLERATED
any amount
any amount
1 serve/day
serve/day
none
NEGL I G I BLE
LOW
MODERATE
H IGH
VERY HIGH
*
ONE SERVE :
_
One i tem (app l e . orange , etc . )
One s l i ce (waterme l on , rockme lon , p i neapp le , etc . )
One cupfu l ( 1 50g) ( su l tanas , berr i es , grapes , etc . )
Equ iva l ent of one cupfu l ( 150g)
One ha l f cupfu l ( 80g )
One tab lespoon
One teaspoon
One g lass or cup ( 1 5Oml )
Fru i ts :
Vegetab les :
Nuts :
Sweets :
Herbs/spi ces :
Dr i nks :
*
THE FOLLOWI NG AMOUNTS ARE APPROXI MATELY EQU IVAL ENT :
1 serve fram the MODERATE group
serve fram the HIGH group
serve or less fram the VERY HIGH group
_
*
_
AS A GENERAL RULE :
Those foods w it h the strongest f l avour (tart , ac i d , sp i cy) and aroma have the h i ghest content of
sa 1 icylates .
ESTABL I SH I NG YOUR T HRESHOLD LEVEL
If you have just started your low sa l i cylate d iet you shou ld not eat any foods from the moderate co l umn
for 4 - 6 weeks fram commencement of the d iet . After th i s per iod a gradua l introduct i on of these foods
can be a l lowed . You can have a 1/4 serve of any of the moderate foods every th ird day for a per i od of
two weeks . I f there i s no adverse react i on you then have a 1/4 serve every second day for a further
per i od of two weeks . Aga in i f there i s no adverse react i on you can have a 1/4 serve every day for
another two weeks gradua l ly bu i ld i ng up to a 1/2 serve per day for two weeks and then one fu l l serve
per day for a further two weeks . After ten weeks of t h i s gradua l introduct i on you can try 1 - 3 serves
per day prov i ded t here i s no adverse react ion .
F i rst two weeks - 1/4 serve every !hi!9 day
i .e .
Second two weeks - 1/4 serve every second day
Th i rd two weeks - 1/4 serve every day
Fourth two weeks - 1/2 serve every day
1 serve every day
F i ft h two weeks US ING THE SAL I CYLATE CHART
1.
2.
3.
Foods from the NEGL I G I BLE and LOW col umns can usua l ly be comb i ned free ly, w it h one another and
w i t h foods fram the MODERATE or H IGH co lumn , as d ictated by your threshol d .
Foods from the MODERATE col umn may be camb i ned w i th foods from the HIGH col umn , prov i ded you do
not exceed your da i ly threshold leve l .
Foods from the VERY H I GH co l umn shou l d on ly be taken very rarely and i n sma l l amounts , accord i ng
to your t hresho l d .
NOTE 1 :
THE EFFECTS OF SALI CYLATES HAY BE CUMULAT IVE , AND YOU MAY BEG I N TO REACT ADVERSELY ONLY AFTER
SEVERAL DAYS OF EXCEED I NG YOUR THRESHOLD .
NOTE 2 :
FOR THOSE WHO ARE ALSO SENS ITIVE TO AMI NES AND M . S . G.
Foods l i sted in CAP I TALS conta i n SMALL amounts of AMI NE S
Foods l i sted i n CAPITALS conta i n LARGE amounts o f AMI NES
Foods marked w i th * conta i n natura l M . S . G .
