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Deutsches Ärzteblatt International⏐⏐Dtsch Arztebl Int 2009; 106(21): 359–70 359
MEDICINE
T
he term food intolerance is used to describe a
range of food related complaints of varying etiolo-
gy. Besides structural and functional causes, it is also
necessary to distinguish between a toxic and non-toxic
pathogenesis of the intolerance (Figure 1).
Food intolerance of functional origin is often caused
only by an isolated functional disorder (such as lactase
deficiency in the small intestine) and is initially unac-
companied by any other anatomical or morphological
changes in the gastrointestinal tract. Food intolerance of
structural etiology, on the other hand, has its origin in an
anatomically and morphologically demonstrable dis-
ease involving a structural alteration in the gastrointestinal
tract. This results secondarily in food-associated symp-
toms. Small intestinal diverticula, for example, lead to
bacterial overgrowth of the small intestine, which in
turn causes postprandial meteorism and diarrhea.
Toxic reactions are due to the actions of toxins, which
may be of bacterial, plant, or fungal origin, for example
arising from food contamination, as well as other toxins
such as glycoalkaloids.
Nontoxic reactions are divided into two further principal
mechanisms: immunologically and non-immunologically
mediated reactions (1–3). Overall, non-immunologically
mediated reactions account for the majority of all reactions
to food (15% to 20%). The immune system is not
specifically involved in these cases, and therefore non-
immunologically mediated forms of food intolerance are
not allergies. This spectrum embraces pseudoallergic and
pharmacological effects caused by:
>salicylates, biogenic amines (such as histamine,
tyramine, serotonin etc.),
>sulfites (present in wine and medications),
>sodium glutamate (flavor enhancer),
Definition
The term food intolerance is used to describe a
range of food related symptoms of varying etiology.
CONTINUING MEDICAL EDUCATION
The Differential Diagnosis
of Food Intolerance
Yurdagül Zopf, Hanns-Wolf Baenkler, Andrea Silbermann,
Eckhart G. Hahn, Martin Raithel
SUMMARY
Introduction: More than 20% of the population in
industrialized countries suffer from food intolerance or
food allergy.
Methods: Selective literature search for relevant publications
in PubMed and the Cochrane Library combined with further
data from the interdisciplinary database on chronic
inflammatory and allergic diseases of the Erlangen
University Hospital.
Results: The majority of cases of food intolerance (15% to
20%) are due to non-immunological causes. These causes
range from pseudoallergic reactions to enzymopathies,
chronic infections, and psychosomatic reactions that are
associated with food intolerance. The prevalence of true
food allergy,i.e., immunologically mediated intolerance
reactions, is only 2% to 5%.
Conclusions: The differential diagnosis of food intolerance
is broad. Therefore, a structured diagnostic algorithm with
input from multiple clinical disciplines should be applied.
The treatment consists of eliminating the offending
substance from the diet as well as medications and
psychosomatic support, when indicated.
Dtsch Arztebl Int 2009; 106(21): 359–70
DOI: 10.3238/arztebl.2009.0359
Key words: Food intolerance, food allergy, diagnosis,
provocative testing, histamine intolerance
Medizinische Klinik 1, Gastroenterologie, Friedrich-Alexander-Universität Erlan-
gen-Nürnberg: Dr. med.Zopf, Prof. Dr.med. Hahn, Prof. Dr.med. Raithel
Medizinische Klinik 3 – Rheumatologie, Immunologie und Allergologie, Frie-
drich-Alexander-Universität Erlangen-Nürnberg: Dr. med. Baenkler
Psychosomatische und Psychotherapeutische Abteilung in der Psychiatrischen
und Psychotherapeutischen Klinik, Friedrich-Alexander-Universität Erlangen-
Nürnberg: Dipl.-Psych. Silbermann
360 Deutsches Ärzteblatt International⏐⏐Dtsch Arztebl Int 2009; 106(21): 359–70
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colorants and preservatives (such as tartrazine,
benzoates, sorbates etc.),
sweeteners (aspartame), or
due to enzymopathy.
The range of differential diagnoses of the non-
immunologically mediated forms of food intolerance
further includes chronic infections (such as lambliasis),
neuroendocrine tumors (such as carcinoid), and psycho-
somatic reactions that cause or can imitate symptoms of
intolerance (1, 2, 4–8) (Figures 1 and 2). The specifically
immunologically mediated forms of food intolerance
are subsumed under the term food allergy and, considering
the rising prevalence of food intolerance, pose a differ-
ential diagnostic problem for patients and physicians
alike. The incidence of food allergies is subjectively
overestimated. In one survey, one fourth of the popula-
tion claimed to be suffering from food allergy (2, 4, 7).
The actual prevalence in adults is 2% to 5%, with the
different organ systems (skin, gastrointestinal tract, car-
diovascular system, lungs etc.) being described with dif-
fering frequency as the site of manifestation of the allergy
depending on the patient sample studied (3, 4, 6, 9, 10).
The prevalence in young children is higher at 5% to
10%, with different foods being responsible for the food
allergies in children and adults (e-Table 1).
The learning objectives of this article are to equip the
reader to
differentiate exactly between food intolerances and
food allergies
acquire knowledge of the broad range of differen-
tial diagnoses of food allergies and food intolerances
employ a structured approach to the differential
diagnosis of food allergies and food intolerances.
Method
A selective literature search including national guide-
lines and the databases PubMed, the Cochrane Library,
and the Erlangen University interdisciplinary data register
of chronic inflammatory and allergic diseases was
undertaken to establish the current state of knowledge
relating to food intolerances.
The search included German and English language
publications and the authors' personal data resources.
The articles consulted were selected on the basis of the
authors' own subjective assessments and extensive clin-
ical experience. A formal meta-analysis or structured
evaluation of all the publications was not undertaken
and is hardly practically feasible in view of the volume
of available literature.
