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 50,000 although there may be variation geographically. It can affect people of any ethnic group or gender. Usually it presents in childhood, with the mean age of onset being between 8 and 12 years.
Aetiology and pathophysiology
The oedema is triggered by increased permeability of the blood vessels. Bradykinin is the main mediator involved in most cases. 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.
A number of different types are recognised. The vast majority are types I and II, and most of the published research papers and guidelines relate to these types only.
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 caused by one of hundreds of possible different mutations in the SERPING1 gene, which codes for C1‐INH. They are inherited as autosomal dominant.
C1-INH is normal.
- HAE with mutation in the Factor XII gene (HAE‐FXII).
- HAE with mutation in the angiopoietin‐1 gene (HAE‐ANGPTI).
- HAE with mutation in the plasminogen gene (HAE‐PLG).
- HAE due to unknown mutations (HAE‐UNK).
These other rare types are not part of the discussion below, but there are some similar clinical features and some of the treatment options may be relevant.
Types I and II usually present in childhood, although may be unrecognised initially. Symptoms may worsen with puberty. 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).
Note that facial, lip or mouth swelling can progress to involve the larynx.
- 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. (Present in at least 75% of cases).
- 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.
- Absence of urticarial wheals (although some may have co-existent urticarial conditions as these are reasonably common).
The recommended initial tests are:
- Serum complement factor 4 (C4) level.
- C1 inhibitor (C1-INH) antigenic protein level.
- C1-INH function (if available).
NB: 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 helpful in some cases, particularly where genetic counselling is needed.
- 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.
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, scopes of upper airway or GI tract.
- Long-term prophylactic drugs if required.
- Avoidance of triggers.
- Vaccination against common illnesses such as flu.
- 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 and hepatitis A.
Pharmaceutical agents used in treating HAE
- C1-INH concentrates. These are first-line treatment options for acute and prophylactic use. They work rapidly (within 30 minutes to a few hours) and may be given intravenously or subcutaneously. They are licensed for self-administration[7, 8]:
- Plasma-derived C1-INH concentrate: Available as Berinert®, Cinryze® or Cetor® - the latter not in the UK.
- Recombinant C1-INH concentrate: Conestat alfa - (Ruconest®).
- Bradykinin receptor inhibitor: icatibant (Firazyr®).
- Kallikrein inhibitor: ecallantide (not available in the UK.)
- 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).
- Antifibrinolytic drugs - eg, tranexamic acid. These inhibit the fibrinolytic pathway and spare C1 INH. Evidence for this is weak, but some people may find them helpful for long-term prophylaxis, particularly when other treatment options are unavailable or contra-indicated.
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. Ecallantide is another first-line option where available.
- 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 or icatibant immediately (the patient may have their own supply). The emergency doses are:
- Berinert® - 20 units/kg intravenously.
- Cinryze® - 1000 units intravenously.
- Icatibant - 30 mg subcutaneously (adults aged >18 years).
- This is a medical emergency. 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 acute medication - 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
- 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.
- Tranexamic acid and androgens are not recommended for acute attacks as efficacy is minimal.
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.
- For anaesthesia, intubation carries a major risk of laryngeal oedema.
- With dental treatment, even 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.
- Procedures which may touch on the upper airway or upper GI tract can precipitate attacks (bronchoscopy, gastroscopy, etc).
- Prophylaxis does not guarantee freedom from laryngeal oedema, so vigilance is always necessary during and after procedures.
Prophylaxis for procedures (eg, surgery, scopes, dental work):
- Give C1-INH as close to the procedure as possible.
- The dose has not been definitively established but is usually recommended to be 1,000 units or 20 units/kg of plasma-derived C1-INH.
- A second, equal dose should be available during the procedure.
- Repeat daily as needed until there is no further risk of angio-oedema.
- FFP may be used as a second line option. Androgens may also be used but guidelines advise C1-INH is very much preferred.
- 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.
Medication for long-term prophylaxis
This should be considered if there are frequent and/or severe attacks or if treatment for acute attacks is ineffective or unavailable. Treatment should be reviewed by a specialist at least once a year. 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, the recommended first-line treatment is plasma-derived C1-INH - specifically Cinryze® in the UK. This should be given twice weekly subcutaneously.
Androgens (eg, danazol) can be used as second-line, but have significantly more potential for adverse effects, interactions and contra-indications. They are contra-indicated in childhood (until growing has finished) and with pregnancy, lactation, hepatitis or cancer. Anti-fibrinolytics are not recommended for prophylaxis in most cases.
Cost of treatment is an issue. NHS commissioning guidelines in 2016 recommended C1-INH treatment in people who have two or more clinically significant attacks per week and only for those who are intolerant of oral treatments such as danazol, or in whom these are contra-indicated. International guidelines in 2018, however, advise C1-INH treatment as first-line for all those who require prophylactic treatment. The definition of those who are affected severely enough to warrant prophylactic treatment is an individualised one in these guidelines. A 2014 UK consensus statement intriguingly states "Treatment of HAE should follow international guidance and standards, whilst considering the resources available in the UK", followed by "Patients should take their medication according to clinical need rather than financial considerations".
- Pregnant women should be monitored by a specialist in HAE.
- Diagnostic tests should be interpreted with caution in pregnancy as levels of C1-INH change during pregnancy.
