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Significance of salicylate intolerance in diseases of the lower gastrointestinal tract

  • Waldkrankenhaus St. Marien

Abstract and Figures

Salicylate intolerance is defined as a nonspecific antigen-induced pseudo-allergic hypersensitivity reaction which can occur upon contact of an organism with salicylic acid, its derivatives or other related organic or inorganic acids of similar chemical structure. Since the effects of nonsteroidal anti-inflammatory drugs (NSAID) intolerance are by no means always severe or life-endangering but may just as well present as oligosymptomatic or local disorders (e.g. abdominal pain, diarrhea, we decided to evaluate the characteristics of patients with salicylate intolerance on the basis of gastroenterological case material of Medical Department I of Erlangen University. On the basis of the findings from the Erlangen interdisciplinary data register of chronic inflammatory gastrointestinal disease, the signs and symptoms of NSAID intolerance were found to constitute a diagnosis of great practical import to clinical medicine (allergology, dermatology, immunology, other disorders etc.) including gastroenterology. For approx. 2-7% of all patients with inflammatory bowel syndrome and food allergies this poses a new diagnostic and therapeutic challenge which may concern physicians from any of the disciplines involved. When presented with patients with chronic active disease who are suffering from these symptoms one should, therefore, in future give greater thought to the possibility of salicylate intolerance, all the more as there are meaningful dietetic, diagnostic and therapeutic options available for these persons.
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1Dept. of Medicine I, Gastroenterology, Functional Tissue Diagnostics, Erlangen University
2Dept. of Medicine III, Immunology and Allergology, Erlangen University, Erlangen Germany,
3Weiden Medical Laboratory, Bavaria, Germany,
Salicylate intolerance is defined as a nonspecific antigen-induced pseudo-allergic
hypersensitivity reaction which can occur upon contact of an organism with salicylic
acid, its derivatives or other related organic or inorganic acids of similar chemical
structure. Since the effects of nonsteroidal anti-inflammatory drugs (NSAID)
intolerance are by no means always severe or life-endangering but may just as well
present as oligosymptomatic or local disorders (e.g. abdominal pain, diarrhea, we
decided to evaluate the characteristics of patients with salicylate intolerance on the
basis of gastroenterological case material of Medical Department I of Erlangen
University. On the basis of the findings from the Erlangen interdisciplinary data
register of chronic inflammatory gastrointestinal disease, the signs and symptoms of
NSAID intolerance were found to constitute a diagnosis of great practical import to
clinical medicine (allergology, dermatology, immunology, other disorders etc.)
including gastroenterology. For approx. 2-7% of all patients with inflammatory
bowel syndrome and food allergies this poses a new diagnostic and therapeutic
challenge which may concern physicians from any of the disciplines involved. When
presented with patients with chronic active disease who are suffering from these
symptoms one should, therefore, in future give greater thought to the possibility of
salicylate intolerance, all the more as there are meaningful dietetic, diagnostic and
therapeutic options available for these persons.
Key words: salicylate intolerance, lower gastrointestinal tract
Salicylate intolerance is defined as a nonspecific antigen-induced pseudo-
allergic hypersensitivity reaction which can occur upon contact of an organism
with salicylic acid, its derivatives or other related organic or inorganic acids of
similar chemical structure (1, 2) . The spectrum of salicylate intolerance
(NSAID intolerance) triggers comprises not only aspirin, nonsteroidal
antiphlogistics and other salicylate-containing drugs but also certain foods
containing salicylic acid in various concentrations, preservatives and colorants.
Since this type of pseudo-allergic hypersensitivity reaction is not limited to one
specific substance (such as aspirin) but can be triggered by any of a whole
group of substances it is preferable to speak of NSAID intolerance rather than
salicylate intolerance (1).
Although many people come in contact with the above-named groups of
substances, the exact frequency of salicylate intolerance in the population is still
not known to date. NSAID intolerance is observed more frequently in adults than
it is in children, and this is taken as an indication of its being an acquired disorder
(pseudo-allergy) (1). First reports of frequency data have now become available
for certain patient groups. For example, 2 to 4 per cent of patients being treated
at allergology outpatient clinics are found to be NSAID intolerant (1). Among the
patients of otorhinolaryngology clinics 15 to 20 per cent of those with chronic
rhinitis, nasal polyps, sinusitis and nonallergic asthma are also found to be
intolerant to salicylate. In the area of gastroenterology, reliable systematic data on
the incidence of salicylate intolerance have not been reported to date. In view of
the fact that certain groups of gastroenterological disease (e.g. IBD =
Inflammatory Bowel Disease) are treated with salicylate containing drugs, the
issue of NSAID intolerance in these patients is of great clinic significance,
especially as regards differential diagnostics (3-7).
The clinical picture of salicylate intolerance (NSAID intolerance) is
characterized by systemic as well as local (oligosymptomatic) manifestations.
The classical triad of intolerance to acetylsalicylic acid (ASA triad) comprises
the occurrence of polyposis nasi, nonallergic asthma and angioedema as well as
laryngeal edema following contact with substances containing acetylsalicylic
acid (1,2). Angioedema, laryngeal edema and asthma attacks are often
manifestations of an acute pseudo-allergic episode, whereas polyposis nasi and
chronic sinusitis can be a chronic sequel of an unrecognized salicylate
intolerance. Table 1 shows further systemic (typical), local or oligosymptomatic
(atypical) symptoms of salicylate intolerance, all of which may be of an acute
or chronic nature (2-7).
In distinction from systemic symptoms, which constitute a general immune
response of the entire organism, there may also be local symptoms in the
gastrointestinal tract. To date there has been no specific research on the question why
in some persons NSAID intolerance manifests itself in a general systemic
hypersensitivity while in others it produces symptoms that are more or less local and
organ-specific. However, the presentation of such gastrointestinal symptoms,
whether or not accompanied by systemic manifestations, can pose considerable
difficulties of differential diagnosis, and the possibility of NSAID intolerance should
therefore always be drawn into consideration in patients not responding to therapy.
