Angioedema is a vascular reaction with localised dilatation and increased permeability of blood vessels which results in tissue swelling. Hereditary angioedema (HAE) is a rare autosomal dominant disorder which presents as recurrent episodes of angioedema without urticaria or pruritus. The skin and mucosal tissues of the upper respiratory tract and gastrointestinal tract are often affected, with severity ranging from mild cutaneous swelling to life-threatening laryngeal oedema. Swelling is self-limited and usually resolves within two to five days without treatment. However, fatal asphyxiation may occur if there is laryngeal involvement. Unlike other causes of angioedema (i.e. angioedema resulting from an allergic reaction), the swelling that occurs with HAE is due to the excessive production of bradykinin, a potent vasodilatory peptide.

While there are several different types of HAE, the most well-characterised types are those caused by a deficiency or dysfunction of C1 inhibitor (C1-INH). Only these types will be discussed here. C1-INH is a protease inhibitor which inhibits steps in multiple pathways including coagulation, fibrinolytic and kinin-generating pathways. Since C1-INH normally limits the production of bradykinin, if C1-INH is deficient or dysfunctional, bradykinin production is allowed to continue unchecked. Bradykinin is a vasoactive peptide mediator which leads to increases in vascular permeability and angioedema.

Patients with HAE have the condition from birth and generally present with recurrent episodes of angioedema as children or young adults. Seventy-five percent of patients with HAE will experience their first episode by the age of 15. While not discussed in this article, there is also an acquired form of C1-INH deficiency which may present in older patients without a family history of angioedema.

Symptoms

Patients with HAE often present with recurrent episodes of angioedema without urticaria or pruritus and/or recurrent episodes of self-limited, colicky, abdominal pain. Attack frequency ranges from weekly to one to two episodes per year.

HAE attacks tend to fall into three categories:

  • Cutaneous attacks;
  • Gastrointestinal attacks; and
  • Laryngeal/pharyngeal attacks.

Cutaneous attacks are common and are not generally dangerous (unless the facial or neck area are affected). While any site can be involved, the extremities, face, and genitals are most commonly affected. An attack typically begins with a tingling sensation and develops over the next 24 hours to swelling, pain and dysfunction. Symptoms typically subside over 48 to 72 hours but may last up to five days.

Gastrointestinal attacks often present with colic, nausea, vomiting, or diarrhoea due to oedema in the bowel wall. Hypotension may also occur. Symptoms typically last between one to three days.

Laryngeal attacks are rarer, accounting for less than 1% of all angioedema episodes. However, this is the most serious manifestation of HAE. Laryngeal oedema may present as a sensation of throat swelling, change in voice quality, difficulty swallowing secretions, or difficulty breathing. When laryngeal swelling does occur, it usually develops over several hours, with the majority of cases resolving before complete airway obstruction. Tooth extraction and surgery are common triggers for laryngeal attacks.

Patients may exhibit prodromal symptoms which usually occur within 24 hours before the onset of angioedema. These symptoms can include fatigue, nausea, myalgia, and flu-like symptoms. Patients may also exhibit a non-urticarial, non-pruritic prodromal rash which appears as mottled skin or a “chicken-wire” patterned rash. This is most often observed on the chest and may not be adjacent to the area of swelling.

A family history of angioedema is often noted. However, approximately 25% of cases result from new mutations, so a positive family history is not required for diagnosis.

Diagnosis

If HAE is suspected, a trial with high-dose antihistamines (i.e. two to four times the normal dose) may be undertaken. Since HAE does not respond to antihistamines or glucocorticoid therapy, further investigations for HAE should be undertaken if angioedema continues whilst on therapy.

HAE should be a high clinical suspicion where:

  • The patient develops recurrent episodes of angioedema without urticaria lasting two to five days (without treatment);
  • A trial of high dose antihistamines, if appropriate, did not prevent symptoms;
  • The patient is not taking ACE inhibitors or NSAIDs; and
  • The history does not suggest food, latex, or other allergic causes.

Where there is a high suspicion of HAE, patients should be screened for HAE using complement testing. C4, C1-INH level, and C1-INH functional assays may be used to test for deficiency or dysfunction of C1-INH. Low levels of C1-INH plus low levels of C4 (a natural substrate for C1 esterase), or low functioning levels of C1-INH suggest HAE. Results should be confirmed by repeat testing before making a definitive diagnosis.

