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Medical Papers

Diagnosis of Intolerance

Dr David L. J. Freed, MB, MD, MIBiol

Several classic diseases of hitherto-unknown aetiology have been shown, in recent years, to be due at least in some cases to intolerance of common foods and environmental pollutants. The method used to determine this is the double-blind challenge. In principle (though not necessarily in practice) this is very easy; you persuade the patient to attend on a day when his symptoms are absent or very mild (so that they can be recognised if provoked); you administer the food or the inhalant via its natural route, and you watch to see whether, after a suitable delay, symptoms occur. If the symptoms are purely subjective, like headache, you rely on the patient to tell you whether or not it has happened, and thus you rely on his honesty and his resistance to suggestion. To allow for that possibility you administer the substance in disguised form, giving either the substance under question or else an inert placebo without telling him which it is, and without yourself being aware of it (a third party - usually the pharmacist - prepares the sample and labels it A or B, keeping the code secret until after the experiment is over).

Ingestants can be administered, in slurry form, by gastric tube, or freeze-dried in opaque gelatin capsules, or else mixed into a flavoursome stew (needless to say the capsules or the stew have first been tested by themselves to confirm that they are indeed inert in this individual). Inhalants are administered by aerosol, usually at concentrations so low that there is no taste as it crosses the buccal cavity.

How many challenges do we need to do?

If the patient correctly identifies the first challenge as either active or placebo, he might have done that by lucky chance, and the probability that he really is sensitive to the substance is precisely 50/50 (p = 0.5). If he correctly identifies two challenges in a row, the probability of lucky chance drops to 0.5 x 0.5 = 0.25:- still quite likely. Three correct identifications - still less likely to be due to lucky chance (p = 0.125), but still possible. Exactly the same likelihood of tossing a coin heads three times in a row. Only when the probability of lucky chance drops below p = 0.05 (five correct identifications in a row) do we feel intuitively that this really cannot be; there must be a pattern here. The null hypothesis (lucky chance) is for practical purposes disproved; he really is sensitive to this substance.

Using this procedure, a number of classic diseases of hitherto-unknown aetiology have been shown to be diet-related in many cases, and these may be referred to as the "new allergic diseases".

(Let us not, I pray, get bogged down with nomenclature. I am fully aware that the precise definition of "allergy" is controversial (1) For the purposes of these information sheets I normally use the popular definition, in which allergy is any symptom repeatedly caused by a food or inhalant that does not usually cause symptoms. If I am compelled for the sake of accurate expression to adopt the stricter, academic definition, I will say so).


This is now one of the most rewarding of illnesses to treat, a classic example of how a life-ruining condition can respond to ridiculously simple kitchen remedies. The commonest triggers are "the six C''s" - Cow-milk, Cigarette smoke, Caffeine, Chocolate, Citrus fruits and (oral) Contraceptives. Fifty percent of all sufferers are cured by avoiding these things, and a further percentage will get better once they stop all ergot-containing medications (2,3). (Hypothesis-matchers will note that this is NOT the tyramine list; tyramine is a factor only in a minority). There seems to be no common thread connecting the six Cs, and how they cause headache is unclear (4).

Most sufferers will be found to have "trigger points" or "rheumatic patches" (see elsewhere on this site) in the skin at the back of the neck and often the temples (4,5). You can identify them by rolling a skin fold between fingers and thumb; the skin feels thickened and the patient yelps! Rheumatic-patch treatment by intra dermal injection of a chelating agent such as sodium salicylate or EDTA offers useful palliation (4).

I am of the opinion that migraine and tension headache are actually variants of the same pathologic process, because the range of incitant foods is the same and rheumatic patches are detectable in both.

If avoidance of the six Cs is not sufficient to improve matters, further dietary manipulation and probably desensitisation will be required; coupled with rheumatic-patch treatment this therapeutic package hardly ever fails in those who come to me. At one time I became so confident that I offered a money-back guarantee; I withdrew that offer after an experience with one chap who swore that his headaches were just as bad as ever - I was sure that they were improved but I was unable to prove it, so I had to pay up!

Patients should be warned to expect a withdrawal syndrome when they give up foods and drinks they were previously consuming daily. The symptoms are very similar to those of heroin withdrawal (though not as severe or long-lasting) and I suspect that similar biochemical mechanisms are responsible. Not all patients experience this phenomenon, but if they do, they can safely be reassured that they are on the right lines and that they will improve. Dietary elimination should continue for at least two weeks and preferably longer, as some cases take some time to start improving.

