GeneticsTier 2Medical Sciences concept

Atypical HUS - complement regulatory gene defects (Factor H, Factor I, MCP)

Core concept

Complement-mediated TMA - failure to restrain alternative pathway C3 tick-over on the endothelial surface
- Loss of regulation -> C3b amplification -> C5a (anaphylatoxin) + C5b-9 (MAC) on glomerular and microvascular endothelium
- -> endothelial activation, subendothelial swelling, platelet-fibrin thrombi -> MAHA + thrombocytopenia + organ injury
Two-hit disease - a germline regulatory defect plus a complement-amplifying trigger
- Triggers: infection (including gastroenteritis and influenza), pregnancy/post-partum, surgery, transplantation, malignancy, drugs, autoimmune disease
- Penetrance of a causative variant is only ~50% - which is why family history is often absent and why an identified variant does not by itself make the diagnosis
A genetic variant is found in only ~60-70%; a negative panel does not exclude aHUS

Genes - loss of regulators, or gain of activators

Gene	Protein	Direction	Frequency	Note
CFH	Factor H	Loss	~20-30% - commonest	Mutations cluster in SCR19-20, the surface-binding domain, so plasma factor H level is often normal
CD46 (MCP)	Membrane cofactor protein	Loss	~10-15%	Membrane-bound -> best prognosis, low transplant recurrence
CFI	Factor I	Loss	~4-10%	Serine protease cofactor for C3b cleavage
C3	C3	Gain (activating)	~5-10%	Convertase resists decay
CFB	Factor B	Gain	~1-4%	Hyperfunctional convertase
THBD	Thrombomodulin	Loss	~3-5%	Links coagulation and complement
DGKE	Diacylglycerol kinase epsilon	Loss	~2%	Not complement-mediated - infants <1 y; does not respond to eculizumab
CFHR1-5 / anti-FH antibody	-	-	~6-10% (higher in children)	CFHR3-CFHR1 deletion + acquired anti-factor-H IgG -> treat with plasma exchange plus immunosuppression

C3 may be low or normal - a normal C3 does not exclude aHUS; C4 is characteristically normal (alternative pathway)
Because factor H mutations are usually in the C-terminal surface-recognition domains, fluid-phase regulation is intact - hence normal C3 with disease confined to endothelium

Distinguishing the thrombotic microangiopathies

	ADAMTS13	Discriminator
TTP	<10%	Neurological > renal; ADAMTS13 inhibitor/antibody
aHUS	>10% (normal)	Renal-predominant, often severe AKI; diagnosis of exclusion
STEC-HUS	Normal	Bloody diarrhoea, Shiga toxin / STEC PCR positive, child
Secondary TMA	Normal	Pregnancy/HELLP, malignant hypertension, drugs (gemcitabine, quinine, VEGF inhibitors, calcineurin inhibitors), transplant, SLE/APS, cobalamin C, sepsis/DIC

PLASMIC score stratifies pre-test probability of severe ADAMTS13 deficiency while the assay is pending
The renal biopsy shows TMA but cannot tell you which TMA - the aetiology is biochemical and genetic

Send ADAMTS13 before the first plasma exchange - the sample is uninterpretable afterwards
Empiric PLEX while awaiting ADAMTS13, because untreated TTP is rapidly fatal; stop and switch once ADAMTS13 returns >10%
Eculizumab or ravulizumab is the definitive therapy for complement-mediated aHUS - start early, before dialysis-dependence is fixed
- Meningococcal vaccination (ACWY + B) plus antibiotic prophylaxis before or with the first dose
- Response is judged by platelets and renal function, not by C3 level
Genotype guides transplant risk
- CFH, CFI, C3, CFB (circulating factors made in the liver) -> recurrence 50-90% after kidney transplant
- CD46/MCP (membrane-expressed, replaced by the graft) -> recurrence <20%
- Secondary/environmental TMA has a much lower recurrence risk
- -> complement-inhibitor prophylaxis peri-transplant in high-risk genotypes; combined liver-kidney is an alternative for CFH
Pregnancy-associated aHUS is typically post-partum and does not resolve with delivery - distinguishing it from HELLP/pre-eclampsia
Test the family only with counselling - incomplete penetrance means an identified variant is a risk factor, not a diagnosis

3 more sections, plus exam facts

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