1. Introduction
Primary hyperparathyroidism (PHPT) is the third most common endocrine disorder worldwide [
1]. It results from an abnormal parathyroid hormone (PTH) secretion from the parathyroid glands, leading to elevated serum calcium (SCa) and low serum phosphorus (SP) levels. Classic symptoms include bone, kidney, and neuropsychological disorders [
2]. However, most PHPT are currently diagnosed before their occurrence. Mild PHPT (defined by moderate hypercalcemia with respect to normal but inappropriate PTH level, or elevated PTH level alone) is now the most common form of PHPT, accounting for about 80% of cases [
3].
Cardiovascular (CV) mortality is increased among patients with both classic PHPT [
4,
5] and mild PHPT [
6,
7,
8]. CV risk factors such as arterial hypertension [
6,
9], pre-diabetes and diabetes mellitus [
10], and dyslipidemia [
11] are more prevalent among these patients.
According to the Fourth International Workshop, the current indications for parathyroidectomy (PTX) when symptoms are not present take into account the age of the patient, the calcium level, and the presence of bone and kidney disorders, but not the presence of an elevated CV risk [
12]. Although PTX seems to improve CV mortality in classic PHPT, its effects in mild PHPT remain controversial. Few studies reported a decrease in CV risk after PTX, including the improvement of lipid [
13] and glucose metabolism [
14,
15]. Notably, PTX could improve lipid metabolism by decreasing total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), while it could increase high-density lipoprotein cholesterol (HDL-C) plasma levels [
11,
15,
16,
17]. However, these data remain controversial as other studies did not report such improvement in patients with mild PHPT [
17,
18].
Regarding glucose metabolism, PTX has been suggested to improve insulin resistance with a decrease in the Homoeostasis Model Assessment of Insulin Resistance (HOMA-IR) [
15], which is a proxy of insulin resistance taking into account fasting blood glucose and insulin [
19]. Moreover, PTX has been shown to increase serum adiponectin levels [
17], an adipokine strongly correlated with insulin sensitivity [
20]. On the other hand, other studies suggested that PTX does not improve insulin secretion, with no significant change in Homoeostasis model assessment of beta cell function (HOMA-B), a proxy of insulin secretion [
21].
Among the actors of cholesterol metabolism, the proprotein convertase subtilisin/kexin type 9 (PCSK9), a member of the proprotein convertase family secreted in plasma by hepatocytes, plays a major role by promoting the lysosomal degradation of the LDL receptor (LDLR) [
22]. In concordant studies, loss-of-function variants in PCSK9 were shown to protect against CV diseases, suggesting a pro-atherogenic action of PCSK9 by increasing plasma LDL-C [
23]. Therefore, therapeutic inhibition of circulating PCSK9 with human monoclonal antibodies (alirocumab and evolocumab) has been quickly developed to lower plasma LDL-C levels and CV events [
24,
25].
The aim of the present study was to assess the 1-year effects of PTX on lipid profile, glucose metabolism, and plasma PCSK9 level in a prospective cohort of patients with either classic or mild PHPT. Our hypothesis was that PTX is associated with lipid and glucose metabolisms’ improvement in PHPT.
4. Discussion
This monocentric, prospective, and observational cohort showed that PTX was associated with an improvement of glucose metabolism parameters 1 year after surgery and with variations in lipid parameters that differed depending on the severity of PHPT. While serum TC and LDL-C levels increased in all patients, serum TG levels decreased only in patients with classic PHPT. Furthermore, this study is the first to show that plasma PCSK9 levels decreased in mild PHPT patients after PTX.
