Unveiling the impact of hereditary angioedema: a study on quality of life in Brazilian adults

Abstract

Hereditary Angioedema (HAE) is a rare and severe genetic disorder caused by the deficiency of C1 Esterase Inhibitor (C1-INH), leading to unexpected and potentially fatal episodes of edema. This study assessed the quality of life (QoL) of adults with HAE in a Brazilian cohort, which comprised 29 adult patients with a confirmed HAE diagnosis, recruited from a public referral hospital. Participants completed the international HAE-specific quality of life questionnaire (IHAE-QoL v.1.1) at three time intervals: baseline, 6 months, and 1 year. This instrument assesses multiple QoL domains, including physical, emotional, social, and treatment-related aspects. Data were analyzed using SPSS v.29.0. and descriptive statistics. Group comparisons were conducted using chi-square, Student’s t-test, and Mann–Whitney U tests. The results showed statistically significant differences in the impact of HAE on QoL between sexes. While 42.9% of males reported work/study limitations, 90.9% of females expressed concern over treatment availability. Additionally, 57.1% of men reported a moderate impact on social life. The findings highlight the substantial impact of HAE on patients’ quality of life and highlight sex-specific challenges, reinforcing the need for targeted interventions to enhance disease management and QoL.

Key words
Hereditary Angioedema; Quality of Life; C1INH; Adults; Brazil

INTRODUCTION

Hereditary Angioedema (HAE) is a rare and severe genetic disorder characterized by recurrent episodes of edema in various body tissues, potentially affecting the skin, the gastrointestinal tract, and the upper airways. These attacks are unpredictable and can be potentially fatal when they affect the upper respiratory tract (Kruk et al. 2020, Maurer et al. 2022, Veronez et al. 2021). The disease is caused by a deficiency or dysfunction of C1 Esterase Inhibitor (C1-INH), a regulatory protein in the kinin pathway. HAE classification is based on C1-INH levels as follows: type I (quantitative deficiency), type II (functional deficiency), and a third type, characterized by normal C1-INH levels, but with the involvement of additional genetic mutations (Giavina-Bianchi et al. 2022, Kruk 2019, Chong-Neto 2023, Bork et al. 2021). Although HAE affects both sexes, women often experience more severe symptoms, possibly due to the influence of female hormones on the modulation of the kinin cascade (Prior et al. 2012, 2016, Caballero & Prior 2017).

The prevalence of HAE in Brazil is approximately 1 case per 65,000 individuals (ranging from 1:10,000 to 1:160,000) with a global rate of 1 in 50,000 people (Kruk et al. 2020). The quality of life (QoL) of individuals with HAE is often affected due to the unpredictable nature of the attacks, the emotional impact of the disease, and challenges in accessing appropriate treatment. Studies have suggested that the fear of attacks and uncertainty about treatment can lead to social isolation, anxiety, and depression (Chong-Neto 2023, Vanya et al. 2023). To assess this issue, the International Health-Related Quality of Life Instrument for Adult Patients with Hereditary Angioedema (IHAE-QoL v.1.1) was created to assess the impact of HAE on patients’ quality of life using a targeted questionnaire. This instrument was validated in several countries, including Brazil (Prior et al. 2012, 2016, Caballero & Prior 2017).

However, to date, no studies have been conducted in Brazil using the IHAE-QoL v.1.1 to assess the quality of life of patients with HAE. Therefore, the objective of this study was to analyze the quality of life of adults with HAE in a Brazilian cohort, identifying the main challenges faced by these patients and potential sex-related differences that may occur.

