• Hives (urticaria): raised and swollen welts with blanched centers (wheals) that may coalesce to become giant welts. Limited to the superficial portion of the skin.
• Angioedema: Eruptions similar to hives, but with larger swollen areas that involve structures beneath the skin.
• Chronic versus acute: Recurrent episodes of urticaria and/or angioedema of less than six weeks’ duration are considered acute, while attacks persisting beyond this period are designated as chronic.
• Special forms: Special forms have characteristic features (dermographism, cholinergic urticaria, solar urticaria, cold urticaria).
Hives (urticaria) are an allergic reaction in the skin characterized by white or pink welts or large bumps surrounded with redness. These lesions are known as wheal and flare lesions and are caused primarily by the release of histamine (an allergic mediator) in the skin. About 50% of patients with hives develop angioedema—a deeper, more serious form involving the tissue below the surface of the skin.
Hives and angioedema are relatively common conditions: it is estimated that 15 to 20% of the general population has had hives at some time. Although persons in any age group may experience acute or chronic hives and/or angioedema, young adults (from the end of adolescence through the third decade of life) are most often affected.1,2
The basic cause of hives involves the release of inflammatory mediators from mast cells or basophils—white blood cells that play a key role in allergies. Mast cells are widely distributed throughout the body and are found primarily near small blood vessels, particularly in the skin, while basophils circulate in the blood. The classic allergic reaction occurs as a result of complexes of allergic antibodies (IgE) and antigens (foreign molecules) binding to mast cells and basophils and stimulating the release of histamine and other inflammatory compounds. However, other factors appear to be more important in stimulating the release of histamine in hives.
Causes
Hives can be produced as a result of reactions to various physical conditions. The most common forms of physical urticaria are dermographic, cholinergic, and cold urticaria. These are briefly described in the table opposite. Less common types of physical urticaria or angioedema include contact, solar, pressure, heat contact, aquagenic, vibratory, and exercise-induced.
Dermographism
Dermographism, or dermographic urticaria, is a readily elicited hive formation that evolves rapidly when moderate amounts of pressure are applied. This pressure may occur as a result of simple contact with another human being, furniture, bracelets, watchbands, towels, or bedding.
The frequency of dermographic urticaria has been estimated at 1.5 to 5% in the general population. It is the most common type of physical urticaria and is found twice as frequently in women as in men, with the average age of onset in the third decade. The incidence is much greater among the obese, especially those who wear tight clothing.
Dermographic lesions usually start within one to two minutes of contact as a generalized redness in the area; this effect is replaced within three to five minutes by a welt and surrounding reflex urticaria. Maximal edema usually occurs within 10 to 15 minutes. While the redness (erythema) generally regresses within an hour, the edema can persist for up to three hours.
Dermographism may be associated with other diseases, including parasite infection, insect bites, hormonal changes, thyroid disorders, pregnancy, menopause, diabetes, immunological alterations, other urticarias, drug therapy (during or following), chronic candidiasis, angioedema, and elevated blood levels of eosinophils (another type of white blood cell linked to allergies).
Cholinergic Urticaria
Cholinergic, or heat-reflex, urticaria (commonly referred to as “prickly heat rash”) is the second most frequent type of physical urticaria. These lesions, which depend upon stimulation of the sweat gland, consist of pinpoint wheals surrounded by reflex erythema. The wheals arise at or between hair follicles and develop most often on the upper trunk and arms.
The three basic types of stimuli that may produce cholinergic urticaria are passive overheating, physical exercise, and emotional stress. Typical eliciting activities, besides physical exercise, may include taking a warm bath or sauna, eating hot spices, or drinking alcoholic beverages. The lesions usually arise within 2 to 10 minutes after provocation and last for 30 to 50 minutes.
A variety of systemic symptoms may also occur, suggesting a more generalized mast cell release of the mediators than just in the skin. Headache, swelling around the eyes, tearing, and burning of the eyes are common symptoms. Less frequent symptoms include nausea, vomiting, abdominal cramps, diarrhea, dizziness, low blood pressure, and asthma attacks.
Cold Urticaria
Cold urticaria is a hives reaction of the skin when it comes into contact with cold objects, water, or air. Lesions are usually restricted to the area of exposure and develop within a few seconds to minutes after the removal of the cold object and rewarming of the skin. The lower the object’s temperature, the faster the reaction.