Causes of non-immunological food
intolerance
Salicylates, biogenic amines
Sulfites
Sodium glutamate
Colorants and preservatives, sweeteners
Enzymopathies
Prevalence of food allergy
in adults: 2% to 5%
in young children: 5% to 10%
Overview of range
of food intolerance
reactions
Examples of important functional and structural causes of food intolerances; anti-tTG anti-
bodies, antibodies to tissue transglutaminase ; EHEC, entero-toxic Escherichia coli ; ETEC,
entero-hemorrhagic Escherichia coli; CIBD, chronic inflammatory bowel disease
FIGURE 2
FIGURE 1
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Differential diagnosis: non-immunologically
mediated food intolerances
Since the population prevalence of functional and struc-
tural, non-toxic and non-immunologically mediated
clinical presentations (Figures 1 and 2) are much com-
moner (15% to 20%) than the immunologically mediated
true allergies (2% to 5%) or toxic disease mechanisms,
diagnostic evaluation should initially consider the non-
immunologically mediated differential diagnoses when
it is uncertain what is causing the patient's symptoms
(e.g. carbohydrate malabsorption, neurodermatitis, pan-
creatic insufficiency, mastocytosis, [Figure 3]). This
should always be performed before embarking upon
detailed immunological investigation aimed at detecting
the presence of a systemic or local food allergy. This also
appears relevant in view of the frequent association of
carbohydrate malabsorption, histamine intolerance, or
infections with atopic diseases or food allergy. It is also
necessary to rule out the presence of other underlying
diseases, intolerances, and pathologies predisposing to
food intolerance by means of serum analysis, diagnostic
imaging techniques, endoscopic examinations and
histological analyses, for example in order to avoid
overlooking chronic inflammatory bowel disease, celiac
disease, a lymphoma, mastocytosis or tumors etc. (1, 4,
6, 11).
Since this article describes the differential diagnosis
of food intolerances and food allergies based on the
Erlangen interdisciplinary data register of chronic
inflammatory and allergic gastrointestinal diseases,
because of the enormously broad spectrum involved, the
respective differential diagnoses are listed only in sum-
marized form; detailed descriptions can be found in the
literature sources cited.
Differential diagnosis of non-immunologically
mediated food intolerances (non-allergic food
intolerances)
A transient (single occurrence with complete remission)
or chronic (permanent symptoms due to persisting trig-
gering factors) reaction (such as abdominal, autonomic
nervous or systemic symptoms) usually does not allow
direct inference of the presence of an allergy, intolerance,
infection, intoxication, or hyperalimentation but always
requires taking an exact medical history and, if necessary,
targeted diagnostic measures.
Depending on the patient's medical history, a
functional or structural cause of the food intolerance
will be suspected (Figures 1 and 2). A suitable basic
Primary differential diagnosis
If the cause of the symptoms is uncertain, first
consider the non-immunologically mediated
differential diagnoses and perform specific
diagnostic testing.
Further diagnostic measures
comprise differentiated immunological diagnosis
for detection of a systemic or local food allergy.
Overview of diagnostic approaches to the differential diagnostic spectrum of food
intolerances and allergies; *1both clinical pictures can also coexist;
ESR, erythrocyte sedimentation rate; GPT, glutamate pyruvate transaminase;
NSE neuron specific enolase; ERCP, endoscopic retrograde cholangio-pancreaticography
FIGURE 3
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Carbohydrate malabsorption
Carbohydrate malabsorption is a frequent
consequence of an enzyme disorder.
Intolerances
Medication with sulfonamides and metronidazole
can lead to the manifestation of intolerance.
CIBD, chronic inflammatory bowel diseases
TABLE 1
Important examples of intolerances due to enzyme deficiency and transport disorder
Enzyme structure Target structure Primary deficiency Secondary deficiency or disorder
Carbohydrates
Combined disaccharide Lactose, sucrose, autosomal recessive Bowel inflammation
malabsorption syndrome and other disaccharides (infections, celiac disease, CIBD)
Isolated disaccharide Disaccharide Bowel inflammation
intolerances (infections, celiac disease, CIBD)
GLUT 5 transport defect Fructose Bowel inflammation
(infections, celiac disease, CIBD)
Lactase (β-galactosidase) Lactose – congenital Bowel inflammation
– autosomal recessive (very rare) (infections, celiac disease, CIBD)
– physiological (from age 3–5 years)
Saccharase Sucrose autosomal recessive Bowel inflammation
(sucrase isomaltase) sucrase-isomaltase deficiency (infections,celiac disease, CIBD)
Maltase (alpha-glucosidase) Maltose autosomal recessive Medication with acarbose, miglitol
Trehalase Trehalose autosomal recessive Bowel inflammation
(infections, celiac disease, CIBD)
Galactase Galactose autosomal recessive Bowel inflammation
(infections, celiac disease, CIBD)
Biogenic amines
e.g. Diamine oxidase Histamine etc. autosomal recessive Bowel inflammation
(infections, celiac disease, CIBD)
Other intolerances
Fructose intolerance Fructose autosomal recessive
aldolase B
Glucose-6-phosphate Fava beans X-chromosomally inherited Medication with sulfonamides
dehydrogenase enzyme defect
Alcohol dehydrogenase Acetaldehyde Medication with metronidazole
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diagnostic program is then implemented. The full gamut
of diagnostic modalities outlined in Figure 3 will not be
required for every patient but should be applied on a
case by case basis with reference to the history, clinical
findings, and possible differential diagnoses, as well as
previous findings, in a cost conscious manner (4, 8, 11).
Diagnostic imaging procedures, endoscopy, histology,
and stool examinations can assist in diagnosing diseases
of structural etiology involving different types of food
intolerances, such as fat intolerance in patients with
gallstones, reflux esophagitis, or pancreatic insufficiency.
Chemical laboratory tests are used, for example, to
detect eosinophilia, increased inflammatory activity, or
IgA antibody deficiency, and autoantibody assays
(transglutaminase, anti-enterocyte antibodies etc.) can
provide evidence of, for example, chronic inflammatory
bowel disease or an infection.
