A 28-year-old Indian woman presents with recurrent episodes of angioedema affecting her lips, tongue, and throat over the past 6 months. She denies urticaria or pruritus. On examination, she is afebrile with normal vital signs. Laboratory investigations reveal normal C1q levels, normal C4 levels, and normal C1-inhibitor protein levels. However, her C1-inhibitor function is markedly reduced (15% of normal activity). She has no family history of angioedema. What is the most likely diagnosis?

Explanation

## Diagnosis: Hereditary Angioedema Type II ### Clinical Presentation The patient presents with recurrent angioedema without urticaria — a hallmark of hereditary angioedema (HAE). The absence of pruritus and normal vital signs rule out anaphylaxis or allergic angioedema. ### Complement Pathway Defect **Key Point:** HAE results from dysregulation of the contact system and bradykinin generation, mediated by C1-inhibitor (C1-INH) dysfunction. The critical finding here is: - **Normal C1-INH protein levels** (quantity is normal) - **Markedly reduced C1-INH function** (activity is severely impaired) This functional deficiency with normal protein quantity is pathognomonic for **HAE Type II**. ### Comparison of HAE Types | Feature | HAE Type I | HAE Type II | HAE Type III | |---------|-----------|-----------|-------------| | **C1-INH Protein Level** | ↓ (< 50% normal) | Normal (80–120%) | Normal | | **C1-INH Function** | ↓ Proportionally | ↓↓ Markedly (< 50% activity) | Normal | | **C4 Level** | ↓ | ↓ | Normal | | **Frequency** | 85% of HAE cases | 15% of HAE cases | Rare; bradykinin pathway | | **Mechanism** | Reduced synthesis | Dysfunctional protein | Factor XII/kallikrein mutations | ### Why C4 is Low in Both Type I and II **Clinical Pearl:** Even though C1-INH protein is normal in Type II, its dysfunction prevents adequate inhibition of C1s, leading to uncontrolled activation of the classical complement pathway and consumption of C4. This is why C4 is low in both types. ### Pathophysiology 1. Defective C1-INH (Type II) fails to inhibit Factor XIIa and kallikrein 2. Excessive bradykinin generation from high-molecular-weight kininogen (HMWK) 3. Bradykinin → increased vascular permeability → angioedema 4. C1s activation → C4 consumption (hence low C4 despite normal C1-INH quantity) ### Key Distinguishing Feature **High-Yield:** The **functional assay** (C1-INH activity/esterase inhibitor activity) is essential for diagnosis. Type II HAE is identified by normal or near-normal C1-INH protein concentration with reduced functional activity. ### Clinical Management Implications - **Acute attacks:** Bradykinin B2-receptor antagonist (icatibant) or kallikrein inhibitor (ecallantide) - **Prophylaxis:** C1-INH concentrate, danazol, or tranexamic acid - **Avoid:** ACE inhibitors (worsen bradykinin-mediated angioedema) [cite:Harrison 21e Ch 310]