Widespread local exposure and generalized hives can be accompanied by flushing, headaches, chills, dizziness, rapid heartbeat, abdominal pain, nausea, vomiting, muscle pain, shortness of breath, wheezing, or unconsciousness. Cold urticaria has been observed to accompany a variety of clinical conditions, including viral infections, parasitic infestations, syphilis, multiple insect bites, penicillin injections, dietary changes, and stress.1
Drugs are the leading cause of hives in adults. In children, hives are usually due to foods, food additives, or infections. Most drugs are composed of small molecules incapable of inducing antigenic/allergenic activity on their own. Typically, they produce allergic effects by binding to larger molecules and inducing the immune system to develop allergic antibodies to the new molecule complex. Alternatively, drugs can interact directly with mast cells to induce the release of histamine. Many drugs have been shown to produce hives. The two most common drugs that produce hives are antibiotics and aspirin.
Antibiotics
Antibiotics, including penicillin and related compounds, are the most common cause of drug-induced hives. At least 10% of the general population is thought to be allergic to penicillin; of these people, nearly 25% react with hives, angioedema, or anaphylaxis.2
Penicillin and related contaminants can exist undetected in foods. It is not known to what degree penicillin in the food supply contributes to hives. However, hives and anaphylactic symptoms have been traced to penicillin in milk,3 soft drinks,4 and frozen dinners.5 In one study of 245 patients with chronic hives, 24% had positive skin tests and 12% a positive RAST (a blood test for allergies; see the chapter “Food Allergy” for further information) for penicillin sensitivity.6 Of the 42 patients who were sensitive to penicillin, 22 improved clinically on a diet free of dairy products, while only 2 out of 40 patients with negative skin tests improved on the same diet. This study would seem to provide indirect evidence that penicillin in the food supply contributes to hives.
In an attempt to provide direct evidence, penicillin-contaminated pork was given to penicillin-allergic volunteers. No significant reactions were noted other than transient itching in two volunteers.7 Penicillin in milk appears to be more allergenic than penicillin in meat. Presumably this is because penicillin breaks down into more allergenic compounds in the milk.
Aspirin
The frequency of aspirin sensitivity in patients with chronic hives is at least 20 times greater than it is in people without hives.8–12 Hives is a more common indicator of aspirin sensitivity than is asthma. In addition to exerting direct effects, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to dramatically increase gut permeability and increase the absorption of allergens from the digestive tract, which may also trigger hives.
Daily administration of 650 mg aspirin for three weeks has been shown to desensitize patients with hives who have aspirin sensitivity. While taking the aspirin, patients also became nonresponsive to foods to which they usually reacted (pineapple, milk, egg, cheese, fish, chocolate, pork, strawberries, and plums).13
Although any food can be the causative agent, the most common offenders are: milk, fish, meat, eggs, beans, and nuts. Individuals with eczema or asthma are most likely to experience hives as a result of classic allergic (IgE-mediated) mechanisms.
A basic requirement for the development of a food allergy is the absorption of the allergen through the intestinal barrier. Several factors are known to significantly increase gut permeability, including compounds called vasoactive amines ingested in foods or produced by bacterial action on essential amino acids, alcohol, NSAIDs, and possibly many food additives. In addition, several investigators have reported alterations in gastric acidity, intestinal motility (contractions of the intestine that propel the food through), and other functions of the digestive tract in up to 85% of patients with chronic hives.14–17 These alterations may in turn temporarily or permanently alter the barrier and immune function of the gut wall and predispose an individual to allergic reactions.
In one study of 77 patients with chronic hives, 24 (31%) were diagnosed as having no gastric acid output, and 41 (53%) were shown to have low gastric acid output.16 Treatment with a hydrochloric acid supplement and a vitamin B complex gave impressive clinical results, highlighting the importance of correcting any underlying digestive factor in the treatment of chronic hives. (See the chapter “Digestion and Elimination” for further discussion.)
Food additives are a major factor in many cases of chronic hives in children. Colorants (azo dyes), flavorings (salicylates, aspartame), preservatives (benzoates, nitrites, sorbic acid), preservatives (hydroxytoluene, sulfite, gallate), and emulsifiers/stabilizers (polysorbates, vegetable gums) have all been shown to produce hives in sensitive individuals.
The importance of controlling food additives is demonstrated by a study of 64 patients with hives. After two weeks on an additive-free diet, 73% of the patients had a significant reduction in their symptoms.17
Tartrazine
Tartrazine (FD & C Yellow #5) is one of the most widely used colorants that can trigger hives.18 It is added to almost every packaged food and to many drugs, including some antihistamines, antibiotics, steroids, and sedatives. Reactions to this food additive are so common that its use has been banned in some countries (e.g., Sweden).19
In the United States, the average daily per capita consumption of certified dyes is 15 mg, of which 85% is tartrazine. Among children, consumption is usually much higher. Tartrazine sensitivity has been estimated to occur in 0.1% of the population; however, we think it is much more common.