Abbreviations

HAE: Hereditary angioedema

IHAE-Qol 1.1: International Health Related Quality of Life Instrument for Adult Patients with Hereditary Angioedema

SPSS: Statistical Package for the Social Sciences

GEE: Generalized Estimating Equations

C1INH: C1 Esterase Inhibitor

Qol: Quality of life

SERPING 1: Serpin family G member 1

F12: Coagulation Factor XII

FXII: Factor XII

ANGPTH 1: Angiopoietin 1

PLG: Plasminogen

KNG: Kininogen

MYOF: MyoferlinHS3S: Heparan Sulfate-Glucosamine 3-O-Sulfotransferase

CPN: Carboxypeptidase N

CAAE: Certificate of Presentation for Ethical Consideration

Inc: Incorporated

PASW: Predictive Analytics Software

SD: Standard Deviation

IQR: Interquartile Range

X2: Chi-Squared

(n): Absolute frequencies

(%): Relative frequencies

(t): Student’s t-test

±: plus or minus

P: P-value

ICF: Informed Consent Form

BMI: Body Mass Index

Kg: Kilogram

m2: Meter

CAPES: Coordination for the Improvement of Higher Education Personnel

MATERIALS AND METHODS

Participants

The study included 29 participants (22 females and 7 males) with a confirmed diagnosis of Hereditary Angioedema (HAE), with 58.1% having HAE with C1-INH deficiency, 6.9% having HAE with C1-INH dysfunction, and 34.5% having HAE with normal C1-INH levels, with a mean age of 42 years. The participants completed the IHAE-QoL v.1.1 questionnaire at three distinct time intervals: at the initial consultation, after six months, and after one year. The inclusion criteria were adult individuals (>18 years old) with a confirmed diagnosis of hereditary angioedema (HAE), either due to C1 esterase inhibitor (C1-INH) deficiency or dysfunction, or with normal C1-INH levels and a clinical diagnosis compatible with HAE, who have completed the entire questionnaire and provided written informed consent. The exclusion criteria were patients who did not meet the inclusion criteria. The study followed the ethical guidelines of the Helsinki Declaration.

Quality of Life Assessment Instrument (IHAE-QoL)

The participants’ quality of life was assessed using the International Health-Related Quality of Life Instrument for Adults with Hereditary Angioedema (IHAE-QoL v.1.1). The questionnaire consists of 44 items categorized into nine domains, addressing general health, physical, social, emotional, aesthetic, and treatment-related factors.

Responses follow a Likert scale ranging from 1 to 6 or from 1 to 5, depending on the domain evaluated. The total score is calculated by summing the domain scores, with higher values indicating a better quality of life and lower values reflecting a worse quality of life.

Statistical Analysis

Data analysis was performed using the SPSS software (version 29.0). Descriptive statistics were presented as means and standard deviation (±SD) or medians [interquartile ranges – IQR], depending on the normality of the data assessed by the Shapiro-Wilk test. Categorical variables were expressed as absolute and relative frequencies (%).

Group comparisons were conducted using the Chi-square test (χ²) for categorical variables, the Student’s t-test for continuous variables with a normal distribution, and the Mann-Whitney test for continuous variables with a non-normal distribution.

To assess differences over time, Generalized Estimating Equations (GEE) were used with Bonferroni correction for multiple comparisons. Asymmetric data were analyzed using GEE models with a gamma distribution and a log-link function. The statistical significance level adopted was 5% (p < 0.05).

RESULTS

Sociodemographic and Clinical Characteristics

Of the 69 participants initially recruited, 40 were excluded for not meeting the inclusion criteria (4 were under 18 years old, 8 did not complete the instruments, 3 declined consents, and 25 were lost to follow-up). Thus, 29 participants (22 females and 7 males) were included in the final analysis.

The mean age (±SD) of the participants was 42.34 ± 17.64 years (males: 41.14 ± 15.53 years; females: 42.73 ± 18.58 years; t, p = 0.840). The majority of participants (72.4%) were aged 30 years or older. Regarding body composition, the average height of males (1.73 ± 0.02 m) was significantly greater than that of females (1.61 ± 0.06 m, t, p ≤ 0.001), however, the Body Mass Index (BMI) did not exhibit statistically significant difference between sexes (males: 25.63 ± 3.08 kg/m²; females: 28.33 ± 6.05 kg/m²; t, p = 0.271).

