Sorry I dont know if anyone has seen this already, I found it very interesting as Im sure many have intolerances here.
Easier to see actual website to read article.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695393/
The Differential Diagnosis of Food Intolerance
Yurdagül Zopf, Dr. med.,*,1 Eckhart G. Hahn, Prof. Dr. med.,1 Martin Raithel, Prof. Dr. med.,1 Hanns-Wolf Baenkler, Dr. med.,2 and Andrea Silbermann, Dipl.-Psych.3
Author information ► Article notes ► Copyright and License information ►
See letter "Correspondence (letter to the editor): Clinical Relevance" in volume 107 on page 39b.
See letter "Correspondence (letter to the editor): Correction Required" in volume 107 on page 39a.
See letter "Correspondence (reply): In Reply" in volume 107 on page 40b.
See letter "Correspondence (letter to the editor): Bacteriological Stool Examinations" in volume 107 on page 40a.
This article has been cited by other articles in PMC.
Go to:
Abstract
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.
Keywords: Food intolerance, food allergy, diagnosis, provocative testing, histamine intolerance
The term food intolerance is used to describe a range of food related complaints of varying etiology. Besides structural and functional causes, it is also necessary to distinguish between a toxic and non-toxic pathogenesis of the intolerance (Figure 1).
Figure 1
Overview of range of food intolerance reactions
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 unaccompanied 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 disease involving a structural alteration in the gastrointestinal tract. This results secondarily in food-associated symptoms. 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.
Definition
The term food intolerance is used to describe a range of food related symptoms of varying etiology.
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),
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 psychosomatic reactions that cause or can imitate symptoms of intolerance (1, 2, 4– 8) (Figures 1 and and2).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 differential diagnostic problem for patients and physicians alike. The incidence of food allergies is subjectively overestimated. In one survey, one fourth of the population 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, cardiovascular system, lungs etc.) being described with differing 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).
Figure 2
Examples of important functional and structural causes of food intolerances; anti-tTG antibodies, antibodies to tissue transglutaminase; EHEC, entero-toxic Escherichia coli; ETEC, entero-hemorrhagic Escherichia coli; CIBD, chronic inflammatory bowel disease ...
E-Table 1
Common allergens in food allergies
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 differential diagnoses of food allergies and food intolerances
employ a structured approach to the differential diagnosis of food allergies and food intolerances.
Go to:
Method
A selective literature search including national guidelines 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 clinical 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%
Go to:
Differential diagnosis: non-immunologically mediated food intolerances
Since the population prevalence of functional and structural, non-toxic and non-immunologically mediated clinical presentations (Figures 1 and and2)2) are much commoner (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, pancreatic 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).
Figure 3
Overview of diagnostic approaches to the differential diagnostic spectrum of food intolerances and allergies; *1 both clinical pictures can also coexist;
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 summarized form; detailed descriptions can be found in the literature sources cited.
Go to:
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 triggering 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.
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.
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.
Depending on the patient’s medical history, a functional or structural cause of the food intolerance will be suspected (Figures 1 and and2).2). A suitable basic 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 compromise 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 understood to include primary organ pathologies of the gastrointestinal tract (such as achalasia), while functional disease is characterized by normal morphology but an isolated functional impairment (such as lactase deficiency).
Diagnostic procedures
Endoscopy, histology, and stool examinations can reveal structural and infectious diseases that may be associated with various food intolerances.
Go to:
Carbohydrate malabsorption
Carbohydrate absorption is significantly affected by disorders 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 malabsorption etc. [Table 1]). Carbohydrates cannot be absorbed in the small intestine of patients with, for example, 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 carbohydrates, 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 deficiency states and transport disorders are listed in Table 1.
Table 1
Important examples of intolerances due to enzyme deficiency and transport disorder
Small bowel bacterial overgrowth
If the H2 breath 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.
Go to:
Small bowel bacterial overgrowth
If the H2 breath tests for fructose, lactose and sorbitol (and possible lactulose) are positive, bacterial overgrowth of the small intestine should be considered as a possible cause of the food intolerance. As with carbohydrate 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, diabetes mellitus, and patients who are medicated with immunosuppressives or proton pump inhibitors are especially affected. An H2 breath test for glucose should be performed to rule out small bowel bacterial overgrowth.
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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 obstruction, 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 vasodilatation, 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, bronchospasm and, with a rapid rise in histamine concentration, shock or cardiac arrest (12, 13). The gastric acid secretion and smooth muscle contraction which already starts when there are slight increases in histamine levels explains 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 intolerance are listed in the e-Box (12, 14).
E-Box
Foods with high histamine content
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)
Foods that inhibit diaminooxidase
Especially other amines (black tea, maté tea, colorants), alcohol
Foods that release increased amounts of histamine
Citrus fruits, nuts, wheat germ, alcohol (acetyldehyde)
Other accompanying factors that promote histamine release
Infections, sports, emotional upset (stress), chronic diseases (e.g. chronic renal insufficiency), medications (NSAIDs, acetylsalicylic acid (ASA), metamizole, radiographic contrast media, opiates)
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Salicylate intolerance
The prevalence of salicylate intolerance in Europe is 2.5% (8). The classical symptoms of salicylate intolerance 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 intolerance 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).
