Hereditary angioedema

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Hereditary angioedema
Classification and external resources
Swollen hand during a hereditary angioedema attack..jpg
Swollen right hand during a hereditary angioedema attack.
ICD-10D84.1 (ILDS D84.110)
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Hereditary angioedema
Classification and external resources
Swollen hand during a hereditary angioedema attack..jpg
Swollen right hand during a hereditary angioedema attack.
ICD-10D84.1 (ILDS D84.110)

Hereditary angioedema (types I and II) (also known as "HAE") is a rare, autosomal dominantly inherited blood disorder that causes episodic attacks of swelling that may affect the face, extremities, genitals, gastrointestinal tract and upper airways.[1][2][3]:152

Swellings of the intestinal mucosa may lead to vomiting and painful, colic-like intestinal spasms that may mimic intestinal obstruction. Airway edema may be life-threatening. Episodes may be triggered by trauma, surgery, dental work, menstruation, some medications, viral illness and stress; however, this is not always readily determined. [4] This disorder affects approximately one in 10,000–50,000 people.

Hereditary angioedema (HAE) is caused by a deficiency of the C1 esterase inhibitor, a protein of the complement system, a part of the immune system. 80-85% of mutations produce low levels of C1-inhibitor (type I); 15-20% of mutations produce normal levels of ineffective C1-inhibitor protein (type II).[1][5] Type III is a very rare recently documented form: It mainly affects females and is exacerbated by high estrogen levels e.g. oral contraceptives and pregnancy. HAE type III is not due to C1 INH deficiency; it is linked to an increase in kininogenase activity leading to elevated levels of bradykinin.[6]


The underlying cause of HAE is attributed to autosomal dominant inheritance of mutations in the C1 inhibitor (C1-INH gene or SERPING1 gene), which is mapped to chromosome 11 (11q12-q13.1).[1] More than 200 mutations of this gene have been linked to the clinical HAE manifestations.2-4 The majority of HAE patients have a family history; however, 25% are the result of new mutations.[7] The low level of C1 inhibitor in the plasma leads to increased activation of pathways that release bradykinin, the chemical responsible for the angioedema due to increased vascular permeability, and the pain seen in individuals with HAE.[1]

Hereditary angioedema type III is caused by mutations in F12 gene coding for a serine protease called Factor XII.


Complement tests
C4 (C)FB (A)C3CH50Conditions
 ·PSG, C3 NeF AA
 · ·HA, C4D
 · · ·TCPD
 · /↓SLE

Recognizing HAE is often difficult due to the wide variability in disease expression. The course of the disease is diverse and unpredictable, even within a single patient over their lifetime. This disease may be similar in its presentation to other forms of angioedema resulting from allergies or other medical conditions, but it is significantly different in cause and treatment. When hereditary angioedema is misdiagnosed as an allergy it is most commonly treated with steroids and epinephrine, drugs that are usually ineffective in treating a hereditary angioedema episode. Other misdiagnoses have resulted in unnecessary exploratory surgery for patients with abdominal swelling and other hereditary angioedema patients report that their abdominal pain was wrongly diagnosed as psychosomatic.[2]

HAE accounts for only a small fraction of all cases of angioedema. To avoid potentially fatal consequences such as upper airway obstruction and unnecessary abdominal surgery, the importance of a correct diagnosis cannot be over-emphasized. View [2].

Consider Hereditary Angioedema (HAE) if a patient presents with:

[8][9] A blood test, ideally taken during an episode, can be used to diagnose the condition. Measure: serum complement factor 4 (C4), C1 inhibitor (C1-INH) antigenic protein, C1 inhibitor (C1-INH) functional level if available.

Analysis of complement C1 inhibitor levels may play a role in diagnosis. C4 and C2 are complementary components.


Treatment with ACE inhibitors is contraindicated in this condition, as these drugs can lead to bradykinin accumulation, which can precipitate disease episodes.[10][11]

Long-term prophylaxis

Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prophylaxis. There are now several phase III clinical trials recently published in HAE prophylaxis and therapy and these have led to the licensing of pdC1INH (Berinert®, CSL Behring; Cinryze®, ViroPharma; Cetor-n®, Sanquin) in many parts of the world; bradykinin receptor antagonist (Icatibant, Firazyr®, Jerini/Shire) in Europe; kallikrein inhibitor(Ecallantide, Kalbitor®, Dyax) in the United States; and recombinant C1-INH replacement therapy (rhC1INH; conestat alfa; Rhucin®, Pharming) in Europe. Tranexamic acid has been showed to be relatively ineffective therapy. Danazol prophylaxis remains an option but therapeutic agents are now being used more for prophylaxis because of danazol adverse events. [12] For patients requiring long-term prophylaxis, home therapy which allows patients to self-administer product, is considered an integral part of allowing patients a normal quality of life.

Short-term prophylaxis

Short-term prophylaxis is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–11/2 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days.


The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1 inhibitor concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1 inhibitor concentrate is only available to patients who are participating in special programs. In emergency situations where C1 inhibitor concentrate is not available, fresh frozen plasma (FFP) can be used as an alternative, as it also contains C1 inhibitor.

