Long-Term Prognosis and Systemic Impact of Acromegaly: Analyses Utilizing Korean National Health Insurance Data
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Abstract
Acromegaly is a rare endocrine disorder caused by excessive growth hormone secretion. Its low prevalence poses challenges in studying its long-term prognosis and systemic effects. To address this research gap, we conducted five studies using nationwide cohort data from the Korean National Health Insurance Database (NHID). This review consolidates the findings of these studies, which examined various long-term effects of acromegaly. The results demonstrated significant associations between acromegaly and increased mortality, a higher prevalence of mortality, cardiovascular outcomes, neurodegenerative diseases, depression, end-stage kidney disease, respiratory complications, specifically bronchiectasis, spine & hip fracture, and malignancy. These findings highlight the critical need for early diagnosis, comprehensive care, and long-term monitoring, and underscore the importance of a multidisciplinary approach in managing acromegaly.
The Namgok Award is the highest scientific award of the Korean Endocrine Society, and is given to honor an individual who has made excellent contributions to progress in the field of endocrinology and metabolism. The Namgok Award is named after the pen name of Professor Hun Ki Min, who founded the Korean Endocrine Society in 1982. Professor Cheol-Young Park received the Namgok Award at the the 2024 Symposium for Academia, Research, and Industry & Autumn Congress of the Korean Endocrine Society in November 2024.
INTRODUCTION
Acromegaly, primarily caused by growth hormone (GH)-secreting pituitary adenomas, is a rare endocrine disorder with an estimated prevalence of 40 to 130 cases per million population and an estimated incidence between two and three cases per million people per year [1,2]. In South Korea, the prevalence of acromegaly was 68.1 cases per million people [3]. The average annual incidence was 3.44 cases per million and remained stable over time [3]. The incidence was notably higher in women compared to men [3,4]. The rarity of this condition has historically posed challenges in conducting large-scale, comprehensive studies on its long-term prognosis and systemic impact. However, the advent of large national health insurance databases has led to new methodological possibilities for research on rare diseases like acromegaly. In Korea, the National Health Insurance Database (NHID) provides a unique opportunity for such research. This extensive database contains longitudinal data for 97% of the Korean population, linked to the National Death Registry, national health screening program, and the rare incurable disease registry [5]. Leveraging this comprehensive dataset, our research team has conducted a series of studies exploring the long-term impact of acromegaly on patient health. This review synthesizes the findings from our recent publications and compares them with the existing literature to provide a comprehensive overview of the systemic effects and long-term prognosis of acromegaly. We discuss eight key areas: mortality, cardiovascular outcomes, neurodegenerative diseases, depression, end-stage kidney disease (ESKD), respiratory complications, specifically bronchiectasis, spine & hip fracture, and malignancy (Table 1).
Summary of Key Findings and Implications from Acromegaly Studies Utilizing Korean National Health Insurance Data
RESEARCH METHODOLOGY
Our research methodology leveraged the extensive data available in the Korean NHID, which encompasses approximately 97% of the Korean population [2]. This comprehensive database provided a wealth of information, including demographics, medical treatments, procedures, and prescriptions. A notable feature of the NHID is its rare incurable disease registry, which enabled accurate identification of acromegaly cases. In our studies, we identified acromegaly cases using the corresponding rare incurable disease registration code (V112) [2]. For each investigation, we carefully selected controls from the general population, matching them to acromegaly cases based on age, sex, and other relevant factors to ensure comparable cohorts. The studies typically involved long-term follow-up periods, ranging from 7 to 10 years, enabling us to assess long-term outcomes effectively. Our statistical approach primarily utilized Cox proportional hazard models to estimate hazard ratios (HRs) for various outcomes, adjusting for potential confounding factors. This method allowed us to quantify the increased risk associated with acromegaly for different health outcomes. To gain deeper insights, the studies included subgroup analyses based on age, sex, and comorbidities, helping to identify high-risk groups within the acromegaly population. However, this methodology has certain limitations. Due to the relatively small number of acromegaly cases, we were unable to utilize the national health screening data, which restricted our ability to collect comprehensive clinical indicators. Additionally, we could not access hormone test data such as GH and insulin-like growth factor-1 (IGF-1) levels, which are crucial in the diagnosis and monitoring of acromegaly. These limitations constrained our ability to analyze certain clinical aspects of the disease in depth. Nonetheless, this robust, nationwide population-based methodology allowed us to overcome many limitations of previous smaller-scale studies. In particular, this methodology made it possible to conduct comprehensive analyses of the long-term outcomes of acromegaly. By utilizing such a large and representative database, we were able to generate statistically powerful results that offer valuable insights into the prognosis and systemic impacts of this rare endocrine disorder. However, the inability to fully incorporate detailed clinical indicators and hormone test data should be considered when interpreting our findings.