Tartrazine sensitivity is extremely common (20 to 50%) in individuals who are sensitive to aspirin.18 Like aspirin, tartrazine is a known inducer of asthma, hives, and other allergic conditions, particularly in children. Both compounds inhibit the enzyme cyclooxygenase; this inhibition results in a higher production of allergic compounds known as leukotrienes in some individuals. These compounds are roughly 100 times more potent than histamine in producing an allergic reaction.
In addition, tartrazine (as well as benzoate and aspirin) increases the production of lymphokine leukocyte inhibitory factor; this effect results in an increase in the number of mast cells throughout the body. Biopsies of patients with hives show that over 95% have more mast cells than individuals without hives.20
Diets that eliminate tartrazine, as well as other food additives, have in many cases been shown to be of great benefit to sensitive individuals.
Food Flavorings
Salicylates (Aspirin-like Compounds). A broad range of salicylic acid esters are used to flavor such foods as cake mixes, puddings, ice cream, chewing gum, and soft drinks. The mechanism of action of these agents is thought to be similar to that of aspirin.
Salicylates are also found naturally in many foodstuffs. Most fruits, especially berries and dried fruits, contains salicylates; raisins and prunes have the highest amounts. Salicylates are also found in appreciable amounts in licorice and peppermint candies. Moderate levels of salicylate are found in nuts and seeds. Vegetables, legumes, grains, meat, poultry, fish, eggs, and dairy products typically contain insignificant levels of salicylates. Salicylate levels are especially high in some herbs and condiments, including curry powder, paprika, thyme, dill, oregano, and turmeric. Although intake of these herbs and spices tends to be relatively small, they can make a significant contribution to dietary salicylate intake.
Average salicylate intake from foods is in the range of 10 to 200 mg per day.21 Dietary salicylates may be a significant factor for aspirin-sensitive individuals.
Other Flavoring Agents. Other flavoring agents, such as cinnamon, vanilla, menthol, and other volatile compounds, may produce hives in some individuals. The artificial sweetener aspartame (NutraSweet) has also been shown to induce hives.22
Food Preservatives
Benzoates. Benzoic acid and benzoates are the most commonly used food preservatives. Although the incidence of adverse reactions to these compounds in the general population is thought to be less than 1%, the frequency of reactions in patients with chronic hives varies from 4 to 44%.
Fish and shrimp frequently contain extremely high quantities of added benzoates. This may be one reason adverse reactions to these foods are so common in patients with hives.
BHT and BHA. Butylated hydroxytoluene (BHT) and butylated hydroxyanisol (BHA) are the primary antioxidants used in prepared and packaged foods. Typically, 15% of patients with chronic hives test positive to oral challenge with BHT. The use of chewing gum containing BHT was enough to induce hives in one patient.23
Sulfites. Like tartrazine, sulfites have been shown to induce asthma, hives, and angioedema in sensitive individuals.24 Sulfites are ubiquitous in foods and drugs. They are typically added to processed foods to prevent microbial spoilage and to keep them from browning or changing color. The earliest known use of sulfites was in the treatment of wines with sulfur dioxide by the Romans.
Sulfites are used to preserve many foods, especially dried fruit, prepared salads, items at salad bars, wine, and beer. Wine and beer drinkers typically consume up to 10 mg sulfites per day even with moderate drinking (two to three glasses of wine or beer). Sulfites are also used as preservatives in many pharmaceuticals. Sulfites can cause asthma as well as hives.
Normally, the enzyme sulfite oxidase metabolizes sulfites to safer sulfates, which are excreted in the urine. Those with a poorly functioning sulfoxidation system, however, have an increased ratio of sulfite to sulfate in their urine. Sulfite oxidase is dependent on the trace mineral molybdenum. Although most nutrition textbooks list molybdenum deficiency as uncommon, an Austrian study of 1,750 patients found that 41.5% were molybdenum deficient.25 Molybdenum deficiency may produce sulfite sensitivity. If so, supplementation (200 mcg per day) may be beneficial.
