Investigating the risk of metabolic and cardiovascular comorbidities among patients with parathyroid cancer: a nationwide representative cohort study in Taiwan

Parathyroid cancer is a rare malignant endocrine neoplasm that occurs in one case per 10 million people in the USA [1] but has shown increasing incidence in the last few decades [2]. Parathyroid cancer accounts for 0.005% of all cancers and the 5-year and 10-year overall survival rates range from 81 to 92% and 49 to 77%, respectively [2‐6]. Although patients usually undergo frequent surgical interventions for multiple recurrences, there is currently no universally recommended staging system, standardized treatment or management protocol for parathyroid cancer. There are several possible explanations for this situation. First, despite initial clinical assessment of rare parathyroid cancer, there may be insufficient evidence for further analysis. Second, most cases are confirmed only upon postoperative histological examination, as unclear pathophysiology limits preoperative and intraoperative diagnosis [7]. Third, in contrast to most cancers, survival is generally correlated with tumor size, lymph nodes, and distant metastasis; however, the morbidity and mortality rates from parathyroid cancer are usually a consequence of metabolic complications rather than tumor burden [8].

Patients with parathyroid cancer often have severe hyperparathyroidism, and elevated serum parathyroid hormone (PTH) levels (> tenfold) [9, 10], which leads to marked hypercalcemia and clinical symptoms such as fatigue, bone complications, renal manifestations, and cardiac arrhythmia [11]. In addition to the typical target organs regulated by PTH, the links between metabolic and cardiac comorbidities and hyperparathyroidism are conflicting. Research has revealed that primary hyperparathyroidism may be associated with higher insulin resistance [12], elevated blood pressure [13], increased body weight [14], abnormal lipid profile, severe coronary artery calcification score, and myocardial infarction [15, 16], while other analyses refute the association between hyperparathyroidism and metabolic and cardiovascular diseases [17‐20]. Previous research has shown that primary hyperparathyroidism may be associated with hypertension, diabetes, and cardiovascular disease. Compared to the general population, patients with primary hyperparathyroidism were 3.1 and 2.64 times more likely to develop hypertension and diabetes, respectively [21].

Hypercalcemia and insulin resistance are known contributors to metabolic and cardiovascular diseases. Considering the rarity of parathyroid cancer cases and its poor prognosis as a result of its concomitant association with hypercalcemia, there remains a lack of evidence on the long-term metabolic and cardiovascular consequences of parathyroid cancer which requires further attention. Hence, this nationwide representative cohort study aimed to assess the link between parathyroid cancer and hypertension, diabetes, and hyperlipidemia risk and evaluate chronic metabolic disease persistence after adjusting for competing mortality events.

A total of 72 patients with parathyroid cancer and 360 sex- and age-matched general population ≥ 20 years of age who were enrolled in the National Taiwan Cancer Registry Database cohort from 2007 to 2019 participated in the present study. According to various primary outcome assessments, both the enrolled cohort with and without parathyroid cancer had exclusive pre-existing comorbidities. We included the study population with no past specific comorbidities for each outcome. The final number of patients with and without parathyroid cancer in the hypertension, diabetes, hyperlipidemia, atrial fibrillation, coronary artery disease, and heart failure cohorts were 45 and 340, 58 and 311, 68 and 330, 70 and 344, 69 and 335, and 64 and 307, respectively (Fig. 1).

Considering the interesting outcome of heart failure, among the 64 primary parathyroid cancer patients and 307 individuals of the general population without primary parathyroid cancer, the mean (SD) age at the index date was 55.6 (13.3) and 55 (13.1) years old, 38 (59.4%) and 181 (59%) were women, and 42 (65.6%) and 222 (72.3%) resided in urban areas (Table 1). Patients with parathyroid cancer were more likely to have chronic kidney disease, nephrolithiasis, and osteoporosis (Additional file 1: Table S1).

Our main finding from this 12-year observation of a national parathyroid cancer cohort was that parathyroid cancer was significantly associated with an increased risk of diabetes mellitus, hyperlipidemia, and heart failure, independent of several chronic diseases adjusted and death competing. Using Cox regression stratified by the years since cancer diagnosis, our findings demonstrated that the highest odds appeared within 6 years, and the trend persisted for decades.

