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METHODS FOR DETECTION OF FOOD INTOLERANCE

Authors:
  • University Hospital Lozenetz

Abstract and Figures

Literature data show that about 60% of the world's population suffers from food intolerance to at least one food antigen. This intolerance can cause various symptoms-mainly digestive disturbances, but also skin irritations, neurological disturbances, musculoskeletal symptoms, etc., which need to be diagnostically clarified. In most cases, allergen consumption causes an exacerbation of clinical signs. For food intolerance, the presence of specific IgE and IgG antibodies can be observed. Some subclasses of IgG (mainly IgG4) inhibits the degranulation of basophils and mast cells and the activation of the complement cascade. However, various studies have shown that people with inflammatory and alimentary intolerance have had IgG directed against food antigens alone, but not IgE. On the other hand, skin tests are rarely positively influenced by food allergies that are mainly bound to IgE antibodies. Moreover, IgE-related food allergy develops within the next hour after food intake, while intolerability to food allergens and specific IgG/IgG4 antibodies show a delayed response of 24 to 120 hours, and persistent symptoms may occur. This is also beneficial in testing patients in a more distant period of consumption of certain food allergens. Provocative and elimination diets may be used as additional diagnostic tools for food intolerance. Unfortunately, they depend heavily on motivation and performance of patients. The aim/purpose of this review is to describe the available methods for food intolerance diagnostics, particularly the determination of specific IgG antibodies to food antigens, and compare their usefulness in clinical practice as reliable diagnostic tools.
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RAdvFoodSci: 2018: 1(3): 106-119 ISSN: 2601-5412 106
METHODS FOR DETECTION OF FOOD INTOLERANCE
Tsvetelina VELIKOVA1*, Alexander KUKOV2, Viktoriya GEORGIEVA3, Milena
PERUHOVA3, Nonka YURUKOVA3, Antoaneta MIHOVA1, Tsanka MEHANDZHIYSKA
MARINOVA4,6, Gergana MIZGOVA4, Velislava TERZIEVA1, Galina ZHELEZOVA5,
Iskra ALTANKOVA1, Ludmila IVANOVA6
1Clinical Immunology, University Hospital Lozenetz, Kozyak 1 str, 1407 Sofia, Bulgaria
(tsvelikova@medfac.mu-sofia.bg )
2AA Medical Bulgaria Ltd, Golo bardo 8 str, 1407 Sofia, Bulgaria
3Clinic of Internal Medicine, Gastroenterology Ward, University Hospital Lozenetz, Kozyak 1 st, 1407 Sofia,
Bulgaria
4Laboratory of Microbiology and Virology, University Hospital Lozenetz, Kozyak 1 str, 1407 Sofia, Bulgaria
5Department of Biology, medical genetics and microbiology, Faculty of Medicine, Sofia University St. Kliment
Ohridski, Kozyak 1 str, 1407 Sofia, Bulgaria
6Department of Neurology, Psychiatry, Physiotherapy and Rehabilitation, Preventive Medicine and Public
Health, Faculty of Medicine, Sofia University St. Kliment Ohridski, Kozyak 1 str, 1407 Sofia, Bulgaria
Article History:
Received 01 June 2018
Revised 15 July 2018
Accepted 17 July 2018
Keywords:
food intolerance
food allergy
food allergen
specific IgG antibodies
methods for detection
Abstract:
Literature data show that about 60% of the world's population suffers from food
intolerance to at least one food antigen. This intolerance can cause various
symptoms - mainly digestive disturbances, but also skin irritations, neurological
disturbances, musculoskeletal symptoms, etc., which need to be diagnostically
clarified. In most cases, allergen consumption causes an exacerbation of
clinical signs. For food intolerance, the presence of specific IgE and IgG
antibodies can be observed. Some subclasses of IgG (mainly IgG4) inhibits
the degranulation of basophils and mast cells and the activation of the
complement cascade. However, various studies have shown that people with
inflammatory and alimentary intolerance have had IgG directed against food
antigens alone, but not IgE. On the other hand, skin tests are rarely positively
influenced by food allergies that are mainly bound to IgE antibodies. Moreover,
IgE-related food allergy develops within the next hour after food intake, while
intolerability to food allergens and specific IgG/IgG4 antibodies show a delayed
response of 24 to 120 hours, and persistent symptoms may occur. This is also
beneficial in testing patients in a more distant period of consumption of certain
food allergens. Provocative and elimination diets may be used as additional
diagnostic tools for food intolerance. Unfortunately, they depend heavily on
motivation and performance of patients. The aim/purpose of this review is to
describe the available methods for food intolerance diagnostics, particularly
the determination of specific IgG antibodies to food antigens, and compare
their usefulness in clinical practice as reliable diagnostic tools.
T VELIKOVA, A KUKOV, V GEORGIEVA, M PERUHOVA, N YURUKOVA, et al.
Methods for detection of food intolerance
RAdvFoodSci: 2018: 1(3): 106-119 ISSN: 2601-5412 107
1. Introduction
The human organism has developed a very high
degree of tolerance to food proteins. Sometimes,
however, especially when the intestinal barrier is
impaired, the immune system can recognize
uncooked food proteins as foreign and activate the
immune system to neutralize and destroy these food
particles [1,2]. There is no doubt that the consumed
foods have a great impact on people health and
quality of life. Over the last few decades, the
discussion of abnormal nutritional reactions and the
health problems associated with them, has been
gaining increasing interest in [3].
