U01.02.020 Complement disorders

Understanding complement system disorders is crucial for mastering immunology topics in USMLE Step 1. These disorders are broadly categorized into complement protein deficiencies and complement regulatory protein deficiencies. Below is a structured overview of these disorders.

Complement Protein Deficiencies

1. Early Complement Deficiencies (C1-C4)

Clinical Features:
- Increased risk of severe and recurrent pyogenic sinus and respiratory tract infections.
- Increased risk of systemic lupus erythematosus (SLE).

Deficiency	Associated Features
C1-C4	Recurrent bacterial infections, susceptibility to SLE

2. Terminal Complement Deficiencies (C5–C9)

Clinical Features:
- Increased susceptibility to recurrent Neisseria bacteremia, as the terminal complement components form the membrane attack complex (MAC), critical for defense against Neisseria species.

Deficiency	Associated Features
C5-C9	Recurrent Neisseria infections (e.g., meningitis, septicemia)

Complement Regulatory Protein Deficiencies

1. C1 Esterase Inhibitor Deficiency

Condition: Hereditary Angioedema
Pathophysiology:
- Unregulated activation of kallikrein leads to increased bradykinin, causing angioedema.
Clinical Features:
- Episodes of non-pitting, non-pruritic edema (commonly in the face, GI tract, and extremities).
- Low C4 levels are a diagnostic marker.
Management:
- ACE inhibitors are contraindicated (as they increase bradykinin levels).

Feature	Details
Pathophysiology	↑ Kallikrein → ↑ Bradykinin
Diagnostic Marker	↓ C4 levels
Contraindications	ACE inhibitors

2. Paroxysmal Nocturnal Hemoglobinuria (PNH)

Pathophysiology:
- Defect in the PIGA gene prevents the formation of glycosylphosphatidylinositol (GPI) anchors required for complement inhibitors (e.g., DAF/CD55 and MIRL/CD59).
- This defect leads to complement-mediated intravascular hemolysis.
Clinical Features:
- Dark urine (hemoglobinuria), especially in the morning.
- Decreased haptoglobin due to hemolysis.
Diagnosis:
- Flow cytometry to detect deficiency of CD55/CD59 on erythrocytes.
Complications:
- Increased risk of venous thrombosis and aplastic anemia.

Feature	Details
Genetic Defect	PIGA gene mutation
Complement Inhibitors Affected	DAF/CD55, MIRL/CD59
Key Symptoms	Dark urine, hemolysis

Points to Remember

Early complement deficiencies (C1-C4) are associated with bacterial infections and autoimmune diseases (e.g., SLE).
Terminal complement deficiencies (C5-C9) lead to susceptibility to Neisseria infections.
C1 esterase inhibitor deficiency causes hereditary angioedema; avoid ACE inhibitors.
PNH is a complement regulatory defect with hallmark intravascular hemolysis and dark urine.

Key Takeaways for USMLE Step 1

Understand the difference between complement protein and regulatory protein deficiencies.
Pay attention to associated clinical features and diagnostic markers:
- C4 levels in hereditary angioedema.
- Flow cytometry for CD55/CD59 in PNH.
Recognize the contraindications, such as ACE inhibitors in hereditary angioedema.
Link the deficiencies with the pathogens they predispose to (e.g., Neisseria for C5-C9).

Bibliography and References

Abbas, A. K., Lichtman, A. H., & Pillai, S. Basic Immunology: Functions and Disorders of the Immune System.
Kumar, V., Abbas, A., & Aster, J. Robbins Basic Pathology.
Kaplan AP. Hereditary angioedema: Pathogenesis and diagnosis.

USMLE Step 1 Review Series

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