What Is HAE?

Hereditary angioedema (HAE) is characterized by unpredictable episodic swelling without pruritus. Attacks can be severe, sometimes life-threatening, causing significant morbidity and disability.1,2

Patients with HAE are subject to localized attacks of subcutaneous and/or submucosal swelling. Typical therapies for angioedema are ineffective in patients with HAE; thus, a correct diagnosis is crucial.

Depending on the severity of the disease, some patients will have frequent attacks, while others may have a few throughout the year.2 Many people have their first attack in childhood; attacks typically worsen after puberty and persist through adulthood.2

Physical exertion, stress and trauma are among the most commonly reported triggers of an attack.3

Source: https://ghr.nlm.nih.gov/gene/SERPING1
Gösswein T, Kocot A, Emmert G, Kreuz W, Martinez-Saguer I, Aygören-Pürsün E, Rusicke E, Bork K, Oldenburg J, Müller CR. Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res. 2008;121(3-4):181-8. doi: 10.1159/000138883. Epub 2008 Aug 28

Types of Hereditary Angioedema28

HAE can be broadly divided into 2 fundamental types:1

  • HAE due to C1 inhibitor (C1INH) deficiency (HAE-C1INH)
  • HAE with normal C1INH (HAE-nl-C1INH)

Patients with HAE Types I and II have a mutation on the SERPING1 gene, causing a deficiency or dysfunction in the plasma protein C1 inhibitor (C1-INH).4 For 75% of patients, the mutation is autosomal dominant and heterozygous for the deficiency;13 for the other 25%, the mutation is spontaneous.1,2

HAE-C1INH is further divided into 2 subtypes: Type I HAE and Type II HAE.1

  • HAE Type I is a quantitative and functional deficiency of C1-INH. Due to C1 inhibitor deficiency, the body does not make enough C1-INH and it does not work properly. Type I is the most common, with 85% of people having this type.2
  • HAE Type II is a function deficiency, whereby the body makes normal to high amounts of C1-INH, but it does not work properly. 15% of people have Type II.

Type I

HAE type I: most common with 85% of HAE patients affected

Type II

HAE type II: 15% of HAE patients affected

HAE with normal C1-INH

HAE with normal C1-INH: normal levels of C1-INH and it functions normally. Extremely rare.

Image: https://www.discoverhae.com/what-is-hereditary-angioedema (page 3,4)

Epidemiology

HAE accounts for approximately 2% of clinical angioedema cases. It affects 1 in ~67,000, so there are roughly 6,000 people in the U.S. living with the disease;6 attacks lead to 15,000–30,000 ED visits per year.7 The average HAE patient has 26 attacks per year (~2 attacks per month); however, there are rare reports of patients with more than 100 HAE attacks per year.2

Because the condition is so rare, and often misdiagnosed, exact numbers are difficult to calculate. There are no apparent differences in prevalence based on sex or ethnicity.8

Pathophysiology11

C1‐INH is a broad-spectrum serine proteinase inhibitor, named for its ability to inhibit C1—the first component of the complement cascade. It also inhibits other circulating enzymes such as kallikrein and activated coagulation factor XII (FXIIa).

Produced primarily in the liver, C1-INH is a major regulator of the complement, fibrinolytic, contact, and coagulation cascades. In HAE, the deficiency or dysfunction in C1-INH causes these cascades to continue unchecked. The end result is an overproduction of bradykinin, a type of nonapeptide. By binding to the B2 receptor on vascular endothelial cells, bradykinin causes vascular permeability, leading to edema, ascites, and hypotension.

Attack Presentation

Source: Source: MacGinnitie, Andrew J. 2013. “Pediatric hereditary angioedema.” Pediatric
Allergy and Immunology 25 (5): 420-427. doi:10.1111/ pai.12168. http://dx.doi.org/10.1111/pai.12168.

References

  • [1] Busse PJ, Christiansen SC, Riedl MA, Banerji A, Bernstein JA, Castaldo AJ, Craig T, Davis-Lorton M, Frank MM, Li HH, Lumry WR, Zuraw BL. US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema. J Allergy Clin Immunol Pract. 2021 Jan;9(1):132-150.e3. doi: 10.1016/j.jaip.2020.08.046. Epub 2020 Sep 6. PMID: 32898710.
  • [2] Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT. The humanistic burden of hereditary angioedema: Impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc. 2010;31(5):407-414.
  • [3] 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.
  • [4] Gösswein T, Kocot A, Emmert G, et al. Mutational spectrum of the C1INH (SERPING1) gene in patients with hereditary angioedema. Cytogenet Genome Res. 2008;121(3-4):181-188.
  • [6] Kado RK, Carlson J, Wild LG. Can HAE be Identified and Diagnosed Earlier if a Complement 4 Level is Done on All Patients Presenting with Acute Angioedema. J Allergy Clin Immunol./i> 2011;127(2):AB47.
  • [7] Frank MH. Hereditary angioedema. Medscape. August 30, 2018. https://emedicine.medscape.com/article/135604-overview.
  • [8] Cicardi M, Zuraw BL. Angioedema Due to Bradykinin Dysregulation. J Allergy Clin Immunol Pract. 2018;6(4):1132-1141.
  • [11] Gelincik A and Demir S. Hereditary Angioedema. May 31, 2017. DOI: 10.5772/intechopen.68208
  • [13] Zeerleder S, Levi M. Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment. Ann Med. 2016;48(4):256-227.
  • [28] Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-The 2021 revision and update. Allergy. 2022;77(7):1961-1990.