C1 Esterase Inhibitor Deficiency



  • A hereditary and acquired form of recurrent angioedema. The attacks are usually without urticaria.
  • Has been classified into a number of types, including
    • Hereditary angioedema (HAE) type I (transmitted as autosomal dominant)
    • HAE type II (transmitted as autosomal dominant)
    • Acquired angioedema (AAE) types I, II, III, and IV
  • HAE type I
  • Accounts for ∼85% of the C1 esterase deficiencies, insufficient levels of normal C1-esterase inhibitor (C1-INH) protein due to a genetic alteration that leads to impairment of messenger RNA (mRNA) transcription or translation and therefore decreased enzyme synthesis. Often thought of as quantitative deficiency.
  • HAE type II
  • Patients have normal levels of less functional C1-INH. May be thought of as a qualitative deficiency.
  • HAE type III
  • An estrogen-dependent form; typical clinical features of type I with normal C1-INH level and function and normal C4
  • These cases are all female and have dominant mode of inheritance; poorly understood mechanism.
  • In acquired deficiency of C1-INH, there appears to be a normal ability to synthesize the enzyme; however, the enzyme is metabolized at an increased rate. This syndrome may be seen in patients with autoimmune diseases or malignancy and usually occurs after the 4th decade of life.
  • AAE type I
  • Very rare syndrome usually associated with lymphoproliferative (usually B-cell) carcinomas, autoimmune diseases, and paraproteinemias. Because of the other disease processes, complement-activating factors and idiotype–anti-idiotype complexes act to increase consumption of C1-INH.
  • AAE type II
  • Develops when an autoantibody is produced against the C1-INH protein. When these antibodies adhere to the C1-INH molecule, conformational change occurs, leading to decreased function or enhanced metabolism. This type is often associated with autoimmune disorders.
  • AAE type III
  • Associated with sex hormones (specifically in pregnancy)
  • AAE type IV
  • Drug-induced AAE, particularly associated with ACE inhibitors or angiotensin receptor blockers
  • AAE forms may be differentiated from HAE by genetic studies and serologically by significantly decreased C1q, C1r, and C1s levels and decreased functional activity of the enzyme in AAE.





HAE types I and II are transmitted as autosomal dominant.


  • C1-INH is a single-chain polypeptide with a molecular weight of 108 kD. The gene has been identified on chromosome 11 (11q12–q13.1). It is involved in the control of vascular permeability.
  • C1-INH is a member of the serpin family of serine protease inhibitors produced in the liver.
  • This protein inhibits the classic complement pathway by inhibiting activation of C2 and C4. In the fibrinolytic system, C1-INH inhibits formation of plasmin, the activation of C1r and C1s, and the formation of bradykinin from kininogen.
  • Deficiency of this enzyme results in activation of the classic complement system along with fibrinolysis and kinin formation, which is felt to participate in the production of angioedema.
  • Kinin is known to cause similar histologic lesions to histamine but without pruritus.
  • The complement activation leads to production of C2b, a product that also has kinin-like activity, and bradykinin, a vasoactive peptide that may also participate in the formation of angioedema.

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