Hereditary angioedema (HAE) is a rare genetic disease that causes individuals to experience repeated swelling of the skin and mucous membranes (layers of cells that line internal organs in the body), which can occur all over the body. It is a chronically debilitating and potentially life-threatening disease.1
The first symptoms of HAE usually occur in childhood and adolescence.1 HAE swelling episodes, also known as HAE ‘attacks’, can affect your skin, abdomen and throat. Attacks often get worse over a period of 12 hours to a day, then gradually resolve over the following 2–5 days.2 They can be extremely painful, disfiguring and debilitating, and you may find they interfere with your ability to carry out normal daily activities.2
HAE varies greatly from person to person: some may have several attacks per week, while attacks for others are rare.2 The number and severity of attacks can also vary within the same person, as well as the pain related to the attacks. You may have more attacks for certain periods of time, for example, during puberty, pregnancy or during stressful periods of life such as exams; or you may have periods with fewer attacks.
HAE can affect a range of locations on the body. In a study of over 200 patients with HAE, the proportion of patients that experienced HAE attacks at various locations was:3,4
break
Skin swelling is the most common symptom of HAE and can occur anywhere on your body, but often affects your face, hands, feet and genitals.5 These attacks typically last 2–5 days2 and are different to allergy-related swelling, as they do not itch and are not usually accompanied by hives.5
Occasionally, swelling can occur in the membrane layer lining internal organs in the abdomen. When this happens, you may experience severe stomach pain, nausea, vomiting and diarrhoea. Abdominal symptoms can occur without skin swellings, and the pain from these attacks can be mistaken for other conditions such as appendicitis.2,6,7
Some people with HAE may experience swelling in the throat, which requires emergency attention, and can be life-threatening, particularly if their HAE is undiagnosed.8 Signs that you might be experiencing an attack affecting the throat include difficulty swallowing, tightness or a feeling of a ‘lump in the throat’, shortness of breath and/or vocal changes such as loss of voice, hoarseness, or a rough voice.9 If you notice any of these symptoms, you should seek emergency care right away.
Prodromal symptoms are warning signs of a potential oncoming attack and can vary between each person. Before an attack, you may feel fatigued, malaise, tingling sensations and mild itching. Some people may also develop a rash, which is round in shape producing a map-like pattern on the skin.10
Most HAE attacks happen spontaneously and unexpectedly. However, there are various triggers that can cause a swelling attack and these may be specific to each person.11
HAE is genetic disorder caused by a faulty gene (SERPING1 gene) which is usually inherited from one or both of your parents. However, in some cases (~25%), HAE can also occur due to a new genetic mutation which is not inherited from parents.1,2
All carriers of the faulty SERPING1 gene can develop symptoms and can pass the defective gene onto their children. There is a 50% chance of HAE being inherited by your child if you or your partner carries the defective gene.1 Only those who have HAE are at risk of passing it to their children, meaning children without HAE cannot pass HAE onto the next generation.1 Men and women have the same likelihood of inheriting HAE.2
In most cases of HAE, the faulty SERPING1 gene results in either too little (type I) or non-functioning (type II) C1 esterase inhibitor (C1-INH) – a protein that acts like a ‘brake’ in regulating several biological pathways. However, there are also patients with normal levels of C1-INH that could have HAE, due to mutations in other genes. People with HAE with normal C1-INH will experience largely the same symptoms.1
Without enough C1-INH to act as a ‘brake’, some biological pathways may be inadequately controlled, causing specific proteins to be produced at abnormal levels.1
To understand how this works, we must look at the ‘HAE cascade’. A cascade is a series of interactions that occur in your body, resulting in the symptoms you experience. In the biological pathway that leads to swelling during an HAE attack, C1-INH regulates several steps so that they do not run uncontrollably. Without enough functional C1-INH, as is the case with many people with HAE, this cascade is at risk of being activated without control, resulting in overproduction of a molecule called bradykinin. During an HAE attack, excessive amounts of bradykinin are produced, which causes blood vessels to become leaky, and the fluid leaks out of the blood vessels into the surrounding tissue resulting in the swelling that patients experience.
Simplified ilustration of the contact activation pathway and its role in an HAE attack. Adapted from Zuraw BL. N Engl J Med.2008.
HK = high molecular weight kininogen
The genetic defect that commonly causes HAE means that your body cannot properly produce the protein C1-INH.
In the HAE cascade, C1-INH is responsible for regulating the production of bradykinin. Once the cascade has started, if there is not enough C1-INH to regulate the process, bradykinin is overproduced which causes the leakiness of your blood vessels to increase.
Consequently, more fluid can enter the tissues surrounding the vessels, causing an HAE attack that is characterized by swelling and pain.1
Early diagnosis of HAE can save lives, especially in those who experience swelling of the throat, which poses a risk of suffocation. However, as HAE is a rare disease and its symptoms may mimic those of other, more common, medical conditions, it is often misdiagnosed by doctors as an allergic reaction. If therapies for allergies are given, they will not help to resolve your attack. In the case of severe abdominal pain caused by HAE swelling in the gastrointestinal tract, doctors may diagnose a food allergy/intolerance or appendicitis. This can even sometimes result in marked delays in receiving the correct diagnosis or unnecessary procedures.7
To diagnose HAE, your doctor will take a blood sample. The blood can then be assessed to measure C1-INH protein levels and whether the C1-INH is functioning correctly.
If tests confirm a diagnosis of HAE, it is recommended that the whole family should 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 organised between yourself and your physician to potentially prevent and treat the unpredictable and debilitating attacks.1
1. Maurer M, Magerl M, Betschel S, Aberer W, Ansotegui IJ, Aygören-Pürsün E, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022;77(7):1961–90.
2. Bork K, Anderson JT, Caballero T, Craig T, Johnston DT, Li HH, et al. Assessment and management of disease burden and quality of life in patients with hereditary angioedema: a consensus report. Allergy Asthma Clin Immunol. 2021;17(1):40.
3. Azmy V, Brooks JP, Hsu FI. Clinical presentation of hereditary angioedema. Allergy Asthma Proc. 2020;41(Suppl 1):S18-s21.
4. Bork K, Meng G, Staubach P, Hardt J. Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course. Am J Med. 2006;119(3):267-74.
5. Bernstein JA. Severity of hereditary angioedema, prevalence, and diagnostic considerations. Am J Manag Care. 2018;24(14 Suppl):S292-s8.
6. Mendivil J, Murphy R, de la Cruz M, Janssen E, Boysen HB, Jain G, et al. Clinical characteristics and burden of illness in patients with hereditary angioedema: findings from a multinational patient survey. Orphanet J Rare Dis. 2021;16(1):94.
7. Zanichelli A, Longhurst HJ, Maurer M, Bouillet L, Aberer W, Fabien V, et al. Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting. Ann Allergy Asthma Immunol. 2016;117(4):394-8.
8. Bork K, Hardt J, Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol. 2012;130(3):692-7.
9. Farkas H. Management of upper airway edema caused by hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6(1):19.
10. Magerl M, Doumoulakis G, Kalkounou I, Weller K, Church MK, Kreuz W, Maurer M. Characterization of prodromal symptoms in a large population of patients with hereditary angio-oedema. Clin Exp Dermatol. 2014;39(3):298-303.
11. Zotter Z, Csuka D, Szabó E, Czaller I, Nébenführer Z, Temesszentandrási G, et al. The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency. Orphanet J Rare Dis. 2014;9:44.
12. Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. 2020;382(12):1136-48.
13. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-36.
