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Normocalcemic primary hyperparathyroidism (NPHPT), a phenotype of primary hyperparathyroidism, is characterized by elevated parathyroid hormone levels in the setting of persistently normal serum calcium. Diagnosis of NPHPT can be challenging and requires that secondary causes of hyperparathyroidism be excluded. The natural history of NPHPT remains inconclusive. Although biochemically less severe, the skeletal and renal complications of NPHPT vary across studies, primarily due to underlying selection bias. Due to limited data, there is currently no consensus regarding medical and surgical treatment. Recent studies on parathyroidectomy have indicated that normocalcemic patients present more often with negative preoperative localization studies and multiglandular disease, which complicates successful surgical management. In addition, postoperative improvements in bone mineral density and nephrolithiasis vary, raising questions about the optimal treatment approach. Further studies are needed to provide better evidence-based guidance for normocalcemic patients.

Purpose 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.

Hyperparathyroidism is due to increased activity of the parathyroid glands, either from an intrinsic abnormal change altering excretion of parathyroid hormone (primary or tertiary hyperparathyroidism) or from an extrinsic abnormal change affecting calcium homoeostasis stimulating production of parathyroid hormone (secondary hyperparathyroidism). Primary hyperparathyroidism is the third most common endocrine disorder, with the highest incidence in postmenopausal women. Asymptomatic disease is common, and severe disease with renal stones and metabolic bone disease arises less frequently now than it did 20–30 years ago. Primary hyperparathyroidism can be cured by surgical removal of an adenoma, increasingly by minimally invasive parathyroidectomy. Medical management of mild disease is possible with bisphosphonates, hormone replacement therapy, and calcimimetics. Vitamin D deficiency is a common cause of secondary hyperparathyroidism, particularly in elderly people. However, the biochemical definition of vitamin D deficiency and its treatment are subject to much debate. Secondary hyperparathyroidism as the result of chronic kidney disease is important in the genesis of renal bone disease, and several new treatments could help achieve the guidelines set out by the kidney disease outcomes quality initiative.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of \"Hyperparathyroidism. Primary\" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

Treatment of primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism due to idiopathic hypercalciuria (SHPT-IH) is markedly different. Robust diagnostic tools to differentiate between both entities are however lacking. Evaluate the thiazide challenge test (TCT) in clinical practice, its aid in clinical decision making, and evaluate the accuracy (sensitivity, specificity) and potentially useful parameters of the TCT. Monocentric observational retrospective cohort study from January 2017 to November 2023 in an outpatient Endocrinology department, Ghent University Hospital (Belgium). Twenty-five adult patients with hypercalciuria, elevated parathyroid hormone (PTH), and high-normal or elevated serum calcium underwent a TCT. Outcome measures were serum, urinary biochemical parameters before and after testing, clinical and imaging outcomes, treatment, and follow-up. Patients with a TCT-based working diagnosis of PHPT show greater increases in albumin-adjusted calcium and total serum calcium concentration than patients with SHPT-IH (+0.11 ± 0.10 vs +0.0071 ± 0.10 mmol/L; P = .025 and +0.14 ± 0.12 vs +0.012 ± 0.15 mmol/L; P = .024, respectively). The TCT-based working diagnosis of PHPT has a sensitivity of 81.8%, a specificity of 77.8%, and a likelihood ratio of 3.68 of estimating a correct final diagnosis. Urinary calcium excretion, PTH, calcium-phosphorous ratio, PTH inhibition rate, and the parathyroid function index do not differ significantly in patients with PHPT compared with those with SHPT-IH. The TCT aids in discriminating patients with PHPT from those with SHPT-IH based on a rise in serum calcium. Other parameters are not different between both groups. Larger prospective trials are necessary to further define the diagnostic potential of the TCT, its most appropriate biochemical outcome variables, and decision cut-offs.

