-
IgG Food Intolerance Support Papers
Genesis Diagnostics Ltd, Eden Research Park, 8 Henry Crabb Road,
Littleport, CB61SE
[email protected]
Tel: +44(0)1353 862220
Fax: +44(0)1353 863330
Genesis Diagnostics Ltd is a subsidiary of Omega Diagnostics
Group PLC February 2009
mailto:[email protected]�
-
Paper 01 Dietary advice based on food specific IgG Results
Geoffrey Hardman, Gillian Hart, University of York, Heslington,
York, UK Nutrition and food science Vol 37 No 1 2007 pp 16-23
Paper 02 Food elimination based on IgG antibodies in irritable
bowel syndrome: a randomised controlled trial. W Atkinson, T A
Sheldon, N Shaath, PJ Whorwell Gut 2004:53 1459-1464 doi: 10.1136
Paper 05 Food allergy in irritable bowel syndrome: new facts and
old fallacies. E Isolauri, S.Rautava, M.Kalliomaki Gut 2004; 53
1391-1393 10.1136 Paper 06 A prospective audit of Food Intolerance
among Migraine patients in primary care clinical practise. Trevor
Rees, David Watson, Susan Lipscombe, Helen Speight, Peter Cousins,
Geoffrey Hardman and Andrew J. Dowson. Headache care Vol.2 No 2
2005 105-110 Paper 07 Celiac Disease. Peter H.R Green M.D. and
Christopher collier, M.D. PhD The New England Journal of Medicine
2007; 357:1731-43 Paper 08 Alterations of food antigen-specific
serum immunoglobulins G and E in patients with irritable bowel
syndrome and functional dyspepsia. X.L.Zuo, Y.Q. Li, W.J.Li, Y.T.
Guo, X.F. Lu, J.M. Li and P.V. Desmond Clinical and Experimental
Allergy, 37, 823-830 Paper 10 IgG Antibodies against Food Antigens
are Correlated with Inflammation and Intima Media Thickness in
Obese Juveniles M. Wilders-Truschnig, H.Mangge, C.Lieners,
H.J.Gruber, C Mayer, W Marz Exp Clin Endocrinol Diabetes 2008;
116:241-245 Paper 12 A Vegan diet free of gluten improves the signs
and symptoms of Rheumatoid Arthritis.. I Hafstöm, B.Ringertz, A.
Spångberg, L. Von Zweigbergk, S. Brannemark, I. Nylander,
J.Rönnelid, L.Laasonen, L.Klareskog. British Society of
Rheumatology, 2001 pp 1175-1179 Paper 13 The gut-joint axis: cross
reactive food antibodies in rheumatoid arthritis. M Hvatum, L
Kanerud, R Hällgren, P Brandtzaeg Gut 2006:55 1240-1247 originally
published online 16 feb 2006 Paper 14 Toward an understanding of
Allergy and In-Vitro Testing By Mary James N.D Great Smokies
Diagnostic Laboratory
-
IRRITABLE BOWEL SYNDROME
Food elimination based on IgG antibodies in irritable
bowelsyndrome: a randomised controlled trialW Atkinson, T A
Sheldon, N Shaath, P J Whorwell. . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . .
See end of article forauthors’ affiliations. . . . . . . . . . .
. . . . . . . . . . . .
Correspondence to:Dr P J Whorwell,Department of
Medicine,University Hospital ofSouth Manchester,Manchester M20 2LR,
UK;[email protected]
Revised version received13 April 2004Accepted for publication13
April 2004. . . . . . . . . . . . . . . . . . . . . . .
Gut 2004;53:1459–1464. doi: 10.1136/gut.2003.037697
Background: Patients with irritable bowel syndrome (IBS) often
feel they have some form of dietaryintolerance and frequently try
exclusion diets. Tests attempting to predict food sensitivity in
IBS have beendisappointing but none has utilised IgG
antibodies.Aims: To assess the therapeutic potential of dietary
elimination based on the presence of IgG antibodies
tofood.Patients: A total of 150 outpatients with IBS were
randomised to receive, for three months, either a dietexcluding all
foods to which they had raised IgG antibodies (enzyme linked
immunosorbant assay test) ora sham diet excluding the same number
of foods but not those to which they had antibodies.Methods:
Primary outcome measures were change in IBS symptom severity and
global rating scores. Non-colonic symptomatology, quality of life,
and anxiety/depression were secondary outcomes. Intention totreat
analysis was undertaken using a generalised linear model.Results:
After 12 weeks, the true diet resulted in a 10% greater reduction
in symptom score than the shamdiet (mean difference 39 (95%
confidence intervals (CI) 5–72); p = 0.024) with this value
increasing to26% in fully compliant patients (difference 98 (95% CI
52–144); p,0.001). Global rating also significantlyimproved in the
true diet group as a whole (p =0.048, NNT=9) and even more in
compliant patients(p = 0.006, NNT=2.5). All other outcomes showed
trends favouring the true diet. Relaxing the diet led to a24%
greater deterioration in symptoms in those on the true diet
(difference 52 (95% CI 18–88); p = 0.003).Conclusion: Food
elimination based on IgG antibodies may be effective in reducing
IBS symptoms and isworthy of further biomedical research.
Irritable bowel syndrome (IBS) is a common disorder whichcauses
abdominal pain, abdominal distension, and boweldysfunction,
characterised by loose bowels, constipation, or
a fluctuation between these two extremes.1 This
conditionsignificantly impairs quality of life and places a large
burdenon health care resources.2 Treatment of IBS is largely
basedon the use of antispasmodics, antidepressants, and
medica-tions that modify bowel habit, depending on
whetherconstipation or diarrhoea is the predominant problem.1
Thenotorious inadequacies of current drug therapy lead to
muchpatient dissatisfaction and a tendency for patients to seek
avariety of alternative remedies, especially of a dietary
nature.IBS is likely to be a multifactorial condition involving
a
number of different mechanisms although the prominence ofany
particular factor may vary from patient to patient.1 3
However, patients often strongly believe that dietary
intoler-ance significantly contributes to their symptomatology
andsome sufferers seem to benefit from eliminating certain
foodsfrom their diet. Detection of food intolerance is often
difficultdue to its uncertain aetiology, non-specific
symptomatology,and relative inaccessibility of the affected organ.
Thus mostprevious studies have relied on the use of exclusion
diets,which are extremely labour intensive and time consuming.4
5
Attempts to ‘‘test’’ for food intolerance in IBS have
largelyfocused on ‘‘classic’’ food allergy based on the presence of
IgEmediated antibody responses, although it appears that
these‘‘immediate type’’ reactions are probably quite rare in
thiscondition.6–10 It is therefore possible that adverse reactions
tofood in patients with IBS might be due to some other form
ofimmunological mechanism, rather than dietary allergy.
Suchreactions could be mediated by IgG antibodies,
whichcharacteristically give a more delayed response
followingexposure to a particular antigen11 and have been
implicatedin some cases of food hypersensitivity.12–14 However,
thismechanism is controversial and is considered by some to be
physiological15–17 especially as IgG food antibodies can
bepresent in apparently healthy individuals.18–20 It has
pre-viously been suggested that IgG food antibodies may have arole
in IBS21 and it was therefore the purpose of this study toformally
evaluate, in a randomised controlled trial, thetherapeutic
potential of an elimination diet based on thepresence of IgG
antibodies to food in patients with IBS.
PATIENTS AND METHODSPatientsAll patients with uncomplicated IBS
(all bowel habitsubtypes) attending the Gastroenterology Department
atthe University Hospital of South Manchester were
consideredeligible for the study, and those aged between 18 and75
years, who satisfied the Rome II criteria,22 were invited
toparticipate. Tertiary care patients were excluded from thestudy.
All patients had normal haematology, biochemistry,and endoscopic
examination when indicated. Coeliac diseasewas excluded using the
tissue transglutaminase test and ahydrogen breath test was used for
excluding lactose intoler-ance. Patients were also excluded from
participating in thestudy if they had any significant coexisting
disease or ahistory of gastrointestinal surgery, excluding
appendicect-omy, cholecystectomy, and hiatus hernia repair. The
studywas approved by the local ethics committee and all
patientsprovided written informed consent.
MethodsThe study used a double blind, randomised,
controlled,parallel design in which patients were randomised to
either a‘‘true’’ diet or a ‘‘sham’’ diet control group. At
screening,
Abbreviations: IBS, irritable bowel syndrome; ELISA, enzyme
linkedimmunosorbant assay; AU, arbitrary unit; HAD, hospital
anxiety anddepression scale; QOL, quality of life; NNT, number
needed to treat
1459
www.gutjnl.com
-
blood was taken and sent, with only a numerical identifier,
toYorkTest Laboratories Ltd (York, UK) where an enzymelinked
immunosorbant assay (ELISA) test was performed todetect the
presence of IgG antibodies specific to a panel of 29different food
antigens. This test has been described in detailelsewhere23 and
involves specimens being diluted 1/50, 1/150,and 1/450 with each
dilution applied to an allergen panel.Each test was calibrated
using 0 arbitrary unit (AU) and25 AU standards prepared from a
serum with a high IgG titreto a cow’s milk allergen extract. A
positive control serum at45 AU was applied to each test. The test
results were obtainedfrom the 1/150 dilution of the specimen. Where
a highspecimen background was observed, the test results
wereobtained from the 1/450 dilution. The threshold for a
positive(reactive) result was selected as three times the
backgroundsignal obtained by the same sample against a no
foodallergen coated control well equivalent to 3 AU. Test
resultswere scored as positive or negative only, relative to this
cutoff.Staff based at the YorkTest Laboratories produced a true
and sham diet sheet for each patient. The sham dieteliminated
the same number of foods to which a patientexhibited IgG antibodies
but not those particular foods. Thegoal was to try and include in
the sham diet an equallydifficult to eliminate staple food for
every staple food in thetrue diet. Thus cow’s milk was (generally)
replaced withpotato, wheat with rice, and yeast with whole egg,
where thiswas possible. Nut reactivities were replaced with other
nutsin the sham diet, and legumes with other legumes, but thiswas
not systematised.The true and sham diet sheets for each patient
were sent to
the University of York, again with only a number
foridentification. Patients were allocated to one of the two
dietsheets based on a randomisation schedule developed using
arandom computer number generator. Thus patients wouldreceive
either an elimination diet based on their truesensitivity results
(true diet) or a sham diet. All patientsand clinical staff in the
Gastroenterology ResearchDepartment and YorkTest Laboratory were
blinded to thegroup assignment of all patients for the duration of
the study.Patients were given their allocated diet sheet by staff
at the
Gastroenterology Research Department and asked to elim-inate the
indicated foods from their diet for a period of12 weeks. They also
received a booklet with advice oneliminating the different foods
and the telephone contactdetails of a free nutritional advisor whom
they were able tocontact for further advice if necessary.Symptoms
were assessed using a questionnaire scoring
system validated for use in IBS, including the IBS
symptomseverity score (range 0–500).24 This is a system for
scoringpain, distension, bowel dysfunction, and general well
being,with mild, moderate, and severe cases indicated by scores
of75–175, 175–300, and .300, respectively. A reduction inscore of
50 or over is regarded as a clinically significantimprovement.24
Non-colonic symptomatology,25 such aslethargy, backache, nausea,
and urinary symptoms, wasassessed and scored using visual analogue
scales (range 0–500). Quality of life (QOL) was measured using an
instru-ment proven to be sensitive to change in IBS (range
0–500).26–28
Anxiety and depression were evaluated using the hospitalanxiety
and depression scale (HAD).29 This instrument scoresanxiety and
depression up to a maximum score of 21 for eachparameter, with a
score above 9 indicating significantpsychopathology. Data on these
measures were recorded atbaseline and after 4, 8, and 12 weeks of
the dietaryintervention period. In addition, at 4, 8, and 12
weeks,patients were asked to give a global rating of their IBS
usingthe question, ‘‘Compared with your IBS before you startedthe
food elimination diet, are you now: terrible, worse,
slightly worse, no change, slightly better, better, or
excel-lent?’’ The atopic status of all patients entering the study
wasalso assessed.During the treatment phase, patients were allowed
to take
concomitant medication provided it had been constant for
sixmonths prior to the start of the study. They were encouragednot
to alter medication use during the course of the trial butany
changes were recorded. Any patient withdrawing fromthe study was
encouraged to complete a final symptomquestionnaire at week 12 and
their reasons for withdrawalwere recorded. At the end of 12 weeks,
patients were asked toresume consumption of the foods they had been
advised toeliminate in order to assess the effect of their
reintroduction.Patients were then reassessed after four weeks using
thesame measures and the result compared with their scores atthe
end of the elimination phase.