The spread of food intolerance in Europe is
unknown. Using nutritional challenges as a diagnostic
criterion, the prevalence of food reactions in Europe
has been estimated between 3 and 4%, both in
children and adults [4] but there is not enough
objective data to conclude on this trend. About 75%
of the food reactions among children are to antigens
such as eggs, peanuts, cow's milk, fish and various
nuts, whereas about 50% of adult food reactions are
to the following antigens: latex and Rosaceae fruits,
Apiaceae, and different nuts and peanuts [4,5].
Geographical variations in the distribution of food
reactions are due to differences in genetic regional
and local factors such as pollen exposure or dietary
habits. Thus, the extrapolation of data on the
distribution of the specific food reactions from one
European country to the entire European population
has a limited accuracy because of the
abovementioned differences in dietary exposure and
habits [5].
The abnormal responses to food antigens could
be classified mainly as immune-mediated and non-
immune-mediated (Figure 1). Immune-mediated
adverse reactions to foods have clinical manifestation
with variable severity and duration that may affect
different organs and systems. Anaphylactic reactions
to food are IgE-mediated and can occur at any age.
Non-IgE-mediated food allergies include a wide range
of diseases, including atopic dermatitis, protein-
induced enterocolitis, and eosinophilic oesophagitis
[6-10].
Figure 1. Classifications of the abnormal responses to food antigens
The concepts of food allergy and food intolerance
are often mixed by healthcare professionals, patients,
and the general audience. Food allergy is an
abnormal response to certain food ingredients that
occurs as a result of a specific immune system
response involving IgE antibodies. IgE - mediated
allergic reactions are of a rapid type immune reaction
associated with activation of Th2 cells. They affect
about 2 - 3% of the population [11]. Symptoms usually
occur within few minutes to two hours after eating a
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Methods for detection of food intolerance
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particular food, including urticaria, oral allergic
syndrome, angioedema, cough, shortness of breath,
vomiting, diarrhea, and, in rare cases, a generalized
(systemic) anaphylactic reaction (with all its
complications, including cardiovascular symptoms
and generalised collapse). Most commonly, such
allergic reactions are caused by eggs, milk, soy,
peanuts, hazelnuts, walnuts and seafood [11-13].
Food intolerance, in contrast to IgE-mediated
allergy, affects about 60% of the population [12]. Both
immune and non-immune-mediated reactions are
involved in food intolerance development (Figure 1).
One of the best-known immune mechanisms of
nutritional intolerance is associated with the formation
of specific IgG antibodies. These antibodies form
complexes with food proteins that accumulate in
various tissues and organs of the body, resulting in
inflammatory processes. They may cause a wide
range of symptoms and reactions (Table 1) [5, 14-16].
These reactions occur more slowly - few hours to few
days after the ingestion of a particular food but may
persist for many years without any suspicion of the
cause [13].
Table 1. Clinical features of food intolerance
Gastrointestinal
Respiratory
Neurological
Rheumatological
Nausea
Vomiting
Diarrhea
Oral allergy syndrome
Gastro-oesophageal
reflux disease
Abdominal pain
Enteropathies
Infantile colic
Constipation
Rhinitis
Rhino-
conjunctivitis
Sinusitis
Asthma
Cough
Laryngeal
oedema
Migraine
Headache
Disturbed
concentration
depression
Arthritis
Muscular pain
and weakness
Hypersensitivity, another term in the food
reactions field, describes an unfavorable clinical
response in which the exact nature of the underlying
pathophysiology is unknown. Sometimes this term is
used more widely to describe all unfavorable food
reactions, including immunologically mediated
diseases and nutritional intolerance. In this review,
"food hypersensitivity" will not be used due to its
ambiguity [5].
2. Immune responses to food antigens
The gut is the largest lymphoid organ in the body.
To avoid allergic reactions due to excessive
penetration of antigens into the intestinal lamina
propria, the vulnerable gut mucosa is supported by
specialized anti-inflammatory immune defenses,
including secretory IgA (SIgA) antibodies and
hyporesponsiveness to innocuous agents,
particularly dietary antigens and the commensal gut
microbiota [17]. The protection of the gut mucosa
from foreign protein antigens is also guaranteed by
the presence of intact epithelial layer that possesses
tight junctions, digestive enzymes, peristaltic
movement and other nonspecific defense systems.
Bearing in mind that substantial amounts of intact
food proteins are absorbed by the gut after eating
(130190 g of food protein), it is obvious that oral
tolerance is a robust adaptive immune function [18].
It can be suggested that normally food antigens are
not able to react with the gut immune system.
However, it has been shown that undigested
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macromolecules such as food allergens pass through
the intestinal barrier as intact proteins, interacting with
the local intestinal immune system and could be
transported to other body sites [19]. The existence of
increased gastro-intestinal barrier permeability
facilitates this process. Through penetration of the
epithelium of the digestive tract, food antigens
encounter immune cells which are part of the
gastrointestinal-associated lymphoid tissue (GALT)
[19]. The role of GALT is to maintain immune
homeostasis, maneuvering between protecting the
organism from pathogens and sustaining the immune
tolerance to antigens considered as harmless [20].
Therefore, GALT could identify food allergens as
harmless and tolerate them, or as pathogens causing
defensive or excessive hypersensitivity reactions
[19]. However, the allergenic activity of a food can be
reduced, left unchanged or even increased with food
processing. Due to the multitude of food allergenic
proteins and their different behavior to the same
treatment, it is difficult to predict the impact of food
processing on the structural and allergic properties of
allergenic foods/ingredients. Although the effects of
different (technological and cooking) treatments on
the IgE-binding capacity of several allergens have
been studied, there is less information on the effects
of treatment on clinical reactivity [5].