Chronic urticaria and angioedema

Once the bane of the dermatology departments, this unpleasant and sometimes dangerous affliction is another of the "new allergic conditions", and very rewarding to treat. About 50% respond to simple dietary avoidances. The common triggers in this case are the artificial food additives, in particular azo dyes (E102, E104 etc) and preservatives (6). Fruits can also be a major problem. Remember to warn all patients and their relatives that a sweet drink that proudly claims to contain "no artificial flavourings or colouring's" will probably still contain preservatives - close perusal of the small print on the label is mandatory.

Cases that fail to respond to the simple diet will require more complex diets and desensitisation, and I have sometimes encountered unexpected allergies. I recall one woman who turned out to be allergic to her husband's semen; fortunately it proved easy to desensitise. Chronic urticaria is one condition in which I have to concede partial defeat fairly often, in that they improve but do not lose the problem completely. I assume this is because of exotic sensitivities that I have not tracked down, and the cost-effectiveness of further detective work is dubious. In this case I will prescribe the little-known anti protease drug tranexamic acid (Cyclokapron), which has an unexplained beneficial effect far greater than that of antihistamines or steroids (7). The patient should take one 0.5 G tablet at the first sign of an attack, then a further tablet every half-hour, up to a maximum of 30 tablets per day or until the attack starts to subside. Side-effects include nausea and hypertension and there is a theoretical risk (not so far seen in practice) of enhancing any thrombotic process.

Angioedema affecting the larynx is potentially life-threatening and you dare not play around with it. Issue the patient with a self-injection kit of adrenaline and make sure he/she knows how to use it accurately and swiftly, even in half-light or when half-swooned. The kit must be carried on the person, not in the handbag or in the car. The side-effects of adrenaline are trivial in comparison with the risk of sudden death and the patient must be told emphatically that they are to self-inject immediately there is the slightest hint of an attack. They must NOT fool around with clothing or alcohol swabs; the needle must be thrust straight through the clothing into the nearest limb, subcutaneously, and the patient must report to Casualty immediately afterwards. It is far preferable to be embarrassed once or twice by false alarms, or even to have an abscess from a dirty injection, than to suffocate to death.

Irritable bowel and Crohns disease

These are both diagnoses that should be made by the gastroenterology experts, since other, more sinister, diseases must always be excluded first. Treatment, however, is as much up to the GP as the specialist, and dietary manipulations have shown spectacular success in recent years (8,9). In my view dietary eliminations should always be tried before steroids and surgery, and probably even before sulphasalazine and related drugs, since the potential side-effects of diet are milder than those of conventional treatments.

American allergist Dr Joe Miller has coined the memorable phrase "Irritable bowel and Crohn's disease are a piece of cake", and this is a reminder that the commonest incitants of these diseases are the common constituents of cake, namely, wheat flour, sugar, egg, milk, chocolate, and fruits. To this list I would add other grains such as rye, barley and oats, plus the common legumes (peas, beans and lentils) and potato. The foods that remain permissible make up what is loosely termed a "stone-age diet", viz meats, fishes, and green-leaf vegetables. One can live perfectly healthily on this sort of diet, but it is grievously boring and socially restricting. Nevertheless, we should not allow this to stand in the way of a drug-free, non-surgical cure; if that's what it takes, that's what it takes. Much anxiety is expressed by physicians (though rarely, curiously, by surgeons) about the alleged dangers of elimination diets (10).

Coming from a group of gentlemen that saturate their clients with toxic drugs at the drop of a hat, I think that is mainly humbug. However, there are such things as dietitians available to the GP, and if you feel diffident about managing the nutrition of a patient on an elimination diet, by all means call in the expert. Modern dietitians are fully au fait with the complexities of "allergy diets" and are anxious to put their expertise to use. Three weeks of diet is all you need to find out if this is going to work or not, and in that short time there is no danger of malnutrition.

If a couple of weeks on a stone-age diet doesn't stop the illness, prescribe oral nystatin also, and if that combination doesn't do the trick you will need to call for help; desensitisation is going to be required.

Few patients fail to respond to that therapeutic package. I cannot say the same for ulcerative colitis, which seems genuinely to be a different sort of disease; I have far less confidence with that although some of my colleagues report success in the long-term (11).

While on the topic of disordered bowels, this will be an apt point to bring in dietary fibre. While not dissenting from the popular view on its usefulness, I must mention that "fibre" is NOT a synonym for "wheat bran". Some constipated patients find that their constipation gets worse, not better, when they consume wheat bran. This is because of the exorphins of wheat (12), which are small peptides derived from partially digested wheat protein. As the name implies, exorphins have a weak morphine-like effect, including constipation. The other effect to look out for is a state of dreamy detachment, of being an onlooker to the world (not an unpleasant sensation but decidedly odd) which these patients often feel after consuming bread. You may not have heard this complained of, because patients are afraid to mention it, but it is commoner than you think.