Secondary hyperparathyroidism (SHPT) is characterized by excessive serum parathyroid hormone levels in response to decreasing kidney function, and tertiary hyperparathyroidism (THPT) is often the result of a long-standing SHPT. To date, several genes have been associated with the pathogenesis of primary hyperparathyroidism (PHPT). However, the molecular genetic mechanisms of uremic hyperparathyroidism (HPT) remain uncharacterized. To elucidate the differences in genetic alterations between PHPT and SHPT/THPT, the targeted next-generation sequencing of genes associated with HPT was performed using DNA extracted from parathyroid tissues. As a result, 26 variants in 19 PHPT or SHPT/THPT appeared as candidate pathogenic mutations, which corresponded to 9 (35%) nonsense, 8 (31%) frameshift, 6 (23%) missense, and 3 (11%) splice site mutations. The MEN1 (23%, 6/26), ASXL3 (15%, 4/26), EZH2 (12%, 3/26), and MTOR (8%, 2/26) genes were frequently mutated. Sixteen of 25 patients with PHPT (64%) had one or more mutations, whereas 3 (21%) of 21 patients with SHPT/THPT had only 1 mutation (p = 0.001). Sixteen of 28 patients (57%) with parathyroid adenoma (PA) had one or more mutations, whereas 3 of 18 patients (17%) with parathyroid hyperplasia (PH) had just one mutation (p = 0.003). Known driver mutations associated with parathyroid tumorigenesis such as CCND1/PRAD1, CDC73/HRPT2, and MEN1 were identified only in PA (44%, 7/16 with mutations). Our results suggest that molecular genetic abnormalities in SHPT/THPT are distinct from those in PHPT. These findings may help in analyzing the molecular pathogenesis underlying uremic HPT development.

Normocalcemic primary hyperparathyroidism (NPHPT), a variant of primary hyperparathyroidism (PHPT) characterized by persistently elevated parathyroid hormone (PTH) levels and normal serum calcium, has gained recognition as a substantial subset of PHPT cases. Despite its increasing prevalence, the precise pathophysiology and natural progression of NPHPT remain enigmatic. This in-depth literature review explores recent advancements in our understanding of NPHPT, encompassing pathophysiology, clinical presentation, diagnostic approaches, medical and surgical management options. By synthesizing this wealth of information, this review aims to contribute to a more nuanced and informed approach to the treatment of patients grappling with NPHPT. As our understanding of the condition continues to evolve, the knowledge gathered from this review has the potential to significantly enhance the quality of care and outcomes for individuals afflicted with NPHPT, ultimately improving their overall well-being and prognosis. •Normocalcaemic Primary Hyperparathyroidism (NPHPT) is a Distinct Clinical Entity.•Comprehensive Review of Diagnostic Criteria and Challenges.•Outlines Therapeutic Efficacy and Decision-making.

Abstract Context It remains unclear whether risk of cardiovascular diseases is increased in patients with mild (<1.45 mmol/L) to moderate (≥1.45 to 1.60 mmol/L) primary hyperparathyroidism (PHPT). Objective We aimed to determine the short-term effect of parathyroidectomy (PTX) on arterial stiffness, cholesterol levels, and blood pressure (BP). Design This study was a clinical trial randomly allocating patients to either PTX or a control group (no surgery). Follow-up was performed 3 months after surgery in the PTX group and 3 months after baseline in the control group. Setting University hospital. Participants We recruited 79 patients with PHPT; 69 participants completed the study. Main Outcomes Office and ambulatory 24-hour BP, pulse wave velocity (PWV), augmentation index, and fasting plasma cholesterol levels. Results At baseline, participants had a median level of ionized calcium of 1.41 mmol/L (range, 1.33 to 1.60 mmol/L) and PTH of 10.4 pmol/L (4.5 to 30.4 pmol/L). Median age was 64 years (range, 18 to 81) and 72% were females. Following PTX, plasma total cholesterol levels decreased significantly compared with the controls (P = 0.04). Changes in PWV, augmentation index, and ambulatory 24-hour BP did not differ between groups, except for an increase in ambulatory diastolic BP following PTX. However, in patients with baseline levels of ionized calcium ≥1.45 mmol/L, PWV decreased significantly in response to PTX compared with the control group (P = 0.03). Conclusion PTX may decrease risk of cardiovascular diseases in PHPT by lowering total cholesterol levels, although ambulatory diastolic BP increases in response to surgery. Patients with moderate to severe hypercalcemia may benefit from PTX by a decrease in PWV. Effect of parathyroidectomy on arterial stiffness and BP in patients with primary hyperparathyroidism. No beneficial effect on arterial stiffness and BP was observed after PTX.

