Parathyroid diseases and metabolic syndrome

Purpose Parathyroid diseases are related to parathyroid hormone (PTH) dysregulation by parathyroid cells or alteration of PTH function. They include hyperparathyroidism (PTH excess), hypoparathyroidism (PTH deficiency) and pseudohypoparathyroidism (PTH resistance). Little is known about correlation between parathyroid diseases and metabolic syndrome (MetS). Methods An electronic-based search using PubMed was performed until October 2022 and articles were selected based on relevance of title, abstract, English language and publication in peer-reviewed journals. Results Possible association between PTH alterations and the diverse manifestation of MetS have been proposed and it could be supposed that MetS may negatively influence parathyroid diseases. Available data show significant association for hyperparathyroidism and pseudohypoparathyroidism. Conclusions This review highlights the possible implications between MetS and parathyroid diseases. Given the increasing MetS global prevalence and the higher parathyroid diseases awareness and diagnosis, it may be interesting to further explore the possible role of alterations in parathyroid homeostasis in the development of MetS components with dedicated prospective studies.

Metabolic syndrome (MetS) is a set of diseases of high cardiometabolic risk, with steadily increasing incidence in the adult population, considerable social impact and health care costs [11]. It depends on geographic and sociodemographic factors, European MetS prevalence has been estimated as 41% in men and 38% in women [12].The most recent International Diabetes Federation (IDF) criteria states that central obesity (waist circumference ≥ 94 cm for men and ≥ 80 cm for women) allows the diagnosis of metabolic syndrome along with two of the following [13]: systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg, fasting blood glucose ≥ 100 mg/ dl (5.6 mmol/L), HDL cholesterol < 40 mg/dl in men or < 50 mg/dl in women, triglycerides > 150 mg/dl. Therefore, MetS is characterized by the coexistence of abdominal obesity, atherogenic dyslipidemia, elevated blood pressure and glucose alterations, which together increase the risk of developing chronic conditions such as type 2 diabetes mellitus and cardiovascular disease [14]. Parathyroid hormone (PTH) is involved in the calcium homeostasis, increasing calcium resorption from the skeleton and calcium kidney resorption. Both metabolic and cardiovascular complications of parathyroid diseases may share common pathogenetic mechanisms with the features of MetS [1,15]. Although kidney and bone represent the primary target organs for PTH, many additional tissues also express PTH receptors, thus additional effects of PTH should be considered [1]. PTH promotes phospholipase C-b, increasing the amount of free intracellular calcium in both adipocytes and skeletal muscle [16]. There is evidence that the increase of intracellular calcium in adipocytes interferes with insulin-stimulated glucose uptake. Furthermore, in view of the common progenitor between adipocytes and osteoblasts, it has been postulated that PTH might play a role on their differentiation [16]. Noteworthy, a possible association between elevated PTH levels and increased body weight has been proposed by a meta-analysis in which body weight values were elevated in both hypercalcemic and eucalcemic populations with hyperPTH [17]. Also, Elevated PTH levels may promote hypertension, due to its correlation with aldosterone levels PTH could directly stimulate aldosterone synthesis. PTH may also contribute to endothelial dysfunction increasing peripheral vascular resistance [18]. The current review provides an overview of the available evidence regarding the possible interplay between PTH diseases and MetS or its components.

Materials and methods
We performed an electronic-based search using PubMed until October 2022. Literature search was systematically performed through online databases including MEDLINE (via PubMed). The entree terms included "metabolic syndrome", "parathyroid disease", "hyperparathyroidism" "hypoparathyroidism", "pseudoparathyroidism", "obesity", "diabetes mellitus", "dyslipidemia", "PTH". This was complemented by a carefully handsearching reference to find additional studies and expand the search. The articles were selected based on relevance of title and abstract, English language and publication in peer-reviewed journals. Primary studies and case series dealing with patients affected by parathyroid diseases and reporting data on metabolic aspects were included.

