As PHPT is a common endocrine disorder, a nationwide approach is needed to identify the trend of the incidence and prognostic factors of the disease. In this nationwide retrospective cohort study in Korea, the incidence of PHPT patients who underwent parathyroidectomy increased over time, from 1.7 in 2002 to 10.1/100,000 person-years in 2018. Most patients were diagnosed in their mid-50s, and over two-thirds of the patients were women. During a median of 5.9 years of follow-up, 6.0%, 8.2%, and 6.2% of the patients experienced death, cardiovascular diseases, and cerebrovascular diseases, respectively. Patients with a history of cardiovascular diseases, mood disorders, or genitourinary stones had a higher mortality risk. Patients with a history of hypertension, cerebrovascular diseases, diabetes mellitus, or mood disorders showed an increased risk of cardiovascular diseases. In particular, patients with a history of mood disorders have an increased risk of cerebrovascular diseases.
In the present study, we demonstrated that the incidence of PHPT increased over time in Korea, as in other countries. To the best of our knowledge, this is the first nationwide study of PHPT in Asia. Several nationwide studies of PHPT in the Caucasian population already exist [2, 3]. The representative study of the United States was from the Rochester Epidemiology Project, which showed a rapid increase in disease prevalence after introducing calcium level measurements in general check-ups and in patients with genitourinary stones [2, 3]. A similar increasing trend has been observed in the European countries [4, 9]. A 3-fold increase in incidence was observed in Denmark from 1998 to 2010 (16/100,000 person-years in 2010) . The authors suggested that increasing calcium measurements largely explained the upward trend of the disease. In the same context, the similar rise in PHPT incidence in Korea can be partly explained by the increase in calcium level measurements during check-ups . In addition, the incidence of PHPT in Korea (10.1/100,000 person-years in the present study) was lower than that previously reported in the Caucasian population. Consistent with our results, a previous multi-ethnic study also reported that the incidence of PHPT was lower in the Asian populations . However, because the study only included participants who underwent parathyroidectomy, the actual number of patients may be higher than that reported in the present study. Additional nationwide studies in the Asian populations are required.
In this study, the patients with a history of genitourinary stones had an increased risk of mortality. Genitourinary stones are a common complication of PHPT that 15–60% of patients with PHPT experience at baseline [12, 13]. In the general population, stones are often associated with risk factors of atherosclerosis, such as obesity, diabetes, hypertension, and dyslipidemia [14–16], leading to an increased risk of subclinical atherosclerosis . In line with these results, a large population-based cohort study showed that patients with genitourinary stones had a higher risk of subsequent acute myocardial infarction and stroke than those without stones . In addition, other studies have shown that patients with a history of stones have a significantly elevated risk of coronary heart diseases [19, 20]. However, data on the risk of genitourinary stones on mortality in patients with PHPT, not in the general population, are lacking. It is clinically essential to address the risk of genitourinary stones in patients with PHPT because they already have an increased risk of mortality owing to hypercalcemia and other risk factors [7, 21]. According to the present study, as there is a possibility that genitourinary stones may exacerbate the risk, patients with PHPT and stones could be considered a subgroup that requires prompt treatment. Although the risk of cardiovascular events was elevated, but marginally significant in multivariate analysis in patients with a history of genitourinary stones, further larger nationwide studies with sufficient events may clarify this association.
