BACKGROUND: Primary hyperparathyroidism (PHPT), a condition that manifests in various clinical forms, is a significant health concern. Normocalcemic primary hyperparathyroidism (NPHPT) is characterized by normal calcemia despite elevated parathyroid hormone (PTH) levels. Vitamin D deficiency can contribute to the clinical spectrum and complexity of NPHPT. Low vitamin D levels can elevate PTH, making it difficult to distinguish between NPHPT and secondary hyperparathyroidism. Additionally, it might mask hypercalcemia, leading to an underestimation of the disease severity. Our study aims to shed light on these complexities by investigating normocalcemic and hypercalcemic PHPT patient\'s clinical, hormonal, and biochemical patterns, including their vitamin D status.    Materials: In this retrospective study, we enrolled 60 PHPT patients with autonomous parathyroid function confirmed using a combination of ultrasonography, radionuclide scan, and parathyroid function index calculation. We evaluated the albumin-corrected calcemia, calciuria, PTH, 25(OH)D level, serum phosphate, bone mineral density, and major clinical symptoms (fracture, nephrolithiasis). A comparative analysis and a correlation study were performed between normo- and hypercalcemic and vitamin D-deficient and vitamin D-non-deficient groups.
RESULTS:  The median age was 62 years, 51.66% (31/60) being normocalcemic and 46.66% (29/60) presenting a deficient 25(OH)D level. In the group with 25(OH)D below 20 ng/mL, we observed a reduced level of albumin-corrected calcemia, without a significant increase of PTH compared to the adequate 25(OH)D level group. The frequency of the NPHPT and the risk of fracture were significantly higher in the deficient 25(OH)D group (20/60, 33.33% and 8/60, 13.33%) than in the adequate one (11/60, 18.33% and 1/60, 1.66%) with OR=4.7 (p<0.004) and OR=9.7 (p<0.027), respectively. We also found a positive correlation between PTH and adenoma size, the parathyroid function index and adenoma size, as well as PTH and phosphate levels. However, the correlation between 25(OH)D and phosphate levels was negative and moderate (rho=-0.504, p<0.001), adding a new layer of complexity to our understanding of these relationships.
CONCLUSIONS: Our study provided significant insight into the link between vitamin D status and normocalcemic PHPT. We found that vitamin D-deficient patients with normocalcemic PHPT have an increased fracture risk, which requires meticulous monitoring and possible supplementation with vitamin D. This should be done carefully to avoid exacerbating hypercalcemia or hypercalciuria. Further research is needed to refine these management strategies and deepen our understanding of the complex relationships between the analyzed parameters.

Primary hyperparathyroidism (PHPT) is commonly diagnosed in the setting of hypercalcemia, whereas normocalcemic primary hyperparathyroidism (NHPT) may be misdiagnosed.
Our objective was to compare hypercalcemic hyperparathyroidism (HPHPT) versus NHPT hypercalciuric renal stone patients.
We took advantage of a routine calcium load test performed in hypercalciuric renal stone patients to assess retrospectively among PHPT patients, prevalence and characteristics of NHPT and HPHPT under a calcium restricted diet.
Among 1671 hypercalciuric patients included, 91 patients have a final diagnosis of PHPT(post load ionized calcium (iCa)>1.31 mmol/L and PTH>30 pg/ml). Prevalence of NHPT is 40% of all PHPT, however according to total serum calcium 4/35 NHPT and 7/56 HPHPT would have been misclassified in the other group. 18/35 NHPT and 40/56 HPHPT underwent parathyroidectomy. No significant characteristics related to parathyroid weight, stone composition or bone remodeling biomarkers is detected between groups. Whereas iCa is higher in HPHPT in fasting state and after calcium load, we found no difference for calcium diet, 24-hour calciuria, or calcitriol. Of notice, renal calcium excretion (FECa) post load increases by 303% in NHPT but only 176% in HPHPT (p=0.01) likely explained by a lesser PTH decrease (p=0.02). However, a strong negative association (p<0.0001) detected between pooled pre and post load iCa and PTH only in NHPT group suggests a persistent efficient PTH-CaSR control within parathyroid glands in this group.
Our data show the relevance of dynamic tests to unmask NHPT in hypercalciuric renal stone patients.

