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Synonyms: HAE, hereditary angioneurotic oedema, C1-inhibitor deficiency, C1-esterase inhibitor deficiency, familial angioneurotic oedema, hereditary bradykinin-induced angioedema, hereditary non histamine-induced angioedema
Hereditary angio-oedema (HAE) is a rare genetic condition causing episodes of angio-oedema - including life-threatening laryngeal oedema. Episodes can be unpredictable, or triggered by factors such as trauma, drugs or dental treatment.
The incidence is approximately 1 in 50-100,000 with no ethnic variation.
Aetiology and pathophysiology
The oedema is triggered by increased permeability of the blood vessels; probably bradykinin is the main mediator involved. Bradykinin is generated from plasma kinins by kallikrein or kallidin.
The net result is episodes of massive local oedema, ie angio-oedema. (In angio-oedema, the swelling is subcutaneous or submucosal rather than epidermal, so urticaria is absent.) The affected organs in HAE are the skin and mucosa, including the upper airway and gastrointestinal (GI) tract.
HAE types I and II
Types I and II are clinically identical, involving deficiency or malfunction of the protein C1 inhibitor (C1-INH) - also called C1 esterase inhibitor. C1-INH is part of the complement system, coagulation system and fibrinolytic system.
- Type I has low levels of C1-INH (the majority of cases).
- Type II has impaired function of C1-INH.
Types I and II are due to mutations of the C1-INH gene and are inherited as autosomal dominant.
HAE type III
This is a different and recently documented form:
- It mainly affects females and is exacerbated by high oestrogen levels - eg, oral contraceptives or pregnancy.
- HAE type III is not due to C1-INH deficiency; it is linked to an increase in kininogenase activity leading to elevated levels of bradykinin.
- Some cases are associated with coagulation factor XII gene mutations.
Types I and II usually present in childhood, although may be unrecognised initially. Symptoms may worsen with puberty. Type III usually presents in the second decade of life. Often there is a family history, but new mutations also occur.
Recurrent episodes of angio-oedema and/or abdominal pain - may involve:
Laryngeal oedema - can be fatal:
Symptoms and signs of laryngeal oedema
- Throat - sore, tight, itchy, lump, 'something stuck', or dysphagia.
- Voice changes - high-pitched, hoarse, rough or with a resonant, 'barky' cough or unable to speak.
- Symptoms/signs of respiratory distress - eg, stridor, dyspnoea, fear of suffocation, anxiety/agitation; the patient may grasp his/her throat with the thumb and index fingers (the universal choking sign).
- Localised subcutaneous swelling:
- The oedema is circumscribed and non-pitting.
- There is no urticaria or itching.
- There may be prodromal burning, tingling, erythema or a serpiginous rash (erythema marginatum).
- Abdominal symptoms:
- May give a clinical picture of intestinal obstruction or an acute abdomen with tenderness and guarding.
- Symptoms include abdominal pain (can be severe or sudden in onset), nausea and vomiting, diarrhoea, constipation and abdominal distention.
- Large fluid shifts with ascites or hypovolaemic shock may occur.
For pictures of angio-oedema, see DermNet NZ reference.
Pattern of attacks
- The typical time course of attacks is onset over several hours, but symptoms can sometimes evolve much faster. Untreated, symptoms usually increase over two days and subside after two to five days. Abdominal pain can be sudden in onset.
- Frequency of attacks varies between individuals - eg, from weekly to annually; they can be unpredictable.
- Precipitating factors for attacks include:
- Trauma or surgery, including minor trauma or dental treatment.
- Psychological stress.
- Prolonged standing or repetitive daily activities.
- Drugs - angiotensin-converting enzyme (ACE) inhibitors, oestrogens (progestogens may be protective).
- There may be no obvious trigger.
- In pregnancy, symptoms may improve or worsen.
Pointers to a diagnosis of HAE are:
- Family history.
- Recurrent episodes of non-urticarial swelling lasting >24 hours, and unresponsive to antihistamines.
