Hereditary Angioedema (HAE) Testing Solutions

Hereditary angioedema (HAE) is a rare disease (orphan) with episodic swelling (edema) associated with the deficiency or dysfunction of complement 1 esterase inhibitor (C1-INH) that can result in attacks in various anatomic areas with ranges in severity including death. Laryngeal edema can result in asphyxiation; abdominal angioedema attacks can lead to unnecessary surgery and delay in diagnosis and cutaneous attacks can be disfiguring and disabling.

In contrast to acquired angioedema, which is a secondary process, HAE is associated with genetic variations. Initial laboratory assessment involves testing for C1-INH levels, complement 4 (C4) levels, functional C1-INH activity, and C1q levels.

What is C1-esterase Inhibitor (C1-INH)?
  • A multi-specific 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)
    • Kallikrein
    • Plasmin
HAE Pathophysiology
Possible disorders associated with C1-INH deficiency include:
  • Hereditary Angioedema
    • 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
Epidemiology:

Genetic inheritance:

  • Autosomal Dominant (up to 25% for de novo variants)
  • SERPING1 Gene Variants

Incidence:

  • 1 in 50,000 worldwide population
  • Male – Female ration 1:1
  • Age: usually manifests in childhood around puberty

Risk Factors:

  • Genetics
  • Stress – physical and mental stressors
  • Drugs – estrogens

Diagnostic Testing to differentiate the 3 types of HAE types, via complement testing (genetic testing is also available)

  • Type I HAE is characterized by the following (85% of cases):
    • Low C1 esterase inhibitor (C1-INH) protein/antigen level
    • Low C4 level
    • Normal C1q level
  • Type II HAE is characterized by the following (15% of cases):
    • Normal or elevated, but dysfunctional, C1-INH level
    • Low C4 level
    • Normal C1q level
  • HAE with normal C1 inhibitor levels is characterized by the following (rare):
    • Normal C1-INH level
    • Normal C1-INH functional assay
    • Normal C4 and C1q level
    • Factor XII (or plasminogen, angiopoetin 1, or kininogen) mutation may be present

Complement values in angioedema

Type

Subtype

C4

C1INH

Antigen

C1INH

Function

C1q

HAE due to C1INH deficiency

Type I

Low

Low

Low

Normal

 

Type II

Low

Normal

Low

Normal

HAE with normal C1INH

fXII Mutation

Normal

Normal

Normal

Normal

 

Unknown cause

Normal

Normal

Normal

Normal

Acquired C1INH deficiency

Low

Low

Low

Low

ACE-I related

Normal

Normal

Normal

Normal

Allergic

Normal

Normal

Normal

Normal

Unknown etiology

Histaminergic

Normal

Normal

Normal

Normal

 

Nonhistaminergic

Normal

Normal

Normal

Normal

ACE-I = angiotensin-converting enzyme inhibitor; C1INH = C1 inhibitor; HAE = hereditary angioedema.

Hereditary Angioedema (HAE) Test Panel