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

Complement C4 total, Serum
Complement C1 Esterase Inhibitor, Antigenic, Serum (C1-INH)
Complement C1 Esterase Inhibitor, Functional, Chromogenic Assay
Complement C1q, Quantitative
Complement C1 Esterase Inhibitor, Functional, Factor XIIa, plasma
Complement C1 Esterase Inhibitor, Functional, Kallikrein, plasma
Complement C1 Esterase Inhibitor, Functional, C1s