hives

Angioedema
Classification and external resources
Allergic angioedema. Note that this child is unable to open his eyes due to swelling.
ICD-10	D84.1 , T78.3
ICD-9	277.6, 995.1
OMIM	606860 106100 610618
DiseasesDB	13606
MedlinePlus	000846
eMedicine	emerg/32 med/135 ped/101
MeSH	D000799

Angioedema (BE: angiooedema) or Quincke's edema is the rapid swelling (edema) of the dermis, subcutaneous tissue,^[1] mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis.^[1] The term angioneurotic oedema was used for this condition in the belief that there was nervous system involvement, but this is no longer thought to be the case.

Cases where angioedema progresses rapidly should be treated as a medical emergency, as airway obstruction and suffocation can occur. Epinephrine may be life-saving when the cause of angioedema is allergic. In the case of hereditary angioedema, treatment with epinephrine has not been shown to be helpful.

Classification

Angioedema is classified as either acquired or hereditary. Acquired angioedema is usually caused by allergy and occurs together with other allergic symptoms and urticaria. It can also happen as a side-effect to certain medications, particularly ACE inhibitors.

Hereditary angioedema (HAE) exists in three forms, all of which are caused by a genetic mutation that is inherited in an autosomal dominant form. They are distinguished by the underlying genetic abnormality. Types I and II are caused by mutations in the SERPING1 gene, which result in either dimished levels of the C1-inhibitor protein (type I HAE) or dysfunctional forms of the same protein (type II HAE). Type III HAE has been linked with mutations in the F12 gene, which encodes the coagulation protein Factor XII. All forms of HAE lead to abnormal activation of the complement system, and all forms can cause swelling elsewhere in the body, such as the digestive tract. If HAE involves the larynx it can cause life-threatening asphyxiation.^[2]

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 or painful. 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. Tracheal 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.^[3] 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, edema 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

Bradykinin plays a critical role in all forms of hereditary angioedema.^[4] This peptide is a potent vasodilator and increases vascular permeability, 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. Dampening or inhibiting bradykinin has been shown to relieve HAE symptoms.

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 (aka: C1-inhibitor or C1INH), and continuous production of kallikrein, another process inhibited by C1INH. This serine protease inhibitor (serpin) normally inhibits the association of C1r and C1s with C1q to prevent the formation of the C1-complex, which - in turn - activates 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).^[5] It has been linked with mutations in the factor XII gene.^[6]

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. In contrast, consumption of bromelain in combination with turmeric may be beneficial in reducing symptoms.^[7]

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.

Management

Allergic

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

ACE inhibitors can induce angioedema.^[8][9][10] ACE inhibitors block the enzyme ACE so that it can no longer degrade bradykinin; thus bradykinin accumulates and causes angioedema.^[8][9] This complication appears more common in African-Americans.^[11] In people with ACE inhibitor angioedema, the drug needs to be discontinued and an alternative treatment needs to be found, such as an angiotensin II receptor blocker (ARB)^[12] which has a similar mechanism but does not affect bradykinin. However, this is controversial as there are small studies that have shown that patients with ACE inhibitor angioedema can develop it with ARBs as well.^[13][14]

Hereditary

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. 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.

Acquired

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 [1].

History

Dr Heinrich Quincke first described the clinical picture of angioedema in 1882,^[15] though there had been some earlier descriptions of the condition.^[16][17][18]

Sir William Osler remarked in 1888 that some cases may have a hereditary basis; he coined the term hereditary angio-neurotic edema.^[19]

The link with C1 esterase inhibitor deficiency was proved in 1963.^[20]

See also

• Hereditary angioedema
• Gleich's syndrome (unexplained angioedema with high eosinophil counts)
• Drug-induced angioedema

References

External links

• International Patient Organization for C1 inhibitor Deficiencies
• Israeli HAE Patient Organization
• Online Symptom Diary for Patients with Hereditary Angioedema
• US Hereditary Angioedema Association
• UK Patient organisation for HAE
• All About HAE