Pathophysiologically speaking, symptoms of salicylate intolerance can be
explained by an overproduction of leukotriene metabolites, since salicylate
intolerant patients who have come in contact with salicylate containing
substances show a marked inhibition of cyclooxygenase (COX-1), which is
continuously expressed in the body (Fig. 1) (2, 8). On one side this leads to a
diminished production of typical cyclooxygenase products (e.g. tissue-protective
prostaglandin derivatives, prostacyclin, thromboxan), while on the other it
accelerates the metabolization of arachidonic acid towards leukotriene A4 (9).
Leukotriene A4 undergoes rapid enzymatic conversion, either to leukotriene B4,
a strong chemotactic agent, or via leukotriene C4 synthase to leukotriene C4.
This product can then be decomposed to leukotrienes D4 and E4. Leukotrienes
C4 through E4 are collectively referred to as SRS (slow reacting substances of
Table 1. Acute und chronic pseudoallergic disease manifestations resulting from salicylate
intolerance (NSAID-intolerance)
I Systemic manifestations, acute or chronic
angioedema*, larynx edema
asthma bronchiale*
chronic urticaria
fever, generalised pruritus
reccurent nose swelling, secretion, rhinorrhea
sinusitis & polyposis nasi*
rare manifestations
shock, death
myocarditis, pericarditis, interstitial nephritis, pulmonal infiltrates etc.
* ASA - Triad: Mygind N. Allergology: Textbook & Atlas, Blackwell Verlag 1998; pp.64- 66
II Gastrointestinal manifestations, acute or chronic
acute phase late or chronic phase
erosion, meteorism fibrosis, strictures, (fistula ?4)
pain2, edema, swelling4
diarrhea2, colitis1-3
1Werlin SL. J Paediatr 1978; 92: 450-451, 2Pearson DJ. Br Med J 1983; 287: 1675,
3Chakraborty TK. Gut 1987; 28: 613-615, 4Pearson M. Gut 1993; 34: 783-787
III Oligosymptomatic manifestations, Cave: atypical, isolated symptoms
from I and/or II
anaphylaxis) (8,9). The variety of symptoms of salicylate intolerance in a tissue
or person may be explainable by different expression rates or differences in the
control and/or activation of leukotriene A4 hydrolase or leukotriene C4
synthase. The leukotriene B4 path is primarily involved in maintaining
inflammatory processes (e.g. chronic colitis), whereas the leukotriene C4 path is
more involved in triggering typical pseudo allergic mechanisms (e.g.
angioedema, asthma, urticaria) (1,8,9). This differentiation into a largely
proinflammatory leukotriene B 4 path and a largely pseudo-allergic leukotriene
C4 through E4 path finds its continuation in a differentiation of receptors by
which these effects are mediated. (cys-L T - B4R and cys- L T - D4R, (9)). Both
these leukotriene receptors are G protein coupled membrane proteins, yet they
are responsible for different manifestations of salicylate intolerance. Leukotriene
B 4 is considered to act as a strong chemotactic signal ( of similar strength as
complement factors). It activates T8 suppressor cells, inhibits T4 helper cells and
is supposed to stimulate IgE synthesis. The main leukotriene receptor mediated
effects of leukotrienes C4, D4 and E4 are bronchoconstriction, bronchial
hyperreactivity, mucus production and vasodilatation (1). Furthermore, both
leukotriene groups are thought to act as powerful contractors of nonvascular
smooth musculature (1, 8, 9).
Since the effects of NSAID intolerance are by no means always severe or life-
endangering but may just as well present as oligosymptomatic or local disorders
Fig. 1 Eicosanoid metabolism and the mechanism of NSAID-intolerance
( e.g. abdominal pain, diarrhea (2,5), (Table 1), it was decided to evaluate the
characteristics of patients with salicylate intolerance on the basis of
gastroenterological case material of Medical Department I of Erlangen University
(MS - Access database, interdisciplinary data register of chronic inflammatory
and allergic bowel diseases).
From a source population of 1097 fully documented cases entered into the interdisciplinary data
register of chronic inflammatory and allergic gastrointestinal diseases over the past 8 years an
extract was made of those containing any of the terms aspirin intolerance, salicylate intolerance
and NSAID intolerance. The subset thus obtained was classified into the disease groups ulcerative
colitis, gastrointestinally mediated allergy (GMA), Crohn's disease and a control group consisting
of patients with carbohydrate malabsorption or irritable bowel syndrome. Intolerance diagnoses of
any of the three types named above were only accepted if there were records prepared by a
physician documenting the occurrence of clinically manifest symptoms following the intake of
aspirin, salicylates (e.g. mesalazine) and/or other nonsteroidal antiphlogistics and this was
additionally confirmed by a physician's original findings. Persons suspected of having NSAID
intolerance were tested either by oral single-blind placebo-controlled aspirin provocation or by
mesalazine provocation. In many cases this was supplemented by a blood test for leukocyte
eicosanoid production (10). The demographic, clinical and laboratory chemical characteristics of
these patients were systematically evaluated on the basis of the patient records present.
Diagnoses of grade I to IV gastrointestinally mediated allergies (GMA) were considered valid
if confirmed by oral double-blind placebo-controlled provocation tests (11,12), while diagnoses of
IBD were verified on the basis of established clinical, endoscopic, histological, radiological and
laboratory chemical characteristics ( 13,14).
Five persons (4 cases of ulcerative colitis, 1 case of Crohn' s disease) undergoing single-blind
provocation with mesalazine (500 mg Pentasa capsules) were additionally monitored for urinary
methylhistamine over the entire test duration (5 - 7 days).
The protocol and informed consents were reviewed and approved by Institutional Ethical
Committee at Erlangen-Nuremberg, Germany and informed consent was obtained from each
Immunological mediator diagnostics
Urinary methylhistamine excretion was determined by patients collecting 12-hour night urine
(18:00- 06:00 hrs) while on a normal balanced or mixed diet that was known to cause the relevant
complaints followed by a low-allergen elimination diet (e.g. potato and rice diet, tea and mineral
water, later a rice-only or potato-only diet) (15-17). Balanced diet (day 1-2) and low-allergen meals
(day 3-4) as well as rice-only and potato-only meals were only allowed to be taken until 2 p.m. (15,17).
