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

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

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
Test Name and Number Recommended Use Limitations Follow Up
C-1-Esterase Inhibitor Panel 0050139
Method: Immunoturbidimetry/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Quantitative Nephelometry

Determine C1-esterase inhibitor levels and diagnose hereditary angioedema (HAE)

Tests for C1-esterase inhibitor levels and complement C4 levels

 

May want to test for C2 to confirm C1-esterase deficiency and rule out complement deficiency

Complement Component 1Q Level 0099130
Method: Radial Immunodiffusion
Helps differentiate hereditary from acquired angioedema    
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
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