Food Emulsifiers and Stabilizers
Various compounds are used to emulsify and stabilize many commercial foods to ensure that the solids, oils, and liquids do not separate out. Most of the foods that contain these compounds contain other additives as well, such as preservatives, and dyes. Polysorbate in ice cream has been reported to induce hives, and vegetable gums such as acacia, gum arabic, tragacanth, quince, and carrageenan may also induce hives in susceptible individuals.4
Infections are a major cause of hives in children. In adults, immunological tolerance to many microorganisms apparently occurs owing to repeated antigen exposure. The role of bacteria, viruses, and yeast (Candida albicans) in hives is briefly reviewed below. Chronic trichomonas infections have also been found to cause hives.
Bacterial Infections
Bacterial infections contribute to hives in two major settings: in acute streptococcal tonsillitis in children and in chronic dental infections in adults. In the first setting, acute hives predominate, while in the second, chronic hives predominate.1
Viral Infections
Hepatitis B is the most frequent cause of virally induced hives. Hives have also been strongly linked to infectious mononucleosis and may develop several weeks before the disease is manifested clinically. The incidence of hives during infectious mononucleosis is 5%.
Candida
The association between Candida albicans and chronic hives has been suggested in several clinical studies. The proportion of patients with chronic hives who react positively to an immediate skin test with candida antigens is 19 to 81%, compared with 10 to 15% of people without hives.26,27 It appears that sensitivity to Candida albicans is an important factor in at least 25% of patients who have chronic hives. Approximately 70% of patients who have a positive skin reaction to Candida albicans also react to oral provocation tests using foods prepared with baker’s or brewer’s yeast.
Treatment with the drug nystatin has shown that elimination of the candida organism can achieve a cure in a number of sensitive individuals. However, in one study more patients (18 of 49) responded to nystatin plus a yeast-free diet than to nystatin alone (9 of 49). The yeast-free diet excluded breads, sausages, wine, beer, cider, grapes, raisins, vinegar, tomato, ketchup, pickles, and prepared foods containing yeast.27
Further support for the importance of diet can be found in a study of 36 patients with a positive skin prick test to candida. Only 3 patients became symptom-free from taking nystatin alone, compared with 23 who had diet therapy that included avoiding food allergies and yeast following the nystatin therapy.28 Obviously the best approach is to focus on both elimination of yeast and avoidance of food allergies.
In one study involving 236 cases of chronic hives, psychological factors (stressors) were reported to be the most frequent primary cause.29 Stress appears to play an important role by decreasing intestinal secretory IgA levels.
In one study of 15 patients who had chronic hives, relaxation therapy and hypnosis were shown to provide significant benefit.30 Patients were given an audiotape and asked to use the relaxation techniques described on the tape at home. At a follow-up examination 5 to 14 months after the initial session, six patients were free of hives and an additional seven reported improvement.
Therapeutic Considerations
The treatment goals in hives are straightforward: identify and eliminate the factors that are causing the release of histamine and other allergic compounds and decrease the body’s overreactivity. As noted above, allergy (to foods, food additives, and drugs) and stress are common causes of hives. The best diagnostic test (and therapy) appears to be an elimination diet.
The strictest elimination diets allow only water, lamb, rice, pears, and vegetables. Those foods most commonly associated with inducing hives (milk, eggs, chicken, fruits, nuts, and additives) should definitely be avoided. Foods containing vasoactive amines should be eliminated even if no direct allergy to them is noted. The primary foods to eliminate are cured meat, alcoholic beverages, cheese, chocolate, citrus fruits, and shellfish. Also, the importance of eliminating food additives cannot be overstated. If food additives do, in fact, increase the number of mast cells in the skin, they may also do the same in the small intestine, thereby greatly increasing the risk of developing a leaky gut.
In addition to an elimination diet, there are several other factors that can be helpful, such as ultraviolet light therapy, vitamin C, vitamin B12, fish oils, quercetin, and thyroid hormone. These factors are discussed below.
Ultraviolet light (from sunlight or tanning beds) has been shown to be of some benefit to patients with chronic hives.31,32 Both ultraviolet A (UVA), the non-burning type of sunlight, and ultraviolet B (UVB), the one that causes a sunburn, have been used. Patients with cold, cholinergic, and dermographic hives experience the greatest therapeutic response.
Vitamin C
High-dose vitamin C therapy may help hives (as well as other allergic conditions) by lowering histamine levels.33 Vitamin C prevents the secretion of histamine by white blood cells and increases the detoxification of histamine. Dosages of at least 2,000 mg per day appear necessary to produce these effects.