OBJECTIVE: To investigate the occurrence of arrhythmias in patients with normocalcemic (NC) primary hyperparathyroidism (PHPT) compared to both hypercalcemic PHPT patients and control subjects by means of 24-h Holter ECG.
METHODS: Thirteen NCPHPT postmenopausal patients were enrolled and age-matched with 13 hypercalcemic PHPT patients and 13 controls. Every subject underwent basal ECG, 24-h Holter ECG and mineral metabolism biochemical evaluation.
RESULTS: PHPT patients had higher mean serum calcium levels compared to both NCPHPT and controls; there was no difference in mean serum calcium levels between NCPHPT and controls. Both NCPHPT and PHPT patients had significantly higher mean PTH levels compared with controls. There were no differences in ECG parameters between the three groups, except for QTc interval. PHPT patients had normal QTc interval values, but significantly shorter mean values compared with those of controls and NCPHPT patients. During 24-h Holter ECG recording, 100% of PHPT patients had supraventricular premature beats (SVPBs), compared to 46% of NCPHPT (p = 0.005) and to 53% of controls (p = 0.01). PHPT patients experienced ventricular premature beats (VPBs) (69.2%) vs 15% of NCPHPT patients (p = 0.01) and 23% of controls (p = 0.04). There was no difference between NCPHPT and controls subjects concerning occurrence of both VPBs and SVPBs.
CONCLUSIONS: NCPHPT patients did not experience an increased occurrence of arrhythmias compared to controls, while PHPT patients showed an increased occurrence compared to both controls and NCPHPT. Our findings are most probably related to the short QTc interval caused by hypercalcemia observed in PHPT patients, but not in NCPHPT.

Cure after surgery for normocalcemic primary hyperparathyroidism (NHPT) is defined as parathyroid hormone (PTH) normalization. However, an increase of PTH is frequently observed in cured patients with hypercalcemic primary hyperparathyroidism (HHPT). Therefore, this criterion must be redefined. A single-center retrospective study was performed including all patients who underwent surgery for Primary Hyperparathyroidism from 2013 to 2019. Cure rates of different types of hyperparathyroidism were analyzed. PTH reduction was studied as a possible criterion to define cure in patients with NHPT. One-hundred and eighty-six patients were included: 173 with HHPT and 13 with NHPT. After a mean follow-up of 33.4 months, 174 (93.6%) patients were considered cured. Cure was more frequent in the group of patients with HHPT (97.1% vs. 46.2%, p < 0.001). In the multivariate analysis, surgical failure was associated with NHPT and multiglandular disease. Forty-nine (30.1%) cured patients with HHPT had an increased PTH during the follow-up. When decline of PTH levels was studied in patients with HHPT to define cure, the area under curve was 0.92. A cut-off value of 40% in PTH reduction achieved a sensitivity and specificity of 83.4% and 80.0%. If cure was defined as a 40% reduction of PTH, cure rate in the group of patients with NHPT would increase to 69.2%. Patients with NHPT had a lower cure rate than patients with HHPT. A significant number of cured patients with HHPT had an increased PTH during follow-up. A 40% reduction in PTH levels is proposed as an alternative definition for cure in patients with NHPT.

Parathyroidectomy has ameliorated cardiovascular risk factors in patients with hypercalcemic primary hyperparathyroidism (PHPT), but the effect of parathyroidectomy on normocalcemic PHPT is not exactly known. This case-controlled study aimed to investigate the effect of parathyroidectomy on cardiovascular risk factors in patients with normocalcemic and hypercalcemic PHPT.
Subjects with normocalcemic PHPT (n = 35), age- and sex-matched hypercalcemic PHPT (n = 60) and age- and sex-matched control (n = 60) were included. Cardiometabolic disorders were investigated with traditional cardiometabolic risk factors and the Framingham cardiovascular risk score (CRS) before and 6 months after parathyroidectomy.
Diabetes, dyslipidemia, hypertension, obesity, insulin resistance, osteoporosis, having fractures were similarly increased in the hypercalcemic and normocalcemic PHPT groups (p > 0.05) compared with the controls (p < 0.05). Blood pressures, glucose metabolism (glucose, insulin, HOMA-IR) and lipid profiles were similarly increased in the PHPT groups (p > 0.05) compared with the controls (p < 0.05). After parathyroidectomy, blood pressures, serum total cholesterol, and HOMA-IR were decreased in both PHPT groups (p < 0.05). CRS was lower in the controls (5.74 ± 3.24, p < 0.05). After parathyroidectomy, CRS was decreased in the normocalcemic (11.98 ± 10.11 vs. 7.37 ± 4.48) and hypercalcemic (14.62 ± 11.06 vs. 8.05 ± 7.72) PHPT groups. Increased blood pressures were independent predictors of serum iPTH.
The normocalcemic and hypercalcemic PHPT groups had similarly increased cardiovascular risk factors, even independently of serum calcium. Parathyroidectomy ameliorated the increased cardiovascular risk factors in both normocalcemic and hypercalcemic PHPT.