- Laryngeal oedema.
- Recurrent, unexplained abdominal pain and vomiting.
- Symptoms starting in childhood and worsening in adolescence.
The recommended initial tests are:
- Serum complement factor 4 (C4) level.
- C1 inhibitor (C1-INH) antigenic protein level.
- C1-INH function (if available).
Note: tests must be done off treatment. Interpretation of results may be difficult, especially in young children. Tests of children aged <1 year may not be reliable and should be confirmed after age 1.
Genetic testing may be used in some cases, but requires a research laboratory.
- If low C4 and C1-INH levels (always confirm by a second measurement):
- If there is a positive family history, the patient has HAE type 1.
- If there is no family history, measure serum C1q antigenic protein (C1q) and consider age of onset (early onset and normal C1q suggests HAE type 1; later onset and/or low C1q suggests acquired angio-oedema).
- If C4 quantity is low but C1-INH normal or high (always confirm by a second measurement):
Measure C1-INH function (requires a suitably equipped laboratory).
- If C1-INH function is reduced, diagnosis is HAE type 2.
- If normal, consider other causes of low complement C4.
- If C4 and C1-INH protein are normal, repeat tests during an attack. If still normal, consider drug-induced angio-oedema or rarer HAE types (HAE type III, HAE-FX, HAE-unknown).
- Diagnosis of HAE type III is from the clinical picture.
- Kininogenase activity measurement and genetic analysis for F12 gene mutations may be considered.
Baseline tests after diagnosis
- Because treatment may involve blood products and androgens, baseline investigations are advised: FBC, liver and renal function, lipid profile, serology for blood-borne infections, urinalysis and liver/spleen ultrasound.
- Acquired angio-oedema.
- Idiopathic angio-oedema.
- Allergic angio-oedema.
- ACE inhibitor-induced angio-oedema.
- Emergency treatment of attacks (see box below).
- Patient education and awareness; may need own supply of emergency treatment.
- Good links with A&E departments.
- Short-term cover for procedures - eg, dental treatment.
- Long-term prophylactic drugs if required.
- Avoidance of triggers.
- Testing of family members is recommended owing to the potential seriousness of an attack.
- Patients likely to receive blood products should have immunisation against hepatitis B ± hepatitis A).
Plasma-derived C1-INH concentrate:
- Available as Berinert® in Europe and the USA, Cetor® in the Netherlands or Cinryze® in the USA.
- A purified blood product; has been used since the 1980s.
- It shortens the time to relief of attack; it acts in about 30-60 minutes.
- A bradykinin receptor inhibitor, licensed in 2008 (for adults >18 years only).
- It shortens the time to relief of attack; it acts in 40-60 minutes.
Antifibrinolytic drugs - eg, tranexamic acid:
- These inhibit the fibrinolytic pathway and spare C1 INH.
Attenuated androgens - eg, danazol:
- These increase hepatic production of C1-INH.
- There are cautions regarding long-term side-effects. Avoid in children and pregnancy (with certain exceptions for short-term use, see below).
Emergency treatment of acute HAE attacks
- Acute attacks should be treated as soon as possible with C1-INH or icatibant (except in the case of peripheral oedema only). Treatment is most effective when given early. If these drugs are not available, there are possible alternatives (below).
- Attacks do not respond to glucocorticoids or antihistamines.
- Adrenaline (epinephrine) gives only a transient and modest benefit.
- Supportive care is essential, including appropriate airway management, intravenous fluids and pain relief.
Where there is dyspnoea, weak voice, dysphagia or other laryngeal symptoms:
- Give C1-INH (Berinert®) or icatibant immediately (the patient may have their own supply). The emergency doses are:
- Plasma-derived C1-INH (Berinert®) - 20 units/kg intravenously.
- Icatibant - 30 mg subcutaneously (adults aged >18 years).
- Admit to intensive care.
