Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare disorder with autosomal-dominant inheritance in which a deficiency of the C1-esterase inhibitor plasma protein results in the excessive release of bradykinin and increased vascular permeability. Consequently, recurrent episodes of severe swelling develop that affect the face, limbs, abdomen, and airways.^1,2 These episodes and their impact on the patient’s overall health play a role in determining the prognosis of HAE patients.

Prognosis Overview

Before advances were made in the effectiveness of medications to prevent and manage acute episodes of HAE-associated swelling, mortality rates ranged from 20% to 30%. Now that effective therapies for the prevention and management of acute attacks of HAE have been developed, the prognosis for patients with this disease has improved.³ 

In an Italian study, people with HAE had an average life expectancy similar to that of the general population. On average, female patients lived until 78.2 years of age, whereas male patients lived until 72.6 years of age. Cancer and cardiovascular diseases were the primary causes of death in this cohort of 1113 individuals. Only 5 patients with HAE died during an acute attack of laryngeal edema.⁴  

During acute attacks, laryngeal edema obstructs the airways and may result in death due to asphyxiation. Abdominal attacks causing severe pain may prompt unnecessary surgeries, diagnostic delays, and opioid dependence. HAE attacks affecting the subcutaneous tissues result in disfigurement and disability, decreasing quality of life.³

Although patient-reported measures of outcome that focus on the severity and frequency of HAE attacks are useful tools, researchers in a recent study determined that if the burden of disease is to be reduced and treatment is to be effective, individualized quality-of-life assessments must evaluate the severity and frequency of attacks within the broader context of how HAE interferes with patients’ functioning at work, at school, within the family, and at social events, and with their physical activity. This information can be used to develop individualized treatment plans to help patients with HAE attain their personal goals and decrease the burden of disease.⁵ 

Factors Improving Prognosis

A prompt and accurate diagnosis allows HAE attacks to be managed appropriately with the correct treatments. Because histamine does not play a role in the development of acute attacks, antihistamine medications are ineffective for reducing symptoms during an acute attack.³ 

Androgen therapies can be used to manage and decrease short- or long-term adverse effects, whereas intravenous therapy to replace the CI-esterase inhibitor plasma protein enzyme can improve the medical status of patients with HAE during acute exacerbations.³

The identification and prevention of potential triggers of HAE attacks (eg, infections, menstruation, stress, physical exertion, weather changes, fatigue, pregnancy, mechanical trauma, minor injuries, surgeries or other medical procedures, and certain medications) improve prognosis. Increased awareness or complete avoidance of the triggers of HAE attacks facilitates adequate prophylaxis before exposure.⁶ However, attacks may occur without precipitating triggers.⁷

The long-term use of attenuated androgens or antifibrinolytic agents for prophylaxis reduces the probability of severe attacks of HAE.⁷

Factors Affecting Prognosis

Age at Onset of Disease

An early age at the onset of HAE attacks worsens the prognosis in comparison with a later age at onset.³ 

Gender

Although no sex predominance is observed in HAE,⁷ a 2017 study demonstrated that phenotypic expression of HAE with C1-esterase inhibitor deficiency was more common in women; however, the severity of HAE symptoms was the same regardless of gender. Among 59 female patients with HAE in this study, symptoms were worsened by the hormonal changes occurring during pregnancy (84%), following exogenous estrogen treatment (40%), and during menstruation (29%).⁸ 

Obstetricians and gynecologists who care for female patients with HAE must remain aware of the potential complications of the disease during pregancy, labor, and delivery, and with contraception. Additionally, several treatments for HAE are contraindicated during pregnancy; therefore, safe and effective alternatives must be selected before conception for optimal management of the patient’s symptoms during pregnancy.⁹ 

Race

HAE occurs in individuals of every race and ethnic background.⁶

References

1. Hereditary angioedema. MedlinePlus. Accessed June 28, 2022.
2. Frank MM. Hereditary angioedema: background. Medscape. Updated August 30, 2018. Accessed June 28, 2022.
3. Frank MM. Hereditary angioedema: prognosis. Medscape. Updated August 30, 2018. Accessed June 28, 2022.
4. Perego F, Gidaro A, Zanichelli A, et al. Life expectancy in Italian patients with hereditary angioedema due to C1-inhibitor deficiency. J Allergy Clin Immunol Pract. 2020;8(5):P1772-1774. doi:10.1016/j.jaip.2020.01.007
5. Bork K, Anderson JT, Caballero T, 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. doi:10.1186/s13223-021-00537-2
6. 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
7. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Int Med. 2001;161(20):2417-2429. doi:10.1001/archinte.161.20.2417
8. Takejima P, Garcia JFB, Aun MV, Kalil J, Motta AA, Giavina-Bianchi P. Gender influence on hereditary angioedema with C1-inhibitor deficiency. J Allergy Clin Immunol. 2017;139(2 Suppl):AB237. doi:10.1016/j.jaci.2016.12.762
9. Banerji A, Riedl M. Managing the female patient with hereditary angioedema. Womens Health (Lond). 2016;12(3):351-361. doi:10.2217/whe.16.6

Reviewed by Kyle Habet, MD, on 6/29/2022.

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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.