Hereditary angioedema

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Hereditary angioedema

Malcolm W. Greaves

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Classic hereditary angioedema (HAE) is an autosomal dominantly inherited disease with a prevalence of 1 : 50 000 due to mutations in the C1-esterase inhibitor (C1-INH) gene on chromosome 11 (11q12-q13.1), though de novo mutations are frequent. It is mediated by the protease kallikrein and the nonapeptide bradykinin, acting on B2 receptors, and is manifested by painless, non-pruritic swellings of subcutaneous and submucosal tissues, including abdominal organs and the upper airway. It is characterized by a quantitative (type 1, 85%) or functional (type 2, 15%) defect of the inhibitor of the first component of complement (C1-INH). Estrogen-dependent hereditary angioedema (type 3) has recently been reported predominantly in women with no detectable abnormality of complement components. A mutation in the gene encoding for factor 12 has been identified in some of these families. Acute abdominal pain simulating an ‘acute abdomen’ is an important presentation. Fatalities are possible in these hereditary angioedemas.

Management strategy

Therapy for HAE is dependent on three considerations:

Acute angioedema

Acute presentations of HAE are treated optimally with intravenous vapor-sterilized C1-INH concentrate. This treatment is safe, and no proven cases of viral transmission have been reported since this sterilization process was adopted. Reduction in swelling is usually significant within minutes, and substantial within two to three hours. Fresh frozen plasma (FFP), which contains C1-INH, can be used if concentrate is unavailable; however, FFP carries a higher risk of inadvertent viral transmission (HIV, hepatitis) and theoretically could exacerbate angioedema owing to the presence of C1 esterase substrate. The kallikrein–bradykinin mediator pathway is the target of new approaches to treatment of acute HAE. Ecallantide, a kallikrein inhibitor given subcutaneously in dosage 30 mg proved safe and effective for acute attacks. The swellings of HAE are mediated by bradykinin, a product of the action of kallikrein on its substrate kininogen. Bradykinin acts on B2 receptors, and its specific antagonist icatibant, 30 mg subcutaneously, has been proven effective in acute attacks of HAE. The administration of subcutaneous icatibant for acute HAE in a domiciliary setting by health care professionals, or even by self-administration after suitable training, is being explored. Laryngeal edema may require tracheostomy, intubation, and/or other life-support measures. Patients should be admitted routinely for 24 hours after acute episodes, as relapses, which may be life-threatening, are common.

Long-term prophylaxis

Generally, long-term prophylaxis is appropriate in those patients with at least one or more attacks of angioedema per month, and in those with severe symptoms. However, patients could have infrequent attacks and still present with laryngeal edema. Even first-episode angioedema can be fatal. The 17α-alkylated androgens danazol and stanozolol are first-line prophylactic medications that are effective in preventing angioedema in types 1 and 2 HAE. The lowest possible dose of androgen should be used to obtain clinical remission, regardless of C1-INH or C4 levels. Side effects include hirsuties, deepening of voice, and menorrhagia. These attenuated androgens are unsuitable for long-term treatment of hereditary angioedema in children, in pregnant women, and for the treatment of acute attacks. However, they are safe and effective in adults, provided they are closely supervised with clinical biochemical and radiological assessments. In some patients alternate-day therapy can be achieved. Hepatocellular adenoma and hepatocellular carcinoma have been reported in patients on long-term danazol. Other prophylactic therapies include antifibrinolytics (e.g., tranexamic acid, epsilon-aminocaproic acid – EACA), but these are of less certain value. In patients with mild infrequent attacks avoidance of provoking factors, including estrogens and angiotensin-converting enzyme (ACE) inhibitors, may be sufficient. For long-term management in selected cases, patients’ carers can be trained to administer intravenous C1 inhibitor concentrate for occasional acute attacks if no medical facilities are at hand, thereby obviating the necessity for regular prophylaxis.

Prevention of relapse due to dental and surgical interventions

In all patients, prior to elective surgical, dental, or other invasive procedures, higher-dose androgens can be used for 5–10 days. If an emergency procedure is necessary, C1-INH concentrate or FFP can be administered.

