Reviewer: S. Randhawa, M.D., Assistant Professor at NSU
Dr Heinrich Quincke first described the clinical picture of angioedema in 1882, hence the eponym Quincke's edema. Sir William Osler remarked in 1888 that some cases may have a hereditary basis; he coined the term hereditary angio-neurotic edema.
Bradykinin is the important mediator behind the symptoms of angioedema. Bradykinin is a potent vasodilator, leading to rapid accumulation of fluid in the interstitium. This is most obvious in the face, where the skin has relatively little supporting connective tissue, and edema develops easily.
Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema:
1. ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin.
2. In hereditary angioedema, bradykinin formation is caused by continuous activation of the complement system due to a deficiency in one of its prime inhibitors, C1-esterase inhibitor (C1INH), and continuous production of kallikrein, another process inhibited by C1INH. This serine protease inhibitor normally inhibits the conversion of C1 to C1r and C1s, which - in turn - activate other proteins of the complement system.
Angioedema (AE) Classification (click to enlarge the image):
Angioedema (AE) can be allergic or non-allergic. There are 5 types of non-allergic angioedema (AE):
- acquired AE
- hereditary AE (HAE)
- ACE-inhibitor induced AE
- idiopathic AE, can occur with chronic urticaria
- pseudoallergic AE, e.g. reaction to NSAIDs
There are 3 types of HAE that are differentiated by C4 and C1-INH levels
- type I HAE - low C4, low C1-INH function, low C1-INH antigen level
- type II HAE - low C4, low C1-INH function, normal C1-INH antigen level
- type III HAE - all normal
Angioedema is divided in 2 categories: acquired and hereditary.
Autosomal dominant - 11 chromosome
Androgens for prophylaxis
Angioedema involves swelling of the deep dermal and subcutaneous/submucosal tissues. Approximately 50% of patients have both urticaria and angioedema. Angioedema is non-pitting and non-hot.
Angioedema: a 24-hour photo diary by a patient posted on Flickr. The patient took pictures of herself and uploaded them to the photo sharing website Flickr under a Creative Commons license. She had the impression her symptoms were due to urticaria but since the process affects the subcutaneous tissues (note the upper lip edema), the more likely diagnosis is angioedema and urticaria.
When you see a patient with angioedema, the first question is: "are you on ACE inhibitor?" ARBs are well tolerated as an alternative therapy with a reported cross-reactivity of less than 5-10%.
ACE-inhibitor-induced angioedema affecting the upper lip
Acquired angioedema (AAE) rarely starts after 50 years of age.
Acquired angioedema is divided into:
- Type I seen in lymphoproliferative disoders characterized by massive amounts of immune complexes
- Type II - autoantibodies to C1 inhibitor
Both type I and II have low C1q level AND low C4/C2 levels. In contrast, in HAE the C1q level is normal.
C1 protein, showing subunits C1r, C1s, and the C1q tails. Image source: Wikipedia. Patients with acquired angioedema have low C1q levels AND low C4/C2 levels. In contrast, in hereditary angioedema (HAE) the C1q level is normal.
Classical and alternative complement pathways. Image source: Wikipedia.
Hereditary Angioedema (HAE)
Hereditary angioedema (HAE) is an autosomal dominant condition associated with episodic attacks of nonpitting edema. Patients with HAE have low levels of C1 inhibitor (a serine protease inhibitor). Edema is caused by unregulated generation of bradykinin. In HAE the C1q level is normal which differentiates from acquired angioedema type I and II.
C1 inhibitor is low
C1 q level is normal
11 years is the mean age of onset
11 years before the diagnosis is made, on average
Oral contraceptives can unmask HAE -- estrogens unmask the disease, androgens are used for treatment.
Barium swallow can show bowel wall edema seen as "coin stacking" on X-ray.
C1q, C4, C2
C1-esterase inhibitor - qualitative and quantitative
In HAE and AAE, C4 levels are low during angioedema episodes but may be normal between attackes.
To differentiate between AAE and HAE, the C1q level should be measured.
The hallmarks of AAE are low C1q, C2, C4, and C1-INH levels.
In HAE, C1q levels are usually normal or only slightly decreased (rarely less than 50% of the normal values).
