Hereditary Angioedema - C1-INH Deficiency

Hereditary angioedema (HAE) is an episodic swelling disease associated with the deficiency or malfunction of C1-esterase inhibitor.

Epidemiology

• Incidence – 1/50,000
• Age
  • Congenital form – usually occurs in childhood
  • Acquired form – onset occurs later
• Sex – M:F, equal

Risk Factors

• Genetics
• Pressure applied to an extremity
• Stress
• Ingested estrogens, pregnancy
• Lymphoproliferative disorder

Inheritance

• Autosomal dominant inheritance
  • 25% are de novo mutations
• Mutations in SERPING1 gene

Pathophysiology

• C1-esterase inhibitor (C1-INH) is a multispecific, protease inhibitor
• C1-INH regulates the enzymes of the complement, coagulation, fibrinolytic and kinin-forming systems, including the following
  • C1r and C1s subunits of activated first component of complement
  • Activated Hageman factor (factor XIIa) and Hageman factor fragments
  • Activated plasma thromboplastin antecedent (PTA or factor XIa)
  • Prekallikrein (Fletcher factor)
  • Plasmin
• HAE is a hereditary quantitative deficiency or qualitative defect in C1-INH
  •  Deficiency of functionally active component may lead to life-threatening angioedema
  • Types
    • Type 1 – 85%
      • Low production or absence of C1-INH levels
    • Type 2 – 15%
      • Dysfunctional C1-INH
    • Type 3 (familial angioedema) – rare
      • Normal C1-INH levels
• Acquired C1-INH deficiency – qualitative defect in C1-INH
  • Associated with a variety of diseases, including lymphoid malignancies

Clinical Presentation

• Symptoms typically begin in childhood, worsen in puberty, and have an unpredictable course throughout adulthood
• Transient, recurrent attacks of nonpruritic, deep-seated swelling of various tissues occur throughout the body without the presence of urticaria
  • Typically involves arms, legs, hands, trunk, face, mouth, larynx, airway, genitals and tongue
• Gastrointestinal tract often involved, with recurrent episodes of cramping, abdominal pain, nausea and emesis (most frequent presenting complaint in children)
• Most frequent cause of death is airway obstruction secondary to laryngeal edema
• Presence of autoimmune diseases (especially glomerulonephritis) is higher in these patients
• Typical and predictable course
  • Many attacks, preceded by prodrome (tingling sensation)
  • Swelling gradually increases over the first 24 hours then gradually subsides over the next 48-72 hours