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 is an autosomal dominant inherited form, due to mutations in the SERPING1 gene, which results in deficiency of the blood protein C1-inhibitor. This form is called hereditary angioedema (HAE) or occasionally by the outdated term "hereditary angioneurotic edema" (HANE). In this condition, the swelling may also occur in the digestive tract and other organs. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) is a coding of diseases and signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or diseases, as classified by the World Health Organization (WHO). ... // C00-D48 - Neoplasms (C00-C14) Malignant neoplasms, lip, oral cavity and pharynx (C00) Malignant neoplasm of lip (C01) Malignant neoplasm of base of tongue (C02) Malignant neoplasm of other and unspecified parts of tongue (C03) Malignant neoplasm of gum (C04) Malignant neoplasm of floor of mouth (C05) Malignant neoplasm of... // S00-T98 - Injury, poisoning and certain other consequences of external causes (S00-S09) Injuries to the head (S00) Superficial injury of head (S01) Open wound of head (S02) Fracture of skull and facial bones (S03) Dislocation, sprain and strain of joints and ligaments of head (S04) Injury of cranial nerves... The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... MedlinePlus (medlineplus. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... British English (BrE, BE, en-GB) is the broad term used to distinguish the forms of the English language used in the United Kingdom from forms used elsewhere in the Anglophone world. ... An eponym is the name of a person, whether real or fictitious, who has (or is thought to have) given rise to the name of a particular place, tribe, discovery, or other item. ... This page is about the condition called edema. ... Beyond overall skin structure, refer below to: See-also. ... The mucous membranes (or mucosa) are linings of ectodermic origin, covered in epithelium, that line various body cavities and internal organs. ... An allergy is an abnormal, acquired sensitivity to a given substance, including pollen, drugs, or numerous environmental triggers. ... This article does not cite any references or sources. ... Captopril, the first ACE inhibitor ACE inhibitors, or inhibitors of Angiotensin-Converting Enzyme, are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure, in most cases as the drugs of first choice. ... C1-inhibitor (C1inh) is a serine protease inhibitor (serpin) protein, the main function of which is inhibition of the complement system. ... For the Physics term GUT, please refer to Grand unification theory The gastrointestinal or digestive tract, also referred to as the GI tract or the alimentary canal or the gut, is the system of organs within multicellular animals which takes in food, digests it to extract energy and nutrients, and...

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. {{Otheruses4|the medical term|the Australian television series|Medical Emergenc an immediate threat to a persons life or long term health. ... The airways are those parts of the respiratory system through which air flows, to get from the external environment to the alveoli. ... Suffocation can mean two things: Suffocation, or Asphyxia, is a medical condition where the body is depraved of oxygen. ... “Adrenaline” redirects here. ... “Adrenaline” redirects here. ...

In the past, angioedema was referred to by the term angioneurotic edema, which wrongly implied that the phenomenon was due to neurosis. In modern psychology, the term neurosis, also known as psychoneurosis or neurotic disorder, is a general term that refers to any mental imbalance that causes distress, but (unlike a psychosis or personality disorder) does not prevent rational thought or an individuals ability to function in daily life. ...

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. This article includes a list of works cited or a list of external links, but its sources remain unclear because it lacks in-text citations. ... An itch (Latin: pruritus) is an uncomfortable sensation felt on an area of skin that causes a person or animal to desire to scratch that area. ...

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. Stridor is a high pitched sound heard on inspiration that is indicative of airway obstruction. ... General Name, symbol, number oxygen, O, 8 Chemical series nonmetals, chalcogens Group, period, block 16, 2, p Appearance colorless (gas) very pale blue (liquid) Standard atomic weight 15. ... This article or section needs copy editing for grammar, style, cohesion, tone and/or spelling. ... Respiratory arrest is the cessation of the normal tidal flow of the lungs due to paralysis of the diaphragm, collapse of the lung or any number of respiratory failures. ...