MORTALITY RISK
The literature presents strong evidence of a significant association between acromegaly and increased mortality risk; however, this association has weakened over time due to advancements in acromegaly treatment strategies. A meta-analysis of 18 studies from 1965 to 2008 revealed mortality rates at least twice as high as those observed in the general population [6]. That study showed that before 1984, the standardized mortality ratio (SMR) was 2.2 (95% confidence interval [CI], 1.8 to 2.8), but it significantly decreased to 1.3 (95% CI, 1.1 to 1.6) after 1984 [6]. Another meta-analysis, which included 16 studies conducted between 1970 and 2005, also found a similar trend: the SMR prior to 1995 was 2.11, which decreased to 1.62 after 1995 [7]. The authors suggested that this trend might be due to a shift in acromegaly treatment strategies from radiotherapy to transsphenoidal surgery [7]. Following these two meta-analyses, several observational studies have indicated that the SMR for acromegaly patients has become comparable to that of the general population. This change has been attributed to advancements in acromegaly treatment, including transsphenoidal surgery and new medical therapies [8-11].
These discrepancies highlighted the need for larger, population-based studies with longer follow-up periods. Our research, utilizing the extensive Korean NHID, addressed this gap by analyzing data from 1,874 acromegaly patients and 9,370 matched controls over a median follow-up of 7.5 years [12]. Acromegaly patients exhibited a significantly higher mortality risk than controls (HR, 1.59; 95% CI, 1.25 to 2.02) adjusted by age and sex [12]. Although the mortality rate in acromegaly patients was 1.59 times higher than in controls, this association weakened in the lag-time analysis (first 4 years [HR, 1.66; 95% CI, 1.15 to 2.40] vs. time lag over 4 years [HR, 1.45; 95% CI, 1.03 to 2.05]), and disappeared in the lag-time analysis after adjusting for diabetes, hypertension, and dyslipidemia (time lag over 4 years: HR, 1.18; 95% CI, 0.81 to 1.71) [12]. This is consistent with a recent systematic review and meta-analysis, which suggested that mortality in acromegaly can be normalized through biochemical control and has declined over the past decade due to the increased use of somatostatin analogues as adjunctive therapy [13]. Kim et al. [14] reported comparable findings using data from the Korean NHID. They found that individuals with acromegaly exhibited a higher risk of all-cause mortality compared to the control group (HR, 1.74; 95% CI, 1.38 to 2.19). This association was more pronounced in women (HR, 2.17; 95% CI, 1.61 to 2.93) than in men (HR, 1.36; 95% CI, 0.95 to 1.93) [14]. While vascular and respiratory diseases have traditionally been considered the leading causes of death in acromegaly, recent data indicate that malignancy may now be the most common cause of mortality [8-10]. Kim et al. [14] also reported that malignancy was the primary cause of death in this population, as in the general population.