After that the patient ate no more until the next morning (tea and mineral water permitted). The urine
monitoring was accompanied by a documentation of clinical symptom scores in the course of the
collection days. Urine was treated with 10% acetic acid and submitted to the Buchwald-Schultis
laboratory for methylhistamine measurement by tandem mass spectroscopy (Weiden/Bavarian,
Germany) (sensitivity 2.6 ng/ml, intraassay and interassay variation 3.2 and 4.1%). In view of the fact
that mediator values vary considerably between individuals, methylhistamine excretion values were
standardized by setting them in relation to creatinine excretion and body surface area (15-17).
Furthermore, mediator values were determined as average values for each 2-day diet phase (15).
The clinical and laboratory chemical parameters under study were evaluated statistically by
descriptive methods (frequencies) and by calculating means and standard deviations.
Significance calculations were based on the Mann - Whitney test, and outcomes with p < 0.05
were declared significant.
Frequencies of NSAID intolerance in major gastroenterological diseases
As Table 2 shows, a small percentage of those patients with a major
gastroenterological disease showed a NSAID intolerance that was either
clinically well-documented or confirmable by provocation. According to the
present literature, NSAID intolerance is most frequently associated with
ulcerative colitis and GMA, whereas only 2.1% of patients with Crohn' s disease
are intolerant to salicylate.
Major laboratory chemical and clinical parameters in the NSAID intolerant
patient groups
In terms of the basic laboratory chemical parameters such as erythrocyte
sedimentation rate, eosinophils and serum IgE, NSAID intolerant patients showed
no clear trend towards pathologically altered laboratory values (Table 3). An
interesting finding in the clinical parameters is that mesalazine medication was
ineffective in more than half of ulcerative colitis patients with salicylate
intolerance. Further possible indicators of salicylate intolerance include patient
reports of intolerance to (developing complaints from) aspirin, mesalazine or
potatoes, since in the disease groups under study 14- 40% of NSAID intolerant
patients reported complaints of this type.
disease group total number clinically documented confirmed by challenge total sum
(n = patients) NSAID-intolerance NSAID-intolerance NSAID-
(n = patients or %, (n = patients or %, intolerance
respectively) respectively) (%)
Crohns disease 332 6/332 (1.8%) 1/332 (0.3%) 7 (2.1%)
ulcerative colitis 215 9/215 (4.2%) 7/215 (3.2%) 16 (7.4%)
GMA 374 12/374 (3.2%) 10/374 (2.7%) 22 (5.9%)
malabsorption, 176 1/176 (0.6%) - 1 (0.6%)
colon irritabile etc.
Table 2 Frequency of NSAID - intolerance from the Erlangen interdisciplinary data register
of chronic inflammatory and allergic bowel diseases
Mediator diagnostics based on methylhistamine excretion in NSAID intolerant
patients with gastrointestinal allergy under different diets
In 9 of 22 (40.9%) patients with confirmed gastrointestinal allergy and salicylate
intolerance it was possible to measure urinary methylhistamine excretion during the
diet phases of unrestricted diet, potato and rice diet and potato-only or rice-only
diet. MA patients showed clearly elevated urinary methylhistamine levels while on
a unrestricted diet, regardless of whether they were salicylate tolerant or intolerant.
One remarkable finding is that salicylate tolerant allergy patients (disregarding
cases of potato or rice allergy, which are rare) show a rapid decrease in
methylhistamine production after changing to a hypoallergenic potato and rice diet
(p = 0.005 versus unrestricted diet), potato-only diet (p < 0.005) or rice-only diet (p
< 0.006) and eventually reach normal methylhistamine elimination values (Fig. 2),
(15), whereas salicylate intolerant patients continue having greatly elevated urinary
methylhistamine values after changing to the potato and rice diet (p = 0.08 versus
unrestricted diet) or to the potato-only diet (p = 0.06). Salicylate intolerant patients
only return to normal methylhistamine elimination values after changing to a rice-
only diet (p = 0.008). The complaints reported by the 9 salicylate intolerant allergy
patients (40.9%) when on a potato and rice or potato-only diet are therefore partly
Table 3 Clinical and laboratory characteristics of NSAID - intolerant patients
Crohns disease ulcerative colitis GMA carbohydrate
7/332 16/225(5.9%) 22/374 malabsorption,
(5.9%) (5.9%) colon irritable etc.
1/176 (0.6%)
history and clinical data
atopy 3/7 (42.8%) 8/16 (50.0%) 10/22 (45.4%) 0/1 (0.0%)
abdominal pain,
diarrhoe from 1/7 (14.2%) 6/16 (37.5%) 7/22 (31.8%) 1/1 (100.0%)
5-ASA ineffective 2/7 (28.6%) 10/16 (62.5%) - -
adverse reaction 2/7 (28.6%) 4/16 (25.0%) 9/22 (40.9%) 0/1 (0.0%)
to potato
important laboratory and immunological parameters
sedimentation 14 ± 18 12 ± 11 5±3 2
rate (mm 1 hour)
N: < 10
eosinophils 420 ± 210 510 ± 86 440 ± 204 384
(n/µl) N: < 400
serum - IgE 66.7 ± 113 108 ± 225 76 ± 94 32
(KU/L) N: < 100
attributable to the effects of the elevated methylhistamine production which results
from the salicylate content of potatoes.
Mediator diagnostics based on methylhistamine excretion in NSAID intolerant
patients with chronic IBD following single-blind oral provocation with mesalazine
Five persons with chronic IBD and associated salicylate intolerance gradually
developed clinical complaints starting on the second day of oral application of 3
x 500 mg mesalazine daily. 2 of 5 patients (40%) developed abdominal pain from
test day 2 onward. From test day 3 on this was compounded by an increase in
stool frequency (3 of 5 persons; 60%), flatulence (2 of 5 persons; 40%) and
pruritus (1 of 5 patients; 20%). From test day 4 on stools not only became more
frequent but also more liquid/diarrhetic (4 of 5 patients; 80%).