Cardiovascular diseases and mortality
HyperPTH has been associated with different features of MetS. An increased prevalence of overweight, impaired glucose tolerance (IGT), dyslipidemia and hypertension has been reported both in asymptomatic and overt hyperPTH. In these patients, hypercalcemia and metabolic syndrome could play a role in cardiovascular risk. In detail, chronic hypercalcemia may cause severe and symptomatic presentations, leading to the development of hypertension, myocardial hypertrophy and shortening of QT interval with arrhythmia [19]. Recent studies ( Table 2) have investigated the relationship between hyperPTH and cardiovascular mortality. In a cohort of 172 patients with hyperPTH that didn't undergo to surgery and with hypercalcemia, cardiovascular mortality was higher compared to normocalcemic controls and was correlated with hypercalcemia with a hazard ratio (HR) of 1.72 (95% CI, 1.24-2.37; p < 0.001). Cardiovascular diseases were significantly over-expressed as causes of death in hypercalcemic patients, while hyperPTH patients presented an increased prevalence of features of MetS, such as hypertension, diabetes, and dyslipidemia [20]. Parathyroid surgery could improve the cardiovascular outcome of hyperPTH patients, however there are few randomized clinical trials. A recent review focused on the effect of parathyroidectomy on cardiovascular risk in hyperPTH patients, finding evidence that parathyroidectomy could be associated with a reduced cardiovascular mortality, especially in hypercalcemic patients [21]. Moreover, it has been demonstrated that patients with hyperPTH have substantial cardiac structural and functional abnormalities, such as diastolic dysfunction,

Obesity
The role of hyperPTH in obesity is highly debated. There are some evidences that hyperPTH patients present a higher prevalence of obesity compared to healthy controls. A metanalysis conducted by Bollad et al. reviewed 17 studies, analyzing data of 617 patients with primary hyperPTH and 1248 controls. HyperPTH patients were 3.34 kg heavier than controls (95% CI, 1.97-4.71; p < 0.00001). Further analysis demonstrated that average weight and body mass index (BMI) were higher in hyperPTH patients than controls (respectively 3.1 kg of weight and 1.1 kg/m 2 of BMI; p < 0.00001) [17]. Excess of PTH can promote an increase in body weight according to a proposed mechanism in which an increased intracellular calcium concentration, induced by PTH, inhibits the lipolytic response to catecholamines in adipocytes ( Fig. 1) [16]. Reversely, obesity impacts the course of hyperPTH. It has been demonstrated that obese hyperPTH patients, compared to non-obese patients, presented a higher prevalence of hypercalciuria (41 vs 23%, p = 0.01) and nephrolithiasis (36 vs 21%, p = 003), but a lower rate of osteoporosis [23]. In a recent study, authors proved a positive correlation between PTH levels and body weight, BMI and visceral adipose tissue area (VAA). Interestingly, this correlation turned to be negative in the PTH range of 147-2511 pg/ml (third tertile of their study), giving to the correlation an inverted U-shape relationship and suggesting that a marked increase in PTH levels is the cause of the decrease in body weight and BMI in these patients. This behavior could be explained as a consequence of hypercalcemia or malnutrition due to gastro-intestinal manifestation of hyperPTH. Alternatively, animal studies provided evidence that exposure to high levels of PTH can induce increased expression of thermogenesis genes, resulting in white adipose browning and muscle wasting [24,25].

Impaired glucose tolerance and diabetes
Prevalence of impaired glucose tolerance and diabetes in hyperPTH patients resulted higher compared with general population, with a prevalence of 25 and 10%, respectively. In particular, prevalence of impaired fasting glucose, impaired glucose tolerance and diabetes is increased in all hyperPTH patients, both symptomatic and asymptomatic [26,27]. However, the lack of long-term prospective trials leads to a reduced understanding of glucose metabolism alterations in these patients. Several studies demonstrated that patients with hyperPTH present a reduced insulin sensitivity, basal and after stimulus [27]. The impact of therapy on glucose

Lipid alterations
Regarding lipid metabolism, several studies have identified an atherogenic lipid profile in patients with hyperPTH, characterized by an increase in LDL cholesterol and triglycerides levels and a reduction in HDL cholesterol. However, an improvement in these parameters has not been observed after 3 [29], 6 and 12 months [30] after parathyroidectomy, even after the exclusion of patients already treated with lowering cholesterol drugs [29]. These data suggest that surgery seems to play a marginal role in dyslipidemia in hyperPTH patients. Contrasting results have been observed in patients with mild hyperPTH, since several studies find a reduction in total cholesterol, LDL cholesterol (even in patients on treatment) and triglycerides levels and an increase in HDL cholesterol levels [31]. Although parathyroidectomy improves dyslipidemia only in patients with mild hyperPTH, a role of PTH in lipid metabolism should be considered [31].

