Correspondence
Bradykinin-Mediated Angioedema
N Engl J Med 2002; 347:621-622August 22, 2002
- Article
To the Editor:
Angioedema is a nonitchy, pale swelling of subcutaneous or submucosal tissue that tends to recur chronically and can become life-threatening if the swelling occurs in the upper airways or can be very painful if it occurs in the gastrointestinal tract. Angioedema presenting together with urticaria1 usually responds well to antihistamines and corticosteroids, whereas angioedema without urticaria is frequently resistant to such therapy but may respond to a C1 esterase inhibitor, tranexamic acid, or both2 — therapies that can reduce bradykinin generation. These findings raise the question of whether bradykinin mediates angioedema.
We measured plasma bradykinin in patients with angioedema, with or without urticaria, during acute attacks, periods of remission, or both (Figure 1Figure 1
Plasma Bradykinin Levels in Six Patients with Angioedema Due to Hereditary C1-Inhibitor Deficiency, Four Patients with Angioedema Related to Angiotensin-Converting–Enzyme (ACE) Inhibitors, and Four Patients with Urticaria and Angioedema That Responded to Antihistamines (Histaminergic Angioedema).).3 Six patients with hereditary C1-inhibitor deficiency had very high bradykinin levels during attacks of antihistamine-resistant angioedema. This finding confirms previous data showing that bradykinin clearly increases during acute angioedema in such patients but is normal or marginally increased during remission.3 Previous studies in two other patients with C1-inhibitor deficiency showed that bradykinin levels in blood draining from an angioedematous site were three and eight times as high as the levels in systemic circulation.4 In three patients with a history of angioedema related to the use of angiotensin-converting–enzyme (ACE) inhibitors, bradykinin levels were high during ACE-inhibitor treatment. In a fourth, previously described patient,3 the bradykinin level was 47.0 pM during an attack of angioedema and decreased to 3.2 pM after withdrawal of the ACE inhibitor.In contrast, four patients with urticaria and angioedema that responded to antihistamines had normal levels of bradykinin during acute attacks of angioedema. In one of these patients, who had angioedema of one arm, venous bradykinin levels were normal in both arms.
Bradykinin appears to be involved in angioedema related to hereditary C1-inhibitor deficiency and in angioedema related to ACE inhibitors; both conditions are resistant to antihistamines. In contrast, bradykinin is minimally involved in urticarial angioedema that is responsive to antihistamines.
Hereditary or acquired deficiencies of C1 inhibitor, which lead to overproduction of bradykinin, are rare. However, nonurticarial angioedema is most frequently related to the use of ACE inhibitors. ACE, which is identical to kininase II, metabolizes bradykinin to its breakdown products. When ACE inhibitors are administered, ambient bradykinin levels increase. Angioedema is a complication of ACE-inhibitor therapy, with an incidence of 0.1 to 0.7 percent.5 Given that approximately 35 million persons with hypertension or heart failure are currently being treated with ACE inhibitors, one might anticipate more than 100,000 cases of angioedema per year. An awareness of this issue and an understanding of the pathophysiology of angioedema — as suggested by Osler in 1888 — can guide clinicians in providing appropriate therapy and can save lives.
5 ReferencesJuerg Nussberger, M.D.
University Hospital Lausanne, CH-1011 Lausanne, Switzerland
juerg.nussberger@chuv. hospvd. ch Massimo Cugno, M.D.
Marco Cicardi, M.D.
Maggiore Hospital, 20112 Milan, Italy1
Kaplan AP . Chronic urticaria and angioedema. N Engl J Med 2002;346:175-179
Full Text | Web of Science | Medline2
Agostoni A ,Cicardi M . Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 1992;71:206-215
Web of Science | Medline3
Nussberger J ,Cugno M ,Amstutz C ,Cicardi M ,Pellacani A ,Agostoni A . Plasma bradykinin in angio-oedema. Lancet 1998;351:1693-1697
CrossRef | Web of Science | Medline4
Nussberger J ,Cugno M ,Cicardi M ,Agostoni A . Local bradykinin generation in hereditary angioedema. J Allergy Clin Immunol 1999;104:1321-1322
CrossRef | Web of Science | Medline5
Brown NJ ,Snowden M ,Griffin MR . Recurrent angiotensin-converting enzyme inhibitor-associated angioedema. JAMA 1997;278:232-233
CrossRef | Web of Science | Medline
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1
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Marco Cicardi, Massimo Cugno. 2011. 18 Kallikrein-kinin system in angioedema. , 289-306.