Data analysisQuestionnaires were scored by an assessor blinded
to therandomisation. The primary outcome measures were changesin
IBS symptom severity score and global impact score at12 weeks.
Changes in non-colonic symptoms, QOL, and HADscores were regarded
as secondary outcome measures. Twosample t tests were used to
establish whether there was anoverall difference in the change in
continuous outcomemeasures between the two groups of patients.
Patients wereanalysed according to the group to which they
wererandomised, independent of their adherence to the diet.The
global impact score, an ordered categorical variable, wasanalysed
using a Wilcoxon Mann-Whitney test to comparethe numbers in the
active and sham groups showingsignificant improvement (‘‘better’’
or ‘‘excellent’’), no sig-nificant change (‘‘slightly worse’’, ‘‘no
change’’, or ‘‘slightlybetter’’), and significant deterioration
(‘‘worse’’ or ‘‘terri-ble’’). The number needed to treat (NNT) was
calculatedfrom the global impact score by calculating the
reciprocal ofthe difference in probability of a significant
improvementbetween the treatment and control groups. General
linearmodelling in SPSS was used to explore whether there was a
��������� ������� ������� �����
��������� ������� ������� �����
�� ������� ��� ������� ������� ������
�� ������� ��� ������� ������� ������
��������������
�������� ������ � �� ���� �����
������ ���!�
������� �� "����"��� ����
#���� ������ ����
�$ %�����&� �� ��� �������� ��$�
'��( �� ������� ��$�
)�� "��"���� �� �����&
��� ��*�
#���� ������ ��$�
�* %�����&� �� ��� �������� �����
'��( �� ������� ����
)�� "��"���� �� �����&
��� ����
#���� ������ ����
�� '��� �� �����& �" ! '��� �� �����& �"
�������� �����+,���������
Figure 1 Study flow diagram.
1460 Atkinson, Sheldon, Shaath, et al
www.gutjnl.com
-
relationship between the change in symptoms from baselineand
treatment group, patient characteristics (for example,IBS subtype,
history of atopy, number of foods to whichsensitive, and
concomitant medication) and adherence to thediet.30
Sample size calculationIt was estimated that approximately 40%
of the placebo armwould report a significant improvement in
symptoms. It wascalculated that a sample size of 55 patients would
be requiredin each group to detect, with 90% power, a difference of
30%points in the proportion reporting such an improvement (thatis,
70% in the treatment arm) as statistically significant at the5%
level. Assuming a 20% dropout rate, a minimum of 138patients would
need to be entered into the trial. Thus weaimed to recruit a total
of 150 patients into the study.
RESULTSRecruitment of patients and their flow through each stage
ofthe study is illustrated in fig 1, as recommended by the
CONSORT statement.31 In summary, between January 2001and July
2002, 176 patients were eligible for the study, ofwhich 26 (15%)
were excluded from participation, leaving150 patients who were all
found to be sensitive to at least onefood. Seventy five of these
were randomised to receive anelimination diet based on their true
food sensitivity resultsand 75 patients to a sham diet. Data from
131 (87%) patientswho gave 12 week data were available for the
intention totreat analysis: 65 and 66 patients from the true and
shamgroups, respectively.
Patient characteristicsThe patients were typical of those with
IBS in secondary carepractice, the majority being women. Patients,
on average, hadexperienced symptoms of IBS for over a decade and
werefound to be sensitive to approximately 6–7 foods (range 1–19).
Baseline demographic and clinical characteristics of thetwo groups,
including the use of concomitant medication,were found to be
similar with the exception of the IBSsymptom severity score which
was slightly higher in thetreatment group (table 1). Thirty per
cent of patients werefound to be atopic.The frequency of foods
excluded from the diet is shown in
table 2. Adherence was lower in those on the true dietalthough
no specific adverse events were recorded in eithergroup. Twenty
four patients withdrew from the study in thetrue diet group (mainly
because of difficulty in following thediet) and 13 from the sham
diet group (for a variety ofreasons). However, 12 week data were
obtained from 14 ofthose who withdrew in the true diet group and
four in thesham diet group. There were no significant
differences
Table 1 Baseline characteristics of the patients
Group True diet (n = 75) Sham diet (n = 75)
Age (y) (range, SD) 44 (17–72; 12.9) 44 (19–74; 15.2)No of males
(%) 7 (9.3%) 13 (17.3%)No of foods to which sensitive 6.65 (3.66)
6.63 (4.1)Symptom duration (y) 11.5 (9.9) 10.1 (7.5)IBS symptom
severity score 331.9 (70.8) 309.0 (78.5)Non-colonic features score
459.1 (160.7) 452.6 (170.1)Quality of life score 640.1 (252.6)
639.3 (222.3)HAD anxiety score 9.5 (4.6) 9.5 (4.5)HAD depression
score 5.3 (3.4) 6.0 (3.6)No of diarrhoea predominant patients (%)
37 (52.1%) 41 (56.9%)No of constipation predominant patients (%) 19
(26.8%) 16 (22.2%)No of alternating predominant patients (%) 15
(21.1%) 15 (20.8%)
Results are expressed as mean (SD).HAD, hospital anxiety and
depression scale.
Table 2 Frequency of foods excluded from the diet (%
ofpatients)
Food Treatment group Sham group
Barley 26.7 9.3Corn 22.7 14.7Rice 8 54.7Rye 8 25.3Wheat 49.3
8Milk 84.3 1.3Beef 24 9.3Chicken 21.3 13.3Pork 5.3 36Cabbage 12
24Celery 5.3 21.3Haricot bean 17.3 14.7Pea 38.6 1.3Potato 9.3
61.3Soy bean 22.7 10.7Tomato 4 44Apple 1.3 33Orange 6.7
29.3Strawberry 0 20Almond 28 12Brazil nut 22.7 17.3Cashew nut 49.3
8Peanut 10.7 20Walnut 2.7 29.3Cocoa bean 1.3 21.3Shellfish 21.3
10.7Fish mix 17.3 28Whole egg 57.3 26.7Yeast 86.7 0
��� ������ ��
���� �� ���������
�����������������
���� ����������
�
���
����
����
����
!�
"#�
$��
�"�
����
�#
Figure 2 Mean change in symptom severity scores at 12
weeksaccording to degree of adherence. Difference between the
groups withhigh adherence: 101 (95% confidence interval 54, 147);
***p,0.001.
Food elimination based on IgG antibodies in IBS 1461
www.gutjnl.com
-
between baseline characteristics of the 19 who were lost
tofollow up and those for whom 12 week data were obtained.
Primary outcomesIBS symptom severityPatients in the true diet
group experienced a 10% greaterreduction in symptom severity than
those allocated to thesham diet, with change in scores of 100 and
61.5, respectively(mean difference 39 (95% confidence interval (CI)
5.2, 72.3);p=0.024): a standardised effect size of 0.52 (see fig
3A).There were no differences in the response to the diet in
termsof age, sex, IBS bowel habit subtype, or IBS duration.
Inaddition, there was no difference in response to the diet
between atopic and non-atopic patients. There was however
astatistically significant interaction between treatment groupand
both adherence to the diet and number of foods to whichpatients
were sensitive. For patients sensitive to the averagenumber of
foods who fully adhered to their allocated diet, a26% difference in
reduction in symptom severity score wasobserved in favour of the
true diet (a difference in score of 98(95% CI 52, 144), p,0.001: a
standardised effect size of 1.3).This benefit increased by a
further 39 points (12%) (95% CI 7,70; p= 0.016) for each food to
which they were sensitiveover and above the average number. These
results were notmaterially altered by carrying out an ANCOVA
analysis (inwhich the final score is the dependent variable and
thebaseline score is included as a covariate) instead of
modellingchange in scores.30 The interaction between treatment
groupand adherence is demonstrated in fig 2 which shows agreater
reduction in symptoms with full adherence in thetrue diet but not
in the sham diet group. Figure 3A and 3Bshow the average change in
symptom severity score over12 weeks for the group as a whole and
for those who fullyadhered, respectively. This reveals that most
improvements insymptoms are fully achieved within two months.
