Contents

Search

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.

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: 1) allergic reactions a) food allergies: peanuts, shrimp b) latex, hymenoptera stings 2) direct mast cell stimulated release of histamine - radiocontrast media, NSAIDs, opioids 2) urticaria 3) anaphylaxis 4) C1 esterase inhibitor deficiency (hereditary angioneurotic edema) 5) acquired C1 esterase deficiency associated with: a) adenocarcinoma b) lymphoproliferative disorder, lymphophoma, MUGUS c) autoimmune disease: lupus erythematosus 6) pharmacologic agents - angiotensin-converting enzyme (ACE) inhibitor (bradykinin-mediated) - radiocontrast media, NSAIDs, opioids 7) possibly stress & emotional factors Epidemiology: - 1 in 300 patients prescribed ACE inhibitors - 1 in 100 African Americans [9] Pathology: 1) mast cell release of histamine & other mediators - often associated with urticaria, bronchospasm & hypotnesion 2) generally occurs in association with urticaria 3) angioedema involves deeper layers of the dermis & subcutaneous tissues in contrast to urticaria which involves only the epidermis & superficial layers of the dermis 4) edema is noninflammatory 5) may involve the skin, mucous membranes, viscera, & brain 6) angioedema due to ACE inhibitor or ARNI is mediated by bradykinin - bradykinin-mediated angioedema is not associated with urticaria 7) hereditary form is a complement disorder & is not related to release mediators by mast cells 8) acquired C1 esterase deficiency: a) autoantibodies to C1 inhibitor b) tumor-mediated complement fixation overwelming the synthetic capacity for C1 esterase c) diminished serum complement C1 esterase inhibitor, C1q, C2, C4 Genetics: - see hereditary angioedema Clinical manifestations: 1) episodic edema of extremities, lips, face & tongue 2) onset is sudden & lasting hours to days 3) edema may involve skin, oropharynx, genitalia [5] 4) severe cases may lead to airway obstruction [6] 5) angioedema without urticaria suggests C1 esterase inhibitor deficiency 6) genital edema in a child riding a bicycle suggests hereditary angioedema 7) urticaria in association with angioedema suggests other than hereditary form 8) non-pitting pruritic or burning wheals, single or multiple a) face b) tongue c) larynx (common in hereditary form) d) hands e) feet f) genitalia 9) pruritic lesions generally resolve without treatment 10) lesions of hereditary angioedema are not pruritic 11) gastrointestinal (GI) complaints a) due to edema of intestinal mucosa b) nausea/vomiting c) diarrhea d) abdominal pain e) symptoms of intestinal obstruction in patients with hereditary form (duration 3-5 days) 12) arthralgia, purpura, or fever may be present 13) trauma, manual labor or dental extraction may precipitate attacks in hereditary angioedema * image [11] Laboratory: 1) C1-esterase inhibitor assay 2) C1 esterase in serum a) deficiency in hereditary form b) normal in food allergy, drug-induced angioedema, idiopathic angioedema c) obtain functional & antigenic levels [5] 3) diminished complement C4 in hereditary form a) serum C4 can be monitored to assess efficacy of treatment b) C4 in normal in food allergy, drug-induced angioedema, idiopathic angioedema c) obtain function & antigenic levels for diagnosis [5] 4) diminished serum complement C2 during attacks 5) diminished complement C1 in acquired form (i.e. C1q) 6) complete blood count (CBC) 7) erythrocyte sedimentation rate (ESR) 8) serum beta-tryptase within 4 hour confirms diagnosis; a negative value does not exclude 9) urinalysis 10) liver function tests 11) specific testing according to presentation - cryoglobulins, rheumatoid factor, anti SS-A, anti SS-B, Reiter protein reagin, hepatitis serologies (A, B, C), HIV, CH50 11) skin biopsy: ineffective treatment or suspected vasculitis Radiology: chest X-ray Complications: - cerebral edema or epiglottal edema may cause death Management: 1) assess for signs of airway compromise if swelling involves airway 2) assess for impending shock (see anaphylaxis) 3) epinephrine a) signs of airway compromise b) impending shock c) effective by racemic nebulized form or SC injection d) hereditary form does not respond to epinephrine e) ACE inhibitor-induced angioedema may not respond to epinephrine [4,8] - no clear role for epineprine in the treatment of bradykinin-mediated angioedema associated with ARNI or ACE inhibitors [5] 4) endotracheal intubation - priority over IM epinephrine (MKSAP19) [5] - if signs of laryngeal edema [4,8] - despite not visualizing larynx [5] 5) emergency tracheostomy if endotracheal intubation unsuccessful 6) antihistamines (hydroxyzine, diphenhydramine) a) will not cause harm in ACE inhibitor induced angioedema b) will not cause harm in complement-mediated angioedema 7) glucocorticoids 8) icatibant is effective for ACE inhibitor-induced angioedema [10] 9) androgens for hereditary form a) testosterone b) danazol c) stanozolol 10) C1 inhibitor therapy is investigational 11) epsilon-aminocaproic acid & tranexemic acid may be useful for C1-inhibitor deficiency 12) stop offending drug if drug-induced - if due to ACE inhibitor, ARB is reasonable alternative [7] - 2% of patients with angioedema on an ACE inhibitor also get angioedema on an ARB [9] - wait at lease 4 weeks after stopping an ACE inhibitor to start an ARB [9] 12) plasma kallikrein inhibitor ecallantide (Kalbitor) FDA-approved in 2009

Related

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

Specific

hereditary angioedema; hereditary angioneurotic edema (HANE, HAE)

General

edema (swelling, tumefaction, tumescence)

References

  1. Stedman's Medical Dictionary 24th ed, Williams & Wilkins, Baltimore, 1982
  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 829-39
  3. DeGowin & DeGowin's Diagnostic Examination, 6th edition, RL DeGowin (ed), McGraw Hill, NY 1994, pg 864
  4. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 25-26
  5. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16 American College of Physicians, Philadelphia 1998, 2006, 2012 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  6. Prescriber's Letter 11(7):31 2004
  7. Veterans Administration, Pharmacy, Mather, CA
  8. Malde B, Regalado J, Greenberger PA. Investigation of angioedema associated with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Ann Allergy Asthma Immunol. 2007 Jan;98(1):57-63. PMID: 17225721
  9. Prescriber's Letter 21(7): 2014 Safe Use of ARBs in Patients with ACE Inhibitor-Associated Angioedema. Detail-Document#: 300722 (subscription needed) http://www.prescribersletter.com
  10. Bas M et al A Randomized Trial of Icatibant in ACE-Inhibitor-Induced Angioedema. N Engl J Med 2015; 372:418-425. January 29, 2015 PMID: 25629740 http://www.nejm.org/doi/full/10.1056/NEJMoa1312524
  11. Li HH, Kaliner MA (image) Medscape: Angioedema http://emedicine.medscape.com/article/135208-overview
  12. Saini S, Shams M, Bernstein JA, et al. Urticaria and angioedema across the ages. J Allergy Clin Immunol Pract. 2020;8:1866-1874. PMID: 32298850
  13. Rosenbaum S, Wilkerson RG, Winters ME, et al. Clinical practice statement: what is the emergency department management of patients with angioedema secondary to an ACE-inhibitor? J Emerg Med. 2021;61:105-112. PMID: 34006418