Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare condition with autosomal-dominant inheritance characterized by recurrent episodes of severe swelling, affecting predominantly the face, extremities, gastrointestinal tract, and airways. About one-third of patients develop a non-itchy rash called erythema marginatum during HAE attacks. The most severe complication of acute attacks of HAE is caused by laryngeal edema, which obstructs breathing and may cause life-threatening asphyxiation. Episodes related to gastrointestinal tract can cause nausea, vomiting, and abdominal pain.¹ 

HAE is caused by mutations in the SERPING1 or F12 gene. Mutations in the SERPING1 gene result in a deficiency or dysfunction of the C1-esterase inhibitor plasma protein. As a result, the release of excessive amounts of bradykinin causes an increase in vascular permeability and leakage of fluid from the vasculature into surrounding tissues. Mutations in the F12 gene increase the activity of the factor XII protein, also resulting in the release of excessive amounts of bradykinin, with increased vascular permeability and episodes of severe swelling.¹

Triggers such as trauma, emotional stress, infection, surgical or medical procedures, hormonal changes during menstruation or pregnancy, and changes in the weather may cause episodes of swelling, although swelling can also occur without a known trigger.^1,2

Common HAE Comorbidities

Results from a survey of 242 patients in multiple countries with a diagnosis of HAE, published in 2021, described frequent comorbidities, of which anxiety (26%), gastrointestinal disorders (17.8%), depression (16.9%), hypercholesterolemia (13.6%), and hypertension (12.8%) were the most common.³

A population-based cohort study from Sweden, published in 2022, compared 239 patients who had HAE with 2383 people in the general population. In the patients with HAE, the researchers identified an increased risk for cardiovascular disease (odds ratio, 1.83), especially arterial thromboembolic disease (odds ratio, 6.74); venous thromboembolic disease (odds ratio, 4.20); hypertension (odds ratio, 1.64); and hyperlipidemia (odds ratio, 2.01).⁴ 

This same study noted that patients with a diagnosis of HAE also had an increased risk for autoimmune disorders (odds ratio, 1.65), including systemic lupus erythematosus (SLE) and autoimmune thyroiditis leading to hypothyroidism. Additionally, the risk for having 2 or more autoimmune disorders was higher in the HAE population. Autoimmune disorders occurred more frequently in women with HAE, and systemic lupus erythematosus was 72 times more likely to occur in patients with HAE. According to the prescription register, patients with HAE often took medications to treat hypertension, hyperlipidemia, and hypothyroidism.^4,5

Another study confirmed higher rates of SLE (9.54% vs 2.25%), Hashimoto thyroiditis/autoimmune thyroiditis (3.18% vs 0.98%), connective tissue disorders (3.18% vs 0.23%), and Sjögren syndrome (1.73% vs 0.23%) in a comparison of patients with HAE (n=36) vs the general population (n=1730). Patients with HAE also were more likely to have more than one autoimmune disorder in comparison with the general population (11.56% vs. 3.18%).⁶

A self-reported survey of 445 patients with HAE conducted in the United States in 2017 that was published in 2020 listed anxiety and depression as the most common comorbidities. According to the Hospital Anxiety and Depression Scale, anxiety and depression affected 35.3% and 20.9% of patients with HAE, respectively. The frequency of acute attacks of HAE and hospitalization correlated with the severity of anxiety and depression.^7,8 

Additional reported comorbidities included arthritis (19.3%), hypertension (19.3%), hypercholesterolemia (14.6%), asthma (14.6%), sleep apnea (10.3%), anemia (9.9%), diabetes (6.5%), and heart disease (2.2%).^7,8

Effect of Comorbidities on the Treatment of HAE

Long-term prophylaxis to prevent acute HAE attacks is a critical component of the management of patients with HAE. The type of medication used for long-term prophylaxis is customized for the individual patient according to multiple factors, including the frequency, severity, and location of acute attacks, the presence of comorbidities, and response to treatment. Patients on long-term prophylaxis should be monitored regularly for tolerability and efficacy of the treatment and on-demand therapy should be available to treat any breakthrough HAE attacks.⁹

References

1. Hereditary angioedema. MedlinePlus. Accessed June 30, 2022.
2. 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
3. Mendivil J, Murphy R, de la Cruz M, 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. doi:10.1186/s13023-021-01717-4
4. Sundler Björkman L, Persson B, Aronsson D, Skattum L, Nordenfelt P, Egesten A. Comorbidities in hereditary angioedema—a population‐based cohort study. Clin Transl Allergy. 2022;12(3):e12135. doi:10.1002/clt2.12135
5. Pinto V. HAE patients found to be at higher risk of developing other diseases. Angioedema News. April 4, 2022. Accessed June 30, 2022.
6. Tachdjian R, Borra S, Shrestha S, et al. Burden of autoimmune disorders among patients with hereditary angioedema in the United States. J Allergy Clin Immunol. 2020;145(2):AB102. doi:10.1016/j.jaci.2019.12.621
7. Banerji A, Davis KH, Brown TM, et al. Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States. Ann Allergy Asthma Immunol. 2020;124(6):600-607. doi:10.1016/j.anai.2020.02.018
8. Impact of hereditary angioedema on patients. Discover HAE. Accessed June 30, 2022.
9. Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations, and treatment. Br J Hosp Med. 2019;80(7):391-398. doi:10.12968/hmed.2019.80.7.391

Reviewed by Debjyoti Talukdar, MD, on 6/30/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.