Salicylate intolerance
The prevalence of salicylate intolerance is 2.5% in Europe.
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.
E-Table 2
Salicylate content of foods as nutritive triggers of symptoms in salicylate intolerance
If dietary therapy alone is insufficient, treatment with leukotriene receptor blockers or deactivation with acetylsalicylic acid should be attempted (5) (see supplementary case report).
Case Report The Differential Diagnosis of Food Intolerance
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 pollinosis and chronic eosinophilia. Serological tests showed IgE (92 U/L) still in the upper range of normal and an elevated methylhistamine level in urine (14 µg/mmoL creatinine x m² BSA [BSA, body surface 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 medications including mesalazine led to complete remission 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 diseases known. Family history of atopic dermatitis.
The patient received drug treatment for the colitis with prednisolone and 5 ASA from 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 professional 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 protein), 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 significantly concentration-dependent increased release of these immune mediators on rye (23).
An elimination diet of wheat, rye and soya produced a complete remission which has now been persisting for more than four years. Concluding diagnosis: local (seronegative), IgE-mediated allergic enterocolitis.
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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 evaluation of the possible differential diagnoses and therefore attempt to distinguish the patient’s condition from other chronic diseases.
Food allergy
Food allergy shows the greatest complexity among the food intolerances and allergic diseases.
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General principles of allergy diagnosis
For the diagnosis of food allergy it should be considered that different sensitivities and specificities may be observed 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 precise medical history, physical examination, and an analysis of the pattern of symptoms and time course. Demonstration of a provoked, allergen induced reaction in the patient or organ system is regarded as the gold standard (2, 6, 11, 16). Diagnostic approaches vary according to the allergy specialist and dermatologist (e.g. oral allergy syndrome, cutaneous reactions), the lung specialist and otorhinolaryngologist (e.g. nasal or bronchial obstruction) or the internal specialist and gastroenterologist (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 manifestations (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).
Figure 4
Immunological mechanisms in food allergies (gastrointestinally mediated Grade I-IV allergies) according to Coombs and Gell
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
*1 modified from (8, 16)
Gold standard
Demonstration of a provoked allergy-induced reaction in the patient or organ system is regarded as the gold standard.
Easier to see actual website to read article.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695393/
The Differential Diagnosis of Food Intolerance
Yurdagül Zopf, Dr. med.,*,1 Eckhart G. Hahn, Prof. Dr. med.,1 Martin Raithel, Prof. Dr. med.,1 Hanns-Wolf Baenkler, Dr. med.,2 and Andrea Silbermann, Dipl.-Psych.3
Author information ► Article notes ► Copyright and License information ►
See letter "Correspondence (letter to the editor): Clinical Relevance" in volume 107 on page 39b.
See letter "Correspondence (letter to the editor): Correction Required" in volume 107 on page 39a.
See letter "Correspondence (reply): In Reply" in volume 107 on page 40b.
See letter "Correspondence (letter to the editor): Bacteriological Stool Examinations" in volume 107 on page 40a.
This article has been cited by other articles in PMC.
Go to:
Abstract
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.
Keywords: Food intolerance, food allergy, diagnosis, provocative testing, histamine intolerance
The term food intolerance is used to describe a range of food related complaints of varying etiology. Besides structural and functional causes, it is also necessary to distinguish between a toxic and non-toxic pathogenesis of the intolerance (Figure 1).
Figure 1
Overview of range of food intolerance reactions
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 unaccompanied 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 disease involving a structural alteration in the gastrointestinal tract. This results secondarily in food-associated symptoms. 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.
Definition
The term food intolerance is used to describe a range of food related symptoms of varying etiology.
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),
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 psychosomatic reactions that cause or can imitate symptoms of intolerance (1, 2, 4– 8) (Figures 1 and and2).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 differential diagnostic problem for patients and physicians alike. The incidence of food allergies is subjectively overestimated. In one survey, one fourth of the population 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, cardiovascular system, lungs etc.) being described with differing 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).
Figure 2
Examples of important functional and structural causes of food intolerances; anti-tTG antibodies, antibodies to tissue transglutaminase; EHEC, entero-toxic Escherichia coli; ETEC, entero-hemorrhagic Escherichia coli; CIBD, chronic inflammatory bowel disease ...
E-Table 1
Common allergens in food allergies
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 differential diagnoses of food allergies and food intolerances
employ a structured approach to the differential diagnosis of food allergies and food intolerances.
Go to:
Method
A selective literature search including national guidelines 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 clinical 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%
Go to:
Differential diagnosis: non-immunologically mediated food intolerances
Since the population prevalence of functional and structural, non-toxic and non-immunologically mediated clinical presentations (Figures 1 and and2)2) are much commoner (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, pancreatic 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).