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. An allergen is any substance (antigen), most often eaten or inhaled, that is recognized by the immune system and causes an allergic reaction. ... Binomial name L. This article is about the legume. ... Idiopathic means arising spontaneously or from an obscure or unknown cause. ...

In hereditary angioedema, there is often no direct identifiable cause, although mild trauma and other stimuli can cause attacks. There is usually no associated itch or urticaria, as it's 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. In medicine, a trauma patient has suffered serious and life-threatening physical injury resulting in secondary complications such as shock, respiratory failure and death. ... Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. ... The term acute abdomen refers to a sudden, severe pain in the abdomen that is less than 24 hours in duration. ... Appendicitis (or epityphlitis) is a condition characterized by inflammation of the appendix[1]. While mild cases may resolve without treatment, most require removal of the inflamed appendix, either by laparotomy or laparoscopy. ... A laparotomy is a surgical maneuver involving an incision through the abdominal wall to gain access into the abdominal cavity. ... Laparoscopic surgery, also called keyhole surgery (when natural body openings are not used), bandaid surgery, or minimally invasive surgery (MIS), is a surgical technique. ...

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. Schematics of shorthand for complete blood count commonly used by physicians. ... An electrolyte is a substance containing free ions that behaves as an electrically conductive medium. ... In medicine (nephrology) renal function is an indication of the state of the kidney and its role in physiology. ... Liver function tests (LFTs or LFs), are groups of clinical biochemistry laboratory blood assays designed to give a doctor or other health professional information about the state of a patients liver. ... The most abundant secretory granule-derived serine proteinase contained in mast cells that has recently been used as a marker for mast cell activation. ... A complement protein attacking an invader. ... C1-inhibitor (C1inh) is a serine protease inhibitor (serpin) protein, the main function of which is inhibition of the complement system. ...

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 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 defence, which is permanently overactive due to the lack of regulation by C1-INH. An antihistamine is a drug which serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions, through action at the histamine receptor. ... Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger similar effects. ...

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. Spacefilling model of bradykinin Bradykinin is a physiologically and pharmacologically active peptide of the kinin group of proteins, consisting of nine amino acids. ... Peptides (from the Greek πεπτος, digestible), are the family of short molecules formed from the linking, in a defined order, of various α-amino acids. ... Vasodilation is where blood vessels in the body become wider following the relaxation of the smooth muscle in the vessel wall. ... Connective tissue is one of the four types of tissue in traditional classifications (the others being epithelial, muscle, and nervous tissue. ... “Hurting” redirects here. ...

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. A complement protein attacking an invader. ... Kallikrien (KLK) enzymes are a group of serine proteases found in many different tissues and body fluids. ... Serine protease inhibitors or serpins (short for serine protease inhibitor) are a group of proteins that inhibit peptidases (old name: proteases). ... Coagulation is a complex process by which blood forms solid clots. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Thrombosis is the formation of a clot or thrombus inside a blood vessel, obstructing the flow of blood through the circulatory system. ...

There are three types of hereditary angioedema:

• Type 1 - decreased levels of C1INH (85%);
• Type 2 - normal levels but decreased function of C1INH (15%);
• Type 3 - 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] According to OMIM, it is associated with Factor XII.

Angioedema can be due to antibody formation against C1INH; this is an autoimmune disorder. This acquired angioedema is associated with the development of lymphoma. Sex-linked genes are those carried on the mammalian X chromosome but not the Y chromosome. ... This article is about human pregnancy in biological females. ... Hormonal contraception refers to birth control methods that act on the hormonal system. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... Hageman factor is a plasma protein now usually known as factor XII. It is part of the coagulation cascade and activates factor XI and prekallikrein. ... Each antibody binds to a specific antigen; an interaction similar to a lock and key. ... Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. ... This article is about lymphoma in humans. ...

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. Alcoholic beverages. ... Binomial name J.Presl Cassia (Chinese cinnamon) is also commonly called (and sometimes sold as) cinnamon. ...

