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Angioedema

Angioedema Overview Definition Etiology Risk Factors Signs and Symptoms Differential Diagnosis Diagnosis Physical Examination Laboratory Tests Pathology/Pathophysiology Treatment Options Treatment Strategy Drug Therapies Complementary and Alternative Therapies Patient Monitoring Other Considerations Prevention Complications/Sequelae Prognosis Pregnancy References
Overview Definition

Angioedema is a well-circumscribed, nonpitting swelling of the subcutaneous tissues of the skin and mucosa, which is typically nonpruritic. Sites of involvement include eyelids, lips, tongue, larynx, palms, soles, genitalia, and gastrointestinal tract. The condition results from the activity of inflammatory mediators that cause dilation and enhanced permeability of venules and capillaries. Sources of these inflammatory mediators include:

  • Increased activity of the kinin pathway 
  • Abnormalities of complement metabolism 
  • Activation of mast cells in the dermis 

The latter is typically associated with urticaria and pruritis. Angioedema may be distinguished clinically from other types of edema (e.g., congestive heart failure, hypoalbuminemia) by the rapidity of onset (minutes to hours) and by a distribution that is asymmetric and not localized to dependent areas of the body.

Both acquired and inherited forms of the illness exist. Acquired angioedema (AAE) may be acute or chronic (longer than 6 weeks in duration) whereas hereditary angioedema (HAE) is typically chronic and recurrent. Acute AAE is reported to occur in approximately 10% to 20% of the population, while HAE is reported to occur in approximately 0.01% of the population. However, the frequency of angioedema is likely higher than reported because of the self-limited nature of most attacks.

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Etiology

HAE

Hereditary angioedema is an autosomal dominant disorder caused by abnormalities in the amount or function of C1 inhibitor (C1 INH)—a plasma protein that degrades the first component of the complement cascade, thereby preventing excessive complement activation.

  • Type I HAE results from insufficient production of C1 INH, leading to decreased or absent levels of this protein (85% of cases). It is the most commonly identified genetic defect of the complement system. 
  • Type II HAE is caused by a dysfunctional C1 INH protein; C1 INH levels are normal or elevated. 

AAE

Acute AAE has a number of causes including:

  • IgE-mediated mast cell activation due to exposure to: various foods (e.g., fish, nuts); naturally occurring dyes (e.g., annatto, carmine); contact lens solution (papain enzyme—also found in meat tenderizer and used to clarify beer); radiocontrast dyes (may also lead to angioedema through nonimmunologic mechanisms as well); insect venom; pollen; cold (e.g., in association with cold-induced urticaria)
  • Treatment with angiotensin-converting enzyme (ACE) inhibitors, which results in decreased degradation of bradykinin, a potent vasodilator. This adverse drug reaction occurs in 0.1% to 0.2% of patients, generally within 1 hour to 1 week of exposure, but possibly months to years following start of this medication; lingual swelling common 
  • Other drugs (e.g., nonsteroidal anti-inflammatory drugs including aspirin and indomethacin) 
  • Idiopathic 

Chronic and recurrent AAE results from an acquired deficiency of C1 INH. Although both sexes and all ages may be affected, this form of angioedema typically occurs in women aged 40 to 50 years. The average duration of the illness is 5 years, though cases lasting up to 20 years have been reported. Specific causes of chronic AAE include:

  • B-cell lymphoproliferative disorders (e.g., leukemia, Hodgkin's) that may be associated with excessive complement activation resulting in consumption of C1 INH (AAE may precede diagnosis of one of these disorders.) 
  • Benign oligoclonal or monocolonal gammopathies with autoantibodies to C1 INH—rare 
  • Connective tissue disorders (primarily SLE)
  • Angioedema-eosinophilia syndrome (also known as episodic with eosinophilia)— rare, non-life-threatening 
  • Idiopathic 

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Risk Factors
  • Trauma, even minor
  • Sudden temperature change
  • Intense physical exercise
  • Dental procedures/oropharyngeal instrumentation 
  • Stress/anxiety
  • Puberty and menses—increased disease activity
  • Anaphylaxis
  • ACE inhibitors—avoid in people with history of angioedema, regardless of cause
  • Cystic ovaries—women with HAE often have cystic ovaries 