Figure 3
Overview of diagnostic approaches to the differential diagnostic spectrum of food intolerances and allergies; *1 both clinical pictures can also coexist;
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 summarized form; detailed descriptions can be found in the literature sources cited.
Go to:
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 triggering 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.
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.
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.
Depending on the patient’s medical history, a functional or structural cause of the food intolerance will be suspected (Figures 1 and and2).2). A suitable basic 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 compromise 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 understood to include primary organ pathologies of the gastrointestinal tract (such as achalasia), while functional disease is characterized by normal morphology but an isolated functional impairment (such as lactase deficiency).
Diagnostic procedures
Endoscopy, histology, and stool examinations can reveal structural and infectious diseases that may be associated with various food intolerances.
Go to:
Carbohydrate malabsorption
Carbohydrate absorption is significantly affected by disorders 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 malabsorption etc. [Table 1]). Carbohydrates cannot be absorbed in the small intestine of patients with, for example, 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 carbohydrates, 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 deficiency states and transport disorders are listed in Table 1.
Table 1
Important examples of intolerances due to enzyme deficiency and transport disorder
Small bowel bacterial overgrowth
If the H2 breath 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.
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Small bowel bacterial overgrowth
If the H2 breath tests for fructose, lactose and sorbitol (and possible lactulose) are positive, bacterial overgrowth of the small intestine should be considered as a possible cause of the food intolerance. As with carbohydrate 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, diabetes mellitus, and patients who are medicated with immunosuppressives or proton pump inhibitors are especially affected. An H2 breath test for glucose should be performed to rule out small bowel bacterial overgrowth.
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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 obstruction, 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 vasodilatation, 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, bronchospasm and, with a rapid rise in histamine concentration, shock or cardiac arrest (12, 13). The gastric acid secretion and smooth muscle contraction which already starts when there are slight increases in histamine levels explains 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 intolerance are listed in the e-Box (12, 14).
E-Box
Foods with high histamine content
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)
Foods that inhibit diaminooxidase
Especially other amines (black tea, maté tea, colorants), alcohol
Foods that release increased amounts of histamine
Citrus fruits, nuts, wheat germ, alcohol (acetyldehyde)
Other accompanying factors that promote histamine release
Infections, sports, emotional upset (stress), chronic diseases (e.g. chronic renal insufficiency), medications (NSAIDs, acetylsalicylic acid (ASA), metamizole, radiographic contrast media, opiates)
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Salicylate intolerance
The prevalence of salicylate intolerance in Europe is 2.5% (8). The classical symptoms of salicylate intolerance 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 intolerance 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).
Salicylate intolerance
The prevalence of salicylate intolerance is 2.5% in Europe.
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.
E-Table 2
Salicylate content of foods as nutritive triggers of symptoms in salicylate intolerance
If dietary therapy alone is insufficient, treatment with leukotriene receptor blockers or deactivation with acetylsalicylic acid should be attempted (5) (see supplementary case report).
Case Report The Differential Diagnosis of Food Intolerance
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 pollinosis and chronic eosinophilia. Serological tests showed IgE (92 U/L) still in the upper range of normal and an elevated methylhistamine level in urine (14 µg/mmoL creatinine x m² BSA [BSA, body surface 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 medications including mesalazine led to complete remission 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 diseases known. Family history of atopic dermatitis.
The patient received drug treatment for the colitis with prednisolone and 5 ASA from 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 professional 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 protein), 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 significantly concentration-dependent increased release of these immune mediators on rye (23).
An elimination diet of wheat, rye and soya produced a complete remission which has now been persisting for more than four years. Concluding diagnosis: local (seronegative), IgE-mediated allergic enterocolitis.
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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 evaluation of the possible differential diagnoses and therefore attempt to distinguish the patient’s condition from other chronic diseases.
Food allergy
Food allergy shows the greatest complexity among the food intolerances and allergic diseases.
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General principles of allergy diagnosis
For the diagnosis of food allergy it should be considered that different sensitivities and specificities may be observed 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 precise medical history, physical examination, and an analysis of the pattern of symptoms and time course. Demonstration of a provoked, allergen induced reaction in the patient or organ system is regarded as the gold standard (2, 6, 11, 16). Diagnostic approaches vary according to the allergy specialist and dermatologist (e.g. oral allergy syndrome, cutaneous reactions), the lung specialist and otorhinolaryngologist (e.g. nasal or bronchial obstruction) or the internal specialist and gastroenterologist (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 manifestations (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).
Figure 4
Immunological mechanisms in food allergies (gastrointestinally mediated Grade I-IV allergies) according to Coombs and Gell
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
*1 modified from (8, 16)
Gold standard
Demonstration of a provoked allergy-induced reaction in the patient or organ system is regarded as the gold standard.