Hereditary angioedema (HAE) is a rare hereditary disease characterised by episodes of painful swelling (oedema) in the skin and the mucous membranes of the gastrointestinal tract. Swelling may also occur in the respiratory tract and, in rare cases, other organs. Two forms of the disease, HAE types I and II, have been recognised for many years. A few years ago a third form , HAE type III, was also described. There is an acquired form (acquired angioedema, AAE), which is not described in this information material.
Angioedema was first described by German physician Heinrich Quincke in 1882. He named the condition “angioneurotic oedema,” but the name used currently is hereditary angioedema or HAE. The addition of “hereditary” to the name followed the American physician William Osler’s description of the hereditary form, which was published a few years after Quincke’s report.
The exact prevalence of hereditary angioedema remains unknown, but studies estimate that fewer than two individuals in 100,000 have the disease. This indicates that at the most 200 people in Sweden are affected. Currently (2011) slightly more than 150 cases of the disease have been identified in Sweden, of which 30 are children.
Hereditary angioedema is caused by mutations in a gene governing the production of a blood protein known as C1 inhibitor (C1-INH). The SERPING1gene is located on the long arm of chromosome 11 (11q12-q13.1). So far, more than 200 different mutations in this gene have been identified. Some cause the protein to be defective, while other mutations cause a protein deficiency. Approximately 85 per cent of individuals with hereditary angioedema type I have low C1-INH levels. Type II patients have normal or elevated levels of the protein, but it does not function normally.
C1-INH has a regulatory function in the complement system. The complement system, which forms part of the immune system, consists of a series of proteins (complement factors), numbered C1-C9. The system functions as a biochemical cascade (in which the products of one reaction are consumed in the next reaction) where C2 and C4 are consumed when C1 is activated. C1-INH controls the activation of C1. A deficiency of C1-INH causes an uncontrolled overproduction of the proteins kallikrein and bradykinin. Increased levels of bradykinin cause the blood capillaries to leak fluid into neighbouring tissue, resulting in painful swelling.
HAE type III is caused by mutations in the F12 gene located on chromosome 5 (5q33-qter). F12 codes for coagulation factor XII, while the C1-INH level is normal.
C-INH deficiency may also affect the fibrinolysis system, a process in the body which affects coagulation of the blood. This is caused by the insufficient inhibition of kallikrein, which leads to elevated amounts of plasma in the circulatory system. Although C1-INH deficiency can affect the coagulatory and fibrinolysis systems, it has not been established that people with hereditary angioedema have an increased risk of blood clots or haemorrhages.
The inheritance pattern of hereditary angioedema is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.
In most people the syndrome is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.
Hereditary angioedema is characterised by episodic attacks of swelling which, left untreated, last for between two and five days. The symptoms may appear in early childhood, but in most cases the onset occurs at or around puberty. The episodes usually occur at intervals of weeks or months, but some people experience only isolated attacks. After an attack, people with the disease often experience severe fatigue. They have no symptoms between attacks. The severity of the disease varies significantly and the frequency of episodes tends to decrease over the years, particularly in post-menopausal women.
Individuals with hereditary angioedema can often predict the onset of an attack. They feel unwell and cold, and may experience tingling sensations in the skin. Some people develop red, ring-shaped or irregular, round rashes. Although the swelling does not itch it may be tender and tight, and in severe cases it feels as if the skin may crack. Swelling can appear everywhere on the skin, including the genital areas and under the soles of the feet. Generally, swelling develops over a day or two, and then gradually shrinks over two or three days. It has a tendency to recur in the same place. During one and the same episode swelling may migrate to neighbouring areas; for example from the right cheek via the lips to the left cheek, ear or part of the throat, and back again. Severe swelling affecting the arms and legs may restrict mobility. It is particularly problematic when swelling affects the soles of the feet, as they become painful under pressure.
