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Angioedema
Classification and external resources
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), also known by its eponym Quincke's edema, is the rapid swelling (edema) of the skin, mucosa and submucosal tissues. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings S00-T14 - Injury (S00-S09 Head ( Superficial Injury of head ( Superficial injury of The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases 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 The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books British English or UK English ( BrE, BE, en-GB) is the broad term used to distinguish the forms of the English language used in the Oedema (or Edema in American English formerly known as dropsy or hydropsy, is the increase of Interstitial fluid in any organ &mdash swelling The skin is the outer covering of living tissue of an animal (or plant The mucous membranes (or mucosae; singular mucosa) are linings of mostly endodermal origin covered in Epithelium, which are involved in Apart from the common form, mediated by allergy, it has been reported as a side effect of some medications, specifically ACE inhibitors. Allergy is a disorder of the Immune system often also referred to as Atopy. Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease ACE inhibitors, or inhibitors of '''A'''ngiotensin-'''C'''onverting '''E'''nzyme, are a group of Pharmaceuticals that are used primarily in treatment of Hypertension

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). Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby C1-inhibitor ( C1-inh, C1 esterase inhibitor) is a Serine protease inhibitor (serpin protein the main function of which is the inhibition of the Hageman factor is a plasma protein now usually known as factor XII. 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. The larynx (plural larynges) colloquially known as the voicebox, is an organ in the Neck of Mammals involved in protection of the

Cases where angioedema progresses rapidly should be treated as a medical emergency as airway obstruction and suffocation can occur. A medical emergency is an Injury or Illness that is acute and poses an immediate risk to a person's 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. 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 be helpful.

In the past, angioedema was referred to by the term angioneurotic edema, which wrongly implied that the phenomenon was due to neurosis. This article describes the term in psychology For the experimental metal band see Neurosis (band.

Contents

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 tongue is the large bundle of Skeletal muscles on the floor of the Mouth that manipulates Food for chewing and swallowing (deglutition The swelling can also occur elsewhere, typically in the hands. The swelling can be itchy. Itch ( Latin: pruritus) is an unpleasant Sensation that evokes the desire or Reflex to scratch 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. Stridor is a high pitched sound resulting from turbulent air flow in the upper airway Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the Intubation is required in these situations to prevent respiratory arrest and risk of death. In Medicine, intubation refers to the placement of a tube into an external or internal orifice of the body Respiratory arrest is the cessation of Breathing. It is a Medical emergency and it usually is related to or coincides with a Cardiac arrest.

Sometimes, there has been recent exposure to an allergen (e. An allergen is a nonparasitic Antigen capable of stimulating a Type-I hypersensitivity reaction in atopic individuals g. peanuts), but more often the cause is either idiopathic (unknown) or only weakly correlated to allergen exposure. The peanut, or Groundnut ( Arachis hypogaea) is a species in the Legume family Fabaceae native to South America, Mexico Idiopathic is an Adjective used primarily in Medicine meaning arising spontaneously or from an obscure or unknown cause.

In hereditary angioedema, there is often no direct identifiable cause, although mild trauma, including dental work and other stimuli, can cause attacks. Treatment of physical trauma is described here and in First aid. 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. Abdominal pain can be one of the Symptoms associated with transient disorders or serious disease 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. The term acute abdomen refers to a sudden severe Abdominal pain that is less than 24 hours in duration 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. Appendicitis (or epityphlitis) is a condition characterized by Inflammation of the appendix. A laparotomy is a surgical procedure involving an incision through the Abdominal wall to gain access into the Abdominal cavity. Laparoscopic surgery, also called Minimally invasive surgery (MIS, bandaid surgery, Keyhole surgery, or pinhole surgery

