Angioneurotic oedema

Hereditary angioneurotic oedema is an autosomal dominantly inherited condition caused by a deficiency of C1 esterase inhibitor (1).

C1 esterase inhibitor is a protein which is produced mainly in the liver and to some extent by activated Monocytes and other cell types. C1 esterase inhibitor is the main regulator in the activation of

• complement system
• contact system (kallikrein-kinin system)
• coagulation cascade, fibrinolytic pathway (to a lesser extent) (2), (3)

In the presence of decreased C1 esterase inhibitor,

• inappropriate activation of compliment pathway
• increase in kallikrein production (leading to bradykinin formation which is a vascular permeability factor) occurs (2), (3).

Dysregulation of both the complement and contact systems is considered to be the main pathogenic mechanism of hereditary angioedema (3).

Clinically the patient suffers oedema of the skin and mucosal surfaces. Fatalities may occur if the airway is compromised.

Hereditary angioneurotic oedema affects about one in 50,000 individuals in any race (4):

• inherited in an autosomal dominant manner
• the frequency and severity of symptoms varies; affected individuals may have few, or no symptoms
• hereditary angioedema (HAE) is due to C1 inhibitor (C1-INH) deficiency
  • (HAE-C1-INH) is a genetic disease characterized by recurrent attacks of subcutaneous and/or submucosal swelling (5)
    • (HAE-C1-INH) is an autosomal-dominant disorder resulting from mutations in the SERPING1 gene
    • HAE-C1-INH is caused by either quantitative deficiencies or dysfunctional production of C1-INH, leading to uncontrolled plasma kallikrein activity, excessive release of bradykinin, and consequent angioedema
    • attacks are unpredictable, often associated with significant morbidity, and potentially fatal as a result of asphyxiation due to laryngeal angioedema (6)
      • mean frequency of attacks in untreated patients is approximately every 2 weeks
      • with individual attacks lasting 3 to 5 days before fully resolving
      • combination of asphyxiation risk, unpredictability, severity, and frequency of attacks justify prophylactic treatment; the possibility of passing HAE-C1-INH to the next generation contributes to a severe disease burden with markedly reduced quality of life

Notes (7):

• acquired forms of C1 inhibitor deficiency
  • may result from autoantibody binding of C1 inhibitor, or depletion of C1 inhibitor due to C1 activation by paraprotein
  • investigations typically show reduced levels of complement C4 and may reveal low levels of C1 inhibitor and the presence of a paraprotein
• considering sub-classification of inherited C1 esterase deficiency (8):
  • type I HAE
    • about 85% of patients have type I HAE (type I C1-INH-HAE), which is characterized by a deficiency in C1 esterase inhibitor (C1-INH) levels
  • type II HAE (type II C1-INH-HAE)
    • accounts for about 15% of cases and is associated with abnormal function of C1-INH in the presence of normal C1-INH levels
  • types I and II of HAE are caused by mutations in the SERPING1 gene, which encodes C1-INH
  • tyep III HAE
    • in this type of HAE - both levels and function of C1-INH are normal (HAE-nl-C1INH)
    • associated with specific genetic mutations (i.e., F12, ANGPT1, HS3ST6, PLG, MYOF, and KNG1), although many patients with HAE-nl-C1INH have no currently identified genetic mutation

Reference:

• 1. Tarzi M.D et al. An evaluation of tests used for the diagnosis and monitoring of C1 inhibitor deficiency: normal serum C4 does not exclude hereditary angio-oedema. Clin Exp Immunol. 2007; 149(3): 513-516
• 2. Davis A.E. New treatments addressing the pathophysiology of hereditary angioedema. Clin Mol Allergy. 2008; 6:2
• 3. Gompels M.M et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol. 2005; 139(3): 379-394
• 4. Zuraw B.L. Hereditary angioedema. NEJM 2008: 359:1027-1036
• 5. Farkas H, Stobiecki M, Peter J, et al. Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study. Clin Transl Allergy. 2021;11(4):e12035. doi:10.1002/clt2.12035
• 6. Zuraw B et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol. 2021 Jul;148(1):164-172.e9. doi: 10.1016/j.jaci.2020.10.015. Epub 2020 Oct 21. PMID: 33098856
• 7. Powell RJ et al; British Society for Allergy and Clinical Immunology (BSACI). BSACI guidelines for the management of chronic urticaria and angio-oedema.Clin Exp Allergy. 2007 May;37(5):631-50.
• 8. Valerieva A, Longhurst HJ. Treatment of hereditary angioedema-single or multiple pathways to the rescue. Front Allergy. 2022 Sep 12;3:952233.