The observed kinetics of urinary methylhistamine elimination yielded further
evidence of an involvement of methylhistamine in the pathology of salicylate
intolerance, since provocation with mesalazine resulted in an increase in
methylhistamine elimination around significance threshold through to test day 5
(Fig. 3). Starting from an elevated baseline average, expressed in terms of
µg/mmol creatinine x m2body surface area, methylhistamine production rose
from 8.7 ± 5.2 to peak values of 12.8 ± 8.5 (p = 0.07).
Fig. 2 Metylhistamine production in patients with gastrointestinally mediated allergy (GMA) with
and without salicylate intolerance (NSAID-intolerance)
Although reports and case collections on salicylate intolerance in patients with
gastroenterological diseases have been available since the early 1970s (3-5, 18),
there have to date been no systematic studies on the frequency of NSAID
intolerance in the field of gastroenterology. In a control group with carbohydrate
malabsorption or irritable bowel syndrome which had been extracted from the
Erlangen interdisciplinary data register of chronic inflammatory gastrointestinal
disease on the basis of the three criteria clinically well documented intolerance
reaction to NSAID, aspirin and/or mesazaline, proof of a clearly pathologically
elevated leukotriene production in peripheral blood cells (10) and proof of
intolerance by single-blind mesazaline provocation, the frequency of NSAID
intolerance was found to be 0.6%.
The rate of NSAID intolerance in cases of Crohn's disease was found to be 2.1
%, whereas in persons with gastrointestinal allergy or ulcerative colitis this
condition was found far more frequently, at rates of 5. 9% and 7.4%, respectively.
On systematic evaluation these data thus show that the wide spectrum of NSAID
intolerance is also of significance to gastroenterology and should be more
carefully taken into account (3, 7, 8, 18, 19). This applies not only to IBD, which
Fig. 3 Metylhistamine production in chronic Inflammatory Bowel Disease and NSAID intolerance
during oral mesalazine challenge
is often treated with 5-aminosalicylic acid preparations, but probably also to
microscopic colitides as well as to certain reported cutaneous, pulmonal and
gastroenterological intolerance reactions (17-19). For NSAID intolerance is not
only associated with the known intolerance reactions following the ingestion of
aspirin, NSAID or mesalazine; it can also lead to symptoms from salicylates that
are naturally contained in foods (pineapple, berries, curry, spices, potatoes, citrus
fruits etc.), from food additives, preservatives and colorants with a chemical
structure similar to that of salicylic acid (e.g. benzoic acid, tartrazine etc. (1,19))
and even from drugs with similar organic acid structures (e.g. disodium
cromoglycinic acid). The last named substance can cause considerable confusion
in the differential diagnostics and treatment of allergic gastrointestinal diseases.
Exacerbation of abdominal pain or diarrhea following the intake of disodium
cromoglycate (acid) or mesazaline is therefore seen as a clear indication for a
thorough examination for NSAID intolerance.
The standard diagnostic procedure consists in progressive oral provocation
with aspirin or mesazaline starting with a dose adjusted to the severity of the
reported intolerance symptoms (e.g. 100 - 250 - 500 mg lysine-aspirin or 250 - 500
- 1000 mg mesalazine (1,2). It is well known that such provocative treatment can
cause life-endangering reactions (e.g. acute bronchospasm, generalized
flush/urticaria, hypotension etc.), and it should therefore only be performed at
impatient facilities by duly trained and experienced physicians. Whereas acute
systemic or nasal, pulmonal or vascular reactions may take only a few hours to
develop, chronic, organ-related symptoms such as gastroenterological or other
oligosymptomatic manifestations (e.g. abdominal pain, diarrhea, pruritus etc.) may
still appear after several test days (1, 2, 4, 8). As an alternative to oral provocation
it is also possible to use a blood test for eicosanoid production in peripheral blood
cells to identify persons wit NSAID intolerance (10). If the observed clinical
reactions and symptoms are in agreement with the anamnestic findings and the
blood test shows a significant increase in leukotriene production in peripheral
blood cells after adding of 5-aminosalicylic acid or lysine-aspirin to the leukocyte
preparation, then in vivo oral provocation testing with all its complex monitoring
procedures attains no more than a confirmatory role. Oral provocation testing
should therefore only be used in cases where a discrepancy is found between the
anamnestic findings, clinical symptoms and/or the peripheral blood cell test.
When patients show clinical signs of NSAID intolerance such as intolerance to
aspirin, ineffectiveness or aggravation of symptoms after administration of
mesazaline or complaints after ingestion of salicylate-containing foods (e.g.
potatoes) and their complaints manifest themselves as symptoms of the ASA triad
(angioedema, nonallergic bronchial asthma polyposis nasi), this should prompt an
examination for salicylate intolerance (1-3, 8). Many routine laboratory
parameters such as blood picture, eosinophils, erythrocyte sedimentation rate or
serum IgE levels are not helpful in identifying NSAID intolerance as a functional
disorder of the eicosanoid metabolism. The only indication that a IBD patient's
recumng complaints may not attributable to the underlying inflammatory disease
but to other causes (e.g. postinflammatory stricture, small bowel intestinal
bacterial overgrowth) and/or the manifestation of an oligosymptomatic salicylate
intolerance may be the absence of an elevated erythrocyte sedimentation rate - a
frequent phenomenon - or of inflammatory processes (e.g. C reactive protein,
protein electrophoresis). In cases where IBD complaints persist in absence of any
observable inflammatory process it may take a specific anamnesis for tolerance of
aspirin and/or any of the above-named foods, temporary interruption of 5-amino
salicylate medication or peripheral blood tests for leukotriene production to obtain
the first substantial indication of NSAID intolerance. Far from being only of
academic interest to IBD patients, the discovery that they are NSAID intolerant
can be very significant for their long-term prospects. Today there are effective
desensitization methods available, which are used successfully in interdisciplinary
therapies performed in cooperation with allergologists or immunologists (1, 20-
25). One implication of this, for example, is that patients with ulcerative colitis
need no longer be deprived of effective anti-inflammatory treatments, which also
reduce their risk for dysplasia. Furthermore, by making a targeted search for
NSAID intolerance one can avoid putting patients with chronic active disease
caused by salicylate intolerance (absence of inflammation) on immune suppressive
medication (e.g. azathioprine, cyclosporine) without a justifiable indication for
this. IBD patients with NSAID intolerance who do not wish to be desensitized to
aspirin (e.g. patients with stomach disorders) or mesazaline still have therapeutic
alternatives at their disposal such as leukotriene receptor blocker medication for
conservative treatment or E. coli preparations in ulcerative colitis.