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. Ibuprofen (INN) (IPA: ) (from the earlier nomenclature iso-butyl-propanoic-phenolic acid) is a non-steroidal anti-inflammatory drug (NSAID) originally marketed as Nurofen and since under various trademarks including Act-3, Advil, Brufen, Dorival, Herron Blue, Panafen, Motrin, Nuprin and Ipren or Ibumetin (Sweden), Ibuprom (Poland), IbuHEXAL, Moment (Italy... Aspirin, or acetylsalicylic acid (IPA: ), (acetosal) is a drug in the family of salicylates, often used as an analgesic (to relieve minor aches and pains), antipyretic (to reduce fever), and as an anti-inflammatory. ... Acetaminophen (USAN) or paracetamol (INN), is a popular analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains. ...

Therapy

Allergic angioedema

In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. Cetirizine, marketed as Zyrtec, 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. Cetirizine hydrochloride (IPA sɛ.ˈtɪɹ.ɪ.ˌzin) is a major metabolite of hydroxyzine, and a racemic selective H1 receptor antagonist used in the treatment of allergies, hay fever, angioedema, and urticaria. ... Glucocorticoids are a class of steroid hormones characterised by an ability to bind with the cortisol receptor and trigger similar effects. ...

Bradykinin mediated angioedema

Drug induced angioedema

In ACE inhibitor use, the medication needs to be discontinued, and all similar drugs need to be avoided. There is a certain degree of controversy whether angiotensin II receptor antagonists are safe in patients with a previous attack of angioedema. Losartan, the first ARB Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs), AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system. ...

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. Androgen is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of masculine characteristics in vertebrates by binding to androgen receptors. ...

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. Tranexamic acid (commonly marketed as Cyclokapron) is often prescribed for excessive bleeding. ...

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 for HAE

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 bradikinin 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. Categories: Possible copyright violations ... The granting of the orphan drug status is designed to encourage the development of drugs which are necessary but would be prohibitively expensive/un-profitable to develop under normal circumstances. ... Icatibant, a peptidomimetic consisting of ten amino acids, is a very effective and highly specific antagonist of bradykinin B2 receptors. ... Jerini company logo Jerini AG is a pharmaceutical company based in Berlin, Germany, focusing on the discovery and development of novel peptide-based drugs. ... The granting of the orphan drug status is designed to encourage the development of drugs which are necessary but would be prohibitively expensive/un-profitable to develop under normal circumstances. ...

Acquired angioedema

In acquired angioedema 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]. Tranexamic acid (commonly marketed as Cyclokapron) is often prescribed for excessive bleeding. ... Cinnarizine is an anti histaminic drug which is mainly used for the contol of vomiting due to motion sickness. ...

History

Dr Heinrich Quincke first described the clinical picture of angioedema in 1882. ^[2] Sir William Osler remarked in 1888 that some cases may have a hereditary basis; he coined the term hereditary angio-neurotic edema.^[3] Heinrich Irenaeus Quincke (* 26 August 1842 in Frankfurt (or); †   19. ... Year 1882 (MDCCCLXXXII) was a common year starting on Sunday (link will display the full calendar) of the Gregorian calendar (or a common year starting on Friday of the 12-day slower Julian calendar). ... Sir William Osler Sir William Osler, 1st Baronet (July 12, 1849 – December 29, 1919) was a Canadian-born physician. ... For the toll-free telephone number see Toll-free telephone number Year 1888 (MDCCCLXXXVIII) was a leap year starting on Sunday (click on link for calendar) of the Gregorian calendar (or a leap year starting on Friday of the 12-day slower Julian calendar). ...

References

1. ^ Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000;356:213-7. PMID 10963200.
2. ^ Quincke H. Concerning the acute localized oedema of the skin. Monatsh Prakt Derm 1882;1:129-131.
3. ^ Osler W. Hereditary angio-neurotic oedema. Am J Med Sci 1888;95:362-67.

The Lancet is one of the oldest and most respected peer-reviewed medical journals in the world, published weekly by Elsevier, part of Reed Elsevier. ...

External links

• US Hereditary Angioedema Association
• All About HAE