An alternative source of dietary fibre, for those whose constipation becomes worse on taking bran, is green-leaf vegetables.

Hyperactivity, ADHD

This is a value judgment as much as a diagnosis, but few pediatricians nowadays seem to doubt that the condition exists. We owe a debt of gratitude to Professor John Soothill, formerly of Great Ormond Street Hospital, for assembling the team and the resources to do the crucial experiment on dietary management of these children (13). This pioneering work has been confirmed (14,15) and one can state with a high degree of certainty that the condition (and the related condition of delinquency) is indeed related to diet in many cases.

Adults also suffer food reactions of this type but are more socially-controlled, being expressed in spouse abuse, irritability and petty crime instead. What diet? Since the days of Feingold (16), artificial additives and fruits have been popularly held in suspicion (as for chronic urticarias see above), but Soothill showed that the classic food allergens - milk and wheat - are equally commonly implicated. Since these are daily staples, and since we are dealing with children whose dietary fads are already horrendous, I am of the view that the diet should be supervised by a dietitian unless the doctor has acquired sufficient expertise of his own in this field. In fact it is never necessary to force a child to eat, however faddy he is. If the parents ensure that no "naughty" food is available to him in the house, he will eventually eat good food. The process should be accompanied by explanation.

Afterword on the dangers of elimination diets

Although I think that the dangers have been grossly exaggerated (as compared with the dangers of long term drug usage) it would be unfair to deny that they exist. This is especially so for children, whose major source of protein, calcium and vitamins may be milk (the commonest food allergen). Elimination diets are also expensive, time-consuming, irksome and socially restricting. They may cause drastic realignments in family tensions. They may lead to isolation, introspection, hypochondria, malnutrition and poverty. Watch out.


1) Freed DLJ The immunology of allergy.
in Rees AR, Purcell H (eds) Disease and the Environment;
Wiley, Chichester, 1982.

2) Egger J, Carter CM, Wilson J et aI; Is migraine food allergy?
Lancet 1983, ii: 865-8.

3) Grant EEC; Food allergies and migraine. Lancet 1979, I: 966-9.

4) Fox WW, Freed DLJ. Understanding Arthritis: the Clinical Way Forward;
Macmillan, Basingstoke, 1990.

5) Travell JG, Simons DG: Myofascial Pain and Dysfunction: the Trigger Point Manual;
Williams & Wilkins, Baltimore, 1983.

6) Supramaniam G, Warner JO: Artificial food additive intolerance in patients with angio-oedema and urticaria.
Lancet 1986, ii: 907-9.

7) Freed DLJ, Buisseret P, Lloyd M et al: Angioedema responding to antiprotease therapy but without abnormality of the complement system.
Clin Allergy 1980, 10: 21-23.

8) Alun Jones V, McLaughlan P, Shorthouse M: Food intolerance: a major factor in irritable bowel syndrome.
Lancet 1982, ii: 115-117.

9) Alun Jones V, Dickinson RJ, Workman E et al: Crohn's Disease: maintenance of remission by diet.
Lancet 1985, ii: 177-180.

10) David TJ: Unhelpful recent developments in the diagnosis and treatment of allergy and food intolerance in children.
in Dobbing J (ed): Food Intolerance;
Bailliere Tindall, Eastbourne, 1987, pp 203-204.

11) McEwen LM, Allergy and EPD. 2003, McEwen Laboratories, Henley-on-Thames RG9 1HX.

12) Zioudrou C, Streaty RA, Klee WA: Opioid peptides derived from food proteins: the exorphins.
J Biol Chem 1979, 254: 2446-9.

13) Egger J, Carter CM, Graham PJ et al: Controlled trial of oligo- antigenic diet treatment in the hyperkinetic syndrome.
Lancet 1985, I: 540-5.

14) Graham P: Dietary aspects of management in childhood hyperactivity.
In. Dobbing J (ed), Food Intolerance;
Bailliere Tindall, Eastbourne, 1987, pp 59-67.

15) Egger J, Stolla A, McEwen LM: Controlled trial of hyposensitization in children with food-induced hyperkinetic syndrome.
Lancet 1992, 339: 1150-53.

16) Feingold BF: Hyperkinesis and learning disabilities linked to artificial food flavors and colors.
Am J Nurs 1975, 75: 797-803.

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