Contents A. Case study B. More information C. Editors' comments D. References E. CPD questions (South Africa)

Index

A. Case study
A 20-month-old girl was referred with a diagnosis of wheat allergy after not improving on a "wheat-free" diet. She was still experiencing gastrointestinal symptoms such as diarrhoea and abdominal cramps approximately 2-3 times per week. The girl was breast-fed until the age of 1 year, and solid foods were introduced at 6 months. Wheat, however, was introduced only at 14 months, whereafter the symptoms started presenting. Skin prick tests were negative for wheat, but wheat allergy was diagnosed because of a strong clinical history of adverse reactions to wheat.

WHAT ARE THE POSSIBLE REASONS FOR THE CHILD NOT IMPROVING?

• The diagnosis made was not correct


• Non-compliance by the mother or caretaker


• Hidden allergens that the mother or caretaker is not aware of are still included in the diet


• There is another food or substance that the child is reacting to as well, in addition to the wheat

THOUGHT PROCESS:
What are the possibilities that one needs consider at this point?

• Is the reaction caused by wheat, gluten, or either plus another food/substance?


• Is there any other underlying allergic condition such as hayfever or asthma that could be a further indication that an allergy is present? In this case there was not.


• Type of reaction:
  These symptoms can be the result of allergic or non-allergic causes. Allergy symptoms can involve the gastrointestinal tract (abdominal cramps, nausea and vomiting, oral allergy syndrome), but gastrointestinal problems are evident in children with Celiac Disease (CD) as well. These problems can manifest as abnormal stools (ranging from diarrhoea, to soft and bulky, clay-coloured, foul-smelling stools and constipation), abdominal distension, pain, flatulence, nausea, vomiting and intestinal malabsorption. (Symptoms can also be mild, presenting as iron deficiency, failure to thrive or poor school performance - discussed below.) If we compare CD with wheat allergy, both have separately typical sets of symptoms, but some symptoms are quite similar to each other. Wheat intolerance was unlikely, as flatus and bloating were not prominent features.


• Onset of symptoms:
  Onset of symptoms is usually delayed in CD, compared to an allergy, in which symptoms can be either acute or delayed.


• Race:
  Although it was not relevant in this case, in general the ethnic background of the child might provide a strong indication of CD being the cause, as it primarily affects caucasians of northwestern European descent and rarely affects Africans, people of Mediterranean extraction or Asians.


• Family history:
  CD and allergies can both be inherited. A child is more likely to have either if there is a family history present, especially if one or both parents had/have it. Wheat allergy may be present in the absence of a family history, but CD is probably always inherited. However, as coeliac disease can be silent or latent, a family history is not always reliable. There was no apparent family history of either in this case.

SO, WHAT CAN WE DO AT THIS POINT?

• Reassess the patient's diagnosis.


• Repeat the skin prick test or do an IgE blood test, unless suspicion of CD is prominent, in which case an antigliadin IgA test should be done. (Endomysial antibody and/or transglutaminase are more specific/accurate tests, and IgA can eliminate IgA deficiency.)


• Implement a food-symptom diary to identify a pattern between ingested food and the symptoms experienced.


• Always refer for endoscopy/biopsy before an elimination diet if blood tests are positive. (Negative blood tests despite positive family history can indicate latent coeliac disease. The disease may develop at any stage triggered by stresses or aging.)


• Go directly onto an elimination diet and challenge with wheat.

THOUGHT PROCESS:
Reassessing the diagnosis is always important, as aspects can easily be overlooked and some conditions can change or become more apparent over time. A thorough clinical history was done. Up to this point the mother was convinced that the reaction was to wheat, but was confused about the cause of the persisting symptoms.

Should we consider doing another skin prick test or do a blood test?
First, we need to consider the possible reasons for the initial skin prick test having been negative:

• The reaction is to wheat, but is a non-IgE cellular response.


• The reaction is due to CD (which is not IgE mediated).


• The reaction is due to wheat intolerance (unlikely, as mentioned before).


• The patient was on antihistamines (which suppress skin histamine response) at the time of the skin prick test, or the skin prick test failed to pick up intestinal allergy.


