angioneurotic edema; angioedema; atrophedema; Bannister's disease; Milton's disease; Quincke's disease; periodic or Quincke's edema; giant urticaria or hives; urticaria gigans, gigantea, or tuberosa.

Introduction

Periodically recurring epiosodes of noninflammatory swelling of the skin, mucous membranes, viscera, & brain, of sudden onset & lasting hours to days, occasionally with arthralgia, purpura, or fever.

Etiology

• allergic reactions
  • food allergies: peanuts, shrimp
  • latex, hymenoptera stings
• direct mast cell stimulated release of histamine
  • radiocontrast media, NSAIDs, opioids
• urticaria
• anaphylaxis
• C1 esterase inhibitor deficiency (hereditary angioneurotic edema)
• acquired C1 esterase deficiency associated with:
  • adenocarcinoma
  • lymphoproliferative disorder, lymphophoma, MUGUS
  • autoimmune disease: lupus erythematosus
• pharmacologic agents
  • angiotensin-converting enzyme (ACE) inhibitor (bradykinin-mediated)
  • radiocontrast media, NSAIDs, opioids
• possibly stress & emotional factors

Epidemiology

• 1 in 300 patients prescribed ACE inhibitors
  • 1 in 100 African Americans

Pathology

• mast cell release of histamine & other mediators
  • often associated with urticaria, bronchospasm & hypotnesion
• generally occurs in association with urticaria
• angioedema involves deeper layers of the dermis & subcutaneous tissues in contrast to urticaria which involves only the epidermis & superficial layers of the dermis
• edema is noninflammatory
• may involve the skin, mucous membranes, viscera, & brain
• angioedema due to ACE inhibitor or ARNI is mediated by bradykinin
  • bradykinin-mediated angioedema is not associated with urticaria
• hereditary form is a complement disorder & is not related to release mediators by mast cells
• acquired C1 esterase deficiency:
  • autoantibodies to C1 inhibitor
  • tumor-mediated complement fixation overwelming the synthetic capacity for C1 esterase
  • diminished serum complement C1 esterase inhibitor, C1q, C2, C4

Genetics

• see hereditary angioedema

Clinical manifestations

• episodic edema of extremities, lips, face & tongue
• onset is sudden & lasting hours to days
• edema may involve skin, oropharynx, genitalia
• severe cases may lead to airway obstruction
• angioedema without urticaria suggests C1 esterase inhibitor deficiency
• genital edema in a child riding a bicycle suggests hereditary angioedema
• urticaria in association with angioedema suggests other than hereditary form
• non-pitting pruritic or burning wheals, single or multiple
  • face
  • tongue
  • larynx (common in hereditary form)
  • hands
  • feet
  • genitalia
• pruritic lesions generally resolve without treatment
• lesions of hereditary angioedema are not pruritic
• gastrointestinal (GI) complaints
  • due to edema of intestinal mucosa
  • nausea/vomiting
  • diarrhea
  • abdominal pain
  • symptoms of intestinal obstruction in patients with hereditary form (duration 3-5 days)
• arthralgia, purpura, or fever may be present
• trauma, manual labor or dental extraction may precipitate attacks in hereditary angioedema

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Laboratory

• C1-esterase inhibitor assay
• C1 esterase in serum
  • deficiency in hereditary form
  • normal in food allergy, drug-induced angioedema, idiopathic angioedema
  • obtain functional & antigenic levels
• diminished complement C4 in hereditary form
  • serum C4 can be monitored to assess efficacy of treatment
  • C4 in normal in food allergy, drug-induced angioedema, idiopathic angioedema
  • obtain function & antigenic levels for diagnosis
• diminished serum complement C2 during attacks
• diminished complement C1 in acquired form (i.e. C1q)
• complete blood count (CBC)
• erythrocyte sedimentation rate (ESR)
• serum beta-tryptase within 4 hour confirms diagnosis; a negative value does not exclude
• urinalysis
• liver function tests
• specific testing according to presentation
  • cryoglobulins, rheumatoid factor, anti SS-A, anti SS-B, Reiter protein reagin, hepatitis serologies (A, B, C), HIV, CH50
• skin biopsy: ineffective treatment or suspected vasculitis

Radiology

chest X-ray

Complications

• cerebral edema or epiglottal edema may cause death

Management

• assess for signs of airway compromise if swelling involves airway
• assess for impending shock (see anaphylaxis)
• epinephrine
  • signs of airway compromise
  • impending shock
  • effective by racemic nebulized form or SC injection
  • hereditary form does not respond to epinephrine
  • ACE inhibitor-induced angioedema may not respond to epinephrine
    • no clear role for epineprine in the treatment of bradykinin-mediated angioedema associated with ARNI or ACE inhibitors
• endotracheal intubation
  • priority over IM epinephrine (MKSAP19)
    • if signs of laryngeal edema
      • despite not visualizing larynx
• emergency tracheostomy if endotracheal intubation unsuccessful
• antihistamines (hydroxyzine, diphenhydramine)
  • will not cause harm in ACE inhibitor induced angioedema
  • will not cause harm in complement-mediated angioedema
• glucocorticoids
• icatibant is effective for ACE inhibitor-induced angioedema
• androgens for hereditary form
  • testosterone
  • danazol
  • stanozolol
• C1 inhibitor therapy is investigational
• epsilon-aminocaproic acid & tranexemic acid may be useful for C1-inhibitor deficiency
• stop offending drug if drug-induced
  • if due to ACE inhibitor, ARB is reasonable alternative
    • 2% of patients with angioedema on an ACE inhibitor also get angioedema on an ARB
    • wait at lease 4 weeks after stopping an ACE inhibitor to start an ARB
• plasma kallikrein inhibitor ecallantide (Kalbitor) FDA-approved in 2009

More general terms

• edema (swelling, tumefaction, tumescence)

More specific terms

• hereditary angioedema; hereditary angioneurotic edema (HANE, HAE)

Additional terms

• complement C1 inhibitor; C1 esterase inhibitor (SERPING1, Cinryze, Berinert)
• complement C1s

Patient information

angioneurotic edema patient information