Determinants of quality of life in Hereditary Haemorrhagic Telangiectasia: the relative roles of bleeding, anaemia and visceral involvement

Determinants of quality of life in Hereditary Haemorrhagic Telangiectasia: the relative roles of bleeding, anaemia and visceral involvement | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Determinants of quality of life in Hereditary Haemorrhagic Telangiectasia: the relative roles of bleeding, anaemia and visceral involvement Pernille Darre Haahr, Jens Kjeldsen, Simon Tholander, Mikael Kjær Poulsen, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9114234/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background and aims Hereditary haemorrhagic telangiectasia (HHT) is a multisystem vascular disorder characterised by recurrent bleeding and visceral arteriovenous malformations (AVMs). Although anaemia and reduced quality of life (QoL) are common, the relative contribution of disease manifestations to patient-perceived health status remains unclear. This study aimed to assess the prevalence of iron deficiency (ID) and anaemia and to evaluate the impact of disease manifestations on QoL and health utility in patients with HHT. Methods In this cross-sectional cohort study, all known patients with HHT from two Danish regions were invited to participate. Participants underwent clinical assessment, laboratory testing and completion of the Epistaxis Severity Score (ESS), the Short Form-36 (SF-36) and the EQ-5D-5L questionnaires. Visceral AVM data were obtained from routine clinical screening. Multivariable linear regression analyses were performed to identify factors independently associated with QoL and health utility. Results A total of 152 patients were included. The prevalence of ID and anaemia was 20.3% and 19.1%, respectively. Most patients had no or mild epistaxis; however, higher ESS scores were independently associated with lower haemoglobin levels and increased odds of anaemia. In multivariable analyses, increasing ESS was significantly associated with lower SF-36 vitality and general health scores and reduced EQ-5D-5L index values. Iron deficiency was independently associated with lower health utility, whereas visceral AVMs were not independently linked to QoL outcomes. Conclusion In this population-based HHT cohort, epistaxis severity was more strongly associated with impaired QoL and health utility than visceral organ involvement. These findings highlight the importance of systematic assessment and management of bleeding and iron deficiency in HHT. Hereditary haemorrhagic telangiectasia epistaxis iron deficiency anaemia quality of life EQ-5D-5L SF-36 arteriovenous malformations Figures Figure 1 Highlights • The prevalence of iron deficiency (20.3%) and anaemia (19.1%) was lower than previously reported in referral-based HHT cohorts. • Increasing epistaxis severity was independently associated with lower haemoglobin levels and reduced quality of life across multiple domains. • Iron deficiency, but not anaemia per se, was independently associated with lower health utility (EQ-5D-5L index). • Visceral arteriovenous malformations were not independently associated with impaired quality of life after adjustment for bleeding severity and other factors. Background Hereditary Haemorrhagic Telangiectasia (HHT) is a rare, multisystem vascular disorder characterised by the development of mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs). The condition is caused by pathogenic variants in the genes involved in the transforming growth factor beta (TGF-β) signalling pathway, leading to abnormal vascular remodelling and fragile blood vessels prone to bleeding( 1 – 5 ). HHT follows an autosomal dominant inheritance pattern and has an estimated prevalence of 1–2 per 10,000 individuals( 6 , 7 ). The diagnosis of HHT is established according to the Curaçao criteria, which encompasses recurrent and spontaneous epistaxis, mucocutaneous telangiectasias at characteristic sites, visceral arteriovenous malformations (most commonly affecting the lungs, liver or brain), and a first-degree family history of HHT. The presence of three or more criteria confirms a definite diagnosis( 8 ). These criteria reflect the heterogeneous and multisystem nature of the disease. As reflected by the Curaçao criteria, HHT exhibits a wide clinical spectrum. Disease severity varies widely, ranging from asymptomatic individuals to patients experiencing severe or life-threatening complications related to bleeding or visceral AVMs, including high output heart failure, pulmonary hypertension, cerebral abscess, and stroke( 9 ). Epistaxis is the most common manifestation, with approximately 50% of patients experiencing their first episode before the age of 12 years and up to 95% affected during their lifetime( 10 , 11 ). In addition to nasal bleeding, gastrointestinal involvement is a significant source of chronic blood loss, occurring in approximately 13–30% of patients with HHT, with increased bleeding after the 5th decade of life( 12 , 13 ). Recurrent bleeding from these sites may lead to iron depletion and anaemia. Previous studies have reported anaemia prevalences ranging from 50% to 75% in patients with HHT, although estimates vary depending on study population and recruitment setting( 14 – 16 ). Visceral AVMs further contribute to disease burden. Pulmonary AVM (PAVM) occur in approximately 45–75% of patients with HHT, with prevalences varying by genetic subtype( 9 , 17 ). PAVMs result in right-to-left shunting, increasing the risk of paradoxical embolization and cerebral complications such as stroke and brain abscess. The shunt may also impair gas exchange, leading to hypoxaemia and exertional dyspnoea( 9 , 17 ). Hepatic vascular malformations (HVMs) are reported in 44–78% of patients with HHT( 18 – 20 ). In most cases they remain asymptomatic; however extensive intrahepatic shunting may alter hepatic haemodynamics and increase venous return to the right atrium, potentially leading to high output heart failure. In some patients, vascular shunting may also contribute to pulmonary hypertension or portal hypertension with ascites and variceal formation( 7 , 21 ). Cerebral vascular malformations (CVMs) are less common and are identified in approximately 10% of patients with HHT, again with prevalences varying with HHT genetic subtype( 22 ). Although the annual risk of rupture is low, CVMs may result in intracranial haemorrhage. In addition, even unruptured lesions may cause symptoms such as headache, seizures, migraines or focal neurological deficits( 9 , 23 ). Taken together, the multisystem involvement of HHT, encompassing recurrent bleeding and visceral AVMs with potential cardiopulmonary and neurological consequences, represents a substantial and multifaceted disease burden. Even when not immediately life-threatening, chronic manifestations such as epistaxis, iron deficiency (ID), anaemia, dyspnoea or fatigue may interfere with daily functioning and social participation Health related quality of life is known to be reduced in patients with HHT compared with the general population( 24 , 25 ). This impairment is likely multifactorial, and previous studies have suggested associations with recurrent epistaxis, gastrointestinal bleeding, ID, fatigue and cardiopulmonary complications( 24 – 26 ). However, the relative contribution of individual disease manifestations, particularly bleeding severity, anaemia and visceral organ involvement to patient-reported quality of life and health utility remains incompletely understood. Thus, the aim of this study was to assess the prevalence of ID and anaemia and to evaluate the independent associations of bleeding severity, iron status, and visceral arteriovenous malformations with patient-perceived quality of life and health utility in HHT. Methods This cross-sectional cohort study invited all known patients with HHT residing in the Regions of Zealand and Southern Denmark who were followed at the Danish HHT Centre. All eligible patients were identified through the Danish HHT database, which includes individuals with a clinical diagnosis established according to the Curaçao criteria and/or genetic confirmation, and asymptomatic relatives identified through clinical assessment and genetic testing. Eligible patients were contacted by personal E-mail (E-Boks), followed by a telephone contact within two weeks. Patients who provided written informed consent were enrolled in the study and underwent the study procedures. The study was approved by the Danish Ethics Committee (ID S-20210037). Clinical evaluation All participants underwent a structured clinical assessment, including a standardised interview addressing comorbidities, current and previous medication use. Bleeding assessment Epistaxis severity was assessed using the validated Epistaxis Severity Score (ESS) questionnaire, which captures bleeding frequency, duration and intensity ( 27 , 28 ). Based on the total ESS score, epistaxis severity was categorised into four groups: no epistaxis (0–1), mild ( 1 – 4 ), moderate ( 4 – 7 ) and severe ( 7 – 10 ). Blood samples were obtained from all participants and analysed for haemoglobin, ferritin, and other relevant biochemical parameters. ID was defined as a ferritin concentration < 30 µg/L. Anaemia was defined according to sex-specific World Health Organization criteria as haemoglobin < 12 g/dL in women and < 13 g/dL in men. Visceral manifestations Information on PAVM and CVM was obtained from the Danish HHT database. These data were derived from routine clinical screening performed at the Danish HHT Centre over the past decade, with the majority of cerebral magnetic resonance imaging (MRI) examinations conducted within the past five years. Screening for PAVMs at the Danish HHT Centre includes contrast-enhanced echocardiography, followed by computed tomography in cases with a positive screening result. Treatable PAVMs were managed according to international guidelines( 29 , 30 ). HVMs