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Hereditary and Acquired Angioedema

(Acquired C1 Inhibitor Deficiency)

By

Peter J. Delves

, PhD, University College London, London, UK

Last full review/revision Oct 2020| Content last modified Oct 2020
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Hereditary angioedema and acquired angioedema (acquired C1 inhibitor deficiency) are caused by deficiency or dysfunction of complement 1 (C1) inhibitor, a protein involved in the regulation of the classical and lectin complement activation pathways, and also of the kinin, clotting, and fibrinolytic pathways. 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 not only affects complement activation but also results in increased levels of bradykinin because C1 inhibitor inhibits activated kallikrein (required for the generation of bradykinin) in the kinin system pathway.

Complement activation pathways

The classical, lectin, and alternative pathways converge into a final common pathway when C3 convertase (C3 con) cleaves C3 into C3a and C3b. Ab = antibody; Ag = antigen; C1-INH = C1 inhibitor; MAC = membrane attack complex; MASP = MBL-associated serine protease; MBL = mannose-binding lectin. Overbar indicates activation.

Complement activation pathways

Hereditary angioedema

Hereditary angioedema has 2 main types:

  • Type 1 (80 to 85%): Characterized by C1 inhibitor deficiency

  • Type 2 (15 to 20%): Characterized by C1 inhibitor dysfunction

Inheritance is autosomal dominant. Clinical presentation is usually during childhood or adolescence.

A rare type of hereditary angioedema (hereditary angioedema type 3) is characterized by normal C1 inhibitor levels. The prevalence of this type of hereditary edema is unknown; this type occurs primarily in women.

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, systemic lupus erythematosus [SLE], dermatomyositis).

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

Triggers

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

  • Ingestion of certain foods

Angioedema may be aggravated by emotional stress.

Symptoms and Signs

Symptoms and signs of hereditary and acquired angioedema 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 gastrointestinal tract is often involved, with variable 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

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, clinicians should suspect hereditary angioedema.

Levels of C4, C1 inhibitor, and C1q (a component of C1) are measured. Hereditary angioedema (types 1 and 2) 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 C1q levels

  • Type 2 hereditary angioedema: Normal or increased C1 inhibitor levels and normal C1q levels

  • Acquired C1 inhibitor deficiency: Low C1q levels

  • Type 3 hereditary angioedema: Normal C1 inhibitor and C4 levels

Treatment

  • For acute attacks, C1 inhibitor, ecallantide, icatibant, or lanadelumab

  • For prophylaxis, attenuated androgens

Acute attacks are treated with one of the following:

  • Purified plasma-derived human C1 inhibitor

  • Ecallantide (a recombinant protein that acts as a reversible inhibitor of kallikrein)

  • Icatibant (a synthetic decapeptide that acts as a reversible, competitive antagonist of the bradykinin type 2 receptor)

  • Lanadelumab (a recombinant humanized monoclonal antibody that binds to plasma kallikrein and blocks its activity)

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, conestat alfa, is also available.

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 orally 3 times a day, danazol 200 mg orally 3 times a day) 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 (eg, danazol, stanozolol) 5 days before the procedure until 2 days afterward. If C1 inhibitor is available, some experts advocate giving it 1 hour before high-risk procedures rather than attenuated androgens for short-term prophylaxis.

Key Points

  • Onset is usually during childhood or adolescence for hereditary angioedema or during later adulthood for acquired angioedema, 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, icatibant, or lanadelumab, 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.

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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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