| Hereditary angioedema | |
|---|---|
| Classification and external resources | |
 Swollen right hand during a hereditary angioedema attack. |
|
| ICD-10 | D84.1 (ILDS D84.110) |
| ICD-9 | 277.6 |
| OMIM | 106100 |
| DiseasesDB | 1821 |
| MedlinePlus | 001456 |
| eMedicine | article/1048994 |
| MeSH | D054179 |
Hereditary angioedema (types I and II) (also known as "HAE" or "Quincke edema" after discoverer Heinrich Quincke) is a rare, inherited blood disorder that causes episodic attacks of swelling that may affect the face, extremities, genitals, gastrointestinal tract and upper airways. :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. 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. Some mutations produce low levels of C1-inhibitor (type I); others produce normal levels of ineffective C1 protein (type II).
The underlying cause of HAE is attributed to autosomal-dominant inheritance of mutations in C1-INH gene (SERPING1 gene), which is mapped to chromosome 11 (11q12-q13.1). 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.
Hereditary angioedema type III has separate pathogenesis, being caused by mutations in F12 gene coding for a serine protease called Factor XII.
| C4 (C) | FB (A) | C3 | CH50 | Conditions |
|---|---|---|---|---|
| · | ↓ | ↓ | ↓ | PSG, C3 NeF AA |
| ↓ | · | ↓ | · | HA, C4D |
| · | · | · | ↓ | TCPD |
| ↓ | · /↓ | ↓ | ↓ | SLE |
| ↑ | ↑ | ↑ | ↑ | inflammation |
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. View Diagnosis Algorithm Flowchart.
Consider Hereditary Angioedema (HAE) if a patient presents with:
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.
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. 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 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.
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. Approved by the FDA on August 25, 2011. 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.
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.
Ecallantide, a peptide inhibitor of kallikrein, has received orphan status for HAE and has shown positive results in phase III trials.
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.
No studies have been done on these agents in relation to HAE type III.
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