CARDIOVASCULAR OUTCOMES
Acromegaly is associated with well-known cardiovascular disease risk factors, including hypertension, diabetes, and dyslipidemia. Cardiovascular diseases are the leading cause of death among patients with acromegaly [7,10,15]. Autopsy studies have reported a high frequency of left ventricular hypertrophy, fibrosis, and myocardial infarction [16]. Echocardiography-based studies have found a high prevalence of cardiomyopathy in acromegaly patients, with rates ranging from 11% to as high as 80% [17]. Several studies have documented the links between acromegaly and both arrhythmias and heart failure, although these associations have not been thoroughly quantified in large-scale, long-term research [18-20]. Similar to the recent shift in mortality trends among patients with acromegaly, recent studies have shown discordant results regarding the association between acromegaly and cardiovascular disease [21,22]. Our research aimed to address this knowledge gap by examining these outcomes in a large cohort of acromegaly patients. The analysis revealed that acromegaly patients had a similar risk of myocardial infarction and stroke compared to the general population (HR, 1.24; 95% CI, 0.90 to 1.72) after adjusting for age and sex. This risk diminished further after accounting for type 2 diabetes, hypertension, and dyslipidemia (HR, 0.98; 95% CI, 0.69 to 1.39) [12]. However, acromegaly patients showed a significantly higher risk of developing atrial fibrillation (HR, 1.83; 95% CI, 1.29 to 2.60) and heart failure (HR, 1.95; 95% CI, 1.37 to 2.77) than controls after adjusting for age and sex [12]. The risk of developing atrial fibrillation was particularly elevated during the first 4 years after acromegaly diagnosis, emphasizing the importance of early cardiovascular assessment. These findings are crucial for improving cardiovascular monitoring and management strategies in acromegaly patients. Overt heart failure is rare in acromegaly patients, occurring in only 1% to 4% of those with untreated and uncontrolled disease [23]. In our study, 2.30% of patients with acromegaly were diagnosed with heart failure during a mean follow-up period of 7.38±3.25 years [12]. In lag time analysis, the risk of heart failure in patients with acromegaly, compared to controls, remained unchanged during follow-up after adjusting for age and sex [12]. However, it decreased after adjusting for type 2 diabetes, hypertension, and dyslipidemia, which are established risk factors for heart failure [12]. Other study utilizing the Korea NHID found that the prevalence of heart failure was higher in the acromegaly group compared to the control group, both during the overall study period (5.6% vs. 2.6%, P<0.001) and the prediagnostic period (3.1% vs. 1.2%, P<0.001) [4]. Our findings indicate that comprehensive treatment for acromegaly may reduce the risk of cardiovascular events. Future research should explore treatment approaches aimed at further decreasing cardiovascular complications in individuals with acromegaly.
NEURODEGENERATIVE DISEASES
The potential link between acromegaly and neurodegenerative diseases had been largely unexplored, despite some evidence suggesting that IGF-1 is involved in neurodegeneration. The GH-IGF-1 axis plays a vital role in brain function, contributing actively to neurogenesis, myelination, and brain biochemistry. Some studies have demonstrated cognitive impairment in patients with acromegaly, particularly in memory and executive functions, which have been linked to reduced beta activity in the left medial temporal cortex [24-26]. Furthermore, a few studies have demonstrated an association between elevated levels of IGF-1 and Parkinson’s disease [27-29]. In our study, we utilized the NHID to investigate whether patients with acromegaly have an increased risk of neurodegenerative diseases. Our findings revealed that acromegaly was associated with a significantly higher risk of Parkinson’s disease (HR, 2.61; 95% CI, 1.41 to 2.61) [30]. While no overall increased risk of dementia was observed throughout the total observation period, acromegaly was linked to an elevated risk of all-cause dementia (HR, 2.30; 95% CI, 1.36 to 3.88), Alzheimer’s disease (HR, 2.23; 95% CI, 1.19 to 4.17), and non-Alzheimer’s dementia (HR, 6.55; 95% CI, 1.75 to 24.48) during the first 3 years of observation [30]. Notably, the presence of diabetes at the time of acromegaly diagnosis was associated with an increased risk of dementia, but not Parkinson’s disease [30]. These findings are significant as they reveal a previously unrecognized complication of acromegaly and suggest potential mechanisms linking growth factors to neurodegenerative processes. Further research is required to clarify the relationship between IGF-1/GH levels and neurodegenerative diseases.
DEPRESSION RISK
The insidious and chronic, debilitating nature of acromegaly significantly impacts a patient’s quality of life [31] and is strongly linked to psychological disturbances [32]. Several studies with relatively small samples have reported an increased prevalence of depression among patients with acromegaly [25,33,34]. However, the psychological effects of acromegaly, particularly the risk of depression, have not been extensively explored in large-scale research. We investigated the risk of depression in patients with acromegaly using a large population dataset from NHID, and found that patients with acromegaly had a significantly higher risk of depression than the control group (HR, 1.18; 95% CI, 1.02 to 1.38) [35]. Notably, this increased risk was evident only in untreated acromegaly patients (HR, 1.43; 95% CI, 1.12 to 1.82), with the risk being particularly elevated during the first 3 years after diagnosis (HR, 1.83; 95% CI, 1.31 to 2.56) [35]. In contrast, patients who received treatment for acromegaly exhibited a similar incidence of depression to that of the control group [35]. These findings provide a foundation for developing targeted screening strategies to reduce the risk of depression in acromegaly patients.
