Complement is known to be a collection of components which act individually and collectively to protect the body from something foreign “invading” it.
It is a part of the immune system.
From historic observation each component has been assigned normal levels. The “tick over” levels . The Goldilocks levels -“just right”.
They are are measured as volumes. What is a normal volume can vary slightly between laboratories doing the testing but there is usually a “normal” range , for example
- C3 75–175 mg/dL (or roughly 0.75–1.75 g/L; other labs often 80–180 or 90–180 mg/dL).
- C4 14–40 mg/dL (or roughly 0.14–0.40 g/L; other labs 10–45 mg/dL).
- CH50 ≥41 U/mL (often 41–90 or 41–95 U/mL depending on lab).
- AH50 ≥46% of 30-75 U/mL
- Factor B (CFB) 15.2–42.3 mg/dL.
- Factor H (CFH) 18.5–40.8 mg/dL (other labs ~12–56 mg/dL).
- Factor I (CFI) Typically ~2.5–5 mg/dL (less standardized).
- sC5b-9 (soluble membrane attack complex / sMAC / TCC) ≤250 ng/mL (some labs upper limit ~300 ng/mL; normal mean often ~100–200 ng/mL).
- Less routinely measured individual components (C1q, C1r, C1s, C2, C5, C6, C7, C8, C9, properdin, etc.) have their own reference ranges but are usually only tested if a specific deficiency is suspected (e.g., via CH50/AH50 screening). C3 and C4 are the most commonly ordered individual proteins.:
So given those ranges, someone with aHUS, i.e. the uncontrolled complement TMA version, would be expected to have abnormal levels. So what is typically found.
- C3: Often low (consumption due to alternative pathway overactivation), but only in ~30–50% of cases — many patients have normal C3.
- C4: Typically normal
- CH50 and AH50: Often decreased due to consumption/activation).
- Factor B: Frequently low due alternative pathway consumption).
- Factor H and Factor I: May be low in cases of genetic deficiency or autoantibodies, but often normal levels
- sC5b-9 (sMAC): Frequently elevated (marker of terminal complement activation; can be markedly high, e.g., hundreds to thousands ng/mL vs. normal ≤250 ng/mL). This is one of the more consistent findings.
- Other activation markers (Bb, C5a, C3a): Often elevated when measured.
Some are within the normal range and for others the use of terms “often” “typically” “frequently” “may” “can be” mean “not always” and levels within the normal range are still possible to confuse matters.
These would be the results for all aHUS/cTMA patients whether having identified genetic mutations or not. But could there be differences?
Routine complement testing (C3, C4, CH50/AH50, factor levels, sC5b-9) often remains normal in both groups because complement dysregulation in cTMA is frequently surface-restricted (on endothelium) rather than causing massive fluid-phase consumption.
Abnormalities, when present, can reflect consumption or activation during active disease.
- C3 levels — The strongest difference comes from direct comparisons: In one cohort of aHUS patients, those with complement gene mutations (carriers) had significantly lower C3 levels than non-carriers (idiopathic/no mutation group): 0.65 g/L vs. 0.81 g/L (p = 0.04).
- Certain mutations drive this more strongly (e.g., C3 gain-of-function mutations are associated with low C3 in ~70–76% of cases).
- In contrast, mutations like CD46/MCP often show normal C3.
- Overall in aHUS, low C3 occurs in only a minority (~15–50% depending on cohort and timing), but it is more frequent when a genetic defect is identified.
- Specific complement regulators (Factor H, Factor I, Factor B) — Genetic cases (especially quantitative loss-of-function mutations in CFH or CFI) more often show low levels.
- Idiopathic cases, by definition, have normal levels of CH50 and activation markers (sC5b-9, Bb, C5a) but these are often abnormal (low CH50 or elevated sC5b-9) during acute flares in both groups, reflecting terminal pathway activation. Some studies show no significant difference in these markers between mutation-positive and mutation-negative patients.
- Abnormal circulating profiles (low C3 + high C5a/sC5b-9) occur in roughly 47–64% of aHUS patients overall, irrespective of genetic status or disease phase
So there are some differences within the overall patient populations depending on genetic predisposition but in both subgroups levels can still be normal.
It hard to imagine that someone can be extremely ill with aHUS/cTMA and yet the levels of the part of the body that is self afflicting that person can be not too little and not too much and just right. Yet on the endothelium surface an almighty over activation is reeking havoc.
Is that where a rapid specific and sensitive measure should be focussed for a specific diagnosis?
It is ironic that which is normal is still causing aHUS/cTMA patients so much trouble.
Complement is complex.
Article No. 796