Global impact scoreThe reported global rating of change by
treatment group isshown in table 3. The difference in mean ranking
(70.9 v60.3) was statistically significant (p=0.048). When this
wasrepeated including only patients who fully adhered to theirdiets
(table 3), a greater percentage difference favouring thetrue diet
was found (p=0.001). The NNT was 9 in the groupas a whole and 2.5
in patients fully adherent to the diet.
Secondary outcome measuresAs can be seen from fig 4A and 4B, all
data show changesfavouring the true diet group and are consistent
with theresults for the primary outcomes. These trends were
furtherstrengthened after adjustment for adherence and number
offood sensitivities but only reached statistical significance
fornon-colonic symptomatology (p=0.05). There were nosignificant
changes in medication use during the course ofthe trial.
Reintroduction of eliminated foodsOf the 131 patients who gave
12 week data, 93 (41 in the trueand 52 in the sham diet groups)
agreed to attemptreintroduction of foods they had been asked to
eliminateand provided further follow up data on the primary
outcomesmeasures. Of these, 62% reported full adherence and
37%moderate adherence to the previous elimination diet. MeanIBS
symptom severity score increased (that is, worsening ofsymptoms) by
83.3 in the true group and by 31 in the sham
� � � ��
���� ����
�
������������
���� ��������
���
���
���
���
�
����������
�� �
����
!
� � � ��
���� ����
��� ������������
���� ��������
���
���
���
���
�
����������
�� �
����
�
Figure 3 (A) Average symptom severity scores over time for the
groupas a whole. Difference in mean change from baseline at 12
weeks: trueversus sham 39 (95% confidence interval 5, 72);
*p=0.024. (B) Averagesymptom severity scores over time for the full
adherence group.Difference in mean change from baseline at 12
weeks: true versus sham98 (95% confidence interval 52, 144);
***p,0.001.
Table 3 Global impact score at 12 weeks
Treatment group
True diet(n (%))
Sham diet(n (%))
All patientsSignificantly worse 3 (4.7) 8 (12.1)No significant
change 44 (67.2) 47 (71.2)Significantly improved 18 (28.1) 11
(16.7)Total 65 66 NNT = 9
Patients fully adhering to the dietSignificantly worse 1 (4.2) 5
(12.5)No significant change 10 (41.7) 29 (72.5)Significantly
improved 13 (54.1) 6 (15)Total 24 40 NNT = 2.5
1462 Atkinson, Sheldon, Shaath, et al
www.gutjnl.com
-
group, a statistically significant difference of 52 (24%) (95%CI
18, 86; p=0.003). The change in global score
followingreintroduction of foods is shown in table 4. This
indicates areversal of the pattern observed during the active
treatmentphase, with more patients in the true diet group
showing
worsening of health compared with the sham diet
group(p=0.047).
DISCUSSIONA clinically significant improvement in IBS
symptomatologywas observed in patients eliminating foods to which
theywere found to exhibit sensitivity, as identified by an
ELISAtest for the presence of IgG antibodies to these foods.
Thenumber needed to treat of 9 for the group as a whole and 2.5for
patients closely adhering to the diet are both considerablybetter
than the value of 17 achieved after three months oftreatment with
tegaserod,32 a drug that has been recentlylicensed in the USA for
use in IBS. IBS symptom severity andglobal rating scores were
chosen as primary outcomemeasures in this study as they represented
the most directmeasure of clinical improvement in this condition
based onpatient self assessment. Rather than using the
traditionalmethod of classifying global improvement as any
valueexceeding adequate relief of symptoms, we used a muchstricter
definition requiring patients to report symptoms asbeing either
‘‘better’’ or ‘‘excellent’’ compared with pretreat-ment levels.
Despite this, the diet still achieved a significantimprovement.
However, as might be expected, the placeboresponse using this end
point was somewhat lower than thatusually reported in IBS treatment
trials which have used lessdemanding criteria. The observation that
patients on thesham diet also improved, although to a lesser
extent,emphasises the importance of conducting double
blindrandomised controlled trials of such non-drug interventionsin
order to avoid overestimating their potential.Most patients with
IBS have attempted at least some form
of dietary modification, which in some cases can be veryextreme.
Conflicting results have been reported usingexclusion diets4 5
33–36 and this approach also suffers fromthe limitation that it has
to be empirical. Thus potentiallyoffending foods can only be
identified after their eliminationand subsequent reintroduction.
This time consuming processwould be much reduced if the offending
foods could beidentified beforehand. Attempts to do this using
IgEantibodies have been disappointing8–10 but the results of
thisstudy suggest that measuring IgG antibodies may be muchmore
rewarding. The response to the IgG based diet in ourtrial did not
correlate with atopic status, the prevalence ofwhich was found to
be no greater than that occurring in thegeneral population.37
The observation that adherence to the diet is critical
indetermining a good outcome in the ‘‘true’’ diet group but notthe
‘‘sham’’ group is indicative of the fact that the diet is
an‘‘active treatment’’ which if not adhered to, does not seem
tohave an effect. This notion is further supported by
theobservation that a significantly greater deterioration
wasobserved in subjects in the true diet group compared withthose
in the sham group when they reintroduced eliminatedfoods at the end
of the diet phase of the trial. Furthermore,the improvement of 98
in the symptom severity score in thosefully adherent in the true
diet group is well above the value of
���
���
��
�
���
���
��
�
���
�
���
�
���
�
���
�
���
�
���
�
�����������
����������
����
����
����
����
����
����
����
����
���
���
���
���
���
���
�
�������� ��
���������
���� ���� ���� ����
���� ���� ���� ����
�
������������
�����������
���
���
�
�������� ��
����������
������
����
� ������
!��
�� �"
�"�
#���������
��$���
Figure 4 (A) Mean change in the secondary outcome measures of
non-colonic symptoms and quality of life for the group as a whole
and the fulladherence group. (B) Mean change in the secondary
outcome measuresof anxiety and depression for the group as a whole
and the fulladherence group.
Table 4 Global rating following reintroduction of foodsrelative
to the end of the elimination phase
Treatment group
True diet group(n (%))
Sham diet group(n (%))
Significantly worse 17 (41.5) 13 (25)No significant change 23
(56.1) 35 (67.3)Significantly improved 1 (2.4) 4 (7.7)Total 41
(100) 52 (100)
Food elimination based on IgG antibodies in IBS 1463
www.gutjnl.com
-
50, which is regarded as being of clinical significance both
invalidation studies24 and clinical practice.26–28 It was
interestingto note that patients exhibiting a greater number
ofsensitivities, as determined by the IgG test, experienced
agreater symptom reduction if they adhered to the true but notthe
sham diet.There is currently considerable interest in the concept
that
at least in some patients, IBS may have an
inflammatorycomponent.38–42 Most of the work in this area has
centred onpost dysenteric IBS, with gut pathogens being viewed as
theinitiators of this process which can be identified by
subtlechanges on histology.38 However, if, as indicated in this
study,IgG antibodies to food are important in the pathogenesis
ofIBS in some patients, they too may be of relevance. Not
allpatients exhibiting histological features consistent with
postdysenteric IBS give a history of a previous dysenteric
illness.This is usually assumed to be due to the fact that this
hasbeen forgotten by the patient but our results may suggest
analternative mechanism for immune activation and inflam-mation
without the need for prior infection.It is now well recognised that
up to 70% of patients with
IBS have evidence of hypersensitivity of the rectum,43
whichprobably extends to involve most of the gut in
manyindividuals.44 It is possible that this hypersensitivity
renderspatients more reactive to a low grade inflammatory
processwhich would not necessarily cause symptoms in a
normalindividual. This would explain why excluding foods to
whichpatients have IgG antibodies might be particularly
beneficialin IBS despite the fact that these antibodies may also
bepresent in the general population. Indeed, if this mechanismis
particularly important in IBS, it might be anticipated thatIgG food
antibodies would be relatively common in thiscondition, as was the
case in our study.Many patients with IBS would prefer a dietary
solution to
their problem rather than having to take medication, and
theeconomic benefits of this approach to health services
areobvious. It is well known that patients expend large sums
ofmoney on a variety of unsubstantiated tests in a vain attemptto
identify dietary intolerances. The results of this studysuggest
that assay of IgG antibodies to food may have a rolein helping
patients identify candidate foods for eliminationand is an approach
that is worthy of further biomedical andclinical research.
Authors’ affiliations. . . . . . . . . . . . . . . . . . . .
.
W Atkinson, N Shaath, P J Whorwell, Department of
Medicine,University Hospital of South Manchester, Manchester, UKT A
Sheldon, Department of Health Sciences, University of York,
York,UK
REFERENCES1 Drossman DA, Camilleri M, Mayer EA, et al. American
Gastroenterological
Association Technical Review on Irritable Bowel Syndrome.
Gastroenterology2002;123:2108–31.
2 Lea R, Whorwell PJ. Quality of life in irritable bowel
syndrome.Pharmacoeconomics 2001;19:643–53.
3 Talley NJ, Spiller R. Irritable bowel syndrome: a little
understood organicbowel disease? Lancet 2002;360:555–64.
4 Jones VA, McLaughlan P, Shorthouse M, et al. Food intolerance:
a majorfactor in pathogenesis of irritable bowel syndrome. Lancet
1982;2:1115–17.
5 Nanda R, James R, Smith H, et al. Food intolerance and the
irritable bowelsyndrome. Gut 1989;30:1099–104.
6 Zwetchkenbaum J, Burakoff, R. The irritable bowel syndrome and
foodhypersensitivity. Ann Allerg 1988;61:47–9.
7 Zar S, Kumar D, Benson M. J. Review article: food
hypersensitivity andirritable bowel syndrome, Aliment Pharm Ther
2001;15:439–43.
8 Petitpierre M, Gumowski P, Girard JP. Irritable bowel syndrome
andhypersensitivity to food. Ann Allergy 1985;54:538–40.
9 Barau E, Dupont C. Modifications of intestinal permeability
during foodprovocation procedures in pediatric irritable bowel
syndrome. J PediatrGastroenterol Nutr 1990;11:72–7.
10 Roussos A, Koursarakos P, Patsopoulos D, et al. Increased
prevalence ofirritable bowel syndrome in patients with bronchial
asthma. Respir Med2003;97:75–9.
11 Crowe SE, Perdue MH. Gastrointestinal food hypersensitivity:
basicmechanisms of pathophysiology. Gastroenterol
1992;103:1075–95.
12 el Rafei A, Peters SM, Harris N, et al. Diagnostic value of
IgG4 measurementsin patients with food allergy. Ann Allergy
1989;62:94–9.
