- Email: [email protected]
Correlations of clinical parameters with quality of life in patients with acromegaly: Taiwan Acromegaly Registry
Journal of the Formosan Medical Association (2019) 118, 1488e1493
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Original Article
Correlations of clinical parameters with quality of life in patients with acromegaly: Taiwan Acromegaly Registry Fen-Yu Tseng a, Szu-Tah Chen b, Jung-Fu Chen c, Tien-Shang Huang a, Jen-Der Lin b, Pei-Wen Wang c, Wayne Huey-Herng Sheu d, Tien-Chun Chang a,* on behalf of the Acromegaly Registry Study Group a
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Department of Internal Medicine, Linkuo Chang Gung Memorial Hospital, Taoyuan, Taiwan c Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan d Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan b
Received 7 February 2019; received in revised form 23 April 2019; accepted 8 May 2019
KEYWORDS Taiwan acromegaly registry; Quality of life; Clinical parameters
Background/Purpose: The objectives of this study were to evaluate the associations between clinical parameters and quality of life (QOL) of patients with acromegaly in Taiwan and to identify the impacts of hormone control, regimens, or co-morbidities on acromegalic patients’ daily life. Methods: From 2013 to 2015, subjects with acromegaly were recruited through five medical centers. Clinical data were recorded. The QOL of enrolled patients were assessed by using Acromegaly Quality of Life Questionnaire (AcroQoL). Results: This study enrolled 272 acromegalic subjects (117 males, 155 females). Remission, defined by normalization of IGF-1, had significant positive association with QOL scores in psychological/appearance (PSY/APP) dimension (b Z 6.760, p Z 0.023). Somatostatin analogues therapy had negative associations with total score and score in psychological (PSY) dimension (b Z 4.720, p Z 0.046 and b Z 5.388, p Z 0.035, respectively). Diabetes mellitus had negative associations with score in PSY dimension and psychological/personal relations (PSY/PER) dimensions (b Z 5.839, p Z 0.034 and b Z 7.516, p Z 0.013, respectively). Cerebral vascular accident (CVA) had significant negative associations with total score and scores in physical (PHY), PSY, and PSY/PER dimensions (b Z 26.632, p Z 0.013; b Z 28.353, p Z 0.024; b Z 25.648, p Z 0.026; and b Z 34.586, p Z 0.006, respectively). All these associations remained significant even after adjusted with sex and age.
* Corresponding author. Department of Internal Medicine, National Taiwan University Hospital No.7, Chung-Shan South Road, Taipei, 100, Taiwan. Fax: þ886 2 23916956. E-mail address: [email protected] (T.-C. Chang). https://doi.org/10.1016/j.jfma.2019.05.007 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Taiwan Acromegaly Registry: Correlations of clinical parameters with quality of life
1489
Conclusion: Our analysis suggested that not only hormone control but also therapeutic regimens and presence of co-morbidities might affect QOL of patients with acromegaly in some dimensions. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction Acromegaly is a chronic disease. Patients with acromegaly usually presented symptoms related to the pituitary tumor or the hypersecretion of growth hormone (GH).1,2 The hypersecretion of GH may increase serum levels of insulinlike growth factor 1 (IGF-1), which may affect energy homeostasis, and cause complications in metabolic, cardiovascular, or skeletal systems.1,2 Previous reports suggested increasing risks of diabetes, hypertension, neoplasm, or mortality in patients with acromegaly.3e7 Hormone control is important for long-term prognosis of acromegaly.8,9 Nadir of GH after oral glucose tolerance test (OGTT) or IGF-1 normalization had been suggested for defining remission of acromegaly.9e12 Acromegaly may significantly affect patients’ quality of life (QOL).13 Badia et al. developed Acromegaly Quality of Life Questionnaire (AcroQoL) to assess the impacts of acromegaly.13 This questionnaire contains 22 items. Among them, 8 were of physical (PHY) dimension and 14 were of psychological (PSY) dimension. Items of psychological dimension were further divided into 7 of appearance (PSY/ APP) dimension and 7 of personal relations (PSY/PER) dimension. Using a 5 point Likert scale, the AcroQoL measures either the frequency of occurrence or the degree of agreement with the items.13 The global scores of the QOL ðXÞ22 were calculated by the formula ð11022Þ 100. AcroQoL was reported to be useful for monitoring treatment response of acromegaly.13e16 The Taiwan Acromegaly Registry Study was performed in five large medical centers in Taiwan, including National Taiwan University Hospital, Linkou Chang Gung Memorial Hospital, Taichung Veterans General Hospital, Kaohsiung Chang Gung Memorial Hospital, and Chi Mei Medical Center. Through this registry, we identified the profiles of patients with acromegaly in Taiwan.17 We also reported the QOL scores of the enrolled patients. By using AcroQoL, the global QOL scores of the patients at enrollment were about 64.5 18.3.17 The QOL scores remained relatively stable during the 1 year following-up period after entry to the survey.17 With the attempt to identify predictors of QOL, we further analyzed the associations between clinical parameters and the QOL scores in individual dimension in this study.
Subjects and methods The Taiwan Acromegaly Registry was sponsored by the Endocrine Society of Taiwan, Republic of China and was approved by Independent Ethics Committee (IEC) or Institutional Review Board (IRB) in each study site. Diagnosis of
acromegaly was based on clinical presentations, elevated IGF-1 and/or GH levels, non-suppressible GH during OGTT, image studies, and/or pathology reports. Patients with diagnosis of acromegaly and were still under clinical followup after the index day (January 1, 2009) by expertise at the study sites were enrolled after signing the inform consent. Patient enrollment started in January 2013. Those who would not complete AcroQoL questionnaire were excluded from the study. All the enrolled patients were kept on follow-up for 1 year. Patients were kept on regimens as clinically indicated.17 No treatment was involved in this non-interventional, registry-based cohort study. Participation to this registry would not affect the patient/physician relationship and the physicians’ prescriptions or therapeutic managements of the patients. Clinical data were collected by reviewing medical record. QOL was assessed by using AcroQoL. Mean QOL score in each domain was calculated. The continuous variables were described by mean standard deviation (S.D.). Categorical variables were described by the numbers and percentages. Not all patients had complete laboratory data during the following-up period.17 We used the clinical data and QOL scores at enrollment (first visit) to minimize the bias from missing data. Statistical analysis was carried out using SAS software version 9.3. Associations between QOL scores and clinical data were analyzed by linear regression with a p < 0.05 considered as statistically significant.