In many cases, intolerances or food intolerances only
develop during the course of the various underlying and
concomitant diseases. Some individuals with chronic
inflammatory bowel disease, for example, develop
meteorism, flatulence, and diarrhea after ingesting milk
because of lactase deficiency (Figure 2) (1, 4, 8, 11).
These intolerances should be identified at an early stage
since they aggravate the disease course and complicate
dietary management and hence considerably compro-
mise quality of life. The Erlangen database shows that a
major diagnostic problem is that today it is often
attempted only to exclude structural diseases by means
of serological or instrumental diagnostic tests, while the
positive detection of functional disorders often remains
inadequate. Diseases of structural etiology are under-
stood to include primary organ pathologies of the gas-
trointestinal tract (such as achalasia), while functional
disease is characterized by normal morphology but an
isolated functional impairment (such as lactase defi-
ciency).
Carbohydrate malabsorption
Carbohydrate absorption is significantly affected by dis-
orders such as lactase deficiency (intolerance of milk
sugar) and diseases affecting the transport of certain
mono- and disaccharides. Impairments of the digestion
and absorption of simple carbohydrates are the
commonest non-immunological food intolerances in the
European population (lactose, fructose, sorbitol malab-
sorption etc. [Table 1]). Carbohydrates cannot be
absorbed in the small intestine of patients with, for ex-
ample, lactase deficiency or a transport defect (such as
GLUT 5 in fructose transport, or GLUT 2 for glucose,
galactose and fructose transport) and therefore reach the
large intestine in osmotically active form. Here, they are
metabolized by bacterial decomposition to short-chain
fatty acids, methane, carbon dioxide, and hydrogen
which induce meteorism, flatulence, abdominal pain,
and diarrhea (1, 4, 8, 11). Since many foods contain car-
bohydrates, carbohydrate intolerance in the form of
malabsorption of fructose, sorbitol and lactose can lead
to many undifferentiated intolerances without an exact
knowledge of the inducing foods. Other enzyme defi-
ciency states and transport disorders are listed in Table 1.
Small bowel bacterial overgrowth
If the H2breath tests for fructose, lactose and sorbitol
(and possible lactulose) are positive, bacterial over-
growth of the small intestine should be considered as a
possible cause of the food intolerance. As with carbohy-
drate malabsorption, this condition often leads to
meteorism, flatulence, diarrhea, and pain in a non-
specific pattern involving a variety of foods. Patients
with postoperative changes, peristaltic disorders, diabe-
tes mellitus, and patients who are medicated with
immunosuppressives or proton pump inhibitors are
especially affected. An H2breath test for glucose should
be performed to rule out small bowel bacterial overgrowth.
Diagnostic procedures
Endoscopy, histology, and stool examinations can
reveal structural and infectious diseases that may
be associated with various food intolerances.
Small bowel bacterial overgrowth
If the H2breath tests for fructose, lactose, sorbitol
(if necessary, also lactulose) are positive, small
bowel bacterial overgrowth should be considered
as a possible cause of food intolerance.
FIGURE 4 Immunological
mechanisms in food
allergies (gastro-
intestinally mediated
Grade I-IV allergies)
according to
Coombs and Gell
364 Deutsches Ärzteblatt International⏐⏐Dtsch Arztebl Int 2009; 106(21): 359–70
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Histamine intolerance
Histamine intolerance is caused by a disorder of the
metabolism of mainly exogenously supplied histamine
(histamine-rich foods and semiluxuries). This is most
commonly attributed to a deficiency of the enzyme
diaminoxidase (DAO) which is responsible for the
extracellular biotransformation of histamine (12, 13).
But histamine-N-methyltransferase (HNMT) responsible
for intracellular histamine breakdown may also be
involved. About 1% of the total German population of
82 Mill. is affected by histamine intolerance, 80% being
middle-aged women (13).
The symptoms of histamine intolerance are highly
variable and affect almost all organs. These range from
typical cutaneous effects of histamine (erythema, pruritus,
flush, urticaria), gastrointestinal complaints (flatulence,
colics, diarrhea), respiratory complaints (nasal obstruc-
tion, rhinorrhea, asthma attacks), cardiac complications
(hypo- and hypertension, arrhythmias) to headache or
dysmenorrhea (13, 14).
A slight increase in histamine concentration above
the normal range already causes incipient vasodilata-
tion, increased secretion of gastric fluid and mucus, and
contraction of the smooth muscles. A further increase
leads to tachycardia, arrhythmias, and typical cutaneous
reactions. There may also be hypotension, broncho-
spasm and, with a rapid rise in histamine concentration,
shock or cardiac arrest (12, 13). The gastric acid secre-
tion and smooth muscle contraction which already starts
when there are slight increases in histamine levels ex-
plains why many people with food intolerances and
allergies in whatever form have unspecific abdominal
symptoms such as dyspepsia, a sensation of bloating and
tension or pain. Typical trigger factors of histamine in-
tolerance are listed in the e-Box (12, 14).
Salicylate intolerance
The prevalence of salicylate intolerance in Europe is
2.5% (8). The classical symptoms of salicylate intoler-
ance are respiratory complaints (blocked or runny nose,
sinusitis, nasal polyposis, bronchial asthma), but can
also lead to gastrointestinal complaints with meteorism,
flatulence, diarrhea and, rarely, to colitis with strictures
and ulcers (5, 14). The pathogenesis of salicylate intoler-
ance is based on an inhibition of cyclooxygenase-1 by
salicylates and other non-steroidal pain medications, but
also by salicylate-containing foods and other acids
(such as benzoic acid or colorants) resulting in reduced
prostaglandin synthesis (5).
In intolerant individuals this leads to activation of the
leukotriene metabolism with increased formation of
LTB4 and/or LTC4-E4.
