•Thiazide challenge: in a normocalcemic patient with hypercalciuria and a high serum PTH concentration, a thiazide challenge test has been proposed to help in differentiating SHPT due to a renal calcium leak from normocalcemic [28]. After 2 weeks of thiazide treatment (50 mg/day), a new set of laboratory tests will be performed. If the initial hypercalciuria was due to a renal calcium leak, calciuria and PTH will be significantly reduced (often normalized) without hypercalcemia. If the initial hypercalciuria was due to NPHPT, hypercalcemia may be unmasked with only a moderate decrease in PTH concentration, which usually remains elevated. It must be noted that salt intake must be strictly limited during the thiazide treatment period for the test to be efficient.
•Calcium load test: a calcium loading test has also been proposed; it is a useful tool for this diagnosis if it shows that serum PTH is not sufficiently decreased when calcemia rises starkly above the upper normal limit [29]. Calcium and PTH levels were measured before, 60, 120, and 180 min after oral administration of 1 g of calcium gluconolactate. By calculating the product P, defined as circulating PTH nadir (pg/mL) × peak calcium concentration (mg/dL) (normal threshold 260), and ratio R, defined as relative PTH decline/relative calcium increment (normal threshold 17), the combined parameters diagnose normocalcemic hyperparathyroid patients with 100% sensitivity and 87% specificity [29].
•Kidney function: in the RECORD-IT (Report of Comorbidities in Non-Dialysis Renal Disease Population in Italy) study cohort, 31.5% of nondialysis chronic kidney disease (CKD) patients with KDIGO stage 3b–5 with PTH above this value did not receive any PTH-lowering pharmacologic treatment [30].
Fig. 3. PHPT-related symptoms and signs. AF, atrial fibrillation; VT, ventricular tachyarrhythmia; eGFR, estimated glomerular filtration rate.
Clinical Features
Most patients with NPHPT are postmenopausal women with a mean BMI higher than that of HPHPT patients [21]. It is relevant to note that PTH-related disorders also occur in NPHPT patients (Fig. 3; Table 1), supporting the need to be extensively evaluated at diagnosis and follow-up. Here, the available data about the prevalence of the PTH-related disorders are summarized:
Kidney Disease
Lowe et al. [31] evaluated 37 patients with NPHPT and found rather high prevalence rates of nephrolithiasis (14%). Similarly, Amaral et al. [32] compared patients with NPHPT and mild HPHPT and found no difference in the prevalence of fractures and nephrolithiasis between the groups. The frequency of nephrolithiasis was 18.2% in NPHPT and 18.9% in the HPHPT patients.
Bone disease
Charopoulos et al. [33] examined the effects of PHPT in the skeleton by using peripheral quantitative CT comparing NPHPT with HPHPT. Catabolic effects were detected in both groups, but were more pronounced in hypercalcemic subjects than in normocalcemic subjects. Cortical geometric properties were also adversely affected in NPHPT subjects; however, trabecular properties were preserved in NPHPT [33]. There was no difference in the trabecular bone score (TBS) between NPHPT and HPHPT patients. However, there was a reduction in the TBS of patients with asymptomatic HPHPT that was related to PTH levels but had no repercussion on bone mass. Higher levels of PTH seem to be responsible 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