classical and lectin complement activation pathways
(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]).)
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
Acquired C1 inhibitor deficiency
Complement is consumed in neoplastic disorders (eg, B-cell lymphoma) or immune complex disorders.
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. 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).
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.
Diagnosis
Measurement of complement levels
Low levels of C4, even between episodes
Other findings include
1).
Diagnosis reference
1. Zuraw BL, Bernstein JA, Lang DM, et alJ Allergy Clin Immunol 131 (6):1491-1493, 2013. doi: 10.1016/j.jaci.2013.03.034
Treatment
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 angioedema 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 ≤ 2 standard doses of an on-demand medication for treatment of acute attacks (2).
Pearls & Pitfalls
|
Treatment references
1. Moldovan D, Bernstein JA, Cicardi MImmunotherapy 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
Attenuated androgens
Short-term prophylaxis
Short-term prophylaxis1).
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.
