Hereditary Angioedema - C1-INH Deficiency

Diagnosis

Indications for Testing 

• Recurrent angioedema, laryngeal edema, or abdominal pain in the absence of urticaria
• Family history

Laboratory Testing

• Initial testing – C1 through C4
  • C4, C1-INH protein quantities normal
    • Confirm C4, C1-INH normal values during attack
    • Suspect other types of angioedema
  • C4, C1-INH protein quantities decreased – angioedema due to C1-INH deficiency
    • Confirm by second measurement of C4 and C1-INH
      • Family history of angioedema – hereditary angioedema
      • No family history of angioedema – measure C1Q and consider age of onset of symptoms
        • Earlier age of onset and/or C1Q normal – hereditary angioedema
        • Later age of onset and/or low C1Q – acquired angioedema
• C1-INH typing
  • Type 1 – low antigenic and functional levels; if C1Q is low, suspect acquired angioedema
  • Type 2 – normal antigenic level but low functional level
  • Type 3 – normal antigenic and functional levels
• Genetic testing not necessary

Differential Diagnosis

• Allergic urticaria or angioedema
• Idiopathic or cold-induced angioedema
• Angiotensin-converting enzyme (ACE)-associated angioedema
• Nonsteroidal anti-inflammatory drug (NSAID)-associated angioedema
• Angioedema with urticarial vasculitis
• Acquired angioedema
  • Lymphoproliferative disorders (lymphoma, B-cell, T-cell)
  • Autoimmune disease
  • Neoplasia

Clinical Background

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 spontaneous mutations
• Mutations in C1-INH 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 in C1-INH
  • Type 1 or null – 85%
  • Type 2 or dysfunctional – 15%
  • Deficiency of functionally active component may lead to life-threatening angioedema
  • Rare type 3 defect (familial angioedema) associated with similar clinical presentation but normal C1-INH levels
• Acquired C1-INH deficiency is a qualitative (functional) deficiency of inhibitor
  • 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 but recurrent attacks of non-pruritic, 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

Treatment 

• Therapy for congenital defect is non-virilizing androgen treatment, which partially corrects the biochemical defect
• Aminocaproic acid
  • May be used for preoperative prophylaxis
  • Contraindicated in patients with thrombotic tendencies
• C1 inhibitor concentrate

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Complement Component 2 0050148 Method: Quantitative Radial Immunodiffusion	Rule out complement component 2 deficiency
Complement Component 3 0050150 Method: Quantitative Immunoturbidimetry	Rule out complement component 3 deficiency
Complement Component 4 0050155 Method: Quantitative Immunoturbidimetry	Rule out complement component 4 deficiency
C1-Esterase Inhibitor 0050140 Method: Quantitative Nephelometry	Diagnose HAE; lacks complement component 4 test
C1-Esterase Inhibitor Functional 0050141 Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Diagnostic Algorithm

  C1-INH Deficiency Testing Algorithm