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N. Javaud, O. Fain, B. Bernot, F. Adnet, F. Lapostolle. (2011) Angiœdème bradykinique secondaire aux inhibiteurs de l’enzyme de conversion : instaurer le traitement en préhospitalier. Annales Françaises d'Anesthésie et de Réanimation 30:11, 848-850
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M. Maurer, M. Bader, M. Bas, F. Bossi, M. Cicardi, M. Cugno, P. Howarth, A. Kaplan, G. Kojda, F. Leeb-Lundberg, J. Lötvall, M. Magerl. (2011) New topics in bradykinin research. Allergy 66:11, 1397-1406
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Laura Beltrami, Andrea Zanichelli, Lorenza Zingale, Romualdo Vacchini, Stefano Carugo, Marco Cicardi. (2011) Long-term follow-up of 111 patients with angiotensin-converting enzyme inhibitor-related angioedema. Journal of Hypertension 29:11, 2273-2277
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M. Volpe. (2011) Should all patients at high cardiovascular risk receive renin-angiotensin system blockers?. QJM
CrossRef7
C. E. Hack, A. Relan, E. S. van Amersfoort, M. Cicardi. (2011) Target levels of functional C1-inhibitor in hereditary angioedema. Allergyno-no
CrossRef8
Thomas Renné. (2011) The procoagulant and proinflammatory plasma contact system. Seminars in Immunopathology
CrossRef9
Marcus Maurer, Markus Magerl. (2011) Long-term prophylaxis of hereditary angioedema with androgen derivates: a critical appraisal and potential alternatives. JDDG: Journal der Deutschen Dermatologischen Gesellschaft 9:2, 99-107
CrossRef10
Randy L. Webb, Gary M. Ksander. 2010. Endogenous Vasoactive Peptides. .
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Marcus Maurer, Markus Magerl. (2010) Hereditary angioedema: an update on available therapeutic options. JDDG: Journal der Deutschen Dermatologischen Gesellschaft 8:9, 663-672
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Erin Banta, Timothy J Craig. (2010) Overview of ecallantide in the treatment of hereditary angioedema types I and II. Therapy 7:5, 565-571
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Alencia V. Woodard-Grice, Amelia C. Lucisano, James B. Byrd, Elizabeth R. Stone, William H. Simmons, Nancy J. Brown. (2010) Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema. Pharmacogenetics and Genomics 20:9, 532-536
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Murat Bas, Thomas K. Hoffmann, Bernd Tiemann, Vu Thao-Vi Dao, Christos Bantis, Vera Balz, Hans-Jürgen Schultz-Coulon, Thomas Stark, Patrick Schuler, Jens Greve, Katrin Ivens, Henning Bier, Georg Kojda. (2010) Potential genetic risk factors in angiotensin-converting enzyme-inhibitor-induced angio-oedema. British Journal of Clinical Pharmacology 69:2, 179-186
CrossRef15
Srikanth Katragadda, Rohit R Arora. (2010) Role of Angiotensin-Converting Enzyme Inhibitors in Vascular Modulation: Beyond the Hypertensive Effects. American Journal of Therapeutics 17:1, e11-e23
CrossRef16
J.M. Neutel. (2010) Choosing among renin-angiotensin system blockers for the management of hypertension: from pharmacology to clinical efficacy. Current Medical Research and Opinion 26:1, 213-222
CrossRef17
C. Göggelmann, A. Filusch, F.J. Meyer. (2009) Pulmonale Effekte kardialer Therapie und vice versa. Der Pneumologe 6:6, 399-404
CrossRef18
Qing Ling Duan, Karen Binkley, Guy A. Rouleau. (2009) Genetic analysis of Factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema. Journal of Allergy and Clinical Immunology 123:4, 906-910
CrossRef19
S. Grigoriadou, H. J. Longhurst. (2009) Clinical Immunology Review Series: An approach to the patient with angio-oedema. Clinical & Experimental Immunology 155:3, 367-377
CrossRef20
K. Scherer, A. Bircher. (2009) Unerwünschte Arzneimittelreaktionen an der Haut. Der Internist 50:2, 171-178
CrossRef21
Massimo Cugno, Andrea Zanichelli, Fabrizio Foieni, Sonia Caccia, Marco Cicardi. (2009) C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends in Molecular Medicine 15:2, 69-78
CrossRef22
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CrossRef23
Werner Aberer, Birger Kränke. (2008) Clinical manifestations and mechanisms of skin reactions after systemic drug administration. Drug Discovery Today: Disease Mechanisms 5:2, e237-e247