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Signs and Symptoms
  • Subcutaneous and submucosal edema—burning, painful, tensely swollen, typically nonpruritic; progresses in 24 to 48 hours, regresses in <72 hours
  • Dyspnea, hoarseness
  • Throat tightness
  • Upper airway—buccal, lingual, then oropharyngeal edema that does not extend below the larynx; airway obstruction
  • Gastrointestinal—anorexia, vomiting, abdominal pain, diarrhea with resolution; more common with HAE
  • Cutaneous lesions—extremities, face, genitalia most common; mottling or faint rash
  • Conjunctival or periorbital edema
  • Angioedema-eosinophilia syndrome—urticaria, pruritus, fever, myalgias, oliguria, weight gain, leukocytosis

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Differential Diagnosis
  • Anaphylaxis
  • Urticaria
  • Periorbital cellulitis
  • Contact sensitivities
  • Atopic dermatitis 
  • Cutaneous or systemic mastocytosis
  • Alcoholism
  • Foreign body in airway 
  • Myocardial infarction 
  • Brain stem infarct or ischemia 

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Diagnosis Physical Examination

Tight, swollen skin may be apparent at site. Abdominal rigidity or guarding occurs with gastrointestinal involvement.

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Laboratory Tests
  • Urinalysis to check for increased excretion of histamine

HAE Type I

Serum C4 is chronically, profoundly low (best diagnostic test). If low, the following tests should be performed:

  • C1 INH assay—low levels or absence confirms diagnosis 
  • 15% to 20% of patients will have normal or increased C1 INH levels; in these cases functional assays should be decreased 
  • Other complement proteins: C2 low (especially during an attack), C1, C3, and C5 normal or near normal

HAE Type II

  • C1 INH decreased function 
  • Antigenic C1 INH protein is normal or elevated

AAE

  • C1 protein depression—distinguishes it from HAE 
  • Anti-C1 antibodies
  • Diminished C1 INH accompanied by low levels of C1q, CH50, C1, C2, C3, and C4 activity 
  • Angioedema-eosinophilia syndrome—elevated WBC count, predominance of eosinophils; skin biopsy reveals perivascular CD4+ T lymphocyte infiltration

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Pathology/Pathophysiology

HAE

  • Edema of bowel wall, luminal narrowing and possibly obstruction 

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Treatment Options Treatment Strategy

During an attack, the first priority is to ensure patency of airway; CPR and transportation to an emergency facility may be necessary. Remove all known or potentially offending agents. In the case of laryngeal edema, tracheostomy should be performed. Between attacks, some patients require chronic maintenance therapy, while others with infrequent episodes may elect to manage attacks as they arise and avoid toxic medications. Most attacks abate within 4 days whether or not medication is administered. Children are more responsive to treatment with epinephrine, corticosteroids, or antihistamines than are adults. Following stabilization and treatment of acute situation, all possible etiologic factors (e.g., food, drugs) should be identified and eliminated. Long-term management may require referral to an allergist, dermatologist, or another specialist.

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Drug Therapies

HAE

  • Epinephrine—for acute attacks (0.3 mL 1:1000); generally poor response; self-administration kits
  • Fresh frozen plasma transfusions—necessary for acute, life-threatening attacks; may be used as prophylaxis as well as before provocation (2 units 12 to 24 hours before exposure) 
  • Systemic glucocorticoids 
  • Vapor-heated infusions of C1 INH inhibitor—used in acute, life-threatening attacks although may be used as prophylaxis as well; significantly reduces abdomen and genitourinary tract symptoms and severity of edema; not widely available 
  • Androgens (danazol, 200 to 600 mg/day, or stanozolol, 2 to 5 mg/day)—stimulate C1 INH synthesis by the normal gene, causing C4 level to return to normal; for chronic maintenance therapy or may be used 1 week prior to a procedure as prophylaxis; titrate dose to lowest effective level; potential side effects include menstrual irregularities, weight gain, muscle cramps, myalgias, and elevated transaminases. Should not be used in children or during pregnancy. 
  • Fibrinolysis inhibitors (e.g., aminocaproic acid, tranexamic acid)—inhibit plasmin, which may activate C1; replace androgens for children and during pregnancy; can be used for short- and long-term prophylaxis

