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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.

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.

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.

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.

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.

Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women. The clinical presentation of PHPT has evolved over the past 40 years to include three distinct clinical phenotypes, each of which has been studied in detail and has led to evolving concepts about target organ involvement, natural history, and management. In the present review, I provide an evidence-based summary of this disorder as it has been studied worldwide, citing key concepts and data that have helped to shape our concepts about this disease. PHPT is now recognized to include three clinical phenotypes: overt target organ involvement, mild asymptomatic hypercalcemia, and high PTH levels with persistently normal albumin-corrected and ionized serum calcium values. The factors that determine which of these clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is used, vitamin D deficiency is present, and whether parathyroid hormone levels are routinely measured in the evaluation of low bone density or frank osteoporosis. Guidelines for parathyroidectomy apply to all three clinical forms of the disease. If surgical guidelines are not met, parathyroidectomy can also be an appropriate option if no medical contraindications are present. If either the serum calcium or bone mineral density is of concern and surgery is not an option, pharmacological approaches are available and effective. Advances in our knowledge of PHPT have guided new concepts in diagnosis and management.

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.

Abstract Context Primary hyperparathyroidism (PHPT) is an endocrine disorder that is treated surgically, and some correlation between the size of the responsible lesion and preoperative clinical data is assumed. Objective The purpose of this study was to predict tumor volume of the lesion responsible for PHPT from preoperative clinical data. Methods Participants comprised patients with surgically treated PHPT who underwent initial surgery in our department between January 2000 and December 2021. The volume of parathyroid gland removed was used as the primary outcome and associations with preoperative clinical data were assessed by multivariable analysis. Results A positive correlation was identified between parathyroid tumor volume and both preoperative intact parathyroid hormone (PTH) (Spearman's r = 0.503) and calcium values (Spearman's r = 0.338). Data for intact PTH value and tumor volume were logarithmically transformed (ln-PTH = log-transformed intact PTH value; ln-volume = log-transformed tumor volume). Multiple regression analysis revealed male sex, ln-PTH and calcium values as significant predictors of ln-volume, with standardized regression coefficients of 0.213 (95% CI 0.103-0.323), 0.5018 (95% CI 0.4442-0559), and 0.322 (95% CI 0.0339-0.149), respectively. The adjusted R2 for this model is 0.320. Conclusion Preoperative serum intact PTH value is associated with tumor volume of the lesion responsible for PHPT. A rough estimation of the tumor size would provide responsible physicians with opportunities to add further imaging tests or plan appropriate surgical strategies.

Background 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. Methods 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. Results 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. Conclusion 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.