FOOD SAL I CYLATE CONTENT
Neg l ig ib le
.EB.Y.!I
BANANA
pear
(pee led)
Low
Moderate
H i gh
Very H i gh
go lden de l i c i ous
app le ( pee led )
PAWPAW
panegranate
custard app l e
AVOCADO
grapefru i t
granny sm i th
app le
jonathan
app le
KIWI FRUIT
lyc hee
mandar i n
mu l berry
nectar i ne
PAS S I ON FRUIT
peach
tange lo
watenne lon
apr i cot
b l ackberry
b l ackcurrant
b l ueberry
boysenberry
cherry
cranberry
currant
DATE
GRAPE*
guava
l oganberry
ORANGE
P I NEAPPLE
ill
llr:1Q!1
loquat
mango
pear (wi th pee l )
pers imnon
red de l i c i ous
appl e
rhurbarb
tamari 1 10
e!J!1
PR UNE*
ra i s i n
RASPBERRY
redcurrant
rockme lon
st rawberry
su l tana
youngberry
VE§ETABLES
bamboo shoot
cabbage
ce lery
lettuce
potato ( pee led )
swede
dr i ed beans
dr i ed peas
brown lent 1 1 s
red lent 1 1 S
NUTS
poppyseed
bru sse l sprout
chive
choko
green beans
green peas
l eek
mungbean spout
red cabbage
sha l l ot
CASHEWS
asparagus
beetroot
BROCCOLI *
carrot
cau l i f l ower
marrow
MUSHROOM*
on i on
parsn i p
pumpk i n
SP INACH
sweetcorn*
sweet potato
turn i p
BRAZ IL
COCONUT
HAZELNUTS
MACADAM lA
PEANUTS
PECANS
P I NENUTS
P I STACHIO
SESAME SEEDS
SUNFLOWER SEEDS
WALNUTS
a lfa l fa sprout
broadbean
cuc l.I11b er
EGGPLANT
watercress
caps icLm
champi gnon
ch icory
end i ve
GHERKI N
hot pepper
�
rad i sh
IQ!1A!Q
PRODUCTS*
zucc h i n i
ALMOND
waterchestnut
Cont inued
Neg l i g i b le
Low
Moderate
H igh
Very H i gh
a l l sp ice
bay l eaf
cardamon
carraway
c i nnamon
c loves
g i nger
nutmeg
pepper ( b lack )
pepper (wh i te )
p imiento
WHITE VINEGAR
an i seed
cane 1 1 a
cayenne
cumi n
curry
di 1 1
f i ve sp i ce
garam masa la
mace
MARM ITE*
m i nt
mi xed herbs
mustard
oregano
papr ika
rosemary
sage
tarragon
tunner ic
VEGEMITE*
WORSTER SAUCE*
HERBS and SP IC,S
gar l i c
ma l t v i negar
pars l ey
saffron
SOY SAUCE*
TANDORI
van i 1 1a
SWE,TS
carob
COCOA
mapl e syrup
wh i te sugar
carame l s
gol den syrup
mo lasses
honey
l i cori ce
peppermi nts
COFFE,
Harr i s instant
Bushe l l s i nstant
Robert Tinms
i nstant
92.EEli
ill
ill
ill
CEREAL COFFEE
dande l i on
Ecco
Bambu
CEREAL COFFEE
Reform
BEVERAGES
�
Andron i cus
Pab lo i nstant
decaffe i nated
�
Aktav ite
M i lo
Ova lt i ne
ALCOHOL
gin
vodka
wh i sky
camani l le
roseh i p
Harr i s Mocha
Internat iona l
Roast instant
Meccona instant
Nescafe i nstant
decaffe i nated
fru i t
OTHER
coke
fru i t ju ice
roseh i p syrup
ALCOHOL
BEER
BRANDY*
c i der
�*
a l l brands
peppermi nt
CEREAL COFFEE
Nature ' s cuppa
ALCOHO L
l i queur*
port*
RUH*
WI N,*
APPENDIX
11
GUI DELI NES FOR THE USE OF THE AMI NE C HART
*
AVERAGE AMOUNT TOLERATE D
AM I NE CONTENT
any amount
5 serves/day
1 serve/day
1/10 serve/day
none
NEGL I G I BLE
LOW
MODERATE
HIGH
VERY H IGH
*
Amounts equ i va l ent to one serve :
Fru i t s
Vegetab les
t!Y1!