AAE

  • Epinephrine (see above for dosing) or antihistamines (e.g., hydroxyzine)—for acute attacks
  • Plasmapheresis; immunosuppressive agents 
  • Glucocorticoids—for idiopathic; angioedema-eosinophilia syndrome 
  • Androgens (see above for dosing and side effects)—for lymphoproliferative disorders, connective tissue disorders, autoimmunities

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Complementary and Alternative Therapies

Angioedema may respond favorably to long-term nutritional and herbal support as prophylaxis. In addition, it may be effective to use herbs and supplements to alleviate mild symptoms, particularly for chronic and recurrent forms of angioedema. In an emergency setting, protection of airway remains the top priority and no new substances, including herbs or supplements, should be introduced until the person is stable. Dietary intervention, such as the elimination of inciting foods or food additives, may help reduce or eliminate recurrent angioedema (Farnam and Grant 1985; Paganelli et al. 1991). If used prophylactically, homeopathic remedies may be useful in alleviating mild symptoms and reducing the frequency and severity of episodes.

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Nutrition

Oligoallergenic Diet and Other General Dietary Guidelines

As outlined in the section on Etiology, certain foods and food additives may elicit angioedema in susceptible individuals. In addition, both immunologic and nonimmunologic mechanisms have been implicated (Farnam and Grant 1985).

  • Most food-related angioedema occurs from an IgE-mediated reaction following ingestion of common inciting agents such as seafood, nuts, legumes (e.g., peanuts), eggs, chocolate, milk, and berries.
  • Direct mast cell degranulation and release of histamine or other mediators may occur with certain foods, including egg whites, citrus fruits, and strawberries. 
  • Food additives such as tartrazine (FD&C yellow dye No. 5) may cross-react with specific drugs (namely aspirin and other nonsteroidal anti-inflammatory medications) possibly leading to angioedema.
  • Sulfites, used as antioxidant or freshening agents (preservatives) in many foods and beverages, can cause angioedema in sensitive individuals. 

A detailed history of foods or food preservatives recently added to the diet (including substances such as gum, toothpaste, vitamins, or laxatives) is important in the workup of those with suspected food sensitivities. Most physicians agree that certain clinical and laboratory tests are needed before a patient can be diagnosed with chronic angioedema. These tests include food diaries, skin testing, elimination diets, and double-blind food challenges with suspicious foods (Farnam and Grant 1985). Elimination diets remove suspected foods or food additives from the diet and symptoms are monitored for improvement. Special care must be taken with provocation or reintroduction studies in patients with prior or potential anaphylactic reactions.

As outlined in the section on Signs and Symptoms, persons with urticaria and angioedema may have variability in presentation and treatment response. The finding that some patients have increased gastrointestinal permeability to food antigens may help identify a subgroup of angioedemic patients who could benefit from an oligoallergenic diet. Gastrointestinal symptoms, more common with HAE, include anorexia, abdominal pain, nausea, vomiting, and diarrhea. Elucidating specific pathophysiologic mechanisms in select groups of patients with different features may help guide future research and treatments (Paganelli et al. 1991).

Flavonoids

  • Quercetin (a naturally occurring flavonoid), 200 to 400 mg tid before meals, has been used clinically for prevention of allergic reactions such as angioedema because of its ability to modify IgE-mediated reactions by inhibiting mast cell degranulation.
  • Citrus-based flavonoids, such as rutin, hesperidin, quercitrin (converted to quercetin in the gastrointestinal tract), and naringin (found in grapefruit juice), should be avoided in the case of citrus sensitivity and when taking calcium channel-blockers because the natural substances tend to increase bioavailability of this class of drugs (Pizzorno and Murray 1999).

