The basic pathophysiology of urticaria involves the release of inflammatory mediators from mast cells or basophilic leukocytes, both of which have high-affinity receptors for immunoglobulin E (Ig E).⁴ Although this inflammation classically occurs as a result of IgE–antigen complexes interacting with these cells, other non–IgE-mediated mechanisms are probably also critical in many patients with urticaria, including prostaglandins, leukotrienes, cytokines and chemokines. A growing body of evidence shows that at least 40% of patients with chronic idiopathic urticaria have clinically relevant functional autoantibodies to the high-affinity IgE receptor on basophils and mast cells. The term autoimmune urticaria is used for this subgroup of patients presenting with continuous ordinary urticaria.⁵

Pathophysiology

The signs and symptoms of acute and chronic urticaria show consistent patterns despite the many diverse etiologic and initiating factors (see later) that have been found, yet the pathogenesis cannot be entirely ascribed to any one mechanism. However, at present, it appears that mast cells and mast cell–dependent mediators play the most prominent role in the pathogenesis of urticaria.⁶

Mast cells are widely distributed throughout the body and are found primarily near small blood vessels, particularly in the skin. The granule-containing mast cell is a secretory cell capable of releasing both preformed and newly synthesized molecules, termed mediators. These mediators (listed in Box 211-1) play key roles in the pathogenesis of both immunologic and nonimmunologic inflammatory reactions. The three distinct sources of mediators are as follows:

• Preformed mediators, which are contained in the granules and are released immediately

• Secondarily formed mediators, which are generated immediately or within minutes by the interaction of the primary mediators and nearby cells and tissues

• Granule matrix–derived mediators, which are preformed but slowly dissociate from the granule after discharge and remain in the tissues for hours

BOX 211-1 Mast Cell–Derived Mediators

Preformed, rapidly released:

• Histamine

• Eosinophil chemotactic factors of anaphylaxis (ECF-A)

• Eosinophil chemotactic oligopeptides

• Neutrophil chemotactic factor

• Superoxide anions

• Exoglycosidases (β-hexosaminidase, β-δ-galactosidase,^* β-glucuronidase)

• Serotonin ^*

• Arylsulfatase A

Secondary or newly generated:

• Slow-reacting substances (SRS-A): leukotrienes (LT) C, LTD, LTE

• Prostaglandins

• Monohydroxyeicosatetraenoic acids (HETEs)

• Hydroperoxyeicosatetraenoic acids (HPETEs)

• Thromboxanes

• Platelet-activating factor (PAF)^*

• Prostaglandin-generating factor of anaphylaxis (PGF-A)

Preformed, granule-associated:

• Heparin

• Proteases (chymotrypsin/trypsin)

• Peroxidase ^*

• Superoxide dismutase ^*

• Arylsulfatase B

• Inflammatory factors of anaphylaxis (IFA)^*

Data from Keahey TM. The pathogenesis of urticaria. Dermatol Clin 1985;3:13-28.

^* Found in mast cells of species other than human.

The most common immunologic mechanism is mediated by IgE.

The early vascular changes appear to be the result of mast cell–dependent vasoactive mediators, particularly histamine and some secondarily generated end products of arachidonic acid metabolism. The wheal-and-flare reactions occur within minutes of initiation and last 30 to 60 minutes.

Histamine and other mediators can be released by other nonallergic mechanisms as well. Neuropeptides are known to cause mast cell degranulation and may well be involved in dermographism and emotional exacerbation of urticaria. The more prolonged and delayed reactions reflect leukocytic infiltration in response to the release of mast cell granule–derived chemotactic factors. These late-phase reactions develop over time and are characterized by erythema, edema, and induration beginning within 2 hours and lasting 12 to 24 hours. Leukocyte infiltration may contribute to the urticarial tissue response by inducing a second wave of mast cell activation or by releasing toxic lysosomal enzymes and mediators characteristic of the type of infiltrating cell.

The actual events initiated by the mediators also depend on the tissues into which they are released. For example, the release of histamine into the skin primarily produces pruritus and vascular permeability, whereas histamine release into the lungs may induce bronchospasm.

Helicobacter pylori has been implicated as a causative agent in chronic urticaria. However, two reviews of the trials showing the benefit of H. pylori eradication in patients with chronic urticaria have arrived at conflicting conclusions, one saying the benefit is weak and another that it is statistically significant.^7,⁸ Including testing for H. pylori seems reasonable; if positive, a decision to proceed with this management should be considered carefully in the context of relative harms/burdens and benefits as well as patient values and preferences.

Causes of Urticaria

Fundamental to the treatment of urticaria is the recognition and control of causative factors.