Results Between January 2013 and April 2015, the Taiwan Acromegaly Registry enrolled 272 patients (117 males, 155 females) with acromegaly from the 5 study sites. The analyzed cohort had a mean age of 41.8 12.1 years at diagnosis and a mean age of 51.4 12.9 years at the time of the survey. All the recruited patients completed AcroQOL at enrollment. The mean total QOL score at enrollment was 64.5 18.3. The QOL score in PHY dimension, PSY dimension, PSY/APP dimension, and PSY/PER dimension was 64.6 21.6, 64.4 19.8, 54.8 23.2, and 74.0 21.5, respectively (Table 1). Defined by GH < 2.5 mg/L, the GH normalization rate was 66.8% (173 of 259 with data available). Defined by nadir GH after OGTT <2 ug/L, the remission rate at enrollment was 59.5% (25 of 42 with data available). Defined by IGF-1 normalization, the remission rate was 35.4% (94 of 265 with data available) (Table 1). Comorbidities and regimens were summarized as Table 1. Linear regression analysis revealed that somatostatin analogs (SSA) regimens (octreotide long-acting release (LAR) or lanreotide) and presence of cerebral vascular accident (CVA) had significant negative associations with total
1490 Table 1
F.-Y. Tseng et al. Characteristics of study subjects. N (%)
Male Age of diagnosis (years) Age of enrollment (years) Random GH (mg/L) (N Z 259) Random GH normalization Nadir GH after OGTT (mg/L) (N Z 42) Nadir GH after OGTT < 2 mg/L IGF-1 (ng/mL) (N Z 265) IGF-1 normalization QOL score: Total QOL score: PHY QOL score: PSY QOL score: PSY/APP QOL score: PSY/PER Prior pituitary tumor surgery Prior radiotherapy Dopamine agonists Somatostatin analogs Thyroxine Glucocorticoid Sexual hormone Diabetes mellitus Hypertension Dyslipidemia Cardiovascular disease CVA Osteoarthritis Cancer
Mean S.D.
117 (43.0%) 41.8 12.1 51.4 12.9 3.4 10.2 173/259 (66.8%) 9.5 37.1 25/42 (59.5%) 319.2 187.6 94/265 (35.4%) 64.5 64.6 64.4 54.8 74.0
18.3 21.6 19.8 23.2 21.5
258 (94.8%) 76 (27.9%) 82 (30%) 174 (64%) 43 (15.8%) 14 (5.1%) 26 (9.6%) 76 (27.9%) 102 (37.5%) 36 (13.2%) 6 (2.2%) 3 (1.1%) 7 (2.6%) 16 (5.9%)
GH: growth hormone; OGTT: oral glucose tolerance test; IGF-1: insulin-like growth factor 1; QOL: quality of life; PHY: physical dimension; PSY: psychological dimension; PSY/APP: psychological/appearance dimension; PSY/PER: psychological/personal relations dimension; Dopamine agonists: bromocriptine or cabergoline; Somatostatin analogs: octreotide long acting release or lanreotide; CVA: cerebral vascular accident.
QOL score (b Z 4.720, p Z 0.046; and b Z 26.632, p Z 0.013, respectively). Negative association existed between CVA and PHY score (b Z 28.353, p Z 0.024). PSY score was negatively associated with SSA regimens, diabetes mellitus (DM), and CVA (b Z 5.388, p Z 0.035; b Z 5.839, p Z 0.034, and b Z 25.648, p Z 0.026, respectively). PSY/APP score was negatively associated with random GH levels, serum IGF-1 levels, and sexual hormone supplement (b Z 0.542, p Z 0.046; b Z 0.016, p Z 0.034; and b Z 9.819, p Z 0.041, respectively) and positively associated with IGF-1 normalization (b Z 6.760, p Z 0.023). QOL score in PSY/PER dimension had negative associations with DM and CVA (b Z 7.516, p Z 0.013; and b Z 34.586, p Z 0.006, respectively) (Table 2). After adjustment with sex and age, the associations between total score and use of SSA, total score and CVA, PHY score and CVA, PSY score and SSA regimens, PSY score and DM, PSY score and CVA, PSY/APP score and normalization of IGF-1, PSY/PER score and DM, and PSY/PER score and CVA remained statistically significant (Table 3). The associations between SSA regimens and total QOL scores or PSY scores were further evaluated by adjustment with sex, age, and remission (yes vs no) in linear regression analysis. Defined by random GH normalization, the
associations between SSA regimens and total QOL scores or PSY scores became statistically insignificant (b Z 4.635, p Z 0.060, and b Z 5.017, p Z 0.060, respectively). Defined by nadir GH after OGTT <2 mg/L, the associations between SSA regimens and total QOL scores or PSY scores remained statistically significant (b Z 15.578, p Z 0.018, and b Z 16.763, p Z 0.036, respectively). Defined by IGF1 normalization, the associations between SSA regimens and total QOL scores or PSY scores became statistically insignificant (b Z 4.509, p Z 0.065, and b Z 5.087, p Z 0.054, respectively).
Discussion As our previous report, the Taiwan Acromegaly Registry revealed a comparable time lag from the onset of symptoms to diagnosis of acromegaly, and comparable rates of macroadenomas, co-morbidities, or remissions with other countries.10e12,17 The QOL scores of our patients were also comparable to other studies.14e17 In our study, the lower scores in PSY/APP domain were considered as related to the high frequencies of facial changes and growth of hands and feet.17 Analysis in this study revealed associations of QOL in
Taiwan Acromegaly Registry: Correlations of clinical parameters with quality of life
1491
Table 2 Linear regression analysis with quality of life scores as dependent variables and clinical data as independent variables (total N Z 272). QOL score b(p) Sex (female vs male) Age at diagnosis (years) Age at enrollment (years) Random GH (mg/L) Nadir GH after OGTT (mg/L) IGF-1 (ng/mL) Random GH normalization (yes vs no) Nadir GH after OGTT <2 mg/L (yes vs no) IGF-1 normalization (yes vs no) Prior surgery (yes vs no) Prior radiotherapy (yes vs no) Dopamine agonists (yes vs no) Somatostain analogs (yes vs no) Thyroxine (yes vs no) Glucocorticoid (yes vs no) Sexual hormone (yes vs no) Diabetes mellitus (yes vs no) Hypertension (yes vs no) Dyslipidmeia (yes vs no) Cardiovascular disease (yes vs no) CVA (yes vs no) Osteoarthritis (yes vs no) Cancer (yes vs no)
Total
PHY
PSY
PSY/APP
PSY/PER
1.377 (0.543) 0.075 (0.482) 0.013 (0.879) 0.239 (0.260) 0.124 (0.089) 0.006 (0.266) 2.911 (0.224)
2.679 (0.314) 0.040 (0.753) 0.056 (0.589) 0.051 (0.839) 0.118 (0.135) 0.001 (0.843) 0.623 (0.826)
3.695 (0.130) 0.141 (0.218) 0.011 (0.908) 0.405 (0.079) 0.127 (0.128) 0.011 (0.082) 4.218 (0.105)
3.611 (0.206) 0.217 (0.113) 0.078 (0.482) 0.542 (0.046)* 0.161 (0.119) 0.016 (0.034)* 3.953 (0.198)
3.778 (0.159) 0.065 (0.600) 0.056 (0.591) 0.268 (0.288) 0.093 (0.283) 0.006 (0.356) 4.484 (0.115)
1.947 (0.741)
4.460 (0.482)
0.512 (0.939)
3.098 (0.710)
2.075 (0.764)
4.008 (0.089) 3.980 (0.228) 0.631 (0.797) 0.019 (0.993) 4.720 (0.046)* 0.847 (0.783) 2.212 (0.662) 5.668 (0.136) 4.313 (0.054) 0.794 (0.736) 3.458 (0.269) 12.168 (0.144) 26.632 (0.013)* 0.237 (0.973) 1.704 (0.705)
2.928 (0.293) 7.106 (0.067) 0.484 (0.667) 1.244 (0.659) 3.550 (0.203) 0.388 (0.915) 8.953 (0.132) 6.064 (0.175) 3.293 (0.274) 3.092 (0.264) 1.187 (0.747) 12.224 (0.212) 28.353 (0.024)* 9.842 (0.236) 3.256 (0.539)
4.624 (0.070) 2.193 (0.539) 1.269 (0.631) 0.680 (0.793) 5.388 (0.035)* 1.552 (0.640) 1.640 (0.765) 5.441 (0.185) 5.839 (0.034)* 0.520 (0.838) 4.755 (0.159) 12.136 (0.177) 25.648 (0.026)* 5.996 (0.432) 0.817 (0.867)
6.760 (0.023)* 0.296 (0.944) 2.711 (0.381) 1.553 (0.608) 5.676 (0.058) 0.853 (0.826) 0.506 (0.937) 9.819 (0.041)* 4.162 (0.198) 0.717 (0.810) 6.468 (0.102) 14.168 (0.178) 16.711 (0.217) 2.064 (0.818) 0.700 (0.902)
2.489 (0.378) 4.091 (0.297) 0.173 (0.953) 0.192 (0.946) 5.100 (0.070) 2.251 (0.538) 3.787 (0.530) 1.064 (0.814) 7.516 (0.013)* 1.757 (0.530) 3.043 (0.413) 10.104 (0.308) 34.586 (0.006)* 9.929 (0.237) 0.933 (0.862)
*: p < 0.05. QOL: quality of life; GH: growth hormone; OGTT: oral glucose tolerance test; IGF-1: insulin-like growth factor 1; Dopamine agonists: bromocriptine or cabergoline; Somatostatin analogs: octreotide long acting release or lanreotide; CVA: cerebral vascular accident; PHY: physical dimension; PSY: psychological dimension; PSY/APP: psychological/appearance dimension; PSY/PER: psychological/personal relations dimension.
