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What is Hereditary Angioedema (HAE)?

Hereditary angioedema (HAE) is a rare, serious, potentially life-threatening genetic disorder occurring in 1 in 50,000 to 1 in 150,000 people worldwide. In Europe, approximately 10,000 people are affected.1

People with hereditary angioedema (HAE) are unable to make enough of the functional blood protein, C1-esterase inhibitor (C1-INH). Lack of this inhibitor results in overproduction of an inflammatory substance called bradykinin, which causes leakage of fluid from blood vessels and build-up of excessive fluid, which is the cause of localised swelling.2,3

HAE causes repeated episodes of spontaneous angioedema – or swelling – that can occur at any time and in almost any part of the body but more predominantly in the hands, feet, face, airway (throat) and internal organs. Most people experience their first episode in childhood or adolescence. HAE is not an allergy or allergic reaction.5

HAE symptoms can start to occur at a very early age, but there are also examples of this occurring later in life. As incidents of suffocation due to throat swelling can occur within families with HAE, making a timely diagnosis is extra important.4

What causes HAE?

HAE is usually caused by the lack of, or low levels of, a blood protein called C1 esterase inhibitor (C1-INH), or sometimes this protein doesn’t work properly.6 In rare cases, the cause of HAE is unknown. DNA contains genes which carry the information for the C1 INH protein defect, which explains why HAE runs in families. If one parent has HAE, their children (male and female) will have a 50% chance of inheriting the condition.7

The absence of family history does not rule out an HAE diagnosis because there can be spontaneous changes to the C1 inhibitor gene. These patients can also pass on the defective gene to their offspring.7

Symptoms and triggers

Emotional factors (e.g., exam stress, relationship problems), small surgical procedures (e.g., dental work) and hormonal fluctuations (e.g., during pregnancy, puberty, or menstruation) are sometimes enough to trigger a swelling episode.8-10 It is also possible that medicines used to lower blood pressure, called angiotensin converting enzyme (ACE) inhibitors, can prompt an episode.11 Other potential triggers include infections, insect bites, certain foods, heat and cold. Often, the exact cause of an episode is unknown.8

Warning signs and symptoms of an HAE episode

Accidental injury

Infection (e.g. cold or flu)

Emotional stress

Surgery, particularly dental surgery

Hormonal fluctuations

Check your signs and symptoms:

Some people have warning signs and symptoms that an episode is coming, which may appear as early as 16 hours beforehand.4 Knowing your own warning signs can help you to make sure you are treated as early as possible. Discomfort at the site of the swelling and a non-itchy, spreading rash with a wavy border are two examples.2-3
Other warning signs and symptoms may include:

Fatigue / weakness / lack of energy

Mood swings

Headache

Tingling

Nausea

Thirst

Joint or muscle pain

HAE episodes

The frequency of HAE episodes varies between people and tends to be unpredictable: some people may have very few episodes, while others may have episodes every few days.2 Episodes may start in one part of the body and spread to another before they disappear.14 Swelling typically builds up over the first 24 hours,14 and episodes can last for 2-5 days if not treated.2 They may affect any part of the body, but the most common sites are:2,14,15

The severity of symptoms varies among family members and people who start to get symptoms at an early age often have more severe HAE than those who start to develop symptoms at a later age.18

Swelling in the arms and legs is usually less painful; however, abdominal (belly) symptoms may become worse with time, so it is important to treat all episodes as early as possible.19 Prompt treatment is particularly important for people with swelling of the face and/or mouth, even if this seems mild, to make sure the swelling does not spread to the airways and prevent the person from breathing.20

Types of HAE23

Type C1-INH level C1-INH functionality Men/Women Occurrence

123

 		Low Normal Equal ~85% of people with HAE

223

 		Normal Abnormal Equal ~15% of people with HAE

HAE with normal, functioning C1-INH23

 		Normal Normal More common in women than men Extremely rare

Diagnosis

Due to the complexity of the disease and its potential risks, it is essential that HAE patients receive an accurate diagnosis early in the disease course. The diversity of symptoms and their similarity to other conditions and/or other types of swelling lead to confusion among those doctors who are not familiar with HAE.13,20

Typical symptoms that patients can look out for include:24,25

The diagnosis of HAE is made by a thorough clinical evaluation, a detailed patient history, and blood tests that test levels of the protein called C4 antigen.26 Other protein levels such as C1 and C2 can also be tested for. Ultrasound, CT scans, and X-rays may be used to demonstrate swelling.27

In Europe, expert centres have sufficient specialised, comprehensive care to make a reliable diagnosis.20 Diagnosis is obtained by laboratory tests performed on a blood sample. The blood of HAE patients shows a decreased concentration of C1-inhibitor and/or reduced activity of C1 inhibitor. The concentration of C4 antigen levels is also usually reduced in people with HAE.26

Important

A timely diagnosis can improve your quality of life!