END-STAGE KIDNEY DISEASE RISK
Compared with other acromegaly-related complications, including cardiovascular disease, osteoarthropathy, diabetes, respiratory disease, and neoplasia, limited data are available on kidney complications in patients with acromegaly. A study involving 30 patients with acromegaly revealed significant alterations in kidney structure and function, which persisted even 1 year after disease remission [36]. Another recent case-control study involving 48 patients with acromegaly found that active acromegaly was associated with a 25% higher estimated glomerular filtration rate (eGFR) and remission of acromegaly following surgical treatment was linked to a reduction in eGFR 3 months post-surgery [37]. Moreover, there is a lack of longitudinal data on kidney complications in patients with acromegaly. To address this, we examined the risk of ESKD in 2,187 patients with acromegaly and 10,935 age- and sex-matched controls without acromegaly (1:5 ratio) over an average follow-up period of 6.51±3.20 years [38]. We found that patients with acromegaly had a 4.35-fold higher risk of developing ESKD than controls without acromegaly (95% CI, 2.63 to 7.20) [38]. This association remained significant even after adjusting for factors such as age, sex, diabetes, and hypertension (HR, 2.29; 95% CI, 1.24 to 3.75) [38]. A mediation analysis showed that acromegaly contributed to the risk of ESKD both directly and indirectly through mediators such as diabetes and hypertension [38]. Unfortunately, interventions such as pituitary surgery and somatostatin analogues did not alter this association [38]. These results emphasize the need for timely, comprehensive management and long-term follow-up for patients with acromegaly to mitigate the risk of ESKD. However, further studies are necessary to determine the most effective treatment strategies to reduce this risk.
BRONCHIECTASIS IN ACROMEGALY
Respiratory complications in acromegaly arise from both structural and functional changes in the entire respiratory system. Obstructive sleep apnea is a frequent complication, affecting between 20% and 100% of patients with acromegaly [39]. However, the association between acromegaly and bronchiectasis had not been extensively studied. A study by Camilo et al. [40] reported bronchiectasis in approximately 35% of patients with acromegaly, making it the second most common abnormality observed on chest computed tomography (CT) after air-trapping. However, the study’s small sample size, involving only 20 acromegaly patients and an equal number of controls, along with its cross-sectional design, limited the generalizability of the findings [40]. Another study examining lung function and structure in patients with acromegaly found no changes in lung parenchyma on chest CT scans, but exhibited a reduced ability to diffuse carbon monoxide [41]. Given the inconsistent results of prior studies regarding structural lung complications in acromegaly and the unclear underlying mechanisms, we conducted a study to explore whether structural lung damage occurs in acromegaly patients in a real-world setting. We found that acromegaly patients had a significantly higher risk of developing bronchiectasis than controls (HR, 1.49; 95% CI, 1.15 to 1.94) after adjusting for age, sex, household income, place, type 2 diabetes, hypertension, and dyslipidemia [42]. However, further studies are needed to elucidate the mechanisms underlying this association and to develop strategies for the early detection and management of bronchiectasis in acromegaly patients.
FRACTURE IN ACROMEGALY
GH and IGF-1 are hormonal regulators of skeletal metabolism. Their excess is linked to increased bone turnover, resulting in structural damage to both cortical and trabecular bone [43]. Over the past decade, multiple studies have reported an increased risk of fractures in individuals with acromegaly, particularly affecting the vertebrae [44-47]. However, these studies involved a relatively small number of patients due to the rarity of the condition. Kwon et al. [48] conducted a study using the Korea NHID to investigate the risk of both hip and vertebral fractures in patients with acromegaly. This nationwide cohort study, which included 1,777 patients with acromegaly and had a follow-up period of approximately 8.5 years, revealed that individuals with acromegaly had a significantly higher risk of clinical vertebral fractures (HR, 2.09; 95% CI, 1.58 to 2.78) and hip fractures (HR, 2.52; 95% CI, 1.61 to 3.95) compared to controls [48]. The increased risks of clinical vertebral and hip fractures in patients with acromegaly were time-dependent and consistently observed both during and beyond the first 7 years of follow-up [48]. Another study, also using the Korea NHID to assess fracture risk in patients with acromegaly, included 931 patients with acromegaly who had not received osteoporosis medications and were treated exclusively with surgery [49]. Over a median follow-up of 4.5 years, the study found no significant differences in the overall risks of vertebral and non-vertebral fractures between the acromegaly and control groups [49]. However, the risk of hip fractures was notably higher (HR, 2.73; 95% CI, 1.32 to 5.65), while the risk of non-hip and non-vertebral fractures was lower (HR, 0.40; 95% CI, 0.17 to 0.98) [49]. Interestingly, hip fractures were notably more frequent in patients with hypogonadism [49]. Both studies highlighted the importance of regular monitoring for fragility fractures in patients with acromegaly, focusing not only on vertebral fractures but also on hip fractures.
