Hereditary Angioedema - C1-INH Deficiency


Indications for Testing 

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

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 (eg, autoimmune disorder)
    • 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, consider subtyping
        • No family history of angioedema – measure C1Q
          • 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

  • Cutaneous edema
    • Allergic urticaria/angioedema
    • Drug induced angioedema (eg, ACE inhibitors NSAIDS)
    • Contact dermatitis
    • Acquired angioedema
    • Urticarial vasculitis associated with angioedema
    • Idiopathic or cold-induced angioedema
    • Cellulitis
    • Parasitic infection (eg, Trichinella spp)
    • Autoimmune conditions
  • Laryngeal edema
    • Peritonsillar abscess

Clinical Background

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


  • 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 


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


  • 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

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

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

Aid in diagnosis of 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

Aids in the diagnosis of C1q deficiency

Helps differentiate hereditary from acquired angioedema

Complement Component 4 0050155
Method: Quantitative Immunoturbidimetry

Evaluate for complement consumption

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

Follow-up test for complement activity screening when CH50 is low or absent and AH50 is normal and high suspicion remains for complement deficiency

Complement Component 3 0050150
Method: Quantitative Immunoturbidimetry

Rule out complement component 3 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