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Causes

There are several different forms of HAE that are currently recognised and genetically identifiable.1

HAE is primarily caused by mutations in the serine protease inhibitor G1 (SERPING1) gene that encodes C1-esterase inhibitor (C1-INH), including:1-3

 

Type I HAE

Type II HAE

Characterised by low antigenic and functional C1-INH levels1,2

Characterised by normal or elevated antigenic but low functional C1-INH levels1,2

Occurs in approximately 85% of HAE cases1

Occurs in approximately 15% of HAE cases1

 

Within the contact pathway (kallikrein–kinin system), C1-INH inhibits the production of bradykinin by interfering with plasma kallikrein activity. Dysregulation of plasma kallikrein activity within the kallikrein–kinin system leads to the cleavage of high-molecular weight kininogen (HMWK) and excess bradykinin production, which can lead to attacks.4,5

Other and rarer (≤1% of cases) forms of HAE that do not involve mutations of C1-INH include:

  • Coagulation factor 12 gene mutation (HAE-FXII), also known as HAE Type III: mainly affects females and is exacerbated by high oestrogen levels e.g. oral contraceptives and pregnancy1,2,6
  • Angiopoietin-1 gene mutation (HAE-ANGPTI)2
  • Plasminogen gene mutation (HAE-PLG)2

 

Triggers

While many HAE attacks occur with no identifiable trigger, some may be associated with:7,8,9

 

 

Emotional stress

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Dental and surgical procedures

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Physical exertion

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Physical injury / minor trauma

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Hormonal changes

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e.g. puberty, menstruation, oestrogen-containing contraceptives, pregnancy, menopause

ACE inhibitors

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Repetitive motion or contact

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Illnesses or infections

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Fatigue

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References: 

  1. Banerji A, et al. Allergy Asthma Proc 2015;36(3):213–7.
  2. Zuraw B. J Allergy Clin Immunol 2018;141(3):884–5.
  3. Angioedema News. Available from: https://angioedemanews.com/angioedema-types/ Accessed August 2021.
  4. Longhurst H, et al. Lancet 2012;379(9814):474–81.
  5. Suffritti C, et al. Clin Exp Allergy 2014;44(12):1503–14.
  6. Banerji A, et al. Womens Health 2016;12(3):351–61.
  7. Maurer M, et al. Allergy 2018;73(8):1575–96.
  8. Caballero T, et al. J Investig Allergol Clin Immunol 2016;26(6):383–6. 
  9. Zotter Z, et al. Orphanet J Rare Dis 2014;9:44.
Job code: C-ANPROM/UK//2467 Date of preparation: August 2021