This condition is detected by a blood cell test
(heparinized blood) with incubation of 5-acetylsalicylic
acid and arachidonic acid or by provocation tests (nasal,
bronchial, oral [5]).
The recommended treatment is abstinence from the
inducing substances; the most important foods concerned
are listed in e-Table 2.
If dietary therapy alone is insufficient, treatment with
leukotriene receptor blockers or deactivation with
acetylsalicylic acid should be attempted (5) (see supple-
mentary case report).
Differential diagnosis of immunologically
mediated food intolerance: food allergy
Among the food intolerances and immunologically
mediated diseases, food allergy exhibits the greatest
complexity. This is due to the heterogeneous pattern of
clinical symptoms associated with food allergies
(including intra-individually). Diagnostic assessment
should also include the much more common non-
immunological intolerances and diseases of other etiology.
Since it is rarely clear at the patient's first visit to a
medical practice whether a food intolerance is of non-
immunological or immunological etiology or is due to a
combination of the two mechanisms, diagnosis of food
allergy should focus not only on identifying a specific
trigger factor but should also include a detailed evalua-
tion of the possible differential diagnoses and therefore
attempt to distinguish the patient's condition from other
chronic diseases.
General principles of allergy diagnosis
For the diagnosis of food allergy it should be considered
that different sensitivities and specificities may be ob-
served between the various diagnostic tests, depending
on the Coombs and Gell type I–IV allergy (Figure 4),
systemic or local manifestation, type of symptom onset
(immediate: <2 hours, intermediate: 2 to 24 hours,
delayed >24 hours), intestinal or extraintestinal
manifestation, the disease group examined, the allergen
present, and the medical discipline involved (2, 4, 8–11,
15, 16). The experienced clinician will therefore base
his or her diagnostic strategies and procedure on a pre-
cise medical history, physical examination, and an
analysis of the pattern of symptoms and time course.
Demonstration of a provoked, allergen induced reaction
Salicylate intolerance
The prevalence of salicylate intolerance is 2.5% in
Europe.
Food allergy
Food allergy shows the greatest complexity
among the food intolerances and allergic diseases.
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in the patient or organ system is regarded as the gold
standard (2, 6, 11, 16). Diagnostic approaches vary ac-
cording to the allergy specialist and dermatologist (e.g.
oral allergy syndrome, cutaneous reactions), the lung
specialist and otorhinolaryngologist (e.g. nasal or bron-
chial obstruction) or the internal specialist and gastroen-
terologist (e.g. abdominal cramps, colitis), since they
are dealing with different patient clientèles, differential
diagnoses, cross reactions (box), and types of allergies.
Clear guidelines are available for IgE-mediated food
allergies (6, 17), although the frequency of IgE-mediated
food allergies varies among young children and adults
and between the different allergens and organ manifes-
tations (4, 6, 8, 9, 11, 15–17). In contrast to seropositive
IgE-mediated food allergy, for the non-IgE-mediated
reaction and for atypical, oligosymptomatic or chronic
disease manifestations a more extensive, differentiated,
stepwise diagnostic procedure is often required before
provocation testing is performed (2, 4, 9, 11, 18, 19).
Stepwise diagnostic procedure
for food allergies
Specific allergological routine diagnosis begins with
taking a dietary history, completing a nutrition diary,
performing skin tests (e.g. prick test) for food extracts,
environmental antigens, mould fungi, spices etc., assay
of total IgE and the suspected allergen specific IgE anti-
bodies in serum, in order to detect evidence of IgE spe-
cific sensitization (4, 8–11, 20). If clinically unequivocal
postprandial reactions are observed which are consistent
with the results of skin tests and antigen specific IgE
sensitization, this diagnostic approach can in many
cases already exactly define and identify the IgE-mediated
allergic disease (1, 4, 8, 10, 20). With the typical combi-
nation of intestinal and extraintestinal symptoms imme-
diately after allergen ingestion with monovalent or oligo-
valent sensitization, oral provocation testing in atopy
(IgE-mediated allergy) is confirmatory in nature but is
still regarded as the diagnostic gold standard (9–11, 16).
If the elimination diet is unequivocally successful with
this constellation, oral provocation as a confirmatory
reaction is unnecessary from the clinical perspective.
The diagnosis of food allergy becomes much more
difficult if oligo- to polyvalent IgE sensitizations are
present, if the patient's symptoms are atypical (chronic
clinical picture) or if local IgE-mediated or delayed
reactions (non-IgE-mediated allergy types II–IV), or
contradictory signs of sensitization are present. Although
the structured, blinded oral provocation test is the gold
standard in this case, with this constellation initially the
Gold standard
Demonstration of a provoked allergy-induced
reaction in the patient or organ system is regarded
as the gold standard.
Stepwise diagnostic procedure for food
allergies
>Dietary history
>Nutrition diary
>Skin tests
>Total IgE assay
BOX
Examples of common cross-allergies*1
>>Pollen associated food allergies
Tree pollen (birch, alder, hazelnut) + pomaceous fruit (apple, pear, cherry)
+ nuts (hazelnut, walnut, pistachio)
Grass, cereal pollen + flours (wheat, rye, oats) + tomato, kiwi,celery
>>Celery-mugwort-spice syndrome
Mugwort pollen + spice (aniseed, parsley, chamomile) + celery, raw carrot,
nuts
>>Latex fruit syndrome
Latex products + fruit (pineapple, kiwi, avocado) + potato, banana, nuts
>>Other cross-reactive allergies
Feathers (e.g. bird species) + hen's egg + poultry meat + giblets
House dust mite allergy + crustaceans and molluscs
*1modified from (8, 16)
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non-immunologically mediated differential diagnoses
should be considered and ruled out and oral provocation
testing should be placed at the end of the diagnostic
chain. Besides the aforementioned diagnostic modalities
for IgE-mediated food allergies, a search is made for
signs of a non-IgE-mediated food allergy that show to
what extent the suspicion of an allergic reaction is justified
(Figure 3). When important differential diagnoses are
ruled out and the routine diagnostic parameters (skin
tests, antigen specific IgE) are uninformative, the pres-
ence of a local IgE-mediated (seronegative) form of
allergy, a non-IgE mediated allery, or an intolerance
may be considered (1, 9–11, 18, 20–22). For non-IgE-
mediated type II–IV allergies, the diagnostic repertoire
is much smaller than for systemic immediate-type reac-
tions.
