Angioedema: Symptoms, Causes & Treatment

Angioedema is an acute, episodic swelling involving the deep dermis, subcutaneous tissue, and mucous membranes — anatomically deeper than urticaria (hives), which affects the superficial dermis. It most commonly affects the lips, eyelids, face, tongue, and larynx, and may extend to the extremities or bowel wall (abdominal angioedema causing colic and vomiting). Laryngeal involvement is a medical emergency that can cause fatal asphyxia within minutes if untreated.

Angioedema is mechanistically classified into: (1) Histamine-mediated (allergic, IgE-dependent): triggered by foods (peanuts, shellfish, tree nuts), drugs (penicillin, NSAIDs), insect stings, or latex; usually accompanied by urticaria and other anaphylaxis features — responds to epinephrine, antihistamines, and corticosteroids. (2) Bradykinin-mediated — ACE inhibitor-induced (1–3% of ACEI users): ACEI block bradykinin degradation, causing vascular leakage; typically presents as isolated face/tongue/laryngeal swelling without urticaria; does NOT respond to epinephrine or antihistamines; resolves with ACEI discontinuation. (3) Hereditary angioedema (HAE): autosomal dominant C1-esterase inhibitor deficiency or dysfunction causing uncontrolled complement and bradykinin cascade activation; recurrent episodes from minor trauma, emotional stress, infection, or estrogen; managed with specific agents not steroids/antihistamines.

Early recognition of the angioedema subtype is critical because treatment strategies differ substantially between histamine-mediated and bradykinin-mediated subtypes.

• Sudden non-pitting swelling of lips, eyelids, tongue, face, or extremities
• Hoarseness, dysphagia, or muffled voice suggesting laryngeal involvement
• Stridor, dyspnea — laryngeal angioedema is a life-threatening emergency
• Abdominal colic and vomiting in visceral angioedema (especially HAE)
• Absence of urticaria and non-response to antihistamines suggests bradykinin-mediated mechanism

• Allergic (IgE-mediated): foods (peanuts, shellfish, tree nuts, wheat), drugs (penicillin, aspirin, NSAIDs), insect venom, latex
• ACE inhibitor-induced: bradykinin accumulation from impaired degradation
• Hereditary angioedema (HAE): C1-inhibitor deficiency (Type I), C1-inhibitor dysfunction (Type II), or factor XII mutation (Type III)
• Triggers for HAE: minor trauma, emotional stress, infection, surgery, estrogen-containing medications
• Idiopathic: no identifiable cause in up to 40% of cases

Diagnosis is clinical, supported by subtype identification. For suspected HAE: C4 level (persistently low), C1-inhibitor level and functional activity. For allergic type: skin prick testing, specific IgE (RAST). Review all medications for ACE inhibitors or ARBs. In HAE attacks, tryptase is normal (unlike anaphylaxis). Family history is key for HAE. Idiopathic angioedema is diagnosed by exclusion.

Allergic angioedema: IM epinephrine (0.3–0.5 mg auto-injector) + H1/H2 antihistamines + systemic corticosteroids; supplemental oxygen; monitor for biphasic anaphylaxis. Laryngeal angioedema: IV epinephrine, nebulized epinephrine, early intubation or surgical airway if swelling progresses. ACE inhibitor-induced: discontinue ACEI (switch to ARB — much lower risk); icatibant or C1-inhibitor concentrate for acute severe episodes. HAE: on-demand treatment with C1-inhibitor concentrate, icatibant (bradykinin B2-receptor antagonist), or ecallantide; long-term prophylaxis with lanadelumab, berotralstat, or subcutaneous C1-INH.

• Asphyxia from laryngeal swelling — the primary cause of death in untreated or delayed HAE attacks
• Unnecessary laparotomies when abdominal HAE attacks are misdiagnosed as surgical emergencies
• Significant anxiety, social impairment, and reduced quality of life in patients with frequent recurrences

• Avoid known allergic triggers; carry prescribed epinephrine auto-injector at all times
• Immediately discontinue ACE inhibitors at first episode of angioedema; do not rechallenge
• HAE prophylaxis: lanadelumab SC every 2–4 weeks or berotralstat daily for frequent attackers
• Educate patients and families on emergency self-administration of C1-INH or icatibant