Pre-diabetes and diabetes mellitus are frequent among patients with PHPT [
10]. If a positive effect of PTX has been previously strongly suggested in the context of classic PHPT [
10,
14,
28], few studies have shown such benefits in mild PHPT [
15]. A randomized, controlled trial comparing 54 operated with 62 non-operated mild PHPT patients showed no modification in FPG and plasma insulin levels and HOMA-IR 2 years after surgery [
17]. Other observational studies also reported such an absence of improvement [
29,
30]. However, these studies are limited by their low number of patients, and, on the other hand, two of them also reported an increase in serum adiponectin levels after surgery [
17,
29], suggesting an improvement of insulin sensitivity [
31]. In the present study, both FPG and HOMA-IR were slightly decreased after PTX in the whole population, while FPG and fasting plasma insulin were decreased in mild PHPT patients in association with increased adiponectin levels, showing a beneficial effect of PTX on glucose homeostasis. The similar but non-significant trend for a decrease in FPG and fasting plasma insulin in patients with classic PHPT is likely the result of a lack of statistical power. Indeed, the significant increase in serum adiponectin concentrations observed also suggests an improvement of insulin resistance following PTX in this population. The absence of significant concomitant changes in HOMA-B, reflecting beta cell function, suggests that this improvement could be mainly mediated by an improved peripheral insulin sensitivity. Indeed, although an elevated serum PTH level could induce pancreatic beta cell dysfunction [
32], both elevated serum PTH and calcium levels are also known to impair peripheral insulin sensitivity [
30,
32,
33]. However, no correlation was found between the changes in phosphocalcic and glucose metabolism parameters following PTX, suggesting that indirect mechanisms are implicated. It is worth noting that, although they are easily available, HOMA-IR, HOMA-B, and serum adiponectin levels are indirect markers for insulin resistance and insulin secretion. Performances of HOMA-IR could be modified by BMI [
34], and HOMA-B could be modified by age [
35]. Therefore, these results should be confirmed by the gold standard method, which is the hyperinsulinemic-euglycemic clamp for insulin resistance and hyperglycemic clamp for insulin secretion. Furthermore, given the low magnitude of FPG and HOMA-IR improvement, despite a more important change in plasma insulin and adiponectin levels, the clinical significancy of such changes deserves to be studied in the long term.
The present study showed that the mean serum TG level was only decreased after PTX in patients with classic PHPT. This result is in line with a positive correlation between SCa and TG levels at baseline, and between the post-operative variations of these two variables in the whole population and in both sub-groups. Such a correlation between SCa and serum TG levels has already been suggested by others [
36,
37,
38]. It is, thus, not surprising that the only group showing a decreased serum TG level was the one that displayed the most important variation in SCa level after PTX (i.e., patients with classic PHPT). In contrast, Farahnak et al. showed a slight but significant decrease in serum TG after PTX in 49 mild PHPT patients [
16]. However, the variation of SCa after PTX in mild PHPT (2.61 (±0.12) pre-operatively to 2.27 (±0.0) mmol/L post-operatively) was more important than in the present study, which supports our hypothesis. In the study of Beysel et al., plasma TG level decreased significantly after PTX only in normocalcemic but not in hypercalcemic PHPT [
15]. However, hypercalcemic patients in that study presented a lower hypercalcemia than in the present study (2.8 (±0.17) mmol/L), and the mean TG levels in normocalcemic and hypercalcemic PHPT patients (159 (±61) and 160 (±67) mg/dL, respectively) were higher, which could explain these differences. In the present study, a significant increase in HDL-C in patients with classic PHPT not taking lipid-lowering medications was also observed, which is in line with previous observations [
11,
15].
Unexpectedly, mean serum total cholesterol, LDL-C, and apoB-100 levels were slightly but significantly increased after PTX in all sub-groups, even after exclusion of patients taking lipid-lowering medication. This contrasts with others studies that showed either no modification [
17,
28,
39] or even a decrease [
11,
15] of total cholesterol and/or LDL-C levels. In our study, BMI was slightly but significantly increased in the whole population and in patients with classic PHPT, as previously reported [
40,
41]. Improved quality of life 12 months after PTX especially in patients with higher hypercalcemia [
42] and a relative lipolytic activity of PTH [
43] could explain this finding. It can be hypothesized that this observation can be related with the increase in cholesterol parameters in plasma, although a recent meta-analysis failed to find a correlation between these variables [
41]. However, the observation of decreased plasma TG level and improved insulin sensitivity despite an increased BMI after PTX in patients with classic PHPT strengthens these findings.
