Hereditary and Acquired Angioedema

(Acquired C1 Inhibitor Deficiency)

By Peter J. Delves, PhD, University College London, London, UK

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Allergic, Autoimmune, and Other Hypersensitivity Disorders
Overview of Allergic and Atopic Disorders
Allergic Rhinitis
Anaphylaxis
Angioedema
Hereditary and Acquired Angioedema
Autoimmune Disorders
Drug Hypersensitivity
Food Allergy
Mastocytosis

Hereditary angioedema and acquired angioedema (acquired C1 inhibitor deficiency) are caused by deficiency or dysfunction of C1 inhibitor, a protein that regulates the classical complement activation pathway. 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 inhibits activated kallikrein (required for the generation of bradykinin) in the kinin system pathway.

Acquired C1 inhibitor deficiency

C1 inhibitor deficiency may be acquired when

Complement is consumed in neoplastic disorders (eg, B-cell lymphoma) or immune complex disorders.
C1 inhibitor autoantibody is produced in monoclonal gammopathy.
Rarely, C1 inhibitor autoantibody is produced in autoimmune disorders (eg, SLE, dermatomyositis).

Clinical presentation is usually at an older age, when patients have an associated disorder.

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.

Diagnosis

Measurement of complement levels

Levels of C4, C1 inhibitor, and C1q (a component of C1) are measured. Hereditary angioedema or acquired C1 inhibitor deficiency is confirmed by

Low levels of C4 (and C2, if measured)
Decreased C1 inhibitor function

Other findings include

Type 1 hereditary angioedema: Low C1 inhibitor levels and normal levels of C1q
Type 2 hereditary angioedema: Normal or increased C1 inhibitor levels and normal C1q levels
Acquired C1 inhibitor deficiency: Low C1q levels

If angioedema is not accompanied by urticaria and recurs without any clear cause, clinicians should suspect hereditary angioedema or acquired C1 inhibitor deficiency. If family members have it, they should suspect hereditary angioedema.

Treatment

For acute attacks, C1 inhibitor, ecallantide, or icatibant
For prophylaxis, attenuated androgens

Acute attacks are treated with purified human C1 inhibitor, ecallantide, or icatibant. 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 (recombinant human C1 esterase inhibitor [rhC1INH], or conestat alfa) is available in Europe.

If the airways are affected, securing an airway is the highest priority. Epinephrine may provide transient benefit in acute attacks when airways are involved. However, the benefit may not be sufficient or may be temporary; then endotracheal intubation may be necessary. Corticosteroids and antihistamines are not effective.

Analgesics, antiemetics, and fluid replacement can be used to relieve symptoms.

Pearls & Pitfalls

Antihistamines and corticosteroids are not effective for hereditary or acquired angioedema.

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 than attenuated androgens for short-term prophylaxis.

Key Points

Onset is usually during childhood or adolescence (hereditary) or during later adulthood (acquired), often in patients with a neoplastic or an autoimmune disorder.
Mild trauma, viral illness, cold exposure, pregnancy, or ingestion of certain foods may trigger attacks; emotional stress may aggravate them.
Measure complement levels; low levels of C4 and decreased C1 inhibitor function indicate hereditary angioedema or acquired C1 inhibitor deficiency.
For acute attacks, use purified human C1 inhibitor, ecallantide, or icatibant, and for symptom relief, use analgesics, antiemetics, and fluids; antihistamines and corticosteroids are ineffective.
For prophylaxis (long-term and short-term—eg, before dental or airway procedures), consider attenuated androgens (eg, stanozolol, danazol); a C1 inhibitor can also be considered for short-term prophylaxis.