13 Host A, Husby S, Gjesing B, et al. Prospective estimation of
IgG, IgG subclassand IgE antibodies to dietary proteins in infants
with cow’s milk allergy. Levelsof antibodies to whole milk protein,
BLG and ovalbumin in relation to repeatedmilk challenge and
clinical course of cow’s milk allergy. Allergy1992;47:218–29.
14 Awazuhara H, Kawai H, Maruchi N. Major allergens in soybean
and clinicalsignificance of IgG4 antibodies investigated by IgE and
IgG4 immunoblottingwith sera from soybean-sensitive patients. Clin
Exp Allergy 1997;27:325–32.
15 Barnes RMR, Johnson PM, Harvey MM, et al. Human serum
antibodiesreactive with dietary proteins: IgG subclass
distribution. Int Arch Allergy ApplImmunol 1988;87:184–8.
16 Lessof MH, Kemeny DM, Price JF. IgG antibodies to food in
health anddisease. Allergy Proc 1991;12:305–7.
17 Husby S, Mestecky J, Moldoveanu Z, et al.Oral tolerance in
humans. T cell butnot B cell tolerance after antigen feeding. J
Immunol 1994;152:4663–70.
18 Haddad ZH, Vetter M, Friedmann J, et al. Detection and
kinetics of antigen-specific IgE and IgG immune complexes in food
allergy. Ann Allergy1983;51:255.
19 Husby S, Oxelius VA, Teisner B, et al. Humoral immunity to
dietary antigens inhealthy adults. Occurrence, isotype and IgG
subclass distribution of serumantibodies to protein antigens. Int
Arch Allergy Appl Immunol1985;77:416–22.
20 Kruszewski J, Raczka A, Klos M, et al. High serum levels of
allergen specificIgG-4 (asIgG-4) for common food allergens in
healthy blood donors. ArchImmunol Ther Exp 1994;42:259–61.
21 Finn R, Smith MA, Youngs GR, et al. Immunological
hypersensitivity toenvironmental antigens in the irritable bowel
syndrome. Br J Clin Pract1987;41:1041–3.
22 Drossman DA, Corazziari E, Talley NJ, et al. Rome II: a
multinationalconsensus document on functional gastrointestinal
disorders. Gut1999;45:1–81.
23 Foster AP, Knowles TG, Hotston Moore A, et al. Serum IgE and
IgG responsesto food antigens in normal and atopic dogs, and dogs
with gastrointestinaldisease. Vet Immunol Immunopathol
2003;92:113–24.
24 Francis CY, Morris J, Whorwell PJ. The irritable bowel
scoring system: Asimple method of monitoring IBS and its progress.
Aliment Pharmacol Therap1997;11:395–402.
25 Whorwell PJ, McCallum H, Creed FH, et al. Non-colonic
features of irritablebowel syndrome. Gut 1986;27:452–6.
26 Houghton LA, Heyman DJ, Whorwell PJ. Symptomatology, quality
of life andeconomic features of irritable bowel syndrome—the effect
of hypnotherapy.Aliment Pharmacol Ther 1996;10:91–5.
27 Gonsalkorale WM, Toner BB, Whorwell PJ. Cognitive change in
patientsundergoing hypnotherapy for irritable bowel syndrome. J
Psychosom Res2004;56:271–8.
28 Gonsalkorale WM, Houghton LA, Whorwell PJ. Hypnotherapy in
irritablebowel syndrome: a large scale audit of a clinical service
with examination offactors influencing responsiveness. Am J
Gastroenterol 2002;97:954–61.
29 Zigmond AS, Snaith RP. The hospital anxiety and depression
scale. ActaPsychiatr Scand 1983;67:361–70.
30 Everitt BS, Pickles A. Statistical aspects of the design and
analysis of clinicaltrials. London: Imperial College Press
Publishers, 2003:108–42.
31 Altman DG, Schulz KF, Moher D, et al. The revised CONSORT
statement forreporting randomized trials: explanation and
elaboration. Ann Intern Med2001;134:663–94.
32 Novick J, Miner P, Krause R, et al. A randomised, double
blind, placebocontrolled trial of tegaserod in female patients
suffering from irritable bowelsyndrome with constipation. Aliment
Pharmacol Ther 2002;16:1877–88.
33 Niec AM, Frankum B, Talley NJ. Are adverse reactions to food
linked toirritable bowel syndrome? Am J Gastroenterol
1998;93:2184–90.
34 Burden S. Dietary treatment of irritable bowel syndrome:
current evidence andguidelines for future practice. J Hum Nutr Diet
2001;14:231–41.
35 Bentley SJ, Pearson DJ, Rix KJB. Food hypersensitivity in
irritable bowelsyndrome. Lancet 1983;2:295–7.
36 McKee AM, Prior A, Whorwell PJ. Exclusion diets in irritable
bowel syndrome:Are they worthwhile? J Clin Gastroenterol
1987;9:526–8.
37 Durham SR, Church MK. Principles of allergy diagnosis. In:
Holgate ST,Church MK, Lichtenstein LM, eds. Allergy, 2nd edn.
London: Mosby,2001:3–16.
38 Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal
mucosalenteroendocrine cells, T lymphocytes, and increased gut
permeabilityfollowing acute Campylobacter enteritis and in
post-dysenteric irritable bowelsyndrome. Gut 2000;47:804–11.
39 Gonsalkorale WM, Perrey C, Pravica V, et al. Interleukin 10
genotypes inirritable bowel syndrome: evidence for an inflammatory
component? Gut2003;52:91–3.
40 Collins SM, Piche T, Rampal P. The putative role of
inflammation in the irritablebowel syndrome. Gut 2001;49:743–5.
41 Collins SM. A case for an immunological basis for irritable
bowel syndrome.Gastroenterology 2002;122:2078–80.
42 Chadwick VS, Chen W, Shu D, et al. Activation of the mucosal
immune systemin irritable bowel syndrome. Gastroenterology
2002;122:1778–83.
43 Mertz H. Review article: visceral hypersensitivity. Aliment
Pharmacol Ther2003;17:623–33.
44 Francis CY, Houghton LA, Whorwell PJ. Enhanced sensitivity of
the whole gutin patients with irritable bowel syndrome.
Gastroenterology1995;108:601(abstract).
1464 Atkinson, Sheldon, Shaath, et al
www.gutjnl.com
-
LEADING ARTICLE
Food allergy in irritable bowel syndrome: new facts and
oldfallaciesE Isolauri, S Rautava, M Kalliomäki. . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
Gut 2004;53:1391–1393. doi: 10.1136/gut.2004.044990
The notion of food allergy in irritable bowel syndrome (IBS)is
not new. However, recent evidence suggests significantreduction in
IBS symptom severity in patients on eliminationdiets, provided that
dietary elimination is based on foodsagainst which the individual
had raised IgG antibodies.These findings should encourage studies
dissecting themechanisms responsible for IgG production against
dietaryantigens and their putative role in IBS. . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
See end of article forauthors’ affiliations. . . . . . . . . . .
. . . . . . . . . . . .
Correspondence to:Dr E Isolauri, Departmentof Paediatrics,
TurkuUniversity CentralHospital, 20520 Turku,Finland;
[email protected]
Revised version received10 June 2004Accepted for publication19
June 2004. . . . . . . . . . . . . . . . . . . . . . .
Bringing empirical observations ad fontesadvances science. In
astrophysics, the term‘‘black hole’’ was introduced to describe
an
extremely dense star which had collapsed into asingularity under
its own gravity. A black holeradiates nothing; it absorbs all
matter and energyfalling within its sphere. The name was coinedonly
after revisiting the initial theoreticalachievements of Karl
Schwarzschild, whenobservations made outside the earth’s
atmos-phere gave astrophysicists empirical x ray data ona new type
of cosmic object. In allergology, incontrast, adherence to a
paradigm wherebyallergy is defined by the presence of specific
IgEantibodies has hampered disentanglement. As aresult, allergy
remains a dubiously defined termwith no unambiguous empirical
content orexplanatory power. The time has come to seizeupon the
available empirical data and plungeinto the original theory of
Clemens von Pirquet.The term allergy was introduced by von
Pirquet to denote a changed immunologicalreactivity which
manifests itself on secondexposure to an antigen (reviewed by
Kay1). Thisaltered reactivity is uncommitted, giving noindication
of the direction of change; equallyharmful and protective immune
reactivityreflects prior encounter (see fig 1). In modernterms,
altered reactivity can be seen to evinceeither the most common mode
of immuneresponse elicited by the intestinal immunesystem,
tolerance, recently defined as anymechanism by which a potentially
injuriousimmune response is prevented, suppressed, orshifted to a
non-injurious class of immuneresponse,2 or abrogation of such an
activelymaintained process, which is currently linkedto
immunoinflammatory disease. Reassessmentof the original theory of
allergy is important as itwould appear that it is not the
immunologicalresources gained during antigen exposure, mea-surable
by specific antibodies or specificallyresponding lymphocytes, which
are decisive for
the presence or absence of disease, but thecomplex cascade of
events determining their use.The notion of food allergy in
irritable bowel
syndrome (IBS) resurfaces in scientific thinkingin this issue of
Gut3 on the basis of a solidrandomised placebo controlled trial
conducted byAtkinson and colleagues (see page 1459).Determination
of serum IgG antibodies againstfoods was used to guide the
construction ofelimination diets.The presence of specific IgG class
antibodies is
often accepted as uncommitted or protective‘‘altered
reactivity’’, unlike those of the IgE class.Detection of antigen
specific IgE is invariablytaken as an attribute of causality, a
conditioncalled ‘‘IgE mediated disease’’ and, more speci-fically,
of ‘‘allergy’’.1 However, empirical data areaccumulating to suggest
that transient increasesin antigen specific IgE antibodies prevail
in mosthealthy asymptomatic children during the firstfive years of
life.4 Secondly, generation of theseantibodies (sensitisation) on
antigen exposuremay not necessarily induce clinical disease(atopic
disease).5 Thirdly, reducing the risk ofatopic disease does not
necessitate reduction ofsensitisation6–8 and, finally, resolution
or aggra-vation of clinical disease is not invariablyassociated
with a corresponding alteration inantibody concentration. Bearing
these limita-tions in mind, however, the clinician maysuccessfully
profit from determination of specificIgE to complete the clinical
history in an attemptto identify potential offending antigens in
asymptomatic patient’s diet for the explicitdiagnostic
elimination-challenge procedure.9
This is precisely what Atkinson et al did, withspecific IgG
antibodies.3 They identified a sig-nificant reduction in IBS
symptom severity inpatients on elimination diets, provided
thatdietary elimination was based on foods againstwhich the
individual had raised IgG antibodies;fully compliant patients
showed the best clinicalimprovement. The reverse pattern was
observedafter reintroduction of the respective foods.
