ANGIOEDEMA/ HEREDITARY ANGIOEDEMA/ ACQUIRED ANGIOEDEMA/
DRUG-INDUCED ANGIOEDEMA/ CHRONIC IDIOPATHIC ANGIOEDEMA
Angioedema refers to massive localized edema which results in localized, temporary disfigurement without associated pruritus. Both the skin and visceral organs may be involved. This phenomenon is commonly the result of an acute allergic reaction to a dietary or environmental allergen or a medication. Rarely, some cases occur secondary to abnormalities of the complement system and will be discussed below.
HEREDITARY ANGIOEDEMA (HAE)
This is an autosomal dominant disorder with a frequency of 1:10,000 to 1:150,000 persons, although approximately 25% occur as spontaneous genetic mutations in persons without a family history. Attacks are characterized by edema of the skin (nonpitting and lacking associated pruritus) or visceral organs most commonly the upper respiratory and gastrointestinal tracts. Attacks may be triggered by trauma, medical procedures, emotional stress, menstruation, birth control pills, or certain medications, although a trigger is not always identified. Infection with Helicobacter pylori is also a potential trigger of chronic recurrent attacks, and appropriate testing for this infection should be done in all recurrent and refractory cases. Attacks often last 2-5 days. Gastrointestinal tract involvement is heralded by anorexia, vomiting, varying degrees of abdominal pain (may mimic a surgical abdomen), ascites, and diarrhea. Respiratory involvement may affect the nasal mucosa, sinus mucosa or larynx. Laryngeal involvement may result in acute upper airway obstruction and necessitate tracheostomy. The lower components of the pulmonary system are never involved.
This disease results when C1-inhibitor (C1-INH) levels are inadequate (type 1 disease) or when adequate levels of a dysfunctional mutant variant of this protein are produced (type 2 disease). When C1-INH function is impaired (due to either low levels or dysfunctional C1-INH), then activation of the first component of the complement system occurs without regulation.
There are three types of disease. Types 1 and 2 occur in all races and without a sexual predominance. The third type of disease has been described only in women. Type 1 disease is more frequent (80 to 85% of cases) and is the result of decreased C1 esterase inhibitor (C1-INH) production. Type 2 disease is the result of production of normal or even elevated levels of a defective C1-INH. There is an association with autoimmune disorders mostly in the female portion of this patient population.
When the diagnosis is suspected in an asymptomatic individual, measurement of the serum C1-INH activity should be performed. If this is low further testing is needed in the form of quantitative C1-INH and C1q levels. The C1-INH level distinguishes the type of disease with a low level in type 1, and a normal or elevated level in type 2. The C1q level should be normal and thus serves to distinguish between HAE and acquired angioedema in which the C1q level and the C1-INH activity are low. During an acute flare, C2 and C4 levels are severely depressed and at times undetectable. Heparinization spuriously elevates the C1-INH activity; therefore, the test should be repeated one week after discontinuation of heparin therapy to confirm the results. Type 3 disease occurs exclusively in female patients, and is often associated with pregnancy and oral contraceptive therapy. Clinically, type 3 is similar to types 1 and 2; however, the biochemical abnormalities are lacking when C1-INH and complements are measured. Therefore, the diagnosis is based on the history, physical exam, and response to appropriate therapy.
Therapy for acute attacks is with intravenous purified C1 esterase inhibitor concentrate although currently this is not available in the U.S. Since the concentrate is not available, androgens should be administered along with antifibrinolytics during acute attacks. Intravenous fresh frozen plasma (FFP) is an effective form of prophylactic therapy prior to surgical or dental procedures when administered as two units 12-24 hours prior to the procedure, but should not be used as abortive therapy in an acute attack. Attenuated androgens equivalent to a daily dose of 600 mg of danazol may be an effective prophylaxis when give for the 10 days prior to a surgical or dental procedure. When patients are plagued by frequent recurrent attacks, prophylaxis may be administered in the form of danazol (200-800 mg/day), stanozolol (2-12 mg/day), methyltestosterone (10-30 mg/day), aminocaproic acid, and tranexamic acid. Patients should be counseled to avoid estrogens and ACEI as they may aggravate this condition.
ACQUIRED ANGIOEDEMA (AAE)
Unlike HAE in which there is decreased production of C1-INH or production of an abnormal poorly functioning C1-INH, AAE is the result of increased destruction of C1-INH. First attacks of this form of disease occur later in life during or after the fourth decade. There are two types of AAE. In type 1 disease, the complement system is continuously activated by autoantibodies resulting in increased consumption of C1-INH and ultimately depressed levels. In type 2 disease, autoantibodies bind and inactivate the C1-INH directly. As stated above, patients with AAE will have depressed C1-INH activity and C1-INH levels just like HAE type 1 patients; however, patients with AAE unlike HAE patients will also have markedly decreased levels of C1q. Type 1 disease is often associated with underlying disease states such as chronic lymphocytic leukemia, lymphosarcoma, multiple myeloma, macroglobulinemia, essential cryoglobulinemia, rheumatologic diseases, and rarely certain carcinomas (rectal, gastric and breast).
Treatment for acute attacks is the same as above for HAE; however, the response to therapy may be variable. Secondary treatment measures include aggressive supportive respiratory care with intubation and ventilation when needed, subcutaneous epinephrine (0.2-0.3 mL of 1:1000 concentration Q 20-30 minutes prn up to 3 doses), plus nebulized racemic epinephrine (1:1000mixture). Successful secondary treatment with antihistamines or glucocorticoids (methylprednisolone 500-1000 mg/day) is anecdotal at best. When patients manifest multiple attacks, prophylactic therapy should be considered. Prophylaxis may consist of attenuated androgens (danazol, stanozolol, and methyltestosterone) or antifibrinolytic agents (tranexamic acid and aminocaproic acid) although type 2 patients may respond poorly to androgen therapy. Treatment of the underlying disease if identified is the best therapeutic approach.
CHRONIC IDIOPATHIC ANGIOEDEMA (CIA)
CIA is similar in clinical presentation to HAE except that pruritus is a common symptom and laryngeal edema uncommon. Antihistamines and corticosteroids form the cornerstone of therapy.
DRUG-INDUCED ANGIOEDEMA
ACE inhibitors
Angiotensin II receptor antagonists
Antibiotics
Narcotics
NSAIDs