Another indirect yet objective parameter for recognizing NSAID intolerance
is, perhaps surprisingly, the level of urinary methylhistamine. For although
methylhistamine excretion is an unspecific parameter, all persons with IBD and
salicylate intolerance showed a moderate increase in methylhistamine and a
gradual progression of symptoms upon mesazaline provocation. Since NSAID
intolerance is known to be associated with a disturbance of the eicosanoid
metabolism with inhibition of cyclooxygenase 1, one would expect the
measurement of urinary leukotriene excretion to yield a far more clearly
pathological mediator profile than the measurement of methylhistamine, as is the
case with salicylate intolerant asthma patients (2, 8, 19). Possibly the increase in
urinary methyl histamine in NSAID intolerance can be explained as an
accompanying phenomenon of the elevated production of leukotriene B4 and/or
leukotrienes C4, D4 and E4, since the strong inflammatory and chemotactic
effects of leukotriene B4 and the permeability increasing effects as well as
allergic, inflammatory effects of leukotrienes C4 - E4 can result in an activation
of histamine-containing cells (mast cells, eosinophils) as well as of immune cell
populations that interact with mast cells (e.g. eosinophils, T cells etc. (9, 10, 26-
29). Furthermore, mast cells, basophils and eosinophilic granulocytes, on account
of their capacity to produce leukotrienes, are regarded as the chief effector cells
implicated in NSAID intolerance (1, 25, 26), and atopic persons have an
especially elevated risk for developing NSAID intolerance (25).
These facts are also reflected in the persistently high rate of methylhistamine
excretion in patients with gastrointestinal allergy and salicylate intolerance who
are on a salicylate containing diet. For NSAID-intolerant and allergic patients
only show a recovery from pathologically elevated methylhistamine production
back to the normal range when they abstain from potatoes and the salicylate they
contain. Since person with food allergies have an enlarged pool of mast cells,
eosinophils and basophils, this effect is particularly visible in their
methylhistamine excretion rates. Persistently high methylhistamine excretion
rates in persons on a potato/rice diet or a potato-only diet are therefore considered
an important indication today for excluding a rare potato or rice allergy and/or for
salicylate testing. Since NSAID intolerance in persons with food allergies poses
an additional dietetic challenge, including abstention from salicylate-containing
foods (e.g. pineapple, berries, curry, spices, potatoes, citrus fruits etc.) as well as
food additives (colorants and preservatives (1, 8, 19), one should always consider
the therapeutic option of an interdisciplinary desensitization program for these
persons, similarly to cases of IBD. However, continuous administration of
salicylates (e.g. long-term aspirin therapy) promotes the resorption of allergens
from the gastrointestinal tract, and any salicylate desensitization treatment should
therefore be preceded by an accurate diagnosis of the triggering allergens, for
example by double-blind oral provocation or ex vivo biopsy testing (12).
Salicylate desensitization can only bring about sufficient symptom relief if
accompanied by consistent abstention from allergens.
Speaking on the basis of our findings from the Erlangen interdisciplinary data
register of chronic inflammatory gastrointestinal disease, the signs and symptoms
of NSAID intolerance constitute a diagnosis of great practical import to clinical
medicine (allergology , dermatology, immunology, other disorders etc.) including
gastroenterology. For approx. 2- 7% of all patients with IBD and food allergies
this poses a new diagnostic and therapeutic challenge which may concern
physicians from any of the disciplines involved. When presented with patients
with chronic active disease who are suffering from these symptoms one should
therefore in future give greater thought to the possibility of salicylate intolerance,
all the more as there are meaningful dietetic, diagnostic and therapeutic options
available for these persons.
1. Mygiend N, Dahl R, Pedersen S. Allergologie Textbuch und Farbatlas (Hrsg. Merk FA).
Blackwell Wissenschaftsverlag Berlin, Wien 1998; 1. deutsche Ausgabe: pp. 64- 66.
2. Christie PE, Tagari P, Ford-Hutchinson A W, et al. Urinary Leukotriene E4 concentrations
increase after aspirin challenge in aspirin-sensitive asthmatic subjects. Am Rev Respir Dis 1991;
143: 1025-1029.
3. Chakraborty TK, Bhatia D, Heading RC, Ford MJ. Salicylate induced exacerbation of ulcerative
colitis. Gut 1987; 28: 613- 615.
4. Pearson DJ, Stones NA, Bentley SJ, Reid H. Proctocolitis induced by salicylate and associated
with asthma and recurrent nasal polyposis. Br Med J 1983; 287: 1675.
5. Austin CA, Cann PA, Jones TH, Holdsworth CD. Exacerbation of diarrhea and pain in patients
treated with 5-amino salicylic acid for ulcerative colitis. Lancet 1984; I: 917.
6. Borum ML, Ginsberg A. Hypersensitivity to 5ASA suppositories. Dig Dis Sci 1997; 42:
7. Weidenhiller M, Raithel M, Hahn EG. Hypersensitivity to 5-ASA suppositories (letter to the
editor). Dig Dis Sci 1999; 44: 2552-2553.