If HAE is diagnosed, then first-degree relatives of the patient should also be offered diagnostic testing for HAE.

It should also be noted that there is a form of HAE where patients have normal complement studies. Oestrogen also tends to exacerbate swelling in this type of HAE.

Differential diagnosis

There are a number of differential diagnoses for HAE. These include:

  • Allergic reaction and anaphylaxis – may involve cutaneous and laryngeal swelling. However, these reactions are caused by mast cell mediators, tend to be rapidly progressive, and involve multiple organ systems simultaneously. As such, patients may also present with symptoms such as urticaria, wheezing, vomiting, diarrhoea, and hypotension. Unlike angioedema caused by allergic reactions, patients with HAE should not exhibit urticaria or pruritus and should not respond to antihistamines, adrenaline, and glucocorticosteroids.
  • Drug-induced angioedema – may be precipitated by medications such as angiotensin-converting enzyme (ACE) inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs). However, with drug-induced angioedema, complement studies should be normal.
  • Allergic contact dermatitis, e.g. from cosmetics or poison ivy – may present as facial swelling; however, the patient will often complain of pain and burning of the skin. Unlike HAE, the condition will also be responsive to glucocorticoid treatment.

Other conditions that may present as swelling in the facial and neck region include thyroid disorders, autoimmune conditions, and tumours. However, unlike HAE which is episodic, these conditions progress over time and are persistent.

Treatment

HAE does not respond to adrenaline, glucocorticoids, or antihistamines. First-line therapies for HAE are medications that replace C1-INH or block the production or function of bradykinin. For less severe attacks of HAE (e.g. those affecting the extremities or trunk), a wait and see response may be acceptable. However, in laryngeal attacks or cutaneous attacks involving the face and neck, treatment must be initiated due to the potential for airway involvement and asphyxiation. When HAE is diagnosed, an emergency care plan should be constructed so that the patient knows where to access treatment if they require it.

First-line therapies

  • C1 inhibitor (C1-INH) concentrate: Cinryze® and Berinert® are both plasma-derived C1-INH concentrates which are administered as a slow intravenous injection
  • Synthetic bradykinin B2-receptor antagonist: icatibant (Firazyr®) – can be administered as a subcutaneous injection

Early treatment during an attack has been shown to result in improved efficacy and a reduction in the duration of symptoms. If given later on in an attack, a slower more gradual response may be seen. During laryngeal attacks, intubation should be attempted immediately if stridor or signs of respiratory arrest are present as none of the available therapies are universally effective in all cases, and even first-line therapies take 30 minutes or more to begin working.

Plasma-derived C1-INH concentrate

Treatment with C1-INH concentrate replaces the deficient protein, and thus eliminates the underlying cause of HAE.

Cinryze® has a standard recommended dose of 1000 units for adult and adolescent patients. However, the dose of Berinert® used to treat acute episodes is based upon weight, with the recommended dose being 20units/kg.

  • If weight ≤50kg, administer 1000 units
  • If weight >50kg, and ≤75kg, administer 1500 units
  • If weight >75kg and ≤100kg, administer 2000 units
  • If weight >100kg, administer 2500 units

Plasma-derived C1-INH should be reconstituted and warmed to body temperature before administration. In emergency situations, it can be administered without pre-warming. The solution must not be shaken during reconstitution, as this can cause denaturation of the protein.

Stabilisation or improvement in symptoms is usually seen within 30 minutes, however, if symptoms continue to worsen or do not improve, a second dose can be administered.

Adverse effects are rare but include headache, fever, and anaphylaxis.

Bradykinin B2-receptor antagonist

Icatibant is a synthetic polypeptide that antagonises the bradykinin B2 receptor.

Dosage is 30mg administered by slow subcutaneous injection. If the response is inadequate, a second (and even third) dose may be administered after six hours (maximum of three doses in a 24 hour period).

The most common adverse effect of icatibant is mild, transient pain at the injection site. Other less common adverse effects include nausea, fever, dizziness, headache, and increase in transaminases.

Second-line therapies

If no first-line therapies are available, then fresh frozen plasma (FFP) may be used to treat acute laryngeal attacks and severe gastrointestinal attacks. FFP is dosed at two units initially, which can be repeated every two to four hours until there is clinical improvement.