Regarding marital status, 55.2% of participants were married or living with a partner, while 37.9% were single. The majority (72.4%) were of Caucasian descent, and 58.6% had completed high school.

Clinical Characteristics and Use of Therapies

The median age [IQR] of symptom onset was 15 years (3 – 52 years), with no significant differences between sexes (Mann-Whitney, p = 0.784). It was found that 85.7% of males exhibited symptoms before the age of 18, while 40.9% of females reported manifestations before the age of 10. This sex difference was statistically significant (χ², p = 0.036).

Most participants were diagnosed with HAE due to C1-INH deficiency (58.6%), while 34.5% had normal C1-INH levels. Regarding the severity of attacks, 51.7% reported mild attacks, 69.0% moderate attacks, and 86.2% severe attacks.

The most commonly utilized medications were Danazol® (55.2%), Firazyr® (34.5%), Berinert® (13.8%), and Transamin® (13.8%).

Impact of HAE on Quality of Life (IHAE-QoL v.1.1)

Initial Assessment (Baseline)

At the initial administration of the questionnaire, significant differences between sexes were identified:

42.9% of males reported that the disease frequently limited their ability to concentrate at work or in studies (χ², p = 0.013).

90.9% of females expressed constant concern regarding treatment availability.

42.9% of males reported a considerable impact on their social life (χ², p = 0.015).

57.1% of males reported that HAE limited their academic and professional productivity (χ², p = 0.028).

81.8% of females reported extreme fear of suffocation attacks, compared to 42.9% of males.

Six-Month Follow-Up

After six months, the following changes were observed:

42.9% of males reported a greater impact of HAE on performing planned activities.

40.9% of females reported that the disease did not significantly disrupt their daily activities.

28.6% of males mentioned a significant impact on free time and leisure activities (χ², p = 0.041).

Additionally, a trend towards statistical significance was observed for:

Difficulties accessing treatments for other diseases (χ², p = 0.056).

Concerns over treatment availability (χ², p = 0.067).

One-Year Follow-Up

After one year, the results showed that 57.1% of males continued to report a moderate impact of the disease on their social life, while 54.5% of females did not perceive the same effect (χ², p = 0.006).

All results obtained from the baseline, 6-month, and 12-month questionnaire responses are shown in Figure 1.

Figure 1
HAE-QoL v1.1 Domain Score by sex per time interval. This figure shows the progression of scores across nine quality of life domains from the HAE-QoL v1.1 instrument over three time intervals: baseline, 6-month follow-up, and 1-year follow-up. Each panel compares male (blue) and female (red) participants. Higher scores indicate greater perceived quality of life.

IHAE-QoL v.1.1 Scores Analysis

In the aesthetic domain, males exhibited a higher median [IQR] (5 [2 – 5]) compared to females (1 [1 – 2], Mann-Whitney, p = 0.028).

In the emotional and physical function domains, males had lower average scores (9.71 ± 3.90 and 22.14 ± 7.58, respectively) compared to females (12.18 ± 2.59 and 28.05 ± 7.40, t, p = 0.063 and p = 0.079, respectively).

GEE analysis results showed significant differences in the “Treatment” domain of the IHAE-QoL v1.1, with females reporting lower quality of life compared to males (p = 0.013, Bonferroni post hoc p ≤ 0.05). The analyses included aggregated and specific comparisons between the time intervals assessed (baseline, 6 months, and 1 year).

DISCUSSION

The quality of life (QoL) of individuals with hereditary angioedema (HAE) extends beyond the relief of physical symptoms through the use of pharmacological treatment. The disease´s strong unpredictability significantly impacts emotional, social, psychological, and functional dimensions, potentially resulting in anxiety, depression, and social isolation (Chong-Neto 2023, Vanya et al. 2023).

This study examined the QoL of Brazilian individuals with HAE using the IHAE-QoL v.1.1, identifying significant differences between sexes. Our results showed that males reported a greater impact of the disease on their professional and social life, while females expressed greater concern about treatment and fear of severe attacks. These findings have been supported by previous research.