Mucous membranes in all parts of the body may be involved, but of the internal organs, the intestines and stomach are most frequently affected. Swelling affecting the lining of the intestines can give rise to colicky pain, nausea, vomiting and diarrhoea. Symptoms may be severe enough to be mistaken for appendicitis, ileus (often known as bowel obstruction) or another acute abdominal disease. Swelling in the urinary tract may cause symptoms resembling a urinary tract infection, including bladder and lower back pain and a burning sensation when urinating. Many women also experience cramping in the lower abdomen.
In some cases, sufficient fluid leaks into tissue from the blood vessels (hypovolemia) to cause a drop in blood volume sufficient to cause fainting.
The condition may be life-threatening if swelling obstructs the airways (laryngeal oedema). Although initial symptoms may be relatively mild, they can become severe within hours as the respiratory passages swell. Studies indicate that approximately 50 per cent of all hereditary angioedoma patients experience one or more attacks involving respiratory obstruction.
In very rare cases oedemas may present in brain tissue leading to headaches, speech problems, paralysis and seizures.
Although most attacks are not attributable to a specific cause, a few precipitating factors have been identified:
Female sex hormones (oestrogen)
Trauma or pressure on skin or mucous membrances caused, for example, by surgery, dental work, cycling or horse riding
Infections and stress
Certain medications, particularly ACE inhibitors
In women, symptoms are often associated with menstrual periods. During pregnancy, some women note an increase in the number of attacks, while others report a decrease. Oral contraceptives and other hormonal therapies involving oestrogen are known triggers of hereditary angioedema, as they have a negative effect on protein production in general. This affects C1-INH in particular, where the level is already low. The onset of the disorder is more often related to puberty in women than in men.
The disease can lead to psychological difficulties and to self-imposed limitations on daily life as the individual’s appearance changes dramatically during an attack when, for example, the face swells. Periodic episodes of swelling, and fear of them occurring, may have a negative effect on daily life, leading to increased absences from school or work. With the correct treatment, chances are good for the individual to lead a full, active life.
The diagnosis is made by establishing the total volume of the C1-INH protein, as well as the functionality of the protein found. The disease can also be identified by measuring the level of C4, another protein in the immune complement system. Where levels of C1-INH are low, the concentration of C4 is reduced as consumption rates of the protein increase. The complement factor C4 is best measured during an attack. At such times it is low, while between episodes levels may be normal.
Pre-natal diagnosis is possible but rarely used in cases of hereditary angioedema. DNA analysis can establish the presence of a mutation in theSERPING1 gene, confirming a diagnosis. When the diagnosis is made, the family should be offered genetic counselling.
In HAE type III, C1-INH and C4 are not affected, while the clinical picture is similar to HAE I and II. HAE III may be diagnosed through a mutation analysis of the gene which codes for blood coagulation factor XII (F12) on chromosome 5.
Currently there is no cure for hereditary angioedema, but there are medications which can prevent or alleviate attacks. As the disease can often be confused with allergic reactions, a correct diagnosis is very important to prevent inappropriate treatment. Antiallergic medications including adrenalin, cortisone and antihistamine generally have little or no effect on this condition.
In severe cases of airway obstruction it may be necessary to intubate (place a flexible plastic tube into the windpipe to maintain an open airway), particularly if treatment has been inappropriate, or has been started late. To avoid the need for a tracheotomy (a surgically created opening into the windpipe) it is important that intubation is carried out at an early stage.
A concentrate of C1-INH can be produced using blood plasma, which in cases of acute attacks may be given intravenously. When a person receives C1-INH concentrate, levels of the protein in the blood rise, pain ceases and swelling shrinks. The earlier it can be given, the quicker the attack subsides. Often, people with hereditary angioedema keep the concentrate at home and either administer it themselves, or take it with them when they seek medical help. Self-administration is now an accepted method of treatment. One unit (U) should correspond to the amount of C-INH found in a millilitre of plasma. There are currently two medications produced from blood plasma which are approved for self-medication.