• Techniques used were flawed.


• The reaction is not to wheat at all.


• Presence of parasitic infection


• Post-enteritis syndrome


• Carbohydrate intolerances such as lactose or fructose intolerance or overconsumption

The benefit of redoing a skin prick test is that one can ensure that the correct techniques are used and that the child is not on any medication that can influence the results. The benefit of doing a blood test is that one can determine the total serum-IgE level (to find out if there is any IgE-mediated reaction taking place - even if it is not to wheat; this is only the case if parasitic infections, etc., have been ruled out, as total IgE can be elevated in these cases - but not specific IgE), as well as the serum-specific IgE level to wheat. Blood tests were therefore done, but the total serum-IgE and the serum-IgE levels for wheat were not elevated. What can this mean? The reaction that is taking place is non-IgE mediated, which still includes the possibility of non-IgE cell-mediated allergy as well as CD. As noted, both of these can have delayed reaction times, and symptoms can be diarrhoea and abdominal cramps (as in this patient).

As a further step to identify the cause of symptoms, the mother was asked to keep a food-symptom diary. The problem with implementing an elimination diet at this stage is that, if further diagnostic tests for CD are done, the results can appear normal. For example, the avoidance of gluten by CD patients results in a decrease in the serum-antigliadin IgA and IgG levels, which thus may be at normal levels on elimination diets.

The food-symptom diary was scrutinized, and it was confirmed that the mother and other caretakers were complying well with a wheat-free diet. Also, notably, the child was not ingesting any rye or barley. She was receiving oat porridge some mornings, but was not reacting with any acute or noticeable delayed reactions. Symptoms commonly appeared approximately 1 day after the ingestion of "wheat/gluten-free" pasta.

There are many studies that suggest that oats are safe in CD. Thus, the oats in the girl's diet would probably not exacerbate CD, unless she was ingesting excessive amounts or there was contamination by other gluten-rich foods present.

The mother was sure that she had done thorough research on the "wheat/gluten-free" pasta and that it was obtained from a reputable source. After obtaining more information on the product, it was determined that the pasta was, in actual fact, made from spelt. The manufacturing company was marketing it on their website (http://www.purityfoods.com/index2.html) as a "wheat/gluten-free" pasta that had been "used successfully, under physicians' supervision, as a wheat substitute for people who have wheat allergies". This is incorrect, as spelt (and also dinkel) is in actual fact non-hybridized wheat and is not tolerated by wheat-allergic persons. This type of mistake is widespread.

CD and wheat allergy are thus still possibilities. CD and wheat allergy can also be present at the same time. What would be the next step at this point? As mentioned above, an elimination diet is not recommended before antigliadin IgA and IgE is measured. An endoscopy with intestinal biopsy may be required for certainty. Antigliadin IgA and IgG antibodies to gliadin were found to be at normal levels, which indicates that CD is unlikely. CD should, however, not be excluded as a possibility yet. An intestinal biopsy can be done if one needs to rule CD out totally. But when spelt was excluded from the diet, the child improved rapidly. This rapid response would be more in line with an allergy response than with CD, as CD symptoms take longer to improve.

After a symptom-free period, the child was challenged with wheat, rye and barley one by one and reacted only with wheat. This confirms the diagnosis of a non-IgE cell-mediated wheat allergy.

TIP for Allergy Advisor users: For assessing the diet history and food-symptom diary, the "Hidden allergens" function under the Management bar can be used to search for possible hidden allergens that might be present in the diet. The program also has wheat-free and gluten-free diet sheets that can be adapted to the individual and printed out. The diet sheets include foods allowed, foods restricted, ingredient items to avoid on labels (hidden allergens) and examples of substitutes that can be used. Also under the Management bar, "Substitutes and Recipes" enable you to print out recipes and substitutes for the patient to take home.