To our knowledge, our study is the first national population-based analysis to demonstrate evidence of an association between parathyroid cancer and metabolic and cardiovascular comorbidities. Although no previous studies have examined the association among parathyroid cancer patients, the results are consistent with prior investigations of the increased incidence of diabetes, metabolic syndrome, obesity, and coronary artery disease among individuals with primary hyperparathyroidism [23]. Observational studies have reported a 38.9% increase in the prevalence of insulin resistance [12] and an 8–59% increase in metabolic syndrome [16, 24] in patients with primary hyperparathyroidism, compared to the general population. Furthermore, other data including systolic blood pressure, 24-h pulse wave velocity, 5.1-fold positive coronary artery calcification score [25], and left ventricular mass index were associated with serum PTH level in patients with primary hyperparathyroidism [26]. Current studies also demonstrated a significant likelihood of cardiovascular risk with a 3.5-fold odds ratio of coronary artery disease [12] and stroke in patients with primary hyperparathyroidism compared to the general population. Our findings confirmed the association between high PTH serum levels and the consequences of metabolic and cardiac disorders. In contrast, previous studies have shown an elevated prevalence of hypertension among patients with primary hyperparathyroidism (OR: 1.2–1.5, p value < 0.0001) as compared to the general population [23], although this association was not observed in our study. It is possible that the sample size of our parathyroid cancer cohort was too small to demonstrate a significant difference. Association between parathyroid cancer and coronary artery disease risk was difference by age subgroup. However, wider confidence intervals in relation to the estimate coronary artery disease might indicate the association instability and further research would be warrant.

The role of parathyroid hormone levels in modulating human metabolism has generated intense research interest, denoted by the plethora of mechanisms that underpin various epidemiologic studies. For example, one study reported that hyperfunction of PTH induces reduction of insulin-stimulated glucose uptake by decreasing GLUT4 expression and suppressing insulin signaling [27]. A meta-analysis of 17 pooled studies showed that individuals with primary hyperparathyroidism were 3.34 kg heavier in terms of body weight (95% CI: 1.97–4.71) and had increased body mass index of 1.13 kg/m² (95% CI: 0.28–2.55) compared to the general population [14]. Although the link between obesity and hyperparathyroidism is unclear, the current study hypothesized that excess PTH reduces the adipocyte lipolytic response to catecholamine by increasing calcium influx. Another epidemiological study demonstrated that elevated LDL/HDL ratio, elevated triglyceride levels, and low HDL levels were significantly associated with normo-calcemic hyperparathyroidism as compared to the general population [28].

Numerous factors might explain the alternative physiological effects on the heart by PTH. The PTH receptor is found in cardiac myocytes, vascular smooth cells, and endothelial cells. By direct vasorelaxant mechanism on vascular smooth muscle, PTH could induce direct vasodilation effects on vascular smooth cells [29]. Other studies have shown that PTH accelerates the formation of vascular atherosclerosis and remodeling by stimulating vascular growth factors [30]. Severe excess PTH results in left ventricular hypertrophy and remodeling by numerous factors, such as increasing vascular calcification, accelerating atherosclerosis, increasing chronotropy and hypertrophy of cardiomyocytes, and overt metabolic syndrome including insulin resistance, dyslipidemia, and overweight [31]. Consequently, both hypercalcemia and metabolic syndrome can lead to cardiovascular risk among patients with hyperparathyroidism. Additionally, the alternation of left ventricle mass thickening and arrhythmia triggered by PTH hyperfunction results in metabolic variables and cardiovascular risk as noted in epidemiological studies. This is consistent with our observation of significantly increasing long-term incidence of diabetes, hyperlipidemia, and heart failure.

Our results have important implications for current evidence regarding the clinical care of primary parathyroid cancer. From an endocrinological perspective, comprehensive consideration of metabolic and cardiac complications, not only skeletal comorbidity, may provide pragmatic benefits to parathyroid cancer patients and improve their long-term quality of life. Regarding the pathophysiological reasons for the higher standardized incidence rate of diabetes, hyperlipidemia, and heart failure among parathyroid cancer patients, further epidemiological studies on the association between PTH serum levels and insulin resistance, lipid profile, and severity of endothelial calcification should be conducted.

In summary, the findings of this national cohort study demonstrated that adult parathyroid cancer patients had a significantly higher incidence of diabetes mellitus, hyperlipidemia, and heart failure than the general population. Additionally, the evidence suggests that adult parathyroid cancer survivors experience long-term metabolic and cardiovascular comorbidities; thus, further research is warranted.