different domains with clinical parameters. After adjustment with sex and age, normalization of IGF-1 had positive association with score in PSY/APP dimension. SSA regimens had negative associations with total score and PSY score.
DM had significant negative associations with PSY and PSY/PER scores. CVA had significant negative associations with total score and scores in PHY, PSY, and PSY/PER dimensions. Our analysis suggested that not only hormone
Table 3 Linear regression analysis with quality of life scores as dependent variables and clinical data as independent variables (total N Z 272), adjusted with sex and age at enrollment. QOL score b(p) Total Random GH (mg/L) IGF-1 (ng/mL) IGF-1 normalization (yes vs no) Somatostain analogs (yes vs no) Sexual hormone (yes vs no) Diabetes mellitus (yes vs no) CVA (yes vs no)
PHY
PSY
PSY/APP
PSY/PER
0.526 (0.054) 0.014 (0.063) 6.424 (0.031)* 4.831 (0.044)*
5.352 (0.038)*
26.753 (0.012)*
6.256 (0.028)* 26.038 (0.024)*
28.004 (0.026)*
8.977 (0.065)
7.528 (0.016)* 34.849 (0.006)*
*: p < 0.05. QOL: quality of life; GH: growth hormone; IGF-1: insulin-like growth factor 1; Somatostatin analogs: octreotide long acting release or lanreotide; CVA: cerebral vascular accident; PHY: physical dimension; PSY: psychological dimension; PSY/APP: psychological/appearance dimension; PSY/PER: psychological/person relation dimension.
1492 control but also use of regimens and presences of comorbidities might affect QOL of patients with acromegaly. The AcroQoL was developed as a disease-specific questionnaire by Badia et al.13 Comparing with other questionnaires, Rowles et al. concluded AcroQoL as a patient-friendly measure of disease activity.14 Webb et al. reported that male acromegalic patients had better AcroQoL scores than female patients, but age had no correlations with QOL scores.15 Vandeva et al. suggested older age as independent negative predictors of QOL in all scales.16 They also reported that female gender negatively predicted all scales except the PSY/APP dimension.16 Our analysis revealed no associations between age or sex with QOL scores. Studies evaluating correlations between hormone control and QOL of acromegalic patients had controversial results. Several studies reported that there was no correlation between biochemical control and any measure of QOL.14,15 Vandeva et al. suggested remission as an independent predictor of total score improvement.16 However, other studies reported that QOL has been reduced even in successfully treated acromegalic patients.18e20 Original disease statuses, treatment modalities, and responses to regimens varied between acromegalic patients. In order to achieve remission, some patients might have to receive repeated operation, radiotherapy, or various medications. In spite of hormonal remission, symptoms such as facial changes or osteoarthritis may persist. Even with remission, acromegalic patients’ QOL may thus be jeopardized. Kauppinen-Ma ¨kelin et al. reported that health-related QOL was related to nadir GH after OGTT in an inverted U-shaped fashion.21 The best QOL could be achieved by normalization to IGF-1 and levels of nadir GH between 0.3 and 1.0 mg/L.21 In this study, random GH had negative association with PSY/APP score. This association became insignificant after adjusted with sex and age. Random GH normalization had no correlations with QOL scores. The nadir GH after OGTT or remission defined by nadir GH < 2 mg/L was not correlated with QOL scores, but levels of IGF-1 were negatively associated with PSY/APP score. Remission defined by IGF-1 normalization was positively correlated with PSY/APP score. The positive correlations between IGF-1 normalization and PSY/APP scores remained significant after adjusted with sex and age. Compared to random GH or nadir GH after OGTT, our analysis suggested IGF-1 normalization as a better predictor of PSY/APP score. Psychological symptoms, physical symptoms, and treatments may affect acromegalic patients’ QOL.16,22 Prior radiotherapy had been reported to have negative associations with QOL.16,18,23 Several studies suggested that the use of SSA was associated with worse QOL,16,24 while others reported that use of SSA improved QOL.25,26 Analysis in this study revealed no correlation between prior radiotherapy and QOL scores, while use of SSA was negatively associated with total score and score in PSY dimensions. Use of SSA is strictly regulated by National Health Insurance in Taiwan. Reimbursement for SSA will be approved if a patient has recurrent or residual tumor after surgery and/or radiotherapy. Use of SSA usually indicates relatively not wellcontrolled disease status after surgery and/or radiotherapy. Those patients thus might have impaired QOL. Our analysis also revealed that patients under sexual hormone supplement had worse PSY/APP score. This association became insignificant after adjusted with sex and age. The
F.-Y. Tseng et al. negative associations between SSA regimens and total or PSY scores persisted with adjustment by sex, age and remission defined by nadir GH after OGTT <2 ug/L, but not remission defined by random GH normalization or IGF-1 normalization. In this study, not all patients had concurrent random GH, nadir GH, or IGF-1 data. The real impacts of remission on the associations between SSA regimens and QOL scores deserve further investigation. Patients with acromegaly may develop comorbidities impairing their QOL. Webb et al. reported that worse QOL was associated with the presence of coexisting DM.27 Acromegaly patients in this study had prevalence of DM, hypertension, or cancer comparable to other countries.2,10,12,17 Our analysis revealed that patients with DM had lower PSY score and PSY/PER score than those without DM. Patients had encountered CVA had significantly worse QOL than those without CVA. Significant impairment in QOL scores in patients with CVA could be identified in total scale, PHY scale, PSY scale, and PSY/PER subscale. The limitations of this study were: First, status at diagnosis could affect long-term outcome. In this registry, patients were enrolled several years after their first diagnosis of acromegaly. We did not include the initial data in the analysis. Second, not all patients had random GH, IGF-1, and nadir GH after OGTT data at enrollment to the study. Among 272 study subjects, the missing rates for IGF1, random GH, and nadir GH was 2.6%, 4.8%, and 84.6%, respectively. Our analysis suggested positive correlations of IGF-1 normalization with QOL score in PSY/APP dimension. The missing rate for IGF-1 was only 2.6%. Thus, the analysis might not be biased by missing IGF-1 data. Our analysis revealed no correlation between nadir GH and QOL scores. Since the missing rate of nadir GH was high, we could not infer whether there was truly no correlation between nadir GH with QOL scores. Third, regimens or co-morbidities were divided as categorical variables (yes vs no). Severity of diseases and kinds or doses of medications were not considered in the analysis. Fourth, psychological or physical symptoms could affect patients’ QOL. We did not analyze the correlations between symptoms and QOL scores. Fifth, socioeconomic status may affect QOL.28,29 We did not evaluate patients’ socioeconomic status. Sixth, study subjects were enrolled through five medical centers. The impacts of physicians and treatment modalities in different study sites were not analyzed. In conclusion, the present study evaluated the associations between clinical parameters and acromegalic patients’ QOL. Remission defined by IGF-1 normalization had positive correlation with QOL in PSY/APP dimension. SSA use, DM, and CVA had negative associations with QOL scores, either in total or in some dimensions.