‘‘IBS appears to result from an interplaybetween susceptibility
genes and impairedgut barrier functions, immunological
dysre-gulation, together with bacterial and viralinfections and
other environmental factors’’
In common with allergic disease, IBS appearsto result from an
interplay between susceptibility
Abbreviations: IBS, irritable bowel syndrome; PRR,pattern
recognition receptor
1391
www.gutjnl.com
-
genes and impaired gut barrier functions,
immunologicaldysregulation, together with bacterial and viral
infectionsand other environmental factors. It is no easy matter
todescribe succinctly ‘‘gut barrier function’’. In the
gastro-intestinal tract, the external and internal environments are
inclose proximity. The dilemma of the mucosal surface of
theintestine is to fend off the constant challenge from
antigens,such as microorganisms, in mounting a brisk response
topathogens, and to enable assimilation of innocuous
antigensderived from food. In order to perform these
opposingfunctions, the intestine is in a state of continuous
immuneresponsiveness, and a delicate balance is generated
andmaintained between concomitant facilitation and suppres-sion of
inflammatory responses.Gut barrier function consists of
physiological and immu-
nological factors which exclude and degrade antigens andrestrict
their adherence, penetration, and transfer. Antigenpresenting
cells, and more precisely dendritic cells, are pivotalin directing
mucosal immune responses.10–12 Three dendriticcell derived signals
are required for an effective T cellresponse.11 The nature of
signal 1 depends on the antigenin question and its processing;
necessary costimulatorymolecules create the second signal and the
pericellularcytokine milieu is the basis of the third. On
antigenrecognition, maturation of dendritic cells and secretion
ofcytokines and chemokines occur. These secretions direct
thepolarisation of a naı̈ve T helper cell to type 1, type 2, or
aregulatory T cell and thus regulate other adaptive
immuneresponses, such as B cell derived immunoglobulin
produc-tion.11 Tolerance to lumenal dietary and microbial antigens
islikely to be achieved through those dendritic cells whichinduce
production of regulatory T cells secreting interleukin10 and
transforming growth factor b.13 These cytokinespromote gut barrier
function by suppressing the productionof both T helper 1 and 2
cytokines,14 overexpression of whichis associated with increased
gut permeability.15 16 Moreover,the anergic T cells induced by
interleukin 10 exposeddendritic cells appear to be able to suppress
other T cells inan antigen specific manner.17 Transforming growth
factor bdownregulates both T helper 1 and 2 responses directly18
andindirectly by modulating the activity of antigen
presentingcells19 and favouring the development of regulatory T
cells.20
After intestinal priming, these cells migrate to the
periphery,thus mediating peripheral tolerance on reactivation.
In
addition to its effects on T cell function, transforming
growthfactor b is a key factor in IgA production21 and
thuscontributes to maintenance of gut barrier function and toimmune
responses at other mucosal surfaces also. Takentogether, ‘‘gut
barrier function’’ strongly depends on antigenprocessing and
presentation and the cytokine milieu in themucosal immune system,
and determines the nature of theimmune response (that is, tolerance
or inflammation)elicited to a particular antigen.
‘‘Inflammation can cause profound alterations in thefunction of
smooth muscle and enteric nerves as well asin deeper neuromuscular
layers’’
In certain circumstances, such as metabolic stress, thepeaceful
coexistence across the barrier is disturbed and aninflammatory
response ensues.22 Abrogated barrier functionof the gut mucosa
leads to greater antigen transfer when theroutes of transport are
also altered, thereby evoking aberrantimmune responses and release
of proinflammatory cytokineswith further impairment of barrier
function. Inflammationcan cause profound alterations in the
function of smoothmuscle and enteric nerves as well as in deeper
neuromuscularlayers.23 Indeed, a subtle inflammatory response and
exag-gerated sensitivity to that type of response has beensuggested
to be causative in IBS. In view of recently reportedalterations in
the immunological defence in IBS,24 thetrigger(s) of the vicious
circle can be depicted among theintraluminal antigens.In this issue
of Gut, Atkinson and colleagues3 describe IgG
antibody responses to dietary antigens of clinical
significanceand an apparent causal relation to symptoms in IBS, in
afashion resembling the elimination-challenge procedure infood
allergy. To broaden this concept, it is intriguing tospeculate that
IBS may perhaps also be associated with IgGantibodies against other
intraluminal antigens such as thosefrom the indigenous microbiota,
partially analogously to lossof tolerance to gut microbiota in
inflammatory boweldisease.25 26
The human gastrointestinal tract harbours a complexcollection of
microorganisms which form the individualmicrobiota typical for each
person. Defence is facilitated byperistalsis, secretion of mucus
and antimicrobial peptidessuch as defensins and cathelicidins, and
commensal induced
Inflammation
Normalrange
IBS?
Th1IBD
Th2Allergicdisease
AntigenExposure
Consolidation of immune reactivity
Naïuncommitted
Toleranceve
Figure 1 An attempt to reformulate the original conception of
the immunological basis of allergy. On exposure to dietary and
microbial antigens, thenaı̈ve immune system matures either to
establish appropriate immune reactivity and tolerance or, in the
case of lack of suppressive and regulatorysignals, develops
inflammatory disease expressed as Th1 skewed autoimmune reactivity
(for example, inflammatory bowel disease (IBD)) or Th2skewed
allergic disease. The exact nature of immune reactivity in
irritable bowel syndrome (IBS) on this axis remains elusive.
1392 Isolauri, Rautava, Kalliomäki
www.gutjnl.com
-
IgA.27 28 Intestinal epithelial cells further contribute to
thehomeostasis of gut barrier function by a scarcity of bothpattern
recognition receptors (PRRs; for example, toll-likereceptors and
nucleotide binding oligomerisation domainproteins) and their
coreceptors, expression of active negativeregulators of PRR
signalling, and secretion of the suppressivecytokines interleukin
10 and transforming growth factor b.13
All of these characteristics assist in preventing unnecessaryand
even hazardous systemic immunity to commensals whileallowing local
protective mucosal immune responses. Inaddition, some specific
strains of non-pathogenic bacteriahave been shown to attenuate
intestinal inflammation byselective inhibition of intracellular
signalling pathwayselicited by diverse potentially deleterious
stimuli.29 30 Ahealthy gut microbiota is thus an indispensable
componentof ‘‘gut barrier function’’.
‘‘A healthy gut microbiota is thus an indispensablecomponent of
gut barrier function’’
The findings of Atkinson and colleagues3 should encouragestudies
dissecting the mechanisms responsible for IgGproduction against
dietary antigens and their putative rolein IBS. This may serve not
only IBS research but also that intoallergy and allergic diseases.
In the perspectives of bothnormal gut barrier function and the
vague findings in a fewstudies of probiotic supplementation in
IBS,31–33 we suggestthat the possible role of the gut microbiota in
the pathogen-esis of IBS may deserve closer attention. If the
host-microbecross talk is misinterpreted in IBS, a working target
for noveltherapeutic interventions beyond elimination diets could
beprovided in modulating the composition and/or activity of thegut
microbiota and promoting gut immune defence. Researchinterest in
the science of nutrition is directed towardsimprovement of defined
physiological functions beyond thenutritional impact of food. The
search for active non-nutritivecompounds is also a focus for
research in the treatment andprevention of allergic diseases.
Authors’ affiliations. . . . . . . . . . . . . . . . . . . .
.
E Isolauri, S Rautava, Department of Paediatrics, University of
Turku andTurku University Central Hospital, FinlandM
Kalliomäki,Massachusetts General Hospital East, Combined Programin
Pediatric Gastroenterology and Nutrition,
Charlestown,Massachusetts, USA
REFERENCES1 Kay AB. Concepts of allergy and hypersensitivity.
In: Kay AB, ed. Allergy and
allergic diseases. Oxford: Blackwell Science Ltd, 1997:23–35.2
Weiner HL. Oral tolerance: immune mechanisms and the generation of
Th3-
type TGF-beta-secreting regulatory cells. Microbes Infect
2001;3:947–54.3 Atkinson W, Sheldon TA, Shaath N, et al. Food
elimination based on IgG
antibodies in irritable bowel symdrome: a randomised controlled
trial. Gut2004;53:1459–64.
4 Kulig M, Bergmann R, Klettke U, et al. Natural course of
sensitization to foodand inhalant allergens during the first 6
years of life. J Allergy Clin Immunol1999;103:1173–9.
5 Lau S, Illi S, Sommerfeld C, et al. Early exposure to
house-dust mite and catallergens and development of childhood
asthma: a cohort study. Lancet2000;356:1392–7.
6 Kalliomäki M, Salminen S, Kero P, et al. Probiotics in the
primary preventionof atopic disease: a randomised,
placebo-controlled trial. Lancet2001;357:1076–9.
7 Riedler J, Braun-Fahrländer C, Eder W, et al. Exposure to
farming in early lifeand development of asthma and allergy: a
cross-sectional survey. Lancet2001;358:1129–33.
8 Jones CA, Holloway JA, Popplewell EJ, et al. Reduced soluble
CD14 levels inamniotic fluid and breast milk are associated with
the subsequent developmentof atopy, eczema, or both. J Allergy Clin
Immunol 2002;109:858–66.
9 Bock SA. Diagnostic evaluation. Pediatrics 2003;111:1638–44.10
Pulendran B, Banchereau J, Maraskovsky E, et al. Modulating the
immune
response with dendritic cells and their growth factors. Trends
Immunol2001;22:41–7.
11 Kapsenberg ML. Dendritic-cell control of pathogen-driven
T-cell polarization.Nat Rev Immunol 2003;3:984–93.
12 Stagg AJ, Hart AL, Knight SC, et al. The dendritic cell: its
role in intestinalinflammation and relationship with gut bacteria.
Gut 2003;52:1522–9.
13 Nagler-Anderson C, Bhan AK, et al. Control freaks: immune
regulatory cells.Nat Immunol 2004;5:119–22.
14 Rissoan MC, Soumelis V, Kadowaki N, et al. Reciprocal control
of T helper celland dendritic cell differentiation. Science
1999;283:1183–6.