were assessed prospectively on the day of study inclusion using Doppler ultrasound and graded according to the established Buscarini criteria( 20 ). CVMs were evaluated using MRI as part of routine clinical screening. Quality of life assessment Health-related quality of life was assessed using the Short Form-36 Health Survey (SF-36) and the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L), both validated in Danish( 31 ). Questionnaires were completed electronically and recorded directly in the research database. The SF-36 comprises 36 items covering eight health domains. Domains scores were transformed to scores ranging from 0 to 100, with higher scores indicating better quality of life( 32 ). The EQ-5D-5L evaluated health-related quality of life across five dimensions: mobility, self-care, activities of daily living, pain/discomfort and anxiety/depression each rated on five levels of severity( 33 , 34 ). Responses were converted into a single index value using a Danish value set, with scores typically ranging from values below 0 (health states considered worse than death) to 1.0 (full health), where higher values indicate better perceived health status. Statistics Baseline characteristics were summarised using descriptive statistics. Continuous variables are presented as means and standard deviations or medians and interquartile ranges, as appropriate. Categorical variables are presented as counts and percentages The prevalence of ID and anaemia were calculated as proportions with corresponding 95% confidence intervals (CIs). Multivariable linear regression models were fitted with haemoglobin concentrations as the dependent variable and ESS, age and sex as independent variable. Furthermore, a logistic regression model was used to evaluate the odds of anaemia in relation to ESS. Quality of life outcomes, including the eight SF-36 domain scores and the Danish EQ-5D-5L index value, were analysed as continuous variables( 35 ). Multivariable linear regression models were fitted with quality-of-life measures as dependent variables and disease manifestations (PAVM, CVM and HVM), epistaxis severity (ESS), anaemia and ID status, age, and sex as independent variables. Results are reported as regression coefficients (β) with 95% CIs. All tests were two-sided, and a p-value < 0.05 was considered statistically significant. Statistical analyses were performed using Stata/BE, version 19 (StataCorp, College Station, TX, USA). Results Study population A total of 201 patients were eligible for inclusion, of whom 152 consented to participation and were enrolled between March 2024 and July 2025 at Odense University Hospital. Reasons for non-participation included lack of time, health-related issues or personal preferences. All included participants had a confirmed diagnosis of HHT, established according to the Curaçao criteria and/or genetic confirmation supported by family history. The cohort comprised of 88 women (57.9%) and 64 men (42.1%), with a mean age of 51 ± 18.7 years (range 18–84). Among the 49 patients who declined participation, mean age was 54 ± 19 years (range 18–86), and 40.8% were women. Baseline characteristics of the study cohort are presented in Table 1 . Table 1 Baseline characteristics of the study cohort. Data are presented as mean (standard deviation) unless otherwise stated. Age, years Total cohort n = 152 51.1 (18.7) Female sex, n (%) 88 (57.9) Body mass index, kg/m 2 26.2 (5.1) Comorbidities Epilepsy, n (%) 1 (0.7) Asthma or COPD, n (%) 17 (11.4) Ischaemic heart disease, n (%) 5 (3.4) Atrial fibrillation, n (%) 10 (6.6) Diabetes (any type), n (%) 9 (6.0) Cancer (any type), n (%) 2 (1.3) Hypertension, n (%) 26 (17.4) Hypercholesterolaemia, n (%) 19 (12.8) Psychiatric disorder, n (%) 8 (5.3) Medication Bevacizumab, n (%) 9 (5.9) Intravenous iron supplement, n (%) 8 (5.2) Oral iron supplement, n (%) 40 (26.3) Prevalence of ID and anaemia Laboratory analyses showed a mean haemoglobin concentration of 13.8 g/dL (SD 1.8) and a median ferritin concentration of 53 µg/L (IQR 32–92.5) (Table 2 ). ID, defined as ferritin < 30 µ/L, was identified in 31 patients, corresponding to a prevalence of 20.3% (95% CI 14.7–27.6%). Anaemia was defined according to World Health Organisation criteria as a haemoglobin concentration < 12 g/dL in women and < 13 g/dL in men. In total, 29 patients (19 women and 10 men) met the criteria for anaemia, corresponding to a prevalence of 19.1% (95% CI 13.6–26.1%). The median age of the patients with anaemia was 68 (IQR 52–76, range 23–82). At the time of inclusion, 40 (26.3%) were receiving oral iron supplementation, while eight patients (5.3%) were receiving intravenous iron supplementation. Table 2 Laboratory findings. Values are presented as mean (SD) unless otherwise stated. Laboratory findings Total cohort n = 152 Haemoglobin, g/dL 13.8 (1.8) (range 6.9–17.6) Ferritin, µ/L, median (IQR) 53 (32–92.5) Transferrin (g/L) 26.4 (12.9) Reticulocytes ×10⁹/L 79.3 (28.3) CRP, mg/L 3 ( 6 ) Bleeding patterns ESS Of the 152 patients included in the study, 150 (98.7%) completed the ESS questionnaire. The mean ESS was 2.9 (SD 1.87, IQR 1.44–4.09). Based on established cut-offs, 28 patients (18.7%) had ESS values between 0 and 1, corresponding to no epistaxis; 82 patients (54.7%) had scores between 1 and 4, corresponding to mild epistaxis; 35 patients (23.3%) had scores between 4 and 7, corresponding to moderate epistaxis; and five patients (3.3%) had ESS values > 7, corresponding to severe epistaxis (Fig. 1 ). In multivariable linear regression analysis, higher ESS score was independently associated with lower haemoglobin concentration (β − 0.23 g/dL per point, 95% CI − 0.36 to − 0.09; p = 0.001), after adjustment for sex and age. Male sex was associated with higher haemoglobin concentrations, whereas increasing age was associated with lower haemoglobin levels. This was further explored in a multivariable logistic regression analysis, in which higher ESS score was independently associated with increased odds of anaemia (OR 1.34 per point, 95% CI 1.05–1.71; p = 0.017), after adjustment for sex and age. Patients with anaemia Among the 29 patients with anaemia, 27 completed the ESS questionnaire. Of these, five (18.5%) reported moderate epistaxis and three (11.1%) reported severe epistaxis, leaving 19 (70.3%) with no or mild epistaxis. Fourteen patients with anaemia (48.3%), also met the criteria for ID. The median ferritin concentration in this subgroup was 33 µ/L (IQR 11–48). Eighteen anaemic patients (62.1%) were receiving iron supplementation at the time of inclusion, including four treated with intravenous iron and 14 receiving oral supplementation. Visceral manifestations Screening results for PAVMs were available for 149 of the 152 patients. PAVMs were identified in 71 (47.7%). Of these, 22 had only micro-PAVM, not eligible for treatment, 48 had undergone at least one embolization procedure, and one patient had previously undergone lobectomy. All 152 patients were evaluated for HVM. HVMs were identified in 103 patients (67.6%). According to the Buscarini grading system, 33 patients (21.7%) had grade 0+, 13 (8.6%) grade 1, 16 (10.5%) grade 2, 17 (11.2%) grade 3 and 24 (15.8%) grade 4. Forty-nine patients (32.2%) had no signs of HVM. CVM screening results were available for 117 patients. CVMs were identified in eight (6.8%), of whom three had undergone surgical treatment. The remaining 109 patients had no evidence of CVM. Quality of life and disease manifestations A total of 150 patients completed the SF-36 and EQ-5D-5L questionnaires. Health-related quality of life assessed from the SF-36 is summarised in Table 3 . Median scores were high for physical functioning, role limitations due to physical health, social functioning, and role limitations due to emotional problems. In contrast, lower median scores were observed for general health and vitality, whereas mental health scores were relatively preserved. Table 3 SF-36 domains scores. Values represent median (IQR) scores on a 0–100 scale, with higher scores indicating better health-related quality of life. SF-36 domain Score, median (IQR) Physical functioning 90 (75–100) Role limitations due to physical health 93.8 (68.8–100) Bodily Pain 90 (67.5–100) General Health 65 (50–80) Vitality 62.5 (43.8–75.0) Social Functioning 100 (62.5–100) Role limitations due to emotional health 100 (66.7–100) Mental Health 80 (65–90) EQ-5D-5L index values were calculated using the Danish value set, with values anchored at 1 (full health) and 0 (death). The median EQ-5D-5L index value was 0.95 (IQR 0.87–1.00), indicating generally good overall health in the cohort. However, EQ-5D-5L index values were left-skewed, with a subset of patients reporting substantially impaired health states. Overall, 37.5% of patients reported full health (EQ-5D-5L health state 11111), while 62.5% reported at least one health problem in one or more EQ-5D dimensions. To identify factors associated with quality of life and health utility, multivariable linear regression analyses were performed using complete-case data (n = 114), reflecting missing values in questionnaire responses and/or covariates, these included HVM grade, PAVM, CVM, ESS, ID, anaemia, age, and sex (Supplementary Table 1). Higher ESS score was consistently associated with poorer outcomes across models. Each 1-point increase in ESS was associated with reduced SF-36 vitality (β − 3.02, 95% CI − 5.38 to − 0.66; p = 0.013), lower SF-36 general health scores (β − 2.55, 95% CI − 4.75 to − 0.35; p = 0.023), and lower EQ-5D-5L index values (β − 0.022, 95% CI − 0.043 to − 0.001; p = 0.041), ID was independently associated with lower EQ-5D-5L index values (β − 0.106, 95% CI − 0.207 to − 0.005; p = 0.040), whereas anaemia was not significantly associated with quality-of-life outcomes after adjustment. Visceral AVMs were not independently associated with EQ-5D-5L index values or SF-36 vitality and general health scores after adjustment. Discussion