ImmunologyTier 1Medical Sciences concept

Hereditary angioedema - diagnostic testing (C4, C1-inhibitor)

Core concept

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dec C1-inhibitor function

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C1-INH also inhibits the classical complement pathway -> continuous C4 consumption
- This is why C4 is the screening test - it is a consequence, not the mechanism
No urticaria, no itch, no response to antihistamine/adrenaline/steroid. If there are weals, it is not HAE.

	C4	C1-INH level	C1-INH function	C1q
HAE type I (~85%)	LOW	LOW	LOW	Normal
HAE type II (~15%)	LOW	NORMAL or high	LOW	Normal
HAE with normal C1-INH (FXII, PLG, ANGPT1, KNG1 mutations)	Normal	Normal	Normal	Normal
Acquired angioedema (AAE)	LOW	Low	LOW	LOW
ACE-inhibitor angioedema	Normal	Normal	Normal	Normal

The single discriminating test between hereditary and acquired is C1q: LOW in acquired, NORMAL in hereditary
- AAE - onset >40 yr, no family history; consumption by B-cell lymphoproliferative disease (MGUS, splenic marginal zone lymphoma, CLL) or anti-C1-INH autoantibody -> investigate for a paraprotein and lymphoma
C4 is the screening test: normal C4 during an attack makes HAE very unlikely; C4 can be normal between attacks in ~5%, so repeat during an attack
Functional C1-INH is low in every C1-INH-deficient type - order it whenever the level is normal but suspicion is high
Confirm with a repeat sample >1 month later; do not diagnose under 12 months of age (C1-INH is physiologically low)
HAE with normal C1-INH - diagnosis is by family history, response to HAE therapy, and genetic testing; often oestrogen-dependent

Attacks: recurrent, self-limiting over 2-5 days, face, limbs, genitals, larynx, and abdominal attacks mimicking a surgical abdomen (bowel wall oedema, ascites on CT) - many patients have had an unnecessary laparotomy
- Laryngeal attacks are the cause of death (~30% mortality if untreated historically)
- Prodrome: tingling, erythema marginatum
- Triggers: trauma (especially dental work), stress, infection, oestrogen (COCP, pregnancy), ACE inhibitors - absolutely contraindicated
Acute attacks - treat any laryngeal/facial/severe abdominal attack early
- C1-INH concentrate IV, icatibant (B2 antagonist) SC, ecallantide; sebetralstat is an oral on-demand kallikrein inhibitor
- Fresh frozen plasma is a last resort only - it contains substrate as well as inhibitor
Long-term prophylaxis (2025 WAO first-line): subcutaneous C1-INH, lanadelumab (anti-kallikrein mAb), garadacimab (anti-FXIIa), donidalorsen, berotralstat (oral)
- Danazol and tranexamic acid are now second-line - androgenic and hepatic toxicity
Short-term prophylaxis before dental or surgical procedures - C1-INH concentrate
Every patient needs an action plan, on-demand therapy at home, and a MedicAlert; screen first-degree relatives

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