Immune response to food can be divided into three
categories depending on the production of different
immunoglobulins IgE, IgG, IgA.
2.1. Type 1 allergies cause classical symptoms
IgE antibodies are responsible for acute allergic
reactions classified as type 1 allergies. They mainly
affect the mucous membranes, the skin, and the
circulation. Classical symptoms are rash, itching of
the skin and mucous membranes, Quincke's edema,
anaphylactic shock [21]. The IgE receptors are
localized throughout the mucosa and react
immediately upon contact with the antigen. They
activate mast cell degranulation and massive
histamine release. Symptoms occur rapidly - between
one second and 30 minutes after ingestion of the food
[22,23]. It is estimated that 2-4% of adults and about
8% of children have IgE mediated allergies [24].
Usually, no blood test is needed to identify foods
responsible for allergies. IgE tests are mainly done for
confirmation of type 1 allergy, whereas IgE screening
for a large number of foods is considered useless.
2.2. IgG antibodies are responsible for delayed
immune reactions to foods
IgG antibodies are responsible for delayed immune
reactions to foods which are classified as Type 3
allergies [25]. Food components must pass through
the intestinal wall to form circulating immune
complexes with the antibodies. Phagocytes are
activated to destroy these immune complexes in the
bloodstream, where they generally do not show
symptoms. IgG responses to antigens located on the
surface of particular tissue lead to the rapid local
destruction of these tissue. If this becomes a
continuous process due to regular intake of allergens,
specific symptoms depending on the organ localization
of immune complexes may occur and the condition
becomes chronic [26]. Symptoms usually occur 2-3
hours to 2-3 days after consuming the allergens. Thus,
it is very difficult to associate a specific food with a
chronic symptom. Therefore, it will be important to
perform a blood test to detect the presence of specific
IgG antibodies directed against food allergens. It is
estimated that approximately 50% of patients suffering
from chronic inflammatory diseases may possess IgG
- mediated delayed food allergies/intolerance [27].
Because of their relatively long half-life, IgG persists
enough to be extremely well suited for determination of
immune responses to foreign food antigens. IgG
antibodies disappear from the bloodstream after 2-3
months to 2 years, depending on the initial blood
concentration, if the food antigens are completely
discontinued from the diet [27].
2.3. IgA antibodies to food are associated with
various pathologies
IgA is the first line of antibodies that are produced
in the early stages of the immune response,
especially in the gastrointestinal tract. IgA has a very
short half-life and disappears when the second line of
antibodies (IgG) is produced. There is evidence that
IgA antibodies are involved in various pathological
processes, such as IgA-mediated nephropathy. They
can form immune complexes with food antigens and
accumulate predominantly in the kidneys where they
can lead to glomerulonephritis [28].
3. Methods for food intolerance diagnostics
The process of diagnosis and treatment of food
intolerance is complex and elusive [29]. The patient's
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Methods for detection of food intolerance
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history, and in particular, the temporal relationship
between exposure and response is a key diagnosis
factor. A family history of atopy will increase the
suspicion of immune-mediated unwanted food
reactions. However, the lack of family history does not
exclude the diagnosis or allergic cause of clinical
symptoms. Investigation of any patient with suspicion
of anaphylaxis due to a possible food allergen is
difficult. Important information related to what food
cause the development of the symptoms can derive
from the disappearance of the symptom when the
food is eliminated from the diet [5].
3.1. Conventional allergy tests which may be
applied to food intolerance diagnostic
Careful family and clinical history are the basis for
diagnosing food intolerance. Food diaries, skin prick
tests (SPT), allergen-specific IgE measurements,
food elimination and food challenges are part of the
standard protocol for diagnosing food allergy and may
be used in food intolerance diagnostic too [3].
Allergen-specific IgE antibodies in serum indicate
sensitization to a particular food, but they are not
diagnostic without a medical history or a change of
the diet. However, skin prick tests remain negative in
food intolerance, and the level of specific IgE shows
existence of the allergy or tendency to allergy which
refers to the reaction of hypersensitivity type 1. Thus,
these tests can’t be used in food intolerance
diagnostics. Using atopic patches to diagnose food
intolerance is controversial. The diagnosis of food
intolerance could be confirmed by the exclusion of the
suspected food and the subsequent alleviation of the
symptoms and the repetition of the symptoms when
re-introducing the food, ideally in double-blind
placebo-controlled food challenges trials, when the
expected symptoms are not life-threatening. Dietary
avoidance of specific foods in combination with
nutritional counseling is the primary task for treatment
of food intolerance. Sometimes individuals with
symptoms related to food intolerance can exert
amelioration of their clinical conditions later in life [3].
There is a need to standardize allergens and their
preparations for diagnostic use, including oral
studies, as well as standard test protocols to facilitate
epidemiological and other multicentre trials
investigating allergic and non-allergic reactions to
food [5].
The diagnosis of immunological adverse reactions
to food and nutrients depends on the clinical insight,
knowledge of the history of the patient and careful
study of the clinical investigations. Diagnosis of food
intolerance is often difficult due to the variability and
subjectivity of the symptoms and the lack of objective
clinical signs [7,11,30]. Having in mind that IgE-
mediated food allergy should be excluded to display
food intolerance, Guidelines and Protocols for Clinical
Diagnosis of Food Allergy were conducted [30] which
include the specific diagnostic tests that are detailed
by several professional bodies and expert reports as
diagnostic procedures for allergic diseases of the
gastrointestinal tract in childhood [30-35].