The predominance of females in the sample (75.9%) is consistent with previous studies, suggesting that although HAE is an autosomal dominant condition, women experience more frequent and severe attacks, possibly due to the influence of female hormones on the regulation of the kinin system (Nunes et al. 2021). Estrogen modulates the activation of Factor XII and kallikrein, leading to increased production of bradykinin, a key mediator in the development of edema (Gompel et al. 2020, Hsu et al. 2022).

Our study shows that females, experiencing more severe attacks, develop greater concern about the availability of treatment and the unpredictability of these attacks. In contrast, males reported a greater social impact and academic/professional performance issues, possibly due to the stigma of the disease and the debilitating attacks that interfere with productivity. These findings are consistent with previous studies, which report a delay in diagnosis for men, leading to later impacts in adulthood. This discrepancy may be attributed to the tendency of women to seek medical assistance and adopt preventive measures for managing HAE (Hsu et al. 2022, Camaño et al. 2023).

The impact of HAE on patients` social lives was also evident: 57.1% of males reported moderate impairment in socialization, while 54.5% of females did not perceive this effect. Liu et al. (2019) highlighted that the unpredictability of edematous attacks can lead to significant social disengagement, especially when visible bodily areas, such as the face, are involved (Raasch et al. 2023).

Our findings suggest that adaptation to HAE may differ between sexes, being influenced by psychological, social, and cultural factors. Males may experience a later impact due to delayed diagnosis, while females suffer more acutely but develop greater adaptive strategies (Jain et al. 2021, Hews-Girard & Goodyear 2021, Liu et al. 2019, Sinnathamby et al. 2023, Karabiber et al. 2022).

In the IHAE-QoL 1.1, higher scores indicate better QoL. The results showed that for males, domain 7 (general health) had higher QoL scores, while domain 1 (overall health condition) had lower scores, indicating worse QoL. For females, domain 9 (treatment) had lower scores, indicating worse QoL, while domain 5 (physical function) had higher scores, indicating better QoL. Studies on QoL in individuals with rare genetic diseases are essential to understand the challenges faced by these individuals and to develop clinically effective management strategies. These findings provide valuable insights to the medical and scientific community about how HAE can disproportionately affect the QoL and well-being of men and women (Prior et al. 2012, 2016, Caballero & Prior 2017).

The limitations of this study include the small sample size, typical in research on rare genetic diseases, the lack of previous studies using this quality of life instrument, and the disproportionate gender ratio, which may pose a methodological constraint in the comparative analysis between males and females regarding quality of life and clinical manifestations of HAE. However, we employed an internationally validated instrument and a robust statistical approach, which strengthens the reliability of the results (Nunes et al. 2021, Mendivil et al. 2021).

This study reinforces the need for individualized approaches in HAE management, considering the differential impact between men and women. The implementation of psychological support initiatives, disease education, and treatment optimization can significantly contribute to improving the QoL of patients. Furthermore, the availability of novel prophylactic therapies has the potential to enhance the treatment of HAE, reducing the frequency and severity of attacks and consequently improving the physical and emotional aspects of the disease (Beard et al. 2022, Perego et al. 2021, Anderson et al. 2021).

CONCLUSIONS

The study findings highlight the significant impact of HAE on quality of life, with notable differences between sexes. While males reported a greater social and professional impact, females expressed greater concern regarding treatment and fear of severe attacks. These findings emphasize the need for personalized strategies for disease management and multidisciplinary support to improve the QoL of patients with HAE. Future studies with larger, multicenter samples are recommended to further investigate these findings.

Acknowledgements

This research was funded by the .Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil, Finance Code 001). Further acknowledgments to all members of the Research Group. We express our gratitude to the participants for their time and patience throughout this study.

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Publication Dates

• Publication in this collection
  27 Oct 2025
• Date of issue
  2025

History

• Received
  21 Feb 2025
• Accepted
  19 May 2025