Hereditary Angioedema (C1 Esterase Inhibitor–Associated Angioedema)

Descriptive text is not available for this imageBASICS

DESCRIPTION

  • C1 esterase inhibitor (C1-INH)–associated angioedema is characterized by recurrent episodes of nonpitting, asymmetric angioedema that most often occurs in three separate locations:
    • Skin and mucosal tissues
    • Laryngeal
    • Gastrointestinal (GI) tract
  • Types of C1-INH–associated angioedema:
    Hereditary angioedema (HAE) Type I: C1-INH deficiency; type II: decreased C1-INH activity; HAE with normal C1-INH (formerly type III): normal C1-INH level and activity
    Acquired angioedema Occurs secondary to an underlying disease process
  • Although episodes are generally self-limited and resolve within a few days, they can be life-threatening due to laryngeal swelling.
  • These acute episodes are not associated with urticaria or pruritus as they are bradykinin-mediated, not histamine-mediated.
  • Prodromal symptoms include fatigue, GI symptoms, myalgias, and rash (erythema marginatum but not urticaria) that can occur 24 hours prior to an acute episode.
  • Individuals can have variations in disease severity over the course of their lifetime that can have an adverse impact on quality of life.

EPIDEMIOLOGY

  • Estimated prevalence is approximately 1 per 50,000 persons.
  • Males and females are equally affected.
  • No evidence of ethnic or racial differences
  • Patients with hereditary forms of angioedema can present as children or young adults (most common in 8- to 12-year-olds), and symptoms frequently worsen in puberty.
  • Those with acquired forms of C1-INH deficiency generally present later in life (>40 years).

RISK FACTORS

Genetics

  • HAE is inherited in an autosomal dominant pattern; as such, family history is typically positive in these patients.
  • Up to 25% of cases arise from de novo mutations.
  • >400 pathogenic variants have been identified in the gene for C1-INH (SERPING1) located on chromosome 11 resulting in the following:
    • Type I HAE is associated with C1-INH deficiency and accounts for approximately 85% of cases of HAE.
    • Type II HAE is associated with decreased CI-INH activity in the setting of normal levels and accounts for approximately 15% of cases of HAE.
    • HAE with normal C1-INH (formerly type III HAE) is associated with normal C1-INH activity and plasma concentrations.
    • Mutations in factor XII, angiopoietin-1, plasminogen, and kininogen-1 have been identified in some families
    • However, the underlying molecular defect has not been identified in the majority of these patients.
  • Disease severity can differ significantly between family members, and factors determining severity are currently not well understood.
  • Acquired
    • Approximately 6–10% of C1-INH associated angioedema cases are acquired later in life.
    • C1-INH deficiency can develop in association with underlying disease:
      • Lymphoproliferative disorders
      • Malignancy
      • Monoclonal gammopathy of undetermined significance
      • Autoimmune disease
    • The mechanism of C1-INH deficiency is thought to be related to increased catabolism of C1-INH or the presence of autoantibodies leading to inactivation.
  • Triggers
    • A variety of triggers have been reported for acute episodes of C1-INH associated angioedema:
      • Emotional stressors (most common)
      • Physical triggers including mild local trauma such as dental procedures
      • Infections such as upper respiratory infections or Helicobacter pylori in the GI tract
      • Medications containing estrogen (oral contraceptives and hormone replacement), tamoxifen, and angiotensin-converting enzyme inhibitors (ACE-Is) that are contraindicated in patients with HAE
      • Hormonal changes in women (perimenstrual, puberty, or pregnancy)

PATHOPHYSIOLOGY

  • C1-INH is a serine protease inhibitor that serves to inhibit various steps in the classical and lectin complement pathways, intrinsic coagulation cascade, and fibrinolytic and kinin-generating pathways.
  • Swelling associated with angioedema is related to the function of C1-INH in the kinin-generating pathway where it serves to inhibit active factor XII and kallikrein.
  • Thus, when C1-INH activity is absent, overactivation of factor XII and kallikrein leads to cleavage of high molecular weight kininogen that results in the release of bradykinin.
  • Bradykinin subsequently leads to enhanced vascular permeability resulting in swelling.
  • In HAE with normal C1-INH (formerly type III HAE), C1-INH is normal, and generation of bradykinin occurs through alternate mechanisms that are not well understood.

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