Meats & f i sh
Cheese
Choco late
Sweets
Herbs/spi ces & other cond iments
Dr i nk s
One i tem (app le , orange , etc . )
One s l i ce ( rockme lon , p ineapp le , etc . )
One cupfu l ( 1 50g) ( berr ies , grapes , etc . )
Equ i va l ent of one cupfu l ( 1 50g)
One ha l f cupfu l ( 80g)
100 grams ( NOTE : ami ne leve ls i ncrease wi th age ing)
60 grams ( 2 average s l i ces)
30 grams ( 3 squares )
One tab lespoon
One teaspoon
One g lass or cup ( 1 5Oml )
AMI NE CONTENT OF FOOD
Negl i g i b l e
FRU I TS
APPLE
APR I COT
BLUE BERRY
GOOSEBERRY
L I ME
PEACH
pear
RHUBARB
STRAWBERRY
VEGETABLES
ASPARAGUS
cabbage
CAPS ICUM
CARROT
ce lery
CORN *
CUCUMBER
french bean
green pea
lettuce
l ima bean
ON ION
potato
RADI SH
soy bean
TURN I P
ZUCCHI N I
Low
Moderate
H i gh
BLACKCURRANT
CHERRY
GRAPEFRUIT
HONEY DEW MELON
MANDARI N
REDCURRANT
ROCKMELON
DATES
KIWI FRU IT
ORANGE
PASS IONFRUIT
pawpaw
TANGER I NE
AVOCADO
banana
F IG
GRAPES *
LEMON
P INEAPPLE
PLUM
RASPBERRY
BROCCOLI *
CAUL I FLOWER
DI LL P ICKLE
OL I VES
EGGPLANT
MUSHROOM *
TOMATO *
Very H i gh
sauerkraut
SP I NACH
Cont inued
Neg l i g i b le
NUTS
ACORN
AMER ICAN CHESTNUT
BUCKEYE NUT
HORSE CHESTNUT
SUNFLOWER
P I NENUT
P I STACHIO
Low
Moderate
H i gh
Very H i gh
ALMOND
BEECHNUT
cashew
COCONUT
MACADAM lA
BRAZ I L NUT
FI LBERT
ENGL I SH WALNUT
MACKERNUT
PECAN
SWEET P IGNUT
BLACK WALNUT
BUTTERNUT
ch icken l i ver
ham
sa lami
sa lmon ( canned )
tuna ( fresh)
bacon
mackere l ( canned)
pork
sardi nes ( canned )
beef 1 i ver
cap l i n ( sa l ted )
ch icken sk i n
f i sh mar i nades
f i sh meat
herr i ng (dr i ed )
herr i ng (p ick led)
herr ing roe
herr i ng ( sa l ted)
herr i ng ( srooked)
mackere l ( dr i ed)
sard i nes ( dr ied)
sausage
tuna ( canned )
MEAT S . CHICKEN AND FISH
beef
chi cken
l amb
CHEESE
cottage cheese
br i e*
camembert *
chesh i re
chedda r cheese
cracker barrel
dan i sh b l ue
dutch g loucester
edam
emnent a l
eng 1 1 sh cheshire
gouda *
gruyere *
jaa l sberg
l e icester
l i ederkratz
l imberger
mozare l la
munster
pannesan *
processed cheese
provol one
roquefort *
romano
st 1 1 ton
sw i ss
wens l eyda l e
Cont i nued
Neg l i g i b le
L ow
Moderate
H i gh
Very H i gh
m i l k choc o l ate
wh i te choco late
dark c hoco late
BONOX *
MEAT EXTRACTS *
soy sauce *
VEGEM ITE *
MARMITE *
SWEETS
COND IMENTS
BEVERAG, S
ALE
CHAMPAGNE
SAKE
STOUT
BEER
CHIANTI
CLARET *
dr i nk ing choco l ate
FRU IT W INES
PORT *
RED WINE *
SHERRY *
WHI TE WINE *
AMI NE REFERENCES
A l len , J . G . and Ha l l , K . J . ( 1980 ) .
B l ackwe l l , B . and Mabb i tt , L . A . ( 1965 ) .
B lackwe l l , 8 . , Mar ley, E . , P r i ce , J. and Taylor , D. ( 1 967) .
B l ackwe l l , 8 . , Mabb i tt , L . A . and Mar l ey , E . ( 1969 ) .
8 l ock , R . J . ( 1951 ) .
Bonnet , G . F . and Nepheux . ( 197 1 ) .
Bou l ton , A . A . , Cookson , 8 . and Pau l ton R . ( 1970 ) .
Chambers , T . L . and Starus k i ew i cz , W . F . ( 1978 ) .
Chaytor , J . P . , Crathorne B . and Saxeby , M . J . ( 1975) .
Coff i n , D . E . ( 1969) .
Coff i n , D . E . ( 1970) .
Co le , 0 . 0 . , Harper , W . J . and Hank i n son , C . L . ( 19 61 ) .