8. Worm M, Vieth W, Ehlers I, Sterry W, Zuberbier T. Increased leucotriene production by food
additives in patients with atopic dermatitis and proven food intolerance. Clin Exp Allergy 2001;
31: 265-273.
9. Ford-Hutchinson A W. Leukotriene antagonists and inhibitors as modulators of IgE-mediated
reactions. Springer Sem Immunopathol 1993; 15: 37-50.
10. Schaefer D, Schmid M, Gode UC, Baenkler HW. Dynamics of eicosanoids in peripheral blood
cells during bronchial provocation in aspirin-intolerant asthmatics. Eur Resp J 1999; 13:
11. Schwab D, Raithel M, Klein P, et al. Immunoglobulin E and eosinophilic cationic protein in
segmental lavage fluid of the small and large bowel identifies patients with food allergy. Am J
Gastroenterol 2001; 96: 508-514.
12. Raithel M, Weidenhiller M, Abel R, et al. Diagnostic use of mucosa oxygenation and histamine
release experiments in patients with gastrointestinally mediated allergy (GMA). Inflamm Res
2003; 52, Suppl 1: S13-S14.
13. Stange EF, Riemann J, von Herbay A et al. Diagnosis and therapy of ulcerative colitis results of
an evidence - based consensus conference of the German Society of Digestive and Metabolic
Diseases. Z Gastroenterol 2001; 39: 19-20.
14. Brignola C, Campieri M, Bazzocchi G, Farruggia P, Tragnone A, Lanfranchi GA. A laboratory
index for predicting relapse in asymptomatic patients with Crohns Disease.Gastroenterology
1986; 91: 1490-1494.
15. Winterkamp S, Weidenhiller M, Wilken V, et al. Standardised evaluation of urinary excretion of
N -tele-methylhistamine in different periods of age in a health population. Inflamm Res 2003;
52: S57 - S58
16. Weidenhiller M, Traenkner A, Schwab D, Hahn EG, Raithel M. Different kinetics of mediator
release can be detected during allergic reactions after oral provocation (double blind placebo -
controlled food challenge ). Inflamm Res 2002; 51 Suppl 1: 29-30.
17. Schwab D, Hahn EG, Raithel M. Enhanced histamine metabolism: A comparative analysis of
collagenous colitis and food allergy with respect to the role of diet and NSAID use. Inflamm
Res 2003; 52(4): 142-147.
18. Werlin SL, Grand RJ. Blody diarrhea -a new complication of sulphasalazine. J Paediatr 1978;
92: 450-451.
19. Williams WR, Pawlowicz A, Davies BH. Aspirin-like effects of selected food additives and
industrial sensitizing agents. Clin Exp Allergy 1989; 19: 533-537.
20. Paraskevopoulos I, Konstantinou G. Desensitization treatment of aspirin- and mesalamine-
sensitive patients with Crohn's disease (letter to the editor). Inflamm Bowel Dis 2005; 11:
21. Turunen U, Elomaa I, Antilla VJ et al. Mesalamine tolerance in patients with inflammatory
bowel disease and previous intolerance or allergy to sulphasalazine or sulfonamides. Scand J
Gastroenterol l987; 22: 798-802.
22. Stelze RC, Squire EN. Oral desensitization to 5-aminosalicylic acid medictions. Ann Allergy
Asthma Immunol l999; 83: 23-24.
23. Gonzalo MA, Alcade MM, Garcia JM et al. Desensitization after fever induced by mesalamine.
Allergy 1999; 54: 1224-1225.
24. Varela S, Diez MS, Gonzalez C et al. Oral desensitization to 5-ASA. Allergy 2002; 57: 371-372.
25. Sanchez-Borges M, Capriles-Hulett A. Atopy is a risk factor for non-steroidal anti-
inflammatory drug sensitivity. Ann Allergy Asthma Immunol 2000; 84: 101-106.
26. Mayatepek E, Hoffmann GF.Leukotrienes: Biosysnthesis, metabolism and pathophysiological
significance. Pediatric Res 1995; 37: 1-9.
27. Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL. Release of leukotrienes,
prostaglandins and histamine into nasal secetions of aspirin-sensitive asthmatics during reaction
to aspirin. Am Rev Resp Dis 1988; 137: 847- 854.
28. Kowalski ML, Grzegorczyk J, Wojciechowska B, Poniatowska M. Intranasal challenge with
aspirin induces cell influx and activation of eosinophils and mast cells in nasal secretions of
ASA-hypersensitive patients. Clin Exp Allergy 1996; 26: 807-814.
Authors address: Martin Raithel, MD, Functional Tissue Diagnostics, Dept. of Medicine I,
Erlangen - Nurnberg University, Ulmenweg 18, 91054 Erlangen, Germany. Telephone/Fax:
E-Mail: Martin.Raithel@
... Aspirin should not be taken by people who are allergic to ibuprofen or naproxen, [117,118], or salicylate intolerance [119,120] or more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID-precipitated bronchospasm. Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers, mild diabetes, or gastritis to seek medical advice before using aspirin [116,120]. ...
... [248] CODEN (USA): JDDTAO these types of drugs" [118,119]. "Aspirin is known to displace several drugs from protein-binding sites in the blood, including the antidiabetic drugs tolbutamide and chlorpropamide, warfarin, methotrexate, phenytoin, probenecid, valproic acid (as well as interfering with betaoxidation, an important part of valproate metabolism), and other NSAIDs. Corticosteroids may also reduce the concentration of Aspirin. ...
