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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, a number of items should be considered:

•Serum calcium, phosphate, and PTH undergo marked circadian variations. Evaluation should always be performed in the morning after an overnight fasting in asymptomatic subjects. In emergency rooms, when symptoms of hyper- or hypocalcemia are evident, evaluation needs to be immediate. Ingestion of food containing significant amounts of calcium will increase serum calcium and decrease PTH; salt, protein, and glucides may increase urine calcium excretion.

•Ionized calcium: when serum total and ionized calcium values in patients with PHPT are compared, ionized calcium values are more frequently elevated than total calcium values [21, 26]. Ionized calcium is highly influenced by the pH; the affinity of albumin for calcium increases when the pH increases, and decreases when the pH decreases. Therefore, ionized calcium will be lower in the case of alkalosis and higher in the case of acidosis. Determination of ionized calcium suffers from frequent preanalytical problems (avoiding venous stasis and tourniquet use, respect for anaerobiosis).

Table 1. Causes of SHPT, which should be ruled out in the diagnostic workout of NPHPT; biochemical markers, normal values, and main treatments are suggested

•Calciuria measured on 24-h urine collections (ideally expressed in mg/kg body weight/24 h) represents intestinal absorption of calcium, while the second morning void obtained after an overnight fast, expressed as a ratio to creatininuria, represents an index of bone resorption as the measured calcium may only come from bone. The reference range of urine calcium excretion has been established in normal subjects whose calcium intake was approximately 1,000 mg/day; therefore, calcium intake should be considered and verified concomitantly with urine collection for 24-h calciuria. Questionnaires are freely available online (for example from the International Osteoporosis Foundation, www.iofbonehealth.org/calcium-calculator).

•Measurement of phosphatemia needs to avoid hemolyzed samples and reference values vary with age: 1.50–2.30 mmol/L in newborns less than 1 month old; 1.50–2.00 mmol/L from 1 month to 2 years; 1.40–1.70 mmol/L from 2 to 12 years; 1.00–1.50 mmol/L from 12 to 16 years, and 0.80–1.40 in adults.

•Phosphaturia, best calculated as TmP/GFR, should be measured in case of hypophosphatemia to determine whether this anomaly is due to renal leak (tubular acidosis, FGF23 excess) or to another cause. A low TmP/GFR in the presence of hypophosphatemia suggests renal phosphate leak.

•Pregnancy: NPHPT should not be diagnosed in pregnant women. Hypoalbuminemia, increased GFR, transplacental transfer of calcium, and increased levels of estrogen all contribute to lowering gestational serum calcium levels and the masking of HPHPT [27].

•Vitamin D replacement: subjects with elevated PTH and normal calcium levels and vitamin D insufficiency may fall into 1 of the following 3 categories: (a) they may have HPHPT and their low calcium level is secondary to the impaired vitamin D status: such patients may become hypercalcemic when their vitamin D is replaced; (b) some of these patients may have elevated PTH due to their impaired vitamin D status: such subjects are expected to achieve normal PTH levels when their vitamin D status is replaced, and (c) those with true NPHPT in whom serum calcium remains normal and PTH is not suppressed after replacement with vitamin D.

•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.