What are your recommendations for recurrent attacks of acute angioedema of lip or tongue in a patient who is not any medication, but lab values are normal for C4 and C1 inhibitor even during acute attacks?
Do you label these patients as type III angioedema?
Are medications like Kalbitor and Firazyr indicated in these patients?
If so, how do you justify their approval by insurance who claim that these meds are not indicated in type III angioedema or in patients with clinical picture of HAE but normal lab values. Thank you.


Thank you for your inquiry.

I will try and deal with your questions as they are asked:

1 .I would not label your patient as having type 3 angioedema. This diagnosis should be reserved for a patient with a positive family history in most instances, and a documented point mutation in the Factor XII gene, Thr309Lis. Such cases are apparently quite rare, and I do not see anything particularly suggestive in the history regarding your patient that would prompt me to consider this diagnosis.

2. Angioedema has been recently classified as histaminergic versus non-histaminergic. In the latter, the episodes are not related to mast cell degranulation or the release of mast cell mediators such as histamine. They are, apparently in the vast majority of cases, due to the production of kinin, but rather through a different pathway than that associated with hereditary angioedema or “angioedema type 3.” Thus, such patients may respond to antagonist of the activity of kinin which would include both ecallantide and icatibant.

3. Justifying the approval of these drugs via insurance is another effort entirely, and I have not had anywhere near universal success. I do not have any “secrets” to offer you in regards to this issue. However, the references below discuss the issue of non-histaminergic angioedema in detail and can be used to bolster your effort to obtain a kinin antagonist for your patient if you should wish to do so.

In addition, we have many responses on our website to very similar questions which also discuss the therapy of recalcitrant angioedema using drugs other than antihistamines, corticosteroids, or bradykinin antagonists. I think that you would find these helpful, and you can readily access these responses by going to the search box and typing in the following search terms:

1. Angioedema
2. Recalcitrant angioedema
3. Angioedema type 3

Thank you again for your inquiry and we hope this response is helpful to you.

1. Annals of Allergy, Asthma, and Immunology 2012; 108(6):460-461.

2. Cougno M, et al. Bradykinin and the pathophysiology of angioedema. International Immunopharmacology 2003 (March); 3(3):311-317.

3. Franzen D, et al. Idiopathic non-histaminergic angioedema-oedema after routine extubation successfully treated with fresh frozen plasma. Anaesthesia 2006; 61(7):698-701.

4. Bouillet L, et al. Non-histaminic angioedema management: diagnostic and therapeutic interest of tranexamic acid. Rev Med Interne 2004 (December); 25(12):924-926. Zuraw BL, Bork K, E Binkley K, Banerji A,Christiansen SC, Castaldo A, Kaplan A, Riedl M, Kirkpatrick C, Magerl M, Drouet C, Cacardi M. Hereditary angioedema with normal C1 inhibitor function: Consensus of an international expert panel. Allergy Asthma Proc 2012 (Dec 13).

5. A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, Khan D, Sheikh J, Weldon D, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D. J Allergy Clin Immunol. 2013 Jun;131(6):1491-1493.e25. doi: 10.1016/j.jaci.2013.03.034.

Phil Lieberman, M.D.

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