In this population-based cohort of patients with HHT, the prevalence of anaemia (19.1%) and ID (20.3%) was substantially lower than previously reported estimates of 50–75%( 14 , 15 ). This difference may reflect variation in study populations, as earlier reports were largely derived from referral centres enriched with symptomatic patients. In contrast, the present cohort included both symptomatic and asymptomatic individuals, thereby potentially providing a broader and more representative estimate of disease burden. Most patients experienced no or mild epistaxis, with ESS values ≤ 4 observed in approximately 73% of the cohort. Nevertheless, increasing epistaxis severity was independently associated with lower haemoglobin concentrations and a higher likelihood of anaemia in multivariable analyses, underscoring the clinical relevance of epistaxis as a contributor to chronic blood loss in HHT. This finding aligns with previous reports demonstrating the high prevalence and clinical impact of epistaxis in this patient population( 10 , 11 ). However, within the subgroup of patients with anaemia, only 27.5% of patients reported moderate-to-severe epistaxis, indicating that anaemia was not restricted to individuals with more severe nasal bleeding. In addition, 48.3% of anaemic patients met the criteria for ID, suggesting depleted iron stores consistent with chronic blood loss. Taken together, these findings highlight the complexity of bleeding patterns in HHT and suggests that anaemia may be due to multiple contributors, including epistaxis and other sources of blood loss, rather than epistaxis alone. The SF-36 and EQ-5D-5L results indicated that the cohort generally reported high levels of health-related quality of life and health utility. Nevertheless, the SF-36 domains vitality and general health were scored lower than the remaining domains and were therefore explored further. In multivariable analyses, increasing epistaxis severity was independently associated with lower vitality and general health scores. Each incremental increase in ESS corresponded to measurable reductions in these domains, highlighting the cumulative burden of recurrent epistaxis. In contrast, visceral AVMs were not independently associated with quality-of-life outcomes. This may reflect that many visceral AVMs remain asymptomatic or are effectively managed through systematic screening and intervention, whereas epistaxis represents a frequent and directly perceived symptom that interferes with daily functioning. Similarly, although overall EQ-5D-5L index values were high, fewer than half of patients reported full health. This indicates the presence of mild but prevalent health impairments within the cohort and suggests a ceiling effect, with a clinically relevant subgroup experiencing reduced health utility. Consistent with the SF-36 findings, higher ESS scores were independently associated with lower EQ-5D-5L index values, whereas organ-specific manifestations were not. These observations align with previous studies identifying epistaxis as the most burdensome manifestation of HHT and a key determinant of reduced quality of life( 24 , 25 , 36 ). Collectively, the results suggest that patient-reported health status is more strongly influenced by symptomatic disease, particularly bleeding severity, than by the presence of visceral AVMs. These findings have important clinical implications: systematic assessment and proactive management of epistaxis and ID may represent key strategies for improving patient-reported outcomes. While screening and treatment of visceral AVMs remain essential to prevent serious complications, addressing chronic bleeding symptoms may have a more immediate and tangible impact on daily functioning and overall well-being Several limitations should be acknowledged. The cross-sectional design precludes causal inference and limits assessment of temporal relationships between bleeding, anaemia, and quality of life. This is particularly relevant in HHT, as disease manifestations may fluctuate over time, a single time-point assessment may not fully capture this variability. Furthermore, data on visceral AVM were partly based on historical screening examinations and may therefore not fully reflect current disease status. Despite these limitations, the study has important strengths. The cohort was drawn from national HHT reference centre and included both symptomatic and asymptomatic individuals, thereby representing a broad clinical spectrum and enhancing generalisability. The use of validated instruments to assess epistaxis severity, health-related quality of life, and health utility strengthens the reliability and comparability of the findings. Finally, the integration of clinical assessments, biochemical parameters, and patient-reported outcomes provides a comprehensive evaluation of disease burden in HHT. Conclusion In this population-based HHT cohort, iron deficiency and anaemia were less prevalent than previously reported. Increasing epistaxis severity was consistently associated with lower haemoglobin levels and poorer quality of life, whereas visceral AVMs were not independently linked to reduced patient-reported outcomes. These findings suggest that bleeding severity may be a central determinant of perceived health status in HHT. Abbreviations AVM Arteriovenous Malformation CVM Cerebral Vascular Malformation CI Confidence Interval EQ-5D-5L EuroQol 5-Dimension 5-Level questionnaire ESS Epistaxis Severity Score TGF-β Transforming Growth Factor Beta HVM Hepatic Vascular Malformation HHT Hereditary Haemorrhagic Telangiectasia ID Iron deficiency IQR Interquartile Range OR Odds Ratio PAVM Pulmonary Arteriovenous Malformation SD Standard Deviation SF-36 36-Item Short Form Health Survey Declarations Ethics approval and consent to participate: The study was approved by the Danish Ethics Committee (ID S-20210037). All participants provided written informed consent prior to participation. Consent for publication : Not applicable. Competing interests: The authors declare that they have no competing interests. Funding: This research received no external funding. Authors' contributions: PDH contributed to conceptualization, formal analysis, investigation, and drafted the original manuscript. PDH also contributed to manuscript review and editing. MKP, JK, ADF, and AK contributed to conceptualization, manuscript review and editing, and supervision. ST contributed to investigation and manuscript review and editing. All authors read and approved the final manuscript. Acknowledgements: The authors want to thank the patients who participated in this study and the staff at the department of gastrointestinal disease for their valuable assistance. Furthermore, a great thanks to excellent statistical advice from our statistician Helene Høgsbro Thygesen. Availability of data and materials: The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. References McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8(4):345–51. Johnson DW, Berg JN, Gallione CJ, McAllister KA, Warner JP, Helmbold EA, et al. A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12. Genome Res. 1995;5(1):21–8. Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363(9412):852–9. Darre Haahr P, Hao Q, Brusgaard K, Larsen MJ, Lange B, Fialla AD et al. Multiple lesion-specific somatic mutations and bi-allelic loss of ACVRL1 in a single patient with hereditary haemorrhagic telangiectasia. Eur J Hum Genet. 2025. Whitehead KJ, Toydemir D, Wooderchak-Donahue W, Oakley GM, McRae B, Putnam A et al. Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT). Int J Mol Sci. 2024;25(14). Kjeldsen AD, Vase P, Green A. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med. 1999;245(1):31–9. Garcia-Tsao G. Liver involvement in hereditary hemorrhagic telangiectasia (HHT). J Hepatol. 2007;46(3):499–507. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1):66–7. Hermann R, Shovlin CL, Kasthuri RS, Serra M, Eker OF, Bailly S, et al. Hereditary haemorrhagic telangiectasia. Nat Rev Dis Primers. 2025;11(1):1. Plauchu H, de Chadarevian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989;32(3):291–7. Porteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992;29(8):527–30. Kjeldsen AD, Kjeldsen J. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol. 2000;95(2):415–8. Vase P, Grove O. Gastrointestinal lesions in hereditary hemorrhagic telangiectasia. Gastroenterology. 1986;91(5):1079–83. Shovlin CL, Awan I, Cahilog Z, Abdulla FN, Guttmacher AE. Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction. Int J Cardiol. 2016;215:179–85. Kasthuri RS, Montifar M, Nelson J, Kim H, Lawton MT, Faughnan ME et al. Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia. Am J Hematol. 2017. Karlsson T, Cherif H. Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler's Disease, Uppsala University Hospital. Ups J Med Sci. 2018;123(3):153–7. Sharathkumar AA, Shapiro A. Hereditary haemorrhagic telangiectasia. Haemophilia. 2008;14(6):1269–80. Ianora AA, Memeo M, Sabba C, Cirulli A, Rotondo A, Angelelli G. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement. Radiology. 2004;230(1):250–9. Memeo M, Stabile Ianora AA, Scardapane A, Buonamico P, Sabba C, Angelelli G. Hepatic involvement in hereditary hemorrhagic telangiectasia: CT findings. Abdom Imaging. 2004;29(2):211–20. Buscarini E, Danesino C, Olivieri C, Lupinacci G, De Grazia F, Reduzzi L, et al. Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia -- results of extensive screening. Ultraschall Med. 2004;25(5):348–55. Haahr PD, Kjeldsen J, Poulsen MK, Kjeldsen AD, Fialla AD. Manifestations of hepatic vascular malformations in hereditary haemorrhagic telangiectasia. Ugeskr Laeger. 2023;185(13). Brinjikji W, Iyer VN, Wood CP, Lanzino G. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg. 2017;127(2):302–10. Kim H, Nelson J, Krings T, terBrugge KG, McCulloch CE, Lawton MT, et al. Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke. 2015;46(5):1362–4. Zarrabeitia R, Farinas-Alvarez C, Santibanez M, Senaris B, Fontalba A, Botella LM, et al. Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT). Health Qual Life Outcomes. 2017;15(1):19. Geisthoff UW, Heckmann K, D'Amelio R, Grunewald S, Knobber D, Falkai P, et al. Health-related quality of life in hereditary hemorrhagic telangiectasia. Otolaryngol Head Neck Surg. 2007;136(5):726–33. discussion 34 – 5. Viteri-Noel A, Patier JL, Bara-Ledesma N, Gonzalez-Garcia A, Fabregate M, Fernandez-San Jose P et al. Genotype-Phenotype Relationship in Hereditary Hemorrhagic Telangiectasia: Quality of Life and Cardiovascular Risk Evaluation. J Clin Med. 2025;14(13). Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope. 2010;120(4):838–43. Hayama M, Maeda Y, Shikina T, Tatehara S, Inokuchi G, Hoag JB, et al. Validation of epistaxis severity score for hereditary hemorrhagic telangiectasia in Japan. Auris Nasus Larynx. 2022;49(3):415–20. Faughnan ME, Mager JJ, Hetts SW, Palda VA, Lang-Robertson K, Buscarini E, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020;173(12):989–1001. Faughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73–87. Bjorner JB, Thunedborg K, Kristensen TS, Modvig J, Bech P. The Danish SF-36 Health Survey: translation and preliminary validity studies. J Clin Epidemiol. 1998;51(11):991–9. Lennox PA, Hitchings AE, Lund VJ, Howard DJ. The SF-36 health status questionnaire in assessing patients with epistaxis secondary to hereditary hemorrhagic telangiectasia. Am J Rhinol. 2005;19(1):71–4. Zhou T, Guan H, Wang L, Zhang Y, Rui M, Ma A. Health-Related Quality of Life in Patients With Different Diseases Measured With the EQ-5D-5L: A Systematic Review. Front Public Health. 2021;9:675523. van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, et al. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 2012;15(5):708–15. Jensen CE, Sorensen SS, Gudex C, Jensen MB, Pedersen KM, Ehlers LH. The Danish EQ-5D-5L Value Set: A Hybrid Model Using cTTO and DCE Data. Appl Health Econ Health Policy. 2021;19(4):579–91. Geirdal AO, Dheyauldeen S, Bachmann-Harildstad G, Heimdal K. Living with hereditary haemorrhagic telangiectasia: coping and psychological distress - a cross-sectional study. Disabil Rehabil. 2013;35(3):206–13. Supplementary Files Supplementarydetails.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 10 Apr, 2026 Reviewers invited by journal 08 Apr, 2026 Editor invited by journal 29 Mar, 2026 Editor assigned by journal 17 Mar, 2026 First submitted to journal 16 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9114234","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":619460282,"identity":"76368815-1f34-46a2-ae7b-446c139814dc","order_by":0,"name":"Pernille Darre Haahr","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0009-2562-127X","institution":"Odense University Hospital: Odense Universitetshospital","correspondingAuthor":true,"prefix":"","firstName":"Pernille","middleName":"Darre","lastName":"Haahr","suffix":""},{"id":619460283,"identity":"5f562d35-7b32-48b2-adcf-71b66fcf9433","order_by":1,"name":"Jens Kjeldsen","email":"","orcid":"","institution":"Odense University Hospital: Odense Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Jens","middleName":"","lastName":"Kjeldsen","suffix":""},{"id":619460284,"identity":"a6ee354c-45a6-4f3a-bdd1-3ea75cc1680f","order_by":2,"name":"Simon Tholander","email":"","orcid":"","institution":"Odense University Hospital: Odense Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Simon","middleName":"","lastName":"Tholander","suffix":""},{"id":619460285,"identity":"18bec757-1c4d-401c-adc7-d9917728189d","order_by":3,"name":"Mikael Kjær Poulsen","email":"","orcid":"","institution":"Odense University Hospital: Odense Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Mikael","middleName":"Kjær","lastName":"Poulsen","suffix":""},{"id":619460286,"identity":"42ee30dd-2997-42dc-982c-d6698af33958","order_by":4,"name":"Annette Dam Fialla","email":"","orcid":"","institution":"Odense University Hospital: Odense Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Annette","middleName":"Dam","lastName":"Fialla","suffix":""},{"id":619460287,"identity":"d80a1831-af87-43a9-86af-db45cd3c5946","order_by":5,"name":"Anette Drøhse Kjeldsen","email":"","orcid":"","institution":"Odense University Hospital: Odense Universitetshospital","correspondingAuthor":false,"prefix":"","firstName":"Anette","middleName":"Drøhse","lastName":"Kjeldsen","suffix":""}],"badges":[],"createdAt":"2026-03-13 11:32:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9114234/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9114234/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107243282,"identity":"99fc2e6b-5568-4df7-b1ce-4e4e5bf9c2a1","added_by":"auto","created_at":"2026-04-19 07:50:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":77184,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of ESS scores.\u003c/strong\u003e Scores are shown in 1-point intervals (0–10). Bars represent the percentage of patients. The dashed line marks the transition from no–mild to moderate–severe epistaxis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9114234/v1/a69c935c8f2c3402a609861d.png"},{"id":107484502,"identity":"f5612fc6-043e-4873-a558-2098cf7c33f4","added_by":"auto","created_at":"2026-04-22 02:32:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":396708,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9114234/v1/d05b0def-0acc-4410-a5d1-f284bbe548a8.pdf"},{"id":107243283,"identity":"aa8912e8-c04a-47d3-84a9-7dea687d7f93","added_by":"auto","created_at":"2026-04-19 07:50:25","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":18842,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarydetails.docx","url":"https://assets-eu.researchsquare.com/files/rs-9114234/v1/225ee03fc190c537919e4399.docx"}],"financialInterests":"","formattedTitle":"Determinants of quality of life in Hereditary Haemorrhagic Telangiectasia: the relative roles of bleeding, anaemia and visceral involvement","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; The prevalence of iron deficiency (20.3%) and anaemia (19.1%) was lower than previously reported in referral-based HHT cohorts.\u003c/p\u003e\u003cp\u003e\u0026bull; Increasing epistaxis severity was independently associated with lower haemoglobin levels and reduced quality of life across multiple domains.\u003c/p\u003e\u003cp\u003e\u0026bull; Iron deficiency, but not anaemia per se, was independently associated with lower health utility (EQ-5D-5L index).\u003c/p\u003e\u003cp\u003e\u0026bull; Visceral arteriovenous malformations were not independently associated with impaired quality of life after adjustment for bleeding severity and other factors.\u003c/p\u003e"},{"header":"Background","content":"\u003cp\u003eHereditary Haemorrhagic Telangiectasia (HHT) is a rare, multisystem vascular disorder characterised by the development of mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs). The condition is caused by pathogenic variants in the genes involved in the transforming growth factor beta (TGF-β) signalling pathway, leading to abnormal vascular remodelling and fragile blood vessels prone to bleeding(\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e). HHT follows an autosomal dominant inheritance pattern and has an estimated prevalence of 1–2 per 10,000 individuals(\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe diagnosis of HHT is established according to the Curaçao criteria, which encompasses recurrent and spontaneous epistaxis, mucocutaneous telangiectasias at characteristic sites, visceral arteriovenous malformations (most commonly affecting the lungs, liver or brain), and a first-degree family history of HHT. The presence of three or more criteria confirms a definite diagnosis(\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e). These criteria reflect the heterogeneous and multisystem nature of the disease.\u003c/p\u003e \u003cp\u003eAs reflected by the Curaçao criteria, HHT exhibits a wide clinical spectrum. Disease severity varies widely, ranging from asymptomatic individuals to patients experiencing severe or life-threatening complications related to bleeding or visceral AVMs, including high output heart failure, pulmonary hypertension, cerebral abscess, and stroke(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEpistaxis is the most common manifestation, with approximately 50% of patients experiencing their first episode before the age of 12 years and up to 95% affected during their lifetime(\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e). In addition to nasal bleeding, gastrointestinal involvement is a significant source of chronic blood loss, occurring in approximately 13–30% of patients with HHT, with increased bleeding after the 5th decade of life(\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e). Recurrent bleeding from these sites may lead to iron depletion and anaemia. Previous studies have reported anaemia prevalences ranging from 50% to 75% in patients with HHT, although estimates vary depending on study population and recruitment setting(\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eVisceral AVMs further contribute to disease burden. Pulmonary AVM (PAVM) occur in approximately 45–75% of patients with HHT, with prevalences varying by genetic subtype(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e). PAVMs result in right-to-left shunting, increasing the risk of paradoxical embolization and cerebral complications such as stroke and brain abscess. The shunt may also impair gas exchange, leading to hypoxaemia and exertional dyspnoea(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHepatic vascular malformations (HVMs) are reported in 44–78% of patients with HHT(\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e). In most cases they remain asymptomatic; however extensive intrahepatic shunting may alter hepatic haemodynamics and increase venous return to the right atrium, potentially