15 Heyman M, Darmon N, Dupont C, et al. Mononuclear cells from
infantsallergic to cow’s milk secrete tumor necrosis factor a,
altering intestinalfunction. Gastroenterology 1994;106:1514–23.
16 Berin MC, Yang PC, Ciok L, et al. Role for IL-4 in
macromolecular transportacross human intestinal epithelium. Am J
Physiol 1999;276:C1046–52.
17 Steinbrink K, Graulich E, Kubsch S, et al. CD4(+) and CD8(+)
anergic T cellsinduced by interleukin-10-treated human dendritic
cells display antigen-specific suppressor activity. Blood
2002;99:2468–76.
18 Lúdviksson BR, Seegers D, Resnick AS, et al. The effect of
TGF-beta1 onimmune responses of naive versus memory CD4+ Th1/Th2 T
cells.Eur J Immunol 2000;30:2101–11.
19 Takeuchi M, Alard P, Streilein JW. TGF-beta promotes immune
deviation byaltering accessory signals of antigen-presenting cells.
J Immunol1998;160:1589–97.
20 Toms C, Powrie F. Control of intestinal inflammation by
regulatory T cells.Microbes Infect 2001;3:929–35.
21 Stavnezer J. Regulation of antibody production and class
switching by TGF-beta. J Immunol 1995;155:1647–51.
22 Nazli A, Yang PC, Jury J, et al. Epithelia under metabolic
stress perceivecommensal bacteria as a threat. Am J Pathol
2004;164:947–57.
23 Collins SM, Piche T, Rampal P. The putative role of
inflammation in the irritablebowel syndrome. Gut 2001;49:743–5.
24 Gonsalkorale WM, Perrey C, Pravica V, et al. Interleukin 10
genotypes inirritable bowel syndrome: evidence for an inflammatory
component? Gut2003;52:91–3.
25 Duchmann R, Kaiser I, Hermann E, et al. Tolerance exists
towards residentintestinal flora but is broken in active
inflammatory bowel disease (IBD). ClinExp Immunol
1995;102:448–55.
26 Lodes MJ, Cong Y, Elson CO, et al. Bacterial flagellin is a
dominant antigen inCrohn disease. J Clin Ivest
2004;113:1296–306.
27 Otte J-M, Kiehne K, Herzig K-H. Antimicrobial peptides in
innate immunity ofthe human intestine. J Gastroenterol
2003;38:717–26.
28 Macpherson AJ, Uhr T. Induction of protective IgA by
intestinal dendritic cellscarrying commensal bacteria. Science
2004;303:1662–5.
29 Haller D, Jobin C. Interaction between resident luminal
bacteria and the host:can a healthy relationship turn sour? J
Pediatr Gastroenterol Nutr2004;38:123–36.
30 Kelly D, Campbell JI, King TP, et al. Commensal anaerobic gut
bacteriaattenuate inflammation by regulating nuclear-cytoplasmic
shuttling of PPAR-cand RelA. Nat Immunol 2004;5:104–12.
31 Nobaek S, Johansson M-L, Molin G, et al. Alteration of
intestinal microflora isassociated with reduction in abnormal
bloating and pain in patients withirritable bowel syndrome. Am J
Gastroenterol 2000;95:1231–8.
32 Sen S, Mullan MM, Parker TJ, et al. Effect of Lactobacillus
plantarum 299v oncolonic fermentation and symptoms of irritable
bowel syndrome. Dig Dis Sci2002;47:2615–20.
33 Kim HJ, Camilleri M, McKinzie S, et al. A randomized
controlled trial of aprobiotic, VSL#3, on gut transit and symptoms
in diarrhoea-predominantirritable bowel syndrome. Aliment Pharmacol
Ther 2003;17:895–904.
Food allergy in IBS 1393
www.gutjnl.com
-
HEADACHE CARE
VOL. 2, NO. 2, 2005, 105–110
© 2005 LIBRAPHARM LIMITED
1742–3430
doi:10.1185/174234305X14962
ORIGINAL ARTICLE
A Prospective Audit of Food Intolerance among Migraine Patients
in Primary Care Clinical PracticeTrevor Rees1, David Watson2, Susan
Lipscombe3, Helen Speight4, Peter Cousins4, Geoffrey Hardman5 and
Andrew J. Dowson61Hawthorns Surgery, Sutton Coldfield, West
Midlands, UK2Hamilton Medical Group, Aberdeen, Scotland3Park
Crescent New Surgery, Brighton, East Sussex, UK4YORKTEST
Laboratories Ltd (YTL), Osbaldwick, York, UK5Centre for Health
Economics, University of York, York, UK6King’s Headache Service,
King’s College Hospital, London, UK
Address for correspondence: Dr Andrew J. Dowson, The King’s
Headache Service, King’s College Hospital, Denmark Hill, London SE5
9RS, UK. Tel./Fax: +44-1428-712546; email:
[email protected]
Key words: Diet – Food intolerance – Migraine – Primary care
This prospective audit was set up to investigate whether
migraine sufferers have evidence of IgG-based food intolerances and
whether their condition can be improved by the withdrawal from the
diet of specific foods identified by intolerance testing. Migraine
patients were recruited from primary care practices and a blood
sample was taken. Enzyme-linked immunosorbent assays (ELISA) were
conducted on the blood samples to detect food-specific IgG in the
serum. Patients identified with food intolerances were encouraged
to alter their diets to eliminate appropriate foods and were
followed up for a 2-month period. Endpoints included identification
of the specific foods that the patients were intolerant to,
assessing the proportion of patients who altered their diet and the
benefit obtained by these patients at 1 and 2 months. Patients
reported the level of benefit on a 6-point scale, where 0 = no
benefit and 5 = high benefit. Sixty one patients
took part in the audit and 39 completed 2 months of
investigation. The mean number of foods identified in the IgG test
was 5.3 for all participants and 4.7 for those successfully
altering their diet. About 90% of patients changed their diet to a
greater or lesser extent following the identification of possible
food intolerances. A marked proportion of the migraine patients
benefited from the dietary intervention, approximately 30% and 40%
reporting considerable benefit at 1 and 2 months, respectively.
Also, over 60% of patients who reintroduced the suspect foods back
into their diets reported the return of their migraine symptoms.
This investigation demonstrated that food intolerances mediated via
IgG may be associated with migraine and that changing the diet to
eradicate specific foods may be a potentially effective treatment
for migraine. Further clinical studies are warranted in this
area.
S U M M A R Y
Paper 0047 105
-
106 A Prospective Audit of Food Intolerance among Migraine
Patients in Primary Care Clinical Practice © 2005 LIBRAPHARM LTD –
Headache Care 2005; 2(2)
Introduction
Dietary components are frequently proposed as precip-itating
factors for migraine, particularly in children and adolescents1,2.
Many different foods have been implic-ated as potential triggers
for migraine attacks, including chocolate, cheese, red wine and
many others3. However, evidence for this interaction is mostly
anecdotal and based on patient reports4. Open studies indicated
that low-fat5 and high carbohydrate6 diets could lead to
improvements in migraine frequency and/or severity. In contrast, no
controlled study has confirmed the incidence of food-evoked
migraine attacks. A controlled study with chocolate failed to show
that it provoked migraine attacks7. An alternative concept of the
relationship of food with migraine is that food cravings occur
during the prodrome phase; the food intake thus being a consequence
of the attack rather than a cause of it8.
Migraine may be precipitated by food via chemical or
immunological mechanisms. Dietary components may affect phases of
the migraine process by influencing release of serotonin and
noradrenaline, causing vaso-constriction or vasodilatation, or by
direct stimulation of trigeminal ganglia, brainstem and cortical
neuronal pathways1. Immunological reactions may be mediated by
Immunoglobulin E (IgE [classical food allergies occurring
immediately after eating]) or, more controv-ersially, by
Immunoglobulin G (IgG [food intolerance involving a delayed
allergic reaction 2–120 hours after eating]). Available evidence
indicates that an IgE mechanism is relatively unimportant in
food-induced migraine9 and a review of the clinical literature
established no clear evidence of an immune dysfunction in migraine
sufferers10. However, the role of a putative IgG mechanism is
presently unknown.
The usual way to treat food intolerance is by food elimination
and re-challenge procedures, which are imprecise, lengthy and
inefficient. As a more efficient alternative to this approach, an
enzyme-linked immunosorbent assay (ELISA) test to a panel of 113
food allergen extracts has been developed (YORKTEST Laboratories
Ltd [YTL], York, UK). This detects raised food-specific IgG in the
serum of people with one or more, usually chronic, conditions.
Patients with raised IgG levels to specific foods are advised to
remove these from their diets and their progress is monitored with
a series of questionnaires. An independent audit of patients
treated in this way between February 1998 and August 1999 showed
that approximately 50% of all patients reported a high or
relatively high response to dietary therapy, based on their levels
of food-specific IgGs11. A randomised, controlled clinical trial
has demonstrated beneficial effects of this form of dietary therapy
on symptom relief for irritable bowel syndrome12.
The present audit was set up to investigate whether migraine
sufferers have evidence of IgG-based food intolerances and whether
their condition can be improved by the withdrawal from the diet of
specific foods identified by intolerance testing.
Patients and Methods
Patients
Established adult migraine patients (age > 18 years) were
recruited from primary care clinical practices by their GPs.
Patients were required to have high-impact headaches. Patients were
diagnosed with episodic migraine (≤ 15 days of headache per month)
or chronic migraine (> 15 days of headache per month), according
to the GP’s usual practices. All patients provided their written
informed consent to take part in the audit.
Study Design
This prospective audit investigated whether migraine patients
identified in primary care clinical practice exhibited food
intolerances measured as elevated IgG levels to specific foods. The
audit also investigated the effect of withdrawing foods associated
with high IgG levels on patients’ migraine attacks over a 2-month
period.
Primary care physicians were briefed on the rationale and
objectives of the audit at a meeting of the UK charity Migraine in
Primary Care Advisors (MIPCA) and agreed to participate. Each
physician recruited up to 20 migraine patients and provided them
with information about the audit. Before entering the study, all
patients completed a baseline questionnaire to record demography
and allergy history and a Headache Impact Test (HIT-613)
questionnaire to record headache severity.
Patients who completed the initial questionnaires were sent a
validated blood testing kit by YTL. Patients took a blood sample by
skin prick as detailed in the leaflet enclosed with the testing kit
and returned the kit to YTL by mail. The blood samples were
processed by YTL on receipt of the questionnaires and blood kit.