B. More information:
Adverse reactions to wheat can be divided into:

A.) Immune reactions: Allergic immune reactions IgE-mediated Non-IgE-mediated cellular response Non-allergic immune reactions Celiac Disease (CD) (producing IgA and IgG antibodies) Non-CD enteropathy B.) Intolerance

A wheat allergy involves an immune reaction in response to an allergen that the body is exposed to. The production of IgE antibodies can be involved or not. The reaction can be IgE-mediated, or it can be a non-IgE-mediated cellular response.¹

Intolerance does not involve the immune system, and the mechanisms responsible for wheat intolerance include:

• an enzyme deficiency


• undigested food as a result of malabsorption syndromes or retrogradation (starch has changed in such a way that the digestive enzymes cannot digest it any longer), which result in bacterial fermentation in the colon, causing specific symptoms.² Under normal circumstances also, some starch escapes digestion and becomes a bacterial substrate in the colon.


• abnormal colonic bacterial flora present as a result of antibiotic therapy, post gastroenteritis or an inappropriate diet, causing fermentation with associated symptoms

The body's different mechanisms of defence involved in each type of adverse reaction to wheat cause symptoms which may be quite different from or confusingly similar to each other. The severity of symptoms can vary considerably within each type of adverse reaction, but the patterns are distinct. An allergy can cause very mild to quite severe reactions (such as life-threatening anaphylaxis), compared to wheat intolerance, which can cause significant discomfort, but is never dangerous. CD can lead to serious long-term complications if left untreated (discussed below).

Wheat allergy may be present in the absence of a family history, but CD is probably always inherited. However, as CD can be silent or latent, a family history is not always reliable.

Proteins and allergens in wheat
Wheat, like all other foods, contains a number of proteins (more than 100), of which some have been identified as allergens. Some are major allegens (more than 50% of wheat-allergic persons react to these allergens) and others minor (less than 50% of wheat-allergic persons react to these allergens). The type and proportions of proteins in a cereal have a major impact in determining the quality and end use properties of the cereal.³ Wheat proteins can be characterized by their solubility:

• water-soluble


• salt-soluble


• alcohol-soluble


• alcohol-insoluble^4,5

Prolamins are alcohol-soluble storage proteins of cereal grains.³

The gliadin proteins are divided into alpha, beta, gamma (all three are toxic to persons with CD) and omega gliadins (non-toxic to persons with CD).^5,8

The major proteins in wheat (albumin, globulin, gliadin and glutenin) vary in proportion according to the type of wheat, and this variability is one reason reactions to different wheat products are not consistent.^4,9,10

More about gluten:

Wheat flour contains between 7 and 12% gluten proteins by weight.1 Gluten is composed of two protein groups, namely gliadins, which give wheat dough its flow characteristics, and glutenins, which provide the elasticity in finished wheat products. These occur in approximately equal amounts, but it is only the gliadin fraction, and in fact only some gliadins, that cause adverse reactions.1,7 Gliadin is a type of prolamin (a group of proteins with similar protein structures). Other grains such as rye, barley, oats and triticale (wheat-rye hybrid) each contain their own prolamins, which cause the same intestinal damage in CD that gliadin causes. This is due to the similarity in protein structure.

By definition, gluten is found only in wheat, although the term is commonly used to refer to any similar prolamin protein in any grain that is harmful to a person with CD.1,5,11,12 The following is a list of the type of prolamin in each grain and the percentage that the prolamin contributes to the grain's protein content: Wheat: Gliadin (69%) Corn: Zein (55%) Barley: Hordein (46-52%) Sorghum: Kafirin (52%) Rye: Secalinin (30-50%) Millet: Panicin (40%) Oats: Avenin (16%) Rice: Orzenin (5%)5

Because the type and proportion of prolamin proteins in these grains vary, the kind of reaction (if any) they are likely to cause also varies.2,9,10,13,14 Corn, rice, other cereal grains such as sorghum, millet, teff, ragi and Job's tears as well as buckwheat, quinoa and amaranth can safely be ingested by a person with CD. Spelt and kamut, however, should be avoided in CD.12,15

What about oats?
The safety of the ingestion of oats is still controversial. The amount of avenin in oats is relatively small compared with the amounts of relevant prolamins present in wheat, barley and rye. Therefore, the quantity of oats consumed may be critical. Although many studies have proven this grain safe to consume, there are still certain factors that need to be considered. Most commercial oat products contain wheat flour or gluten. Contamination of oats with wheat may occur due to the sharing of equipment in grain processing and the rotation of crops (wheat may be grown on the same field as oats were). Therefore, contamination may be the cause of adverse reactions to oats often reported by gluten-sensitive individuals.¹

One should bear in mind that gliadins and other prolamins are only some of the many proteins found in wheat, rye and barley, and that the origin of an adverse reaction to these foods is not necessarily a prolamin.