Prophylaxis

There are a variety of potential triggers for HAE. Stress (mental or physical) and dental procedures are the most commonly reported triggers. Helicobacter pylori infections have been noted to trigger gastrointestinal attacks, and certain medications have also been linked to HAE attacks. These include oestrogen-containing medications, tamoxifen, and ACE inhibitors. Avoidance of triggers is the mainstay for prophylaxis.

Acute prophylaxis

The highest risk procedures which are known to trigger airway oedema in most patients are intubation, oral surgery, and major dental work, as swellings usually occur near the site of surgical trauma. The administration of short-term prophylaxis should be considered before these high-risk surgeries.

Angioedema typically begins within 48 hours of the procedure. As such, patients should be warned that swelling may occur a day or so after the procedure.

Agents that are used for short-term prophylaxis of HAE include C1-INH concentrate and androgens (e.g. danazol).

C1-INH concentrate is probably the most effective therapy for short-term prophylaxis. Icatibant is not used for prophylaxis as it has a short half-life (1-2 hours) and is, therefore, only used to stop an attack once it has commenced. Ideally, a dose of C1-INH concentrate should be administered before the procedure.

The dosing of androgens for HAE prophylaxis is a bit more uncertain. A suggested regimen for danazol is a dose of 400-600mg daily, starting five days before and continuing for three days after a procedure. The Australasian Society of Clinical Immunology and Allergy has suggested the use of danazol at a dose of 10mg/kg/day for five days before and two days after the procedure.

Long-term prophylaxis

Long-term prophylaxis may be considered in patients with frequent or severe episodes of angioedema. Agents which have been used for long-term prophylaxis include C1 inhibitor concentrate, attenuated androgens (e.g. danazol), and antifibrinolytics (e.g. tranexamic acid). Though evidence for their efficacy is lacking, antifibrinolytic agents are preferred over androgens in pregnant or lactating women and children. However, they should not be used in patients with increased risk for thrombosis. Long-term prophylaxis with an androgen derivative is effective, but side effects with long-term use may limit its use. Regular injections of C1 inhibitor concentrate is the preferred agent for pregnant women, and may be used in patients who do not tolerate other therapies, however, they tend to be costly.

Summary

  • Hereditary angioedema (HAE) is a rare autosomal dominant disorder which presents as recurrent episodes of angioedema without urticaria or pruritus. The skin and mucosal tissues of the upper respiratory tract and gastrointestinal tract are often affected, with severity ranging from mild cutaneous swelling to life-threatening laryngeal oedema.
  • Unlike other causes of angioedema (i.e. angioedema resulting from an allergic reaction), the swelling that occurs with HAE is due to the excessive production of bradykinin, often caused by a deficiency or dysfunction of C1-INH.
  • HAE does not respond to adrenaline, glucocorticoids or antihistamines.
  • First line therapies include C1-INH concentrate (Cinryze® and Berinert®) or a synthetic bradykinin B2-receptor antagonist (icatibant).
  • The administration of short-term prophylaxis should be considered before high-risk surgeries (procedures requiring intubation, oral surgery, and major dental work).
  • Long-term prophylaxis may be considered in patients with frequent or severe episodes of angioedema.

References:

  1. Cicardi M, Zuraw B. Hereditary Angioedema: Epidemiology, Clinical Manifestations, Exacerbating Factors, and Prognosis. UpToDate (cited 30/1/18).
  2. Cicardi M, Zuraw B. Hereditary Angioedema: General and Long-term Prophylaxis. UpToDate (cited 30/1/2018).
  3. Cicardi M, Zuraw B. Hereditary Angioedema: Pathogenesis and Diagnosis. UpToDate. (cited 30/01/2018).
  4. Cicardi M, Zuraw B. Hereditary Angioedema: Treatment of Acute Attacks. UpToDate (cited 30/1/2018).
  5. Craig T, Pursun E, Bork K, Bowen T, Boysen H, Farkas H, et al. WAO Guideline for the Management of Hereditary AngioedemaWorld Allergy Organ J. 2012; 5(12): 182-99.
  6. eMims [internet]. New South Wales: UBM Medica Australia Pty Ltd; 2018.
  7. Katelaris C, Smith W, Wong M, Jordan A. Position Paper on Hereditary Angioedema (HAE). Brookvale: Australasian Society of Clinical Immunology and Allergy; 2017.

Subscribe Knowledge Centre Updates

Enter your details to receive Knowledge Centre updates