DermatologyTier 1Disease (DEADMAN)

Cutaneous manifestations of systemic diseases - angioedema

Description

Deep dermal/subcutaneous or submucosal swelling - non-pitting, no urticaria/pruritus in the mast-cell-independent forms
Two mechanistic families with different treatment: mast-cell/histamine-mediated (responds to adrenaline/antihistamines) vs bradykinin-mediated (does not)
Bradykinin forms - hereditary angioedema (HAE), acquired C1-inhibitor deficiency, ACE-inhibitor angioedema

HAE - rare, ~1:50,000, autosomal dominant, usually presents in childhood/adolescence
ACE-inhibitor angioedema - 0.1-0.7% of users, more common in Black patients, more common in women, can occur any time on therapy including years in
Acquired C1-INH deficiency - very rare, typically age >40, associated with lymphoproliferative disease/paraproteinaemia

Bradykinin-mediated

HAE type I (~85%) - C1-INH gene mutation -> low C1-INH level and function
HAE type II (~15%) - normal/high C1-INH level, dysfunctional protein
HAE with normal C1-INH - rare, some with Factor XII mutation, oestrogen-sensitive
Acquired C1-INH deficiency - anti-C1-INH autoantibodies or consumption by an underlying B-cell lymphoproliferative disorder/monoclonal gammopathy
ACE-inhibitor angioedema - dec bradykinin degradation (ACE normally breaks it down) -> bradykinin accumulation -> vascular permeability
Common trigger: oestrogen (OCP, pregnancy, HRT) worsens bradykinin-mediated forms

Mast-cell/histamine-mediated (contrast)

Allergic (IgE), direct mast cell activation - responds to adrenaline, antihistamines, steroids; usually with urticaria

Clinical

Recurrent, self-limiting (2-5 day) swelling of face, lips, tongue, larynx, extremities, GIT (colicky abdominal pain - can mimic surgical abdomen)
No urticaria/wheal, poor/no response to adrenaline or antihistamines - key distinguishing feature from mast-cell angioedema
Laryngeal involvement - life-threatening, can precede by prodrome (tingling, tightness)

Complement studies

Type	C4	C1-INH level	C1-INH function	C1q
HAE type I	Low	Low	Low	Normal
HAE type II	Low	Normal/high	Low	Normal
Acquired C1-INH deficiency	Low	Low	Low	Low (distinguishes from HAE)
ACE-I angioedema	Normal	Normal	Normal	Normal

Low C4 is a good HAE screening test (sensitive between attacks); confirm with C1-INH level and function

A. Acute attack (bradykinin-mediated)

Secure airway early if laryngeal/facial swelling - low threshold for ICU/ENT, does not respond reliably to adrenaline
C1-INH concentrate (plasma-derived or recombinant) - first-line for HAE attacks
Icatibant (bradykinin B2-receptor antagonist) - SC, effective for HAE and ACE-I angioedema
Fresh frozen plasma - alternative if specific agents unavailable (contains C1-INH but also bradykinin precursor - can theoretically worsen)
Adrenaline/antihistamines/steroids - not effective for bradykinin-mediated angioedema but often trialled first pending diagnosis

B. HAE prophylaxis

Long-term: lanadelumab (anti-plasma kallikrein monoclonal, subcut) or berotralstat (oral kallikrein inhibitor) - now preferred over older androgens
Short-term (e.g. pre-procedural): C1-INH concentrate or attenuated androgens (danazol)
Avoid oestrogen-containing contraception and ACE-inhibitors in all HAE patients

C. ACE-inhibitor angioedema

Stop the ACE-inhibitor permanently, avoid ARBs with caution (lower but non-zero cross-risk)
Icatibant or C1-INH concentrate for severe/laryngeal episodes

D. Acquired C1-INH deficiency

Treat/investigate the underlying lymphoproliferative disorder; acute attacks managed as for HAE

HAE - family history (autosomal dominant, ~25% de novo)
Acquired C1-INH deficiency - B-cell lymphoma, monoclonal gammopathy, autoimmune disease
ACE-inhibitor angioedema - hypertension, HFrEF (common indication for the causative drug), history of idiopathic angioedema
Oestrogen exposure (pregnancy, OCP, HRT) - triggers/worsens bradykinin-mediated angioedema

Untreated laryngeal HAE attack - airway obstruction, historically significant mortality before modern prophylaxis/rescue therapy
Recurrent GI attacks - can lead to unnecessary surgery if misdiagnosed as an acute abdomen
Effective prophylaxis (lanadelumab/berotralstat) has substantially reduced attack frequency and quality-of-life burden
ACE-I angioedema - resolves after drug cessation, but can recur even after years of uneventful use, and can still occur on first-ever dose

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