Wheat allergy
Wheat allergy refers specifically to adverse immune reactions to one or more of the proteins/allergens found in wheat. When exposed to an allergen in wheat, an allergic individual's immune system responds through the release of IgE antibodies or through a non-IgE-mediated cellular immune mechanism.^4,16 Inflammatory mediators are released and the allergic symptoms that are experienced result from the specific effect of each inflammatory mediator on the body. If inflammatory mediators are released or their levels enhanced by mechanisms that are independent of the immune system, the reaction is due to an intolerance.⁹

As noted before, allergic reactions to wheat can result from a wide range of proteins/allergens or a combination of these. The majority of wheat allergies involve the albumin and globulin fractions of wheat, but even gluten may also, rarely, induce IgE-mediated reactions.^2,4,9

Wheat allergy may be caused by the ingestion of wheat-containing foods or by inhalation of or contact with flour containing wheat (e.g., Baker's asthma: see below).^2,4

a. How common is wheat allergy?
Clinical experience suggests that it is a relatively common allergy, but there are no accurate figures for prevalence. It is, however, more prevalent in certain groups: for example, wheat allergy is responsible for occupational asthma in up to 30% of individuals in the baking industry.⁴

Wheat allergy is most common in young children, of which the majority will outgrow it within five years. This occurs more quickly if the wheat-containing food is completely avoided. Those who develop the allergy later in life will probably retain it.^4,16

b. What are the symptoms?
Allergic reactions to wheat can be acute or delayed, occurring within minutes or a few hours after eating or inhaling wheat. The symptoms can involve the skin (urticaria, eczema, angioedema, atopic dermatitis), the gastrointestinal tract (abdominal cramps, nausea and vomiting, oral allergy syndrome) and the respiratory tract (asthma or allergic rhinitis).^4,9,16 Wheat is one of the allergens causing Baker's asthma and has also been associated with wheat-dependent exercise-induced reactions (see below).

Baker's asthma: Contact with or inhalation of wheat flour proteins is one of the causes of baker's asthma (an occupational allergy), but allergens other than the wheat itself (e.g., storage mites, yeast and baking additives) may also be causes. Symptoms that may present include rhinitis, skin itching/rash, ocular symptoms (including tearing, itching and conjunctival injection), respiratory symptoms (including coughing, wheezing, shortness of breath and sputum production) and "grain fever".21,22 Wheat-dependent exercise-induced reactions: Exercise within 3 hours of wheat consumption can induce an adverse reaction in susceptible individuals. In some cases, this can also occur when wheat is consumed directly after exercise. Typical symptoms experienced include asthma, urticaria, angioedema, dyspnoea, syncope and anaphylaxis. A diet excluding wheat, rye, and barley is indicated due to cross-reactivity.17,23

Coeliac Disease (gluten-sensitive enteropathy)
CD is a hereditary disorder of the immune system. A key mechanism of the disease is immune-mediated T-lymphocyte activation in the gastrointestinal mucosa following gluten ingestion. Inflammation of the intestinal mucosa and atrophy of the villi occur, and can result in the inadequate absorption of nutrients such as proteins, carbohydrates, fats, vitamins, minerals, and, in some cases, water and bile salts. Undigested foods (including protein and fats) that reach the colon are fermented by bacteria, possibly causing some of the symptoms such as bulky, foul-smelling stools. CD is caused by IgA- and IgG-mediated responses to gluten, and thus is not IgE-mediated, like wheat allergy. The disease is permanent, and damage to the small intestine will occur every time gluten is consumed, regardless whether symptoms are present or not.^{2,4,9,10,11,13,14,24} It has been reported that as little as 0.1 grams of ingested gluten can trigger symptoms.¹

