Laboratory investigations - complement profiles

The three activation pathways

Pathway	Trigger	Recognition
Classical	Immune complexes (IgM > IgG)	C1q -> C1r/C1s -> C4, C2
Lectin	Microbial mannose	MBL/ficolin -> MASP -> C4, C2
Alternative	Spontaneous C3 tick-over on surfaces	C3, factor B, factor D, properdin

All converge on C3 convertase -> C3b -> C5 convertase -> C5b-9 membrane attack complex
Effector functions: opsonisation (C3b), chemotaxis and anaphylatoxins (C3a, C5a), lysis (MAC), immune complex clearance
Regulators: C1-INH, factor H, factor I, CD55 (DAF), CD59 - loss causes disease as surely as deficiency of a component

Complement deficiency accounts for <2% of primary immunodeficiency
C2 deficiency is the commonest classical pathway deficiency in Europeans (~1:20,000)
MBL deficiency in ~5-10% of the population; usually clinically silent

Deficient	Clinical consequence
C1q, C1r/s, C4, C2 (early classical)	SLE-like disease (failed immune complex clearance) + pyogenic encapsulated infection. C1q deficiency has the highest lupus penetrance, >90%
C3	Severe recurrent pyogenic infection + immune complex disease
C5-C9 (terminal/MAC)	*Recurrent Neisseria infection - meningococcal, often atypical serogroups, milder but recurrent*
Properdin (X-linked)	Fulminant meningococcal disease
Factor H / factor I	Atypical HUS, C3 glomerulopathy, age-related macular degeneration
C1-INH	Hereditary angioedema (contact system, not complement, is the effector)
CD55/CD59 (GPI anchor, PIGA)	Paroxysmal nocturnal haemoglobinuria

Test	Measures	Abnormal implies
CH50	Total classical + terminal pathway haemolytic activity	Any deficiency C1-C9 in that route; zero/undetectable CH50 = complete deficiency of a classical or terminal component
AH50	Alternative pathway activity (factor B, D, properdin + C3-C9)	Alternative or terminal deficiency
C3 and C4	Antigenic levels - the easiest components to measure directly	Consumption or deficiency

Interpreting the pair
- Low CH50 + normal AH50 -> classical-specific defect (C1, C2, C4)
- Normal CH50 + low AH50 -> alternative-specific (factor B, D, properdin)
- Both low -> shared terminal component (C3, C5-C9)
CH50 requires a properly handled sample - complement is heat- and time-labile. A "low CH50" is usually a transport artefact

C3	C4	Interpretation
Low	Low	Classical pathway consumption - active SLE, cryoglobulinaemia, serum sickness, post-infectious GN
Normal	Low	C1-INH deficiency (HAE), or inherited C4 null alleles
Low	Normal	Alternative pathway consumption - C3 glomerulopathy, C3 nephritic factor, atypical HUS, post-streptococcal GN
Normal	Normal	Complement not being consumed

C4 falls before and more than C3 in lupus flare - useful monitoring pair
C3 and C4 are acute phase reactants - a "normal" level during active inflammation may represent relative consumption

Recurrent or atypical Neisseria infection, or any second episode of meningococcal disease -> CH50/AH50
Early-onset or familial SLE
Angioedema without weals -> C4 first
Membranoproliferative GN, atypical HUS -> C3, factor H/I, C3 nephritic factor

Meningococcal vaccination (ACWY and B), pneumococcal and Hib for any deficiency of a complement component
- Terminal pathway deficiency: revaccinate on schedule - antibody-mediated opsonisation is the only remaining defence
Consider long-term penicillin prophylaxis in terminal pathway deficiency
Educate on early presentation with fever; family screening (X-linked properdin)
Eculizumab or ravulizumab (anti-C5) requires meningococcal vaccination at least 2 weeks beforehand plus antibiotic prophylaxis - it creates an iatrogenic terminal pathway deficiency
Treat the underlying immune complex disease where deficiency drives lupus

SLE (early classical deficiencies), especially with normal ANA and prominent cutaneous disease
Recurrent Neisseria meningitidis (terminal, properdin)
Atypical HUS, C3 glomerulopathy, dense deposit disease (factor H/I, C3NeF)
Age-related macular degeneration (factor H Y402H)
Hereditary and acquired angioedema (C1-INH)
PNH (CD55/CD59)
Eculizumab/ravulizumab therapy

Terminal deficiency: recurrent meningococcal disease with lower case-fatality than sporadic disease but repeated episodes; often atypical serogroups (W, Y, X)
Early classical deficiency: lupus typically presents young, with severe cutaneous and renal disease
A single episode of meningococcal disease in an adult does not mandate testing; recurrence, family history, or an unusual serogroup does

8 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.