ELISA tests on blood samples were used to detect food-specific IgG
in the serum of the blood samples. Results of the ELISA tests were
sent directly to the patients by YTL, together with a guidebook on
food intolerances and their treatment14.
Patients were free to change their diets to eliminate specific
foods identified by the ELISA tests as possibly causing
intolerance, either on their own initiative or after consultation
with their GP or other healthcare professional. Patients had access
by telephone to a
-
© 2005 LIBRAPHARM LTD – Headache Care 2005; 2(2) A Prospective
Audit of Food Intolerance among Migraine Patients in Primary Care
Clinical Practice Rees et al. 107
professional dietitian to help them with any dietary alterations
that they wished to implement. Follow-up questionnaires were sent
to patients after 1 and 2 months to monitor their progress
(investigation period).
Study Endpoints and Statistical Analyses
The main study endpoints were:
Demographic data on the patient population, and details of their
allergy and headache histories, analysed as descriptive
statistics.Identification of the specific foods to which the
patients could be intolerant, identified from the ELISA tests of
IgG levels and analysed as descriptive statistics.The proportion of
patients who altered their diet due to their ELISA test results,
analysed as descriptive statistics.The benefit obtained at 1 and 2
months by the patients who altered their diet compared with the
situation before diet alteration, analysed as descriptive
statistics. Patients reported their level of benefit on a 6-point
scale, where 0 = no benefit and 5 = high benefit.
Results
Patient Disposition
Sixty-one patients from six UK GP practices (range 1–17 per
centre) were recruited into the audit and completed baseline
assessments. In the investigation period, 46 patients (75.4%)
continued in the study to 1 month and 39 (63.9%) to 2 months.
Baseline Demography and Headache Severity
Table 1 shows the demography of the patients who took part in
the study. The average age was 45.2 years (range 21–68) and most
patients (80%) were women.
•
•
•
•
The majority of patients (78.0%) were in full-time education or
employment. In examining the allergy history, 15 patients (24.6%)
were aware of foods they felt they were allergic to, 42 (68.9%)
were in contact with pets, 12 (20.0%) were in contact with
chemicals or occupational dust, 52 (86.7%) were currently taking
medication and 21 (34.4%) knew about medications they felt they
were allergic to. Fifteen patients (24.6%) were current smokers and
18 (29.5%) had given up smoking. Forty three patients (72.9%) drank
alcohol but only eight drank over seven units per week and only one
drank more than 14 units per week.
Most patients had suffered from headache for a considerable
time; 64% for ≥ 10 years, 20% for 5–10 years and 16% for < 5
years. Patients were severely affected by their headaches (Table
2). Eighty two per cent ‘very often’ or ‘always’ had severe pain,
while 67% were ‘very often’ or ‘always’ limited in their usual
activities during their headaches. Between 87% and 90% of patients
were too tired to work, felt irritation and suffered from lack of
concentration at least sometimes during their attacks. Patients
reported a mean of 10.1 symptoms (range 1–24) associated with their
headaches. Over 80% of patients reported that their headaches
interfered with sleep, leisure and overall comfort. The mean
weighted HIT score at baseline was 64.9 (range 48–78),
corresponding to severe impact13.
Gender Male 12 20.0%Female 48 80.0%
Age group Under 30 10 16.7%30 to 39 9 15.0%40 to 49 14 23.3%50
to 59 21 35.0%60 and over 6 10.0%
Employment status Retired 3 5.1%Sick/disabled 4 6.8%Housewife 3
5.1%Part time 2 3.4%Full time skilled 25 42.4%Full time
semi-skilled 17 28.8%Full time unskilled 2 3.4%Student 2
3.4%Unemployed 1 1.7%
Proportion of patients (%) Headache severity
Never Rarely Sometimes Very often Always
Severe pain 2 0 16 61 21Limit to usual activities 0 2 31 51
16Desire to lie down 2 0 18 41 39Too tired to work 5 8 51 31
5Irritation 5 7 33 39 16Lack of concentration 3 7 38 40 12
Table 1. Baseline demography (n = 61)
Table 2. Severity of patients’ headaches: pain intensity, impact
on daily activities and mood alterations
-
108 A Prospective Audit of Food Intolerance among Migraine
Patients in Primary Care Clinical Practice © 2005 LIBRAPHARM LTD –
Headache Care 2005; 2(2)
Identification of Food Intolerances
Food intolerances identified by IgG testing were analysed for
the 61 patients who took part in the study and for the 39 who
completed the 2 months of investigation. In the total study
population, 60 of 61 patients (98.4%) had reactions to a total of
48 different foods, with an average of 5.3 (range 0–17) reactions
per patient. In the patients who completed 2 months, 38 of 39
patients (97.4%)
had reactions to a total of 36 different foods, with an average
of 4.7 (range 0–17) reactions per patient. Table 3 shows the
distribution of food intolerances in these two populations. The
most frequently reported intolerances (in over 10% of patients in
either population) were to cow’s milk, yeast, egg white, egg yolk,
wheat, gluten (gliadin), corn, cashew nuts, mollusc mix, brazil
nut, cranberry and garlic (Table 3), and were similar in prevalence
in the two populations.
Positive ELISA test ( n [%]) Food
Whole study population ( n = 61)
Patients completing 2 months( n = 39)
Cow’s milk 52 (85.2%) 34 (87.2%) Yeast 37 (60.7%) 22 (56.4%) Egg
white 34 (55.7%) 23 (59.0%) Egg yolk 20 (32.8%) 13 (33.3%) Wheat 19
(31.1%) 12 (30.8%) Gliadin 16 (26.2%) 10 (25.6%) Corn 15 (24.6%) 8
(20.5%) Cashew 12 (19.7%) 7 (17.9%) Mollusc mix 10 (16.4%) 3 (7.7%)
Brazil nut 9 (14.8%) 6 (15.4%) Cranberry 7 (11.5%) 5 (12.8%) Garlic
5 (8.2%) 4 (10.3%) Beef 3 (4.9%) 2 (5.1%) Pork 3 (4.9%) 1 (2.6%)
Ginger 3 (4.9%) 2 (5.1%) Buckwheat 4 (6.6%) 1 (2.6%) Crustacean mix
5 (8.2%) 1 (2.6%) Rye 2 (3.3%) 2 (5.1%) Millet 3 (4.9%) 2 (5.1%)
Rice 1 (1.6%) 1 (2.6%) Soya bean 5 (8.2%) 3 (7.7%) Hazelnut 4
(6.6%) 3 (7.7%) Mustard seed 1 (1.6%) 1 (2.6%) Salmon/trout 2
(3.3%) 1 (2.6%) Plaice/sole 3 (4.9%) 1 (2.6%) Peanut 3 (4.9%) 2
(5.1%) Chicken 3 (4.9%) 1 (2.6%) Lentils 3 (4.9%) 1 (2.6%) Pea 2
(3.3%) 1 (2.6%) Almond 5 (8.2%) 3 (7.7%) Cola nut 3 (4.9%) 1 (2.6%)
Duck 1 (1.6%) 0Lamb 3 (4.9%) 1 (2.6%) Turkey 2 (3.3%) 0White fish 3
(4.9%) 1 (2.6%) Kiwi 4 (6.6%) 2 (5.1%) Pineapple 2 (3.3%)
0Sunflower seed 2 (3.3%) 0Oat 2 (3.3%) 0Haricot bean 3 (4.9%) 2
(5.1%) Coconut 1 (1.6%) 1 (2.6%) Tea 1 (1.6%) 0Carrot 1 (1.6%)
0Barley 1 (1.6%) 0Tuna 1 (1.6%) 0Sesame seed 1 (1.6%) 0Coffee 1
(1.6%) 0Avocado 1 (1.6%) 0
Table 3. Food intolerances in the audit population: number and
proportion of patients with a positive ELISA test to IgG from
various foodstuffs
-
© 2005 LIBRAPHARM LTD – Headache Care 2005; 2(2) A Prospective
Audit of Food Intolerance among Migraine Patients in Primary Care
Clinical Practice Rees et al. 109
Proportion of Patients who Altered their Diets
Of the 46 patients who returned the questionnaire after 1 month
of investigation, 41 (89.1%) patients changed their diets to
eliminate foods identified by the IgG testing and 5 (10.9%) did
not. Of those who changed their diet, 19 (46.3%) reported that they
altered their diets a lot and 22 (53.7%) reported they had made a
‘reasonable attempt’ to avoid the specified foods.
Of the 39 patients who returned the questionnaire after 2 months
of investigation, 22 (56.4%) reported that they altered their diets
a lot and 13 (33.3%) reported they had made a ‘reasonable attempt’
to avoid the specified foods. Two patients reported that they did
not change their diet at all.
Benefit Obtained from Changing Diets
Figures 1 and 2 show the level of benefit reported by patients
after 1 and 2 months, respectively, using the 6-point scale (0 = no
benefit and 5 = high benefit). After 1 month, 27.5% of patients
reported considerable benefit (scoring 4 or 5), while 30.0%
reported little or no benefit (scoring 0 or 1). Of 18 patients who
had retried foods they had stopped taking, five (27.8%) reported a
strong return of migraine symptoms and seven (38.9%) a slight
return. After 2 months, 38.2% of patients reported considerable
benefit (scoring 4 or 5), while 32.4% reported little or no benefit
(scoring 0 or 1). Of 26 patients who had retried foods they had
stopped taking, seven (26.9%) reported a strong return of migraine
symptoms and 11 (42.3%) a slight return.
A limited post hoc analysis was conducted to investigate the
factors possibly associated with benefit. Of the 13 patients who
reported considerable benefit from dieting after 2 months, nine
(69.2%) said they had dieted strictly after 1 month and 12 (92.3%)
after 2 months. Of the 11 patients who reported little or no
benefit after 2 months, only two (18.2%) had dieted strictly after
1 month and five (45.5%) after 2 months. Compared to those who did
not benefit, the patients who benefited were more likely to have
suffered from bloating and sleep deprivation and to have never
smoked (although all patients had given up at least 10 years
previously). Those who reported no benefit from dieting were more
likely to be trying other remedies as well, including avoiding
chocolate and taking sumatriptan and homeopathic remedies. However,
none of the above differences was testable for statistical
significance due to the small number of patients involved.
Discussion
To our knowledge, this is the first investigation of possible
IgG-mediated food intolerances in migraine patients. The patients
who took part were all severely affected by their
migraine, reporting high levels of pain and impact on their
everyday activities. This is a group of patients who are typically
poorly managed in primary care15 and for whom new management
initiatives would be welcome.
