Hereditary Angioedema (HAE)

Synonyms: HAE, hereditary angio-oedema, hereditary angioneurotic oedema, HANE, C1 inhibitor deficiency, C1 esterase inhibitor deficiency

Hereditary angioedema is a rare genetic condition causing episodic angioedema - including possible, dangerous laryngeal oedema. Episodes can be unpredictable, or triggered by trauma, drugs or dental treatment.

HAE affects all races with an estimated prevalence of perhaps 1:50,000. 85% of patients have the type I form of HAE. There may be many undiagnosed cases.²

The protein C1 inhibitor (also known as C1 esterase inhibitor or C1 INH) is either deficient or non-functional. There are 3 forms of HAE:

• Type I has low levels of C1 INH protein
• Type II has normal or elevated levels but mutation impairs its function. Clinically, types I and II behave the same way.
• Type III is a different form, only recently recognised. It only affects women and is precipitated or worsened by high oestrogen levels. C1 INH level/function is normal between attacks. Type III is also known as oestrogen-sensitive HAE or variant HAE.

Genetics^1,3

• For types I and II, the cause is a defect in the C1 inhibitor gene, inherited as autosomal dominant.
• The inheritance pattern of type III is uncertain, probably dominant.
• There are also acquired forms of C1 INH deficiency.

Pathophysiology^1,2

• The affected protein, C1 INH, regulates early activation steps in the classical complement pathway. It also regulates activation of kallikrein and plasmin in the fibrinolytic pathway, and factors XI and XIIa in the coagulation cascade.
• The end result of C1 INH deficiency or malfunction is episodes of massive local oedema, i.e. angioedema. The affected organs are the skin and mucosa, including the upper airway.⁴ Gastro-intestinal involvement seems to be segmental, with massive submucosal oedema mimicking a tumour.
• Attacks may be precipitated by trauma, stress and certain medications (see below), but may also occur without obvious triggers.

Pattern of symptoms

• There may be a family history (but new mutations also occur).
• The typical history is recurrent attacks of angio-oedema and abdominal pain.
• Most patients have attacks during childhood (40% before the age of 5 years), although the diagnosis may not be made until the second or third decade of life. For type III, symptoms usually start in the second decade of life.³
• Frequency and severity of attacks vary between individuals. e.g weekly or six-monthly attacks. The pattern of attacks and their severity can be unpredictable.
• The time pattern of oedema classically:
  • Develops gradually over several hours
  • Increases for 12-36 hours
  • Subsides over 2-7 days
  Abdominal symptoms can have sudden, severe onset with no visible oedema.

Symptoms

• Symptoms are intermittent and may affect skin, abdominal organs or the upper airways.
• Skin is swollen rather than itchy. Skin is not usually painful unless compressed by the swelling.
• There is no improvement with antihistamines, adrenaline or corticosteroids.
• The face, mouth, tongue and larynx can swell, and dangerous or fatal laryngeal obstruction can occur. Facial or lip swelling may progress to affect the larynx. Dysphagia and voice alteration are warning symptoms for laryngeal obstruction.
• Stomach, intestines and bladder may be affected causing pain, nausea, vomiting and diarrhoea. The clinical picture may mimic an acute abdomen or obstruction, therefore, before the diagnosis is known, patients may have laparotomies.

Precipitating factors for attacks

• Trauma or surgery, including minor trauma or dental treatment
• Infections, including dental infections
• Psychological stress
• Drugs: ACE inhibitors, oestrogens (progestogens may be protective)
• In pregnancy, symptoms may be better or worse.

Examination

• Skin and mucous membranes are swollen but with NO urticaria or itch.⁴
• A prodromal erythematous rash can occur.
• Abdomen: ascites, tenderness or intestinal obstruction.

• C1 INH level and function can be assessed; there are various laboratory methods. Discussion with a specialist and the laboratory is necessary.¹
• C4 levels have been regarded as an adequate screening test for HAE,¹ but more recently this has been disputed.⁶
• For young children, especially aged under 1 year, the C1 INH and C4 levels are difficult to interpret, and usually it is necessary to repeat investigations when the child is older.⁵

Research suggests that many so-called cases of HAE have a questionable diagnosis. Therefore a specialist review, and repeat laboratory testing by a different method, are recommended, because the precise diagnosis has implications for treatment.¹

Conversely, HAE may go unrecognised. It is important that children and relatives of HAE patients are tested: awareness of possible airway obstruction and the correct treatment for it could save the patient's life.²

• Allergic reaction
• Drug eruption, especially ACE inhibitor induced angioedema
• Chronic urticaria
• Acquired angioedema
• Idiopathic angioedema

Note: HAE attacks do not respond to antihistamines or corticosteroids. Adrenaline is probably not effective or is much less effective than the correct treatment, with only transient effects at best.⁷ Detailed management is in the consensus statement by Gompels et al¹ and is summarised below.