Hypertension
In several studies, hyperPTH is associated with an increased risk of hypertension, since this feature has been observed with a prevalence of 40-65% in hyperPTH patients, higher than general population [18,32]. Several mechanisms have been proposed to explain this relationship. Calcium is a regulator of the renin-angiotensin-aldosterone system (RAAS). Indeed, chronic hypercalcemia causes an increase in renin activity, through stimulation of Calcium Sensing Receptor (CaSR). Also, elevated PTH levels contribute to hypertension, because this hormone correlates with aldosterone levels in these patients and the possible underlying mechanism is that PTH may directly stimulate aldosterone synthesis. Moreover, PTH action on hypertension could be explained through endothelial dysfunction, increasing sympathetic activity or with a direct effect on vascular smooth muscle cells, leading to an increased peripheral vascular resistance with hypertension [18]. Several studies evaluated reversibility of cardiovascular disease and hypertension in patients with hyperPTH undergoing surgery. Indeed, patients presented a reduction of plasmatic renin activity, angiotensin and aldosterone levels, and consequently a significative reduction in systolic and diastolic blood pressure after parathyroidectomy [18]. Parathyroidectomy improved blood pressure in several studies; blood pressure improvement has been observed already 6 months after surgery in two series of 147 [33] and 726 patients [34]. This improvement is maintained over time in a study that evaluated 501 patients after 2 years from surgery [35].

Chronic kidney diseases
The features of MetS are well-known risk factors for chronic kidney disease (CKD), while their correlation with secondary hyperPTH is still unclear [36]. Bone disease secondary to CKD is associated with an increased mortality rate and incidence of cardiovascular disease. Treatment of risk factors is not sufficient, alone, to prevent vascular calcification and to reduce cardiovascular mortality. However, as Fig. 1 A possible mechanism that correlates hyperparathyroidism and obesity. Hypercalcemia PTH-induced may inhibit the lipolysis leading to an increase in body weight demonstrated in the EVOLVE trial for patients in dialysis, cinacalcet treatment leads to a reduction of PTH level, with no modifications of cardiovascular parameters, except for a mild reduction of blood pressure. In conclusion, hyperPTH secondary to CKD is a major determinant for the development of vascular calcifications and for the increased cardiovascular mortality [37].

Vitamin D deficiency
Vitamin D deficiency has been proposed as a possible factor that can contribute to the development of MetS. Indeed, adipocyte, pancreatic beta cells and muscle cells are target tissues for this vitamin. Several epidemiological studies suggest an association between obesity, insulin resistance, diabetes and a reduced vitamin D activity [38]. In particular, Meng et al. observed lower total 25(OH)D and vitamin D binding protein levels (p < 0.001) in patients with hyperPTH [39]. Moreover, vitamin D concentrations present an inverted correlation with obesity-related parameters as BMI and waist circumference and vitamin D may contribute to build the sarcopenic obesity phenotype [40,41]. In a similar way, vitamin D deficiency is associated with insulin resistance and diabetes, although vitamin D integration is not recommended to prevent or improve diabetes. Vitamin D deficiency has been also associated with hypertension. Several studies demonstrated that vitamin D levers are inversely correlated to renin and angiotensin II levels [42][43][44]. Based on these results, a trial aimed to verify the effect of correcting vitamin D deficiency, but no benefit was found on blood pressure after 8 weeks of therapy, demonstrating that vitamin D isn't a modifiable target for lowering blood pressure in deficient patients [45]. In the evaluation of the vitamin D impact on blood pressure, some author observed that blood pressure modifications were mostly correlated with PTH levels and not with vitamin D, suggesting that hypertension is primarily influenced by PTH levels [46].

