“Top down” and “bottom up” diagnostics

Intolerance to certain foods can be toxic, enzymatic, “pseudoallergic” or allergic and can manifest itself in many ways. An intolerance reaction, unlike a food allergy, is not life-threatening and occurs without immune system involvement.

Reactions such as itching, skin rashes, shortness of breath, or even gastrointestinal symptoms may occur after eating certain foods. While an allergy is a hypersensitivity reaction of the body to certain substances from the environment (allergens), the symptoms of a food intolerance are not based on an overreaction of the immune system, but mostly on an impaired ability of the intestine to properly digest or break down some food components.

Suspicion of food allergy?

An allergy is a malfunction of the immune system in the form of an increased immune response to harmless foreign substances. True food allergies are mostly IgE-mediated reactions of the immediate type (type I allergy). The IgE antibodies are located on mast cells, which release histamine and other messenger substances on contact with the corresponding allergen. It is an allergic reaction occurring immediately after allergen contact. Complaints such as itching, swelling of the mouth and throat, asthmatic and gastrointestinal symptoms occur within minutes to a few hours after consumption of the food. Even small amounts of a food allergen can trigger symptoms in allergy sufferers. Allergic reactions to a food can be severe and in extreme cases can lead to anaphylactic shock. Foods known to cause life-threatening systemic reactions are soy, nuts, fish and crustaceans. Laboratory diagnosis is performed by serological detection of allergen-specific IgE antibodies. For IgE detection tests, highly purified total extracts prepared from native foods via freeze-drying are used as antigens [1]. In vivo/in vitro methods and the oral provocation test are available for the laboratory diagnostic clarification of a food allergy. In the skin prick test, the reaction to food extracts, environmental antigens, molds and spices can be tested. The prick test has a high sensitivity and is mainly used for exclusion diagnosis. The negative predictive value (NPV) is >95% [2]. The prick to prick test used with fresh foods (e.g., pineapple, coffee) has higher sensitivity but lower specificity in some cases. In addition or as an alternative to the prick test, total IgE and allergen-specific IgE can be determined. In patients with systemic reactions, detection of specific IgE against pollen-associated food allergens should be performed [3,4]. For the diagnostic assessment of whether a food allergy is present or not, the agreement between the patient’s clinical information and the test result (prick test/IgE determination) is significant. However, the gold standard for a definitive diagnosis is still the oral provocation test. However, this complex procedure is not necessary in all cases [4]. It may be useful to perform such a test for a rough estimation of the trigger amount or for the detection of augmentation factors in certain pollen-associated food allergies in the sense of an oral allergy syndrome with a matching sensitization pattern. About 60% of all people with an allergy to birch pollen also react to apples because the responsible allergens are similar. Food allergies are less common in adults than in children, but are often lifelong. According to data published in 2019, the prevalence of food allergy with IgE detection in adults in Europe ranges from 0.%–5,6% [5]. Skin symptoms occurred in over one-third of those affected, oral allergy symptoms in over 80%, and rhinoconjunctivitis in about 30% [5].

The immune system is not always to blame

More common than food allergies are intolerances that occur without the involvement of the immune system. In contrast to an allergy, the IgE detection is negative in the case of a pseudoallergy. With regard to symptomatology, in the case of an allergy, reactions are usually faster and more severe. While palate itching, tongue swelling, itching, Quincke’s edema or urticaria are typical for an allergic reaction, digestive complaints such as flatulence, abdominal pain, diarrhea and nausea are usually more prominent in an intolerance. Extraintestinal symptoms such as skin rashes, headache, or sweating may also occur, however. The most common food intolerances involve lactose, fructose, gluten and histamine. Diagnosis of food intolerance is often more difficult than with allergy. Apart from the hydrogen breath test (_H2 breath test) for the detection of an intolerance to lactose, fructose or sorbitol, there are so far no test procedures that clearly prove a non-allergic reaction to certain food components. Diet diary and an elimination diet are the main diagnostic tools. Differentially, it is important to exclude inflammatory bowel disease and irritable bowel syndrome.

Lactose intolerance: This is the most common food intolerance in the world. The cause is reduced activity of the enzyme lactase, which breaks down milk sugar into the monosaccharides glucose and galactose. This results in complaints such as flatulence, cramps or diarrhea. Congenital complete lactase deficiency (agalactasia) is very rare. More common is an age-correlated genetically determined decline in enzyme activity. Small amounts of lactose are usually tolerated by those affected. Secondary lactase deficiency may be due to gastroenteritis, celiac disease, inflammatory bowel disease (IBD), alcohol abuse, or hyperthyroidism. If the underlying disease is treated successfully, lactose utilization usually returns to normal. The H2 breath test is recommended as diagnostic evidence of lactose intolerance; it is a method with a relatively high sensitivity and specificity. In the presence of lactose intolerance, the amount of lactose that causes digestive problems varies greatly from individual to individual [6]. The lactose content of dairy products can be found in nutrition tables. If the product does not contain any other added sugars, the carbohydrate content corresponds to the lactose content. So-called lactose-free milk products have a lactose content below 0.1 g/100 ml and are usually produced by adding lactase. There are also foods with hidden lactose in the form of added whey powder. In case of lactose intolerance, lactose-free or vegetarian milk products, for example soy milk, can be used. Those affected usually get their symptoms well under control by following a low-lactose diet. If the ingestion of relevant amounts of lactose cannot be avoided  (e.g. during an invitation or a visit to a restaurant), lactase preparations can reduce the symptoms. When on a low-lactose diet, ensure adequate calcium intake from other sources (e.g., calcium-rich mineral waters, hazelnuts, broccoli, spinach, kale).