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. A complete blood count ( CBC) also known as full blood count ( FBC) or full blood exam ( FBE) or blood panel, is An electrolyte is any substance containing free Ions that behaves as an electrically conductive medium Renal function, in Nephrology, is an indication of the state of the Kidney and its role in Renal physiology. Liver function tests (LFTs or LFs which include liver enzymes, are groups of Clinical biochemistry laboratory blood assays designed to give information about the Mast cell tryptase levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. Tryptase is the most abundant secretory granule-derived Serine Proteinase contained in Mast cells that has recently been used as a marker for mast cell activation 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. The complement system is a Biochemical cascade that helps clear Pathogens from an organism C1-inhibitor ( C1-inh, C1 esterase inhibitor) is a Serine protease inhibitor (serpin protein the main function of which is the inhibition of the 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. A histamine antagonist is an agent which serves to inhibit the release or action of Histamine. Glucocorticoids (GC are a class of Steroid hormones characterised by an ability to bind with the glucocorticoid receptor ( GR) and trigger similar effects 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. Bradykinin is a Peptide that causes blood vessels to enlarge (dilate and therefore causes blood pressure to lower [1] This peptide is a potent vasodilator, leading to rapid accumulation of fluid in the interstitium. Peptides (from the Greek πεπτίδια, "small digestibles" are short Polymers formed from the linking in a defined order of α- Amino This is most obvious in the face, where the skin has relatively little supporting connective tissue, and edema develops easily. Connective tissue is one of the four types of tissue in traditional classifications (the others being epithelial, Muscle, and Nervous tissue) Bradykinin is released by various cell types in response to numerous different stimuli; it is also a pain mediator. Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm Dampening or inhibiting bradykinin has been shown to relieve HAE symptoms. Bradykinin is a Peptide that causes blood vessels to enlarge (dilate and therefore causes blood pressure to lower

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. Angiotensin I converting enzyme ( ACE,) is an Exopeptidase. Functions It has two primary functions it catalyses the conversion of 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. The complement system is a Biochemical cascade that helps clear Pathogens from an organism Kallikreins (tissue and plasma kallikrein are peptidases (enzymes that cleave peptide bonds in proteins a subgroup of the Serine protease family 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. Serpins are a group of Proteins with similar structures that were first identified as a set of proteins able to inhibit Proteases The name serpin is derived 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. Coagulation is a complex process by which Blood forms Clots It is an important part of Hemostasis (the cessation of blood loss from a damaged vessel whereby Bleeding, technically known as hemorrhaging / haemorrhaging (see American and British spelling differences) is the loss of Blood from Thrombosis is the formation of a blood Clot ( Thrombus) inside a Blood vessel, obstructing the flow of Blood through the Circulatory

There are three types of hereditary angioedema:

Angioedema can be due to antibody formation against C1INH; this is an autoimmune disorder. Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which results in an immune response against its own cells and tissues This acquired angioedema is associated with the development of lymphoma. Lymphoma a type of Neoplasm that originates in Lymphocytes (a type of White blood cell in the vertebrate Immune system)

Consumption of foods which are themselves vasodilators such as alcohol or cinnamon can increase the probability of an angioedema episode in susceptible patients. Cinnamon ( Cinnamomum verum, synonym C zeylanicum) is a small Evergreen Tree 10–15 metres (32 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. Bromelain can refer to one of two Protease Enzymes extracted from the plant family Bromeliaceae, or it can refer to a combination of those enzymes along Turmeric ( Curcuma longa) is a Rhizomatous Herbaceous Perennial plant of the Ginger family Zingiberaceae [4]

The use of ibuprofen or aspirin may increase the probability of an episode in some patients. Ibuprofen ( INN) (ˌaɪbjuːˈpɹəʊfɛn (from the now outdated nomenclature i so- bu tyl- pro panoic- phen olic acid is a Non-steroidal Aspirin, or acetylsalicylic acid (ASA (əˌsɛtɨlsælɨˌsɪlɨk ˈæsɨd is a Salicylate drug, often used as an Analgesic to relieve The use of acetaminophen typically has a smaller, but still present, increase in the probability of an episode. Paracetamol ( INN) (ˌpærəˈsiːtəmɒl -ˈsɛtə- or acetaminophen ( USAN) is a widely-used Analgesic and Antipyretic Medication