3.1.1. Food challenges
The diagnosis of IgE mediated and other
immunologically mediated adverse reactions to food
can only be confirmed by excluding the suspected
food and then alleviating the symptoms, and by
repeating the symptoms of re-administration of the
food. Subjects can be put on open challenges (they
are aware of being challenging with food-disturbing
placebo-free food), or in single-blind placebo-
controlled challenges (subjects do not know whether
the food or placebo is ingested) or double-blind
placebo-controlled nutritional challenges (both
subjects and researchers do not know whether food
or placebo). However, the latter is the gold standard
since all subjective abnormalities are abolished [5].
Allergen-specific serum IgE antibodies indicate
sensitization to a particular food but do not provide
information on the onset or severity of allergic
reactions after oral exposure to this food. Depending
on the incriminated food, high levels of specific IgE
antibodies are a good indication of preventing oral
challenge tests in patients with high sensitivity [35-
37]. However, up to 40% of individuals with significant
allergen-specific IgE levels cannot receive any clinical
symptoms when challenged with this allergen [11].
3.1.2. Skin tests, skin prick test
In cases of suspected IgE-mediated immunological
reactions to food, a skin prick test (SPT) may be
performed. The positive reaction occurs as an
erythema, the diameter of which can be measured to
determine the degree of the reaction. Diagnostic
accuracy and susceptibility to suspected food
allergens varies depending on the possible ingested
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food, and are slightly higher than the measurement of
allergen-specific IgE. Positive tests, however, have
only a 50-60% positive predictive value [38].
Sometimes strong reactions to some allergens can
cause an allergic reaction [39]. Thus, the presentation
of allergens in the food matrix during SPT challenge
should be carefully considered since it may have a
noticeable effect on post-allergic reactions [40].
Moreover, the IgE study is strictly limited to classical
food allergies and the use of SPT test is controversial,
as a matter of fact 99% of all food allergies can be
identified without the test because of the extremely
short onset of symptoms after food intake.
The atopic patch test identifies allergens that can
induce a non-IgE-mediated reaction (delayed
hypersensitivity) [41]. It involves the administration of
an allergen under occlusive dressing for 48 hours on
a non-affected part of the patient's skin, and the
results are scored 20 minutes and 24 hours after
occlusive dressing removal. The test is proposed for
patients affected by atopic dermatitis and
gastrointestinal food allergy [42]. Confirmation of the
test result is necessary for the elimination and
subsequent food induction. However, the specificity
and sensitivity of the atopic correction tests are still
the subjects of debate.
3.1.3. Labial and conjunctive challenges tests
Labial and conjunctival challenges also existed,
mainly for diagnosis in children, but they are not
included in the routine diagnosis due to a lack of
standardization ranging from clinical evidence to a
lack of validation [43,44].
3.1.4. Respiratory function tests
Respiratory function tests (Breathing Functional
Studies) are useful when respiratory signs and
symptoms are present in immunologically mediated
adverse reactions to food. Such tests may include
those for the estimation of airway narrowing and/or
inflammation (bronchopulmonary provocation)
[45,46] but not specific to food allergy.
3.1.5. Flow cytometry
Studies of the peripheral blood mononuclear cell
by flow cytometry and IgE in fecal extracts can be
used as screening tools to identify groups of
potentially allergic patients but their utility in
diagnosing individual food allergy remains to be
demonstrated [47,48]. The Basal Activator (BAT)
assay (e.g., expression of basophile activators as
CD63 and CD203c detected by flow cytometry) is
also proposed for screening although the available
technologies can be optimized and better
standardized [49].
3.1.6. Radioallergosorbent test (RAST)
RAST is a radioimmunoassay for detecting
specific IgE antibodies to suspected or known
allergens to clarify the diagnosis of allergy. The IgE
antibody is associated with immune responses of the
first type of hypersensitivity (classic allergic
response). Thus, if a patient has a high level of IgE
directed against pollen, the test may indicate that the
person is allergic to pollen (or pollen-like proteins)
[50]. The test is carried out by placing the suspected
allergen on the insoluble material, then adding the
patient's serum. If the serum contains antibodies
against the allergen, these antibodies will bind to the
allergen. An isotope-labeled anti-human IgE antibody
is then added to the reaction. If the IgE antibodies are
already bound to the antigen, the isotype-labeled
antibody binds to them and gives a signal. Unbound
anti-human IgE antibodies are washed away. The
amount of radioactivity is proportional to serum IgE
for the respective allergen. The RAST test has high
specificity and sensitivity, only a small amount of
blood from the patient and the appropriate apparatus
is required. The mentioned test shows several
advantages compared to skin challenges: it is not
necessary to stop the patient from antihistamine
therapy and the RAST test can be performed on
patients with severely affected skin (eczema) [51].
Based on the RAST method, the ImmunoCAP test
was developed and widely used as diagnostic test in
many clinical laboratories. In this allergen binding
test, a cellulose capsule is used to ensure the stable
binding of allergens and preservation of their native
structure. After the addition of the patient's serum, the
unbound antibodies are washed away, and an
enzyme linked antibody against human IgE is added.
The complex formed is visualized after the addition of
the substrate and following the fluorescence signal.
After more than 4,000 scientific publications and the
many laboratories using the ImmunoCAP test, this
method has shown its clinical-diagnostic value and
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today the ImmunoCAP test is considered a "gold
standard" in vitro IgE testing [52].
3.1.7. Background for IgG antibody testing
Measurements of IgG and IgG subclasses against
food antigens in serum do not play a role in the routine
diagnosis of food allergy and should not be the basis
for excluding certain foods from the diet. However,
they display an important role in diagnostics of IgG
immune-mediated adverse reactions to foods [53].
