Angioedema

Angioedema (BE: angiooedema), also known by its eponym Quincke's edema, is the rapid swelling (edema) of the skin, mucosa and submucosal tissues. Apart from the common form, mediated by allergy, it has been reported as a side effect of some medications, specifically ACE inhibitors.

Additionally, there are three autosomal dominant inherited forms known, due to mutations in the genes that control the clotting cascade, including the SERPING1 gene, which results in deficiency of the blood protein C1-inhibitor (type I HAE) and the F12 gene, which controls Factor XII (type III HAE). There is an additional type in which C1 levels are normal but C1 function is decreased (type II HAE). All three forms are called hereditary angioedema (HAE) or occasionally by the outdated term "hereditary angioneurotic edema" (HANE). In all forms of HAE, swelling may also occur in the digestive tract and other organs. It is life-threatening when it involves the larynx due to the potential for asphyxiation.

Cases where angioedema progresses rapidly should be treated as a medical emergency as airway obstruction and suffocation can occur. Epinephrine may be lifesaving when the cause of angioedema is allergic. In the case of hereditary angioedema, treatment with epinephrine has not been shown to prevent morbidity or delay the time necessary to treat.

In the past, angioedema was referred to by the term angioneurotic edema, which wrongly implied that the phenomenon was due to neurosis.

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Signs and symptoms

The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell up over the period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands. The swelling can be itchy. There may also be slightly decreased sensation in the affected areas due to compression of the nerves. Urticaria (hives) may develop simultaneously.

In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels. Intubation is required in these situations to prevent respiratory arrest and risk of death.

Sometimes, there has been recent exposure to an allergen (e.g. peanuts), but more often the cause is either idiopathic (unknown) or only weakly correlated to allergen exposure.

In hereditary angioedema, there is often no direct identifiable cause, although mild trauma, including dental work and other stimuli, can cause attacks. There is usually no associated itch or urticaria, as it is not an allergic response. Patients with HAE can also have recurrent episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, non-itchy splotchy/swirly rash. These stomach attacks can last anywhere from 1-5 days on average, and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13-30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. As the symptoms and diagnostic tests are almost indistinguishable from an acute abdomen (e.g. perforated appendicitis) it is possible for undiagnosed HAE patients to undergo laparotomy (operations on the abdomen) or laparoscopy (keyhole surgery) that turns out to have been unnecessary.

HAE may also cause swelling in a variety of other locations, most commonly the limbs, genitals, neck, throat, and face. The pain associated with these swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, oedema develops over a period of 12-36 hours and then subsides within 2-5 days.

Diagnosis

The diagnosis is made on the clinical picture. Routine blood tests (complete blood count, electrolytes, renal function, liver enzymes) are typically performed. Mast cell tryptase levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. When the patient has been stabilized, particular investigations may clarify the exact cause; complement levels, especially depletion of complement factors 2 and 4, may indicate deficiency of C1-inhibitor. HAE type III is a diagnosis of exclusion consisting of observed angioedema along with normal C1 levels and function.

The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic. An important clue is the failure of hereditary angioedema to respond to antihistamines or steroids, a characteristic that distinguishes it from allergic reactions. It is particularly difficult to diagnose HAE in patients whose episodes are confined to the gastrointestinal tract. Besides a family history of the disease, only a laboratory analysis can provide final confirmation. In this analysis, it is usually a reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected. The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.

Pathophysiology

The final common pathway for the development of angioedema seems to be the activation of the bradykinin pathway. This peptide 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. Bradykinin is released by various cell types in response to numerous different stimuli; it is also a pain mediator.

Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema. ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin. 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 (serpin) normally inhibits the conversion of C1 to C1r and C1s, which - in turn - activate other proteins of the complement system. Additionally, it inhibits various proteins of the coagulation cascade, although effects of its deficiency on the development of hemorrhage and thrombosis appear to be limited.