Almost all patients had multiple food intolerances in this
investigation, identified as positive food-specific IgG test
results. Typically, individuals were positive to at least one of
cow’s milk, egg and yeast, together with a small number of more
individual reactions. These results are similar to those reported
for other conditions11,12. Of the patients who took part in the
investigation, about 90% changed their diet to a greater or lesser
extent at both 1 and 2 months.
A marked proportion of the migraine patients benefited from
dietary intervention by cutting out foods for which they had an
elevated IgG level. Approx-imately 30% and 40% reported
considerable benefit at 1 and 2 months, respectively. Reinforcing
this is the fact that over 60% of patients who re-introduced the
suspect foods back into their diets reported the return of their
migraine symptoms. These results are encouraging and indicate that
changing diet to counteract food intoler-
0
5
10
15
20
25
Nobenefit
Highbenefit
% p
atie
nts
20.0
10.0
22.5
13.115.0
12.5
0 1 2 3 4 5
0
5
10
15
20
25
20.6
11.8 11.8
17.6 17.6
20.6
Nobenefit
Highbenefit
0 1 2 3 4 5
% p
atie
nts
Figure 1. Benefit of the diet after 1 month of the
investigation: proportion of patients reporting their level of
benefit on a 6-point scale, where 0 = no benefit and 5 = high
benefit
Figure 2. Benefit of the diet after 2 months of the
investigation: proportion of patients reporting their level of
benefit on a 6-
point scale, where 0 = no benefit and 5 = high benefit
-
110 A Prospective Audit of Food Intolerance among Migraine
Patients in Primary Care Clinical Practice © 2005 LIBRAPHARM LTD –
Headache Care 2005; 2(2)
ances may be an effective treatment for at least some migraine
sufferers.
However, it is not yet possible to recommend this approach for
general clinical use. This investigation was a small audit to
establish a possible relationship between food intolerances and
migraine. In this it was successful, although benefits experienced
by patients may have been due (in part or in whole) to a placebo
effect. There remains a series of questions that need to be
answered before we have proof of this concept:
Do migraine sufferers differ from unaffected people or people
with other disorders in the pattern of IgG that circulates?Do
symptomatic reports of food intolerance correlate with the IgG
data?Are migraine sufferers able to self-identify food
intolerances?Does allergen avoidance lead to an improvement in
migraine and can this be confirmed by re-challenge?
We suggest two follow-up studies that may answer these
questions. Whether migraine patients differ from the general
population and whether self-reported allergies correlate with food
intolerances in migraine sufferers can be examined in a blinded
study investigating the pattern of IgG-related food intolerances in
migraine patients (with and without a history of allergy) and
matched healthy controls without migraine. A small
placebo-controlled study can then be used to study the effect of
diet alteration on migraine symptoms. The study requires a
re-challenge phase, and robust, validated endpoints, over a 3-month
evaluation time.
In conclusion, this pilot audit demonstrated that migraine
attacks may be related to food intolerances mediated via IgG and
that changing the diet to eradicate specific foods may be a
potentially effective treatment for migraine. Further clinical
studies are required to confirm these findings and examine the
clinical importance of this treatment approach.
•
•
•
•
Acknowledgements
The authors are pleased to acknowledge the help of Dr Frances
Carter during the setting up and running of this audit. The audit
was conducted by MIPCA, with help and sponsorship from the Migraine
Action Association and YORKTest Laboratories Ltd.
References 1. Millichap JG, Yee MM. The diet factor in pediatric
and
adolescent migraine. Pediatr Neurol 2003;28:9-15 2. Leira R,
Rodriguez R. Diet and migraine. Rev Neurol 1996;
24:534-8 3. Breslau N, Rasmussen BK. The impact of migraine:
Epidemiology,
risk factors, and co-morbidities. Neurology 2001;56(Suppl. 1):
4-12
4. Peatfield RC. Relationships between food, wine, and
beer-precipitated migrainous headache. Headache 1995;35: 355-7
5. Bic Z, Blix GG, Hopp HP et al. The influence of a low-fat
diet on incidence and severity of migraine headaches. J Womens
Health Gend Based Med 1999;8:623-30
6. Hasselmark L, Malmgren R, Hannerz J. Effect of a
carbohydrate-rich diet, low in protein-tryptophan, in classic and
common migraine. Cephalalgia 1987;7:87-92
7. Marcus DA, Scharff L, Turk D et al. A double-blind
provocative study of chocolate as a trigger of headache.
Cephalalgia 1997;17:855-62
8. Bedell AW, Cady RK, Diamond ML et al. Patient-centered
strategies for effective management of migraine. Springfield,
Missouri: Primary Care Network, 2000
9. Pradalier A, Launay JM. Immunological aspects of migraine.
Biomed Pharmacother 1996;50:64-70
10. Kemper RH, Meijler WJ, Korf J et al. Migraine and function
of the immune system: a meta-analysis of clinical literature
published between 1966 and 1999. Cephalalgia 2001; 21:549-57
11. Sheldon TA. Independent audit of IgG food intolerance tested
patient survey. British Allergy Foundation, 2000
12. Atkinson W, Sheldon TA, Shaath N et al. Food elimination
based on IgG antibodies in irritable bowel syndrome: a randomised
controlled trial. Gut 2004;53:1459-64
13. Kosinski M, Bayliss MS, Bjorner JB et al. A six-item
short-form survey for measuring headache impact: the HIT-6. Qual
Life Res 2003;12:963-74
14. YORKTEST guidebook on food intolerances and their treatment.
York, UK: YORKTEST Laboratories Ltd, 2002
15. Lipton RB, Goadsby PJ, Sawyer JPC et al. Migraine: diagnosis
and assessment of disability. Rev Contemp Pharmacother
2000;11:63-73
CrossRef links are available in the online published version of
this paper:http://www.cmrojournal.com
Paper HC-0047_2, Accepted for publication: 27 January
2005Published Online: 18 February 2005
doi:10.1185/174234305X14962
http://www.ingentaconnect.com/content/external-references?article=0028-3878(2001)56L.4[aid=6673259]http://www.ingentaconnect.com/content/external-references?article=0028-3878(2001)56L.4[aid=6673259]http://www.ingentaconnect.com/content/external-references?article=0887-8994(2003)28L.9[aid=6673258]http://www.ingentaconnect.com/content/external-references?article=0017-8748(1995)35L.355[aid=6368140]http://www.ingentaconnect.com/content/external-references?article=0017-8748(1995)35L.355[aid=6368140]http://www.ingentaconnect.com/content/external-references?article=1524-6094(1999)8L.623[aid=6673257]http://www.ingentaconnect.com/content/external-references?article=1524-6094(1999)8L.623[aid=6673257]http://www.ingentaconnect.com/content/external-references?article=0333-1024(1987)7L.87[aid=6673256]http://www.ingentaconnect.com/content/external-references?article=0333-1024(1997)17L.855[aid=6673255]http://www.ingentaconnect.com/content/external-references?article=0333-1024(1997)17L.855[aid=6673255]http://www.ingentaconnect.com/content/external-references?article=0753-3322(1996)50L.64[aid=6673254]http://www.ingentaconnect.com/content/external-references?article=0333-1024(2001)21L.549[aid=6673253]http://www.ingentaconnect.com/content/external-references?article=0333-1024(2001)21L.549[aid=6673253]http://www.ingentaconnect.com/content/external-references?article=0017-5749(2004)53L.1459[aid=6673252]http://www.ingentaconnect.com/content/external-references?article=0962-9343(2003)12L.963[aid=5908482]http://www.ingentaconnect.com/content/external-references?article=0962-9343(2003)12L.963[aid=5908482]http://www.cmrojournal.comhttp://dx.doi.org/10.1185/174234305X14962
-
T h e n e w e ng l a nd j o u r na l o f m e dic i n e
n engl j med 357;17 www.nejm.org october 25, 2007 1731
review article
Medical Progress
Celiac DiseasePeter H.R. Green, M.D., and Christophe Cellier,
M.D., Ph.D.
From the Department of Medicine, Colum-bia University College of
Physicians and Surgeons, New York (P.H.R.G.); and the Department of
Gastroenterology, Euro-pean Georges Pompidou Hospital, René
Descartes Paris V University, Assistance Publique–Hôpitaux de
Paris, INSERM U793, Paris (C.C.). Address reprint re-quests to Dr.
Green at the Department of Medicine, Columbia University College of
Physicians and Surgeons, 180 Fort Washington Ave., Rm. 956, New
York, NY 10032, or at [email protected].
N Engl J Med 2007;357:1731-43.Copyright © 2007 Massachusetts
Medical Society.
Celiac disease is a unique autoimmune disorder, unique because
the environmental precipitant is known. The disorder was previously
called celiac sprue, based on the Dutch word sprue, which was used
to describe a dis-ease similar to tropical sprue that is
characterized by diarrhea, emaciation, aphthous stomatitis, and
malabsorption.1,2 Celiac disease is precipitated, in genetically
pre-disposed persons, by the ingestion of gluten, the major storage
protein of wheat and similar grains.3 Originally considered a rare
malabsorption syndrome of child-hood, celiac disease is now
recognized as a common condition that may be diag-nosed at any age
and that affects many organ systems. The therapy for the disease is
a gluten-free diet; however, the response to therapy is poor in up
to 30% of patients, and dietary nonadherence is the chief cause of
persistent or recurrent symptoms. Small intestinal adenocarcinoma,
refractory sprue, and enteropathy-associated T-cell lymphoma are
complications of celiac disease that must be ruled out when
alarm-ing symptoms such as abdominal pain, diarrhea, and weight
loss develop despite a strict gluten-free diet.
Patho genesis
Celiac disease results from the interaction between gluten and
immune, genetic, and environmental factors (Fig. 1).
The Role of Gluten
Celiac disease is induced by the ingestion of gluten, which is
derived from wheat, barley, and rye. The gluten protein is enriched
in glutamine and proline and is poor-ly digested in the human upper
gastrointestinal tract. The term “gluten” refers to the entire
protein component of wheat; gliadin is the alcohol-soluble fraction
of gluten that contains the bulk of the toxic components.
Undigested molecules of gliadin, such as a peptide from an
α-gliadin fraction made up of 33 amino acids, are resis-tant to
degradation by gastric, pancreatic, and intestinal brush-border
membrane proteases in the human intestine and thus remain in the
intestinal lumen