C1 esterase inhibitor deficiency

Last edited 10/2021

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