Disclosure statement This study was funded by Ipsen Pharmaceutical Co., and supervised by the Endocrine Society of the R.O.C. (Taiwan).
Conflicts of interest The authors have no conflicts of interest relevant to this article.
Taiwan Acromegaly Registry: Correlations of clinical parameters with quality of life
Acknowledgments We thank all the investigators, the study nurses, the study coordinators, and the patients who contributed to this study. This study was funded by Ipsen Pharmaceutical Company. Financial support for medical editorial assistance was provided by Ipsen Pharmaceutical Company.
16.
17.
Appendix A. Supplementary data 18.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.05.007.
References 1. Melmed S. Acromegaly. N Engl J Med 2006;355:2558e73. 2. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004;25:102e52. 3. Jenkins PJ, Besser M. Acromegaly and cancer: a problem. J Clin Endocrinol Metab 2001;86:2935e41. 4. Melmed S. Acromegaly and cancer: not a problem? J Clin Endocrinol Metab 2001;86:2929e34. 5. Kauppinen-Ma ¨kelin R, Sane T, Reunanen A, Va ¨lima ¨ki MJ, Niskanen L, Markkanen H, et al. A nationwide survey of mortality in acromegaly. J Clin Endocrinol Metab 2005;90:4081e6. 6. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 1994;41:95e102. 7. Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 1998;83:2730e4. 8. Silverstein JM. Need for improved monitoring in patients with acromegaly. Endocr Connect 2015;4:R59e67. 9. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab 2004;89: 667e74. 10. Scho ¨fl C, Franz H, Grussendorf M, Honegger J, JaurschHancke C, Mayr B, et al. Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register. Eur J Endocrinol 2013;168:39e47. 11. Mestron A, Webb SM, Astorga R, Benito P, Catala M, Gaztambide S, et al. Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espan ˜ol de Acromegalia, REA). Eur J Endocrinol 2004;151:439e46. 12. Bex M, Abs R, T’Sjoen G, Mockel J, Velkeniers B, Muermans K, et al. AcroBel-the Belgian registry on acromegaly: a survey of the ’real-life’ outcome in 418 acromegalic subjects. Eur J Endocrinol 2007;157:399e409. 13. Badia X, Webb SM, Prieto L, Lara N. Acromegaly quality of life questionnaire (AcroQoL). Health Qual Life Outcomes 2004;2:13. 14. Rowles SV, Prieto L, Badia X, Shalet SM, Webb SM, Trainer PJ. Quality of life (QOL) in patients with acromegaly is severely impaired: use of a novel measure of QOL: acromegaly quality of life questionnaire. J Clin Endocrinol Metab 2005;90:3337e41. 15. Webb SM, Badia X, Surinach NL, Spanish AcroQol Study Group. Validity and clinical applicability of the acromegaly quality of
19.
20.
21.
22. 23.
24.
25.
26.
27. 28.
29.
1493
life questionnaire, AcroQoL: a 6-month prospective study. Eur J Endocrinol 2006;155:269e77. Vandeva S, Yaneva M, Natchev E, Elenkova A, Kalinov K, Zacharieva S. Disease control and treatment modalities have impact on quality of life in acromegaly evaluated by Acromegaly Quality of Life (AcroQoL) questionnaire. Endocrine 2015;49:774e82. Tseng FY, Huang TS, Lin JD, Chen ST, Wang PW, Chen JF, et al., On behalf of the Acromegaly Registry Study Group. A registry of acromegaly patients and one year following up in Taiwan. J Formos Med Assoc 2019;118:1430e7. Biermasz NR, van Thiel SW, Pereira AM, Hoftijzer HC, van Hemert AM, Smit JW, et al. Decreased quality of life in patients with acromegaly despite long-term cure of growth hormone excess. J Clin Endocrinol Metab 2004;89:5369e76. Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F. Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life. J Clin Endocrinol Metab 2005;90:2731e9. Kyriakakis N, Lynch J, Gilbey SG, Webb SM, Murray RD. Impaired quality of life in patients with treated acromegaly despite long-term biochemically stable disease: results from a 5-years prospective study. Clin Endocrinol (Oxf) 2017;86: 806e15. Kauppinen-Ma ¨kelin R, Sane T, Sintonen H, Markkanen H, Va ¨lima ¨ki MJ, Lo ¨yttyniemi E, et al. Quality of life in treated patients with acromegaly. J Clin Endocrinol Metab 2006;91: 3891e6. Crespo I, Valassi E, Webb SM. Update on quality of life in patients with acromegaly. Pituitary 2017;20:185e8. van der Klaauw AA, Biermasz NR, Hoftijzer HC, Pereira AM, Romijn JA. Previous radiotherapy negatively influences quality of life during 4 years of follow-up in patients cured from acromegaly. Clin Endocrinol (Oxf) 2008;69: 123e8. Postma MR, Netea-Maier RT, van den Berg G, Homan J, Sluiter WJ, Wagenmakers MA, et al. Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly. Eur J Endocrinol 2012;166:585e92. Geraedts VJ, Andela CD, Stalla GK, Pereira AM, van Furth WR, Sievers C, et al. Predictors of quality of life in acromegaly: no consensus on biochemical parameters. Front Endocrinol (Lausanne) 2017;8:40. Caron PJ, Bevan JS, Petersenn S, Houchard A, Sert C, Webb SM, PRIMARYS Investigators Group. Effects of lanreotide Autogel primary therapy on symptoms and quality-of-life in acromegaly: data from the PRIMARYS study. Pituitary 2016;19: 149e57. Webb SM, Badia X. Quality of life in acromegaly. Neuroendocrinology 2016;103:106e11. Guimara ˜esSa ´ AM, Ferreira PAM, Souza MT, Nascimento GC, da Silva Pereira Damianse S, de Carvalho Rocha VC, et al. Higher income and integration into the workforce are the main factors associated with quality of life in acromegalic patients in northeastern Brazil. Internet J Endocrinol 2018;2018: 6135080. Liu S, Adelman DT, Xu Y, Sisco J, Begelman SM, Webb SM, et al. Patient-centered assessment on disease burden, quality of life, and treatment satisfaction associated with acromegaly. J Investig Med 2018;66:653e60.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Original Article
Correlations of clinical parameters with quality of life in patients with acromegaly: Taiwan Acromegaly Registry Fen-Yu Tseng a, Szu-Tah Chen b, Jung-Fu Chen c, Tien-Shang Huang a, Jen-Der Lin b, Pei-Wen Wang c, Wayne Huey-Herng Sheu d, Tien-Chun Chang a,* on behalf of the Acromegaly Registry Study Group a
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Department of Internal Medicine, Linkuo Chang Gung Memorial Hospital, Taoyuan, Taiwan c Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan d Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan b
Received 7 February 2019; received in revised form 23 April 2019; accepted 8 May 2019
KEYWORDS Taiwan acromegaly registry; Quality of life; Clinical parameters
Background/Purpose: The objectives of this study were to evaluate the associations between clinical parameters and quality of life (QOL) of patients with acromegaly in Taiwan and to identify the impacts of hormone control, regimens, or co-morbidities on acromegalic patients’ daily life. Methods: From 2013 to 2015, subjects with acromegaly were recruited through five medical centers. Clinical data were recorded. The QOL of enrolled patients were assessed by using Acromegaly Quality of Life Questionnaire (AcroQoL). Results: This study enrolled 272 acromegalic subjects (117 males, 155 females). Remission, defined by normalization of IGF-1, had significant positive association with QOL scores in psychological/appearance (PSY/APP) dimension (b Z 6.760, p Z 0.023). Somatostatin analogues therapy had negative associations with total score and score in psychological (PSY) dimension (b Z 4.720, p Z 0.046 and b Z 5.388, p Z 0.035, respectively). Diabetes mellitus had negative associations with score in PSY dimension and psychological/personal relations (PSY/PER) dimensions (b Z 5.839, p Z 0.034 and b Z 7.516, p Z 0.013, respectively). Cerebral vascular accident (CVA) had significant negative associations with total score and scores in physical (PHY), PSY, and PSY/PER dimensions (b Z 26.632, p Z 0.013; b Z 28.353, p Z 0.024; b Z 25.648, p Z 0.026; and b Z 34.586, p Z 0.006, respectively). All these associations remained significant even after adjusted with sex and age.