Possible signs of delayed type II–IV food allergies
are (9–11, 15, 17, 21, 23, 24):
>the delayed positive skin test evaluated after 24 to
48 hours
>determination of the C3 and C4 complement fac-
tors (consumption in type II)
>detection of immune complexes (IC-IgG, -IgA,
-IgM and -IgE; for type III)
>cytokine analysis (tumor necrosis factor alpha,
interferon; for type IV).
As an important supplementary component it is also
recommended to use screening techniques to detect the
presence of an allergic disease in the gastrointestinal
tract or increased mediator production with excretion of
methylhistamine in 12-hour urine; allergen identifica-
tion can then be achieved through targeted gastroentero-
logical allergy testing (4, 11, 20, 21). The methylhista-
mine test shows that patients with food allergies and
involvement of the gastrointestinal tract eliminate
significantly more methylhistamine after ingesting
whole food than on a hypoallergenic elimination diet,
such as a hypoallergenic potato-rice diet. Mediator pro-
duction is diet related. In mastocytosis patients it is
much higher and remains elevated at a constant level on
different types of diet. Although this simple functional
test for methylhistamine excretion in urine is not specific
for food allergies, it is very useful for providing objective
evidence of histamine related symptoms (3). This test
determines endogenous histamine, which should be dis-
tinguished from exogenously supplied histamine which
can induce histamine intolerance.
If the clinical problem cannot be defined with the
usual IgE and/or non-IgE based routine diagnostic tests
(Figure 3) in the presence of elevated methylhistamine
excretion, either an oral provocation test (extraintestinal
symptoms) or more extensive medical differential diag-
nostic tests with targeted endoscopic allergy diagnosis
(intestinal symptoms) is advisable. A specimen can be
taken endoscopically. Immunohistochemical analysis is
then performed to determine
>whether and in which intestinal segments intestinal
eosinophilia or increased numbers of mast cells are
present
>whether gross lesions are present in these segments
and whether intestinal IgE antibodies (local type I
allergy) or increased TNF alpha (local type II to IV
allergy) are produced in the intestinal secretion as
the expression of an allergic gastrointestinal tract
(2, 4, 17, 18, 21, 23–25).
For detection of the intestinal IgE antibodies it is rec-
ommended to perform endoscopically controlled seg-
mental intestinal lavage (20, 22), which includes the
entire gastrointestinal tract, but which is particularly
effective in the terminal ileum, cecum, and rectosigmoid
junction (20). Patients with food allergies and atopy or
local Th2 immunodominance (seronegative type I allergy)
much more commonly have intestinal IgE in the rel-
evant intestinal segments. The combination of IgE and
eosinophilic cationic protein (ECP) from the endoscopic
lavage has proved to be a good predictive parameter for
recognizing allergic bowel disease (2, 20). It can be
diagnosed against which foods the intestinal IgE anti-
bodies are directed. In patients with non-IgE-mediated
allergy (types II–IV) it was found that no intestinal IgE
is usually present in the lavage, and rather that elevated
TNF concentrations are found in the absence of inflam-
mation.
In combination with the results of the medical his-
tory, cutaneous, serological or intestinal IgE analysis
(skin, blood, intestine) and the intestinal cytokine
concentrations, finally, a potential range of allergens
corresponding to the presumed allergy type (IgE ver-
sus non IgE) are assessed for their clinical relevance
in the provocation test (2, 11, 16). The guidelines rec-
ommend standardized oral provocation testing (6, 11,
22). Alternatively, mucosal oxygenation and segmental
intestinal lavage can be used to test the suspected
foods. To obviate the need for elaborate oral provoca-
tion testing, the trigger allergens are identified ex vivo
on the basis of their quantitative mediator and cyto-
kine release (2, 21, 23) (see supplementary case
report). Although this method is not explicitly included
Stepwise diagnostic procedure for food
allergies:
Detection of an allergic disease in the gastrointestinal
tract or increased mediator production by
methylhistamine excretion testing.
Detection of intestinal IgE antibodies
Endoscopically guided segmental intestinal lavage
is recommended in the entire gastrointestinal
tract, and is most effective in the terminal ileum,
cecum, and at the rectosigmoid junction.
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in the guidelines at present, it was evaluated in com-
parison to blinded oral provocation testing and was
found to be a valuable additional diagnostic resource
for gastrointestinal allergic manifestations, when oral
provocation is too hazardous or if the patient refuses
provocation testing (2, 21, 23, 25).
Differential diagnosis of diseases associated
with food intolerances
If non-specific evidence of food reactions is found,
other conditions which may present with symptoms
similar to those seen in intolerances or allergies should
be ruled out, such as chronic inflammatory bowel dis-
eases, chronic pancreatitis, irritable bowel syndrome,
eosinophilic gastroenteritis, systemic mastocytosis,
celiac disease, and microscopic colitis.
Infections
The commonest (chronic) infections are lambliasis,
chronic salmonellosis, infections with Blastocystis
hominis, but also infections caused by parasites such as
ameba, ascaris, pinworms, and Strongyloides. Further
infections which because of infection-triggered immune
responses (skin reactions, eosinophilia, IgA elevation,
diarrhea) direct suspicion towards food intolerance as
the cause of the symptoms, are urogenital infections
and/or bacterial overgrowth.
Mastocytosis
The symptoms of systemic mastocytosis can include not
only cutaneous signs but also episodic gastrointestinal
complaints such as nausea, burning abdominal pain,
diarrhea, ulcer diseases, gastrointestinal bleeding and
malabsorption (60% to 80% of affected patients) (e1).
