REVIEWS

Adrenergic urticaria: Review of the literature and proposed mechanism

Sara R. Hogan, MHS,a Joshua Mandrell, MD,b and David Eilers, MDc Maywood, Illinois
Adrenergic urticaria is a rare type of stress-induced physical urticaria characterized by transient outbreaks of red papules surrounded by halos of hypopigmented, vasoconstricted skin. First described in 1985, there are 10 reported cases of adrenergic urticaria in the English-language medical literature. Episodes are caused by various triggers, including emotional upset, coffee, and chocolate, during which serum catecholamines and IgE are elevated, whereas histamine and serotonin levels remain within normal limits. The precise mechanisms leading to the pathogenesis of adrenergic urticaria have yet to be elucidated. Diagnosis can be made by intradermal injection of epinephrine or norepinephrine, which reproduces the characteristic rash, or by clinical observation. Trigger avoidance and oral propranolol are currently the best known treatments for adrenergic urticaria. Nonspecic therapies, including tranquilizers and antihistamines, may also ease symptoms. This article explores the pathophysiology of adrenergic urticaria and proposes a mechanism by which propranolol treats the condition. ( J Am Acad Dermatol 2014;70:763-6.) Key words: adrenergic; adrenoceptor; beta-adrenergic antagonist; propranolol; psychocutaneous; urticaria.

rticaria, a vascular reaction of the skin characterized by wheals, has idiopathic, immunologic, and nonimmunologic causes. The diverse subcategory of physical urticaria contains both common (cholinergic, cold, delayed pressure, dematographic) and uncommon (aquagenic, vibratory, solar, adrenergic) forms. First described in 1985 by Shelley and Shelley,1 adrenergic urticaria is exceedingly rare and distinguished from the more common cholinergic urticaria by the presence of pale, vasoconstricted skin surrounding small red or pink wheals (Fig 1).2 Known triggers include trauma, emotional upset, coffee, chocolate, and ginger.1,2 Associated clinical features include wheezing, heart palpitations, tachypnea, paraesthesias, and malaise.1,2 Diagnosis of adrenergic urticaria is made by intradermal injection of 5 to 15 ng of epinephrine or 3 to 10 ng of norepinephrine in
From the Loyola University Chicago Stritch School of Medicinea; Division of Dermatology, Loyola University Medical Centerb; and Section of Dermatology, Edward Hines, Jr Veterans Affairs Hospital.c Funding sources: None. Conflicts of interest: None declared. Accepted for publication October 31, 2013. Reprint requests: Sara R. Hogan, MHS, Loyola University Chicago Stritch School of Medicine, 2160 S First Ave, Maywood, IL 61053. E-mail: shogan2@lumc.edu. Published online December 27, 2013. 0190-9622/$36.00 2013 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2013.10.062

0.02 mL of saline, which reproduces the characteristic rash, or by a clinically observed response to propranolol, which resolves the rash and suppresses future episodes.1,2 Cholinergic urticaria, by comparison, consists of small papules surrounded by large, red flares that erupt in response to stress, exercise, diaphoresis, and increased body temperature.3 It is diagnosed via intradermal injection of nicotine, acetylcholine, or methacholine, which also recreates the specific rash.3 To our knowledge, 10 cases of adrenergic urticaria have been reported in the medical literature.1,2,4-10,* Our experience with 2 patients with classic clinical lesions and complete response to propranolol suggests this condition is underreported. There exists some overlap of symptoms in adrenergic and cholinergic urticaria. Patients with either diagnosis describe an increase in body temperature, likely because of increased catecholamines or perceived body temperature elevation with sweating. Propranolol, the only known effective therapy for adrenergic urticaria, has also been found to be
*Haustein describes one case of adrenergic pruritus, which presents in a manner similar to adrenergic urticaria, but without characteristic lesions.4 Whether adrenergic pruritus is a subset of adrenergic urticaria or is part of a disease spectrum that includes adrenergic urticaria remains to be seen. This case is not included in our calculation. We do include a case of what we consider to be combined cholinergic urticaria and adrenergic urticaria because of the clinical description and reproduction of hives with both norepinephrine and acetylcholine intradermal injections.8