Vitamin B12
Although blood levels of vitamin B12 are normal in most patients with hives, additional B12 has been anecdotally reported to be of value in the treatment of acute and chronic hives.34,35
Fish Oils
Fish oils may be helpful. In one report, three patients with aspirin-induced urticaria experienced alleviation of symptoms following dietary supplementation with omega-3 fatty acids. All three patients had severe urticaria and asthma. They were on oral corticosteroid therapy (i.e., prednisone) but still experiencing some symptoms. After dietary supplementation with fish oils (3,000 mg EPA + DHA per day) for six to eight weeks, all three experienced resolution of symptoms, allowing discontinuation of systemic corticosteroid therapy. Symptoms relapsed after the dose of fish oil was reduced, indicating that higher dosages may have to be maintained to keep symptoms from reappearing.36 This is not surprising when we consider that the typical diet contains excessive amounts of pro-inflammatory omega-6 fatty acids such as arachidonic acid (see the chapter “Silent Inflammation”).
Quercetin
The flavonoid quercetin inhibits both the manufacture and the release of histamine and other allergic/inflammatory mediators by mast cells and basophils. Because of the poor absorption of quercetin, enzymatically modified isoquercitrin (EMIQ) may be a better choice. For more information, see the chapter “Hay Fever.”
The association of low thyroid function and hives has been established since the 1950s. A subset of patients with chronic hives respond to thyroid hormone, especially if they have antibodies to thyroid tissue.38,39 For example, one study evaluated a group of 624 patients with presumed idiopathic chronic hives and/or angioedema. Of these, 90 patients were found to have thyroid antibodies.39 Forty-six of these patients were treated with L-thyroxine therapy, and eight of them had a remission within four weeks of therapy. Four patients with high thyroid antibody titers repeatedly experienced worsening when therapy was discontinued and had repeated remissions when therapy with L-thyroxine was resumed. Although L-thyroxine did not always improve the patient’s urticaria or angioedema, when it did work the response was dramatic.
QUICK REVIEW
• Fundamental to the treatment of hives are recognition and control of causative factors.
• Drug reactions are the leading cause of hives in adults.
• In children, hives are usually due to foods, food additives, or infections.
• Antibiotics, including penicillin and related compounds, are the most common cause of drug-induced hives.
• Although any food can be the causative agent, the most common offenders are milk, fish, meat, eggs, beans, and nuts.
• Several food additives (e.g., tartrazine, benzoate) and aspirin augment production of a compound that increases the number of mast cells throughout the body.
• Elimination of food additives leads to tremendous improvement in chronic hives in children.
• Chronic candidiasis can be an underlying factor in cases of chronic hives.
• Vitamin C prevents the secretion of histamine by white blood cells and increases the breakdown of histamine.
• Fish oils have been shown to be helpful in resolving chronic hives in some people.
• The flavonoid quercetin inhibits both the manufacture and the release of histamine and other allergic/inflammatory mediators by mast cells and basophils.
• It is important to rule out low thyroid function or the presence of antibodies against the thyroid gland in cases of chronic hives.
TREATMENT SUMMARY
The first goal of treatment is to identify and control all of the factors that promote the hives. Acute hives is usually a self-limiting disease, especially once the eliciting agent has been removed or reduced. Chronic hives also responds to the removal of the eliciting agent.
An elimination diet is of utmost importance in the treatment of chronic hives (see the chapter “Food Allergy”). The diet should eliminate not only suspected allergens but also all food additives.
• A high-potency multiple vitamin and mineral formula as described in the chapter “Supplementary Measures”
• Key individual nutrients:
Vitamin B12 (methylcobalamin): 1,000 mcg per day
Vitamin C: 500 to 1,000 mg three times per day
Magnesium (bound to aspartate, citrate, fumarate, malate, or succinate): 200 to 300 mg three times per day
Vitamin D3: 2,000 to 4,000 IU per day (ideally, measure blood levels and adjust dosage accordingly)
• Fish oils: 3,000 mg EPA + DHA per day
• One of the following:
Grape seed extract (>95% procyanidolic oligomers): 100 to 300 mg per day
Pine bark extract (>95% procyanidolic oligomers): 100 to 300 mg per day
Quercetin: 200 to 400 mg 20 minutes before each meal; or EMIQ, 50–100 mg before each meal
Use relaxation techniques regularly. For example, listen to audiotaped relaxation programs.
Sunbathe for 15 to 20 minutes per day or use a UVA solarium, especially for chronic physical urticaria. Obviously, sunbathing is contraindicated in cases of solar urticaria.