* Corresponding author. Department of Internal Medicine, National Taiwan University Hospital No.7, Chung-Shan South Road, Taipei, 100, Taiwan. Fax: þ886 2 23916956. E-mail address: [email protected] (T.-C. Chang). https://doi.org/10.1016/j.jfma.2019.05.007 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Taiwan Acromegaly Registry: Correlations of clinical parameters with quality of life
1489
Conclusion: Our analysis suggested that not only hormone control but also therapeutic regimens and presence of co-morbidities might affect QOL of patients with acromegaly in some dimensions. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction Acromegaly is a chronic disease. Patients with acromegaly usually presented symptoms related to the pituitary tumor or the hypersecretion of growth hormone (GH).1,2 The hypersecretion of GH may increase serum levels of insulinlike growth factor 1 (IGF-1), which may affect energy homeostasis, and cause complications in metabolic, cardiovascular, or skeletal systems.1,2 Previous reports suggested increasing risks of diabetes, hypertension, neoplasm, or mortality in patients with acromegaly.3e7 Hormone control is important for long-term prognosis of acromegaly.8,9 Nadir of GH after oral glucose tolerance test (OGTT) or IGF-1 normalization had been suggested for defining remission of acromegaly.9e12 Acromegaly may significantly affect patients’ quality of life (QOL).13 Badia et al. developed Acromegaly Quality of Life Questionnaire (AcroQoL) to assess the impacts of acromegaly.13 This questionnaire contains 22 items. Among them, 8 were of physical (PHY) dimension and 14 were of psychological (PSY) dimension. Items of psychological dimension were further divided into 7 of appearance (PSY/ APP) dimension and 7 of personal relations (PSY/PER) dimension. Using a 5 point Likert scale, the AcroQoL measures either the frequency of occurrence or the degree of agreement with the items.13 The global scores of the QOL ðXÞ22 were calculated by the formula ð11022Þ 100. AcroQoL was reported to be useful for monitoring treatment response of acromegaly.13e16 The Taiwan Acromegaly Registry Study was performed in five large medical centers in Taiwan, including National Taiwan University Hospital, Linkou Chang Gung Memorial Hospital, Taichung Veterans General Hospital, Kaohsiung Chang Gung Memorial Hospital, and Chi Mei Medical Center. Through this registry, we identified the profiles of patients with acromegaly in Taiwan.17 We also reported the QOL scores of the enrolled patients. By using AcroQoL, the global QOL scores of the patients at enrollment were about 64.5 18.3.17 The QOL scores remained relatively stable during the 1 year following-up period after entry to the survey.17 With the attempt to identify predictors of QOL, we further analyzed the associations between clinical parameters and the QOL scores in individual dimension in this study.
Subjects and methods The Taiwan Acromegaly Registry was sponsored by the Endocrine Society of Taiwan, Republic of China and was approved by Independent Ethics Committee (IEC) or Institutional Review Board (IRB) in each study site. Diagnosis of
acromegaly was based on clinical presentations, elevated IGF-1 and/or GH levels, non-suppressible GH during OGTT, image studies, and/or pathology reports. Patients with diagnosis of acromegaly and were still under clinical followup after the index day (January 1, 2009) by expertise at the study sites were enrolled after signing the inform consent. Patient enrollment started in January 2013. Those who would not complete AcroQoL questionnaire were excluded from the study. All the enrolled patients were kept on follow-up for 1 year. Patients were kept on regimens as clinically indicated.17 No treatment was involved in this non-interventional, registry-based cohort study. Participation to this registry would not affect the patient/physician relationship and the physicians’ prescriptions or therapeutic managements of the patients. Clinical data were collected by reviewing medical record. QOL was assessed by using AcroQoL. Mean QOL score in each domain was calculated. The continuous variables were described by mean standard deviation (S.D.). Categorical variables were described by the numbers and percentages. Not all patients had complete laboratory data during the following-up period.17 We used the clinical data and QOL scores at enrollment (first visit) to minimize the bias from missing data. Statistical analysis was carried out using SAS software version 9.3. Associations between QOL scores and clinical data were analyzed by linear regression with a p < 0.05 considered as statistically significant.
Results Between January 2013 and April 2015, the Taiwan Acromegaly Registry enrolled 272 patients (117 males, 155 females) with acromegaly from the 5 study sites. The analyzed cohort had a mean age of 41.8 12.1 years at diagnosis and a mean age of 51.4 12.9 years at the time of the survey. All the recruited patients completed AcroQOL at enrollment. The mean total QOL score at enrollment was 64.5 18.3. The QOL score in PHY dimension, PSY dimension, PSY/APP dimension, and PSY/PER dimension was 64.6 21.6, 64.4 19.8, 54.8 23.2, and 74.0 21.5, respectively (Table 1). Defined by GH < 2.5 mg/L, the GH normalization rate was 66.8% (173 of 259 with data available). Defined by nadir GH after OGTT <2 ug/L, the remission rate at enrollment was 59.5% (25 of 42 with data available). Defined by IGF-1 normalization, the remission rate was 35.4% (94 of 265 with data available) (Table 1). Comorbidities and regimens were summarized as Table 1. Linear regression analysis revealed that somatostatin analogs (SSA) regimens (octreotide long-acting release (LAR) or lanreotide) and presence of cerebral vascular accident (CVA) had significant negative associations with total
1490 Table 1
F.-Y. Tseng et al. Characteristics of study subjects. N (%)
Male Age of diagnosis (years) Age of enrollment (years) Random GH (mg/L) (N Z 259) Random GH normalization Nadir GH after OGTT (mg/L) (N Z 42) Nadir GH after OGTT < 2 mg/L IGF-1 (ng/mL) (N Z 265) IGF-1 normalization QOL score: Total QOL score: PHY QOL score: PSY QOL score: PSY/APP QOL score: PSY/PER Prior pituitary tumor surgery Prior radiotherapy Dopamine agonists Somatostatin analogs Thyroxine Glucocorticoid Sexual hormone Diabetes mellitus Hypertension Dyslipidemia Cardiovascular disease CVA Osteoarthritis Cancer
Mean S.D.