The genes for IgE and IgG antibodies are in close
proximity to each other on chromosome 14 and they
are read in sequence. Their production depends on
the presence of interleukins, in particular if
predominantly IL-4 is produced, it can be assumed
that IgE will be produced primarily and an IgE
response will occur. Then, a true Type 1 allergy or the
so-called classic food allergy develops which is
characterized by an immediate reaction after
consumption of the food and can be fatal in case of
anaphylactic shock [54].
In case of sensitization where IL-10 is produced
predominantly (with its anti-inflammatory properties),
mainly IgG4 antibodies will be produced. IgG4 are
considered "blocking antibodies" with respect to IgE,
i.e. they block access of IgE to the allergen. The
concentration of IgG4 is about 10,000 times higher
than the IgE concentration. Therefore, IgG4 can bind
faster and with greater frequency to the allergen than
IgE [54]. Since IgG4 results in the release of only
about 1% of the amount of histamine released by IgE,
very few patients experience allergic symptoms. This
is the reason why when IgG4 is the preferably
produced antibody, the allergy is asymptomatic.
Symptoms may occur only in patients (about 3%) with
deficiency of diamine oxidase enzyme when there is
an abnormal histamine detoxification [55]. For this
reason, IgG4 antibodies may be used to measure
asymptomatic type 1 allergies. IgG4 is considered to
be a sign of tolerance to the antigen [55]. Therefore,
desensitization drives the production of IgG4 and
higher is the IgG4/IgE ratio, more desensitization is
successful. Thus, in 95-97% of patients, the presence
of IgG4 antibodies is a positive feature as they
counteract type 1 allergies (allergens are captured by
IgG4, so few of them can react with IgE and cause
symptoms) [56].
If other interleukins (i.e., IL-12, IFNy) are
synthesized, antibodies of classes IgG1, IgG2 and
IgG3 are mainly produced. They are pro-inflammatory
and responsible for nutrition-related chronic
diseases. Whenever a food product against which
IgG1, IgG2 or IgG3 antibodies is consumed, an
immune complex is formed which is usually deposited
where there are individual specific problems in the
body [55]. These sites of immune complexes
precipitate at small lesions earlier infected (e.g.,
joints), organs with commensal flora (e.g., intestines),
or damaged by environmental toxins areas (e.g.,
mercury in the thyroid gland). It is not easy to predict
what symptoms will occur as it depends entirely on
the patient's health condition. With regular
consumption of food products that cause production
of IgG1-IgG3 antibodies, deposition of immune
complexes leads to chronic inflammation [56].
However, there is a lack of studies supporting the
allegation of symptoms resulting from food immune
complexes deposition in tissues.
This is true, with the exception of non-specific
systemic reactions in which inflammatory processes
play a major role (high blood pressure, iron
deficiency, metabolic syndrome, overweight). In this
case, it turns out that each positive antibody and/or
the corresponding food contributes to the allergic
reaction [56].
3.1.8. Validity of IgG antibody testing
Most of the kits commercially available for routine
testing rely on immunological methods. ELISA
methods are the most widely used, as they are
sensitive and specific to detection of allergenic
proteins and easy to use. However, commercial kits
for quantitative analysis use different extraction
buffers and calibration procedures differ in the quality
of the antibodies used, and the results vary among
trademarks and batches. The major limitations
include matrix effects, inadequate protein extraction,
insufficient specificity due to cross-reactions and
insufficient reproducibility of the results [5].
Contrary to the widespread opinion that the
production of IgG antibodies to allergens is a
physiological phenomenon, it should be borne in mind
that the presence of serum IgG / IgG4 may be a
pathological immune response to certain food
allergens [55,56]. How it can be normal for the body
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to develop a protective response against harmless
food proteins? If these assumptions are true, all
people must have antibodies to gluten, yeast, eggs,
wheat, and milk but his is not the case. Antibody
formation against all food products that are regularly
consumed is not a normal reaction. A total amount of
IgG antibodies and IgG4 alone may be determined.
Which antibodies will be produced depends on which
cytokines are released during initial sensitization with
the antigen as described above. The types of
antibodies determine whether classical food allergy
(IgE-mediated) or asymptomatic food allergy will
develop or immune complexes will form which will
later lead to a chronic inflammatory process and
hence to a delayed food allergy (IgG1 - IgG3
mediated) [55].
In recent years, various clinical trials have been
conducted to study levels of specific IgG antibodies
to certain food antigens in patients with a migraine,
irritable bowel syndrome (IBS), celiac disease,
obesity, Crohn's disease and even schizophrenia and
autism. The results of these studies documented an
improvement of the symptoms in some patients who
followed a diet in which were eliminated some foods,
identified during clinical trials, against which specific
IgG antibodies were produced. IgG4 is unlikely to
cause symptoms of allergy alone, although the
evidence shows a clear ratio of 97% to 3% in favour
of IgG4. The existence of the IgG4 subclass, its
regulation by anti-inflammatory factors and its own
anti-inflammatory properties may help the immune
system to slow down inappropriate inflammatory
responses. However, the primary function of IgG4 is
to influence the immune inflammatory process
induced by complement-binding antibodies, or in the
case of helminth infection or IgE allergy. Due to its
inability to activate the complement or opsonize the
corresponding antigen, IgG4 could not generate
chronic inflammatory process, whereas IgG1 and
IgG3 have strong pro-inflammatory properties [57].