- Give supportive treatment if required: airway management, oxygen, intravenous access, intubation or tracheotomy. NB: consider early intubation if there is progressive laryngeal oedema.
- If C1-INH or icatibant is unavailable, see below for alternatives.
Facial or neck oedema
Treat as potential laryngeal oedema:
- Give drugs - C1-INH or icatibant (as for laryngeal oedema, above).
- Admit and monitor for deterioration or signs of laryngeal involvement.
- Give C1-INH or icatibant (as for laryngeal oedema, above).
- Clinical evaluation and scans to exclude other diagnoses.
- Treat hypovolaemia, pain and vomiting (non-steroidal anti-inflammatory drugs (NSAIDs) may be useful for pain; strong analgesia may be required).
- If the patient is not improving within 90 minutes, consider alternative diagnoses.
Alternative treatments if C1-INH or icatibant is unavailable
The following treatments have also been used anecdotally for acute attacks, but their efficacy in this scenario is uncertain, and C1-INH or icatibant remain first choice:
- Ecallantide (currently available in the USA only - see 'New treatments', below).
- Consider solvent/detergent-treated plasma (SDP) or fresh frozen plasma (FFP). SDP is the safer one. Theoretically, giving plasma may worsen symptoms initially. A suggested dose is 2 units of FFP.
- Some patients taking androgens can abort an attack by doubling their androgen dose at the first symptoms of an acute attack.
- Tranexamic acid - but may be of limited efficacy for acute attacks.
Peripheral oedema attacks
- For peripheral oedema (not involving the face, neck or larynx), a 'watch and wait' approach may be used.
- If required, C1-INH or icatibant (or alternatives) may be given.
- Danazol given early may shorten the attack.
- For anaesthesia, intubation carries a major risk of laryngeal oedema.
- With dental treatment, minor work including local anaesthetic can provoke an attack. There is a risk of delayed HAE symptoms, and deaths have occurred even after minor dental work. Patients must be aware and have access to emergency treatment.
- Prophylaxis does not guarantee freedom from laryngeal oedema, so vigilance is always necessary during and after procedures.
Prophylaxis for minor procedures (eg, minor dental work)
- C1-INH should be available whenever possible.
- If C1-INH is immediately available, then usually no prophylaxis is required. However, consider C1-INH prophylaxis if there is a previous history of attack with such procedures, or if the procedure might involve more than mild manipulation.
- If C1-INH is not available, then use danazol or tranexamic acid prophylaxis (danazol is more effective than tranexamic acid in this scenario). Short-term danazol can be used in children and in the third trimester of pregnancy (avoid in the first and second trimesters of pregnancy). Examples of dose regimens are:
- Danazol 2.5-10 mg/kg/day, maximum 600 mg/day, from five days before until two days after the procedure.
- Tranexamic acid from several days before until two to five days after the procedure.
- Tranexamic acid as a 5% mouthwash may decrease bleeding from dental procedures and may prevent bradykinin formation in saliva.
Prophylaxis for major procedures or intubation
C1-INH is the preferred prophylaxis:
- Give C1-INH at one to six hours before surgery, as close to the procedure as possible.
- The recommended dose is 10-20 units/kg.
- A second, equal dose should be available during the procedure.
- Repeat daily as needed until there is no further risk of angio-oedema.
If C1-INH is unavailable, use:
- Danazol (dose regimen as above for minor procedures) AND SDP or FFP one to six hours before the procedure (as close to the procedure as possible).
- The dose of plasma is 10 ml/kg, or 400-800 ml for an adult.
- SDP is safer than FFP.
- Acute attacks should be treated with C1-INH.
- Prophylaxis: C1-INH is safest. Attenuated androgens are contra-indicated (except short-term prophylaxis in the third trimester, as above). Tranexamic acid is not recommended; it may trigger thrombotic events.
- Labour and delivery:
- C1-INH should be available. It may be given at the onset of labour, depending on the history of HAE attacks during pregnancy.