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. Cetirizine hydrochloride, an Antihistamine, (sɛˈtɪrɨziːn is a major Metabolite of Hydroxyzine, and a Racemic selective H1 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. Glucocorticoids (GC are a class of Steroid hormones characterised by an ability to bind with the glucocorticoid receptor ( GR) and trigger similar effects

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, there are case reports of cross reactivity between ACE-Is and ARBs. Angiotensin II receptor antagonists, also known as angiotensin receptor blockers (ARBs AT1-receptor antagonists or sartans, are a group of

Hereditary angioedema

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

Acute treatment

The aim of acute treatment is to halt progression of the edema 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 edema 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. 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 Danazol is the most commonly used. Danazol is a derivative of the synthetic Steroid Ethisterone, a modified Testosterone. [5] 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 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. Tranexamic acid (commonly marketed as Cyklokapron in the US and as Transamin in Asia 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 edema), 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. Fresh Frozen Plasma ( FFP) is defined as the fluid portion of one unit of Human blood that has been centrifuged separated and frozen solid at -18° C (or colder 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]. In the US, an orphan drug is any drug developed under the Orphan Drug Act of January 1983 ("ODA" a Federal law concerning Rare diseases 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. Icatibant (trade name Firazyr) is a Peptidomimetic drug consisting of ten Amino acids which is an effective and specific antagonist of Jerini AG is a Pharmaceutical company based in Berlin, Germany which focuses on the discovery and development of novel Peptide -based drugs 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. In the US, an orphan drug is any drug developed under the Orphan Drug Act of January 1983 ("ODA" a Federal law concerning Rare diseases

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. Tranexamic acid (commonly marketed as Cyklokapron in the US and as Transamin in Asia is often prescribed for excessive bleeding 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]. Cinnarizine is an anti-histaminic drug which is mainly used for the control of vomiting due to Motion sickness.

History

Dr Heinrich Quincke first described the clinical picture of angioedema in 1882. Heinrich Irenaeus Quincke ( 26 August 1842 - 19 May 1922) was a German internist and Surgeon. Year 1882 ( MDCCCLXXXII) was a Common year starting on Sunday (link will display the full calendar of the Gregorian calendar (or a Common [6] Sir William Osler remarked in 1888 that some cases may have a hereditary basis; he coined the term hereditary angio-neurotic edema. Sir William Osler 1st Baronet ( July 12, 1849 &ndash December 29, 1919 Age 70 was a Canadian Physician. Year 1888 ( MDCCCLXXXVIII) was a Leap year starting on Sunday (click on link for calendar of the Gregorian calendar (or a [7]

See also

References

  1. ^ Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G (2007). Gleich's syndrome or episodic angioedema with eosinophilia is a rare disease in which the body swells up episodically ( Angioedema) associated with raised antibodies Eosinophilia is the state of having a high concentration of eosinophils ( Eosinophil granulocytes in the Blood. "Nonallergic angioedema: role of bradykinin". Allergy 62 (8): 842–56. doi:10.1111/j.1398-9995.2007.01427.x. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17620062.  
  2. ^ 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.  
  3. ^ 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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17186468.   Full text at PMC: 965459
  4. ^ University of Maryland Medical Center. PubMed Central is a free digital database of full-text Scientific literature in biomedical and life sciences Angioedema. http://www.umm.edu/altmed/articles/angioedema-000011.htm
  5. ^ Gelfand JA, Sherins RJ, Alling DW, Frank MM (1976). "Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities". N. Engl. J. Med. 295 (26): 1444–8. PMID 792688.  
  6. ^ Quincke H (1882). "Über akutes umschriebenes Hautödem". Monatsh Prakt Derm 1: 129-131.  
  7. ^ Osler W (1888). "Hereditary angio-neurotic oedema". Am J Med Sci 95: 362-67. doi:10.1097/00000441-188804000-00004. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.  

External links

Dictionary

angioedema

-noun

  1. (pathology) Swelling of the lower layers of the skin, often around the mouth, or of the mucosa or submucosa of the mouth or throat which can appear quickly in response to an allergen or due to other conditions
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