leading to high output heart failure. In some patients, vascular shunting may also contribute to pulmonary hypertension or portal hypertension with ascites and variceal formation(\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCerebral vascular malformations (CVMs) are less common and are identified in approximately 10% of patients with HHT, again with prevalences varying with HHT genetic subtype(\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e). Although the annual risk of rupture is low, CVMs may result in intracranial haemorrhage. In addition, even unruptured lesions may cause symptoms such as headache, seizures, migraines or focal neurological deficits(\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTaken together, the multisystem involvement of HHT, encompassing recurrent bleeding and visceral AVMs with potential cardiopulmonary and neurological consequences, represents a substantial and multifaceted disease burden. Even when not immediately life-threatening, chronic manifestations such as epistaxis, iron deficiency (ID), anaemia, dyspnoea or fatigue may interfere with daily functioning and social participation\u003c/p\u003e \u003cp\u003eHealth related quality of life is known to be reduced in patients with HHT compared with the general population(\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e). This impairment is likely multifactorial, and previous studies have suggested associations with recurrent epistaxis, gastrointestinal bleeding, ID, fatigue and cardiopulmonary complications(\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e). However, the relative contribution of individual disease manifestations, particularly bleeding severity, anaemia and visceral organ involvement to patient-reported quality of life and health utility remains incompletely understood.\u003c/p\u003e \u003cp\u003eThus, the aim of this study was to assess the prevalence of ID and anaemia and to evaluate the independent associations of bleeding severity, iron status, and visceral arteriovenous malformations with patient-perceived quality of life and health utility in HHT.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003eThis cross-sectional cohort study invited all known patients with HHT residing in the Regions of Zealand and Southern Denmark who were followed at the Danish HHT Centre. All eligible patients were identified through the Danish HHT database, which includes individuals with a clinical diagnosis established according to the Curaçao criteria and/or genetic confirmation, and asymptomatic relatives identified through clinical assessment and genetic testing.\u003c/p\u003e\u003cp\u003eEligible patients were contacted by personal E-mail (E-Boks), followed by a telephone contact within two weeks. Patients who provided written informed consent were enrolled in the study and underwent the study procedures.\u003c/p\u003e\u003cp\u003e The study was approved by the Danish Ethics Committee (ID S-20210037).\u003c/p\u003e\u003cp\u003eClinical evaluation\u003c/p\u003e\u003cp\u003eAll participants underwent a structured clinical assessment, including a standardised interview addressing comorbidities, current and previous medication use.\u003c/p\u003e\u003ch3\u003eBleeding assessment\u003c/h3\u003e\u003cp\u003eEpistaxis severity was assessed using the validated Epistaxis Severity Score (ESS) questionnaire, which captures bleeding frequency, duration and intensity (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e). Based on the total ESS score, epistaxis severity was categorised into four groups: no epistaxis (0–1), mild (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e), moderate (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e) and severe (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eBlood samples were obtained from all participants and analysed for haemoglobin, ferritin, and other relevant biochemical parameters. ID was defined as a ferritin concentration \u0026lt; 30 µg/L. Anaemia was defined according to sex-specific World Health Organization criteria as haemoglobin \u0026lt; 12 g/dL in women and \u0026lt; 13 g/dL in men.\u003c/p\u003e\u003ch2\u003eVisceral manifestations\u003c/h2\u003e\u003cp\u003eInformation on PAVM and CVM was obtained from the Danish HHT database. These data were derived from routine clinical screening performed at the Danish HHT Centre over the past decade, with the majority of cerebral magnetic resonance imaging (MRI) examinations conducted within the past five years.\u003c/p\u003e\u003cp\u003eScreening for PAVMs at the Danish HHT Centre includes contrast-enhanced echocardiography, followed by computed tomography in cases with a positive screening result. Treatable PAVMs were managed according to international guidelines(\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e). HVMs were assessed prospectively on the day of study inclusion using Doppler ultrasound and graded according to the established Buscarini criteria(\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e). CVMs were evaluated using MRI as part of routine clinical screening.\u003c/p\u003e\u003cp\u003eQuality of life assessment\u003c/p\u003e\u003cp\u003eHealth-related quality of life was assessed using the Short Form-36 Health Survey (SF-36) and the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L), both validated in Danish(\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e). Questionnaires were completed electronically and recorded directly in the research database.\u003c/p\u003e\u003cp\u003eThe SF-36 comprises 36 items covering eight health domains. Domains scores were transformed to scores ranging from 0 to 100, with higher scores indicating better quality of life(\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe EQ-5D-5L evaluated health-related quality of life across five dimensions: mobility, self-care, activities of daily living, pain/discomfort and anxiety/depression each rated on five levels of severity(\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e). Responses were converted into a single index value using a Danish value set, with scores typically ranging from values below 0 (health states considered worse than death) to 1.0 (full health), where higher values indicate better perceived health status.\u003c/p\u003e\u003cp\u003eStatistics\u003c/p\u003e\u003cp\u003eBaseline characteristics were summarised using descriptive statistics. Continuous variables are presented as means and standard deviations or medians and interquartile ranges, as appropriate. Categorical variables are presented as counts and percentages\u003c/p\u003e\u003cp\u003eThe prevalence of ID and anaemia were calculated as proportions with corresponding 95% confidence intervals (CIs). Multivariable linear regression models were fitted with haemoglobin concentrations as the dependent variable and ESS, age and sex as independent variable. Furthermore, a logistic regression model was used to evaluate the odds of anaemia in relation to ESS.\u003c/p\u003e\u003cp\u003eQuality of life outcomes, including the eight SF-36 domain scores and the Danish EQ-5D-5L index value, were analysed as continuous variables(\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e). Multivariable linear regression models were fitted with quality-of-life measures as dependent variables and disease manifestations (PAVM, CVM and HVM), epistaxis severity (ESS), anaemia and ID status, age, and sex as independent variables. Results are reported as regression coefficients (β) with 95% CIs.\u003c/p\u003e\u003cp\u003eAll tests were two-sided, and a p-value \u0026lt; 0.05 was considered statistically significant. Statistical analyses were performed using Stata/BE, version 19 (StataCorp, College Station, TX, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eStudy population\u003c/p\u003e \u003cp\u003eA total of 201 patients were eligible for inclusion, of whom 152 consented to participation and were enrolled between March 2024 and July 2025 at Odense University Hospital. Reasons for non-participation included lack of time, health-related issues or personal preferences.\u003c/p\u003e \u003cp\u003eAll included participants had a confirmed diagnosis of HHT, established according to the Cura\u0026ccedil;ao criteria and/or genetic confirmation supported by family history.\u003c/p\u003e \u003cp\u003eThe cohort comprised of 88 women (57.9%) and 64 men (42.1%), with a mean age of 51\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7 years (range 18\u0026ndash;84). Among the 49 patients who declined participation, mean age was 54\u0026thinsp;\u0026plusmn;\u0026thinsp;19 years (range 18\u0026ndash;86), and 40.8% were women. Baseline characteristics of the study cohort are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study cohort. Data are presented as mean (standard deviation) unless otherwise stated.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal cohort\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;152\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51.1 (18.7)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale sex, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e88 (57.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26.2 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eComorbidities\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpilepsy, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (0.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthma or COPD, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17 (11.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIschaemic heart disease, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrial fibrillation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10 (6.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes (any type), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (6.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCancer (any type), n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26 (17.