for skeletal health was of 6% [12]. Similarly, a retrospective analysis of biochemical parameters in a Pakistan bone health screening panel detected NPHPT in 8.5% of cases [13]. Nonetheless, the diagnostic criteria used for NPHPT, measurement of the ionized calcium, and exclusion of all causes of SHPT differed throughout the series.
Pathophysiology
Parathyroid tumorigenesis is far from being elucidated. When parathyroid tumors become clinically evident, they are likely to have been present for some time, preventing the opportunity to investigate the tumor initiation. Moreover, follow-up for 10 years did not detect significant progression in more than three-quarters of cases, which can be consistent with a steady state in cell proliferation in most tumors [14]. Though the development of PHPT in animal models has not been carefully investigated, hypercalcemia is associated with parathyroid tumors in all models: homozygous knockout mice for the gene encoding the calcium-sensing receptor (CASR) developed hypercalcemia followed by parathyroid cell hyperplasia [15]; specific overexpression of the gene encoding for cyclin D1 (CCND1) in parathyroid cells also firstly developed hypercalcemia [16], and MEN1 (multiple endocrine neoplasia type 1) mutant mice developed hypercalcemia [17]. Therefore, the available mouse models of parathyroid tumorigenesis do not resemble the clinical presentation of NPHPT. Moreover, data on the specific genetic background of the parathyroid tumors associated with NPHPT are lacking. Therefore, the following hypotheses have been provided so far:
1. Subclinical phase of PHPT: NPHPT may represent an early and/or a mild variety of PHPT [11]. It is postulated that clinical manifestations of PHPT develop chronologically in 2 phases: the first, early/mild phase has normal levels of calcium in the setting of increased PTH, whereas the second phase is recognizable as classical PHPT, where hypercalcemia occurs with increased levels of PTH [18].
2. Response to persistent hypocalcemic stimuli: a primary renal calcium leak leading to SHPT and eventually autonomous hyperparathyroidism has been proposed to explain the absence of hypercalcemia in some cases of PHPT [19]. This hypothesis is also supported by recent data showing that hypercalciuria persists after successful parathyroidectomy in almost a third of PHPT patients [20]. Other variables, which may increase PTH secretion, such as age, BMI, waist circumference, calcium intake, subclinical gastrointestinal disorders, etc., might cumulate in an individual patient to trigger hyperparathyroidism. Therefore, the possibility that NPHPT may represent an early phase of nonclassical SHPT cannot be excluded.
3. Bone and kidney resistance to PTH action: Maruani et al. [21] reported that about 20% of patients with PHPT are able to maintain a normal serum calcium concentration despite the primary increase in PTH secretion, and that the maintenance of a normal serum calcium concentration is in part related to bone and kidney resistance to the biological actions of PTH. In particular, the net bone calcium release, as assessed by the fasting urine calcium and urine creatinine ratio (UCa/UCr), was lower in the normocalcemic than in the hypercalcemic subgroup. The markers of bone turnover were also lower in the normocalcemic than in the hypercalcemic subgroup. The ability of the renal tubule to reabsorb calcium was lower in the former than the latter group of patients. In addition, the ability of PTH to decrease tubular phosphate reabsorption and stimulate synthesis of 1,25-dihydroxyvitamin D is also blunted in patients who remain normocalcemic, compared with those who are hypercalcemic. Therefore, at least 3 PTH-dependent functions of the kidney are attenuated in NPHPT patients despite an identical primary hypersecretion of PTH, demonstrating a partial renal resistance to the physiological actions of PTH. However, the nephrogenous cAMP secretion is indistinguishable between normocalcemic and hypercalcemic matched subgroups, indicating that the amount of serum bioactive PTH (1–84) is the same in both subsets of patients. Estrogen supply appears to induce some degree of bone and kidney resistance to the effects of PTH in PHPT women, similar to what is observed in patients with NPHPT. However, patients with NPHPT had a higher BMI than hypercalcemic patients. This higher BMI could explain a higher residual estrogen production related to a greater mass of adipose tissue, which is an important site of estrogen biosynthesis in postmenopausal women [21].
In line with the potential effect of estrogens as inductors of PTH resistance, an orphan adhesion G protein-coupled receptor, GPR64/ADGRG2, has been discovered expressed in human normal parathyroid glands and overexpressed in parathyroid tumors from PHPT patients. Interestingly, GPR64 physically interacts with CASR and its activation increases PTH release from human parathyroid cells at a range of calcium concentrations [22].
4. Polymorphisms of CASR and PTH genes in NPHPT: A986S polymorphism of the CASR has been evaluated as a determinant of PTH resistance in NPHPT and asymptomatic PHPT [23]. The CASR A986S polymorphism has been extensively linked to PTH resistance and higher calcium levels in population-based studies. Though A986S CASR variants do not seem to be major genetic determinants for the development of PHPT, even in earlier or asymptomatic forms, in NPHPT, only the A986S genotype was an independent predictor of PTH levels even after adjusting for major confounding factors such as vitamin D levels and serum calcium concentrations. Therefore, PTH levels in NPHPT may be partially regulated by the A986S polymorphism, acting as a resistance factor due to a relative loss of CASR function.
PTH gene polymorphisms have been associated with a disease severity in classical PHPT. In asymptomatic PHPT patients, the GG genotype of the rs6254GA polymorphism was associated with a significantly higher PTH level and lower bone mineral density (BMD) at the femoral neck, proximal femur, and lumbar spine. The association failed to be demonstrated in NPHPT patients [24].
Diagnosis
The diagnostic approach to an “isolated” elevated PTH (Fig. 1) may be a step-by-step process: as the first step, causes of evident SHPT should be ruled out; the second step considers the diagnosis of NPHPT if no causes of SHPT are identified and if serum calcium is in the upper half of the normal range; at this point, in order to complete the diagnostic workup, PHPT-related bone and kidney diseases should be evaluated. Some conditions are evident in which it is possible to elevate PTH levels, while others are asymptomatic and need to be investigated. Among these conditions, vitamin D insufficiency occurs frequently.
This diagnostic workup to exclude causes of SHPT (Table 1) has been strongly recommended in the 2 most recent guidelines on the diagnosis and management of asymptomatic PHPT published in 2009 [1] and 2014 [25]. First-line exploration may include serum calcium, albumin, phosphate, PTH, and 25(OH)D, 24-h calciuria, serum creatinine, and estimated glomerular filtration rate (eGFR). A second-line exploration will include ionized calcium, 24-h phosphaturia and creatininuria (and calculation of TmP/GFR), serum alkaline phosphatase, TSH, and magnesium.
In performing the biochemical screening,
