2019 S. Karger AG, Basel
Parathyroid hormone (PTH) is generating great interest as it is a master regulator of the bone metabolism and a marker of cardiometabolic risk. Though PTH has often been used as a marker for the differential diagnosis of hypercalcemic disorders, nowadays it is widely measured in normocalcemic subjects in the set of the diagnostic workflow for osteoporosis and bone metabolic diseases. In this context, most individuals have been diagnosed with normocalcemic primary hyperparathyroidism (NPHPT).
Fig. 1. Spectrum of parathyroid disorders according to serum calcium and PTH levels. ↑, increased; ↓, decreased; ◆, hypercalcemic disorders; ○ (small circles), normocalcemic disorders; ■, hypocalcemic disorders; ○ (large circle), NPHPT. SHPT, secondary hyperparathyroidism; hypo-PTH, hypoparathyroidism; hyper-PTH, hyperparathyroidism; pseudohypo-PT, pseudohypoparathyroidism; N, normal serum PTH levels. Dashed lines indicate the thresholds of serum PTH levels for the diagnosis of hypoparathyroidism (40.0 pg/mL) and hyperparathyroidism (65 pg/mL).
Primary hyperparathyroidism (PHPT) is sustained by autonomous PTH release from one or more parathyroid glands and includes a wide spectrum of clinical presentations (Fig. 1). Besides severe symptomatic and sometimes life-threatening hypercalcemia, PHPT often occurs with mild asymptomatic hypercalcemia. Symptoms related to hyperparathyroidism span throughout the different clinical presentations (Fig. 2). This wide spectrum includes NPHPT, which was firstly recognized in 2008 by the panel of experts of the Third International Workshop on Asymptomatic Primary Hyperparathyroidism [1], who positively answered the question: “Is normocalcemic hyperparathyroidism, which is defined as normal serum calcium with raised PTH in the absence of any common cause of secondary normocalcemic hyperparathyroidism, part of the diagnostic spectrum?”
Fig. 2. Spectrum of PHPT clinical presentations according to serum calcium levels; kidney and bone diseases are transversal to the different clinical presentations. The serum calcium threshold suggested as an indication for parathyroidectomy in asymptomatic PHPT by the most recent guidelines is reported. PTX, parathyroidectomy; eGFR, estimated glomerular filtration rate; FHH, familial hypocalciuric hypercalcemia; *, according the most recent guidelines [25].
Definition
NPHPT is defined as persistent fasting normocalcemia associated with an increased serum PTH concentration.
Fasting Normocalcemia
The diagnostic criteria for NPHPT include consistently normal albumin-adjusted total serum calcium and normal ionized calcium. It should be considered 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
