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Hereditary Angioedema (HAE)

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Epidemiology

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent episodes of severe swelling in various locations throughout the body, including the face, extremities, gastrointestinal tract, and airways. Mutations in the SERPING1 and F12 genes result in 3 types of HAE: type I and II from SERPING1 mutations and type III from F12 mutations.1 

Approximately 75% of individuals with HAE inherit the disorder in an autosomal dominant pattern, while the remaining 25% undergo spontaneous mutations in these genes and do not have a previous family history.2 

These mutations encode for deficient or dysfunctional C1-esterase inhibitor proteins, which normally regulate inflammatory responses in the body. When these proteins are deficient or dysfunctional, inflammatory responses increase, allowing the excessive release of bradykinin, an inflammatory peptide that promotes vascular permeability. This leakage of fluid through blood vessel walls leads to the collection of fluid within the body’s tissues, becoming visible as excessive swelling.1

Incidence

Hereditary angioedema accounts for approximately 2% of clinical angioedema cases, and angioedema affects around 20% of the global population.3

Prevalence

Hereditary angioedema affects 1 in every 50,000 people globally, with reported prevalence ranges from 1:10,000 to 1:150,000.3,4 In the United States, HAE episodes result in 15,000 to 30,000 annual emergency department admissions.3 

Diagnostic delays impact the accuracy of incidence and prevalence estimates. An online survey of US physicians revealed that the average time to diagnosis for HAE ranged from 0 to 6 months in 5.8% of cases to over 10 years in another 5.8% of cases. This survey demonstrated that less than 38% of patients obtained an accurate diagnosis of HAE within 1 to 3 years following symptom onset.5,6

Race

Hereditary angioedema affects people of all races and ethnicities, with no bias toward any ethnic group.3,4 

A study conducted in Norway estimated an HAE prevalence of 1.75 in every 100,000 people.5,7 

Another study conducted in Spain estimated an HAE prevalence of 1.09 in every 100,000 people.5,8

Sex

Hereditary angioedema occurs in men and women at equal rates, although women experience more severe attacks. Type III HAE was initially believed to occur only in women, however, reports of families with men who have type III HAE exist.1,3,4 

Type III HAE attacks often follow elevations in estrogen levels in women during pregnancy or in those taking estrogen hormone replacement therapy, which may offer an explanation as to why type III attacks occur more frequently in women.5 

Age

Although mutations in the SERPING1 and F12 genes are present at birth in many patients with HAE, symptoms caused by C1-esterase inhibitor protein deficiency usually appear in the first or second decade of life. The severity of attacks increases around puberty, whereas swelling during childhood tends to be milder, less frequent, and less visible as abdominal symptoms are more common.3,9 

In one study, researchers analyzed symptom presentation in 209 patients with HAE. In most patients, symptoms began during childhood or adolescence, with an average age of onset of 11.2±7.7 years (range, 1-40 years). Initial HAE attacks began in the first decade of life in 107 (51.2%) patients, in the second decade of life in 79 (37.8%) patients, and at later ages in 23 (11%) patients. In 15 (7.2%) patients, symptoms began within the first year of life. Patients with an earlier onset of symptoms typically experienced a more severe course of the disease than those with a later onset.10

Spontaneously acquired forms of HAE typically present after the fourth decade of life.11 Although HAE causes lifelong symptoms, some people with HAE report decreasing severity of symptoms with aging.3

Hereditary Angioedema Type

Type I HAE is the most frequently diagnosed type, accounting for 80% to 85% of HAE cases. Type II accounts for 15% to 20% of HAE cases, while type III is extremely rare.1,4 

References

  1. Hereditary angioedema. MedlinePlus. Updated April 1, 2009. Accessed June 8, 2022.
  2. Bernstein JA. Severity of hereditary angioedema, prevalence, and diagnostic considerations. Am J Manag Care. 2018;24(14 Suppl):S292-S298. 
  3. Frank MM. Hereditary angioedema: epidemiology. Medscape. Updated August 30, 2018. Accessed June 8, 2022.
  4. Ghazi A, Grant JA. Hereditary angioedema: epidemiology, management, and role of icatibant. Biologics. 2013;7:103-113. doi:10.2147/BTT.S27566
  5. Lumry WR. Overview of epidemiology, pathophysiology, and disease progression in hereditary angioedema. Am J Manag Care. 2013;19(7 Suppl):S103-S110.
  6. Riedl M, Gower RG, Chrvala CA. Current medical management of hereditary angioedema: results from a large survey of US physicians. Ann Allergy Asthma Immunol. 2011;106(4):316-322.e4. doi:10.1016/j.anai.2010.12.012
  7. Stray-Pedersen A, Abrahamsen TG, Frøland SS. Primary immunodeficiency diseases in Norway. J Clin Immunol. 2000;20(6):477-485. doi:10.1023/a:1026416017763
  8. Roche O, Blanch A, Caballero T, Sastre N, Callejo D, López-Trascasa M. Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain. Ann Allergy Asthma Immunol. 2005;94(4):498-503. doi:10.1016/S1081-1206(10)61121-0
  9. Frank MM. Hereditary angioedema clinical presentation. Medscape. Updated August 30, 2018. Accessed June 8, 2022.
  10. 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
  11. Abdulkarim A, Craig TJ. Hereditary angioedema. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 4, 2022. Accessed June 8, 2022.

Reviewed by Hasan Avcu, MD, on 6/26/2022.

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