Physical Urticarias

Urticaria can be produced as a result of reactions to various physical stimuli. The most common forms of physical urticarias are dermographic, cholinergic, and cold urticarias (Table 211-1). These are briefly described here. Less common types of physical urticarias or angioedema are as follows²:

TABLE 211-1 Clinical Aspects of Physical Urticarias

Autoimmune Urticaria

Although much remains unknown regarding the specific pathophysiologic mechanisms underlying most cases of chronic urticaria, a minority seem to have an autoimmune basis. Research has discovered that a significant percentage of patients previously categorized as having idiopathic urticaria have autoantibodies to IgE or the FcεRIα subunit of the high-affinity IgE mast cell receptor.¹⁰ Studies have identified these autoantibodies in 24% to 76% of patients with chronic urticaria. From a clinical perspective, these patients tend to have a somewhat more severe, prolonged course of disease. Middle-aged women are disproportionately represented in the population of patients with urticaria, and higher rates of autoimmunity in this group, particularly for thyroid disease, may account for this preponderance. Thyroid autoantibodies are found more frequently in patients with these IgE receptor autoantibodies (see later discussion of thyroid).

Autoimmune diseases are well known to be associated with bowel permeabilities.¹¹^–¹⁴ Because subclinical impairments of small bowel enterocyte function have been postulated to induce a higher sensitivity to histamine in the digestive tract,¹⁵ it makes sense from a naturopathic standpoint to treat overt and subclinical digestive system permeabilities to decrease systemic inflammatory responses to endotoxins in these autoimmune conditions.

Drugs

Drugs make up the leading cause of urticarial reactions in adults. In children, the reactions are usually due to foods, food additives, or infections.²

Most drugs are composed of small molecules incapable of inducing antigenic/allergenic activity on their own. Typically, they act as haptens that bind to endogenous macromolecules, ultimately causing the production of hapten-specific antibodies. Alternatively, drugs can interact directly with mast cells to induce degranulation. Many drugs have been shown to produce urticaria. Box 211-2 provides a condensed list.¹⁶ The two most common urticaria-inducing drugs, penicillin and aspirin, are briefly discussed here.

BOX 211-2 Drugs That Can Cause Urticaria

• Acetylsalicylic acid

• Corticotropin (adrenocorticotropic hormone)

• Eucalyptus

• Fluorides

• Gold

• Griseofulvin (cold urticaria)

• Paraaminosalicylic acid

• Poliomyelitis vaccine

• Potassium sulfocyanate

Data from Andrews GC. Andrews’ diseases of the skin, ed 7. Philadelphia: WB Saunders, 1982:131.

Penicillin

Antibiotics, including penicillin and related compounds, are the most common cause of drug-induced urticaria. The allergenicity of penicillin in the general population is thought to be at least 10%. Nearly 25% of these individuals display urticaria, angioedema, or anaphylaxis on ingestion of penicillin.^2,¹⁷

An important characteristic of penicillin is that it cannot be destroyed by boiling or steam distillation. This is a problem because penicillin and related contaminants can exist undetected in foods. To what degree penicillin in the food supply contributes to urticarial reactions is not known. However, urticaria and anaphylactic symptoms have been traced to penicillin in milk,¹⁸ soft drinks,¹⁹ and frozen dinners.²⁰ In one study of 245 patients with chronic urticaria, 24% had positive skin test results and 12% had positive results on the radioallergosorbent test for penicillin sensitivity.²¹ Of those 42 patients sensitive to penicillin, 22 experienced clinical improvement with a dairy-free diet, whereas only 2 out of 40 patients with negative skin test results experienced improvement with the same diet. This study would seem to provide indirect evidence of the importance of penicillin in the food supply in urticaria.

In an attempt to provide direct evidence, penicillin-contaminated pork was given to penicillin-allergic volunteers. No significant reactions were noted other than transient pruritus in two volunteers.²² Penicillin in milk appears to be more allergenic than penicillin in meat.¹⁸ Presumably the reason is that penicillin can be degraded into more allergenic compounds in the presence of carbohydrate and metals, suggesting that penicillin in milk may be more allergenic than artificially contaminated meat.¹⁸

Aspirin and Nonsteroidal Antiinflammatory Drugs

Urticaria is a more common indicator of aspirin sensitivity than is asthma (see Chapter 147). The incidence of aspirin sensitivity in patients with chronic urticaria is at least 20 times greater than that in normal controls.²³^–²⁷ Studies (summarized in Table 211-2)²⁸^–⁵⁷ have demonstrated that 2% to 67% of patients with chronic urticaria are sensitive to aspirin.

TABLE 211-2 Provocation Tests with Food Additives in Chronic Urticaria

Aspirin inhibition of cyclooxygenase apparently shunts eicosanoid metabolism toward leukotriene synthesis, thereby increasing smooth muscle contraction and vascular permeability. In addition, aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) have been shown to increase gut permeability dramatically and may alter the normal handling of antigens.^53,⁵⁸ NSAIDs are also known be associated with prolonged and more pronounced autoreactivity in urticaria.⁵⁷ The daily administration of 650 mg of aspirin for 3 weeks has been shown to desensitize patients with urticaria and aspirin sensitivity. While taking the aspirin, patients also became nonresponsive to foods to which they usually reacted, such as pineapple, milk, egg, cheese, fish, chocolate, pork, strawberries, and plums.⁵⁹ Others have noted this effect in patients with asthma, but they have also found that the effect disappears within 9 days after the treatment is stopped, suggesting the loss of effect or a possible placebo response.⁶⁰