for this alteration in microarchitecture texture [34].
Considering the clinical setting, osteoporosis and fragility fractures were diagnosed in 57 and 11% of a series of NPHPT patients [31]. In agreement with these data, 15% of NPHPT patients had a previous history of fractures compared to 10.8% of NPHPT patients in an independent series [32].
Hypertension and Cardiovascular Risk
NPHPT patients had a higher risk of high blood pressure than subjects with normal PTH [35]; in particular, the subjects with NPHPT had higher levels of blood pressure than the subjects in the cohort with normal PTH. After adjustment for all potential confounders, the difference was still statistically significant. NPHPT is therefore a good model to analyze the different effects of hypercalcemia versus hyperparathyroidism on blood pressure. PTH has been shown to increase the cardiovascular risk by: (1) acting on endothelial cells of the vascular walls and myocardium leading to vascular stiffness and left ventricular hypertrophy; (2) activating the renin-aldosterone system, the secretion of cortisol from the adrenal cortex, and sympathetic activity [36].
Besides these data, NPHPT failed to be associated with the coronary calcium score, which is correlated with coronary artery disease [37]. Although there are no data in the current literature on mortality in NPHPT [38], it has been demonstrated that cardiovascular risk factors are almost similar in NPHPT compared to HPHPT, thus strengthening the role of PTH in cardiovascular involvement. Indeed, in the general population, higher serum levels of PTH are associated with increased risk of fatal cardiovascular disease events [39].
Nonetheless, in the general population, PTH correlated positively with baseline body mass index, fat mass, diastolic blood pressure, triglycerides, total and low-density lipoprotein cholesterol, and with the category of coronary artery calcium score. Therefore, some authors suggested that adiposity should be considered as an independent cause of SHPT and that all these cardiometabolic parameters may be relevant to patients with NPHPT, in whom high PTH levels may be a marker of adiposity and cardiometabolic risk rather than always indicating parathyroid autonomy [40].
Glucose Metabolism
Increased rates of insulin resistance and glucose intolerance could not be detected in 18 NPHPT patients [41]. Similarly, Tassone et al. [42] also showed that patients with NPHPT have similar insulin sensitivity and glucose tolerance with age- and sex-matched control subjects. The 4-year follow-up after the first clinical evaluation showed that there are no relevant changes in the glucose tolerance status of patients with NPHPT [43]. Therefore, in contrast with what has been reported in HPHPT patients, glucose metabolism is not affected in NPHPT patients.
Pregnancy
The fetal loss rate increased directly with increasing maternal serum calcium levels and was most evident when measured levels were above 11.4 mg/dL. Because pregnancy is normally associated with a decrease in serum calcium and suppression of PTH, an increased serum calcium level with detectable PTH during this time indicates maternal PHPT. Mild hypercalcemia in gestational PHPT is generally not associated with an increased risk of obstetrical complications [44]. The study lacked NPHPT, therefore data about an increased risk of preeclampsia due to hyperparathyroidism in NPHPT are not available.
Parathyroid Gland Tumors
NPHPT has been reported to be associated with a high incidence of multi-gland disease compared with HPHPT (45 vs. 37%) [45]. The high prevalence of multi-gland involvement may represent a challenge for successful surgery and should be considered in the evaluation for parathyroidectomy. Notably, a case of NPHPT sustained by a histologically diagnosed parathyroid carcinoma has been reported [46].
Natural History
Data relating to NPHPT natural history are scanty. It is thought that years prior to a clinical diagnosis of PHPT, calcium homeostasis shows signs of perturbations. Latent PHPT may be characterized by either NPHPT or normoparathyroid hypercalcemia. Such patients should be offered long-term follow-up to ascertain whether their biochemical profile represents an early state of PHPT. Rejnmark et al. [47] found that the time from inclusion until a diagnosis of PHPT was a median of 5.6 years. Parathyroidectomy was performed in 97%. At the cohort inclusion, undiagnosed PHPT was present in 63% of the cases. Among those without HPHPT at inclusion (n = 43), 55% had NPHPT and 31% had normoparathyroid hypercalcemia. Overall, 25(OH)D levels were lower in the cases. Compared with their matched controls, 25(OH)D levels were lower in NPHPT but not in normoparathyroid hypercalcemia. An adenoma was removed from 78% of the cases with NPHPT, whereas 39% of the cases with normoparathyroid hypercalcemia had parathyroid hyperplasia [47].
Therapeutic Management
Effects of Parathyroidectomy
Considering that surgery is the only potentially curable option for patients with PHPT, there is universal agreement that all symptomatic as well as asymptomatic patients with significant kidney and bone signs of the disease, have clear indications to surgical treatment. Less certain are patients who do not meet the criteria and, in particular, do not experience hypercalcemia. The Fourth International Workshop on the management of symptomatic PHPT [25] proposed an algorithm for the management of NPHPT patients; the panel of experts suggested, based on the monitoring of serum calcium and PTH annually and bone density by DXA (dual-energy X-ray absorptiometry) every 1–2 years, to consider surgery in the following conditions:
•Progression to HPHPT: indication to parathyroidectomy according to the guidelines;
•Progression of the disease, that means worsening of BMD or occurrence of an osteoporotic fracture and/or diagnosis of kidney stones or nephrocalcinosis.
Successful parathyroidectomy has been reported to be followed at 1 year by a significant individual BMD gain in nearly half of NPHPT patients with osteoporosis. Elevated alkaline phosphatase levels above the median could contribute to the therapeutic decision in this context [48, 49].
From a surgical point of view, it should be considered that 63% of PHPT patients with preoperative normal ionized calcium had an adenoma involving a single gland, which was correctly identified by preoperative imaging in 60% of cases. Intraoperative PTH assay identified the cure in 75% of PHPT patients with normal ionized calcium