Patients with HAE should all wear a MedicAlert disk stating the diagnosis and emergency treatment.

Specific investigations

Acute Angioedema

First-line therapies

image C1-INH concentrate A

Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate.

Waytes AT, Rosen FS, Frank MM. N Engl J Med 1996; 334: 1630–4.

Two randomized, placebo-controlled, double-blind studies evaluated the safety and efficacy of vapor-heated infusions of C1-INH concentrate in acute attacks (22 patients) and as prophylaxis (six patients). In the prophylaxis arm, concentrate was administered every third day; in the treatment arm, concentrate was begun within 5 hours of symptoms. A dose of 25 U/kg was used in both groups. Compared to placebo, significantly lower daily symptom scores were found in the prophylaxis group, and a shorter duration of symptoms was found in the treatment group (55 vs 563 minutes). No toxicity was demonstrated, and after 4 years of observation there was no evidence of seroconversion to HIV or hepatitis B or C.

Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema.

Zuraw BL, Busse PJ, et al. N Engl J Med 2010; 363: 513–22.

This is a placebo-controlled study of intravenous administration of nanofiltered pasteurized C1 inhibitor concentrate in 65 patients with hereditary angioedema. This treatment shortened the acute attack from over 4 hours to 2 hours.

C1-INH concentrate has also been effective as short-term prophylaxis in labor induction, tonsillectomy, and maxillofacial surgery. Long-term prophylaxis has not generally been advocated owing to lack of availability, cost, and the potential for infectious transmission. However, this may be considered in children, pregnant women, and patients who do not respond to or tolerate androgens or antifibrinolytics, or if these drugs are contraindicated.

C1-INH can be obtained in Europe from Berinert HS, Aventis Behring, Liederbach, Germany. CSL Behring PA, USA and Viropharma, Maidenhead, UK. It is also available from Viropharma USA but is not licensed for acute administration in the USA.

Second-line therapies

image Fresh frozen plasma D
image Icatibant A
image Ecallantide A

Long-term prophylaxis of hereditary angioedema

First-line therapies

image Danazol A
image Stanozolol B

Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients.

Cicardi M, Castelli R, Zingale LC, Agostoni A. J Allergy Clin Immunol 1997; 99: 194–6.

Thirty-six patients with HAE were treated with attenuated androgens for a median of 125.5 months and compared to 34 patients with HAE who never received prophylaxis. The main side effects were menstrual irregularities (15 of 36) and weight gain (14 of 36). A statistically significant increase in arterial hypertension occurred in 25% of treated patients. No significant changes in hepatic enzymes and ultrasounds were found. Stanozolol seemed to have fewer side effects than danazol.

Side effects in female patients may be troublesome, including menstrual disturbance, deepening of the voice, and hirsuties. In males, prostate changes should be monitored. All patients should have regular liver function tests. Attenuated androgens are contraindicated in pregnancy.

Second-line therapies

image Tranexamic acid A
image Epsilon-aminocaproic acid A

Prevention of relapse due to dental and surgical interventions

First-line therapies

image Fresh frozen plasma B
image Danazol B
image C1-INH concentrate C

Hereditary angioedema type 3

Hereditary angioedema type 3, angioedema associated with angiotensin II receptor antagonists and female sex.

Bork K. Am J Med 2004; 116: 644.

The author describes two unrelated female patients who had normal C1-INH and C4 levels and who experienced severe exacerbations of hereditary angioedema following the administration of losartan and valsartan, respectively.

Acute attacks do not respond to C1-INH concentrate, and antihistamines or corticosteroids are ineffective. The value of antifibrinolytics is unproven. For prevention danazol is worth trying in non-pregnant patients, but substantiation of its value is awaited. All patients should avoid angiotensin-2-receptor antagonists (sartans) and estrogens because these are known to provoke attacks in affected women. Bradykinin antagonists such as icatibant or kallikrein inhibitors such as ecallantide may offer benefit to these patients, although their benefit is unproven.

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