- Regional analgesia (eg, epidural) is preferable to intubation.
- Note - the postpartum period is one of higher risk.
- Good dental care.
- Treat infections promptly; give immunisations.
- Avoid certain drugs:
- Oestrogens - eg, in contraception and hormone replacement therapy. Progesterone contraceptives are preferable and may be protective.
- ACE inhibitors (possibly, angiotensin-II receptor antagonists may be used with caution). For hypertension, beta-blockers and diuretics are preferred.
- Plasminogen activators are a theoretical risk, which may be outweighed by their benefit.
- Treating Helicobacter pylori may be beneficial.
Drugs for long-term prophylaxis
This should be considered if there are frequent, severe attacks (say, >1 per month); or if treatment for acute attacks is ineffective or unavailable. Bear in mind that the number of attacks does not predict either the severity or the airway involvement of future attacks. Also, laryngeal obstruction can occur even when taking prophylaxis.
If required, options are:
- Attenuated androgens (eg, danazol). They are generally contra-indicated in childhood (until growing has finished) and with pregnancy, lactation, hepatitis or cancer.
- Tranexamic acid.
- Regular C1-INH (twice-weekly).
- In type III HAE, progesterone has been used as prophylaxis.
Detailed guidance on long-term prophylaxis is available.
Complications and prognosis
The main risk is death from laryngeal obstruction:
- Laryngeal oedema has a high mortality if untreated.
- It can occur even in children, in a first attack, and in patients with no previous history of airway-obstructing episodes.
- One study of families where there had been such a death, showed a 40% risk of fatal obstruction among their relatives with HAE.
- Misdiagnosis of abdominal pain, or inappropriate laparotomies.
- Complications of treatment - eg, side-effects of androgens.
- There is a risk of infection with the use of blood products, but plasma-derived C1-INH has a good safety record so far.
- Recombinant human C1-INH (Rhucin®, Rhoconest®) received a positive review by the European Medicines Agency, and is to be marketed in the EU.
- The kallikrein inhibitor ecallantide (Kalbitor®, formerly DX-88) was recently approved in the USA for use in HAE attacks, but there is a risk of anaphylaxis. It has not been approved in Europe.
Further reading & references
- HAEI - International Patient Organization for C1-Inhibitor Deficiencies
- Angioedema, Hereditary, Type III, HAE3; Online Mendelian Inheritance in Man (OMIM)
- Ghazi A, Grant JA; Hereditary angioedema: epidemiology, management, and role of icatibant. Biologics. 2013;7:103-13. doi: 10.2147/BTT.S27566. Epub 2013 May 3.
- Longhurst H, Cicardi M; Hereditary angio-oedema. Lancet. 2012 Feb 4;379(9814):474-81.
- Eidelman FJ; Hereditary angioedema: New therapeutic options for a potentially deadly disorder. BMC Blood Disord. 2010 May 14;10:3.
- Bowen T, Cicardi M, Farkas H, et al; 2010 International consensus algorithm for the diagnosis, therapy and management Allergy Asthma Clin Immunol. 2010 Jul 28;6(1):24.
- Farkas H; Management of upper airway edema caused by hereditary angioedema. Allergy Asthma Clin Immunol. 2010 Jul 28;6(1):19.
- Angioedema; DermNet NZ
- Bouillet L; Hereditary angioedema, Orphanet webpage, May 2009
- Cicardi M, Bork K, Caballero T, et al; Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012 Feb;67(2):147-57. doi: 10.1111/j.1398-9995.2011.02751.x. Epub 2011 Nov 30.
- Picone O, Donnadieu AC, Brivet FG, et al; Obstetrical Complications and Outcome in Two Families with Hereditary Angioedema Obstet Gynecol Int. 2010;2010:957507. Epub 2010 May 13.
- Farkas H; Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol. 2010 Jul 28;6(1):18.
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Dr Naomi Hartree
Dr Hayley Willacy
Dr John Cox