Dr Janice Joneja explores this little-known and not very well understood sensitivity to aspirin and related chemicals.

Acetylsalicylic acid (ASA), or Aspirin, is the only form of salicylate that has been definitively shown to cause an adverse reaction. Salicylates, rather than acetylsalicylic acid (1), occur naturally in many foods but although they are suspected of causing adverse reactions in people who are sensitive to acetylsalicylic acid, there have not, as yet, been any research studies that actually show that they do.
   
Up to 25% of people who are sensitive to acetylsalicylic acid also react to the azo dye tartrazine, although it is not known whether the mechanism of action of the two chemicals is similar. (2) Those who are sensitive to acetylsalicylic acid often appear also to be sensitive to benzoates and sulfites. But although a similar mechanism of action is suspected, this cross reactivity has not yet been confirmed by research studies either.

It is the amount of salicylic acid that is probably the crucial factor in salicylate sensitivity.  Consumption of salicylate in food is estimated to be 10 to 200 mg daily (4), whereas the usual dose in a regular aspirin is 325 mg; in extra-strength or arthritis pain relief aspirins, the dose is 600 to 650 mg of acetylsalicylic acid; and in a children’s aspirin, it is 80 mg.

Absorption may also be relevant in the amount of salicylate available. In a medication, ASA is in the ‘free form’ – that is, it is not linked to another compound, and is immediately available to the body. When the salicylate is in a food, it is complexed with many other compounds, so it will not become active until released in its free form, which will take a certain length of time and will reduce the body’s immediate response to the chemical.

Asthma and Salicylate Intolerance

Acetylsalicylic acid (aspirin) sensitivity is more common in asthmatics. Somewhere between 2% and 22% of asthmatics are thought to be sensitive, with sensitivity being more common in adults and rare in children. (5) However, asthmatics who are sensitive to acetylsalicylic acid can usually eat foods containing salicylates without difficulty. No carefully controlled studies have been done to establish whether reducing dietary salicylates would improve their asthma.

Aspirin sensitivity has also frequently been thought to be a cause of urticaria (hives) and angioedema (tissue swelling); respiratory symptoms, including rhinitis and possibly nasal polyps; and digestive tract disturbances. (4)

Salicylate sensitivity (6) has also been implicated in childhood hyperactivity but there is no research to substantiate this. Recent studies indicate a role for benzoates and food dyes in triggering hyperactivity in children; salicylates were not implicated as triggers in these studies. (7)

Acetylsalicylic Acid – mechanism of action

The key event that leads to sensitivity to ASA is the same process that gives aspirin its ability to reduce pain. ASA inhibits the cyclooxygenase pathway of arachidonic acid metabolism; this is an important pathway in the production of some essential media­tors that cause inflammation and that also contribute to the symptoms of allergy. (8)

In an allergic reaction, preformed inflammatory mediators are released from mast cells, which act on tissues to produce symptoms. In addition, some of these preformed mediators are enzymes that promote additional steps in the process. An essential enzyme in this respect is phospholipase A2. This enzyme breaks down phospholipids in cell membranes and releases arachidonic acid (AA) in the process. AA is a key 20-carbon chain omega-6 fatty acid that is the precur­sor (provides the building blocks) for more inflammatory mediators to augment the protective inflammatory response.

Two key enzyme pathways then act on AA to produce two groups of powerful inflammatory mediators: (a) the cyclooxygenase pathway that leads to the produc­tion of the prostanoids (prostaglandins; prostacyclins and thromboxane) and (b) the lipoxygenase pathway that leads to the production of leukotrienes. Each of these groups plays an extremely important role in body processes such as smooth muscle contraction and relaxation and in the widening and narrowing of blood vessels.

Some of these mediators also lead to symptoms such as pain (the prostaglandins) and the bronchospasm of asthma (the leukotrienes). A high level of leukotrienes is found in the inflamed tissues of allergic conditions in the skin such as eczema (9) and urticaria. Antileukotriene drugs are increasingly being used to treat these conditions. (10)

In the treatment of pain, reducing the level of the prostaglandins involved in the process is required. Aspirin achieves this by inhibiting the cyclooxygenase enzyme pathway which leads from AA to prostaglandins. Other analgesics—for example, ibuprofen, acetaminophen, and paracetamol—have a similar effect.

However, by inhibiting one enzyme pathway, a buildup of substrate (AA) leads to enhancement of the other. So inhibition of the cyclooxygenase pathway results in an increased production of leukotrienes via the lipoxygenase pathway. Leukotrienes cause the bronchoconstriction of asthma, thus explaining the observation that many asthmatics are aspirin intolerant. Research also indicates that an additional effect of the process is the release of histamine from mast cells and other granulocytes (e.g., basophils, eosinophils, macrophages, platelets) in a non-immunologically mediated reaction. (4, 11)

Diagnosis and Management of Salicylate Intolerance

There are no laboratory tests to diagnose salicylate intolerance. A clear medical history and analysis of a food and symptom diary that shows suggests that symptoms occur after eating salicylate-rich foods are the best indicators and suggest that a trial elimination and challenge diet of salicylates would be worthwhile.

A diagnosed sensitivity to aspirin is sometimes assumed to indicate a salicylate sensitivity but, because the levels of salicylic acid in aspirin and foods are so different, it is unwise to assume that an aspirin-sensitive person requires a salicylate-restricted diet.