- 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 may be considered but efficacy has not been proven.
- C1-INH concentrates should also be used for pre-procedural prophylaxis during pregnancy.
- Labour and delivery:
- Do not usually trigger acute attacks, but may do so. Close follow-up is required for 72 hours after delivery.
- Vaginal delivery is preferable where possible.
- 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.
Children and adolescents
Plasma-derived C1-INH is approved for use in acute attacks and prophylaxis in childhood. SDP and FFP are second-line options. Trials to investigate the efficacy and safety of recombinant C1‐INH and icatibant in children are ongoing and they are licensed for use in childhood or adolescents in some countries. Anti-fibrinolytics (eg, tranexamic acid 20‐40 mg/kg) are preferable to androgens for prophylaxis in children because of their better safety profile, but efficacy is not known. Individualised treatment plans are needed for children, subject to regular review. Emergency medication needs to be available for school trips, holidays, etc. Teachers, childminders, etc, need information about the condition and management of acute attacks.
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.
- In the UK in 2008, 5 people died from angio-oedema.
- A 2013 UK audit of the 376 patients in England, Wales and Scotland, identified to have hereditary or acquired angioedema (of whom 91% had type I or II HAE), reported a family history of 55 deaths in 33 families, ranging from one to three deaths per family.
- 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.
- Quality of life is affected and the burden of disease reported to be high.
New and future treatments
- The kallikrein inhibitor ecallantide (Kalbitor®, formerly DX-88) is approved in the USA for use in HAE attacks, but there is a risk of anaphylaxis. It has not been approved in Europe.
- Another new kallikrein inhibitor has shown efficacy in trials and is approved in the USA. Lanadelumab is a fully human monoclonal antibody that targets kallikrein and prevents the production of bradykinin. It is administered subcutaneously. It does not currently have a marketing authorisation in the UK for preventing angio-oedema attacks in hereditary angio-oedema, but has been studied in trials in people aged 12 or more who have at least one attack every four weeks. It is under review by the National Institute for Health and Care Excellence (NICE) as a possible treatment option for prophylaxis, and is undergoing further trials.
Further reading and references
Ghazi A, Grant JA; Hereditary angioedema: epidemiology, management, and role of icatibant. Biologics. 20137:103-13. doi: 10.2147/BTT.S27566. Epub 2013 May 3.
Maurer M, Magerl M, Ansotegui I, et al; The international WAO/EAACI guideline for the management of hereditary angioedema-The 2017 revision and update. Allergy. 2018 Aug73(8):1575-1596. doi: 10.1111/all.13384. Epub 2018 Mar 12.
Eidelman FJ; Hereditary angioedema: New therapeutic options for a potentially deadly disorder. BMC Blood Disord. 2010 May 1410:3.
Angioedema; DermNet NZ
Longhurst H, Cicardi M; Hereditary angio-oedema. Lancet. 2012 Feb 4379(9814):474-81.
Longhurst HJ, Tarzi MD, Ashworth F, et al; C1 inhibitor deficiency: 2014 United Kingdom consensus document. Clin Exp Immunol. 2015 Jun180(3):475-83. doi: 10.1111/cei.12584. Epub 2015 May 13.
Li HH; Self-administered C1 esterase inhibitor concentrates for the management of hereditary angioedema: usability and patient acceptance. Patient Prefer Adherence. 2016 Sep 710:1727-37. doi: 10.2147/PPA.S86379. eCollection 2016.
Bork K; A Decade of Change: Recent Developments in Pharmacotherapy of Hereditary Angioedema (HAE). Clin Rev Allergy Immunol. 2016 Oct51(2):183-92. doi: 10.1007/s12016-016-8544-9.
Visy B, Fust G, Bygum A, et al; Helicobacter pylori infection as a triggering factor of attacks in patients with hereditary angioedema. Helicobacter. 2007 Jun12(3):251-7. doi: 10.1111/j.1523-5378.2007.00501.x.
Henry Li H, Riedl M, Kashkin J; Update on the Use of C1-Esterase Inhibitor Replacement Therapy in the Acute and Prophylactic Treatment of Hereditary Angioedema. Clin Rev Allergy Immunol. 2018 Jun 16. pii: 10.1007/s12016-018-8684-1. doi: 10.1007/s12016-018-8684-1.
Farkas H; Pediatric hereditary angioedema due to C1-inhibitor deficiency. Allergy Asthma Clin Immunol. 2010 Jul 286(1):18.
Jolles S, Williams P, Carne E, et al; A UK national audit of hereditary and acquired angioedema. Clin Exp Immunol. 2014 Jan175(1):59-67. doi: 10.1111/cei.12159.
Banerji A, Li Y, Busse P, et al; Hereditary angioedema from the patient's perspective: A follow-up patient survey. Allergy Asthma Proc. 2018 May 139(3):212-223. doi: 10.2500/aap.2018.39.4123.
Syed YY; Lanadelumab: First Global Approval. Drugs. 2018 Oct78(15):1633-1637. doi: 10.1007/s40265-018-0987-2.
Riedl MA, Bernstein JA, Craig T, et al; An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension. Clin Transl Allergy. 2017 Oct 67:36. doi: 10.1186/s13601-017-0172-9. eCollection 2017.