117 (43.0%) 41.8 12.1 51.4 12.9 3.4 10.2 173/259 (66.8%) 9.5 37.1 25/42 (59.5%) 319.2 187.6 94/265 (35.4%) 64.5 64.6 64.4 54.8 74.0
18.3 21.6 19.8 23.2 21.5
258 (94.8%) 76 (27.9%) 82 (30%) 174 (64%) 43 (15.8%) 14 (5.1%) 26 (9.6%) 76 (27.9%) 102 (37.5%) 36 (13.2%) 6 (2.2%) 3 (1.1%) 7 (2.6%) 16 (5.9%)
GH: growth hormone; OGTT: oral glucose tolerance test; IGF-1: insulin-like growth factor 1; QOL: quality of life; PHY: physical dimension; PSY: psychological dimension; PSY/APP: psychological/appearance dimension; PSY/PER: psychological/personal relations dimension; Dopamine agonists: bromocriptine or cabergoline; Somatostatin analogs: octreotide long acting release or lanreotide; CVA: cerebral vascular accident.
QOL score (b Z 4.720, p Z 0.046; and b Z 26.632, p Z 0.013, respectively). Negative association existed between CVA and PHY score (b Z 28.353, p Z 0.024). PSY score was negatively associated with SSA regimens, diabetes mellitus (DM), and CVA (b Z 5.388, p Z 0.035; b Z 5.839, p Z 0.034, and b Z 25.648, p Z 0.026, respectively). PSY/APP score was negatively associated with random GH levels, serum IGF-1 levels, and sexual hormone supplement (b Z 0.542, p Z 0.046; b Z 0.016, p Z 0.034; and b Z 9.819, p Z 0.041, respectively) and positively associated with IGF-1 normalization (b Z 6.760, p Z 0.023). QOL score in PSY/PER dimension had negative associations with DM and CVA (b Z 7.516, p Z 0.013; and b Z 34.586, p Z 0.006, respectively) (Table 2). After adjustment with sex and age, the associations between total score and use of SSA, total score and CVA, PHY score and CVA, PSY score and SSA regimens, PSY score and DM, PSY score and CVA, PSY/APP score and normalization of IGF-1, PSY/PER score and DM, and PSY/PER score and CVA remained statistically significant (Table 3). The associations between SSA regimens and total QOL scores or PSY scores were further evaluated by adjustment with sex, age, and remission (yes vs no) in linear regression analysis. Defined by random GH normalization, the
associations between SSA regimens and total QOL scores or PSY scores became statistically insignificant (b Z 4.635, p Z 0.060, and b Z 5.017, p Z 0.060, respectively). Defined by nadir GH after OGTT <2 mg/L, the associations between SSA regimens and total QOL scores or PSY scores remained statistically significant (b Z 15.578, p Z 0.018, and b Z 16.763, p Z 0.036, respectively). Defined by IGF1 normalization, the associations between SSA regimens and total QOL scores or PSY scores became statistically insignificant (b Z 4.509, p Z 0.065, and b Z 5.087, p Z 0.054, respectively).
Discussion As our previous report, the Taiwan Acromegaly Registry revealed a comparable time lag from the onset of symptoms to diagnosis of acromegaly, and comparable rates of macroadenomas, co-morbidities, or remissions with other countries.10e12,17 The QOL scores of our patients were also comparable to other studies.14e17 In our study, the lower scores in PSY/APP domain were considered as related to the high frequencies of facial changes and growth of hands and feet.17 Analysis in this study revealed associations of QOL in
Taiwan Acromegaly Registry: Correlations of clinical parameters with quality of life
1491
Table 2 Linear regression analysis with quality of life scores as dependent variables and clinical data as independent variables (total N Z 272). QOL score b(p) Sex (female vs male) Age at diagnosis (years) Age at enrollment (years) Random GH (mg/L) Nadir GH after OGTT (mg/L) IGF-1 (ng/mL) Random GH normalization (yes vs no) Nadir GH after OGTT <2 mg/L (yes vs no) IGF-1 normalization (yes vs no) Prior surgery (yes vs no) Prior radiotherapy (yes vs no) Dopamine agonists (yes vs no) Somatostain analogs (yes vs no) Thyroxine (yes vs no) Glucocorticoid (yes vs no) Sexual hormone (yes vs no) Diabetes mellitus (yes vs no) Hypertension (yes vs no) Dyslipidmeia (yes vs no) Cardiovascular disease (yes vs no) CVA (yes vs no) Osteoarthritis (yes vs no) Cancer (yes vs no)
Total
PHY
PSY
PSY/APP
PSY/PER
1.377 (0.543) 0.075 (0.482) 0.013 (0.879) 0.239 (0.260) 0.124 (0.089) 0.006 (0.266) 2.911 (0.224)
2.679 (0.314) 0.040 (0.753) 0.056 (0.589) 0.051 (0.839) 0.118 (0.135) 0.001 (0.843) 0.623 (0.826)
3.695 (0.130) 0.141 (0.218) 0.011 (0.908) 0.405 (0.079) 0.127 (0.128) 0.011 (0.082) 4.218 (0.105)
3.611 (0.206) 0.217 (0.113) 0.078 (0.482) 0.542 (0.046)* 0.161 (0.119) 0.016 (0.034)* 3.953 (0.198)
3.778 (0.159) 0.065 (0.600) 0.056 (0.591) 0.268 (0.288) 0.093 (0.283) 0.006 (0.356) 4.484 (0.115)
1.947 (0.741)
4.460 (0.482)
0.512 (0.939)
3.098 (0.710)
2.075 (0.764)
4.008 (0.089) 3.980 (0.228) 0.631 (0.797) 0.019 (0.993) 4.720 (0.046)* 0.847 (0.783) 2.212 (0.662) 5.668 (0.136) 4.313 (0.054) 0.794 (0.736) 3.458 (0.269) 12.168 (0.144) 26.632 (0.013)* 0.237 (0.973) 1.704 (0.705)
2.928 (0.293) 7.106 (0.067) 0.484 (0.667) 1.244 (0.659) 3.550 (0.203) 0.388 (0.915) 8.953 (0.132) 6.064 (0.175) 3.293 (0.274) 3.092 (0.264) 1.187 (0.747) 12.224 (0.212) 28.353 (0.024)* 9.842 (0.236) 3.256 (0.539)
4.624 (0.070) 2.193 (0.539) 1.269 (0.631) 0.680 (0.793) 5.388 (0.035)* 1.552 (0.640) 1.640 (0.765) 5.441 (0.185) 5.839 (0.034)* 0.520 (0.838) 4.755 (0.159) 12.136 (0.177) 25.648 (0.026)* 5.996 (0.432) 0.817 (0.867)
6.760 (0.023)* 0.296 (0.944) 2.711 (0.381) 1.553 (0.608) 5.676 (0.058) 0.853 (0.826) 0.506 (0.937) 9.819 (0.041)* 4.162 (0.198) 0.717 (0.810) 6.468 (0.102) 14.168 (0.178) 16.711 (0.217) 2.064 (0.818) 0.700 (0.902)
2.489 (0.378) 4.091 (0.297) 0.173 (0.953) 0.192 (0.946) 5.100 (0.070) 2.251 (0.538) 3.787 (0.530) 1.064 (0.814) 7.516 (0.013)* 1.757 (0.530) 3.043 (0.413) 10.104 (0.308) 34.586 (0.006)* 9.929 (0.237) 0.933 (0.862)
*: p < 0.05. QOL: quality of life; GH: growth hormone; OGTT: oral glucose tolerance test; IGF-1: insulin-like growth factor 1; Dopamine agonists: bromocriptine or cabergoline; Somatostatin analogs: octreotide long acting release or lanreotide; CVA: cerebral vascular accident; PHY: physical dimension; PSY: psychological dimension; PSY/APP: psychological/appearance dimension; PSY/PER: psychological/personal relations dimension.