Hypoparathyroidism and pseudohypoparathyroidism
Literature data analyzing the metabolic aspects and associated cardiovascular risk in patients with hypoPTH are lacking and mainly regard the influence of PTH treatment in these patients. On the basis of animal and human studies in which osteocalcin (OC) and undercarboxylated osteocalcin (ucOC) has been shown to regulate glucose metabolism Harsløf et al. conducted a randomized trial enrolling 62 patients with hypoPTH and assigned them double-blind to treatment with 100 g PTH (1-84) administered once daily subcutaneously or placebo for 24 weeks (24w), both groups received optimal calcium and vitamin D supplement (Table 3). Patients underwent at baseline and after 24w measures of body composition (body weight, truncal fat, and total body fat) and dosage of glucose, insulin, adiponectin, leptin, HOMA-IR, OC, and ucOC. In response to treatment, ucOC increased (p < 10 -50 ) and body weight decreased significantly in the PTH-treated group; additionally, in the placebo group body weight increased (p:0.04). Changes in ucOC were inversely linked with changes in total body fat mass (p = 0.03) and body weight (p = 0.004). Therefore, PTH treatment seems to affect body weight independently of glycoinsulinemic metabolism, despite the involvement of OC/ ucOC [47]. A further study analyzed the same population by investigating cardiovascular risk in terms of ECG and blood pressure (BP), showing no significant effects on BP or heart rate after 6-month treatment. However patients allocated to rhyperPTHH(1-84) treatment had a significantly higher heart rate at all three timepoints of measurement on the day of the 24 h study. Because this study didn't show significant correlations between plasma magnesium/Ca 2 levels and heart rate, it appears that the elevated heart rate is probably caused by PTH directly [48]. Furthermore, valve heart calcifications are significantly associated with hyperphosphatemia in a cohort of 37 patients with hypoPTH, in particular Polonine et al. identified a possible cutoff of serum phosphorus > 5.05 mg/dl (p:0.05). Despite, the paucity of evidence in the literature in the area of hypoPTH, several studies have focused on metabolic aspect of pseudoPTH considering that it is often associated with obesity [49][50][51][52]. Obesity and alterations in glucose metabolism have been observed in pseudoPTH population, but a solid association has not yet been recognized. In an observational study, 53 patients with Albright hereditary osteodystrophy (AHO) were evaluated according to anthropometric data and biochemical analysis [52]. This cohort included 40 patients with pseudoPTH type 1A (PHP1a, disruption of maternal Gas allele) and 13 subjects with pseudoPTH (disruption of the paternal allele) confirmed GNAS mutated, between 2 and 82 years old (children sub-group: patients with < 18 years); almost the total PHP1a population was in optimal hormone replacement therapy, no data were available in 4 patients, and the anthropometric measurements preceded GH deficiency diagnosis. In this case, data showed that adult sub-group with PHP1a was characterized by a 3.5-fold higher frequency of severe obesity and a twofold higher prevalence of obesity compared to the general population, additionally children sub-group with PHP1a had an approximately 5.2-fold higher frequency of obesity [52]. The entire PHP1a population had a BMI z-scores of 2.31 ± 0.18 vs 0.65 ± 0.31 of pseudoPTH population (P 0.000032) [52]. Indeed, the prevalence of obesity was 66.7% among PHP1a adults (16.7% were severe obese, BMI > 40 kg/m 2 ), while it was about the same of the general population in pseudoPTH patients and there was no severe obese. In the children sub-group, obese prevalence was 89.3% among PHP1a and no children with pseudoPTH was obese [52]. The weight gain would appear to be related to Gsa subunit activity, but it should be emphasized that obesity, together with hyperphagia, is an early clinical manifestation of pseudoPTH, so metabolic complications could be secondary to this manifestation. For this reason, a study investigated eating behavior in a cohort of 10 patients (2-10 years old) affected by PHP-1a and matched on age, gender and BMI z-score with non-sick siblings (n: 6) and a control group of obese (n: 30) [51]. Current use of appetitesuppressing medications and obesity genetic syndrome were exclusion criteria [51]. The three cohorts were submitted to Hyperphagia Questionnaire (HQ) [53] and Children's Eating Behavior Questionnaire (CEBQ) [54] completed by the primary caregiver [51]. There were no differences between the PHP-1a