Other treatment modalities can stimulate the synthesis of C1 inhibitor, or reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human blood, has been used in Europe since 1979. Several C1 inhibitor treatments are now available in the U.S. Food and Drug Administration and two C1 inhibitor products are now available in Canada. Berinert P (CSL Behring), which is pasteurized, was approved by the F.D.A. in 2009 for acute attacks. Cinryze (ViroPharma), which is nanofiltered, was approved by the F.D.A. in 2008 for prophylaxis. Rhucin (Pharming) is a recombinant C1 inhibitor under development that does not carry the risk of infectious disease transmission due to human blood-borne pathogens.[5]

Newer treatments attack the contact cascade. Ecallantide (Kalbitor, Dyax) inhibits plasma kallikrein, and was approved by the F.D.A. (but not in Europe) for acute attacks in 2009. Icatibant (Firazyr, Jerini) inhibits the bradykinin B2 receptor, and was approved in Europe.[5] Approved by the FDA on August 25, 2011.[13] In hereditary angioedema, specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamines, corticosteroids, or epinephrine.


Data regarding the epidemiology of angioedema is limited. The incidence of HAE is one in 10,000–50,000 people in the United States and Canada. Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year. [14][15]

Society and Culture[edit]

Hereditary angioedema was featured in the third season of House M.D. in the episode "Fools for Love". Hereditary angioedema was determined to have been passed on to a husband and wife from their mutual father.


Clinical development of several new active substances, which intervene in the disease process in different ways, is currently ongoing.

Pharming Group NV announced on 24 June 2010 that the European Medicines Agency has adopted a positive opinion on conestat alfa (trade name Ruconest), a C1-inhibitor for the treatment of acute angioedema attacks.[16]

Ecallantide, a peptide inhibitor of kallikrein, has received orphan status for HAE and has shown positive results in phase III trials.[17]

Icatibant (marketed as Firazyr) is a selective bradykinin receptor antagonist, which has been approved in Europe and was approved in the USA by the FDA in Aug 2011.[18] After initial borderline results this drug was shown to be effective in phase III trials.[19]

Cinryze has been approved by the FDA in October 2008.[20]

Patients' organizations[edit]

There are national associations for HAE patients and their families in a number of countries around the world. These national associations are members of the global organization HAEi - International Patient Organization for C1-Inhibitor Deficiencies. HAEi is dedicated to raising awareness of C1 inhibitor deficiencies around the world. It is a non-profit international network established to promote co-operation, co-ordination and information sharing between HAE specialists and national HAE patient associations in order to help facilitate the availability of effective diagnosis and management of C1 inhibitor deficiencies throughout the world.

Visit the HAEi website [3] for further information on national associations.


  1. ^ a b c d Hemperly, SE; Agarwal, NS; Xu, YY; Zhi, YX; Craig, TJ (July 2013). "Recent Advances in the Management of Hereditary Angioedema". Journal of the American Osteopathic Association 113 (7): 546–555. doi:10.7556/jaoa.2013.006. PMID 23843378. 
  2. ^ a b "What is Hereditary Angioedema?". HAE Canada. 
  3. ^ Konrad, Bork (2010). "Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor". Allergy, Asthma & Clinical Immunology 6 (1): 15. doi:10.1186/1710-1492-6-15. 
  4. ^ What is Hereditary Angioedema
  5. ^ a b c Morgan BP (August 2010). "Hereditary angioedema--therapies old and new". N. Engl. J. Med. 363 (6): 581–3. doi:10.1056/NEJMe1006450. PMID 20818894. 
  6. ^ [1]
  7. ^
  8. ^ Zingale LC, Beltrami L, Zanichelli A, et al. (October 2006). "Angioedema without urticaria: a large clinical survey". CMAJ 175 (9): 1065–70. doi:10.1503/cmaj.060535. PMC 1609157. PMID 17060655. 
  9. ^
  10. ^ Dendorfer A, Wolfrum S, Wagemann M, Qadri F, Dominiak P (May 2001). "Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats". Am. J. Physiol. Heart Circ. Physiol. 280 (5): H2182–8. PMID 11299220. 
  11. ^ Kuoppala A, Lindstedt KA, Saarinen J, Kovanen PT, Kokkonen JO (April 2000). "Inactivation of bradykinin by angiotensin-converting enzyme and by carboxypeptidase N in human plasma". Am. J. Physiol. Heart Circ. Physiol. 278 (4): H1069–74. PMID 10749699. 
  12. ^ Hereditary angioedema: beyond international consensus - circa December 2010 - The Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture
  13. ^ Firazyr [package insert]. Lexington, MA: Shire Orphan Therapies, Inc; 2011.
  14. ^ From the: Pinnacle Health System, Harrisburg Hospital, Department of Internal Medicine, 111 South Front Street, Harrisburg, PA 17101, Update on treatment for her
  15. ^ "Update on treatment of hereditary angioedema" Buyantseva, Larisa, Sardana, Niti and Craig, Timothy
  16. ^ Pharming: Pharming Receives Positive Opinion From European Medicines Agency On Rhucin Product name in Europe changed to Ruconest
  17. ^ Lehmann A (August 2008). "Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery". Expert Opin Biol Ther 8 (8): 1187–99. doi:10.1517/14712598.8.8.1187. PMID 18613770. 
  18. ^ Jerini AG (2008-07-15). "Jerini Receives European Commission Approval for Firazyr (Icatibant) in the Treatment of HAE - Press release". Retrieved 2008-07-28. 
  19. ^ Bernstein JA (January 2008). "Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies". Ann. Allergy Asthma Immunol. 100 (1 Suppl 2): S41–6. doi:10.1016/S1081-1206(10)60585-6. PMID 18220151. 
  20. ^ Reuters: UPDATE 1-US clears Lev Pharma drug for rare swelling disease

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