Treatment of HAE
Treatment of acute HAE attacks
- C1-INH, 20 units/kg, IV infusion
- Icatibant, 30 mg SC, bradykinin B2 receptor antagonist
- Ecallantide, 30 mg SC, kallikrein receptor antagonist
Prophylaxis of HAE attacks
- C1-INH, 1,000 units, IV infusion every 3-4 days
- attenuated androgen, e.g. danocrine 200 mg PO TID
Effective chronic therapy for HAE has been available for decades -- androgens or plasmin inhibitors. Until recently, there was no therapy for acute attacks available in the U.S.
How do male steroids (androgens) work?
Androgens upregulate the gene.
A follow-up study of the long-term use of stanozolol showed that 21 patients with HAE benefited from stanozolol therapy up to 2 mg daily for more than 25 years. Treatment-related symptoms, predominantly hirsutism, menstrual cycle disorders, and weight gain, developed in 10 patients, but these were easily controlled with dose reduction.
In recent years, 5 pharmaceutical companies have developed drugs which stop acute attacks of HAE or can be used for prophylaxis.
There are 2 preparations of C1 inhibitor purified from plasma which have been used in Europe for decades (Cinryze and Berinert P). There is also a recombinant C1 inhibitor (not obtained from plasma). A kallikrein inhibitor (Ecallantide) and a bradykinin type 2 receptor antagonist (Icatibant) are in testing phases. It is likely that HAE treatment will change dramatically in near future.
New therapies for hereditary angioedema (HAE)
In summary, the new products for acute treatment and prophylaxis of hereditary angioedema (HAE) are:
- C1 inhibitor purified from plasma (Cinryze and Berinert P)
- recombinant C1 inhibitor
- kallikrein inhibitor (Ecallantide)
- bradykinin type 2 receptor antagonist (Icatibant), can be given SQ
Recombinant human C1 inhibitor from mammary secretions of trangenic rabbit
C1 inhibitor concentrates
Farkas et al. reported the use of a human C1 inhibitor concentrate therapy for 468 acute attacks in 61 patients with HAE, including 22 children, with efficacy in more than 90% of cases and no reported adverse effects. C1 inhibitor therapy is the best approach from a physiological perspective since it replaces the missing factor. However, the C1 inhibitor has to be administered intravenously which precludes home therapy. Recombinant human C1 inhibitor avoids the infection transmission risks but is difficult to produce.
Kallikrein inhibitors are also effective in reducing HAE symptoms. Angioedema pathogenesis involves the activation of kallikrein to generate bradykinin. A placebo-controlled trial of 48 patients with HAE treated with ecallantide, a kallikrein inhibitor, showed a reduction of HAE attack symptoms in 72% of patients.
Bradykinin type 2 receptor antagonists
A bradykinin type 2 receptor antagonist (Icatibant) has a distinctive advantage over the C1 inhibitor concentrate therapy from the fact that it can be administered subcutaneously. Patients could potentially administer icatibant at home, similar to insulin therapy for diabetes.
International consensus on hereditary and acquired angioedema. Annals, 2012.
New therapies for hereditary angioedema: Disease outlook changes dramatically. Frank et al. JACI, Volume 121, Issue 1, Pages 272-280 (January 2008).
New Directions in the Treatment of Angioedema. Medscape, 2012.
Hereditary angioedema, Supplement of Annals of Allergy, Asthma and Immunology, 01/2008.Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. Farkas et al. J Allergy Clin Immunol 120. 914-917.2007.
Advances in basic and clinical immunology in 2007. Journal of Allergy and Clinical Immunology - Volume 122, Issue 1 (July 2008).
Hereditary Angioedema. NEJM, Volume 359:1027-1036, September 4, 2008.
Angioedema. Maurice Reid, MD. eMedicine.
Angioedema. Nedra R Dodds, MD. eMedicine.
Angioedema Due to Angiotensin Converting Enzyme Inhibitors. Allergy Cases, 01/2008.
Audio: New Therapies on Horizon for Angioedema Attacks. AAAAI, 03/2008.
Angioedema, from Wikipedia, the free encyclopedia.
A 28-Year-Old Woman With Undiagnosed Hereditary Angioedema. Medscape, 2009.
"Traumatic" Angioedema in a Patient on ACEi. Life in the Fast Lane, 2009.
35 years ago: “We probably will never know why you swell, but it’s called Angioneurotic Edema” - things have changed a lot since then. HAEA.org.