hereditary angioedema
Contents
HAE is a rare autosomal dominant disorder of C1 inhibitor deficiency causing recurrent bradykinin-mediated angioedema — swelling that does not respond to epinephrine, antihistamines, or corticosteroids. Attacks involve skin, GI tract, and upper airway. Diagnosis rests on low C4 and C1 inhibitor levels. Acute treatment is plasma-derived C1 inhibitor concentrate (Berinert) IV. Most patients today carry home treatment and an information letter.
quick recognition
- asymmetric, non-gravity-dependent subcutaneous/submucosal swelling
- no hives — if hives are present, it is almost certainly not bradykinin-mediated
- swelling evolves over hours, peaks at 12–36 h, resolves over 2–5 days
- non-pitting, non-pruritic — patients describe tightness, burning, or tingling rather than itch
- face, lips, tongue, larynx, extremities, genitalia, bowel wall
attack triggers
- dental/oral procedures, intubation, endoscopy
- trauma, surgery
- emotional stress, infection
- oestrogen-containing medications (OCP, HRT)
- ACE inhibitors (contraindicated in HAE)
- many attacks have no identifiable trigger
classification
| Type | C4 | C1-INH level | C1-INH function | Notes |
|---|---|---|---|---|
| HAE type 1 (~85%) | low | low | low | reduced production of C1-INH |
| HAE type 2 (~15%) | low | normal/high | low | dysfunctional C1-INH protein |
| HAE with normal C1-INH (rare) | normal | normal | normal | factor XII, plasminogen, or other mutations — specialist diagnosis |
| acquired angioedema (AAE) | low | low | low | onset >40 y, no family history — associated with lymphoproliferative disease |
diagnosis
when to suspect
- recurrent angioedema without urticaria
- angioedema unresponsive to antihistamines, epinephrine, corticosteroids
- family history of angioedema (though ~25% are de novo mutations)
- recurrent unexplained abdominal pain (GI attacks misdiagnosed as acute abdomen)
- onset typically in childhood/adolescence — worsens at puberty
workup
Step 1 — serum C4
- best screening test — low during and between attacks in types 1 and 2
- normal C4 essentially rules out HAE types 1 and 2
- inexpensive, widely available
Step 2 — C1 inhibitor level + C1 inhibitor functional assay
- order if C4 is low or clinical suspicion is high despite normal C4
- distinguishes type 1 (low level) from type 2 (normal level, low function)
Step 3 — C1q level
- normal in HAE, low in acquired angioedema (AAE)
- helps distinguish HAE from AAE in patients presenting >40 y without family history
If clinical suspicion is high and C4/C1-INH are normal, refer to specialist. Do not anchor on normal labs to exclude HAE entirely — but factitious angioedema is more common than HAE with normal C1-INH.
Rarely, patients present with refractory angioedema (generally tongue) but normal exam and vitals. On palpation, tongue is soft and pliable with no oedema. “Swelling” resolves rapidly within minutes or tongue retracts while talking. Consider before pursuing rare diagnoses like HAE with normal C1-INH.
acute treatment
Epinephrine, antihistamines, and corticosteroids are ineffective for bradykinin-mediated angioedema. Do not delay C1 inhibitor concentrate while trialling these agents.
- ABCs, IV access, O₂
- some patients present only with GI attacks/colic — can mimic acute abdomen
plasma-derived C1 inhibitor (Berinert) — preferred inpatient treatment
| Weight | Dose (IV) |
|---|---|
| ≤50 kg | 1000 units |
| 50–75 kg | 1500 units |
| 75–100 kg | 2000 units |
| >100 kg | 2500 units |
- weight-based: 20 units/kg IV by slow infusion (~1000 units per 10 min)
- improvement expected within 30 minutes
- <1% of attacks need a second dose — can repeat if worsening or only partial improvement
- safe in pregnancy and breastfeeding
alternative acute agents
| Agent | Route | Notes |
|---|---|---|
| icatibant (Firazyr) | SC | bradykinin B2 receptor antagonist — patients often self-administer at home |
| recombinant C1-INH (Ruconest) | IV | alternative to pd-C1-INH; contraindicated in rabbit allergy |
| fresh frozen plasma | IV | last resort if specific agents unavailable — contains C1-INH but also substrates that could theoretically worsen attack |
short-term prophylaxis
Indicated before invasive procedures or anticipated stressful events:
- dental/oral surgery
- endotracheal intubation
- endoscopy
- not necessary for uncomplicated vaginal delivery (give for complicated delivery)
Protocol: same dose of IV pd-C1 inhibitor as acute treatment, given 1 hour prior to procedure. Have 2 doses available on demand during procedure.
Attacks can occur hours to several days after a procedure.
long-term prophylaxis
Indicated for frequent or severe attacks — managed by allergist:
| Agent | Route | Mechanism |
|---|---|---|
| subcutaneous pd-C1-INH (Haegarda) | SC twice weekly | C1-INH replacement |
| lanadelumab (Takhzyro) | SC q2–4 weeks | anti-kallikrein monoclonal antibody |
| berotralstat (Orladeyo) | PO daily | kallikrein inhibitor |
- androgens (danazol) — historically used but largely replaced due to adverse effects (hepatotoxicity, virilisation, dyslipidaemia)
- tranexamic acid — modest efficacy, sometimes used in paediatrics or where other agents unavailable
ACE inhibitor–induced angioedema
- bradykinin-mediated — same pathway as HAE but acquired
- duration of ACE inhibitor use is irrelevant — can occur after years
- stop ACE inhibitor permanently
- recurrence may persist for several months after discontinuation
- ARBs are safe to use as alternatives
- C4 and C1-INH levels are normal — do not order HAE workup unless atypical features
- most episodes are self-limited with supportive care
- for severe/airway-threatening episodes, icatibant or pd-C1-INH may be considered (off-label)
special populations
- pregnancy — pd-C1-INH (Berinert) is safe; icatibant and lanadelumab lack safety data; androgens are contraindicated
- oestrogen — exogenous oestrogen (OCP, HRT) can trigger/worsen attacks → use progestogen-only contraception
- children — attacks often begin in childhood; diagnosis should be pursued early if family history positive
what NOT to do
- give epinephrine/antihistamines/corticosteroids for suspected HAE instead of C1 inhibitor concentrate
- use FFP as first-line when specific agents are available
- prescribe ACE inhibitors to patients with HAE
- prescribe oestrogen-containing contraceptives to patients with HAE
- assume absence of family history rules out HAE (~25% de novo)
- dismiss recurrent abdominal pain as functional without considering GI HAE attacks
- order extensive HAE workup for ACE inhibitor–induced angioedema (C4/C1-INH will be normal)
Most patients with HAE nowadays have at-home treatment available through their allergist and carry a letter for other health care providers. Check with the patient — they often know more about their disease than the treating team.