References

  1. Ghazi A, Grant JA. Hereditary angioedema: epidemiology, management, and role of icatibant. Biol Targets Ther. 2013;7:103. doi:10.2147/BTT.S27566
  2. Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med Lond Engl 2005. 2019;80(7):391-398. doi:10.12968
    hmed.2019.80.7.391
  3. Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. 2020;382(12):1136-1148. doi:10.1056/NEJMra1808012
  4. Bork K. Acquired and hereditary forms of recurrent angioedema: Update of treatment. Allergol Sel. 2018;2(1):121-131. doi:10.5414/ALX1561E
  5. Bhivgade S, Melkote S, Ghate S, Jerajani HR. Hereditary Angioedema: Not An Allergy. Indian J Dermatol. 2012;57(6):503. doi:10.4103/0019-5154.103081
  6. Gower RG, Busse PJ, Aygören-Pürsün E, et al. Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on
    Prophylaxis Treatment Strategies. World Allergy Organ J. 2011;4(Suppl 2):S9-S21. doi:10.1097/1939-4551-4-S2-S9
  7. Sabharwal G, Craig T. Pediatric hereditary angioedema: an update. F1000Research. 2017;6:F1000 Faculty Rev-1205. doi:10.12688/f1000research.11320.1
  8. Zotter Z, Csuka D, Szabó E, et al. The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency. Orphanet J Rare Dis. 2014;9:44.
    doi:10.1186/1750-1172-9-44
  9. Williams AH, Craig TJ. Perioperative management for patients with hereditary angioedema. Allergy Rhinol. 2015;6(1):e50-e55. doi:10.2500/ar.2015.6.0112
  10. Savarese L, Bova M, De Falco R, et al. Emotional processes and stress in children affected by hereditary angioedema with C1-inhibitor deficiency: a multicenter, prospective study.
    Orphanet J Rare Dis. 2018;13(1):115. doi:10.1186/s13023-018-0871-x
  11. Longhurst H, Cicardi M. Hereditary angio-oedema. Lancet Lond Engl. 2012;379(9814):474-481. doi:10.1016/S0140-6736(11)60935-5
  12. NHS Commissioning Board. Clinical Commissioning Policy: Treatment of Acute Attacks in Hereditary Angiodema (Adult).; 2013:1-20. Accessed February 1, 2022. https:/
    www.england.nhs.uk/wp-content/uploads/2018/07/Treatment-of-acute-attacks-in-hereditary-angiodema-adult.pdf?UNLID=623146691202083182412
  13. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-1036. doi:10.1056/NEJMcp0803977
  14. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119(3):267-274. doi:10.1016
    j.amjmed.2005.09.064
  15. Piotrowicz-Wójcik, K., Porebski, G., 2020. Life-threatening laryngeal attacks in hereditary angioedema patients. Otolaryngol. Pol. Pol. Otolaryngol. 74, 1–5. https://doi.org/
  16. 10.5604/01.3001.0014.0619 17. Watanabe, T., Yamashita, K., Bessho, K., 2021. Orthognathic Surgery in Hereditary Angioedema With Normal C1 Inhibitor: A Clinical Response to Concentrated C1 Inhibitor Against
    Angioedema Attack. J. Oral Maxillofac. Surg. Off. J. Am. Assoc. Oral Maxillofac. Surg. 79, 463–470. https://doi.org/10.1016/j.joms.2020.07.221
  17. Bygum A, Busse P, Caballero T, Maurer M. Disease Severity, Activity, Impact, and Control and How to Assess Them in Patients with Hereditary Angioedema. Front Med. 2017;4:212.
    doi:10.3389/fmed.2017.00212
  18. Borum M, Ali M. Hereditary angioedema: what the gastroenterologist needs to know. Clin Exp Gastroenterol. 2014:435. doi:10.2147/ceg.s50465
  19. Banerji A, Baş M, Bernstein J et al. Expert Perspectives on Hereditary Angioedema: Key Areas for Advancements in Care across the Patient Journey. Allergy & Rhinology.
    2016;7(3):ar.2016.7.0165. doi:10.2500/ar.2016.7.0165
  20. Nabavi, M., Bahrami, S., Arshi, S., Rezaeifar, A., Bemanian, M.H., Fallahpour, M., Shokri, S., Tehrani, H., 2021. Periodic Severe Angioedema without Exogenous Hormone Exposure. Iran.
  21. J. Allergy Asthma Immunol. 20, 120–124. https://doi.org/10.18502/ijaai.v20i1.5419 22. Balkanci, U.B., Demirkol, D., Yesiltepe Mutlu, G., Birben, E., Soyer, O., Yilmaz, O., Sackesen, C., 2021. A Possibly Fatal Outcome of Oral Contraceptive Therapy: Estrogen Triggered
    Hereditary Angioedema Attack in An Adolescent. J. Clin. Res. Pediatr. Endocrinol. https://doi.org/10.4274/jcrpe.galenos.2021.2021.0053
  22. Riedl M. Recombinant Human C1 Esterase Inhibitor in the Management of Hereditary Angioedema. Clin Drug Investig. 2015;35(7):407-417. doi:10.1007/s40261-015-0300-z
  23. Azmy V, Brooks JP, Hsu FI. Clinical presentation of hereditary angioedema. Allergy Asthma Proc. 2020;41(Suppl 1):S18-S21. doi:10.2500/aap.2020.41.200065
  24. Jacobs J, Neeno T. The importance of recognizing and managing a rare form of angioedema: hereditary angioedema due to C1-inhibitor deficiency. Postgrad Med.
    2021;133(6):639-650. doi:10.1080/00325481.2021.1905364
  25. Grumach A, Veronez C, Csuka D, Farkas H. Angioedema Without Wheals: Challenges in Laboratorial Diagnosis. Front Immunol. 2021;12. doi:10.3389/fimmu.2021.785736
  26. Abuzakouk M, AlMahmeed N, Memisoglu E, McManus M, Alrakawi A. Hereditary Angioedema Type II: First Presentation in Adulthood with Recurrent Severe Abdominal Pain. Case Reports Immunol. 2018;2018:1-5. doi:10.1155/2018/7435870