What is HAE?

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
How do HAE attacks happen?
Symptoms
Diagnosis of HAE

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

Inheritance of HAE

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

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The HAE cascade

 

The HAE cascade

Simplified illustration of the contact activation pathway and its role in an HAE attack. Adapted from Zuraw BL N Eng J Med. 2008. C1-INH, C1-esterase inhibitor; HK, high-molecular weight kininogen. 4-6

Symptoms

Patients usually experience their first symptoms of HAE (HAE attacks) during childhood and adolescence.3 Attacks can occur anywhere on the body but often affect the skin, abdomen and upper respiratory tract. Attacks can be extremely painful, disfiguring and debilitating, interfering with patients’ ability to carry out normal daily activities.2 Symptoms often get worse over a period of 12 hours to a day, then gradually resolve over the following 2–5 days.2 

Alert

HAE varies greatly from person to person, with some patients suffering several attacks per week, while attacks for others are rare.2 HAE 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

 

Attack locations

7The percentages indicate the number of HAE attacks affecting the body system in a global registry study (N=1297 patients; N=8885 attacks). 

9Percentage based on 131,110 attacks in 209 patients in an analysis of outpatients at a German Dermatology Centre

 

 

Skin oedema 

Swelling of the skin is one of the most common symptoms patients with HAE may present with, affecting almost all patients with HAE, and can occur anywhere on the body. Most commonly, swelling occurs on the patient’s face, hands, feet and genitals, and it usually spreads to disfigure the affected site.9,10 

HAE Attack - hand

Image from HAEimages.com.

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HAE Attack - face

Image from HAEimages.com.

HAE attacks are often misdiagnosed as histamine-mediated/allergy-associated oedema, but it should be noted that attacks of HAE are nonpruritic and without wheals.1,8 Skin swellings are localised at a single site, affected by an extended oedema, and can grow and regress over 2–5 days.10 

 

 

Abdominal symptoms

Patients with HAE may experience swelling of the gastrointestinal tract causing them to experience severe abdominal pain, nausea, vomiting and diarrhoea.2,11 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 Approximately 20% of HAE patients may experience abdominal symptoms only, putting them at a particularly high risk for surgical interventions.13

Stomach pain

 

 

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 
Laryngeal attack

 

 

Prodromal symptoms

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

 

Prodromal symptoms_Left
Prodromal symptoms_Right

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Erythema marginatum is a flat, non-pruritic, ring-shaped rash that most commonly affects the trunk in some patients prior to an HAE attack.16 It is more frequent in children, occurring in 42–58% of cases, and it should not be confused with urticaria.1

Erythema marginatum

Erythema marginatum. 

Image from HAEimages.com.

 

 

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 

 

 

potential triggers V3_Left
potential triggers V3_Right

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

Thoughts

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

Types of HAE

 

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.22 The 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

 

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classification

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 
 

misdiagnosis

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

 

HAE table

 

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

  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. 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.
  4. Caccia S, Suffritti C, Cicardi M. Pathophysiology of Hereditary Angioedema. Pediatr Allergy Immunol Pulmonol. 2014;27(4):159-63.
  5. Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol. 2010;104(3):193-204.
  6. Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008;359(10):1027-36.
  7. Zanichelli A, Farkas H, Bouillet L, Bara N, Germenis AE, Psarros F, et al. The Global Registry for Hereditary Angioedema due to C1-Inhibitor Deficiency. Clin Rev Allergy Immunol. 2021;61(1):77-83.
  8. Azmy V, Brooks JP, Hsu FI. Clinical presentation of hereditary angioedema. Allergy Asthma Proc. 2020;41(Suppl 1):S18-s21.
  9. 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.
  10. Agostoni A, Aygören-Pürsün E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114(3 Suppl):S51-131.
  11. 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.
  12. 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.
  13. Koruth JS, Eckardt AJ, Levey JM. Hereditary angioedema involving the colon: endoscopic appearance and review of GI manifestations. Gastrointestinal Endoscopy. 2005;61(7):907-11.
  14. 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.
  15. Magerl M, Doumoulakis G, Kalkounou I, Weller K, Church MK, Kreuz W, et al. Characterization of prodromal symptoms in a large population of patients with hereditary angio-oedema. Clin Exp Dermatol. 2014;39(3):298-303.
  16. Farkas H, Harmat G, Fáy A, Fekete B, Karádi I, Visy B, et al. Erythema marginatum preceding an acute oedematous attack of hereditary angioneurotic oedema. Acta Derm Venereol. 2001;81(5):376-7.
  17.  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.
  18. Bowen T, Cicardi M, Bork K, Zuraw B, Frank M, Ritchie B, et al. Hereditary angiodema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus Algorithm for the Diagnosis, Therapy, and Management of Hereditary Angioedema. Ann Allergy Asthma Immunol. 2008;100(1 Suppl 2):S30-40.
  19. Maurer M, Aygören-Pürsün E, Banerji A, Bernstein JA, Balle Boysen H, Busse PJ, et al. Consensus on treatment goals in hereditary angioedema: A global Delphi initiative. J Allergy Clin Immunol. 2021;148(6):1526–32.
  20. Vincent D, Parsopoulou F, Martin L, Gaboriaud C, Demongeot J, Loules G, et al. Hereditary angioedema with normal C1 inhibitor associated with carboxypeptidase N deficiency. J Allergy Clin Immunol Glob. 2024;3(2):100223.
  21. Reshef A, Buttgereit T, Betschel SD, Caballero T, Farkas H, Grumach AS, et al. Definition, acronyms, nomenclature, and classification of angioedema (DANCE): AAAAI, ACAAI, ACARE, and APAAACI DANCE consensus. Journal of Allergy and Clinical Immunology.
  22. Zuraw BL. Hereditary angioedema with normal C1 inhibitor: Four types and counting. J Allergy Clin Immunol. 2018;141(3):884-5.
  23.  Santacroce R, D'Andrea G, Maffione AB, Margaglione M, d'Apolito M. The Genetics of Hereditary Angioedema: A Review. J Clin Med. 2021;10(9).
  24. Cao Y, Liu S, Zhi Y. Recurrent and acute abdominal pain as the main clinical manifestation in patients with hereditary angioedema. Allergy Asthma Proc. 2021;42(2):131-5.
  25. Patel N, Suarez LD, Kapur S, Bielory L. Hereditary Angioedema and Gastrointestinal Complications: An Extensive Review of the Literature. Case Reports in Immunology. 2015;2015(1):925861.
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