What does a markedly low complement component 4 (C4) level indicate?

What Does a Low C4 Level Indicate?

A markedly low C4 level indicates either C1 inhibitor deficiency (hereditary or acquired angioedema), active autoimmune disease (particularly systemic lupus erythematosus), or complement consumption from immune complex formation. 1, 2

Immediate Diagnostic Algorithm

Step 1: Measure C1 Inhibitor Levels

• Order both C1INH antigen and functional levels immediately when C4 is low, as at least 95% of patients with C1INH deficiency demonstrate reduced C4 levels even between attacks 1, 2
• C4 is an excellent screening tool for C1INH deficiency states, with virtually 100% of patients showing low C4 during angioedema attacks 1

Step 2: Interpret the Pattern

If C1INH deficiency is present:

• Type I HAE: Low C4 + low C1INH antigen + low C1INH function (<50-60% of normal) - accounts for ~85% of cases 1, 3
• Type II HAE: Low C4 + normal C1INH antigen + low C1INH function 1, 3
• Acquired C1INH deficiency: Low C4 + low C1INH + low C1q levels (this distinguishes acquired from hereditary forms) 1, 3

If C1INH levels are normal:

• Consider systemic lupus erythematosus or other autoimmune disease with complement consumption 1, 2
• Low C4 with normal C3 in SLE suggests active disease, particularly lupus nephritis 2
• Measure factor B alongside C4: if both are low, complement consumption is confirmed 1, 4

Step 3: Check for Genetic Deficiency

• Complete C4 deficiency (homozygous) is one of the strongest genetic risk factors for SLE, typically presenting in early childhood 5, 6
• Heterozygous C4A deficiency (C4AQ0) is present in 40-60% of SLE patients across ethnic groups, with relative risk of 2.3-5.3 7

Critical Management Actions

If C1INH Deficiency is Confirmed:

• Immediately discontinue ACE inhibitors or ARBs - they are absolutely contraindicated in C1INH deficiency 1, 2
• Recognize that traditional antihistamines and corticosteroids are ineffective for HAE attacks 1
• The proclivity to swell can continue for at least 6 weeks after ACE inhibitor discontinuation 1

If Autoimmune Disease is Suspected:

• Measure C3 alongside C4, as the pattern helps distinguish between consumption (both low) and classical pathway defects (C4 low, C3 normal) 1, 4
• For established SLE with nephropathy, monitor C3 and C4 every 3 months for the first 2-3 years alongside anti-dsDNA, urine protein/creatinine ratio, and blood pressure 2

Common Pitfalls to Avoid

• Do not rely on a single C4 measurement during active treatment: C4 levels can normalize in patients already receiving therapy for autoimmune disease or HAE; repeat testing during an acute attack or flare is essential 1, 2
• Ensure timely laboratory processing: C4 samples must be sent to the laboratory promptly and placed on ice or refrigerated immediately after drawing, as complement proteins degrade rapidly with warming, leading to falsely low results 1, 4
• Do not assume normal C4 excludes C1INH deficiency in treated patients: When repeated during an HAE attack, the C4 level should be low; a normal C4 level during an attack strongly suggests an alternative diagnosis 1
• Repeat positive screening results once to exclude ex vivo degradation or laboratory error before making definitive treatment decisions 1, 3

When Specific Patterns Emerge

Low C4 with recurrent angioedema:

• If C4 and C1INH are normal, consider HAE with normal C1INH levels (diagnosis of exclusion with strong family history) 1
• A normal C4 level during an attack of angioedema strongly suggests that HAE is unlikely 1

Low C4 in young patients with lupus-like disease:

• Early complement component deficiencies (particularly C4) predispose to SLE-like syndromes presenting in childhood 5, 6
• Complete C4 deficiency is inherited in autosomal recessive fashion and strongly associated with lupus across HLA haplotypes and racial backgrounds 6, 7