different domains with clinical parameters. After adjustment with sex and age, normalization of IGF-1 had positive association with score in PSY/APP dimension. SSA regimens had negative associations with total score and PSY score.
DM had significant negative associations with PSY and PSY/PER scores. CVA had significant negative associations with total score and scores in PHY, PSY, and PSY/PER dimensions. Our analysis suggested that not only hormone
Table 3 Linear regression analysis with quality of life scores as dependent variables and clinical data as independent variables (total N Z 272), adjusted with sex and age at enrollment. QOL score b(p) Total Random GH (mg/L) IGF-1 (ng/mL) IGF-1 normalization (yes vs no) Somatostain analogs (yes vs no) Sexual hormone (yes vs no) Diabetes mellitus (yes vs no) CVA (yes vs no)
PHY
PSY
PSY/APP
PSY/PER
0.526 (0.054) 0.014 (0.063) 6.424 (0.031)* 4.831 (0.044)*
5.352 (0.038)*
26.753 (0.012)*
6.256 (0.028)* 26.038 (0.024)*
28.004 (0.026)*
8.977 (0.065)
7.528 (0.016)* 34.849 (0.006)*
*: p < 0.05. QOL: quality of life; GH: growth hormone; IGF-1: insulin-like growth factor 1; Somatostatin analogs: octreotide long acting release or lanreotide; CVA: cerebral vascular accident; PHY: physical dimension; PSY: psychological dimension; PSY/APP: psychological/appearance dimension; PSY/PER: psychological/person relation dimension.
1492 control but also use of regimens and presences of comorbidities might affect QOL of patients with acromegaly. The AcroQoL was developed as a disease-specific questionnaire by Badia et al.13 Comparing with other questionnaires, Rowles et al. concluded AcroQoL as a patient-friendly measure of disease activity.14 Webb et al. reported that male acromegalic patients had better AcroQoL scores than female patients, but age had no correlations with QOL scores.15 Vandeva et al. suggested older age as independent negative predictors of QOL in all scales.16 They also reported that female gender negatively predicted all scales except the PSY/APP dimension.16 Our analysis revealed no associations between age or sex with QOL scores. Studies evaluating correlations between hormone control and QOL of acromegalic patients had controversial results. Several studies reported that there was no correlation between biochemical control and any measure of QOL.14,15 Vandeva et al. suggested remission as an independent predictor of total score improvement.16 However, other studies reported that QOL has been reduced even in successfully treated acromegalic patients.18e20 Original disease statuses, treatment modalities, and responses to regimens varied between acromegalic patients. In order to achieve remission, some patients might have to receive repeated operation, radiotherapy, or various medications. In spite of hormonal remission, symptoms such as facial changes or osteoarthritis may persist. Even with remission, acromegalic patients’ QOL may thus be jeopardized. Kauppinen-Ma ¨kelin et al. reported that health-related QOL was related to nadir GH after OGTT in an inverted U-shaped fashion.21 The best QOL could be achieved by normalization to IGF-1 and levels of nadir GH between 0.3 and 1.0 mg/L.21 In this study, random GH had negative association with PSY/APP score. This association became insignificant after adjusted with sex and age. Random GH normalization had no correlations with QOL scores. The nadir GH after OGTT or remission defined by nadir GH < 2 mg/L was not correlated with QOL scores, but levels of IGF-1 were negatively associated with PSY/APP score. Remission defined by IGF-1 normalization was positively correlated with PSY/APP score. The positive correlations between IGF-1 normalization and PSY/APP scores remained significant after adjusted with sex and age. Compared to random GH or nadir GH after OGTT, our analysis suggested IGF-1 normalization as a better predictor of PSY/APP score. Psychological symptoms, physical symptoms, and treatments may affect acromegalic patients’ QOL.16,22 Prior radiotherapy had been reported to have negative associations with QOL.16,18,23 Several studies suggested that the use of SSA was associated with worse QOL,16,24 while others reported that use of SSA improved QOL.25,26 Analysis in this study revealed no correlation between prior radiotherapy and QOL scores, while use of SSA was negatively associated with total score and score in PSY dimensions. Use of SSA is strictly regulated by National Health Insurance in Taiwan. Reimbursement for SSA will be approved if a patient has recurrent or residual tumor after surgery and/or radiotherapy. Use of SSA usually indicates relatively not wellcontrolled disease status after surgery and/or radiotherapy. Those patients thus might have impaired QOL. Our analysis also revealed that patients under sexual hormone supplement had worse PSY/APP score. This association became insignificant after adjusted with sex and age. The
F.-Y. Tseng et al. negative associations between SSA regimens and total or PSY scores persisted with adjustment by sex, age and remission defined by nadir GH after OGTT <2 ug/L, but not remission defined by random GH normalization or IGF-1 normalization. In this study, not all patients had concurrent random GH, nadir GH, or IGF-1 data. The real impacts of remission on the associations between SSA regimens and QOL scores deserve further investigation. Patients with acromegaly may develop comorbidities impairing their QOL. Webb et al. reported that worse QOL was associated with the presence of coexisting DM.27 Acromegaly patients in this study had prevalence of DM, hypertension, or cancer comparable to other countries.2,10,12,17 Our analysis revealed that patients with DM had lower PSY score and PSY/PER score than those without DM. Patients had encountered CVA had significantly worse QOL than those without CVA. Significant impairment in QOL scores in patients with CVA could be identified in total scale, PHY scale, PSY scale, and PSY/PER subscale. The limitations of this study were: First, status at diagnosis could affect long-term outcome. In this registry, patients were enrolled several years after their first diagnosis of acromegaly. We did not include the initial data in the analysis. Second, not all patients had random GH, IGF-1, and nadir GH after OGTT data at enrollment to the study. Among 272 study subjects, the missing rates for IGF1, random GH, and nadir GH was 2.6%, 4.8%, and 84.6%, respectively. Our analysis suggested positive correlations of IGF-1 normalization with QOL score in PSY/APP dimension. The missing rate for IGF-1 was only 2.6%. Thus, the analysis might not be biased by missing IGF-1 data. Our analysis revealed no correlation between nadir GH and QOL scores. Since the missing rate of nadir GH was high, we could not infer whether there was truly no correlation between nadir GH with QOL scores. Third, regimens or co-morbidities were divided as categorical variables (yes vs no). Severity of diseases and kinds or doses of medications were not considered in the analysis. Fourth, psychological or physical symptoms could affect patients’ QOL. We did not analyze the correlations between symptoms and QOL scores. Fifth, socioeconomic status may affect QOL.28,29 We did not evaluate patients’ socioeconomic status. Sixth, study subjects were enrolled through five medical centers. The impacts of physicians and treatment modalities in different study sites were not analyzed. In conclusion, the present study evaluated the associations between clinical parameters and acromegalic patients’ QOL. Remission defined by IGF-1 normalization had positive correlation with QOL in PSY/APP dimension. SSA use, DM, and CVA had negative associations with QOL scores, either in total or in some dimensions.
