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Angioedema is an area of swelling (
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
) of the lower layer of skin and tissue just under the skin or mucous membranes. The swelling may occur in the face, tongue,
larynx The larynx (), commonly called the voice box, is an organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal inlet is about ...
, abdomen, or arms and legs. Often it is associated with
hives Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...
, which are swelling within the upper skin. Onset is typically over minutes to hours. The underlying mechanism typically involves histamine or bradykinin. The version related to histamine is due to an allergic reaction to agents such as insect bites, foods, or
medications A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and rel ...
. The version related to bradykinin may occur due to an inherited problem known as C1 esterase inhibitor deficiency, medications known as angiotensin-converting enzyme inhibitors, or a lymphoproliferative disorder. Treatment to protect the airway may include intubation or cricothyroidotomy. Histamine-related angioedema can be treated with antihistamines,
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
s, and
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
. In those with bradykinin-related disease a C1 esterase inhibitor, ecallantide, or icatibant may be used. Fresh frozen plasma may be used instead. In the United States the disease affects about 100,000 people a year.


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 over the period of minutes to 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 Stridor (Latin for "creaking or grating noise") is a high-pitched extra-thoracic breath sound resulting from turbulent air flow in the larynx or lower in the bronchial tree. It is different from a stertor which is a noise originating in the pha ...
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 Respiratory arrest is a sickness caused by apnea (cessation of breathing) or respiratory dysfunction severe enough it will not sustain the body (such as agonal breathing). Prolonged apnea refers to a patient who has stopped breathing for a long p ...
and risk of death. Sometimes, the cause is recent exposure to an allergen (e.g. peanuts), but more often it is either idiopathic (unknown) or only weakly correlated to allergen exposure. In hereditary angioedema (HAE), often no direct cause is identifiable, 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, nonitchy splotchy/swirly rash. These stomach attacks can last one to five 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 13,000 to 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.


Pathophysiology

Bradykinin plays a critical role in all forms of hereditary angioedema. This peptide is a potent
vasodilator Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
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 Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...
, and edema develops easily. Bradykinin is released by various cell types in response to numerous different stimuli; it is also a
pain Pain is a distressing feeling often caused by intense or damaging stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, ...
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 The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
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. The three types of hereditary angioedema are: * 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 Hormonal contraception refers to birth control methods that act on the endocrine system. Almost all methods are composed of steroid hormones, although in India one selective estrogen receptor modulator is marketed as a contraceptive. The origin ...
(exact frequency uncertain). It has been linked with mutations in the factor XII gene. 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 that are themselves vasodilators, such as
alcoholic beverage An alcoholic beverage (also called an alcoholic drink, adult beverage, or a drink) is a drink that contains ethanol, a type of alcohol that acts as a drug and is produced by fermentation of grains, fruits, or other sources of sugar. The c ...
s or
cinnamon Cinnamon is a spice obtained from the inner bark of several tree species from the genus ''Cinnamomum''. Cinnamon is used mainly as an aromatic condiment and flavouring additive in a wide variety of cuisines, sweet and savoury dishes, breakfa ...
, 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. The use of
ibuprofen Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arte ...
or aspirin may increase the probability of an episode in some patients. The use of
acetaminophen Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
typically has a smaller, but still present, increase in the probability of an episode.


Diagnosis

The diagnosis is made on the clinical picture. Routine blood tests ( complete blood count,
electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...
s, kidney 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 steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
, 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. Angioedema is classified as either hereditary or acquired.


Acquired angioedema

Acquired angioedema (AAE) can be immunologic, nonimmunologic, or idiopathic. It is usually caused by allergy and occurs together with other allergic symptoms and urticaria. It can also occur as a side effect to certain medications, particularly
ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
s. It is characterized by repetitive episodes of swelling, frequently of the face, lips, tongue, limbs, and genitals. Edema of the gastrointestinal mucosa typically leads to severe abdominal pain; in the upper respiratory tract, it can be life-threatening.


Hereditary angioedema

Hereditary angioedema (HAE) exists in three forms, all of which are caused by a genetic mutation inherited in an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
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 diminished 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 The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...
, and all forms can cause swelling elsewhere in the body, such as the digestive tract. If HAE involves the
larynx The larynx (), commonly called the voice box, is an organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal inlet is about ...
, it can cause life-threatening asphyxiation. The pathogenesis of this disorder is suspected to be related to unopposed activation of the contact pathway by the initial generation of kallikrein and/or clotting factor XII by damaged endothelial cells. The end product of this cascade, bradykinin, is produced in large amounts and is believed to be the predominant mediator leading to increased vascular permeability and vasodilation that induces typical angioedema "attacks".


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 A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
therapy, which generally leads to a good response. In cases where allergic attack is progressing towards airway obstruction,
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
may be life-saving.


Drug induction

ACE inhibitors can induce angioedema. ACE inhibitors block the enzyme ACE so it can no longer degrade bradykinin; thus, bradykinin accumulates and can cause angioedema. This complication appears more common in African-Americans. 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), which has a similar mechanism but does not affect bradykinin. However, this is controversial, as small studies have shown some patients with ACE inhibitor angioedema can develop it with ARBs, as well.


Hereditary

In hereditary angioedema (HAE), 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 (C1-esterase inhibitor) 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. The medications ecallantide and icatibant may be used to treat attacks. In 2017 these medications cost between 5,700 and 14,000 per dose in the United States, prices that tripled in two years. In those given icatibant, specialists monitor is recommended.


Acquired

In acquired angioedema, HAE types I and II, and nonhistaminergic 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, whereas androgens cannot.


Prophylaxis

Future attacks of HAE can be prevented by the use of androgens such as danazol, oxandrolone or methyltestosterone. These agents increase the level of aminopeptidase P, an enzyme that inactivates kinins; kinins (especially bradykinin) are responsible for the manifestations of angioedema. In 2018, the U.S. Food and Drug Administration approved lanadelumab, an injectable monoclonal antibody, to prevent attacks of HAE types I and II in people over age 12. Lanadelumab inhibits the plasma enzyme kallikrein, which liberates the kinins bradykinin and kallidin from their kininogen precursors and is produced in excess in individuals with HAE types I and II.


Epidemiology

In the U.S., there are as many as 80,000 to 112,000
emergency department An emergency department (ED), also known as an accident and emergency department (A&E), emergency room (ER), emergency ward (EW) or casualty department, is a medical treatment facility specializing in emergency medicine, the acute care of pati ...
(ED) visits for angioedema annually, and it ranks as the top
allergic disorder Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermati ...
resulting in hospitalization.


History

Heinrich Quincke first described the clinical picture of angioedema in 1882, though there had been some earlier descriptions of the condition. William Osler remarked in 1888 that some cases may have a hereditary basis; he coined the term "hereditary angio-neurotic edema". The link with C1 esterase inhibitor deficiency was proved in 1963.


See also

*
Drug-induced angioedema Drug-induced angioedema is a known complication of the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists (ARBs), and Angiotensin-Neprilysin Inhibitor LCZ969.James, William; Berger, Timothy; Elston, Dirk (2005). ''An ...
*
Gleich's syndrome Gleich's syndrome is a rare disease in which the body swells up episodically (angioedema), associated with raised antibodies of the IgM type and increased numbers of eosinophil granulocytes, a type of white blood cells, in the blood ( eosinophilia) ...
(unexplained angioedema with high eosinophil counts) * Ruconest (C1-inhibitor)


References


External links

* {{Disorders of volume state Effects of external causes Medical emergencies Complement deficiency Drug eruptions Wikipedia medicine articles ready to translate Wikipedia emergency medicine articles ready to translate