Summary
Complement C4 is a protein of the classical complement activation pathway, part of the immune system that clears pathogens and immune complexes. C4 is measured together with C3 to investigate and monitor autoimmune diseases — especially systemic lupus erythematosus — and is central to diagnosing hereditary angioedema, where C4 is characteristically low.
C4 acts early in the classical complement pathway, which is triggered by antibody-antigen complexes. When this pathway is activated — as in active lupus — C4 is consumed and its level falls, usually alongside a fall in C3.
A persistently low C4 with normal C3 has specific significance: it is a hallmark of hereditary angioedema, a condition causing recurrent episodes of swelling. Low C4 can also reflect inherited partial C4 deficiency, which is relatively common and predisposes to autoimmune disease.
Like C3, C4 is used to monitor disease activity in lupus and to investigate immune-complex and complement-mediated conditions. The combined pattern of C3 and C4 is more informative than either alone.
What It Is
Complement C4 is synthesised mainly by the liver and is an early component of the classical (and lectin) complement activation pathways. Upon activation, C4 is cleaved into C4a and C4b; C4b combines with C2a to form the classical pathway C3 convertase, linking C4 activation to C3 cleavage.
C4 is encoded by two genes (C4A and C4B) with common copy number variation, so partial inherited C4 deficiency is relatively frequent and is associated with increased autoimmune risk. C4 is consumed during classical pathway activation, so low levels indicate activation or deficiency. A characteristically low C4 (with normal or low C1 inhibitor function) is central to diagnosing hereditary angioedema.
Reference ranges: approximately 0.14–0.54 g/L, varying by laboratory. Interpretation depends on the concurrent C3 level and clinical context.
Functions
Classical pathway immunity
An early component of the classical complement pathway, triggered by antibody-antigen complexes to clear pathogens.
Lupus monitoring
Low C4, usually with low C3, reflects active lupus and is used to monitor disease flares.
Hereditary angioedema diagnosis
A characteristically low C4 is central to diagnosing hereditary angioedema, a cause of recurrent swelling.
Pathway localisation
The C3/C4 pattern distinguishes classical pathway activation (both low) from alternative pathway activation (C3 low, C4 normal).
Reference Ranges
Complement C4
Measured in g/L| Status | Range (g/L) | Range (mg/dL) | What it means |
|---|---|---|---|
| Low | < 0.14 | < 14 | Low C4 — classical pathway activation (lupus), hereditary angioedema, or inherited deficiency. |
| Normal | 0.14–0.54 | 14–54 | Normal complement C4 — no evidence of significant consumption. |
| High | > 0.54 | > 54 | Elevated — acute phase response from inflammation or infection. |
Reference ranges vary between laboratories. C4 is both consumed in immune-mediated disease and raised as an acute phase reactant. Inherited partial C4 deficiency is common. Interpret with C3 and clinical context.
Symptoms of Imbalance
C4 abnormalities reflect underlying autoimmune disease, hereditary angioedema, or complement deficiency rather than causing symptoms directly.
- Recurrent episodes of swelling (hereditary angioedema)
- Symptoms of active lupus (joint pain, rash, fatigue)
- Recurrent infections (with complement deficiency)
- Abdominal pain attacks (angioedema affecting the gut)
- Usually reflects an acute phase response — symptoms of the underlying inflammation or infection
- No specific symptoms from a high C4 itself
Causes of Imbalance
- Active systemic lupus erythematosus
- Hereditary angioedema (C1 inhibitor deficiency)
- Inherited partial C4 deficiency
- Immune-complex glomerulonephritis
- Cryoglobulinaemia
- Severe infection (consumption)
- Acute phase response (infection, inflammation, injury)
- Some malignancies
- Non-active phase of inflammatory disease
FAQs
A low C4 usually means the classical complement pathway is being activated and consumed — most often in active lupus, typically alongside a low C3. A persistently low C4 with a normal C3 has particular significance, pointing toward hereditary angioedema or an inherited partial C4 deficiency. The cause is determined by interpreting C4 alongside C3, autoantibodies, and the clinical picture.
Hereditary angioedema is caused by a deficiency or dysfunction of C1 inhibitor, which normally restrains the classical complement pathway. Without adequate C1 inhibitor, C4 is continuously consumed, so a low C4 is found both during and between attacks. A persistently low C4 is therefore an important screening clue, prompting specific tests of C1 inhibitor level and function to confirm the diagnosis.
Yes. C4 is encoded by genes that vary in copy number between individuals, so inherited partial C4 deficiency is relatively common and can result in a low-normal or low C4 without active disease. However, partial complement deficiency does carry a modestly increased risk of autoimmune conditions, so a persistently low C4 is usually interpreted in the context of symptoms and other immune markers.
The pattern of C3 and C4 helps localise complement activation. Both low suggests classical pathway activation, as seen in active lupus. A low C4 with normal C3 points toward hereditary angioedema or inherited C4 deficiency. A low C3 with normal C4 suggests alternative pathway activation. Measuring them together therefore provides much more diagnostic information than either result alone.
References
- Walport MJ. Complement. Second of two parts. N Engl J Med. 2001;344(15):1140–1144. View source
- Cicardi M, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report. Allergy. 2014;69(5):602–616. View source
- Yang Y, et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus. Am J Hum Genet. 2007;80(6):1037–1054. View source