Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare autosomal dominant condition that can present in 3 types. The most common is type 1, which involves a deficiency in C1 inhibitor (C1INH) protein. Type 2 is associated with dysfunctional C1INH. The rarest form is type 3, which shows normal C1INH levels and function. Hereditary angioedema is associated with angioedema episodes of the face, lips, larynx, abdomen, and extremities. Angioedema occurs due to the activation of the kallikrein-kinin system, resulting in the release of vasoactive peptides followed by edema; in severe cases, this can be fatal.¹ 

The disease occurs in men and women at equal rates, however, women tend to have more severe episodes. Although type 3 HAE was once thought to primarily affect women, there have been cases of affected families with male members who have the disease.^2-4 

In contrast with acquired angioedema with deficient C1INH, which frequently manifests during the fourth decade of life, HAE typically presents in the first 2 decades of life. 

Diagnosis of the disease is aided by a family history of angioedema.⁵ As the disease follows an autosomal dominant inheritance pattern, every child of a person with HAE has a 50% chance of disease inheritance. However, a patient’s negative family history does not guarantee that they do not have HAE. De novo genetic variations may be responsible for up to 25% of cases, implying that many patients may be afflicted in the absence of a family history of HAE.⁶ 

Genetic Risk Factors

Type 1 Hereditary Angioedema

Type 1 HAE (with deficient C1INH) has an estimated prevalence of 1.1 to 1.6/100,000, with no sex differences seen.^5,7 C1INH deficiency occurs due to mutations in the SERPING1 gene. More than 150 distinct SERPING1 gene mutations have been identified. Missense, nonsense, frameshift, deletion, and insertion are among the many SERPING1 mutations that have been found. Due to a lack of C1INH levels, type 1 HAE is characterized by the formation of misfolded or truncated proteins that consequently cannot be released.⁵

Type 2 Hereditary Angioedema

In patients with type 2 HAE (with dysfunctional C1INH), SERPING1 mutations are noted as well. These include residues at or near the active site on the reactive mobile loop that cause mutations in C1INH, which is then secreted in a dysfunctional form.⁵ 

Type 3 Hereditary Angioedema

Patients with type 3 ​​HAE (with normal C1INH level and function) have been found to have mutations mainly in the genes encoding for factor 12, angiopoietin-1, and plasminogen; the rest are described as unknown genes.⁷ 

Triggering Factors

Most patients with HAE are unable to identify any triggers; however, one-third of patients indicate that trauma, typically brought on by prolonged pressure, can trigger an attack of angioedema.^2,3 According to empirical data, physical exertion, mechanical trauma, mental stress, infection (especially viral illnesses), injury, severe pain, surgical or dental procedures, menstruation, pregnancy, weather changes, and some medicinal products may also trigger episodes of swelling.^3,8,9 For the first time, a study analysis looked into the potential contribution of trigger factors of HAE attacks. It was found that 91% of the respondents were able to identify the most common triggers, including physical activity in 71% of cases, mental stress in 59%, and mechanical trauma in 59%.⁹ The individuals identified a trigger factor most frequently with abdominal attacks. Subcutaneous edema was frequently brought on by physical exertion, while abdominal attacks were typically triggered by mental stress. Most upper airway episodes were driven by infection or menstruation.⁹ 

References

1. Patel N, Suarez LD, Kapur S, Bielory L. Hereditary angioedema and gastrointestinal complications: an extensive review of the literature. Case Reports Immunol. 2015;2015:925861. doi:10.1155/2015/925861
2. Hereditary angioedema. MedlinePlus. Updated April 1, 2009. Accessed June 24, 2022.
3. Frank MM. Hereditary angioedema: epidemiology. Medscape. Updated August 30, 2018. Accessed June 24, 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. Abdulkarim A, Craig TJ. Hereditary angioedema. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 4, 2022. Accessed June 24, 2022.
6. Betschel S, Badiou J, Binkley K, et al. The international/Canadian hereditary angioedema guideline. Allergy Asthma Clin Immunol. 2019;15:72. doi:10.1186/s13223-019-0376-8
7. ​​Liu S, Wang X, Xu Y, Xu Q, Zhi Y. Health-related quality of life and its risk factors in Chinese hereditary angioedema patients. Orphanet J Rare Dis. 2019;14(1):191. doi:10.1186/s13023-019-1159-5
8. Hereditary angioedema. National Organization for Rare Disorders (NORD). Accessed June 24, 2022. 
9. 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

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

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.