and obese control groups; both were significantly more fat than the sibling group [51]. These results indicated that children with PHP-1a, with adequate treatment of thyroid hormone and growth hormone replacement, may not be hyperphagic when compared to other obese children because there was no statistically difference between the PHP-1a group and matched controls for total HQ score [51]. These data do not support the hypothesis that obesity in pseudoPTH could be associated with melanocortin-4 receptor (MCR4) malfunction, a Gsa signaling pathways, which can induce hyperphagia Fig. 2. [49,55]. A further hypothesis of correlation between obesity and pseudoPTH concerns energy metabolism. Roizen et al. recruited 12 participants (between 5 and 46 years old) with a diagnosis of PHP1A and AHO features evaluating the REE (resting energy expenditure), biochemical, endocrine, and auxological parameters; controls were a cohort of 156 obese participants. Patients with PHP1A had greater decreases in REE from expected than obese controls, providing evidence of a unique and significant defect that likely accounts for early-onset obesity in this disorder [55]. Finally, among those participants that provided dietary data, they consumed significantly fewer calories than their recommended daily allowance [55]. Hence, these results provide evidence that increased BMI in PHP1A is due principally to decreased REE. Nor were any consistent effects observed between percent expected REE and age, calcium, thyroid hormone, IGF-1 standard deviation score, or GH status in those with PHP1A [55].
Regarding metabolic complications of obesity, patients with PHP1a have not frequently been reported to have Fig. 2 A possible mechanism that correlates PseudoPTH and obesity: Ghrelin (orexigen hormone) and Peptide YY-PYY/glucagon-like peptide 1-GLP-1 (anorexigenic hormones) act at the hypothalamic arcuate nucleus to regulate hunger/satiety signaling. Gsa and cAMP pro-duction are necessary to allow this mechanism, so their defects could bring to a satiety and energy expenditure alteration causing adipose tissue accumulation insulin resistance, despite some case series [56]. Moreover, Germain-Lee et al. described a case of acanthosis nigricans in a cohort of 13 PHP1a patients with normal Hba1c and fasting insulin levels. Considering that acanthosis nigricans is not a typical feature of this condition, these may probably represent obesity related complications in PHP1a patients [57]. In a cross-sectional, case-control study, people with PHP1a were more likely to develop diabetes than those of the same age matched according to percentage of body fat [58]. Indeed, in 8 PHP1a cases hemoglobin A1c (HbA1c) and fasting plasma glucose were significantly higher than in 24 healthy controls (P: 0.04 and P:0.02, respectively) [58]. When compared to similarly obese controls, PHP1a patients had lower insulin sensitivity, indicating that factors other than obesity contribute to lower insulin sensitivity in these patients [58]. A possible mechanism involved is the participation of Gsa in the response to glucagon-like peptide 1 (GLP1) and other incretin hormones in pancreatic islet cells Fig. 2 [59].
Hence, the relationship between metabolic alterations and hypo/pseudoPTH has never been evaluated considering altered PTH homeostasis.

Conclusions
This review highlights the possible implications between MetS and parathyroid diseases, identifying studies showing significant associations only in patient with hyperPTH or pseudoPTH. Regarding hyperPTH, all MetS' components show significant associations, demonstrating how overweight, obesity, hypertension, diabetes and dyslipidemia are more prevalent in hyperPTH patients than in general population. However, a possible pathogenetic mechanism has been hypothesized only for obesity, as PTH-induced hypercalcemia could be responsible for the decrease in adipocyte lipolysis. Moreover, it is necessary to further clarify the role of parathyroidectomy in the improvement or resolution of MetS' components. In pseudoPTH, the association with obesity seems to be caused by Gsa subunit alteration regulating transcriptional cascades of genes involved in the etiopathogenesis of weight gai. On the other hand, literature data are currently insufficient to clarify the role of MetS in hypoparathyroid patient.
Given the increasing MetS global prevalence and the higher parathyroid diseases awareness and diagnosis, it may be interesting to further explore the possible role of alterations in parathyroid homeostasis in the development of MetS components with dedicated prospective studies.