Fructose intolerance: Intolerance of fructose is usually due to malabsorption, i.e. a lack of absorption via the intestinal mucosa. The transporter protein GLUT-5 in the enterocytes of the small intestine plays an important role in this process. If this is not present in sufficient quantities or only functions to a limited extent, fructose enters the colon incorrectly. There, the monosaccharide is broken down by bacteria, leading to the typical symptoms of flatulence, abdominal pain and nausea. Malabsorption can be diagnosed by an H2 breath test. In contrast, hereditary fructose intolerance, which occurs rarely, is the result of a congenital deficiency of the enzyme fructose-1-phosphate aldolase. This leads to a lack of breakdown of fructose and a deposit in the liver. The symptoms first appear in infancy during the transition to complementary foods and range from digestive discomfort to life-threatening symptoms of poisoning. In fructose malabsorption, on the other hand, small amounts of fructose are tolerated. Due to the dependence of GLUT-5 production on the amount of fructose offered, complete avoidance is not recommended to avoid complete loss of absorption capacity. Frequently, persons with fructose malabsorption also do not tolerate sorbitol, since both substances are partly absorbed via the same transport proteins. However, sorbitol intolerance can also occur in isolation. An H2 breath test can also be performed for detection.

Gluten intolerance: Celiac disease is a chronic inflammatory disease of the small intestine that results from a misdirected immune response to the gluten protein and has features of both allergy and autoimmune disease [7]. IgE-mediated wheat allergy, triggered by different protein components (e.g. gluten, wheat albumin or globulin) and wheat-dependent exertion-induced anaphylaxis (“WDEIA”) are to be distinguished from celiac disease. Another form of gluten intolerance is the so-called non-celiac gluten/ wheat sensitivity (“NCGS”) [8]. In addition to gluten, FODMAP (fermentable oligo-, di- and monosaccharides as well as polyols) are suspected triggers [9].

Histamine intolerance: This is another possible cause of discomfort after eating certain foods. In this case, the enzyme diaminooxidase (DAO), which is required for the degradation of histamine, is not sufficiently present or only functions to a limited extent. As a result of the resulting histamine excess, allergy-like symptoms occur in the body (e.g. skin redness, itching, flushing, headaches, gastrointestinal complaints). Affects about 1% of the population, predominantly middle-aged women. Foods with a high histamine content include cheese, red wine, fish and sauerkraut. Fermented foods are generally higher in histamine. Complaints may be exacerbated by certain other biogenic amines and alcohol, due to competitive inhibition of DAO. In addition, there are certain drugs that promote histamine release or decrease DAO activity (e.g., certain antihypertensives, nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, x-ray contrast media, antibiotics, mucolytics). Measurement of DAO activity in blood and urine are of limited diagnostic relevance. More importantly, a dietary allowance based on the evaluation of a food diary. A low-histamine diet is indicated as a therapeutic measure, possibly supplemented by a DAO preparation.

Literature:

1. IMD Institute for Medical Diagnostics Berlin-Potsdam GbR: www.imd-berlin.de
2. mediX: www.medix.ch
3. Henzgen M, et al: Food allergies due to immunological cross-reactions. Guideline of the Food Allergy Working Group of the German Society of Allergology and Clinical Immunology (DGAI) and the Medical Association of German Allergists (ÄDA). Allergo J 2005; 14: 48-59.
4. Niggemann B, et al: Standardization of oral provocation tests in food allergy: guideline. Allergo J 2011; 20: 149-160.
5. Lyons SA, et al. Food Allergy in Adults: Substantial Variation in Prevalence and Causative Foods Across Europe. The Journal of Allergy and Clinical Immunology: In Practice 2019; 7 (6): 1920-1928.e11
6. Labayen I, et al: Relationship between lactose digestion, gastrointestinal transit time and symptoms in lactose malabsorbers after dairy consumption. Aliment Pharmacol Ther 2001; 15: 543-549.
7. S2k guideline Celiac disease, wheat allergy, wheat sensitivity. AWMF Register No. 021/021, as of 2014, currently under revision.
8. Position paper of the Working Group on Food Allergy of the German Society for Allergology and Clinical Immunology (DGAKI): Non-Celiac Gluten/Wheat Sensitivity (NCGS) – a so far undefined clinical picture with missing diagnostic criteria and unknown frequency. Allergo J Int 2018; 27: 147-151.
9. Dieterich W, et al: Influence of low FODMAP and gluten-free diets on disease activity and intestinal microbiota in patients with non-celiac gluten sensitivity. Clin Nutr 2019; 38: 697-707.
10. Scheidegger P, Seifried K: Dermatology: triage of dermatologic blockbusters in family practice. Continuing Education, HAUSARZT PRAXIS 2019; 14(5): 19-28.

Further reading:

• Paschke A : Food allergies. Ernährungs-Umschau 2010(1): 36-41.
• Wildenrath C: Allergy and intolerance. When food makes you sick. Pharmaceutical Newspaper, Sept. 08, 2019, www.pharmazeutische-zeitung.de

DERMATOLOGY PRACTICE 2020; 30(3): 35-36