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Hereditary and Acquired Angioedema

(Acquired C1 Inhibitor Deficiency)

By

James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Medically Reviewed Oct 2022
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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 Complement activation The complement system is an enzyme cascade that helps defend against infection. Many complement proteins occur in serum as inactive enzyme precursors (zymogens); others reside on cell surfaces... read more , and of the kinin, clotting, and fibrinolytic pathways. The main symptom is swelling, often of the face, mouth, and upper airways, which can be severe; itching and urticaria do not occur. 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 3 types:

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

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

  • Type 3 (rare): Characterized by normal C1 inhibitor function and levels

Type 1 and type 2 involve mutations of the gene encoding C1 inhibitor. Inheritance in type 1 is autosomal dominant. Clinical presentation is usually during childhood or adolescence; 75% of patients with type 1 have an episode by age 15.

Type 3 is rare). It is characterized by normal C1 inhibitor and is sometimes due to genetic mutations that result in abnormal forms of factor XII, plasminogen, angiopoietin 1, or kininogen. Type 3 occurs more frequently in females.

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.

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

  • Estrogen-containing drugs and tamoxifen

  • Ingestion of certain foods

Angioedema may be aggravated by emotional stress.

General reference

  • 1. Pappalardo E, Cicardi M, Duponchel C, et al: Frequent de novo mutations and exon deletions in the C1inhibitor gene of patients with angioedema. J Allergy Clin Immunol 106 (6):1147–1154, 2000. doi: 10.1067/mai.2000.110471

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 or is triggered by local trauma, 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, even between episodes

  • Decreased C1 inhibitor level or function

Other findings include

  • Type 1 hereditary angioedema: Low C1 inhibitor protein levels, decreased C1 inhibitor function, and normal C1q levels

  • Type 2 hereditary angioedema: Normal or increased C1 inhibitor protein levels, decreased C1 inhibitor function, and normal C1q levels

  • Acquired C1 inhibitor deficiency: Low C1q levels

  • Type 3 hereditary angioedema: Normal C1 inhibitor level and function and normal C and C1q levels

All first-degree relatives of a patient with confirmed hereditary angioedema should be screened whether they have symptoms or not. Screening should include C1 inhibitor and C4 levels (1 Diagnosis reference 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... read more Diagnosis reference ).

Diagnosis reference

  • 1. Zuraw BL, Bernstein JA, Lang DM, et al: A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor–associated angioedema. J Allergy Clin Immunol 131 (6):1491-1493, 2013. doi: 10.1016/j.jaci.2013.03.034

Treatment

  • For acute attacks, C1 inhibitor, ecallantide, icatibant

For acute attacks, the following are considered first-line treatment:

  • Purified plasma-derived human C1 inhibitor

  • Recombinant C1 inhibitor obtained from the milk of transgenic rabbits

  • 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)

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 C1 inhibitor, 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.

  • Availability of effective on-demand acute therapy for all patients

  • Early treatment to prevent attack progression

  • Treatment of attacks regardless of the site of swelling

  • Incorporation of long-term prophylaxis based on highly individualized decision-making reflecting a physician-patient partnership

Based on these principles, all patients with confirmed hereditary angioedema should have access to ≤ 2 standard doses of an on-demand medication for treatment of acute attacks (2 Treatment references 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... read more Treatment references ).

Pearls & Pitfalls

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

Treatment references

  • 1. Moldovan D, Bernstein JA, Cicardi M: Recombinant replacement therapy for hereditary angioedema due to C1 inhibitor deficiency. Immunotherapy 7 (7):739–752, 2015. doi: 10.2217/imt.15.44

  • 2. Busse PJ, Christiansen SC, Riedl MA, et al: US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract 9 (1):132–150.e3, 2021. doi: 10.1016/j.jaip.2020.08.046

Prevention

Long-term prophylaxis

Drugs used for long-term prophylaxis of hereditary angioedema episodes include

  • Plasma-derived C1 inhibitor (human)

  • Lanadelumab

  • Berotralstat

  • Attenuated androgens

  • Antifibrinolytics (eg, tranexamic acid)

Plasma-derived C1 inhibitor may be given in regular IV infusions or subcutaneous injections as long-term prophylaxis. Patients can be taught to self-administer. Plasma-derived C1 inhibitor is approved for long-term prevention of hereditary angioedema in the US, but recombinant C1 esterase inhibitor is not.

Lanadelumab is a recombinant humanized monoclonal antibody that binds to plasma kallikrein and blocks its activity. Usual dosage is 300 mg subcutaneously every 2 weeks.

Berotralstat is a synthetic small molecule developed to inhibit plasma kallikrein. Dosage is 150 mg orally once a day

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.

Antifibrinolytics (eg, tranexamic acid) have been used as second-line drugs for long-term prophylaxis in children and pregnant women.

Short-term prophylaxis

Short-term prophylaxis for hereditary angioedema 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 (plasma-derived or recombinant) is available, some experts advocate giving it 1 hour before high-risk procedures rather than attenuated androgens for short-term prophylaxis. Plasma products (eg, 2 units of fresh frozen plasma) before procedures are also an option (1 Prevention reference 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... read more Prevention reference ).

Prevention reference

  • 1. Prematta M, Gibbs JG, Pratt EL: Fresh frozen plasma for the treatment of hereditary angioedema. Ann Allergy Asthma Immunol 98 (4):383–388, 2007.

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, recombinant C1 inhibitor, ecallantide, or icatibant, and for symptom relief, use analgesics, antiemetics, and fluids; antihistamines and corticosteroids are ineffective.

  • For long-term prophylaxis, use regular infusions of plasma-derived C1 inhibitor, lanadelumab, or berotralstat.

  • For short-term prophylaxis (eg, before dental or airway procedures), consider C1 inhibitor, attenuated androgens (eg, stanozolol, danazol), or plasma products such as fresh frozen plasma.

Drugs Mentioned In This Article

Drug Name Select Trade
Berinert, Cinryze , HAEGARDA
RYPLAZIM
Nolvadex, Soltamox
Kalbitor
FIRAZYR, SAJAZIR
Cyklokapron, Lysteda
Adrenaclick, Adrenalin, Auvi-Q, Epifrin, EpiPen, Epipen Jr , Primatene Mist, SYMJEPI, Twinject
TAKHZYRO
Orladeyo
RUCONEST
Danocrine
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