Currently, a concentrate of recombinant human C1-INH is also available, produced from purified rabbit milk. The rabbit has received an artificial human C1-INH gene in order to produce C1-INH in its milk. This concentrate has not been approved for self-administration by the patient.
Icatibant is another preparation given during acute attacks. It is a chemically manufactured molecule, given as a subcutaneous injection (under the skin). It works by blocking bradykinin receptors and thus preventing fluid leaking into tissues. An unpleasant, burning sensation may occur immediately after the injection. Icatibant is approved for self-medication.
Tranexamic acid is used to prevent bleeding and can alleviate swelling in approximately 15 per cent of those who have hereditary angioedema. It is usually taken in tablet form but may also be given as an injection.
The use of fresh frozen plasma is another way of alleviating an HAE attack. The plasma contains C1-INH and is available at all Swedish hospitals. As it may contain other components, the condition of certain individuals may deteriorate after treatment.
In the US, ecallantide has been used to treat attacks, but as yet it is not available in Europe. It works by reducing the production of kallikrein. The substance is a recombinant protein produced with the help of yeast bacteria. It is administered as a subcutaneous injection.
Everyone with hereditary angioedema should have the appropriate medication at home for treatment during acute attacks. When it becomes necessary, the patient takes the preparation to the nearest hospital for help with the injection.
In mild attacks, rest can help reduce swelling. Diuretics can also alleviate the condition. Alcohol should be avoided as it can exacerbate swelling.
Preventive treatment may help prevent or alleviate severe and frequent attacks. Such treatment is important before surgical or dental procedures, as they may trigger hereditary angioedema attacks. Preventive treatment may also be necessary before important events so that fear of an attack does not interfere too much with patients’ lives.
Tranexamic acid can be given on a continuous basis, to prevent attacks.
Anabolic steroids can also be used. These are substances which are similar to male hormones, stimulating the body to produce proteins, including C1-INH. It is possible that they have a more specific mechanism which increases the break down of bradykinin. All anabolic steroids have a virilising effect, and may cause increased growth of body hair, increased muscle mass and a deepening of the voice. Some substances are thought to be less virilising, while retaining their effectiveness. Treatment should be carefully monitored as it can result in atherosclerosis and liver damage. Individuals who do not normally take anabolic steroids can be treated with these substances five to six days before a planned surgical intervention and up to three days afterwards.
C1-INH concentrate may also be given as a preventive measure in cases of frequent, severe attacks and before surgical and dental procedures.
It may be a good idea for individuals with the disease to carry with them their ID card with contact information, information about the disease and its treatment, and details on how to reach the attending physician. It can also be helpful for the patient to keep a medical diary to take with him/her to doctors’ appointments. The diary can record where the swelling are localised, how serious they are, and any suspicions about what triggered each attack. Sometimes these observations make it easier to discover patterns in why and when these episodes occur, thus helping the patient avoid triggers and making early treatment possible. ID cards and medical diaries may be ordered from the Primary Immunodeficiency Organisation (PIO). See under “Organizations for the disabled/patient associations, etc.”
Centres of excellence in herediary angioedema are located at: the Respiratory Medicine and Allergy Clinic, Skåne University Hospital in Lund, SE-205 02 Malmö, Sweden; The Dermatology Clinic, Karolinska University Hospital; Astrid Lindgren Children’s Hospital, Solna, SE-171 76 Stockholm, Sweden; Respiratory Medicine and Allergy Clinic, Ryhov County Hospital, SE-551 85 Jönköping, Sweden.
At its annual meeting PIO, Primary Immunodeficiency Organisation, holds a lecture on immunodeficiency for patients and parents. PIO and the Nordic immunodeficiency associations organise regular joint meetings, lasting several days and offering participants the chance to learn and to share experiences. For further information contact PIO. Find address under, “Organizations for the disabled/patient associations” below.