The severity of the symptoms can vary from mild nausea
and pain to acute gastric ulcer and bleeding. The symp-
toms resemble those of the underlying diseases, most li-
kely histamine intolerance or food allergy. The causal
factor is the triggered release of mediators from imma-
ture proliferating mast cells in the bone marrow, gastro-
intestinal tract, or skin (e2). Release may occur sponta-
neously and may be triggered by a wide variety of phy-
sical, pharmacological, and/or psychological stimuli.
The pathogenesis of systemic mastocytosis is based
mainly on a mutation of transmembrane c-kit receptor
tyrosine kinase, which is responsible for the prolifera-
tion and maturation of mast cells. Tyrosine kinase usually
requires stem cell factor for this process. The receptor
can become permanently activated due to a mutation of
the c-kit, however, and thereby increase mast cell prolif-
eration and also facilitate the release of mast cell media-
tors (e1).
A symptom scoring system and the determination of
serum tryptase and methylhistamine excretion in urine
are central diagnostic indicators. The diagnosis has to be
confirmed by a histological analysis of tissue (skin, gas-
trointestinal tract) or bone marrow biopsy to demon-
strate mast cell infiltration.
The most important therapeutic measures are:
>avoiding the known trigger factors
>mast cell stabilization (cromoglycate, corticoste-
roids, cyclosporin)
>reducing mast cell growth (cladribine, interferon)
>antagonizing secreted mediators (H1and H2anti-
histamines, leukotriene receptor blockers) (e2).
The first therapeutic studies evaluating multityrosine
kinase inhibitors such as imatinib as a further option are
now available (e3).
Eosinophilic esophagogastroenteritis
A characteristic feature of eosinophilic esophagogas-
troenteritis is eosinophilic infiltration of the esophageal,
gastric and intestinal mucosa. Isolated organ segments
or their combinations may be affected (1, 2, 4). The typical
complex of symptoms consists in episodic abdominal
pain, nausea, vomiting, and diarrhea.
In 40% to 65% of patients eosinophilia is found in the
differential blood count. Chronic inflammatory bowel
diseases, parasitic infections, and tumors should be
excluded. In addition, evidence of allergy with IgE
Associated diseases are
>infections (such as lambliasis, chronic infections
or bacterial overgrowth)
>mastocytosis
>eosinophilic esophagogastroenteritis
Indicators of mastocytosis
>Cutaneous signs
>Episodic gastrointestinal symptoms such as
nausea, burning abdominal pain, diarrhea
>Ulcer disease
>Gastrointestinal bleeding and malabsorption
TABLE 2
Differential diagnosis of food allergy
Differential diagnoses Findings/diagnostic interventions
Anaphylaxis Allergen, specific IgE, serum tryptase
Angioedema Skin changes, C1 inactivator
Carcinoid Prostaglandins, serotonin, NSE, chromogranin
Pheochromocytoma Blood pressure, catecholamines in urine
Mastocytosis Mediators of mast cell activation
Neuroendocrine tumors (VIP, VIP, gastrin in serum, NSE,chromogranin
Zollinger-Ellison syndrome etc.)
T-cell lymphomas B-symptoms, β2-microglobulin, bone marrow
368 Deutsches Ärzteblatt International⏐⏐Dtsch Arztebl Int 2009; 106(21): 359–70
MEDICINE
elevation or evidence of specific IgE is present in 40%
to 50% of patients as evidence of an associated food
allergy. Esophagogastroduodenoscopy and colonoscopy
with biopsy specimens should be performed for
diagnostic clarification. With abstinence, a hypo-
allergenic liquid diet, and medical treatment (antihista-
mines, budesonide, cromoglicic acid, and predniso-
lone), the prognosis is very good.
Neurovegetative, psychological and somatoform disorders
In addition to other rare organic differential diagnoses
(table 2), food related symptoms should always prompt
consideration of a possible psychological, neurovegeta-
tive, or somatoform component (for example an eating
disorder).
There has been little research to date on the relation-
ship between food allergies and intolerance reactions
and psychological symptoms and stress factors has been
little researched to date. However, the study results
available thus far suggest the existence of indirect and
direct interactions (1, 11). For example, psychoimmuno-
neurological testing has now shown that following the
release of adrenaline as a response to stress, mast cells
are stimulated through noradrenergic nerve fibers and
react by releasing messenger substances such as hista-
mine. On the other hand, chronic physical distress such
as a food intolerance is in itself also a psychological
stressor which compromises quality of life and can
secondarily induce or exacerbate depression and anxiety
disorders.
Conflict of interest statement
The authors declare that no conflict of interest exists according to the
guidelines of the International Committee of Medical Journal Editors.
Manuscript received on 26 January 2009, revised version accepted on
29 April 2009.
Translated from the original German by mt-g.
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Gut 1996; 39: 130–5.
10. Lack G: Clinical practice.Food allergy.N Engl J Med 2008; 359(12):
1252–60.
11. Vatn MH, Grimstad IA,Thorsen L, Kittang E, Refnin I,Malt U et al.:
Adverse reaction to food: assessment by double-blind placebo-
controlled food challenge and clinical, psychosomatic and
immunologic analysis. Digestion 1995; 56: 421–8.
12. Giera B, Straube S,Konturek P, Hahn EG,Raithel M: Plasma
histamine levels and symptoms in double blind placebo controlled
histamine provocation. Inflamm Res 2008; 57 Suppl 1: S73–4.
13. Jarisch R GM, Hemmer W,Missbichler A, Raithel M,Wantke F:
Histamin-Intoleranz. Histamin und Seekrankheit. 2. Aufl. Stuttgart,
New York.Thieme Verlag 2004.
