How is type I and type II hereditary angioedema diagnosed and when is long-term prophylaxis indicated?

Diagnosis and Management of Type I and Type II Hereditary Angioedema

Type I and Type II hereditary angioedema (HAE) are diagnosed through specific laboratory testing showing decreased C4 levels and abnormal C1 inhibitor (C1INH) levels or function, while long-term prophylaxis is indicated for patients with recurrent severe attacks, particularly those affecting the airway or causing significant disability.1

Diagnosis of Type I and Type II HAE

Laboratory Testing Algorithm

• Measure complement C4 level as the initial screening test - a low C4 level is generally present in patients with untreated C1INH deficiency 1, 2
• If C4 is low, measure both C1INH antigen (protein) level and C1INH functional activity 1, 2
• Type I HAE (85% of cases): Low C4 + low C1INH antigen levels + low C1INH functional levels 1, 2
• Type II HAE (15% of cases): Low C4 + normal C1INH antigen levels + low C1INH functional levels 1, 2
• C1INH function should be measured with a chromogenic assay for greatest sensitivity in detecting C1INH functional deficiency 1, 2
• Functional level should be less than 50-60% of the lower limit of normal to be compatible with HAE 1, 2
• Positive screening test results should be repeated once to exclude ex vivo degradation or laboratory error 1, 2

Important Diagnostic Considerations

• A normal C4 level during an HAE attack strongly suggests that a diagnosis of HAE is unlikely 1
• C1q levels are typically normal in HAE but low in acquired C1INH deficiency, helping differentiate between the two conditions 1, 3
• HAE is an autosomal dominant disease, with approximately 75% of patients having a positive family history 1
• The remaining 25% of patients have de novo mutations of the C1INH gene 1, 4
• Type I and Type II HAE are clinically indistinguishable - laboratory testing is required for differentiation 1

Indications for Long-Term Prophylaxis

Primary Indications

• Long-term prophylaxis must be individualized based on the patient's specific clinical situation 1
• Key factors indicating need for prophylaxis include:
  • Recurrent severe attacks affecting the airway 1
  • Attacks causing significant disability 1
  • Limited access to appropriate on-demand treatment 1
  • History of life-threatening attacks, particularly laryngeal edema 1, 5
  • Frequent attacks (typically more than one per month) 1, 5

Prophylactic Treatment Options

• Plasma-derived C1INH replacement provides effective and safe long-term HAE prophylaxis (first-line therapy) 1
• Low-to-moderate doses of anabolic androgens provide effective long-term HAE prophylaxis for many patients 1
• Antifibrinolytic agents provide somewhat effective long-term HAE prophylaxis but are generally less effective than androgens 1
• Lanadelumab, a monoclonal antibody against kallikrein administered subcutaneously, is an effective agent for long-term prophylaxis 5

Monitoring and Adjustments

• The dose and effectiveness of long-term prophylaxis should be based on clinical criteria (attack frequency and severity) and not laboratory parameters 1
• Adjunctive strategies to decrease frequency and severity of HAE attacks include:
  • Avoidance of angiotensin-converting enzyme inhibitors 1
  • Avoidance of estrogen therapy when feasible 1
  • Stress reduction 1

Clinical Pitfalls and Caveats

• C4 levels can be normal if the patient is already receiving treatment; in such cases, testing should be repeated during an angioedema attack 1, 2
• HAE does not skip generations - lack of family history does not exclude diagnosis but suggests a de novo mutation 1
• C1INH antigenic levels alone cannot be used as the only diagnostic test for HAE - functional testing is essential to identify Type II HAE 1
• In pregnancy, plasma C1INH levels decrease due to increased plasma volume, so results should be interpreted with caution 2
• Epinephrine, corticosteroids, and antihistamines are not efficacious and are not recommended for the treatment of HAE attacks 1
• HAE with normal C1INH levels (formerly Type III) is a separate condition with different diagnostic criteria and should not be confused with Types I and II 1, 4