IPOPI, the International Patient Organisation for Patients with Primary Immunodeficiencies, of which PIO is an affiliate, arranges a conference in conjunction with a biennial international medical conference for doctors and nurses interested in immunodeficiencies. Meetings are held in English and are excellent opportunities for learning, and for exchanging information. For further information, contact PIO, under “Organizations for the disabled/patient associations.”
Research into hereditary angioedema is being carried out in several countries including the US, Italy, Hungary, Germany and Spain. There is also research into new methods of treatment with the help of recombinant production (using DNA technology).
At Lund University Hospital, research is underway into developing suitable measuring methods and genetic analyses.
SWEHA is a nationwide Swedish joint project made up of interested doctors and patients. It works to identify the spread of the disease in Sweden as well as the consequences for the individual and community. It is hoped that this research will result in an increased understanding of the disease as well as improved diagnosis and methods of treatment. Everyone with hereditary angioedema is invited to attend. Register with Patrik Nordenfelt or Carl-Fredrik Wahlgren. (Find under “Resource Personnel.”)
An information leaflet on hereditary angioedema summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-10-14). Address: SE-120 88 Stockholm. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email:email@example.com. Postage will be charged for bulk orders.
HAE, hereditary angioedema. Information material is issued by PIO. See address under, “Organizations for the disabled/patient associations.”
AAgostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L et al. Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004; 114: 51-131.
Arlaud GJ, Rossi V, Thielens NM, Gaboriaud C, Bersh B, Hernandez J-F. Structural and functional studies on C1r and C1s: new insights into the mechanisms involved in C1 activity and assembly. Aspects of activation of the classical pathway via C1. Immunobiol 1998; 199: 303-316.
Arnoldsson H, Belin L, Hallberg L, Helander E, Lindholm B, Westling H. Hereditary periodic oedema. Acta Med Scand 1967; 181: 115-124.
Björkander J, Bygum A, Waage Nielsen E. Hereditärt angioödem - svår sjukdom med nya terapialternativ. Läkartidningen 2012; 109: 99-103.
Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006; 119: 267-274.
Bork K, Kleist R, Hardt J, Witzke G. Kallikrein-kinin system and fibrinolysis in hereditary angioedema due to factor XII gene mutation Thr309Lys. Blood Coagul Fibrinolysis. 2009; 20: 325-332.
Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary oedema. Allergy Asthma Clin Immunol 2010; 6: 24.
Cicardi M, Banerji A, Bracho F, Malbrán A, Rosenkranz B, Riedl M et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary oedema. N Engl J Med 2010; 363: 532-541.
Cicardi M, Levy RJ, McNeil DL, Li HH, Sheffer AL, Campion M et al. Ecallantide for the treatment of acute attacks i hereditary oedema. N Engl J Med 2010; 363: 523-531.
Cugno M, Cicardi M, Bottasso B, Coppola R, Paonessa R, Mannucci PM et al. Activation of the coagulation cascade in C1-inhibitor deficiencies. Blood 1997; 89: 3213-3218.
Cugno M, Cicardi M, Coppola R, Agostoni A. Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor deficiencies. Immunopharmacology 1996; 33: 361-364.
Cugno M, Hack CE, de Boer JP, Erenberg AJM, Agostoni A, Cicardi M. Generation of plasmin during acute attacks of hereditary angioedema. J Lab Clin Med 1993; 121: 38-43.
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005; 139: 379-394. Rättelse i Clin Exp Immunol 2005; 141: 189-190.
Longhurst HJ, Farkas H, Craig T, Aygören-Pürsün E, Bethune C, Bjorkander J et al. HAE international home therapy consensus document. Allergy Asthma Clin Immunol 2010; 6: 22.
The Swedish Information Centre for Rare Diseases produced and edited this information material.
The medical expert who wrote the draft of this information material is Professor Janne Björkander, County Hospital Ryhov in Jönköping, Sweden.
The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.
An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.
Publication date: 2011-12-29
Publication date of the Swedish version: 2011-03-17
For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: + 46 31 786 55 90, email:firstname.lastname@example.org.