14. Mahler V: Bei Weinüberempfindlichkeit gibt es viele Verdächtige.
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15. Iacono G, Ravelli A, Di Prima L, Scalici C,Bolognini S, Chiappa S et
al.: Colonic lymphoid nodular hyperplasia in children: relationship to
food hypersensitivity. Clin Gastroenterol Hepatol 2007; 5:361–6.
16. Kleine-Tebbe J, Ballmer-Weber B, Beyer K et al.: In-vitro Diagnostik
von IgE-vermittelten Nahrungsmittelallergien. Leitlinie der Deutschen
Gesellschaft für Allergologie und klinische Immunologie (DGAKI), des
Ärzteverbandes Deutscher Allergologen (ÄDA) sowie der Gesell-
schaft für Pädiatrische Allergologie und Umweltmedizin (GPA) in
Kooperation mit der Österreichischen Gesellschaft für Allergologie
und Immunologie (SGAI). Allergo J 2009; 18:132–46.
17. Niggemann B ES, Fuchs Th, Henzgen M et al.: Standardisierung von
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und klinische Immunologie (DGAKI), des Ärzteverbandes Deutscher
Allergologen (ÄDA) sowie der Gesellschaft für Pädiatrische Allergologie
und Umweltmedizin (GPA).Allergo J 2006; 15: 262–70.
18. Andre F,Andre C, Colin L, Cavagna S: IgE in stools as indicator of
food sensitization. Allergy 1995; 50:328–33.
19. Moneret Vautrin DA, Sainte-Laudy J, Kanny G:Ulcerative colitis
possibly due to hypersensitivity to wheat and egg. Allergy 2001; 56:
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20. Raithel M,Weidenhiller M,Abel R, Baenkler HW, Hahn EG: Colorectal
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21. Paajanen L,Vaarala O, Karttunen R,Tuure T, Korpela R,Kokkonen J:
Increased IFN-gamma secretion from duodenal biopsy samples in
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is characterized by eosinophilic infiltration of the
esophageal, gastric and intestinal mucosa.
Neurovegetative psychological and
somatoform disorders
Research results to date suggest indirect and
direct interactions between food allergies/
intolerance reactions and psychological
symptoms.
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delayed-type cow's milk allergy. Pediatr Allergy Immunol 2005; 16:
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96: 508–14.
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et al.: Mononuclear cells from infants allergic to cow's milk secrete
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Corresponding author
Dr.med. Yurdagül Zopf
Medizinische Klinik 1
Universitätsklinikum Erlangen
91054 Erlangen, Germany
yurdaguel.zopf@uk-erlangen.de
For e-references please refer to:
www.aerzteblatt-international.de/ref2109
Case report, e-Box, and e-Tables available at:
www.aerzteblatt-international.de/article09m359
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MEDICINE
Please answer the following questions to participate in our certified Continuing Medical Education
program. Only one answer is possible per question. Please select the answer that is most appropriate.
Question 1:
Which food intolerance is the commonest among
all reactions to foods?
a) Non-immunological
b) Immunological
c) Somatoform
d) Mastocytosis related
e) Infectious
Question 2:
How high is the prevalence of food allergies in adults?
a) 0% to 1%
b) 2% to 5%
c) 6% to 8%
d) 9% to 11%
e) 12% to 14%
Question 3:
What is a possible cause of a functional food intolerance?
a) Achalasia
b) Chronic pancreatitis
c) Right ventricular failure
d) Obstructive jaundice
e) Enzyme deficiency disorder
Question 4:
Which symptom is typical of carbohydrate malabsorption?
a) Melena
b) Constipation
c) Steatorrhea
d) Diarrhea
e) Hematochezia
Question 5:
What is detected with segmental intestinal lavage?
a) IgD antibodies
b) IgA antibodies
c) IgM antibodies
d) IgE antibodies
e) IgG antibodies
Question 6:
What is a classical symptom of salicylate intolerance?
a) Sinus tachycardia
b) Sinusitis
c) Chronic venous insufficiency
d) Retrosternal pain on pressure
e) Heart failure
Question 7:
With which medication can a small bowel bacterial
overgrowth occur?
a) Proton pump inhibitor
b) ACE inhibitor
c) Anticoagulants
d) Anticonvulsants
e) Antihypertensives
Question 8
Which etiological agent is most commonly associated
with food intolerances?
a) Norovirus
b) Clostridium difficile
c) Giardia lamblia
d) Helicobacter pylori
e) Enterohemorrhagic
Escherichia coli
Question 9:
How is eosinophilic esophagogastroenteritis treated?
a) Reduction diet, non-carbonated mineral water, betamethasone
b) Mashed food, wormwood tea,cortisone
c) Parenteral nutrition, antibiotics,abstention oral fluids
d) Fasting,hypoallergenic liquid diet and prednisolone
a) Enteral nutrition, high-calorie liquid diet,dexamethasone
Question 10:
Of what intolerance is an X-chromosomally inherited enzyme
deficiency the cause?
e) Trehalase deficiency
f) Lactase deficiency
g) Glucose-6-phosphate dehydrogenase deficiency
h) Alcohol dehydrogenase deficiency
i) Galactase deficiency
MEDICINE
Deutsches Ärzteblatt International⏐⏐Dtsch Arztebl Int 2009; 106(21)⏐⏐Zopf et al.: case-report I
Case 1
A 51-year-old female patient with long history of
ulcerative colitis proved refractory to the standard
treatment with mesalazine and steroids.
She reported recurrent postprandial symptoms
and acute episodes. The patient has a history of pol-
linosis and chronic eosinophilia. Serological tests
showed IgE (92 U/L) still in the upper range of nor-
mal and an elevated methylhistamine level in urine
(14 µg/mmoL creatinine x m² BSA [BSA, body sur-
face area]). The functional blood test using peripheral
leucocytes incubated with 5-acetylsalycilic acid
showed a pathological result. This was confirmed
clinically by oral provocation followed by bloody
diarrhea and fever.
Abstention from salicylates in foods and medica-
tions including mesalazine led to complete remis-
sion of the ulcerative colitis.