The interpretation of the IgE/IgG4 ratio is useful to
determine the possibility of an allergic reaction: if it is
higher, there is a high likelihood of an allergic reaction
occurring, whereas the low ratio shows a low-grade
allergic reaction. In conclusion, to identify food
allergens that cause chronic inflammatory diseases is
required the test of total IgG, whereas IgE is
determined only in presence of a type 1 allergy. The
test of IgG4 alone is not recommended for the
individuation of foods responsible for the
development of acute or chronic intolerance [54].
Despite the above-described picture of the role of
IgG antibodies in immune reactions to food, testing
for food-specific IgG antibodies is not a recognized
diagnostic tool for food allergy [26]. However, it can
be applied for food intolerance testing, although
further research is required to clarify the usefulness
of the test. IgG4, in contrast, is believed to be a
marker of exposure to food and possibly of tolerance
[58]. In conclusion for IgG testing for food intolerance,
to identify food allergens that cause chronic
inflammatory diseases, only testing of total specific
IgG to food is required, whereas IgE is determined
only in the presence of immediate type 1 allergy.
Testing of IgG4 alone is not recommended for
determining foods responsible for the development of
acute or chronic food intolerance [56]. Furthermore,
testing for specific IgE/IgG antibodies in food allergy
or intolerance should be done with some precautions
such as obligatory need of good history and possible
challenge testing, and careful interpretation of results
having in mid the possible negative impact of false
positive or negative results [26,56]. In conclusion,
EAACI and CSACI have their concerns on the validity
of specific IgG testing for the purposes of identifying
or predicting adverse reactions to food and strongly
discourages the practice of using them in clinical
practice [56, 59].
3.2. Alternative methods for food intolerance
detection
3.2.1. Antigen leukocyte antibody test (ALCAT)
This test was introduced by Cell Science Systems
more than 25 years ago. Unlike other tests that
determine food sensitivity by measuring IgG or IgE in
patients' sera, the ALCAT does not monitor the
production of antibodies [29]. The patient's blood is
exposed to a panel of over 350 different food
substances, with a focus on the white blood cell
reaction. It is believed that in this way, more potentially
dangerous foods can be diagnosed and eliminated
from the patient's diet. The test is widespread in the
United States and Canada and is recommended as a
reliable source for dietary preparation. This method
determines changes in leucocytes in the presence of
certain allergens. However, no conclusive scientific
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evidence has been obtained to support the use of the
ALCAT test to diagnose food allergies and
intolerances up to date [60-62].
3.2.2. Nambudripad's Allergy Elimination
Technique (NAET)
Applied kinesiology or allergy elimination test of
Nambudripad was introduced by Dr. Nambudripad in
1983. The idea of the test is that some foods can
make the body weaker by blocking certain "energy
powers". The doctor generally determines the
changes in muscle strength while the patient is
holding a food allergen. For example, a practitioner
may cause the patient to hold a glass bottle of milk in
his left hand while checking the strength of the right
hand of the patient. It is believed that muscle
weakness is a sign of an allergy to the test substance.
After the test, a diet is prepared by eliminating the
food. Despite several publications that can be read on
the organization's website, there is still no convincing
scientific evidence of the validity of this test [63].
3.2.3. Basophil / Leukocyte Histamine Release
Test (LHRT)
This test indicates whether certain blood cells are
"activated" after the introduction of specific food
allergens. The most frequent changes in leukocytes
are similar to those seen in allergic reactions as well
as in histamine release. After the addition of the
allergen, it binds to the corresponding IgE antibody
on the surface of the basophils that release
histamine. This test is valid for the determination of
specific IgE antibodies to allergens. Unfortunately,
the results obtained through this study are difficult to
interpret and the LHRT test is traditionally used only
for research purposes. Despite many studies, this test
is still not used for diagnostics [64].
3.2.4. Cytotoxic Assay Tests, Cytotoxicity test
(Bryan's test)
The cytotoxic test for food allergens is an in vitro
procedure dating back to 1947. The fundamental idea
in this test is that mixing the white blood cells of a
patient with an antigen to which the patient is allergic
leads to leukocyte lesions. The patient's blood is
centrifuged, then the leukocytes are dropped onto a
slide, a nutrient extract is added, and the leukocytes
are observed under a microscope for twenty minutes
to the second or fourth hour. The cytotoxic effect is
manifested as deformation or destruction of the cells.
If the number of white blood cells have a decrease,
the patient is considered allergic to the given antigen
[65-67]. The test was distributed by W.T. Bryan in the
early eighties of the last century, but since then no
scientific research has been able to confirm and
prove the diagnostic value of this test. The
determination of an allergy based on the cytotoxicity
test is not recommended by the FDA and the
American Association of Immunology, Allergies, and
Asthma [62,63].
3.2.5. Electrodermal Test, Electroacupuncture
according to Voll (EAV) (Vegatest)
Vega Test (vegetative resonance test) is a method
discovered and developed by the German physician
Reinhold Fol in the fifties of the last century. In 1958,
Dr. Fall and engineer F. Werner began an acoustic
measurement of the electrical resistance of
acupuncture points located on the skin of the human
body with the first apparatus called Dermatron. The
idea behind this test is that each acupuncture point
corresponds to a particular internal organ [68].