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypercholesterolaemia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19 (12.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePsychiatric disorder, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (5.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eMedication\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eBevacizumab, n (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (5.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eIntravenous iron supplement, n (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8 (5.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOral iron supplement, n (%)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40 (26.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePrevalence of ID and anaemia\u003c/p\u003e \u003cp\u003eLaboratory analyses showed a mean haemoglobin concentration of 13.8 g/dL (SD 1.8) and a median ferritin concentration of 53 \u0026micro;g/L (IQR 32\u0026ndash;92.5) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eID, defined as ferritin\u0026thinsp;\u0026lt;\u0026thinsp;30 \u0026micro;/L, was identified in 31 patients, corresponding to a prevalence of 20.3% (95% CI 14.7\u0026ndash;27.6%).\u003c/p\u003e \u003cp\u003eAnaemia was defined according to World Health Organisation criteria as a haemoglobin concentration\u0026thinsp;\u0026lt;\u0026thinsp;12 g/dL in women and \u0026lt;\u0026thinsp;13 g/dL in men. In total, 29 patients (19 women and 10 men) met the criteria for anaemia, corresponding to a prevalence of 19.1% (95% CI 13.6\u0026ndash;26.1%). The median age of the patients with anaemia was 68 (IQR 52\u0026ndash;76, range 23\u0026ndash;82).\u003c/p\u003e \u003cp\u003eAt the time of inclusion, 40 (26.3%) were receiving oral iron supplementation, while eight patients (5.3%) were receiving intravenous iron supplementation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLaboratory findings. Values are presented as mean (SD) unless otherwise stated.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eLaboratory findings\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal cohort\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;152\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaemoglobin, g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.8 (1.8) (range 6.9\u0026ndash;17.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin, \u0026micro;/L, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (32\u0026ndash;92.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransferrin (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.4 (12.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReticulocytes \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79.3 (28.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP, mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBleeding patterns\u003c/p\u003e\n\u003ch3\u003eESS\u003c/h3\u003e\n\u003cp\u003eOf the 152 patients included in the study, 150 (98.7%) completed the ESS questionnaire. The mean ESS was 2.9 (SD 1.87, IQR 1.44\u0026ndash;4.09).\u003c/p\u003e \u003cp\u003eBased on established cut-offs, 28 patients (18.7%) had ESS values between 0 and 1, corresponding to no epistaxis; 82 patients (54.7%) had scores between 1 and 4, corresponding to mild epistaxis; 35 patients (23.3%) had scores between 4 and 7, corresponding to moderate epistaxis; and five patients (3.3%) had ESS values\u0026thinsp;\u0026gt;\u0026thinsp;7, corresponding to severe epistaxis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn multivariable linear regression analysis, higher ESS score was independently associated with lower haemoglobin concentration (β\u0026thinsp;\u0026minus;\u0026thinsp;0.23 g/dL per point, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;0.36 to \u0026minus;\u0026thinsp;0.09; p\u0026thinsp;=\u0026thinsp;0.001), after adjustment for sex and age. Male sex was associated with higher haemoglobin concentrations, whereas increasing age was associated with lower haemoglobin levels. This was further explored in a multivariable logistic regression analysis, in which higher ESS score was independently associated with increased odds of anaemia (OR 1.34 per point, 95% CI 1.05\u0026ndash;1.71; p\u0026thinsp;=\u0026thinsp;0.017), after adjustment for sex and age.\u003c/p\u003e\n\u003ch3\u003ePatients with anaemia\u003c/h3\u003e\n\u003cp\u003eAmong the 29 patients with anaemia, 27 completed the ESS questionnaire. Of these, five (18.5%) reported moderate epistaxis and three (11.1%) reported severe epistaxis, leaving 19 (70.3%) with no or mild epistaxis.\u003c/p\u003e \u003cp\u003eFourteen patients with anaemia (48.3%), also met the criteria for ID. The median ferritin concentration in this subgroup was 33 \u0026micro;/L (IQR 11\u0026ndash;48).\u003c/p\u003e \u003cp\u003eEighteen anaemic patients (62.1%) were receiving iron supplementation at the time of inclusion, including four treated with intravenous iron and 14 receiving oral supplementation.\u003c/p\u003e \u003cp\u003eVisceral manifestations\u003c/p\u003e \u003cp\u003eScreening results for PAVMs were available for 149 of the 152 patients. PAVMs were identified in 71 (47.7%). Of these, 22 had only micro-PAVM, not eligible for treatment, 48 had undergone at least one embolization procedure, and one patient had previously undergone lobectomy.\u003c/p\u003e \u003cp\u003eAll 152 patients were evaluated for HVM. HVMs were identified in 103 patients (67.6%). According to the Buscarini grading system, 33 patients (21.7%) had grade 0+, 13 (8.6%) grade 1, 16 (10.5%) grade 2, 17 (11.2%) grade 3 and 24 (15.8%) grade 4. Forty-nine patients (32.2%) had no signs of HVM.\u003c/p\u003e \u003cp\u003eCVM screening results were available for 117 patients. CVMs were identified in eight (6.8%), of whom three had undergone surgical treatment. The remaining 109 patients had no evidence of CVM.\u003c/p\u003e \u003cp\u003eQuality of life and disease manifestations\u003c/p\u003e \u003cp\u003eA total of 150 patients completed the SF-36 and EQ-5D-5L questionnaires. Health-related quality of life assessed from the SF-36 is summarised in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Median scores were high for physical functioning, role limitations due to physical health, social functioning, and role limitations due to emotional problems. In contrast, lower median scores were observed for general health and vitality, whereas mental health scores were relatively preserved.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSF-36 domains scores. Values represent median (IQR) scores on a 0\u0026ndash;100 scale, with higher scores indicating better health-related quality of life.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSF-36 domain\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eScore, median (IQR)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical functioning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 (75\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRole limitations due to physical health\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93.8 (68.8\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBodily Pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90 (67.5\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeneral Health\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (50\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.5 (43.8\u0026ndash;75.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSocial Functioning\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100 (62.5\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRole limitations due to emotional health\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100 (66.7\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMental Health\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (65\u0026ndash;90)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eEQ-5D-5L index values were calculated using the Danish value set, with values anchored at 1 (full health) and 0 (death). The median EQ-5D-5L index value was 0.95 (IQR 0.87\u0026ndash;1.00), indicating generally good overall health in the cohort. However, EQ-5D-5L index values were left-skewed, with a subset of patients reporting substantially impaired health states. Overall, 37.5% of patients reported full health (EQ-5D-5L health state 11111), while 62.5% reported at least one health problem in one or more EQ-5D dimensions.\u003c/p\u003e \u003cp\u003eTo identify factors associated with quality of life and health utility, multivariable linear regression analyses were performed using complete-case data (n\u0026thinsp;=\u0026thinsp;114), reflecting missing values in questionnaire responses and/or covariates, these included HVM grade, PAVM, CVM, ESS, ID, anaemia, age, and sex (Supplementary Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eHigher ESS score was consistently associated with poorer outcomes across models. Each 1-point increase in ESS was associated with reduced SF-36 vitality (β\u0026thinsp;\u0026minus;\u0026thinsp;3.02, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;5.38 to \u0026minus;\u0026thinsp;0.66; p\u0026thinsp;=\u0026thinsp;0.013), lower SF-36 general health scores (β\u0026thinsp;\u0026minus;\u0026thinsp;2.55, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;4.75 to \u0026minus;\u0026thinsp;0.35; p\u0026thinsp;=\u0026thinsp;0.023), and lower EQ-5D-5L index values (β\u0026thinsp;\u0026minus;\u0026thinsp;0.022, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;0.043 to \u0026minus;\u0026thinsp;0.001; p\u0026thinsp;=\u0026thinsp;0.041),\u003c/p\u003e \u003cp\u003eID was independently associated with lower EQ-5D-5L index values (β\u0026thinsp;\u0026minus;\u0026thinsp;0.106, 95% CI\u0026thinsp;\u0026minus;\u0026thinsp;0.207 to \u0026minus;\u0026thinsp;0.005; p\u0026thinsp;=\u0026thinsp;0.040), whereas anaemia was not significantly associated with quality-of-life outcomes after adjustment. Visceral AVMs were not independently associated with EQ-5D-5L index values or SF-36 vitality and general health scores after adjustment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this population-based cohort of patients with HHT, the prevalence of anaemia (19.1%) and ID (20.3%) was substantially lower than previously reported estimates of 50\u0026ndash;75%(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). This difference may reflect variation in study populations, as earlier reports were largely derived from referral centres enriched with symptomatic patients. In contrast, the present cohort included both symptomatic and asymptomatic individuals, thereby potentially providing a broader and more representative estimate of disease burden.