As a differential diagnosis for ulcerative colitis,
the patient may retrospectively be seen to have had
allergic enterocolitis or salicylate intolerance colitis
spuriously presenting as ulcerative colitis over a
period of years. This underlines the wide range of
symptoms observed in patients with food intolerance
and clearly illustrates that structured diagnosis is
indispensable to verify the reported symptoms.
Case 2
A 47-year-old female lawyer with first diagnosis of
ulcerative proctosigmoiditis in 1998. No other dis-
eases known. Family history of atopic dermatitis.
The patient received drug treatment for the colitis
with prednisolone and 5 ASAfrom 1998 to 2003.
The patient reported recurrent postprandial
symptoms with bloody diarrhea and abdominal pain,
especially after consuming bread and pastries. For
more than three years she had also noticed intolerance
of legumes and oranges.
Prick testing
Positive skin reaction to house dust mites, negative
to spices, foods and mold fungi. Serology: no elevated
IgE (27 U/L), no specific IgE against foods. Antibody
against transglutaminase was negative.
Diagnostic evaluation with oral provocation
could not be performed due to the patient's profes-
sional commitments.
Segmental endoscopic lavage
An elevated total IgE value of 9.3 U/mg protein was
determined in the rectum (normal range <0.35 U/mg
protein) and a specific IgE to soya (0.60 U/mg pro-
tein), rye flour (0.80 U/mg protein) and wheat flour
(0.55 U/mg protein) (22).
Mucosa oxygenation
Testing of the viable intestinal biopsies for the
mediators histamine, eosinophil cationic protein,
mast cell tryptase and TNF-alpha revealed signifi-
cantly concentration-dependent increased release of
these immune mediators on rye (23).
An elimination diet of wheat, rye and soya pro-
duced a complete remission which has now been
persisting for more than four years. Concluding
diagnosis: local (seronegative), IgE-mediated allergic
enterocolitis.
Case Report
The Differential Diagnosis of Food Intolerance
CONTINUING MEDICAL EDUCATION
The Differential Diagnosis
of Food Intolerance
Yurdagül Zopf, Hanns-Wolf Baenkler, Andrea Silbermann,
Eckhart G. Hahn, Martin Raithel
Deutsches Ärzteblatt International⏐⏐Dtsch Arztebl Int 2009; 106(21)⏐⏐Zopf et al.: e-references I
MEDICINE
E-REFERENCES
e1. Horny HP SK,Valent P,Hartmann K: Mastocytosis— A Disease of the
Hematopoietic Stem Cell. Dtsch Arztebl Int 2008; 105(40):686–92.
e2. Buske-Kirschbaum A, Geiben A, Hellhammer D: Psychobiological
aspects of atopic dermatitis: an overview. Psychother Psychosom
2001; 70: 6–16.
e3. Vega-Ruiz A, Cortes JE, Sever M, Manshouri T, Quintas-Cardama A,
Luthra R et al.: Phase II study of imatinib mesylate as therapy for
patients with systemic mastocytosis. Leuk Res 2009.
CONTINUING MEDICAL EDUCATION
The Differential Diagnosis
of Food Intolerance
Yurdagül Zopf, Hanns-Wolf Baenkler, Andrea Silbermann,
Eckhart G. Hahn, Martin Raithel
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MEDICINE
CONTINUING MEDICAL EDUCATION
The Differential Diagnosis
of Food Intolerance
Yurdagül Zopf, Hanns-Wolf Baenkler, Andrea Silbermann,
Eckhart G. Hahn, Martin Raithel
E-BOX
>>FFooooddss wwiitthh hhiigghh hhiissttaammiinnee ccoonntteenntt
Especially microbially produced foods (e.g. long ripened cheese,
pickled cabbage, red wine) and microbially contaminated high-
protein diet (e.g. tuna fish, mackerel,sausage)
>>FFooooddss tthhaatt iinnhhiibbiitt ddiiaammiinnooooxxiiddaassee
Especially other amines (black tea, maté tea, colorants),alcohol
>>FFooooddss tthhaatt rreelleeaassee iinnccrreeaas
seedd aammoouunnttss ooff hhiissttaammiinnee
Citrus fruits, nuts, wheat germ,alcohol (acetyldehyde)
>>OOtthheerr aaccccoommppaannyyiinngg ffaaccttoorrss tthhaatt pprroommoottee hhiissttaammiinnee rreelleeaassee
Infections, sports, emotional upset (stress),chronic diseases
(e.g. chronic renal insufficiency), medications (NSAIDs,
acetylsalicylic acid (ASA), metamizole, radiographic contrast
media, opiates)
Deutsches Ärzteblatt International⏐⏐Dtsch Arztebl Int 2009; 106(21)⏐⏐Zopf et al.: e-tables I
MEDICINE
CONTINUING MEDICAL EDUCATION
The Differential Diagnosis
of Food Intolerance
Yurdagül Zopf, Hanns-Wolf Baenkler, Andrea Silbermann,
Eckhart G. Hahn, Martin Raithel
E-TABLE 1
Common allergens in food allergies
Children, adolescents Adults
E-TABLE 2
Salicylate content of foods as
nutritive triggers of symptoms
in salicylate intolerance
Food Salicylate
content (mg/kg)
Curry 2180
Peppers 2030
Oregano 660
Mustard 260
Cayenne pepper 176
Sultanas 78
Raisins 66
Pepper 60
Oranges 23
Apples 4
Pears 3
Potatoes 1–3
Bananas 0.1
Cow's milk, milk constituents
Hen's eggs (albumin), wheat
Nuts, soya products
Fruit
Mould fungus products
Vegetables, cereals
Meat, fish
Nuts, soya products, celery,pollen-
associated foods (e.g. fruit)
Wheat, rye
Vegetables, oats, milk constituents
Fish, seafood, meat
Mould fungus products
Cow's milk, hen's eggs
Poultry
