Swollen right hand during a hereditary angioedema attack.
|Classification and external resources|
|ICD-10||D84.1 (ILDS D84.110)|
|Patient UK||Hereditary angioedema|
Hereditary angioedema (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.:152 In this form of angioedema, swellings of the intestinal mucous membrane 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. This disorder affects approximately one in 10,000–50,000 people.
The underlying cause of most HAE is autosomal dominant inheritance of mutations in the C1 inhibitor gene (C1-INH gene or SERPING1 gene), which is mapped to chromosome 11 (11q12-q13.1).To date there are over 300 known genetic mutations that result in a deficiency of functional C1 inhibitor protein. The majority of HAE patients have a family history; however, 25% are the result of new mutations. 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.
The most common form of the disorder is HAE type I, which is the result of abnormally low amounts (low serum levels) of C1 inhibitors, which are responsible for maintaining proper balance (homeostasis) in the complement system (specifically, keeping the C1 part of the classical complement pathway from being overactive). This inhibition helps to regulate various body functions (e.g., flow of body fluids in and out of cells). HAE type II is a more uncommon form of the disorder. It occurs as the result of the production of C1 inhibitor that is normal in amount but does not work well (abnormal structure and function). Type II accounts for about 15-20% of HAE. Type III is a very rare, recently documented form: It predominantly affects females and it is influenced by exposure to estrogens or hormone replacement therapy (e.g. oral contraceptives and pregnancy) and is not associated with C1-INH deficiency. 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. Some patients with type III HAE have a mutation in the F12 gene which produces a protein involved in blood clotting.
Symptoms generally begin around puberty but can occur earlier. These individuals have recurrent swelling in the extremities, face, lips, larynx or GI tract. The patients describe a sensation of fullness but not pain or itching in the affected area except for those with abdominal swellings who often experience acute abdominal pain. The latter two presentations are of the most concern because suffocation can occur if the airways are obstructed, and the acute swelling of the abdominal region produces intense pain often resulting in exploratory surgery.
Because hereditary angioedema is an autosomal inheritable disease, there is no gender difference in transmission and both sexes are equally likely to receive the mutated gene from their parent(s). The figure below (courtesy of US National Library Of Medicine) depicts autosomal dominant transmission. Here, the father (individual A) with a mutated gene for HAE, has the disease while his wife (individual B) with 2 non-mutated copies of the C1 inhibitor gene and does not have the disease. The possibility of a cross between them gives the possibilities as shown: two of their offspring will have the disease (HEA) while the others would not.
The affected father who has HAE has mutation on one of his genes (C1-INH). Each one of his children, notwithstanding his/her sex, will have a 50% chance to inherit the mutated C1-INH gene from him. HAE is generally referred to as a "dominant" condition because it only takes a mutation in one of the two C1-INH genes in a carrier to cause the disease.
The prevalence of HAE is relatively low – between 1 in every 10,000 to 1 in every 50,000 persons. Most of people with HAE acquire a C1 esterase inhibitor (C1-INH) mutation from one of their parents. A parent with HAE usually has a 50% probability of transmitting this condition on to one of his/her children of either sex as shown in the figure (HEA Inheritance). In occasions when HAE is not inherited and occurs in people with no previous history of it. This is because there are new impulsive or spontaneous changes in the sperm or egg cell that is responsible for this specific pregnancy. In a review of patients who do not have a history of HAE in their family, but who have relatively low levels of mutated C1-INH with persistent angioedema, 25% of new patients who had HAE had C1-INH changes that do not show signs of being inherited but rather new.
The mutational changes in 1 or both of the carriers' C1 inhibitor genes could have only occurred spontaneously, and just like in the example above, their offspring in this case will have a 50% probability of acquiring the mutated gene from either parent that has HAE.
|C4 (C)||FB (A)||C3||CH50||Conditions|
|·||↓||↓||↓||PSG, C3 NeF AA|
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.
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.
Consider hereditary angioedema (HAE) if a patient presents with:
- Recurrent angioedema (without urticaria)
- Recurrent episodes of abdominal pain and vomiting
- Laryngeal edema
- Positive family history of angioedema
 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.
HAE type I is primarily caused by a deficiency in blood proteins (C1 esterase inhibitors) which normally suppress activation of the complement system. The resultant over-stimulation of this system leads to the production of inflammatory anaphylatoxins, which affects the flow of body fluids between the vascular system and body tissues. This deficiency is responsible for approximately 80-85% of cases.
HAE type II is a less frequently encountered form of this disorder and accounts for 15-20% of cases. In this type, atypical C1-inhibitor proteins are produced which are less capable of suppressing activation of the complement system. Like HAE type I, this results in over-stimulation of this system.
HAE type III is rare and has only been documented recently. Unlike types I and II, this form does not appear to be connected with C1-inhibitor deficiency. This type mainly affects females and appears to be influenced by contact with estrogens and also by hormone replacement therapy (e.g. oral contraceptives). Its pathogenesis is credited to increased activity of the enzyme kininogenase, which leads to rise in the levels of bradykinin. Other patients with type III HAE have alterations in gene F12, which encodes a protein which participates in blood coagulation. Some patients with type III HAE have a mutation in the F12 gene which produces a protein involved in blood clotting.
Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prevention. 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 shown 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. 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 prevention is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–1.5 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. Ruconest (Pharming) is a recombinant C1 inhibitor approved in the US and Europe that does not carry the risk of infectious disease transmission due to human blood-borne pathogens.
The medication ecallantide inhibits plasma kallikrein, and was approved by the F.D.A. (but not in Europe) for acute attacks in 2009. Icatibant inhibits the bradykinin B2 receptor, and was approved in Europe and the USA. 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.
Society and culture
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 boyfriend and girlfriend from their mutual father.
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.
The Assistance Fund Inc. is an American nonprofit organization that offers co-pay assistance for medications that treat HAE and is open to any American Citizens or landed immigrants who have insurance.
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.
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. After initial borderline results this drug was shown to be effective in phase III trials.Cinryze has been approved by the FDA in October 2008.
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- Hereditary angioedema: beyond international consensus - circa December 2010 - The Canadian Society of Allergy and Clinical Immunology Dr. David McCourtie Lecture
- Firazyr [package insert]. Lexington, MA: Shire Orphan Therapies, Inc; 2011.
- From the: Pinnacle Health System, Harrisburg Hospital, Department of Internal Medicine, 111 South Front Street, Harrisburg, PA 17101, Update on treatment for her
- "Update on treatment of hereditary angioedema" Buyantseva, Larisa, Sardana, Niti and Craig, Timothy
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- Pharming: Pharming Receives Positive Opinion From European Medicines Agency On Rhucin Product name in Europe changed to Ruconest
- 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:10.1517/147125184.108.40.2067. PMID 18613770.
- Jerini AG (2008-07-15). "Jerini Receives European Commission Approval for Firazyr (Icatibant) in the Treatment of HAE - Press release". Retrieved 2008-07-28.
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- Reuters: UPDATE 1-US clears Lev Pharma drug for rare swelling disease