General points and shared care

Patients need:

• Information about HAE
• A warning card, medical alert device and a consultant's letter with instructions about emergency treatment and an emergency contact number
• An emergency dose of C1 INH to carry with them when travelling
• Patients should be offered home possession of C1 INH, in a dose to treat airway emergencies
• Good links with local A&E departments

Prevention of attacks

Reduce triggers

• Good dental care.
• Treat infections promptly.
• Avoid oestrogens, e.g. contraception and HRT. Progesterone contraceptives are preferable and may be protective.
• Avoid ACE inhibitors (possibly, angiotensin-II blockers may be used with caution). For hypertension, beta blockers and diuretics are preferred.
• Treating Helicobacter may be beneficial.

Long-term prophylaxis

• This should be considered, according to severity of symptoms for the individual.
• Peripheral angio-oedema of the limbs and trunk only, is inconvenient but not dangerous.
• Options for prophylaxis are:
  • Tranexamic acid
  • Attenuated androgens: danazol, stanozolol or oxandrolone: these have androgenic side-effects
  • C1 INH as long-term prophylaxis (given intermittently at regular intervals).

Monitoring for medication side-effects will be needed (see complications).

Short-term prophylaxis

This is to cover procedures such as dental treatment, surgery or periods of stress. Note that acute attacks can still occur even if prophylaxis is given. Options are:

• C1 INH concentrate up to 24 hours pre-procedure, plus a further dose if needed
• Tranexamic acid started 5 days before procedure and continued until 2 days afterwards
• Attenuated androgens given for 48 hours before and after the procedure

Dental treatment²

• There is a risk of acute attack in the 36 hours following dental treatment: patients should be aware and have immediate access to C1 INH at this time.
• The risk of attack is not necessarily related to the invasiveness of the procedure, e.g. minor dental procedures may precipitate an attack while major dental work may sometimes be problem-free. Prophylaxis with C1 INH(above) is recommended for invasive dental work such as tooth extraction, but prophylaxis does not guarantee safety.
• Deaths after dental procedures have occurred.

Pregnancy

• There is no evidence of any specific problems for the fetus from the disease.
• In one report, most pregnant women did NOT have worsening of HAE during pregnancy.
• Treatment during pregnancy: C1 INH can be used; the safety of tranexamic acid is uncertain; androgens are contra-indicated.
• Delivery and postpartum carry a higher risk of attacks; C1 INH should be considered for short-term prophylaxis at this time, and should be available on the delivery ward
• Local swelling may occur but does not need treatment unless causing problems, e.g. urethral obstruction.

Children

• If there is a family history, children should be tested early, as airway-threatening attacks can occur at any age.
• Attacks are usually less frequent or severe than in adults.
• If long-term prophylaxis is needed, C1 INH has been used successfully. Tranexamic acid has been used in some cases; androgens are avoided if possible.

Acute attacks^1,2

• The main danger is of fatal laryngeal obstruction.
  • This is a significant risk, and can occur even in children, in a first attack, and in patients with no previous history of airway-obstructing episodes.²
  • One study of families where there had been such a death, showed a 40% risk of fatal obstruction among their relatives with HAE.⁸
  • The patients who died in this study had not received emergency C1 INH or cricothyrotomy treatment, and the authors recommend greater awareness among patients and medical staff.
• There is a risk of inappropriate laparotomies, and also of genuine abdominal emergencies being missed.

Complications of treatment¹

• Safety of C1 INH concentrate:
  • Viral safety is a concern, as this is a blood product. Since heat treatment was introduced, there has been no observed transmission of HIV, hepatitis C or hepatitis G.
  • For patients requiring C1 INH, pre-treatment infection screening and immunization for hepatitis A and B should be considered.
• Fresh frozen plasma treatment carries risks of pathogens, anaphylaxis and alloimmunisation, so should only be used for emergencies.
• Side-effects of drug prophylaxis: monitoring is needed for patients taking long-term androgens or tranexamic acid:
  • Monitor cardiovascular risk factors and LFTs
  • Long-term use of androgens has been linked to hepatocellular adenoma, so liver ultrasounds 1-2 yearly are advised.

New treatments are being developed which include:

• Various new forms of C1 INH.
• Kallikrein and bradykinin inhibitors.