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Herbs
  • Bromelain (a proteolytic enzyme derived from pineapple [Ananas comosus]), 80 to 320 mg tid, has been used clinically because of its ability to reduce inflammation by reducing plasma kininogen, thereby inhibiting production of kinins (Pizzorno and Murray 1999). Some recommend use with turmeric (Curcuma longa, 250 to 500 mg tid), which may potentiate the effects. 
  • Devil's Claw Root. Although not studied for angioedema in particular, Devil's claw root (Harpagophytum procumbens) is approved by the Commission E for use as an anti-inflammatory (which may include allergy-based inflammation) (Blumenthal et al. 2000). 
  • Ginkgo biloba extract, 120 mg bid of extract standardized to 24% ginkgo flavone glycosides and 6% terpenes, has been used clinically as an anti-allergenic agent and anti-inflammatory. Monitor carefully with concurrent use of anticoagulants (Pizzorno and Murray 1999). In rare instances, ginkgo may cause an allergic reaction, generally confined to the skin (Blumenthal et al. 2000). 
  • Goldenseal (Hydrastis canadensis), 500 to 2000 mg tid, has been used clinically for food allergies.
  • Licorice root (Glycyrrhiza glabra) is recognized by the World Health Organization for its traditional use as an anti-inflammatory to treat allergic reactions. Licorice root is also thought of as an herb that may help normalize immune function (Blumenthal et al. 2000).

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Homeopathy

Apis has been used traditionally for urticaria and angioedema and may be useful for acute treatment and for prevention of chronic, recurrent cases of these conditions. Because angioedema has a wide variety of presentations and causes, an experienced homeopath should be consulted to determine the correct remedy and potency for each individual case.

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Acupuncture

Although not confirmed by scientific literature, some clinicians report that acupuncture may help reestablish overall balance of immune system, thereby lessening the frequency and severity of allergic responses such as angioedema.

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Patient Monitoring

Closely monitor patients for airway obstruction during attacks.

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Other Considerations Prevention
  • Wear bracelet identifying condition 
  • Eliminate known triggers once identified (e.g., ACE inhibitors, foods, vibratory stimuli); allergy testing with a trained specialist may aid in this identification

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Complications/Sequelae
  • Laryngeal edema—major cause of mortality
  • May progress to anaphylaxis

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Prognosis
  • Upper airway obstruction—30% mortality rate
  • Idiopathic, autoimmune, episodic with eosinophilia—good prognosis

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Pregnancy
  • Hereditary—fewer attacks during pregnancy
  • Avoid androgens; use fibrinolysis inhibitors for prophylaxis 

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References

Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine: Expanded Commission E Monographs. Newton, Mass: Integrative Medicine Communications; 2000:84-87, 160-169, 233-239.

Cicardi M, Bergamaschini L, Cugno M, et al. Pathogenic and clinical aspects of C1 inhibitor deficiency. Immunobiology. 1998;199(2):366-376.

Farnam J, Grant JA. Angioedema. Dermatol Clin. 1985;3(1):85-95.

Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998.

Greaves M, Lawlor F. Angioedema: manifestations and management. J Am Acad Dermatol. 1991;25(1 pt 2):155-161.

Kumar SA, Martin BL. Urticaria and angioedema: diagnostic and treatment considerations. J Am Osteopath Assoc. 1999;99:(3 suppl):S1-S4.

Middleton E, ed. Allergy: Principles and Practice. 5th ed. St. Louis, Mo: Mosby-Year Book; 1998.

Paganelli R, Fagiolo U, Cancian M, Scala E. Intestinal permeability in patients with chronic urticaria-angioedema with and without arthralgia.Ann Allergy. 1991;66(2):181-184.

Pizzorno JE Jr, Murray MT. Textbook of Natural Medicine. Vol. 1. 2nd ed. New York, NY: Churchill Livingstone; 1999:619-623, 746-749, 751-759.

Shah UK, Jacobs IN. Pediatric angioedema: ten years' experience. Arch Otolaryngol Head Neck Surg. 1999;125(7):791-795.

Wagner WO. Angioedema: frightening and frustrating. Cleve Clin J Med. 1999;66(4):203-205.

Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med. 1996;334(25):1630-1634.

Zuraw BL. Urticaria, angioedema, and autoimmunity. Clin Lab Med. 1997;17(3):559-569.

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