Hereditary Angioedema - C1-INH Deficiency

Diagnosis

Indications for Testing

• Recurrent angioedema in the absence of urticaria of
  • Subcutaneous tissues
  • Systemic organs
  • Mouth, larynx, or pharynx
• Family history of angioedema
• Unexplained episode of laryngeal edema

Laboratory Testing

• Initial testing
  • Complement 1 esterase inhibitor (C1-INH), complement 4 (C4)
    • Decreased levels suggest hereditary angioedema
    • Confirm with repeat testing of C1-INH and C4
    • If family history present, consider functional testing for typing
  • Functional C1-inhibitor activity
    • Assists with determination of hereditary angioedema type
  • Consider C1q testing when family history is absent
    • Later age of onset and low C1q suggest acquired angioedema
    • Early age of onset and normal C1q suggest familial angioedema
  • If all results are normal
    • Repeat C4, C1-INH testing during attack
    • Consider other types of angioedema (eg, autoimmune disorder)
• Genetic testing – not necessary for diagnosis

Differential Diagnosis

• Cutaneous edema
  • Allergic urticaria/angioedema
  • Drug-induced angioedema (eg, angiotensin-converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs])
  • Contact dermatitis
  • Acquired angioedema
    • Lymphoproliferative disorders (lymphoma, B-cell and T-cell lymphomas)
    • Autoimmune disease
    • Neoplasia
  • Urticarial vasculitis associated with angioedema
  • Idiopathic or cold-induced angioedema
  • Cellulitis
  • Parasitic infection (eg, Trichinella spp)
  • Autoimmune conditions
• Laryngeal edema – peritonsillar abscess

Background

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 variants
• Variants in SERPING1 gene

Classification

• Hereditary angioedema (HAE) types
  • Type 1 – low complement 1 esterase inhibitor (C1-INH) level and low function (85%)
    • If C1q is also low, suspect acquired angioedema
  • Type 2 – normal C1-INH  level but low function (15%)
  • Type 3 (familial angioedema) – normal C1-INH  and normal function (rare)

Pathophysiology​

• C1-INH
  • Multispecific, protease inhibitor
  • Regulates the enzymes of the complement, coagulation, fibrinolytic, and kinin-forming systems, including
    • 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
  • Possible disorders associated with C1-INH include
    • HAE
      • Hereditary quantitative deficiency or qualitative defect in C1-INH
      • Deficiency of functionally active component may lead to life-threatening angioedema
    • 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