What does a low Complement C4 (complement component 4) level of 15 indicate and how is it managed?

Complement C4 Level of 15: Interpretation and Management

What This Result Indicates

A C4 level of 15 mg/dL is low and strongly suggests C1 inhibitor (C1INH) deficiency, requiring immediate measurement of both C1INH antigen and functional levels to distinguish between hereditary angioedema (HAE) types I and II versus acquired C1INH deficiency. 1

Immediate Diagnostic Steps

Measure C1INH levels immediately:

• Order both C1INH antigen (protein) level AND C1INH functional activity 1, 2
• Functional level must be <50-60% of the lower limit of normal to confirm HAE 3, 2
• Use chromogenic functional assays rather than ELISA-based assays when available, as they provide superior accuracy 2
• Ensure samples reach the laboratory promptly to avoid artificially low results from degradation 1

Interpretation Based on C1INH Results

Type I HAE (85% of cases):

• Low C4 + low C1INH antigen + low C1INH function 1, 2

Type II HAE (15% of cases):

• Low C4 + normal or elevated C1INH antigen + low C1INH function 3, 1, 2

Acquired C1INH deficiency:

• Low C4 + low C1INH antigen/function + low C1q (this distinguishes it from hereditary forms) 1, 2
• Consider this diagnosis particularly if patient is >40 years old or has late-onset symptoms 4

Critical Management Decisions

Discontinue ACE inhibitors or ARBs immediately if the patient is taking these medications—they are absolutely contraindicated in C1INH deficiency 1

Recognize that traditional therapies are ineffective:

• Epinephrine, antihistamines, and corticosteroids do not reliably work for C1INH deficiency-related angioedema 1, 4
• If the patient's swelling previously improved with steroids, this suggests mast cell-mediated angioedema rather than C1INH deficiency 4

Acute attack management:

• Contact system medications (icatibant, ecallantide) are appropriate for acute attacks 1
• C1INH replacement therapy is the definitive treatment for confirmed HAE

Important Pitfalls to Avoid

Do not rely on C4 alone during treatment:

• C4 levels can normalize in patients already receiving HAE therapy 3, 1
• If C4 is normal but HAE is suspected, repeat testing during an active angioedema attack—C4 should be low during attacks in true HAE 3
• A normal C4 level during an attack strongly argues against HAE as the diagnosis 3, 4

Confirm positive results:

• Repeat abnormal screening tests once to exclude ex vivo sample degradation or laboratory error 2

Consider alternative diagnoses:

• If C4 and C1INH levels are normal, consider HAE with normal C1 inhibitor (HAE-nC1INH), diagnosed by exclusion with family history and lack of response to antihistamines 4
• Low C4 can also occur in systemic lupus erythematosus (SLE) and other autoimmune conditions, though the clinical presentation differs markedly from angioedema 5, 6, 7

Special Populations

Pregnancy considerations:

• C1INH levels decrease during pregnancy due to increased plasma volume, so interpret results cautiously 2

Pediatric patients:

• C1INH and C4 levels reach mature adult levels between 6-36 months and 2-3 years of age, respectively 2