According to Chinese traditional medicine, at each
acupuncture points, there are deviations depending
on the health or disease of the body or system of the
patient, and the changes can be measured by the
electrical resistance. In the 1970s, one of Dr. Fall's
students (Dr. Helmut Shimel) simplified the diagnostic
system from approximately 850 points to 60 points,
made minor changes to the equipment and created
the first model of the current system known as
Vegatest. Later it was found that various foods
causing intolerance could be tested using this system
[68]. The method is based on the theory that each
food has a different energy structure that affects the
electromagnetic field and the resonance of the human
body. If a person is tolerant and well-decomposing a
food, the scale readings are above certain values. If
there is an intolerance to the test food, the data is
below these values. This determines the sensitivity to
different nutrients and the individual's response to
them [68].
Vega test is completely safe, easy to perform, not
invasive, can be used by pregnant women. It
determines intolerance to a large number of foods,
depending on the food research panel. This method
of nutritional intolerance research is widespread in
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Europe, the United States, and other countries.
Notwithstanding the many literature and doctors
practicing it, there is still no conclusive scientific
evidence of the diagnostic value of the method [63].
Many studies have found that the electrodeposition
test cannot be used to detect allergies and
intolerances [69]. Studies by Swedish and Italian
scientists also show that the Vega test cannot be
used as a diagnostic method for asthma and atopic
dermatitis. Most clinical associations on immunology
and allergies (FDA, American, European, Australian)
recommend not to use the Vega test to diagnose food
allergies and intolerance, and not to administer diets
solely on the basis of this test.
3.2.6. Hair Analysis Testing
In this test, a strand of hair from the patient is sent
to a laboratory where hair energy fields are analyzed
by "modern biotechnology" methods. The obtained
result is compared to a database and thus determines
the nutritional intolerance of the patient [70]. This
method is not invasive, accessible and easy to apply,
only a bunch of hair should be sent to a laboratory.
Approximately 600 food and non-food
hypersensitivity products can be tested on one hair
sample. Forensic science investigates hair for the
presence of heavy metals (poisons) and narcotics
through mass spectrometry, which is a proven
method and the information obtained is reliable and
useful. However, there is still no convincing scientific
evidence that "energy" and spectral states of hair can
be used to determine food allergy and intolerance.
Many clinical associations reject this method and
recommend that it should not be used for diagnosis
of hypersensitivity and intolerance [70].
3.2.7. Pulse test
The patient's pulse is measured before eating the
food suspected of being intolerant. Fifteen minutes
after food intake, the pulse is counted again, and if
there is an increase of more than 10 heart beats per
minute, it is considered that the patient does not
tolerate the food. The studies, however, show that
there is no connection between heart rate and dietary
tolerance, so this test is not recommended as a
diagnostic [71].
3.3. The future perspectives: Genetic testing
(nutrigenetics)
Certain food intolerances are not immune-
mediated and are due to changes in the function of
enzymes, receptors, etc. There are genetic (PT-PCR)
tests that define polymorphisms in enzymes genes
(i.e., lactose intolerance) and cell surface proteins
(HLA) in celiac disease to identify predispositions to
the development of these diseases. In addition, some
genes can affect the rate of absorption, metabolism
or excretion of the nutrients we consume, as well as
the toxins that come from the environment. The
reaction among different patients could vary a lot and,
accordingly, could determine not only the extent to
which the nutrients will be absorbed but whether they
will have a beneficial or detrimental effect on their
health [72]. An elevated number of studies in this field
are turned to the acquisition of data on genes (e.g.
FABP2, PPARG, APOA5, ADIPOQ) that participate
in and influence fat absorption, also considering that
carbohydrates play a role in the triglycerides
regulation. Studies have shown that certain
polymorphisms in these genes are related to the
ability of a person to better digest or not fat and
carbohydrates. Based on these studies, the risk of
obesity, overeating, and need for physical exercise is
assessed. More research is needed to ascertain
whether genetic tests can be used in diagnostic
practice and whether they provide the information
needed to build a highly effective, personalized diet
[73].
4. Conclusions
The current problem of the diagnostics of
intolerance to some foods is that patients suffering
from this disease may have not only gastrointestinal
symptoms but also symptoms that involve other
organs and systems. Because of the varied clinical
manifestation, these patients turn to different
specialists and eventually remain undiagnosed.
Moreover the diagnosis of a food intolerance often
requires the exclusion of all other causes of organic
and functional illness, which may take up several
years.
The process of diagnosis and treatment of food
intolerance is complex and elusive. Classical tests for
food allergy may be applied for food intolerance
diagnostics. Although they are not a recognized
T VELIKOVA, A KUKOV, V GEORGIEVA, M PERUHOVA, N YURUKOVA, et al.
Methods for detection of food intolerance
RAdvFoodSci: 2018: 1(3): 106-119 ISSN: 2601-5412 116
diagnostic tool for food allergy, the clinical tests to
identify food-specific IgG antibodies can be used to
detect food intolerance. Testing of total specific IgG
to food is required to identify food allergens that
cause chronic inflammatory diseases, whereas IgE is
determined only in the presence of immediate type 1
allergy. To determine the foods responsible for the
development of acute or chronic intolerance, the test
of IgG4 is not recommended, because IgG4 does not
indicate food allergy or intolerance, but rather a
physiological response of the immune system after
exposition to food components. However, further
research is required to clarify the usefulness of the
test. Furthermore, testing for specific IgE/IgG
antibodies in food allergy or intolerance should be
done with some precautions such as the obligatory
need of good history and possible challenge testing,
and careful interpretation of results having in mid the
possible negative impact of false positive or negative
results.
Acknowledgements
The review is created for the purpose of Grant
project 80-10-160/25. 04. 2018, Sofia University,
Medical faculty, Sofia.
Conflict of interests
The authors declare no conflict of interest.