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BACKGROUND: Aspirin is one of the most frequently used and cheapest drugs in medicine. Since its first synthesis in 1897, several medicinal roles and mechanisms of action of Aspirin have become apparent, the latest among these being its role in cancer prevention and treatment. OBJECTIVE: We present a review of Aspirin's biochemistry and pharmacology, as well as the clinical use of Aspirin. The communiqué also suggests possible strategies for maximizing the gain of Aspirin as a wonder-drug of the future. METHODS: The literature search strategy covered printed and online sources, including manual library search (PubMed), Embase, Medline, and Cochrane Library. For papers written in English and published in the last ten years. A systematic analysis of available data was subsequently performed based on the review questions. An estimated 155 articles were found online, and twenty-eight articles utilized in the final analysis. DISCUSSION: Aspirin belongs to the non-steroidal anti-inflammatory drugs with a wide range of pharmacological activities, including analgesic, antipyretic, and antiplatelet properties. Discovery of antiplatelet effects led to the increasing use of Aspirin as an anti-thrombotic agent in the prevention of cardiovascular diseases from the 1980s, and firm evidence supporting its usefulness has continued to accumulate. Aspirin irreversibly inhibits platelet function by acetylating cyclooxygenase (COX), which is involved in the production of a potent platelet stimulator, thromboxane A2. The inhibition of COX-2 by Aspirin forms the basis of its anticipated role in preventing colorectal cancer and Alzheimer's disease and the inhibition of the progression of these diseases. It has been pointed out that the incidence of cardiovascular events tends to be high among patients who are Aspirin resistant, but the reason for this increased incidence remains unclear. CONCLUSION: The emerging future interest is to accrue evidence in favor of Aspirin as the novel therapeutic drug for combating severe acute inflammation and thrombosis associated with the cytokine storm in COVID-19 patients. Notably, a randomized clinical trial, to test a range of potential treatments for COVID-19, includes low-dose Aspirin as anti-inflammatory and antiplatelet treatment.
... Aspirin use has been shown to increase the risk of gastrointestinal bleeding. People with kidney disease, gout or hyperuricemia should not take acetylsalicylic acid because it inhibits the kidney's ability to excrete uric acid [3,4]. It should not be given to children or adolescents to control cold or influenza symptoms, as this has been linked with Reye's syndrome [5,6]. ...
... W naturze występują przede wszystkim w roślinach, dlatego głównym źródłem salicylanów w diecie są produkty pochodzenia roślinnego, takie jak warzywa, owoce, przyprawy oraz zioła. Źródłem salicylanów są również niektóre napoje, takie jak kawa, herbata, a także napoje typu cola oraz napoje alkoholowe [7][8][9]. ...
... Salicylates, one of the food chemicals in the RPAH diet, are thought to be the most likely natural food chemical to cause symptoms [62]. It is suggested that salicylates increase smooth muscle contraction within the gastrointestinal (GI) tract [74]. However, research into the effects of dietary salicylates is limited, and is extrapolated from nonsteroidal anti-inflammatory drug (NSAID) intolerance. ...
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Chronic diarrhoea affects up to 14% of adults, it impacts on quality of life and its cause can be variable. Patients with chronic diarrhoea are presented with a plethora of dietary recommendations, often sought from the internet or provided by those who are untrained or inexperienced. In this review, we summarise the possible causes of chronic diarrhoea that can be managed by diet, the symptom improvement and quality of life benefits but also the potential risks of such dietary treatments. Clinicians need to consider both the benefits and risks of dietary treatments before making dietary recommendations to manage chronic diarrhoea. The pivotal role that dietitians have in ensuring optimal symptom improvement without jeopardising nutritional and overall health is discussed.
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Food intolerance is a non-immunological response induced by a food or food component in a dose that is normally tolerated. It includes pseudo allergic and pharmacological effects caused by: salicylates, biogenic amines, sulphites, sodium glutamate, colours and preservatives, sweeteners, or enzymopathies. The pathophysiology, clinical manifestations, diagnosis and treatment of the most common food intolerances have been presented in this review article. The literature search was done with the help of the following keywords: intolerance, food, additives, carbohydrates and gluten within PubMed, Embase, Scopus, SCIndeks and Hrčak databases. According to the literature, it may be argued that the lack of standardized tests accounts for the discrepancy between the perceived prevalence of food-related adverse effects, which are extremely common, and the actual prevalence of non-immunological reactions to food within these events. Food intolerance is manifested primarily by gastrointestinal and then extraintestinal (neurological, cardiovascular, respiratory and dermatological) signs and symptoms. Diagnosis requires a detailed medical history, physical examination, as well as keeping a diet and symptom diary, implementing an elimination diet and double-blind placebo-controlled oral food exposure tests. Treatment includes dietary modification, supplementation and treatment of the underlying condition in persons with secondary intolerance.
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Functional bowel disorders (FBDs) affect around 20% of the population worldwide and are associated with reduced quality of life and high healthcare costs. Dietary therapies are frequently implemented to assist with symptom relief in these individuals; however, there are concerns regarding their complexity, restrictiveness, nutritional adequacy, and effectiveness. Thus, to overcome these limitations, a novel approach, the 5Ad Dietary Protocol, was designed and tested for its efficacy in reducing a range of gastrointestinal symptoms in those with FBDs. The 5Ad Dietary Protocol was evaluated using a repeated measures design (baseline week and intervention week) in 15 subjects with FBDs. The Food Intolerance Index (FII) (0-100) was used as a composite overall symptom score, along with measures of stool consistency and frequency. The severity of individual symptoms (abdominal pain, bloating, flatulence, bowel urgency, straining, and incomplete defecation) was recorded by the subject using a 4- point Likert scale. Significant improvements occurred in FII score (39.63±16.77 to 18.99±15.54, p=0.000), in stool consistency for baseline constipation (2.14±0.67 to 3.58±0.73, p=0.038), and in frequency of defecation for high baseline stool frequency (16.00±2.11 to 11.44±1.80, p=0.005). Stool consistency and frequency also improved in the respective contrasting subtypes, and severity of all individual symptoms was significantly reduced from baseline. The 5Ad Dietary Protocol proved to be a promising universal approach for varying forms and severities of FBDs; normalising bowel function in both those with constipation and those with diarrhoea. The present study paves the way for future research encompassing a longer study duration and the exploration of underlying physiological mechanisms.
