Complement C3 and C4: what it is, what it tells you and when it’s tested

Complement is a group of blood proteins that helps antibodies clear germs and damaged cells. C3 and C4 are the two measured most often. When your immune system is working hard, for example in some autoimmune conditions, they get used up and fall.

When it’s tested

Doctors mostly order it when they suspect or follow lupus, when there are signs of kidney inflammation, or when you have sudden, repeated swellings of the skin without hives, which can point to hereditary angioedema.

It is also used to follow some autoimmune conditions over time: complement that falls can be a sign the disease is flaring up again.

It is not a test for people who feel well. That is why Rosa does not test it. Instead it looks at high-sensitivity CRP for inflammation, and creatinine, eGFR and a urine test for your kidneys.

What it tells you, and what it does not

Which one is low matters. If both are low, your immune system is often using them up, as in active lupus. If only C3 is very low, doctors think of some kidney conditions. If only C4 is low, there may be an inherited fault in a protein that controls it.

Slightly high values are often seen with inflammation or infection, because the liver makes more. They are usually not a worry.

Complement on its own does not make a diagnosis. It is read alongside your symptoms and other tests.

That is why it is read together with other tests:

• Antinuclear antibodies (ANA): The first test when lupus is suspected
• Urine test: It shows whether your kidneys leak protein or blood
• Creatinine: It shows how well your kidneys filter
• High-sensitivity CRP: It shows whether there is inflammation

Normal C3 and C4 levels

The lab decides what is normal. Many give roughly 90 to 180 mg/dL for C3 and 10 to 40 mg/dL for C4. Your report may print slightly different limits, or use g/L: 90 mg/dL is 0.9 g/L.

A value just outside the limits, on its own and with no symptoms, often means nothing. The trend over time and the other tests are what count.

You do not need to fast or prepare in any special way.

If your C3 or C4 is low or high

• Low C3 and C4: Often your immune system is using them up, as in active lupus. They should be looked at with your doctor.
• High C3 or C4: They usually follow inflammation or infection. They are rarely a problem on their own.

Why C3 and C4 are low

The causes depend on which one falls.

• Both low: active lupus: The best-known cause. There are usually symptoms and a positive ANA too.
• Both low: other conditions: Some types of vasculitis, cryoglobulinaemia and severe infections can use them up.
• Only C3 very low: Points to kidney inflammation, for example after a strep infection, or to rare kidney conditions.
• Only C4 low: It can point to an inherited shortage of C1 inhibitor, which causes angioedema. A normal C4 makes this unlikely.
• The liver makes too little: With severe liver disease both can fall.

What can skew the result

A few things change the value without any disease.

• Ongoing inflammation: A cold or another infection can raise C3 and C4 a little, and hide a fall.
• The lab: Limits differ a little between labs. To follow them over time, it helps to stay with the same one.
• A single test: A value just outside the limits counts for little on its own. Your doctor looks at how it changes from one test to the next.

When to worry

Talk to your doctor if:

• Your C3 and C4 are low and you have joint pain, skin rashes or fever for no reason.
• You have foamy or dark urine, swollen legs or rising blood pressure.
• You keep getting swellings of the skin, face or belly, without hives.
• You have swelling of the tongue, lips or throat, or trouble breathing or swallowing: call 112 or go to the emergency department.

Frequently asked questions

What are normal C3 and C4 levels? Many labs give roughly 90 to 180 mg/dL for C3 and 10 to 40 mg/dL for C4. The range on your own report is what counts.

What does a low C3 mean? If C4 is low too, your immune system is often using them up, as in lupus. If only C3 is low, your doctor mainly looks at the kidneys. A value just below the limit, with no symptoms, may mean nothing.

Low C4 with a normal C3: what does it mean? It can be an inherited shortage of C1 inhibitor, especially if you get repeated swellings without hives. Your doctor may ask for a C1 inhibitor test. Other times it comes from an autoimmune condition or a harmless variant.

Should I worry about high complement? Usually not. C3 and C4 rise a little with inflammation and infections. If you have symptoms, your doctor looks for the cause with other tests.

Does Rosa test complement C3 and C4? No. Rosa measures high-sensitivity CRP, creatinine, eGFR and a urine test, which give signals about inflammation and your kidneys. If your doctor wants complement, they order it separately.

Sources

• Gloucestershire Hospitals NHS, pathology service: complement C3 and C4 test information. Gloucestershire Hospitals NHS, pathology tests and investigations
• Aringer and colleagues, 2019 EULAR/ACR classification criteria for systemic lupus erythematosus. Annals of the Rheumatic Diseases, 2019. PMID 31383717
• Maurer and colleagues, the international WAO/EAACI guideline for the management of hereditary angioedema: the 2021 revision and update. Allergy, 2022. PMID 35006617