As a general rule, adverse food reactions that are not triggered by immunological mechanisms are referred to as food intolerances. In this case, the reaction is reproducible and the severity of the symptoms is dose-dependent, in contrast to allergies.
Enzymatic food intolerance
They are caused by the inability to metabolize some substances present in food due to birth defects. Some are very rare (e.g. phenylketonuria), some are slightly more common (e.g. favism), and others are very common, especially among the adults in Western population (e.g. lactose intolerance). Lactose intolerance, for instance, is a classic case of enzymatic intolerance and depends on a defect of lactase, which is linked to a genetic polymorphism. This enzyme can digest lactose almost completely, with only very small, negligible quantities reaching the colon undigested. In people with lactase defects instead, greater quantities of undigested lactose reach the colon, determining an increased intestinal fermentation which leads to an excessive gas production. The symptomatology is usually represented by bloating, abdominal pain, diarrhoea, and nutrient malabsorption. Lactase deficiency in adults is very frequent. The enzyme is usually present in normal proportion at birth and in the first years of life, but after 3 years its activity begins to decrease. In Western countries, this enzymatic defect often manifests itself during adolescence and is therefore distinguishable from the congenital form, which is evident from birth.
Pharmacological food intolerance
This type of intolerances can manifest themselves with a variety of symptoms; however, in some cases, these are very similar to the symptoms observed with IgE-mediated food allergies, with the only difference being that the immunological tests are negative. In most cases, there is a dose-dependent relationship between the observed symptoms and the exposure to specific substances contained in certain foods. The substances that cause the reaction are biogenic or vasoactive amines, methylxanthines and other substances with pharmacological activity.
- Biogenic or vasoactive amines
Vasoactive amines include dopamine, histamine, noradrenaline, phenylethylamine, serotonin, and tyramine. All these substances may be present in food in quantities which may cause a negative reaction in sensitive people.
Histamine is a diamine and is the chemical mediator of pollen allergies, among others. In fact, it is released into the body as a result of an allergic reaction. Histamine causes the classic symptoms of allergy: vasodilation, itching, smooth muscle contraction. Allergic people very well know antihistamine drugs, which act on histamine receptors to prevent or reduce allergy effects. Eating food which contains large amounts of histamine can cause the same symptoms as a true allergic reaction when released. Histamine in food, results from the degradation of histidine, an amino acid that is contained in all protein foods, hence almost everywhere. The degradation of histidine occurs by specific microorganisms: bacteria, yeasts and moulds present in food both through accidental contact, and added for manufacturing purposes, as it happens during the production of cheese, alcoholic beverages, or fermented foods such as sauerkraut. The longer a food is stored, the more likely it is to contain histamine. In most cases, the ingestion of large quantities of histamine does not produce any sort of disorders and, in sensitive people, the appearance of a reaction depends not only on the dose of histamine ingested, but also, and most importantly on the inactivation of the enzymes that can degrade histamine inside the body. Under normal conditions, histamine is degraded by the enzyme histamine-methyltransferase or di-amino-oxidase (DAO), which is widely produced by the wall cells in the gastrointestinal tract. Under normal conditions, the ingestion of large quantities of histamine does not produce any symptoms; however, the concurrent intake of specific medical drugs[1] or of toxins capable of inactivating di-aminases, is usually associated with the typical symptoms of histamine intoxication. An example is the scombroid syndrome. In this condition, eating rotten fish causes a considerable ingestion of histamine in the gastrointestinal apparatus, since fish contains histidine, which in turn is transformed into histamine by putrefaction and by the gut microflora. Two toxins, also present in the rotten fish, putrescine and cadaverine, block the DAOs because of their di-amines, thus stopping histamine degradation. Consequently, in this intoxication, a generalised histamine effect becomes evident with symptoms such as erythema, vasodilation, palpitations, pressure drop, headache, as well as vomiting and diarrhoea.
In order for histamine-rich foods to induce the symptoms, a simultaneous inhibition of the DAOs is required. For this reason, the possibility that the symptoms could be due to the ingestion of foods rich in histamine should always be considered with caution and taking into consideration any medical drugs taken at the moment of the intoxication. The table below lists the most common foods rich in histamine, the foods known to induce the release of histamine and the foods able to inhibit the DAOs.
| Foods rich in histamine | Foods known to induce the release of histamine | DAO-inhibiting foods |
| · Fermented alcoholic beverages, especially wine, champagne, and beer
· Fermented foods: sauerkraut, vinegar, soy sauce, kefir, yogurt, kombucha, etc · Vinegar-containing foods: pickles, mayonnaise, olives · Cured meats: bacon, salami, pepperoni, luncheon meats and hot dogs · Soured foods: sour cream, sour milk, buttermilk, soured bread, etc · Dried fruit: apricots, prunes, dates, figs, raisins · Most citrus fruits · Aged cheese including goat cheese · Nuts: walnuts, cashews, and peanuts · Vegetables: avocados, eggplant, spinach, and tomatoes · Smoked fish and certain species of fish: mackerel, mahi-mahi, tuna, anchovies, sardines
|
· Alcohol
· Bananas · Chocolate · Cow’s Milk · Nuts · Papaya · Pineapple · Shellfish · Strawberries · Tomatoes · Wheat Germ · Many artificial preservatives and dyes
|
· Alcohol
· Energy drinks · Black tea · Mate tea · Green tea
|
Table 1: Foods rich in histamine, foods that can induce histamine release, and DAO-inhibiting foods.