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The levels of leukotriene C4 (LTC4), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and histamine were measured in nasal lavage fluids obtained from aspirin-sensitive, desensitized aspirin-sensitive, and aspirin-insensitive asthmatics and normal volunteers before and after ingestion of aspirin. Increased levels of LTC4 and histamine were associated with significant decreases in the FEV1 for 3 of 4 aspirin-sensitive asthmatics who had both naso-ocular and bronchospastic reactions to aspirin. In contrast, no increase in LTC4 or histamine release was detected in aspirin-sensitive asthmatics who had only bronchospastic reactions to aspirin. No significant decreases in PGE2 levels or increases in LTB4 levels were detected during these reactions to relatively low doses of aspirin regardless of the clinical symptoms, nor was any increase in mediator release apparent in lavage fluids from normal donors, aspirin-insensitive asthmatics, and desensitized aspirin-sensitive subjects before or after various doses of aspirin. Levels of PGE2 decreased in nasal secretions from normal volunteers, aspirin-insensitive asthmatics, and desensitized aspirin-sensitive subjects after ingestion of 650 mg of aspirin. These decreases were not associated with increased LTC4 or LTB4 or with histamine release, decreased FEV1, or naso-ocular symptoms. In addition, reductions of PGE2 release were similar for normal and desensitized aspirin-sensitive volunteers (63 +/- 11 versus 61 +/- 10%, respectively). The data demonstrate that LTC4 and histamine are released into nasal secretions of aspirin-sensitive asthmatics with naso-ocular and bronchospastic reactions after ingestion of low doses of aspirin without a decrease in the levels of PGE2 and suggest that LTC4 and histamine contribute to the naso-ocular and bronchospastic symptoms characteristic of reactions to aspirin.
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The oral administration of mesalazine (5-aminosalicylic acid) resulted in the exacerbation of ulcerative colitis in two patients intolerant to sulphasalazine whose colitis had previously been quiescent. Although sulphasalazine intolerance is usually attributable to the sulphapyridine moiety, the possibility of salicylate sensitivity should be considered in colitic patients who fail to respond appropriately to sulphasalazine or who experience abdominal pain or diarrhoea while taking the drug.
Urinary leukotriene E4 (LTE4) concentrations have been measured in six asthmatic patients with aspirin sensitivity and in five asthmatic subjects tolerant of aspirin, before and after provocation with aspirin or placebo. Aspirin-sensitive subjects showed an average 21% fall in FEV1 after aspirin challenge whereas control individuals had a 2% fall in FEV1 after ingestion of 100 mg aspirin. The resting urinary LTE4 concentrations in asthmatic subjects sensitive to aspirin were 243 pg/mg creatinine (range 50 to 1,041), and these were on average sixfold greater than those in control asthmatic subjects. Further, there was a mean fourfold increase in urinary LTE4 levels at 3 to 6 h after aspirin, but not placebo, challenge in aspirin-sensitive asthmatic subjects that was not seen in the control asthmatic individuals. Leukotriene release may play a central role in the mechanisms of asthmatic attacks produced by aspirin ingestion.
A number of food additives and industrial chemicals, responsible for inducing symptoms of intolerance in some individuals, have been studied in tests measuring platelet activation by noradrenaline. All the investigated agents inhibited platelet aggregation and this was associated with inhibition of the cyclo-oxygenase-thromboxane pathway. Suboptimal inhibitory concentrations of the agents studied had additive inhibitory effects on platelet aggregation when they were tested in pairs, or when tested with salicylate or aspirin. The results support the theory that some food additives and industrial chemicals induce intolerance because of their aspirin-like properties.
Fifty patients intolerant of or allergic to sulphasalazine (SASP) or sulphonamides were treated with mesalazine. Eighty per cent of patients continued treatment during the time of follow-up (mean, 8.4 months); 14% (7 of 50 patients) had to stop the treatment with mesalazine because of side effects. The patients with allergic reactions, including rash, fever, and systemic manifestations from SASP, were most likely to be intolerant of or allergic to mesalazine (four of seven patients); two of them developed a similar reaction from both SASP and mesalazine. Two patients (2 of 12) with previous haematologic side effects had to discontinue mesalazine treatment, one because of mild neutropaenia and one because of an elevation of liver enzyme values. One patient experienced gastrointestinal side effects from both mesalazine and SASP. Altogether, 4 (4 of 50) patients experienced gastrointestinal symptoms from mesalazine. Two of them had had a flare-up of the symptoms of the colitis when treated with SASP. All side effects were rapidly reversible after withdrawal of the drug. Patients with severe allergic reactions with systemic manifestations from SASP should be treated with caution with 5-aminosalicylic acid preparations.
Currently there are no completely reliable methods for predicting an impending relapse in Crohn's disease. As approximately 50% of patients in remission [Crohn's disease activity index (CDAI) less than 150] show some laboratory abnormalities, we inquired whether these alterations might be of value for predicting relapse. We prospectively studied 41 patients with Crohn's disease who had been showing CDAI less than 150 for at least 6 mo before entering the study and who were not receiving any long-term treatment. The 41 patients were studied at the ninth and at the 18th month after inclusion in the study. Disease activity was monitored by CDAI calculation and by measurement of erythrocyte sedimentation rate, white blood cell count, hemoglobin, albumin, alpha 2-globulin, serum iron, C-reactive protein, alpha 1-glycoprotein, and alpha 2-antitrypsin. Seventeen of the 41 patients had a clinical relapse during follow-up. At the beginning of the study the patients who later relapsed showed a remarkable alteration of acid alpha 1-glycoprotein (p less than 0.0001), alpha 2-globulin (p less than 0.0003), and erythrocyte sedimentation rate (p less than 0.0006), in comparison with the patients who remained in remission. by discriminant analysis a prognostic index with these laboratory investigations provided a high percentage (88%) of accuracy according to the outcome at the 18th month.
Sensitivity to aspirin may lead to asthma, rhinitis, urticaria, and angio-oedema. We report on a patient with proctocolitis whose gastrointestinal symptoms went into complete remission with a diet free of salicylates and known cross reacting substantes but recurred on double blind oral provocation with aspirin.