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Murat Bas, Nadine Kirchhartz, Jessica Hochfeld, Cornelia Tüllmann, Stephanie Kumpf, Tatsiana Suvorava, Marc Oppermann, Dieter Hafner, Henning Bier, Thomas K. Hoffmann, Vera Balz, Georg Kojda. (2008) Potential role of vasomotor effects of fibrinogen in bradykinin-induced angioedema. Journal of Allergy and Clinical Immunology 121:4, 969-975.e2
CrossRef25
R M Fryer, J Segreti, P N Banfor, D L Widomski, B J Backes, C W Lin, S J Ballaron, B F Cox, J M Trevillyan, G A Reinhart, T W Geldern. (2008) Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema. British Journal of Pharmacology 153:5, 947-955
CrossRef26
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CrossRef27
Jonathan A. Bernstein. (2008) Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies. Annals of Allergy, Asthma & Immunology 100:1, S41-S46
CrossRef28
Thomas Renné, David Gailani. (2007) Role of Factor XII in hemostasis and thrombosis: clinical implications. Expert Review of Cardiovascular Therapy 5:4, 733-741
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Konrad Bork, Jorge Frank, Boris Grundt, Peter Schlattmann, Juerg Nussberger, Wolfhart Kreuz. (2007) Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). Journal of Allergy and Clinical Immunology 119:6, 1497-1503
CrossRef30
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CrossRef32
Jerrold H Levy, Penrose S O’Donnell. (2006) The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema. Expert Opinion on Investigational Drugs 15:9, 1077-1090
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C. R. Weiler, R. G. Van Dellen. (2006) Genetic Test Indications and Interpretations in Patients With Hereditary Angioedema. Mayo Clinic Proceedings 81:7, 958-972
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C. Drouet, D. Ponard, L. Bouillet. (2006) Angio-œdèmes iatrogènes par œstrogène : inhibiteurs de l'enzyme de conversion, antagonistes du récepteur de l'angiotensine, membranes de dialyse. La Revue de Médecine Interne 27, S76-S79
CrossRef35
E. W. Nielsen, S. Gramstad. (2006) Angioedema from angiotensin-converting enzyme (ACE) inhibitor treated with complement 1 (C1) inhibitor concentrate. Acta Anaesthesiologica Scandinavica 50:1, 120-122
CrossRef36
M. Bas, T. K. Hoffmann, H. Bier, G. Kojda. (2005) Increased C-reactive protein in ACE-inhibitor-induced angioedema. British Journal of Clinical Pharmacology 59:2, 233-238
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Marie Eve Moreau, Nancy Garbacki, Giuseppe Molinaro, Nancy J. Brown, François Marceau, Albert Adam. (2005) The Kallikrein-Kinin System: Current and Future Pharmacological Targets. Journal of Pharmacological Sciences 99:1, 6-38
CrossRef38
Takeshi Morimoto, Tejal K. Gandhi, Julie M. Fiskio, Andrew C. Seger, Joseph W. So, E. Francis Cook, Tsuguya Fukui, David W. Bates. (2004) An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors. Journal of Evaluation in Clinical Practice 10:4, 499-509
CrossRef39
M. Bas, G. Kojda, H. Bier, T. K. Hoffmann. (2004) Durch ACE-Hemmer induziertes Angio
dem des Kopf-Hals-Bereichs. HNO 52:10, 886-890
CrossRef40
Mark S Dykewicz. (2004) Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management. Current Opinion in Allergy and Clinical Immunology 4:4, 267-270
CrossRef41
Manoj R. Warrier, Cori A. Copilevitz, Mark S. Dykewicz, Raymond G. Slavin. (2004) Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme inhibitor angioedema. Annals of Allergy, Asthma & Immunology 92:5, 573-575
CrossRef42
Jürg Nussberger, Hiroyuki Koike. (2004) Antagonizing the angiotensin II subtype I receptor: A focus on olmesartan medoxomil. Clinical Therapeutics 26, A12-A20
CrossRef43
Massimo Cugno, Jürg Nussberger, Marco Cicardi, Angelo Agostoni. (2003) Bradykinin and the pathophysiology of angioedema. International Immunopharmacology 3:3, 311-317
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Domenic A. Sica, Henry R. Black. (2002) Angioedema in Heart Failure: Occurrence With ACE Inhibitors and Safety of Angiotensin Receptor Blocker Therapy. Congestive Heart Failure 8:6, 334-345
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