Difference Between Type 1 and Type 2 Hereditary Angioedema
The main difference between Type 1 and Type 2 Hereditary Angioedema (HAE) is that Type 1 HAE presents with low C1 inhibitor (C1INH) antigenic and functional levels, while Type 2 HAE presents with normal C1INH antigenic levels but decreased C1INH functional levels. 1
Key Characteristics
Type 1 HAE:
- Accounts for approximately 85% of HAE cases 1
- Characterized by decreased production of C1INH protein
- Results in reduced functional activity to 5-30% of normal 2
- Low C1INH antigenic levels in blood tests
- Low C1INH functional levels
- Caused by mutations in the SERPING1 gene that result in either truncated proteins or misfolded proteins that cannot be secreted 1
Type 2 HAE:
- Accounts for approximately 15% of HAE cases 1
- Normal or even elevated quantities of C1INH protein in blood
- The C1INH protein is dysfunctional 2
- Normal C1INH antigenic levels
- Low C1INH functional levels
- Caused by mutations in the SERPING1 gene typically involving residues at or near the active site on the reactive mobile loop 1
Clinical Presentation
Despite the biochemical differences, Type 1 and Type 2 HAE are clinically indistinguishable 1:
- Both present with recurrent episodes of nonpruritic, nonpitting subcutaneous or submucosal edema
- Common sites of swelling include extremities, face, trunk, abdominal viscera, and upper airway
- Symptoms typically begin in childhood and worsen at puberty 3
- Attacks follow a stereotypical pattern: worsening over 24 hours, peaking, and then slowly resolving over the following 48-72 hours 3
Diagnostic Approach
For both types:
- Screening test is complement component C4, which is low to absent during attacks and often during quiescent periods 1
- C1q protein is normal in both Type 1 and Type 2 HAE (useful to differentiate from acquired angioedema) 4
Differential diagnosis:
- Type 1 HAE: Low C4, low C1INH antigenic level, low C1INH functional level
- Type 2 HAE: Low C4, normal C1INH antigenic level, low C1INH functional level
- C1INH function should be measured with a chromogenic assay for greatest sensitivity 1
Treatment Implications
The treatment approach is identical for both Type 1 and Type 2 HAE since both result from C1INH functional deficiency 1:
- Acute attacks: C1INH concentrate, kallikrein inhibitors (ecallantide), or bradykinin B2 receptor antagonists (icatibant)
- Long-term prophylaxis: C1INH replacement therapy, lanadelumab (anti-kallikrein monoclonal antibody), or in some cases anabolic androgens
Important Considerations
- Both types are autosomal dominant disorders with a 50% chance of transmission to offspring 1
- Both types have the same primary mediator of swelling: bradykinin 1
- A third form of HAE with normal C1INH (previously called Type 3) exists but is distinct from Types 1 and 2 and is much rarer 5
- Functional testing is essential for diagnosis of Type 2 HAE since antigenic levels appear normal 1
Both Type 1 and Type 2 HAE carry significant morbidity and potential mortality risks, particularly with laryngeal attacks, making prompt diagnosis and access to appropriate treatment essential for patient outcomes 1.