that patients with hypercalcemic PHPT (HPHPT) may have normal serum and ionized calcium levels at times during their disease course, though they are hypercalcemic the majority of the time.
Increased Serum PTH Concentrations
Secondary causes of an elevated PTH level must be ruled out, such as renal disease, vitamin D deficiency, renal hypercalciuria, gastrointestinal disorders associated with calcium malabsorption, or the use of loop diuretics and lithium. Therefore, the definition of “elevated PTH,” depending on the upper limit of the PTH reference values, is crucial. It has been demonstrated that excluding subjects with a low serum 25 hydroxyvitamin D [25(OH)D] concentration from a reference population decreased the upper limit of serum PTH by 20–35% depending on the assay considered [2–4]. Other factors may influence serum PTH levels, such as age and BMI.
The motivating purpose for maxPTH creation was the hypothesis that, by defining a more subject-specific, personalized upper limit of normal PTH, the challenge of discriminating between some diagnostic variants of PHPT and secondary hyperparathyroidism (SHPT) may be easier than using a static PTH lab reference range [5]. maxPTH was calculated using the formula maxPTH = 120 – (6·calcium) – [0.5·26(OH)D] + (0.25·age) [5]. The Mi-PTH (MultIdimensional Predictive Hyperparathyroid) model was created based on retrospective data. The model included all the variables of the original maxPTH equation with the inclusion of the subject’s measured PTH level. With Mi-PTH, the model is designed to account for changes in PTH levels that are expected on the basis of the subject’s age, calcium, and 25(OH)D, whereas in primary hyperparathyroid diseases, PTH production is independent of these factors. Of note, serum creatinine levels were not included in this model because the relationship of PTH with creatinine is not clearly linear in nature as it is with vitamin D and calcium. Mi-PTH improved on specificity and PPV for patients with normocalcemic hyperparathyroidism [6].
Similarly, Lavryk and Siperstein [7] created a nomogram by plotting PTH versus calcium for the 2 groups. The comparison of control and disease groups showed a clear demarcation zone on the plots of calcium versus PTH. In the group of PHPT, 70% had classic PHPT presentation with the concomitant elevation of both calcium (>10.5 mg/dL) and PTH (>65 pg/dL); 21% had “normocalcemic” PHPT with calcium <10.5 mg/dL and PTH >65 pg/dL; 6% had “normohormonal” PHPT with calcium >10.5 mg/dL and PTH <65 pg/dL, and 3% had both calcium and PTH within the reference range. Overall, 68.5% of patients had single adenoma, 16% double adenoma, and 15.5% hyperplasia. The nomogram serves as a diagnostic tool to distinguish normal patients from those with PHPT, particularly those with atypical presentations.
It should be remembered that PTH elevation and concomitant normocalcemia can also be detected in HPHPT patients after 1–24 months from successful parathyroidectomy. Patients who had severe hyperparathyroidism with high preoperative serum calcium and PTH levels are more prone to normocalcemic PTH elevation postsurgery [8].
Epidemiology
In the last 2 decades, patients with elevated serum PTH levels and normocalcemia in the absence of secondary causes have been increasingly described. Prevalence widely varies in the different cohorts; in particular:
•General population: in unselected, nonreferral populations, such as The Osteoporotic Fractures in Men (MrOS) study and Dallas Heart Study (DHS), the prevalence was of 0.4 and 0.6%, respectively [9]. Similarly, a survey carried out in 2010 in Pescopagano, a village in Southern Italy [10], detected NPHPT in 0.44% of an unselected sample of the whole community of adults.
•Postmenopausal women: in 5,202 women (aged 55–75 years) attending a population-based mammography screening, NPHPT was diagnosed in 1.4%. Indeed, at repeated examination, just one-third showed persistent normocalcemia and hyperparathyroidism [11], therefore revealing a prevalence overlapping that was defined in the general population.
•Postmenopausal osteoporotic women: the prevalence of NPHPT reported in a postmenopausal series evaluated 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