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effective in some cases of cholinergic urticaria.8,11,12 adrenergic urticaria is associated with increased We suspect that many cases of adrenergic urticaria serum catecholamine levels. The characteristic halo have been included within the diagnosis of cholinhives likely result from catecholamine-induced ergic urticaria, explaining propranolol effectiveness. peripheral vasoconstriction around erythematous This is possibly because of both similarities in prewheals that are consistent with more common types sentation and limitations of current diagnostic of urticaria. One patient with adrenergic urticaria methods. Methacholine testing for cholinergic reported in the literature had an associated diagnosis urticaria has been shown to of vitiligo, a condition be only 30% to 50% sensitive, where patients have been CAPSULE SUMMARY whereas the sensitivity found to have increased cateand specificity of norepicholamine synthesis with Adrenergic urticaria is a rare form of nephrine testing for adrenelevated serum levels of stress-induced physical urticaria. ergic urticaria is unknown.11 norepinephrine.1,2,13Another This article builds on the existing patient experienced adrenNotwithstanding shared clinliterature on adrenergic urticaria to ergic urticarial eruptions ical features, we maintain propose mechanisms of only during episodes of that the pathophysiology is pathophysiology and pharmacologic hypoglycemia, which are distinct for both adrenergic treatment. associated with intense cateand cholinergic urticaria. cholamine release.14,15 The Skin biopsy specimens of Adrenergic urticaria may not be as rare adrenergic urticaria demonhalo hives of adrenergic urtias widely believed, and can be strate edematous tissues with caria also bear morphologic misdiagnosed as the more common nonspecic, inammatory resemblance to pruritic urticholinergic urticaria. inltrate, and electron microcarial papules and plaques of scopy shows mast cell pregnancy, which develop degranulation, leading to the currently accepted near term when catecholamines are high, then theory that pathogenesis is regulated by mast regress after birth when levels return to normal.1,2 1,2,4,9 cells. For brief review, mast cells contain a The strongest support for a catecholaminevariety of receptors, including adrenergic (alpha, mediated pathogenesis of adrenergic urticaria is the beta-2), histaminergic (H-1 and H-2), and highsuccessful use of oral propranolol, a nonselective affinity IgE (FcRI) types. Activation of receptors beta-adrenergic antagonist, as treatment. In all induces, via different signaling cascades, the release reported cases, propranolol, administered in doses of preformed mediators (serotonin, leukotrienes, up to 40 mg 3 times daily, was the most effective prostaglandins, proteases) that contribute to urticaria therapy for adrenergic urticaria and its discontinuaformation.1,4 Laboratory tests performed on patients tion resulted in resurgence of symptoms within 72 hours.1,2,4-10 An exception is 1 patient with coexisduring episodes of adrenergic urticaria show elevated serum norepinephrine, epinephrine, and tent rheumatoid arthritis who initially responded to total catecholamines, and elevated serum IgE (not propranolol, but then failed to respond with further seen in all cases); serum histamine and serotonin treatment.9 Selective beta-1-adrenergic receptor 1,2,4-6,10 levels, however, remain within normal limits. blockers, such as atenolol and bisoprolol, are not In most urticarias, mast cells are activated through IgE receptors and histamine acts as the most important chemical mediator. The observed inconsistent relationship between serum IgE and histamine levels during episodes suggests other mast cell receptors and mediators are responsible for adrenergic urticaria. A mechanism similar to the one we suspect in adrenergic urticaria is observed in cholinergic urticaria, wherein efferent cholinergic nerves of the sympathetic nervous system release acetylcholine directly onto mast cells to initiate cell degranulation (although the precise steps between the liberation of acetylcholine and the appearance of urticaria are also unknown).1 Fig 1. Adrenergic urticaria. Characteristic red urticarial The underlying mechanisms are not entirely papules surrounded by blanched haloes on the right dened, but the existing literature indicates that forearm of authors patient.
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Fig 2. Adrenergic urticaria. Proposed mechanisms of pathophysiology and propranolol action. AMYG, Amygdalae; AU, adrenergic urticaria; BP, blood pressure; Epi, epinephrine; HR, heart rate; LC, locus coeruleus; NorE, norepinephrine.

