What is HAE?

The cause of HAE	How do HAE attacks happen?	Symptoms	Diagnosis of HAE

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HAE-A rare genetic disease

Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disease affecting ~1:50,000 people. Individuals with HAE experience recurring and unpredictable cutaneous and submucosal oedema of various body sites.^{1, 2}

The cause of HAE

Most cases of HAE are caused by a mutation in the SERPING1 gene which encodes the protein C1 esterase inhibitor (C1-INH), resulting in either a deficiency (type I) or dysfunction (type II) of C1-INH. HAE is an autosomal dominant disease; therefore, it is recommend that family members and offspring of diagnosed patients are also tested for HAE. However, 25% of cases occur due to de novo mutations.^{1, 3}

How do HAE attacks happen?

One of the main roles of C1-INH is to regulate the activity of key proteases of the contact system and therefore regulate bradykinin production. Bradykinin is the key mediator of increased vascular permeability in HAE, which is generated when plasma kallikrein cleaves high molecular weight kininogen. With low functional levels of C1-INH in patients with HAE, bradykinin production is not properly regulated and can be overproduced. During HAE attacks, increased activation of bradykinin B2 receptors in blood vessel walls leads to increased vascular permeability and angioedema of cutaneous and submucosal tissue. The contact system is initiated when factor XII (FXII) is activated and in turn activates plasma kallikrein, which cleaves high molecular weight kininogen to produce bradykinin.¹

Watch the video below to learn more about the contact system and the cascade leading to HAE attacks

The HAE cascade

HAE varies greatly from person to person, with some patients suffering several attacks per week, while attacks for others are rare.²HAE implies a high disease burden that includes the frequency and severity of attacks, as well as detriments to quality of life suffered during and between attacks, including interference with activities of daily living and heightened emotional distress.² The frequency of attacks in patients can also vary over the course of their life, for example, during puberty or pregnancy or during stressful periods of life such as exams.¹

Attack locations

Patients can experience symptoms in a range of locations on the body:^7,8,9

Laryngeal oedema

Laryngeal oedema requires emergency attention, and can be life-threatening, particularly in patients who have not yet been diagnosed with HAE.¹⁴ Patients should be made aware of the signs of a laryngeal attack, which include:⁹

Swallowing difficulties
Tightness or a feeling of a “lump in the throat”
Shortness of breath
Vocal changes such as loss of voice, hoarseness or a rough voice

Prodromal symptoms

Prodromal symptoms act as signs of a potential attack and can vary between each person. Common indicating symptoms include:¹⁵

Potential triggers

While most HAE attacks happen spontaneously and unexpectedly, there are various triggers that can cause an attack; however these may be specific for each patient with HAE.¹⁷ Some of the common triggers that may affect patients include:^1,17-19

All patients with HAE should be educated about triggers that may induce attacks.

Some triggers can be prevented, for example, by avoiding the use of oestrogen containing oral contraceptives and ACE inhibitors. Vaccinations can also be given to prevent infections triggering attack, which is particularly common in children. Additionally, good dental care can reduce extractions, need for aggressive dental procedures and prevent acute or chronic intraoral inflammation.

Some triggers are an unavoidable part of a patient’s life, such as strenuous physical activities involving mechanical trauma and stress, so it is important that restriction of suspected triggers is individualised.

Excessive avoidance of suspected triggers should not be encouraged to avoid limiting the patient's normal life.¹

Diagnosis of HAE

Types of HAE

In most cases, HAE is caused by deficiency (type I) or dysfunction (type II) of C1-INH, that results in uncontrolled activation of the contact system and release of bradykinin.³

However, HAE can also be diagnosed in patients with normal C1-INH due to mutations in other genes. People diagnosed with HAE with normal C1-INH (HAE-nC1-INH) experience largely similar clinical symptoms as those with type I or II HAE.¹

HAE-nC1-INH is classified by the gene in which the mutation occurs.

Currently there are 7 known HAE-nC1-INH types classified by the gene in which the mutation occurs;^20,21

HAE-FXII
HAE-PLG (plasminogen)
HAE-KNG (kininogen 1)
HAE- HSST (heparan sulfate glucosamine 3-O-sulfotransferase 6)
HAE- ANGPT (angiopoietin-1)
HAE-MYOF (myoferlin)
HAE-CPN (carboxypeptidase N)
HAE-Unknown

The most common type of HAE-nC1-INH is HAE-FXII, which has been reported in 20-25% of patients with HAE-nC1-INH.²²The mediator of angioedema varies between types of HAE-nC1-INH, and in some cases is still unknown.^1,23

Differential diagnosis

Diagnosis of HAE requires differentiation from mast cell-mediated angioedema and other forms of bradykinin-mediated angioedema to ensure effective treatment.¹

Angioedema can be broadly split into bradykinin-mediated and mast cell-mediated, with the exception of idiopathic angioedema for which the mediator is unknown.¹ Within bradykinin-mediated angioedema, we can further differentiate between C1-INH deficiency angioedema and angioedema with normal C1-INH, which can either be acquired or hereditary.

Due to the rarity of the disease, patients may have been previously misdiagnosed with more common conditions such as allergy-related angioedema, and they may have experienced long diagnostic delays.¹² In the case of severe abdominal pain caused by HAE swelling in the gastrointestinal tract, patients with HAE can be misdiagnosed with a food allergy/intolerance or appendicitis which can result in unnecessary surgery.¹²

Artboard 3 — **Maurer M, et al., Allergy. 2022¹**

Click here for a detailed table summarising the key differences between angioedema types

Early diagnosis is vital!

Early and correct diagnosis of HAE is key, especially due to the potential for laryngeal swellings, which pose a risk of asphyxiation.¹⁴

When should HAE be suspected?¹

Positive family history (75% of patients)
Onset of symptoms in childhood/adolescence
Recurrent and painful abdominal symptoms
Occurrence of upper airway oedema
Failure to respond to antihistamines, glucocorticoids, omalizumab or epinephrine
Presence of prodromal signs or symptoms before swellings
Absence of wheals

Laboratory tests for HAE

After clinical suspicion has been raised, a simple blood test can be used to diagnose HAE by assessing:¹

If tests confirm a diagnosis of HAE, it is recommended that the whole family also be tested, due to the genetic nature of the disease. The earlier HAE can be diagnosed, the quicker a suitable management plan can be implemented for the patient.¹

References

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Guryanova I, Suffritti C, Parolin D, Zanichelli A, Ishchanka N, Polyakova E, et al. Hereditary angioedema due to C1 inhibitor deficiency in Belarus: epidemiology, access to diagnosis and seven novel mutations in SERPING1 gene. Clin Mol Allergy. 2021;19(1):3.
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DNK-AND-0001, 27/02/25