Hereditary angioedema and acquired angioedema are caused by deficiency or dysfunction of C1 inhibitor, a protein that regulates the classical complement activation pathway (see Biology of the Immune System: Complement System). Diagnosis is by measurement of complement levels. C1 inhibitor is used to treat acute attacks. Prophylaxis is with attenuated androgens, which increase C1 inhibitor levels.
C1 inhibitor deficiency or dysfunction results in increased levels of bradykinin because C1 inhibitor also inhibits activated factor X11a and activated kallikrein, which are required for the generation of bradykinin, in the kinin system pathway.
Hereditary angioedema has 2 types:
Inheritance is autosomal dominant. Clinical presentation is usually during childhood or adolescence.
Acquired C1 inhibitor deficiency
C1 inhibitor deficiency may be acquired when
Clinical presentation is usually at an older age, when patients have an associated disorder.
In all forms of hereditary and acquired angioedema, attacks can be precipitated by mild trauma (eg, dental work, tongue piercing), viral illness, cold exposure, pregnancy, or ingestion of certain foods or may be aggravated by emotional stress.
Symptoms and Signs
Symptoms and signs are similar to those of other forms of bradykinin-mediated angioedema, with asymmetric and mildly painful swelling that often involves the face, lips, and/or tongue. Swelling may also occur on the back of hands or feet or on the genitals. The GI tract is often involved, with manifestations that suggest intestinal obstruction, including nausea, vomiting, and colicky discomfort. Pruritus, urticaria, and bronchospasm do not occur, but laryngeal edema may be present, causing stridor (and sometimes death).
Swelling resolves within about 1 to 3 days of onset. In hereditary angioedema, symptoms resolve as complement components are consumed.
Levels of C4, C1 inhibitor, and C1q (a component of C1) are measured. Low levels of C4 (and C2, if measured) and decreased C1 inhibitor function confirm hereditary angioedema or acquired C1 inhibitor deficiency. Other findings include
If angioedema is not accompanied by urticaria and recurs without any clear cause or is present in family members, clinicians should suspect hereditary angioedema or acquired C1 inhibitor deficiency.
Acute attacks are treated with purified human C1 inhibitor, ecallantide, or icatibant (not available in the US). If none of these drugs is available, fresh frozen plasma or, in the European Union, tranexamic acid has been used. A recombinant form of C1 inhibitor is being developed. Epinephrine can provide transient benefit in acute attacks when airways are involved. Corticosteroids and antihistamines are not effective. Analgesics, antiemetics, and fluid replacement can be used to relieve symptoms.
For long-term prophylaxis, attenuated androgens (eg, stanozolol 2 mg po tid, danazol 200 mg po tid) are used to stimulate hepatic C1 inhibitor synthesis. This treatment may be less effective for the acquired form. C1 inhibitor is effective but expensive.
Short-term prophylaxis is indicated before high-risk procedures (eg, dental or airway procedures) if C1 inhibitor is not available to treat an acute attack. Patients are usually given attenuated androgens 5 days before the procedure until 2 days afterward. If C1 inhibitor is available, some experts advocate giving it 1 h before high-risk procedures rather then attenuated androgens for short-term prophylaxis.
Last full review/revision July 2012 by Peter J. Delves, PhD