\u003c/p\u003e \u003cp\u003eMost patients experienced no or mild epistaxis, with ESS values\u0026thinsp;\u0026le;\u0026thinsp;4 observed in approximately 73% of the cohort. Nevertheless, increasing epistaxis severity was independently associated with lower haemoglobin concentrations and a higher likelihood of anaemia in multivariable analyses, underscoring the clinical relevance of epistaxis as a contributor to chronic blood loss in HHT. This finding aligns with previous reports demonstrating the high prevalence and clinical impact of epistaxis in this patient population(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, within the subgroup of patients with anaemia, only 27.5% of patients reported moderate-to-severe epistaxis, indicating that anaemia was not restricted to individuals with more severe nasal bleeding. In addition, 48.3% of anaemic patients met the criteria for ID, suggesting depleted iron stores consistent with chronic blood loss.\u003c/p\u003e \u003cp\u003eTaken together, these findings highlight the complexity of bleeding patterns in HHT and suggests that anaemia may be due to multiple contributors, including epistaxis and other sources of blood loss, rather than epistaxis alone.\u003c/p\u003e \u003cp\u003eThe SF-36 and EQ-5D-5L results indicated that the cohort generally reported high levels of health-related quality of life and health utility. Nevertheless, the SF-36 domains vitality and general health were scored lower than the remaining domains and were therefore explored further.\u003c/p\u003e \u003cp\u003eIn multivariable analyses, increasing epistaxis severity was independently associated with lower vitality and general health scores. Each incremental increase in ESS corresponded to measurable reductions in these domains, highlighting the cumulative burden of recurrent epistaxis. In contrast, visceral AVMs were not independently associated with quality-of-life outcomes. This may reflect that many visceral AVMs remain asymptomatic or are effectively managed through systematic screening and intervention, whereas epistaxis represents a frequent and directly perceived symptom that interferes with daily functioning.\u003c/p\u003e \u003cp\u003eSimilarly, although overall EQ-5D-5L index values were high, fewer than half of patients reported full health. This indicates the presence of mild but prevalent health impairments within the cohort and suggests a ceiling effect, with a clinically relevant subgroup experiencing reduced health utility. Consistent with the SF-36 findings, higher ESS scores were independently associated with lower EQ-5D-5L index values, whereas organ-specific manifestations were not. These observations align with previous studies identifying epistaxis as the most burdensome manifestation of HHT and a key determinant of reduced quality of life(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCollectively, the results suggest that patient-reported health status is more strongly influenced by symptomatic disease, particularly bleeding severity, than by the presence of visceral AVMs. These findings have important clinical implications: systematic assessment and proactive management of epistaxis and ID may represent key strategies for improving patient-reported outcomes. While screening and treatment of visceral AVMs remain essential to prevent serious complications, addressing chronic bleeding symptoms may have a more immediate and tangible impact on daily functioning and overall well-being\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. The cross-sectional design precludes causal inference and limits assessment of temporal relationships between bleeding, anaemia, and quality of life. This is particularly relevant in HHT, as disease manifestations may fluctuate over time, a single time-point assessment may not fully capture this variability. Furthermore, data on visceral AVM were partly based on historical screening examinations and may therefore not fully reflect current disease status.\u003c/p\u003e \u003cp\u003eDespite these limitations, the study has important strengths. The cohort was drawn from national HHT reference centre and included both symptomatic and asymptomatic individuals, thereby representing a broad clinical spectrum and enhancing generalisability. The use of validated instruments to assess epistaxis severity, health-related quality of life, and health utility strengthens the reliability and comparability of the findings. Finally, the integration of clinical assessments, biochemical parameters, and patient-reported outcomes provides a comprehensive evaluation of disease burden in HHT.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this population-based HHT cohort, iron deficiency and anaemia were less prevalent than previously reported. Increasing epistaxis severity was consistently associated with lower haemoglobin levels and poorer quality of life, whereas visceral AVMs were not independently linked to reduced patient-reported outcomes. These findings suggest that bleeding severity may be a central determinant of perceived health status in HHT.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eAVM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eArteriovenous Malformation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eCVM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eCerebral Vascular Malformation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eConfidence Interval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eEQ-5D-5L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eEuroQol 5-Dimension 5-Level questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eESS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eEpistaxis Severity Score\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eTGF-\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eTransforming Growth Factor Beta\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eHVM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eHepatic Vascular Malformation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eHHT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eHereditary Haemorrhagic Telangiectasia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eIron deficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eIQR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eInterquartile Range\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eOR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eOdds Ratio\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003ePAVM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003ePulmonary Arteriovenous Malformation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eSD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eStandard Deviation\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 205px;\"\u003e\n \u003cp\u003eSF-36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003e36-Item Short Form Health Survey\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e \u003cp\u003eThe study was approved by the Danish Ethics Committee (ID S-20210037). All participants provided written informed consent prior to participation.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003e \u003cb\u003eConsent for publication\u003c/b\u003e:\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003ch2\u003eCompeting interests:\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis research received no external funding.\u003c/p\u003e\u003ch2\u003eAuthors' contributions:\u003c/h2\u003e \u003cp\u003ePDH contributed to conceptualization, formal analysis, investigation, and drafted the original manuscript. PDH also contributed to manuscript review and editing. MKP, JK, ADF, and AK contributed to conceptualization, manuscript review and editing, and supervision. ST contributed to investigation and manuscript review and editing. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThe authors want to thank the patients who participated in this study and the staff at the department of gastrointestinal disease for their valuable assistance.\u003c/p\u003e \u003cp\u003eFurthermore, a great thanks to excellent statistical advice from our statistician Helene H\u0026oslash;gsbro Thygesen.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e \u003cp\u003eThe datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMcAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8(4):345\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJohnson DW, Berg JN, Gallione CJ, McAllister KA, Warner JP, Helmbold EA, et al. A second locus for hereditary hemorrhagic telangiectasia maps to chromosome 12. Genome Res. 1995;5(1):21\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363(9412):852\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDarre Haahr P, Hao Q, Brusgaard K, Larsen MJ, Lange B, Fialla AD et al. Multiple lesion-specific somatic mutations and bi-allelic loss of ACVRL1 in a single patient with hereditary haemorrhagic telangiectasia. Eur J Hum Genet. 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWhitehead KJ, Toydemir D, Wooderchak-Donahue W, Oakley GM, McRae B, Putnam A et al. Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT). Int J Mol Sci. 2024;25(14).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKjeldsen AD, Vase P, Green A. Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med. 1999;245(1):31\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia-Tsao G. Liver involvement in hereditary hemorrhagic telangiectasia (HHT). J Hepatol. 2007;46(3):499\u0026ndash;507.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1):66\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHermann R, Shovlin CL, Kasthuri RS, Serra M, Eker OF, Bailly S, et al. Hereditary haemorrhagic telangiectasia. Nat Rev Dis Primers. 2025;11(1):1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlauchu H, de Chadarevian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet. 1989;32(3):291\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePorteous ME, Burn J, Proctor SJ. Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet. 1992;29(8):527\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKjeldsen AD, Kjeldsen J. Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia. Am J Gastroenterol. 2000;95(2):415\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVase P, Grove O. Gastrointestinal lesions in hereditary hemorrhagic telangiectasia. Gastroenterology. 1986;91(5):1079\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShovlin CL, Awan I, Cahilog Z, Abdulla FN, Guttmacher AE. Reported cardiac phenotypes in hereditary hemorrhagic telangiectasia emphasize burdens from arrhythmias, anemia and its treatments, but suggest reduced rates of myocardial infarction. Int J Cardiol. 2016;215:179\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKasthuri RS, Montifar M, Nelson J, Kim H, Lawton MT, Faughnan ME et al. Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia. Am J Hematol. 2017.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarlsson T, Cherif H. Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler's Disease, Uppsala University Hospital. Ups J Med Sci. 2018;123(3):153\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharathkumar AA, Shapiro A. Hereditary haemorrhagic telangiectasia. Haemophilia. 2008;14(6):1269\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIanora AA, Memeo M, Sabba C, Cirulli A, Rotondo A, Angelelli G. Hereditary hemorrhagic telangiectasia: multi-detector row helical CT assessment of hepatic involvement. Radiology. 2004;230(1):250\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMemeo M, Stabile Ianora AA, Scardapane A, Buonamico P, Sabba C, Angelelli G. Hepatic involvement in hereditary hemorrhagic telangiectasia: CT findings. Abdom Imaging. 2004;29(2):211\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuscarini E, Danesino C, Olivieri C, Lupinacci G, De Grazia F, Reduzzi L, et al. Doppler ultrasonographic grading of hepatic vascular malformations in hereditary hemorrhagic telangiectasia -- results of extensive screening. Ultraschall Med. 2004;25(5):348\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaahr PD, Kjeldsen J, Poulsen MK, Kjeldsen AD, Fialla AD. Manifestations of hepatic vascular malformations in hereditary haemorrhagic telangiectasia. Ugeskr Laeger. 2023;185(13).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrinjikji W, Iyer VN, Wood CP, Lanzino G. Prevalence and characteristics of brain arteriovenous malformations in hereditary hemorrhagic telangiectasia: a systematic review and meta-analysis. J Neurosurg. 2017;127(2):302\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim H, Nelson J, Krings T, terBrugge KG, McCulloch CE, Lawton MT, et al. Hemorrhage rates from brain arteriovenous malformation in patients with hereditary hemorrhagic telangiectasia. Stroke. 2015;46(5):1362\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZarrabeitia R, Farinas-Alvarez C, Santibanez M, Senaris B, Fontalba A, Botella LM, et al. Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT). Health Qual Life Outcomes. 2017;15(1):19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeisthoff UW, Heckmann K, D'Amelio R, Grunewald S, Knobber D, Falkai P, et al. Health-related quality of life in hereditary hemorrhagic telangiectasia. Otolaryngol Head Neck Surg. 2007;136(5):726\u0026ndash;33. discussion 34\u0026thinsp;\u0026ndash;\u0026thinsp;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eViteri-Noel A, Patier JL, Bara-Ledesma N, Gonzalez-Garcia A, Fabregate M, Fernandez-San Jose P et al. Genotype-Phenotype Relationship in Hereditary Hemorrhagic Telangiectasia: Quality of Life and Cardiovascular Risk Evaluation. J Clin Med. 2025;14(13).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope. 2010;120(4):838\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHayama M, Maeda Y, Shikina T, Tatehara S, Inokuchi G, Hoag JB, et al. Validation of epistaxis severity score for hereditary hemorrhagic telangiectasia in Japan. Auris Nasus Larynx. 2022;49(3):415\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFaughnan ME, Mager JJ, Hetts SW, Palda VA, Lang-Robertson K, Buscarini E, et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020;173(12):989\u0026ndash;1001.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFaughnan ME, Palda VA, Garcia-Tsao G, Geisthoff UW, McDonald J, Proctor DD, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBjorner JB, Thunedborg K, Kristensen TS, Modvig J, Bech P. The Danish SF-36 Health Survey: translation and preliminary validity studies. J Clin Epidemiol. 1998;51(11):991\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLennox PA, Hitchings AE, Lund VJ, Howard DJ. The SF-36 health status questionnaire in assessing patients with epistaxis secondary to hereditary hemorrhagic telangiectasia. Am J Rhinol. 2005;19(1):71\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou T, Guan H, Wang L, Zhang Y, Rui M, Ma A. Health-Related Quality of Life in Patients With Different Diseases Measured With the EQ-5D-5L: A Systematic Review. Front Public Health. 2021;9:675523.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, et al. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. Value Health. 2012;15(5):708\u0026ndash;15.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJensen CE, Sorensen SS, Gudex C, Jensen MB, Pedersen KM, Ehlers LH. The Danish EQ-5D-5L Value Set: A Hybrid Model Using cTTO and DCE Data. Appl Health Econ Health Policy. 2021;19(4):579\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeirdal AO, Dheyauldeen S, Bachmann-Harildstad G, Heimdal K. Living with hereditary haemorrhagic telangiectasia: coping and psychological distress - a cross-sectional study. Disabil Rehabil. 2013;35(3):206\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hereditary haemorrhagic telangiectasia, epistaxis, iron deficiency, anaemia, quality of life, EQ-5D-5L, SF-36, arteriovenous malformations","lastPublishedDoi":"10.21203/rs.3.rs-9114234/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9114234/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground and aims\u003c/p\u003e\n\u003cp\u003eHereditary haemorrhagic telangiectasia (HHT) is a multisystem vascular disorder characterised by recurrent bleeding and visceral arteriovenous malformations (AVMs). Although anaemia and reduced quality of life (QoL) are common, the relative contribution of disease manifestations to patient-perceived health status remains unclear. This study aimed to assess the prevalence of iron deficiency (ID) and anaemia and to evaluate the impact of disease manifestations on QoL and health utility in patients with HHT.\u003c/p\u003e\n\u003cp\u003eMethods\u003c/p\u003e\n\u003cp\u003eIn this cross-sectional cohort study, all known patients with HHT from two Danish regions were invited to participate. Participants underwent clinical assessment, laboratory testing and completion of the Epistaxis Severity Score (ESS), the Short Form-36 (SF-36) and the EQ-5D-5L questionnaires. Visceral AVM data were obtained from routine clinical screening. Multivariable linear regression analyses were performed to identify factors independently associated with QoL and health utility.\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003eA total of 152 patients were included. The prevalence of ID and anaemia was 20.3% and 19.1%, respectively. Most patients had no or mild epistaxis; however, higher ESS scores were independently associated with lower haemoglobin levels and increased odds of anaemia. In multivariable analyses, increasing ESS was significantly associated with lower SF-36 vitality and general health scores and reduced EQ-5D-5L index values. Iron deficiency was independently associated with lower health utility, whereas visceral AVMs were not independently linked to QoL outcomes.\u003c/p\u003e\n\u003cp\u003eConclusion\u003c/p\u003e\n\u003cp\u003eIn this population-based HHT cohort, epistaxis severity was more strongly associated with impaired QoL and health utility than visceral organ involvement. These findings highlight the importance of systematic assessment and management of bleeding and iron deficiency in HHT.\u003c/p\u003e","manuscriptTitle":"Determinants of quality of life in Hereditary Haemorrhagic Telangiectasia: the relative roles of bleeding, anaemia and visceral involvement","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 07:50:21","doi":"10.21203/rs.3.rs-9114234/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-04-10T19:19:21+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-08T08:04:29+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Orphanet Journal of Rare Diseases","date":"2026-03-29T17:06:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-17T12:43:35+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2026-03-16T11:44:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"96de1cb6-ea4c-4175-9fe8-6581efabc0b8","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-19T07:50:21+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 07:50:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9114234","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9114234","identity":"rs-9114234","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}