Disclosure statement This study was funded by Ipsen Pharmaceutical Co., and supervised by the Endocrine Society of the R.O.C. (Taiwan).
Conflicts of interest The authors have no conflicts of interest relevant to this article.
Taiwan Acromegaly Registry: Correlations of clinical parameters with quality of life
Acknowledgments We thank all the investigators, the study nurses, the study coordinators, and the patients who contributed to this study. This study was funded by Ipsen Pharmaceutical Company. Financial support for medical editorial assistance was provided by Ipsen Pharmaceutical Company.
16.
17.
Appendix A. Supplementary data 18.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.05.007.
References 1. Melmed S. Acromegaly. N Engl J Med 2006;355:2558e73. 2. Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004;25:102e52. 3. Jenkins PJ, Besser M. Acromegaly and cancer: a problem. J Clin Endocrinol Metab 2001;86:2935e41. 4. Melmed S. Acromegaly and cancer: not a problem? J Clin Endocrinol Metab 2001;86:2929e34. 5. Kauppinen-Ma ¨kelin R, Sane T, Reunanen A, Va ¨lima ¨ki MJ, Niskanen L, Markkanen H, et al. A nationwide survey of mortality in acromegaly. J Clin Endocrinol Metab 2005;90:4081e6. 6. Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol (Oxf) 1994;41:95e102. 7. Orme SM, McNally RJ, Cartwright RA, Belchetz PE. Mortality and cancer incidence in acromegaly: a retrospective cohort study. J Clin Endocrinol Metab 1998;83:2730e4. 8. Silverstein JM. Need for improved monitoring in patients with acromegaly. Endocr Connect 2015;4:R59e67. 9. Holdaway IM, Rajasoorya RC, Gamble GD. Factors influencing mortality in acromegaly. J Clin Endocrinol Metab 2004;89: 667e74. 10. Scho ¨fl C, Franz H, Grussendorf M, Honegger J, JaurschHancke C, Mayr B, et al. Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register. Eur J Endocrinol 2013;168:39e47. 11. Mestron A, Webb SM, Astorga R, Benito P, Catala M, Gaztambide S, et al. Epidemiology, clinical characteristics, outcome, morbidity and mortality in acromegaly based on the Spanish Acromegaly Registry (Registro Espan ˜ol de Acromegalia, REA). Eur J Endocrinol 2004;151:439e46. 12. Bex M, Abs R, T’Sjoen G, Mockel J, Velkeniers B, Muermans K, et al. AcroBel-the Belgian registry on acromegaly: a survey of the ’real-life’ outcome in 418 acromegalic subjects. Eur J Endocrinol 2007;157:399e409. 13. Badia X, Webb SM, Prieto L, Lara N. Acromegaly quality of life questionnaire (AcroQoL). Health Qual Life Outcomes 2004;2:13. 14. Rowles SV, Prieto L, Badia X, Shalet SM, Webb SM, Trainer PJ. Quality of life (QOL) in patients with acromegaly is severely impaired: use of a novel measure of QOL: acromegaly quality of life questionnaire. J Clin Endocrinol Metab 2005;90:3337e41. 15. Webb SM, Badia X, Surinach NL, Spanish AcroQol Study Group. Validity and clinical applicability of the acromegaly quality of
19.
20.
21.
22. 23.
24.
25.
26.
27. 28.
29.
1493
life questionnaire, AcroQoL: a 6-month prospective study. Eur J Endocrinol 2006;155:269e77. Vandeva S, Yaneva M, Natchev E, Elenkova A, Kalinov K, Zacharieva S. Disease control and treatment modalities have impact on quality of life in acromegaly evaluated by Acromegaly Quality of Life (AcroQoL) questionnaire. Endocrine 2015;49:774e82. Tseng FY, Huang TS, Lin JD, Chen ST, Wang PW, Chen JF, et al., On behalf of the Acromegaly Registry Study Group. A registry of acromegaly patients and one year following up in Taiwan. J Formos Med Assoc 2019;118:1430e7. Biermasz NR, van Thiel SW, Pereira AM, Hoftijzer HC, van Hemert AM, Smit JW, et al. Decreased quality of life in patients with acromegaly despite long-term cure of growth hormone excess. J Clin Endocrinol Metab 2004;89:5369e76. Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F. Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life. J Clin Endocrinol Metab 2005;90:2731e9. Kyriakakis N, Lynch J, Gilbey SG, Webb SM, Murray RD. Impaired quality of life in patients with treated acromegaly despite long-term biochemically stable disease: results from a 5-years prospective study. Clin Endocrinol (Oxf) 2017;86: 806e15. Kauppinen-Ma ¨kelin R, Sane T, Sintonen H, Markkanen H, Va ¨lima ¨ki MJ, Lo ¨yttyniemi E, et al. Quality of life in treated patients with acromegaly. J Clin Endocrinol Metab 2006;91: 3891e6. Crespo I, Valassi E, Webb SM. Update on quality of life in patients with acromegaly. Pituitary 2017;20:185e8. van der Klaauw AA, Biermasz NR, Hoftijzer HC, Pereira AM, Romijn JA. Previous radiotherapy negatively influences quality of life during 4 years of follow-up in patients cured from acromegaly. Clin Endocrinol (Oxf) 2008;69: 123e8. Postma MR, Netea-Maier RT, van den Berg G, Homan J, Sluiter WJ, Wagenmakers MA, et al. Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly. Eur J Endocrinol 2012;166:585e92. Geraedts VJ, Andela CD, Stalla GK, Pereira AM, van Furth WR, Sievers C, et al. Predictors of quality of life in acromegaly: no consensus on biochemical parameters. Front Endocrinol (Lausanne) 2017;8:40. Caron PJ, Bevan JS, Petersenn S, Houchard A, Sert C, Webb SM, PRIMARYS Investigators Group. Effects of lanreotide Autogel primary therapy on symptoms and quality-of-life in acromegaly: data from the PRIMARYS study. Pituitary 2016;19: 149e57. Webb SM, Badia X. Quality of life in acromegaly. Neuroendocrinology 2016;103:106e11. Guimara ˜esSa ´ AM, Ferreira PAM, Souza MT, Nascimento GC, da Silva Pereira Damianse S, de Carvalho Rocha VC, et al. Higher income and integration into the workforce are the main factors associated with quality of life in acromegalic patients in northeastern Brazil. Internet J Endocrinol 2018;2018: 6135080. Liu S, Adelman DT, Xu Y, Sisco J, Begelman SM, Webb SM, et al. Patient-centered assessment on disease burden, quality of life, and treatment satisfaction associated with acromegaly. J Investig Med 2018;66:653e60.