Tyramine is a protein derivative of tyrosine, which is normally inactivated by specific enzymes, such as the monoamine oxidase (MAOs). In most individuals, the assumption of tyramine with food does not cause any symptomatology. However, individuals with a genetic deficit of MAOs or individuals treated with drugs capable of blocking these enzymes (e.g. some antidepressants), may manifest phenomena of tachycardia, hypertension, headache, fever and facial flushes.
Other monoamines (e.g. dopamine, phenylethylamine, serotonine, etc.) may produce the symptoms typical of food pharmacological intolerance. The symptoms described here are in some cases mainly related to the toxic effect of these substances; others depend on an enzymatic deficit. These substances, their physiological mechanisms, and symptoms, as well as the foods containing them, are listed in the table below.
| Monoamine | Food | Mechanism | Symptoms |
| Dopamine | Broad beans, other leguminous vegetables. | Sympathomimetic Endogenous Noradrenaline Release. | Hypertensive crises. |
| Phenylethylamine | Fermented foods such as cheese, red wine. | Indirect sympathomimetic effect with the release of norepinephrine. | Migraine, hypertensive crises. |
| Serotonin | Fruits, vegetables
High concentration: > 3 g/g: banana, kiwi, pineapple, plum, tomato, walnuts. Medium concentration: 0.1-3 day/days: avocados, dates, grapefruit, melon, black olives, cabbage, figs, spinach, and cauliflower. |
Vasodilatation in skeletal muscles, intracranial and extracranial vasoconstriction. | None
Uncertain endomyocardial fibrosis. |
Table 2: Foods rich in dopamine, phenylethylamine, and serotonine, their mechanisms and symptoms induced.
- Methylxanthines
These are methylated derivatives of xanthine, a deoxypurine. The three methylxanthines present in foods are caffeine, theophylline, and theobromine. Each of them is present in various quantities in coffee, tea, cola, cocoa, milk chocolate and other foods. They work at the level of the central nervous system as adenosine antagonists. By blocking adenosine, these substances are able to produce excitation. Caffeine has a stronger effect in this sense because it competes with the benzodiazepine receptors.
- Other substances with mild pharmacological effects
Other substances that can be found in food can cause intolerances because of their potential pharmacological effects. The table below lists some of these substances and their effects as well as physiological mechanisms.
| Substance | Food | Mechanisms | Symptoms |
| Capsaicin | Peppers (Chili, Red, Paprika, Tabasco, etc.) | The release of substance P from nociceptive nerve fibers which in turn produces vasodilation, smooth muscle stimulation, pain. | A sensation of oral burning. Described as plasma cell gingivitis. Gastritis, nausea, vomiting, abdominal pain, skin contact manifestations. |
| Ethanol | Wines, spirits, etc. | Peripheral vasodilatory effect due to an increase of acetaldehyde as a consequence of reduced aldehyde dehydrogenase (ALDH) enzyme activity
ALDH deficit is common in Asians and uncommon in non-Asians. |
Skin erythema, hypotension tachycardia, drowsiness, nausea and vomiting.
It may occur in individuals with ALDH deficiency and in the case of a pharmacological interaction with disulfuram, metronidazole, griseofulvin, quinacrine, sulfonylurea, phenothiazines, phenylbutazone. |
| Myristicin | Nutmeg | It can be metabolized in vivo to an amphetaminosimile compound with effects similar to LSD. | CNS and cardiovascular symptoms: anxiety, impending death, hallucinations, tachycardia. |
| Psoralen
(Furocumarine) |
Celery, parsley, lime, lemon, bergamot | Phytophotodermatitis from food contact containing psoralen and subsequent sun exposure. | Erythema, linear bubbles, contact vesicles. |
| Solanine
(Glycosidic alkaloid) |
Potato; particularly high levels in the skin; chips can have high levels > 1000 μg/g; | Dose-dependent toxicity. | Vomiting, diarrhoea, abdominal pain, neurological symptoms (headache, dizziness, confusion, visual disturbances, mydriasis, fatigue, loss of consciousness); impairment of vital signs (fever, tachycardia, hypotension, symptoms that may suggest anaphylaxis); in severe cases coma and death. |
| Glycyrrhetinic Acid | Licorice | Inhibition of 11β-hydroxysteroid dehydrogenase with reduced cortisol transformation into cortisone and accumulation of renal cortisol. | Sodium retention, hypokalemia, peripheral edema, dyspnea, hypertension, arrhythmias, polyuria, proximal myopathy, cramping, headache. |
Intolerance to Food Additives
Many additives are used by the food industry. These include colourants, thickeners, preservatives, antimicrobials, antioxidants. Fortunately, the majority of additives do not induce adverse reactions, but some molecules can also give very serious reactions. These symptoms consist of itching, urticaria, rhinitis, asthma, headache, and migraine, and are supported by non-immunological mechanisms yet to be defined. The most common additives that give adverse reactions are sulphites, nitrites and nitrates, sodium glutamate and some colourants.
[1] The drugs that inhibit the DAO include: isoniazid, aminoguanidine, chloroquine, pentamidine, clavulanic acid, dobutamine, pancuronium, imipenem, and others.