effective treatment, though tolazoline, a nonselective competitive alpha-adrenergic receptor antagonist, was shown in 1 patient to block adrenergic urticaria.1,2,4 First-generation antihistamines, ketotifen (a second-generation antihistamine and mast cell stabilizer not available in the United States), and clemastine (an antihistamine and anticholinergic capable of crossing the blood-brain barrier) are also noted to provide some symptomatic relief.1,2,4 Although propranolol is remarkably effective, the mechanism by which it works in treatment of adrenergic urticaria is not well understood. Intradermal injections of propranolol with norepinephrine block halo hive development, whereas injections of atropine with norepinephrine do not, suggesting that propranolol acts at mast cell adrenergic receptors.4 This, however, challenges known mechanisms of mast cell degranulation mast cell beta-2-receptors activate adenylate cyclase, which increase cyclic adenosine monophosphate (cAMP) levels, and prevent degranulation; alpha-2-receptors, in contrast, decrease cAMP levels, and along with alpha-1-receptors, which increase intracellular calcium, facilitate degranulation. A therapy that blocks alpha, but not beta-2receptors, would be the more logical means of preventing degranulation and urticaria. Blockade of beta-adrenoreceptors would even predispose individuals to urticaria because of unopposed alpha-receptor stimulation. We propose that propranolol acts centrally to reduce sympathetic drive,

which in turn reduces peripheral alpha-adrenergic receptor activation of mast cell degranulation. The overwhelming majority of patients with adrenergic urticaria documented in the literature were noted to have a history of emotional lability or psychiatric diagnosis, and to experience considerable stress and/or anxiety at the time of their episodes.1,4,5,7,9,10 Stress causes the locus coeruleus in the brainstem to release norepinephrine via neuronal projections into the limbic system, where it acts on beta-1-adrenergic receptors of the amygdalae, which in turn stimulate sympathetic activation and catecholamine release into the bloodstream (Fig 2).16-18 Multiple studies show that chronic stress causes norepinephrine-mediated overactivation of the amygdalae beta-1-adrenergic receptors, resulting in excessive emotional and sympathetic response to learned stressors.19-21 Propranolol has both labeled and unlabeled uses in the treatment of anxiety, acute panic, and posttraumatic stress disorder. Compared with other beta-antagonists, such as atenolol and bisoprolol, which are less effective in the treatment of adrenergic urticaria, propranolol is extremely lipophilic and readily penetrates the blood-brain barrier. The mechanism of action of propranolol at central beta-adrenoreceptors, although not yet fully understood, likely involves blockade of both acute activation of the limbic system during emotional arousal and long-term development of associations between stressful stimuli and exaggerated sympathetic response (Fig 2).22

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Evidence supporting the use of propranolol in the treatment of other forms of urticaria is mixed. Propranolol has been documented to provide relief in some refractory cases of cholinergic urticaria, which we believe is effective because those cases contain an adrenergic component, in part or in full.2,8 Given these findings, we propose that the diagnosis of adrenergic urticaria does not require norepinephrine intradermal testing and can be made based on both clinical findings and complete response to oral propranolol. Undoubtedly, further research into the pathophysiology of adrenergic urticaria will help explain this interesting physical urticaria and confirm the mechanism by which propranolol is effective.
The authors would like to thank Karie Scrogin, PhD, in the Department of Molecular Pharmacology and Therapeutics at Loyola University Chicago Stritch School of Medicine for her valuable contributions with discussions of this article.

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