MALIGNANCY IN ACROMEGALY
The GH-IGF-1 axis plays a critical role in regulating growth and metabolism. Its involvement in carcinogenesis and tumor progression has raised significant concerns. In the past, uncontrolled acromegaly has been linked to an increased risk of various malignancies [50]. Retrospective studies have indicated that 15% to 24% of deaths in individuals with acromegaly were previously attributed to cancer, with colorectal cancer being the most common, followed by breast, thyroid, prostate, and other cancers [50]. Since cancer risk is age-dependent, it remains unclear whether the observed patterns are due to improved disease control, better management of comorbidities, and increased life expectancy in patients with acromegaly [50]. Previous population-based studies have shown mixed results, with some reporting an increased cancer risk in patients with acromegaly [51-55], while others found no significant elevation in risk [56-58]. Hence, the direct association between acromegaly and cancer risk continues to be a topic of ongoing debate. Park et al. [4] conducted a study using the Korea NHID to investigate the risk of malignancy in patients with acromegaly. The overall risk of malignancy in patients with acromegaly was significantly higher than in controls (HR, 2.82; 95% CI, 2.12 to 3.74) [4]. This risk was more pronounced in females (HR, 3.14; 95% CI, 2.28 to 4.34) compared to males (HR, 2.28; 95% CI, 1.14 to 3.78) [4]. In females, the elevated HR was evident from the prediagnostic period and persisted through the postdiagnostic period. In contrast, males exhibited an increased HR only during the peridiagnostic period. Malignancy risk was notably higher in individuals under 50 years old during the prediagnostic period, whereas in the postdiagnostic period, the risk was significantly elevated in those over 50 years, with no significant increase observed in individuals under 50 years [4]. And thyroid cancer was the most frequently occurring malignancy, followed by colorectal cancer as the second most common [4]. All thyroid and colorectal cancers were identified during the peridiagnosis and postdiagnosis periods, highlighting the importance of implementing an effective malignancy screening strategy at the time of acromegaly diagnosis.
CONCLUSIONS
Our series of studies utilizing the Korean NHID has provided valuable insights into the long-term prognosis and systemic impact of acromegaly. The findings consistently demonstrated associations between acromegaly and increased risks of mortality, cardiovascular diseases, neurodegenerative disorders, depression, and respiratory complications (Table 1). These results have several important implications for the management and care of acromegaly patients. In particular, early diagnosis and treatment are critically important for mitigating the long-term risks associated with acromegaly. Given the diverse range of potential complications (Fig. 1), a multidisciplinary approach to patient care is necessary, involving specialists such as endocrinologists, cardiologists, neurologists, psychiatrists, and pulmonologists. This collaborative strategy ensures comprehensive management of the disease’s systemic effects. Our findings also emphasize the importance of long-term monitoring of various systemic complications, even after initial treatment. The persistent risks observed in treated patients underscore the need for ongoing surveillance. Furthermore, the heterogeneity in outcomes suggests the need for personalized risk assessment and management strategies, considering factors such as age, gender, and comorbidities. Future research should focus on elucidating the mechanisms linking acromegaly to its various systemic effects. This understanding could pave the way for developing targeted interventions to prevent or mitigate these complications. Additionally, studies evaluating the long-term efficacy of various treatment modalities in preventing systemic complications would be highly beneficial. In conclusion, these studies provide robust evidence for the significant and diverse long-term impacts of acromegaly, underscoring the need for comprehensive, long-term care for patients with this rare but impactful endocrine disorder. The findings highlight the complexity of acromegaly management and the importance of a lifelong, patient-centered approach to care, aimed at improving both the length and quality of life for individuals affected by this condition.
Systemic effects of acromegaly based on studies using Korean National Health Insurance Data. IGF-1, insulin-like growth factor-1.
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
ACKNOWLEDGMENTS
We would like to thank Dr. Inmyung Yang (1954–2001) for providing inspiration and relentless mentorship throughout this study. Data from the Korean National Health Insurance Database (NHID) were provided by the Korean National Health Insurance Service (KNHIS). The authors would like to thank the KNHIS for their cooperation.