Some practitioners believe that, although avoiding foods high in salicylates is unlikely to diminish the symptoms of most people sensitive to acetylsalicylic acid, a salicylate-restricted diet may help those who are very acetylsalicylic acid sensitive and have not found any other treatments helpful. Since salicylate intolerance, as in all food intolerances (as opposed to food allergies), is dose-related, it is probably sufficient that a person with suspected salicylate sensitivity avoid foods with the highest levels of salicylate.

Sensitivity to Ingredients With Similar Reactivity to Salicylates

The symptoms that develop from sensitivity to benzoates, azo dyes, and sulphites are often indistinguishable from those resulting from salicylate intolerance, because the mechanism of action of these substances is quite similar. (3) Frequently, salicylate sensitivity has been blamed when the sensitivity is actually to one or more of these other food components. Since a low-salicylate diet is so restrictive and may pose unnecessary nutritional risk, it is often a worthwhile exercise to restrict benzoates, azo dyes, and sulphites (predominantly foods with artificial food additives) for a time-limited trial before complete salicylate avoidance is attempted.

Food Sources of Salicylates

Salicylates are a natural component of a wide range of food plants. It would be extremely difficult, if not impossible, to formulate a nutritionally adequate diet by avoiding all foods that contain salicylate.

Several researchers have developed tables to indicate the level of salicylate in foods. (12–14) However, the reported levels are not entirely consistent between data banks, because the level of salicylate in a food will vary according to plant variety, conditions in the growing environment, and methods of analysis in the laboratory.

Furthermore, the level of salicylate detected in the body (by analysis of a research subject’s serum) varies, probably depending on individual absorption patterns and metabolism of salicylate within the body. (4, 15, 16) There is still a great deal to learn before we can diagnose and manage either aspirin or salicylate intolerance effectively.

A salicylate-restricted diet should not be followed for longer than 4 weeks initially. After this time, sequential incremental dose challenge of salicylate-rich foods should be undertaken to confirm salicylate intolerance.

References

1. Janssen PL, Katan MB, van Staveren WA, Hollman PC, Venema DP. Acetylsalicylate and salicylates in foods. Cancer Lett. 1997;19(1-2):163-164.
2. Ros AM, Juhlin L, Michaelsson G. A follow-up study of patients with recurrent urticaria and hypersensitivity to aspirin, benzoates and azo dyes. Br J Dermatol. 1976;96:19-24.
3. Juhlin L, Michaelsson G, Zetterstrom O. Urticaria and asthma induced by food and drug additives in patients with aspirin sensitivity. J Allergy Clin Immunol. 1972;50:92-98.
4. Baenkler HW. Salicylate intolerance. Dtsch Arztebl Int. 2008;105(8):137-142.
5. Obase Y, Matsuse H, Shimoda T, Haahtela T, Kohno S. Pathogenesis and management of aspirin-intolerant asthma. Treat Respir Med. 2005;4(5):325-336.
6. Feingold B. Hyperkinesis and learning disabilities linked to artificial food flavors and colors. Am J Nurs. 1975;75(5):797-803.
7. Bateman B, Warner JO, Hutchinson E, et al. The effects of a double blind, placebo con­trolled, artificial food colourings and benzoate preservative challenge on hyperactivity in a general population sample of preschool children. Arch Dis Child. 2004;89:506-511.
8. Willis AL, Smith DL. Metabolism of arachidonic acid. In: Cunningham FM, ed. The Handbook of Immunopharmacology and Lipid Mediators. London: Academic Press; 1994: 1-32.
9. Ruzicka T. Leukotrienes in atopic eczema. Acta Derm Venereol Suppl (Stockh). 1989;144:48-49.
10. Nettis E, D’Erasmo M, Di Leo E, et al. The employment of leukotriene antagonists in cu­taneous diseases belonging to allergological field. Mediators Inflamm. 2010; pii: 628171. Epub 2010 Sep 22.
11. Farooque S, Lee T. Mechanisms of aspirin-sensitive respiratory disease—as two compo­nent model. Int Arch Allergy Immunol. 2007;142:59-63.
12. Swain AR, Dutton S, Truswell AS. Salicylates in foods. J Am Dietetic Assoc. 1985;85(5):950-960.
13. Margen S. The Wellness Encyclopedia of Food and Nutrition. University of California at Berkeley. New York: Random House Press; 1992.
14. Pennington JAT, Douglass JS. Bowe’s and Church’s Food Values of Portions Commonly Used. 18th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005.
15. Blacklock CJ, Lawrence JR, Wiles D, et al. Salicylic acid in the serum of subjects not taking aspirin. Comparison of salicylic acid concentrations in the serum of vegetarians, non-vegetarians and patients taking low-dose aspirin. J Clin Pathol. 2001;54:553-555.
16. Baenkler M, Leykauf M, John S. Functional analysis of eicosanoids from white blood cells in sepsis and SIRS. J Physiol Pharmacol. 2006;57:25-34.

Additional Resources
For further information on salicylate intolerance see The Health Professional’s Guide to Food Allergies and Intolerances by Dr Janice Joneja.

You can buy all of Dr Joneja's books here or here in the US.

First published November 2013

For a wide selection of other articles on salicylate intolerance, including some personal experiences see here. For articles on other uncommon allergies and intolerances see here.