Vitamin D deficiency and PHPT are commonly associated, but which influences the other is not known [
44]. This feature could be one of the causes of the increased CV risk in PHPT patients, as vitamin D deficiency is associated with an increased CV risk [
45]. In this line, vitamin D has been shown to be associated with an increased adiponectin secretion [
46] and correlates negatively with ApoB-100 [
47], reinforcing the necessity to correct vitamin D deficiency when treating PHPT.
This study is the first to report a decrease in plasma PCSK9 concentrations 1 year after PTX in patients with mild PHPT. Plasma PCSK9 concentration has been reported to be associated with concentrations of LDL-C and TG as well as FPG and insulin [
22,
48,
49]. In accordance with these observations, the baseline circulating PCSK9 level was correlated with plasma TC and LDL-C levels, confirming its close relationship with LDL-mediated cholesterol metabolism. Unexpectedly, the decreased plasma PCSK9 concentration observed after PTX in mild PHPT patients was not associated with a decreased plasma LDL-C level, which suggests a disconnection between PCSK9 action and LDL-C metabolism in this specific case. A previous report focusing on the kinetics of LDL-C and apoB-100 using stable isotope tracers and their relationship with plasma PCSK9 concentration similarly reported such a disconnection between PCSK9 and LDL-C metabolism in patients with uncontrolled diabetes mellitus [
50]. However, due to its “pleiotropic functions” [
51], circulating PCSK9 level can predict CV outcomes independently from its effects on the LDL-C metabolism [
52].
The reason why PCSK9 appears to be elevated only in mild PHPT patients in comparison with patients with classic PHPT, supported by a negative correlation with albumin-corrected SCa at baseline, remains to be determined. No study, to our knowledge, has explored circulating PCSK9 level in the context of hypercalcemia. However, the calcium-sensing receptor (CaSR) is expressed in hepatocytes [
53], which are the main production sites of circulating PCSK9 [
54]; its activation by SCa could inhibit PCSK9 transcription by activating the mitogen-activating protein (MAP) kinase [
55,
56], although it deserves to be studied. The present study failed to connect the PCSK9 decrease with the drop of serum PTH concentration and SCa after surgery, although the PTH receptor is also present in hepatocytes [
57]. In line with this finding, no correlation was found between serum PTH and plasma PCSK9 levels in dialyzed patients with secondary hyperparathyroidism in a previous study [
58]. These observations suggest an indirect effect of PTX on circulating PCSK9 level. As a possible mechanism, insulin resistance, which has previously been shown to be linked with circulating PCSK9 level [
49,
59], could explain this finding. This hypothesis is supported by the positive correlation between changes in HOMA-IR and plasma PCSK9 level after PTX in patients with mild PHPT not taking lipid-lowering therapy (data not shown). The limitations of circulating PCSK9 measurement include its diurnal rhythm requiring its sampling in the early morning, as well as a gender effect with increased PCSK9 concentrations in post-menopausal women [
22]. However, in our cohort, blood samplings were always performed during the morning hours, limiting this bias. Furthermore, the higher proportion of post-menopausal women in the group with the lower plasma PCSK9 level (i.e., mild PHPT) makes unlikely the assumption that hormonal status could have explained these results.
The major limitation of the present study is the absence of a control group including patients with PHPT who did not undergo PTX. Indeed, in the randomized, controlled trial of Ejlsmark-Swensson et al., the modest improvement of the lipid profile observed after PTX contrasted with a worsening of dyslipidemia in unoperated PHPT patients [
39]. Beyond the observed improvement, such a control group could have shown to what extent PTX can prevent worsening of dyslipidemia. Another limitation is the number of patients excluded from the CoHPT cohort for analysis due to missing data. However, this permitted a strict selection of patients, and the main clinical characteristics of excluded and included populations were not different, which limits this bias. The present study is the largest, to our knowledge, to assess the effects of PTX on metabolic homeostasis in PHPT patients taking their lipid-lowering medication status and the PHPT severity into account.