There are at least four mechanisms involved at bowel level:

• glutaminase (an intestinal enzyme) deficiency


• increased permeability of the bowel to macromolecules, including the allergen


• the production of antibodies to the relevant prolamin, or a fragment of it


• increased production of inflammatory mediators

The onset of noticeable symptoms of CD seems to be dependent on the following: exposure to wheat, as when an infant is weaned (introduction of solids); predisposition through family history; and some kind of "trigger" mechanism. Little is known about this "trigger" but suspected factors include physical or emotional stress, trauma such as surgery or pregnancy, over-exposure to wheat, viral infection, other diseases, and even antibiotics.^13,24,25

a. How common is CD?
CD is one of the most common life-long disorders in certain countries. CD is frequently under-diagnosed, particularly in adults, who may present with only subtle symptoms.^2,4 In some countries the incidence is as high as 1 in 200 (Sweden).⁴

Although there is a definite genetic component, CD is apparently a multigene disease, and is not completely understood.¹⁷ As coeliac disease can be silent or latent, a family history is not always reliable. It primarily affects caucasians of northwestern European decent and rarely affects Africans, people of Mediterranean extraction or Asians. It affects twice as many females as males.^13,25

CD usually develops in childhood but can begin at any age. Typically the disease presents at the age of 6-24 months, after wheat has been introduced into the diet, and in early adult life (30's and 40's).^4,13,16,25

b. What are the symptoms?
The clinical manifestations of the disease vary markedly with the age of the affected person, the duration and severity of the disease and the presence of extra-intestinal pathologic conditions.¹⁴

There is no typical set of symptoms. However, there are "classic" symptoms (diarrhoea, bloating, weight loss, anemia, chronic fatigue, bone pain, and muscle cramps), but CD frequently presents with other symptoms. In some cases only one symptom may be experienced (e.g., anemia, a run-down feeling, or behavioral problems).²⁴

What is dermatitis herpetiformis?
Dermatitis herpetiformis is a form of CD. It is a skin reaction to gluten (granular IgA is deposited under the skin). Dermatitis herpetiformis manifests as a blistering, burning, itchy rash on the extensor surfaces of the body (mainly the back, sacrum, face, trunk, elbows, knees and buttocks, but also inside the mouth) in strikingly symmetrical patterns. In most of these individuals, intestinal biopsies are characteristic of CD regardless of whether gastrointestinal symptoms are present. The treatment is the same as for CD, but it may take two or more years after the initiation of the diet before the rash clears.^1,2,4,24

C. Comments by our editors

For more information on this subject and other allergy and intolerance related topics, visit:
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http://www.allergyadvisor.com
http://users.bigpond.net.au/allergydietitian

