A 28-year-old man from Delhi presents with recurrent pyogenic infections (Staphylococcus aureus and Streptococcus pneumoniae) since childhood, along with episodes of angioedema. Physical examination reveals hepatosplenomegaly. Serum C3 levels are markedly reduced (8 mg/dL; normal 70–150 mg/dL), while C4 is normal. Serum electrophoresis shows no monoclonal spike. Which complement pathway defect is most likely responsible for his clinical presentation?

Explanation

## Clinical Interpretation This patient presents with a classic triad of findings: 1. **Recurrent pyogenic infections** (encapsulated organisms: *S. aureus*, *S. pneumoniae*) 2. **Angioedema** (suggesting dysregulation of C3 activation) 3. **Markedly low C3 with normal C4** ## Complement Pathway Defects: Differential | Finding | Classical Pathway | Alternative Pathway | Terminal Pathway | Lectin Pathway | |---------|-------------------|---------------------|------------------|----------------| | **C3 level** | Normal or slightly low | Markedly low | Normal | Normal | | **C4 level** | Low | Normal | Normal | Normal | | **Infection pattern** | Encapsulated organisms | Encapsulated organisms | *Neisseria* spp. | Encapsulated organisms | | **Angioedema** | Yes (C1-INH deficiency) | Yes (Factor H/I deficiency) | No | Rare | | **Hepatosplenomegaly** | No | Yes (immune complex deposition) | No | No | ## Why Alternative Pathway Deficiency? **Key Point:** Deficiency of Factor H or Factor I (both negative regulators of the alternative pathway) leads to **uncontrolled C3 activation** → **C3 consumption** → **markedly low C3 with normal C4**. **High-Yield:** The alternative pathway is the major amplification loop of complement. Loss of its regulators causes continuous C3 cleavage, explaining: - Severe C3 depletion - Recurrent infections (C3 opsonization is critical for phagocytosis of encapsulated bacteria) - Angioedema (C3a and C5a generation) - Immune complex deposition in kidneys and spleen (hepatosplenomegaly) **Clinical Pearl:** Factor H deficiency is the most common genetic complement deficiency in humans and is associated with membranoproliferative glomerulonephritis (MPGN) and C3 glomerulopathy. **Mnemonic:** **"ALT-C3"** — **ALT**ernative pathway deficiency → **C3** consumption (low C3, normal C4). ## Why Not Classical Pathway? Classical pathway deficiency (C1q, C1r, C1s, C2) causes **low C4 and normal or slightly low C3**. This patient has normal C4, ruling out classical pathway deficiency. Additionally, C1-INH deficiency (hereditary angioedema) does not present with recurrent infections. ## Why Not Terminal Pathway? Terminal pathway defects (C5–C9) cause **selective susceptibility to *Neisseria* species** (meningococcus, gonorrhea), not *Staphylococcus* or *Streptococcus*. C3 and C4 levels are normal. No angioedema. ## Why Not Lectin Pathway? Lectin pathway deficiency (MBL, MASP-2) causes mild infections in infants and young children but typically resolves by adulthood. C3 levels remain normal. Hepatosplenomegaly is not a feature.