In contrast, the present study showed that patients with PHPT and mood disorders had a significantly higher risk of cardiovascular diseases, cerebrovascular diseases, and mortality. It has been reported that mood disorders, especially depression, are common in patients with PHPT as one of the nonclassical symptoms of the disease . Although there is still a lack of data on whether mood disorders are related to atherosclerotic diseases in patients with PHPT, it has been consistently reported that mood disorders increase the risk of cardiovascular diseases and cerebrovascular diseases in the general population [23–27]. In a recent Mendelian randomization study, a genetic predisposition to depressive disorder was associated with an approximately 30% higher risk of atherosclerotic diseases . Activation of the hypothalamic-pituitary-adrenal axis in patients with depression has been suggested to induce insulin resistance and inflammation [28, 29]. In addition, low resilience to psychological stress in patients with depression may play a role in developing cardiovascular or cerebrovascular events [30, 31]. In addition to mood disorders, PHPT itself has been reported to increase insulin resistance and inflammatory signals [32–34]. Therefore, as demonstrated in the present study, mood disorders in patients with PHPT may amplify the tendency to increase the risk of atherosclerotic diseases, which emphasizes the importance of assessing the psychological aspects of patients with PHPT.
The presence of diabetes mellitus and hypertension was an additional risk factor for cardiovascular diseases in patients with PHPT in the present study. Diabetes mellitus and hypertension are common comorbidities, particularly in patients with PHPT [35, 36]. Cardiovascular diseases are a major cause of mortality in patients with diabetes mellitus and hypertension [37, 38]. The main mechanisms have been suggested to be endothelial dysfunction, vascular inflammation, and arterial remodeling, leading to atherosclerosis [39–41]. These mechanisms of diabetes mellitus and hypertension overlap substantially with the effects of PHPT on cardiovascular diseases. It has been reported that parathyroid hormone may cause endothelial dysfunction by inducing reactive oxygen species and inflammatory signals [5, 42]. Therefore, consistent with previous studies, risk of cardiovascular diseases can be exacerbated in patients with PHPT, who also have diabetes mellitus and hypertension. Since patients with PHPT are already at an increased risk of cardiovascular diseases, closer attention is needed to manage these comorbidities. Further population-based studies in Asians with a longitudinal follow-up are needed to validate these findings.
This study has several strengths. First, this is the first nationwide study in Asia to report the incidence and disease course of PHPT. Second, since the study used a national claims dataset, the prevalence of comorbidities was readily identified. In addition, due to the nature of the dataset, there were no cases of follow-up loss. Moreover, this study is the first to report the clinical risk factors of cardiovascular diseases and cerebrovascular diseases, in addition to mortality, in an Asian population. Consequently, we could provide novel insights into the risk of mood disorders and genitourinary stones for cardiovascular events and cerebrovascular events in patients with PHPT. In addition, as this study was based on patients who underwent parathyroidectomy, the study could represent the residual risk even after surgery. Further studies on the effect of mood disorders in patients with PHPT on their outcomes would help in understanding the disease.
This study had some limitations. As this study had a retrospective design, factors that could affect the results, such as the onset of symptoms, family history, and social history of smoking and drinking, could not be obtained from national insurance service records. Additionally, biochemical and histopathological data could not be included in the analysis because of the data source. Therefore, we could not determine the biochemical characteristics of PHPT, especially calcium and parathyroid hormone levels. In addition, patients with comorbidities, such as diabetes mellitus and hypertension, could be overestimated because the operational definitions were based on diagnostic codes. Moreover, without nonsurgical patients, the cohort is biased to include those with symptoms and more severe PHPT. Outcomes in PHPT patients who underwent surgery could be worse than those in overall PHPT patients. Also, patients with secondary hyperparathyroidism could be included that vitamin D deficiency, GI malabsorption, or thiazide use could be included. Further, we could not assess improvement in the complication of PHPT after parathyroidectomy in this study. Finally, the study results were associations, not causation that the increased or reduced risk of outcomes could be epiphenomena with same common risk factors.
In conclusion, the incidence of PHPT has been increasing over time in Korea, similar to the trends in other countries. Moreover, some novel prognostic factors have been identified, such as mood disorders as prognostic factors for mortality, cardiovascular diseases, and cerebrovascular diseases; genitourinary stones as a prognostic factor for mortality. These results emphasize the importance of close follow-up in patients with renal and psychotic complications, even after surgical treatment. Further nationwide representative studies are required to confirm these findings.