Dahl berg , A . C . and Kos i kowsky , F . V . ( 1948) .
Da i s l ey , R . W . and Gudka , H . V . ( 1980 ) .
Feldman , J . M . ( 1983 ) .
Fe ldman , J .M . and Lee , E . M . ( 1985) .
Foo , L . Y . ( 19 67 ) .
Foy, J . M . and Parratt , J . R . ( 1 960) .
Foy, J . M . and Parratt , J . R . ( 1961 ) .
Gent le , J . ( 197 1 ) .
Gonza l o , J . C . R . , Moreno , C . G . , Cerro A . G . and Font , A . M . ( 1979 ) .
Han i ngton , E . ( 1980 ) .
Hedberg , D . L . , Gorden , M .W . and G lueck , B . C . ( 1966 ) .
Horwitz , D . , Lovenberg , Enge lman , K . and Sjoerdsma , A . ( 1964 ) .
Hughes , R . 8 . ( 1 958) . 1
Hurs t , W . J . , Mart i n , R .A . , Zoumas , B . L . and Tarka , S . M . ( 1982 ) .
Kos i kowsky , F . V . and Dah l berg , A . C . ( 1948 ) .
Kuhn , D . M . and Lovenberg , W . ( 1982 ) .
Lovenberg , W . ( 19 73 ) .
Luthy , J . and Sch latter , C . ( 1983 ) .
AM I NE R EFER E NCES
Maga , J . A .
( 1978) .
Ma r l ey , f .
and B l ackwe l 1 , B .
( 19 70 ) .
Moruzz i , G . and Ca l darera , C . M .
( 1 964 ) .
Ough , C . S . ( 197 1 ) .
Overton , M and Lukert , B .
( 1977 ) .
Pechanek , U . , Pfannhayser , W.
P i erpao l i . P . G .
and Wo i d i ch , H.
( 19 72 ) .
Sape ika , N . , Mood i e , I . M .
and Kap lan . f . R .
Saxby , M . J . , Chaytor , J . P .
and Re i d , R . G .
Schwe i tzer . J . W . , Fr i edhoff , A . J .
S l emr , J .
and Beyermann , K .
Sm i th, T . A .
( 19 75 ) .
( 1980- 1981 ) .
( 1981 ) .
and Schwartz , R .
( 1 985) .
( 1980-1 98 1 ) .
Sp i ne l l i , A . M . , Lakr 1 tz , L .
and Wassenman , A . E .
and Koury, B . J .
Sp i ne l l 1 , J .
Stewart , I .
( 1983 ) .
and Wheaton , T . A .
( 1974 ) .
( 1981 ) .
( 1964 ) .
Stock l ey , I . H .
( 1973 ) .
Strong , F . M .
( 1966) .
Trethewi e , f . R .
( 19 79 ) .
Waa lkes ,
T.P. ,
S joerdsma , A . , Creve l i ng , C . R . , We i ssbach ,
H.
and Udenfr i end , S . , Lovenberg ,
W.
and
Sjoerdsma , A . ( 1959 ) .
Wheaton , T . A .
and Stewa rt , I .
Wheaton , T . A .
and Stewart , I .
( 1965 ) .
( 1 969 ) .
Yamamoto , S . , I tano , H . , Kataoka , H .
Yamamoto , S . , Wakabayash i , S .
and Mak i ta , M .
and Mak i ta , M .
( 1 982 ) .
( 1980 ) .
d
A P P EN D I X 1 2
MSG I DE NT I F I ED I N FOODS
Fru i ts
Meat s/ F i sh
Beverages
Vegetab l es
Da i ry
grape
beef
brandy
brocco l i
butterm i l k
grapefru i t
codf i sh
gin
beetroot
camembert
nectar i ne
c h i cken
port
carrot
cow mi lk
orange
duck
wh i skey
corn
dan i sh b l ue
peach
egg
w i ne
mushroan
gruyere
p l t.m
lamb
on i on
human m i lk
prune
mackere l
peas
parmesan
st rawberry
pork
potato
roquefort
sa lmon
sp i nach
tomato
FRE E GLUTAMATE REFERENCES
1.
2.
3.
4.
5.
6.
Bessman , S . P .
and Hoc hste i n , P.
( 1970) .
F i l e r , L . J . , Garantt i n i , 5 . , Kan e , M . R . , Reyno lds , W . A . and Wurtman , R . J .
