A 28-year-old man from Mumbai presents with recurrent pyogenic infections (Staphylococcus aureus abscess, Streptococcus pneumoniae meningitis) and a history of angioedema episodes. Physical examination reveals hepatosplenomegaly. Serum complement levels are measured: C3 = 45 mg/dL (normal 90–180), C4 = 8 mg/dL (normal 15–45). CH50 (total hemolytic complement) is markedly reduced. Which complement component deficiency is most likely responsible for this clinical presentation?

Explanation

## Clinical Presentation Analysis This patient presents with a classic triad of findings: 1. **Recurrent pyogenic infections** (especially encapsulated organisms) 2. **Angioedema** (though less typical for C3 deficiency alone) 3. **Low C3 and C4 with markedly reduced CH50** ## Complement Pathway Interpretation **Key Point:** C3 is the central hub of all three complement pathways (classical, alternative, lectin). Deficiency of C3 results in: - Severely reduced opsonization → recurrent pyogenic infections - Loss of C3a and C5a generation → impaired chemotaxis and anaphylatoxin activity - Markedly reduced CH50 (C3 is essential for all downstream steps) - Both C3 and C4 are consumed in classical pathway activation ## Differential Diagnosis of Complement Deficiencies | Deficiency | Infections | Angioedema | C3 Level | C4 Level | CH50 | Clinical Pearl | |---|---|---|---|---|---|---| | **C3 deficiency** | ✓ Pyogenic (most common) | Rare | ↓↓ | Normal/↓ | ↓↓ | Worst prognosis for infections | | C1-INH deficiency | ✗ | ✓✓ (hallmark) | Normal | ↓ | Normal | Hereditary angioedema (HAE) | | C5 deficiency | ✓ Neisseria only | ✗ | Normal | Normal | ↓ | Selective Neisseria risk | | Properdin deficiency | ✓ Neisseria | ✗ | Normal | Normal | ↓ | X-linked; Neisseria meningitidis | **High-Yield:** C3 deficiency is the **most severe** complement deficiency for overall infection risk because C3 is required for: - Opsonization (C3b coating of pathogens) - Chemotaxis (C3a) - Membrane attack complex formation (C3 → C5 activation) ## Why CH50 is Markedly Reduced CH50 measures the ability of serum to lyse antibody-sensitized red blood cells. Since C3 is absolutely required for: - Classical pathway completion (C3 → C5 → MAC) - Alternative pathway amplification - Lectin pathway convergence ...C3 deficiency eliminates all three pathways' hemolytic capacity. **Clinical Pearl:** Patients with C3 deficiency often develop **post-infectious glomerulonephritis** and **membranoproliferative GN** due to immune complex deposition and lack of C3b-mediated clearance.