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D. References
1. Gluten and grain intolerance, http://www. healthcomm.com
2. http://users.bigpond.net.au/allergydietitian/
3. Shewry PR, Halford NG. Cereal seed storage proteins: structures, properties and role in grain utilization. Jouranl of Experimental Botany 2002;53(370):947-58.
4. http://www.scienceinafrica.co.za
5. Pomeranz Y. Wheat: chemistry and technology. American Association of Cereal Chemists, Inc., USA, 1988
6. Frieri M, Kettelhut B. Food hypersensitivity and adverse reactions. A practical guide for diagnosis and management. Marcel Dekker, Inc. New York. 1999.
7. Armentia A, Rodriguez A, Callejo A, Martin-Esteban M, Martin-Santos J-M, Salcedo G, Pascual C, Sanchez-Monge R, Pardo M. Allergy after ingestion or inhalation of cereals involves similar allergens in different ages. Clin Exp Allergy 2002;32:1216-22.
8. http://www.csaceliacs.org/
9. Joneja JV. Dietary management of food allergies and intolerances - a comprehensive guide 2nd edition. J.A. Hall Publications Ltd., USA, 1998.
10. http://www.nutramed.com/celiac/gluten.htm
11. Smith A. Wheat allergy and gluten intolerance. J All Soc SA 1994;7(2):22-3.
12. Thompson T. Questionable foods and the gluten-free diet: Survey of current recommendations. J Am Diet Assoc 2000: 100(4):463-5.
13. http://allergies.about.com/library/weekly/aa020899.htm
14. Fasano A, Catassi C. Current approaches to diagnosis and treatment of Celiac Disease: an evolving spectrum. Gastroenterol 2001;120:636-651.
15. Kasarda DD. Grains in relation to Celiac (Coeliac) Disease. http://wheat.pw.usda.gov/ggpages/topics/
16. http://www.intelihealth.com/IH/ihtIH/WSIHW000/7945/24481/286178.html?d=dmtContent
17. Palosuo K, Alenius H, Varjonen E, Kalkkinen N, Reunala T. Rye gamma-70 and gamma-35 secalins and barley gamma-3 hordein cross-react with omega-5 gliadin, a major allergen in wheat-dependent, exercise-induced anaphylaxis. Clin Exp Allergy 2001;31(3):466-73.
18. Simonato B, De Lazzari F, Pasini G, Polato F, Giannattasio M, et al. IgE binding to soluble and insoluble wheat flour proteins in atopic and non-atopic patients suffering from gastrointestinal symptoms after wheat ingestion. Clin Exp Allergy 2001;31(11):1771-8.
19. Weiss W, Huber G, Engel KH, Pethran A, Dunn MJ, Gooley AA, Gorg A. Identification and characterization of wheat grain albumin/globulin allergens. Electrophoresis 1997;18(5):826-833.
20. Garcia Casado G, Armentia A, et al. Rye flour allergens associated with baker's asthma. Clin Exp Allergy 1996;26(4):428-35.
21. Manfreda J, Holford-Strevens V, Cheang M, Warren CP. Acute symptoms following exposure to grain dust in farming. Environ Health Perspect 1986;66:73-80.
22. Matsumura Y, Niitsuma T, Ito H. A study of factors contributing to bakers' allergy symptoms. Arerugi 1994;43(5):625-633.
23. Hanakawa Y, Tohyama M, Shirakata Y, Murakami S, Hashimoto K. Food-dependent exercise-induced anaphylaxis: a case related to the amount of food allergen ingested. Br J Dermatol 1998;138(5):898-900.
24. http://www.gluten.net
25. http://wheat.pw.usda.gov/ggpages/topics/
26. Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, Davies-Jones GA, et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 1998;352(9140):1582-5.

E. CPD Questions (for South African dietitians only)

PLEASE ANSWER ALL THE QUESTIONS
1. True or false: A wheat allergy may or may not involve the immune system.
(a.) True
(b.) False

2. Which of the following is not a mechanism responsible for wheat intolerance?
(a.) An enzyme deficiency
(b.) Malabsorption syndromes
(c.) The release of inflammatory mediators
(d.) Retrogradation

3. True or false: The alpha, beta and gamma gliadin proteins are toxic to persons with Celiac Disease, but the omega gliadins are not.
(a.) True
(b.) False

4. Which one of the following is toxic to a person with Celiac Disease?
(a.) Buckwheat
(b.) Millet
(c.) Kamut
(d.) Sorghum

5. Which of the following fractions of wheat does not cause an IgE-mediated allergy?
(a.) Albumin
(b.) Globulin
(c.) Gluten
(d.) None of the above

6. True or false: If inflammatory mediators are released or their levels enhanced by mechanisms that are independent of the immune system, the reaction is due to an intolerance.
(a.) True
(b.) False

7. Wheat-dependent exercise-induced reactions occur when wheat is ingested…
(a.) Within 3 hours after exercise
(b.) Within 3 hours before exercise

8. Which of the following are adverse reactions related to Celiac Disease?
(a.) Bulky, foul-smelling stools
(b.) Anemia-related fatigue
(c.) Ataxia
(d.) All of the above

Answers

1. b. False
2. c. The release of inflammatory mediators
3. a. True
4. c. Kamut
5. d. None of the above
6. a. True
7. b. Within 3 hours before exercise
8. d. All of the above