C4 Deficiency

C4 deficiency arises from loss of the C4A and C4B genes in the major histocompatibility region. Complete deficiency of both is rare and causes severe lupus like disease, while partial C4A deficiency is common and increases the risk of lupus and infection.

Pathophysiology. C4 is needed to form the classical C3 convertase and to clear immune complexes. C4A binds amino groups (immune complexes) and C4B binds hydroxyl groups (microbial surfaces), so loss of C4A impairs immune complex clearance and loss of C4B impairs opsonisation.

Heterozygous C4A deficiency is found in 10 to 15% of Western populations, and complete C4A deficiency in about 1 to 2%. Complete deficiency of both genes is very rare.

C4 gene copy number varies widely, so levels and risk differ between people.

• Complete deficiency: early onset lupus like disease with photosensitive rash, nephritis, arthritis and serositis
• Recurrent bacterial infection: pneumococcal and meningococcal disease, sinopulmonary infection
• Partial C4A deficiency: increased risk of systemic lupus erythematosus, Sjögren syndrome, type 1 diabetes and autoimmune hepatitis
• Henoch-Schönlein purpura and glomerulonephritis in some
• Many people with partial deficiency have no disease

• Total haemolytic complement (CH50): very low in complete deficiency, with normal alternative activation (AH50).
• C4 level: very low or absent, with normal C3.
• C4 gene copy number by multiplex ligation dependent probe amplification or digital PCR, and C4A and C4B allotyping by immunofixation.
• Autoantibodies: antinuclear antibody, anti-dsDNA, anti-Ro.
• Lupus workup: full blood count, creatinine, urinalysis, urine protein-to-creatinine ratio, biopsy as indicated.
• C1 esterase inhibitor level and function if hereditary angio oedema is possible.
• Immunoglobulins and specific antibody responses.

Differential diagnosis.

• Acquired C4 consumption (active lupus, cryoglobulinaemia, immune complex disease)
• Hereditary angio oedema (low C4 with low C1 inhibitor)
• C1q, C1r/C1s and C2 deficiency
• Mannose binding lectin activation defects
• Antibody deficiency
• Systemic lupus erythematosus without complement deficiency

• Complete C4 deficiency with lupus:
  • Hydroxychloroquine 200 to 400 mg orally daily, not over 5 mg/kg of actual body weight daily, with eye screening at baseline and yearly after 5 years of use.
  • Prednisolone 0.5 to 1 mg/kg orally daily (maximum 60 mg) for flares, tapered to the lowest effective dose.
  • Mycophenolate mofetil 1 g orally twice daily for nephritis.
• Vaccination: pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later, meningococcal ACWY and B vaccines, Haemophilus influenzae type b vaccine, and yearly inactivated influenza vaccine.
• Antibiotic prophylaxis after invasive infection or with repeated infection: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily).
• Acute fever or illness: this is possible sepsis. After blood cultures, give ceftriaxone 2 g intravenously (children 50 to 80 mg/kg, maximum 2 g) without waiting for results.
• Partial C4A deficiency without disease: no treatment; counsel about symptoms of lupus and keep vaccinations current.
• Fresh frozen plasma is not given routinely; it is considered only in life threatening infection while antibiotics are given.
• Treat acquired low C4 by treating its cause (lupus flare, cryoglobulinaemia).

Special groups.

• Pregnancy: lupus and anti-Ro antibodies need joint rheumatology and obstetric care.
• Families: test relatives of patients with complete deficiency, because autosomal recessive inheritance means each sibling has a 1 in 4 risk.

Monitoring. Yearly clinical review for infection, rash, joint and renal symptoms. Urinalysis and creatinine yearly, and every 3 months during active lupus. Pneumococcal titres every 3 to 5 years.

Referral and escalation. Refer to immunology and rheumatology. Urgent for fever, meningism, nephritis, or new neurological symptoms.