Allergies Urticaria & Angioedema Print Causes and Risk Factors of Angioedema Allergy, Environment, and Genetics May All Play a Part Medically reviewed by Medically reviewed by Andy Miller, MD on October 09, 2019 Andy Miller, MD, is board-certified in internal medicine and infectious disease by the American Board of Internal Medicine. Learn about our Medical Review Board Andy Miller, MD Written by Written by Daniel More, MD Daniel More, MD, FAAAAI, FACAAI, FACP, is a board-certified allergist and clinical immunologist with a background in internal medicine. Learn about our editorial policy Daniel More, MD Updated on October 09, 2019 Angioedema Overview Symptoms Causes Diagnosis Treatment In This Article Table of Contents Expand Common Causes Genetics Risk Factors View All Angioedema, swelling of the layer of tissue immediately beneath the skin, may be caused by an allergy, a drug reaction, one's environment, or even stress. It may also be hereditary, with a related gene mutation being passed down in families. The underlying mechanism in all cases is a malfunction of the immune system in which chemicals called histamine or bradykinins are abnormally released into the bloodstream. The area of the body affected—face, tongue, throat, arms, or legs—may provide a hint as to the cause, but not always. © Verywell, 2018 Common Causes Acquired angioedema (AAE) can either be immunologic (related to allergy), non-immunologic (triggered by non-allergic causes), or idiopathic (of unknown origin). Unlike angioedema with a purely genetic cause (see below), some of the factors involved in these types may be modifiable. Immunologic Allergy is the most common cause of angioedema, triggered by a reaction to medications, food, insect stings, or other substances such as latex. The cause is considered immunologic because it involves an abnormal response of the immune system. For reasons unknown, the body will sometimes mistake an otherwise harmless substance for a dangerous one and disperse large quantities of histamine into the bloodstream as a means of defense. While histamines are meant to dilate blood vessels so that white blood cells can get closer to the site of an injury, when they are released in the absence of harm, they can trigger an array of adverse symptoms, including hay fever (allergic rhinitis), hives (urticaria), and allergic asthma. Unlike other allergic reactions, angioedema occurs in subcutaneous tissue just beneath the top layer of skin or mucous membrane. The swelling will neither be itchy nor red and can last for several hours or days. When the swelling finally stops, the skin will usually appear normal with no flaking, peeling, or bruising. Non-Immunologic With immunologic angioedema, the cells responsible for instigating the attack are known as mast cells. Mast cells contain granules rich in histamine and, when instructed by the immune system to do so, will undergo a process called degranulation to release histamine into the system. With non-immunologic angioedema, the immune system has nothing to do with the release. Instead, certain chemicals or physiological processes can induce mast cells to degranulate. Reactions will often occur in people with an underlying mast cell disorder, such as mastocytosis. The drugs commonly associated with this include: Opiates, especially codeine and morphineNonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirinIntravenous vancomycin, a powerful antibioticNon-ionic radiocontrast dyes used to enhance X-ray images Other non-immunologic causes include blood transfusion, cancers like lymphoma, autoimmune diseases like lupus, and certain infections such as hepatitis, HIV, cytomegalovirus, and Epstein-Barr virus. Certain physical stimuli such as heat, cold, excessive exercise, vibration, sun exposure, and even emotional stress have been known to cause angioedema. Idiopathic With idiopathic angioedema, there will be no known cause or explanation for the sudden acute swelling. What makes the condition so vexing is that those affected are prone to recurrence, sometimes severe. The face, mouth, and tongue were the areas most commonly affected. Overall, 55 percent of them reported receiving at least one course of high-dose corticosteroids to alleviate swelling. More concerning yet was the fact that 52 percent required at least one visit to the emergency room. Genetics Hereditary angioedema (HAE) is considered an autosomal dominant disorder, meaning that you can inherit the problematic gene from just one parent. There are two types of HAE related to mutations in the SERPING1 gene and a third caused by the mutation of the F1 gene. All three types cause the abnormal activation of the immune system and can cause swelling in all parts of the body. Where HAE differs from AAE is that the main culprit is not histamine. Rather, the attack will be instigated by another naturally occurring compound known as bradykinin. Bradykinin, like histamine, causes the dilation of blood vessels but does so as a means to regulate body functions. For example, the body will release bradykinins to lower the blood pressure or to regulate respiratory or kidney function. The abnormal release of bradykinins can trigger angioedema, most often of the legs, arms, genitals, face, lips, larynx, or gastrointestinal (GI) tract. A minor injury or episode of emotional stress can trigger an attack, but most occur without any known cause. Angioedema of the GI tract can be severe, causing violent vomiting, intense pain, and dehydration from not being able to keep fluids down. If swelling occurs in the throat, it can be life-threatening. Because ACE inhibitors (used to treat high blood pressure) work by sustaining bradykinin levels, they are among the most common cause of drug-induced angioedema (albeit with a different disease mechanism than opiates or aspirin). HAE is considered rare, occurring in one of every 50,000 people, and is often only suspected if someone with angioedema does not respond to antihistamines. Risk Factors There is really no way to explain why some people get angioedema and others with the same health conditions or lifestyles don't. With that being said, you may be at higher risk if you have or have experienced any of the following: You may be at higher risk for angioedema if you've experienced the following:Drug reactions involving a rash or hivesAllergies involving hivesHistory of angioedemaA family history of hives or angioedemaAutoimmune disease such as lupus or Hashimoto's thyroiditis, for which angioedema is a possible symptom If you or a loved one have suffered multiple bouts of angioedema, you may benefit from treatments that can help prevent future attacks. Options include a nightly dose of the antihistamine Zyrtec (cetirizine), if the cause is allergic, or immune-altering drugs such as Kalbitor (ecallantide) or Firazyr (icatibant). How Angioedema Is Diagnosed Was this page helpful? Thanks for your feedback! Sign up for our Health Tip of the Day newsletter, and receive daily tips that will help you live your healthiest life. Sign Up You're in! Thank you, {{form.email}}, for signing up. There was an error. Please try again. What are your concerns? Other Inaccurate Hard to Understand Submit Article Sources Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial policy to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy. Angioedema. Medscape Tarbox JA, Bansal A, Peiris AN. Angioedema. JAMA. 2018;319(19):2054. doi:10.1001/jama.2018.4860 Angioedema. Merck Manual. Professional Edition Hereditary angioedema. Genetics Home Reference. US National Library of Medicine Bernstein JA, Cremonesi P, Hoffmann TK, Hollingsworth J. Angioedema in the emergency department: a practical guide to differential diagnosis and management. Int J Emerg Med. 2017;10(1):15. doi:10.1186/s12245-017-0141-z Lumry WR. Current and emerging therapies to prevent hereditary angioedema attacks. Am J Manag Care. 2018;24(14 Suppl):S299-S307. Additional Reading Bernstein, J.; Lang, D.; Khan, D. et al. "The diagnosis and management of acute and chronic urticaria: 2014 update." J Allergy Clin Immunol. 2014; 133(5):1270-7. Inomata, M. "Recent Advances in Drug-Induced Angioedema." Allerg Int. 2012; 61(4):545-57. DOI: 10.2332/alergolint.12-RAI-0493. Rosenberg, D.; Mathur, S.; and Viswanathan, R. "Clinical Characteristics of Idiopathic Angioedema." J Allergy Clin Immunol. 2017; 139(2):AB235. DOI: 10.1016/j.jaci.2016.12.757. Continue Reading