SummaryDoctors do not know whether treatment of high parathyroid hormone levels is linked to better outcomes in their patients with kidney disease. In this study, lower parathyroid hormone levels at baseline were linked to lower risk of fracture, vascular events, and death in people with kidney disease.PurposeChronic kidney disease (CKD) affects ~ 20% of older adults, and secondary hyperparathyroidism (HPT) is a common condition in these patients. To what degree HPT predicts fractures, vascular events, and mortality in pre-dialysis CKD patients is debated. In stage 3 and 4 CKD patients, we assessed relationships between baseline serum PTH levels and subsequent 10-year probabilities of clinical fractures, vascular events, and death.MethodsWe used Marshfield Clinic Health System electronic health records to analyze data from adult CKD patients receiving care between 1985 and 2013, and whose PTH was measured using a second-generation assay. Covariates included PTH, age, gender, tobacco use, vascular disease, diabetes, hypertension, hyperlipidemia, obesity, GFR, and use of osteoporosis medications.ResultsFive thousand one hundred eight subjects had a mean age of 68 ± 17 years, 48% were men, and mean follow-up was 23 ± 10 years. Fractures, vascular events, and death occurred in 18%, 71%, and 56% of the cohort, respectively. In univariate and multivariate models, PTH was an independent predictor of fracture, vascular events, and death. The hazards of fracture, vascular events and death were minimized at a baseline PTH of 0, 69, and 58 pg/mL, respectively.ConclusionsWe found that among individuals with stage 3 and 4 CKD, PTH was an independent predictor of fractures, vascular events, and death. Additional epidemiologic studies are needed to confirm these findings. If a target PTH range can be confirmed, then randomized placebo-controlled trials will be needed to confirm that treating HPT reduces the risk of fracture, vascular events, and death.

Summary No data on the pharmacological treatment of normocalcemic hyperparathyroidism (NPHPT) are available. We treated 30 NPHPT postmenopausal women with alendronate/cholecalciferol (treated group) or vitamin D alone (control group). Over 1 year, bone mineral density (BMD) increased significantly in treated group, but not in control group. Both treatments did not affect serum or urinary calcium. Introduction Normocalcemic primary hyperparathyroidism (NPHPT) is defined by normal serum calcium and consistently elevated PTH levels after ruling out the causes of secondary hyperparathyroidism. It is likely that subjects with NPHPT may develop kidney and bone disease. As no data on the pharmacological treatment of NPHPT are available, we aimed to investigate the effects of alendronate and cholecalciferol on both BMD and bone biochemical markers in postmenopausal women with NPHPT. Safety of vitamin D was evaluated as secondary endpoint. Methods The study was a prospective open label randomized trial comparing 15 postmenopausal women with NPHPT (PMW-NPHPT), treated with oral alendronate plus cholecalciferol (treated group) and 15 PMW-NPHPT treated only with cholecalciferol (control group). Blood samples were obtained at baseline and after 3, 6, and 12 months. Bone turnover markers (BTM) were measured at baseline, 3, and 6 months, respectively. BMD was assessed at baseline and after 12 months. Results After 1 year of treatment, BMD increased significantly at the lumbar, femoral neck, and hip level in the treated group, but not in the control group ( p  = 0.001). No differences were found between or within groups in serum calcium, PTH, and urinary calcium levels. BTM significantly decreased in the treated group but not in the control group, at 3 and 6 months ( p  < 0.001), respectively. No cases of hypercalcemia or hypercalciuria were detected during the study. Conclusion The results of this study indicate that alendronate/cholecalciferol increases BMD in postmenopausal women with NPHPT. Alendronate/cholecalciferol or vitamin D alone does not affect serum or urinary calcium.