Garatt i n i , S .
( 19 79 ) .
I n st i tute of Food Techno log i st s
Jayaram, R .
Stewart , P .
( 1980 ) .
( 1984 ) .
( 1 980 ) .
( 1979 ) .
APP E N D I X 1 3
FOL L OW-UP QUEST I ON NA I R E F O R R I U/ AO PAT I E NT S
W H O COMPL ETED T H E P R OTOCOL
yes
Have you had any recurrences of your symptoms?
D
no
o
How l on g have you been symptom free?
Have you re laxed your d i et?
If so , wh i c h foods and how much?
IF YES :
How often?
How severe were these ep i sodes?
What med i cat i on d i d you take?
yes
Have they been re l ated to food?
D
Were they acc i denta l ?
Wh i ch foods were i nvo lved?
How much was eaten?
Have you not i ced a comb i ned effect w i th severa l foods?
Have you ever gone back to the e l i m i nat i on d i et for re l i ef?
APP END I X 1 4
FOLLOW-UP QUEST I ON N A I R E F O R R I U/AO PAT I ENTS WHO D I D NOT COMPLETE
THE EL I M I NAT I O N D I ET A N D C HA L L E N GE PROTOCOL
D i d you start the e l i m i nat i on d i et ?
I f so , d i d i t he l p your symptoms?
D i d you rema i n on a mod i f i ed d i et or return to your norma l d i et ?
I f mod i f i ed , what changes d i d you make to your d i et?
D i d you seek he l p or treatment e l sewhere?
If so where?
What treatment d i d you have and what was the outcome?
Are you st i l l gett i ng recurrences of symptoms?
If so , how do you contro l t hem?
no
o
APP E N D I X 1 5
FOL LOW-UP QUEST I O N N A I R E F O R PAT I E NTS WHO COMP L E T E D T H E PR OTOCOL
At t he beg i n n i ng of your e l i m i nat i on d i et ( before you started the cha l l enges ) :
D i d you have a w i t hdrawa l react i on?
yes
no
D i d you become more sens i t i ve to sme l l s?
yes
no
How much d i d you r symptoms improve?
A l l symptoms
d i sappeared
D
D
Muc h
better
0
A l i tt l e
better
No better
at a l l
D
S i nce f i n i sh i ng your c ha l l enges , are you?
0
Comp l ete ly
we l l
D
Much
better
D
A l i tt l e
better
No better
at a l l
D
Worse
D
I f you have had recurrences of symptoms , p lease l i st :
Symptoms ( de sc r i be )
How often?
How severe?
Comments
Are your recurrences t r i ggered by :
Foods
o
P l ease l i s t :
Food/sme l l /other
Sme l l s
D
Other
D
Don ' t know
o
Symptoms t r i ggered
Have you been ab l e to re- i nt roduce any foods you were prev i ous ly unab l e to eat ?
Food
Amount t o l erated per day
Food
Amount to l erated per day
A P P EN D I X 1 6
FOLLOW-UP QUEST I ON NA I R E FOR PAT I E NTS WHO D I D N O T COM P L ET E THE
EL I M I NAT I O N D I ET AND CHA L L E N GE PROTOCOL
What were your reasons for not comp l et i n g the e l i m i nat ion d i et and c ha l l enge programme ?
No improvement on e l i m i nat ion d i et
D i et too str i c t or d i ff i cu l t
D i d not want to take c ha l l enges
Other ( state )
What d i et are you current ly fo l l ow i ng?
An unrestr i cted ( norma l ) d i et
A rest r i cted ( mod i f i ed ) d i et
If you have mod i f i ed your d i et :
Wh i c h foods have you restr i cted?
Do any sme l l s/fumes cause symptoms ? ( l i st )
How are you now , compared to when you were g i ven the e l i m i nat i on d i et?
Comp l ete ly
we l l
D
Muc h
better
D
A 1 i tt l e
better
D i d you seek adv i ce/therapy e l sewhere?
If s o , where?
What adv i c e/therapy was g i ven?
D i d th i s he l p?
D
Just the
same
D
A l i tt le
worse
o
Muc h
worse
D

THE ROLE OF NATURAL SALICYLATES IN FOOD INTOLERANCE

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