Hereditary angioedema and acquired angioedema due to 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 pathwaysC1 inhibitor levels.
(See also Overview of Allergic and Atopic Disorders, Angioedema, and US HAEA [Hereditary Angioedema Association] Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema [2020].)
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 (1).
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
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 (1).
Type 2 results from a dysfunctional C1 inhibitor. Inheritance is autosomal dominant although de novo mutations occur in about 25% of cases (1).
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, adenocarcinoma) 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
Estrogen
Ingestion of certain foods
Angioedema may be aggravated by emotional stress.
General reference
1. Miyata T, Horiuchi T. Biochemistry, molecular genetics, and clinical aspects of hereditary angioedema with and without C1 inhibitor deficiency. Allergol Int 2023;72(3):375-384. doi:10.1016/j.alit.2023.04.004
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).
By permission of the publisher. From Joe E, Soter N. In Current Dermatologic Diagnosis and Treatment, edited by I Freedberg, IM Freedberg, and MR Sanchez. Philadelphia, Current Medicine, 2001.
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 or acquired C1 inhibitor deficiency.
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 C1 inhibitor deficiency: Low C1 inhibitor protein levels, decreased C1 inhibitor function, and normal C1q levels
Type 2 hereditary C1 inhibitor deficiency: 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 C1 inhibitor deficiency: Normal C1 inhibitor level, C1 inhibitor function, and C1q levels
All first-degree relatives of patients with confirmed hereditary C1 inhibitor deficiency should be screened whether they have symptoms or not. Screening should include C1 inhibitor and C4 levels (1).
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
For acute attacks, the following are considered first-line treatment:
1).
Analgesics, antiemetics, and fluid replacement can be used to relieve symptoms.
Treatment of patients with hereditary C1 inhibitor deficiency focuses on 4 core principles (2):
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 at least 2 standard doses of an on-demand medication for treatment of acute attacks (2).
Pearls & Pitfalls
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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
Long-term prophylaxis
Medications used for long-term prophylaxis of hereditary C1 inhibitor deficiency episodes include
Attenuated androgens
C1 inhibitor synthesis. This treatment may be less effective for the acquired form of angioedema.
Short-term prophylaxis
Short-term prophylaxis for hereditary C1 inhibitor1).
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.
