Table 5.
Studies evaluating natural history of normocalcemic hyperparathyroidism
| Study | Study Population; Duration of Follow-up | Definition of NPHPT | Progression to Hypercalcemia |
|---|---|---|---|
| Ayturk et al (24) | 20; 18 mo (6-mo intervals) | Normal Ca and high PTH confirmed in at least 3 measurements. Excluded chronic renal or liver failure, vitamin D deficiency, secondary hyperparathyroidism, treatment with lithium. No treatments with thiazide and loop diuretics, phenytoin, lithium, glucocorticoids, or oral contraceptives during study | None progressed to hypercalcemia |
| Tordjman et al (25) | 20; 4.1 ± 3.2 y | Normal total Ca and high PTH secondary hyperparathyroidism excluded (impaired renal function). Three patients had low vitamin D levels but correction did not alter PTH levels and did not unmask hypercalcemia. Six patients had > 300 mg/24 h urine Ca and were given thiazides without affecting PTH levels. Persistence not checked at baseline | None of the patients developed hypercalcemia. Mean serum calcium levels did not change significantly (baseline vs last) |
| Garcia-Martin et al (19) | 6; 1 y | Normal adjusted Ca and high PTH. 25(OH)D > 30 ng/mL, normal renal function (creatinine clearance > 70 mL/min/1.73 m2). Persistence not checked at baseline | All patients remained normocalcemic |
| Cusano et al (18) | 64; 8 y | Normal albumin-adjusted Ca and high PTH. Excluded renal insufficiency (GFR < 60 mL/min), 25(OH)D ≤ 20 ng/mL, thiazide or lithium use. Persistence not checked at baseline | Hypercalcemia: 1 (1.6%). Persistent normal Ca, high PTH: 13 (20%) |
| Diri et al (26) | 16; 4 y | Normal total Ca and high PTH, 25(OH)D > 20 ng/mL, repeated Ca and PTH measurements 3× with 2-wk intervals, no history of renal or liver diseases, no prescriptions known to affect Ca level | One (6.25%) developed hypercalcemia |
| Kontogeorgos et al (20) | 12; 13 y. First assessment 1995, second 2008 to 2009, participation rate 67% | Normal total Ca and high PTH, 25(OH) ≥ 50 nmol/L, normal renal function | One (8.33%) developed hypercalcemia. Persistent normal Ca, high PTH: 1 (8.33%). Two had vitamin D deficiency, normal Ca, and high PTH |
| Silverberg et al (27) | 22; up to 1 y | Normal adjusted calcium and high PTH. Confirmed on at least 2 occasions, 8 patients had normal ionized Ca, 25(OH) D > 20 ng/mL. Excluded FHH, liver disease, renal disease, urinary calcium > 87.5mmol/24h, GI disease with malabsorption, metabolic bone disease, medications (lithium, thiazide, oestrogens, loop diuretics, bisphosphonates, anticonvulsants) | Three (14%) developed hypercalcemia |
| Siprova et al (16) | 187; 1 to 7 y | Normal total and ionized Ca and high PTH. 25(OH)D ≥ 20 ng/ ml (patients with low vitamin D were treated, and PTH had to be elevated after retested at 3 mo). Excluded cases with renal insufficiency, calcium malabsorption, hypercalciuria, medications (PPI, thiazides, lithium) | 151 (81%) remained normocalcemic for whole follow-up period. 36 (19%) became hypercalcemic |
| Lowe et al (29) | 37; 3.1 ± 0.3 y | Normal adjusted Ca and high PTH, 25(OH)D ≥ 50 nmol/L Excluded cases with renal insufficiency (GFR < 40 mL/min/1.73 m2), liver disease; significant hypercalciuria > 350 mg/24 h, thiazide diuretic or lithium use, other metabolic bone diseases (eg, Paget disease) | Seven (19%) became hypercalcemic. Patients who became hypercalcemic had higher Ca levels, higher urinary calcium excretion, and were older |
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; Ca, calcium; eGFR, estimated glomerular filtration rate; FHH, familial hypocalciuric hypercalcemia; NA, not available; NPHPT, normocalcemic hyperparathyroidism; PHPT: primary hyperparathyroidism; PPI, proton pump inhibitor; PTH, parathyroid hormone.