(See also Overview of Allergic and Atopic Disorders Overview of Allergic and Atopic Disorders Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more , Angioedema, Angioedema Angioedema is edema of the deep dermis and subcutaneous tissues. It is usually an acute but sometimes a chronic mast cell–mediated reaction caused by exposure to a drug (eg, angiotensin-converting... read more and US HAEA [Hereditary Angioedema Association] Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema ).)
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.
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 2 results from a dysfunctional C1 inhibitor. Inheritance is autosomal dominant although de novo mutations occur in about 25% of cases (1 General 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 ).
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
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] Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , dermatomyositis Autoimmune Myositis Autoimmune myositis is characterized by inflammatory and degenerative changes in the muscles (polymyositis, necrotizing immune-mediated myopathy) or in the skin and muscles (dermatomyositis)... read more ).
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)
Estrogen-containing drugs and tamoxifen
Ingestion of certain foods
Angioedema may be aggravated by emotional stress.
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.
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 ).
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
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)
Recombinant C1 inhibitor has similar protease inhibitory activity but a shorter half-life than plasma-derived C1 inhibitor (1 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 ).
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.
Treatment of patients with hereditary angioedema focuses on 4 core principles (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 ):
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 ).
Pearls & Pitfalls
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
Drugs used for long-term prophylaxis of hereditary angioedema episodes include
Plasma-derived C1 inhibitor (human)
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 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 ).
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|
|Adrenaclick, Adrenalin, Auvi-Q, Epifrin, EpiPen, Epipen Jr , Primatene Mist, SYMJEPI, Twinject|
c1 esterase inhibitor