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Article Outline Section 1. Introduction 1.1. Overview 1.2. Relationship of the US Guidelines to other guidelines 1.3. How the Guidelines were developed 1.3.1. The Coordinating Committee 1.3.2. The Expert Panel 1.3.3. The independent, systematic literature review and report 1.3.4. Assessing the quality of the body of evidence 1.3.5. Preparation of the draft Guidelines and Expert Panel deliberations 1.3.6. Public comment period and draft Guidelines revision 1.4. Defining the strength of each clinical guideline 1.5. Summary Section 2. Definitions, prevalence, and epidemiology of food allergy 2.1. Definitions 2.1.1. Definitions of food allergy, food, and food allergens 2.1.2. Definitions of related terms 2.1.3. Definitions of specific food-induced allergic conditions 2.2. Prevalence and epidemiology of food allergy 2.2.1. Systematic reviews of the prevalence of food allergy 2.2.2. Prevalence of allergy to specific foods, food-induced anaphylaxis, and food allergy with comorbid conditions Section 3. Natural history of food allergy and associated disorders 3.1. Natural history of food allergy in children 3.2. Natural history of levels of allergen-specific IgE to foods in children 3.3. Natural history of food allergy in adults 3.4. Natural history of conditions that coexist with food allergy 3.4.1. Asthma 3.4.2. Atopic dermatitis 3.4.3. Eosinophilic esophagitis 3.4.4. Exercise-induced anaphylaxis 3.5. Risk factors for the development of food allergy 3.6. Risk factors for severity of allergic reactions to foods 3.7. Incidence, prevalence, and consequences of unintentional exposure to food allergens Section 4. Diagnosis of food allergy 4.1. When should food allergy be suspected? 4.2. Diagnosis of IgE-mediated food allergy 4.2.1. Medical history and physical examination 4.2.2. Methods to identify the causative food 4.2.2.1. Skin prick test 4.2.2.2. Intradermal tests 4.2.2.3. Total serum IgE 4.2.2.4. Allergen-specific serum IgE 4.2.2.5. Atopy patch test 4.2.2.6. Use of skin prick tests, sIgE tests, and atopy patch tests in combination 4.2.2.7. Food elimination diets 4.2.2.8. Oral food challenges 4.2.2.9. Nonstandardized and unproven procedures 4.3. Diagnosis of non-IgE-mediated immunologic adverse reactions to food 4.3.1. Eosinophilic gastrointestinal diseases 4.3.2. Food protein-induced enterocolitis syndrome 4.3.3. Food protein-induced allergic proctocolitis 4.3.4. Food protein-induced enteropathy syndrome 4.3.5. Allergic contact dermatitis 4.3.6. Systemic contact dermatitis 4.4. Diagnosis of IgE-mediated contact urticaria Section 5. Management of nonacute allergic reactions and prevention of food allergy 5.1. Management of individuals with food allergy 5.1.1. Dietary avoidance of specific allergens in IgE-mediated food allergy 5.1.2. Dietary avoidance of specific allergens in non-IgE-mediated food allergy 5.1.3. Effects of dietary avoidance on associated and comorbid conditions, such as atopic dermatitis, asthma, and eosinophilic esophagitis 5.1.4. Food avoidance and nutritional status 5.1.5. Food labeling in food allergy management 5.1.6. When to re-evaluate patients with food allergy 5.1.7. Pharmacologic intervention for the prevention of food-induced allergic reactions 5.1.7.1. IgE-mediated reactions 5.1.7.2. Non-IgE-mediated reactions 5.1.8. Pharmacologic intervention for the treatment of food-induced allergic reactions 5.1.9. Immunotherapy for food allergy management 5.1.9.1. Allergen-specific immunotherapy 5.1.9.2. Immunotherapy with cross-reactive allergens 5.1.10. Quality-of-life issues associated with food allergy 5.1.11. Vaccinations in patients with egg allergy 5.1.11.1. Measles, mumps, rubella, and varicella vaccine 5.1.11.2. Influenza vaccine 5.1.11.3. Yellow fever vaccine 5.1.11.4. Rabies vaccines 5.2. Management of individuals at risk for food allergy 5.2.1. Nonfood allergen avoidance in at-risk patients 5.2.2. Dietary avoidance of foods with cross-reactivities in at-risk patients 5.2.3. Testing of allergenic foods in patients at high risk prior to introduction 5.2.4. Testing in infants and children with persistent atopic dermatitis 5.3. Prevention of food allergy 5.3.1. Maternal diet during pregnancy and lactation 5.3.2. Breast-feeding 5.3.3. Special diets in infants and young children 5.3.3.1. Soy infant formula versus cow's milk formula 5.3.3.2. Hydrolyzed infant formulas versus cow's milk formula or breast-feeding 5.3.4. Timing of introduction of allergenic foods to infants Section 6. Diagnosis and management of food-induced anaphylaxis and other acute allergic reactions to foods 6.1. Definition of anaphylaxis 6.2. Diagnosis of acute, life-threatening, food-induced allergic reactions 6.3. Treatment of acute, life-threatening, food-induced allergic reactions 6.3.1. First-line and adjuvant treatment for food-induced anaphylaxis 6.3.2. Treatment of refractory anaphylaxis 6.3.3. Possible risks of acute therapy for anaphylaxis 6.3.4. Treatment to prevent biphasic or protracted food-induced allergic reactions 6.3.5. Management of milder, acute food-induced allergic reactions in health care settings 6.4. Management of food-induced anaphylaxis Appendix A. Primary author affiliations and acknowledgments Appendix B. List of abbreviations Reference
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