There are three types of hereditary angioedema:

• Type I - decreased levels of C1INH (85%);
• Type II - normal levels but decreased function of C1INH (15%);
• Type III - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (originally described by Bork et al in 2000, exact frequency uncertain).^[1] It has been linked with mutations in the factor XII gene.^[2]

Angioedema can be due to antibody formation against C1INH; this is an autoimmune disorder. This acquired angioedema is associated with the development of lymphoma.

Consumption of foods which are themselves vasodilators such as alcohol or cinnamon can increase the probability of an angioedema episode in susceptible patients. If the episode occurs at all after the consumption of these foods, its onset may be delayed overnight or by some hours, making the correlation with their consumption somewhat difficult.

The use of ibuprofen or aspirin may increase the probability of an episode in some patients. The use of acetaminophen typically has a smaller, but still present, increase in the probability of an episode.

Therapy

Allergic angioedema

In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. Cetirizine is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require steroid therapy, which generally leads to a good response.

Drug induced angioedema

In ACE inhibitor use, the medication needs to be discontinued, and all similar drugs need to be avoided. There is controversy whether angiotensin II receptor antagonists are safe in patients with a previous attack of angioedema.

Hereditary angioedema

In hereditary angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future.

Acute treatment

The aim of acute treatment is to halt progression of the oedema 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-INH concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes. Fresh Frozen Plasma (FFP) can be used as an alternative to C1-INH concentrate.

Long-term prophylaxis

Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal oedema require long-term prophylaxis. This often involves male sex hormones (androgens), which increase production of C1-INH in the liver through an as yet unknown mechanism. The dose should be kept as low as possible because of its frequent adverse effects. The use of androgens is particularly problematic in children and they must not be taken during pregnancy. Several cases in which patients developed benign liver tumours during treatment with the androgen danazol resulted in the substance being taken off the market in Germany at the beginning of 2005.

As an alternative, drugs known as fibrinolysis inhibitors, such as tranexamic acid, are used, although their effect is comparatively weak and their potential for side effects is questionable.

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 oedema), high-dose androgen treatment is administered for 5-7 days.

New treatment options

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

C1-INH concentrate is not available in the US, so sometimes fresh frozen plasma is used. C1inh concentrate is currently under late-stage development for both acute and prophylactic use [1]and in an acute study. DX-88 is an inhibitor of kallikrein under development as an orphan drug for hereditary angioedema [2]. Icatibant is a selective bradykinin receptor antagonist that is due to be marketed as an orphan drug for hereditary angioedema by Jerini AG, a German pharmaceutical company. Pharming, a Dutch biotechnology company, is developing a recombinant C1 inhibitor for acute attacks of hereditary angioedema. Pharming's rhC1INH product and Jerini's Icatibant are currently in phase III development and have orphan drug status in the US and Europe.

No studies have been done on these agents in relation to HAE type III.

Acquired angioedema

In acquired angioedema, HAE types I and II, and non-histaminergic angioedema, antifibrinolytics such as tranexamic acid or ε-aminocaproic acid may be effective. Cinnarizine may also be useful because it blocks the activation of C4 and can be used in patients with liver disease while androgens cannot[3].

History

Dr Heinrich Quincke first described the clinical picture of angioedema in 1882. ^[3] Sir William Osler remarked in 1888 that some cases may have a hereditary basis; he coined the term hereditary angio-neurotic edema.^[4]

References

1. ^ Bork K, Barnstedt SE, Koch P, Traupe H (2000). "Hereditary angioedema with normal C1-inhibitor activity in women". Lancet 356 (9225): 213–7. PMID 10963200.
2. ^ Cichon S, Martin L, Hennies HC, et al (2006). "Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III". Am. J. Hum. Genet. 79 (6): 1098–104. doi:10.1086/509899. PMID 17186468.
3. ^ Quincke H. Concerning the acute localized oedema of the skin. Monatsh Prakt Derm 1882;1:129-131.
4. ^ Osler W. Hereditary angio-neurotic oedema. Am J Med Sci 1888;95:362-67.