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Background: It has been a matter of debate for long time about the existence of two distinct phenotypes of primary hyperparathyroidism (PHPT) predisposed to either renal or skeletal manifestation., Objective: To differentiate characteristics of symptomatic PHPT patients based on the presence of skeletal or renal involvement., Design: Retrospective analysis of data from the Indian PHPT registry., Patients: PHPT patients were divided into four discrete groups: asymptomatic, presenting with renal manifestations alone, skeletal manifestations alone, and both skeletal and renal manifestations., Measurements: Clinical, biochemical, and tumour weight and histopathological characteristics of these groups were compared., Results: Of the 229 eligible patients, 45 were asymptomatic, 62 had renal manifestations, 55 had skeletal manifestations, and 67 had both skeletal and renal manifestations. Patients with both skeletal and renal manifestations had higher serum calcium levels than those with isolated skeletal involvement [12.5 (11.1-13.7) mg/dL, 11.2 (10.6-12.3) mg/dL, respectively; p < .05]. Serum alkaline phosphatase (AP), plasma parathyroid hormone (PTH) levels, and parathyroid tumour weight were significantly higher in patients with isolated skeletal, and both skeletal and renal manifestations, compared to the other two groups. A preoperative PTH and AP level of 300 pg/mL and 152 U/L, predicted the risk of developing skeletal involvement with sensitivity and specificity of 71%, 70%, and 69%, 67%, respectively., Conclusions: We observed distinct skeletal and renal phenotypic subgroups among PHPT patients with characteristic biochemical and hormonal patterns with higher parathyroid disease burden in patients with skeletal complications compared to those with isolated renal manifestation., (© 2023 John Wiley & Sons Ltd.)

Primary hyperparathyroidism (PHPT) is third most common endocrine disorder characterized by hypercalcemia with elevated or nonsuppressed parathyroid hormone levels by parathyroid tumors. Familial PHPT, as part of multiple endocrine type-1, occurs due to the germline mutation in the MEN1 gene. The involvement and the role of germline MEN1 variations in sporadic PHPT of Indian PHPT patients are unknown. Precise classifications of different types of MEN1 variations are fundamental for determining clinical relevance and diagnostic role. This prospective cohort study was performed on 82 patients with PHPT (with no clinical or history of MEN1) who underwent screening for MEN1 variations through Sanger sequencing. Multilevel computational analysis was performed to determine the structure-function relationship of synonymous, nonsynonymous, and variants of uncertain significance (VUS). Of the 82 PHPT patients, 42 (51%) had 26 germline MEN1 variants, including eight nonsynonymous, seven synonymous, nine VUS, one splice site, and one regulatory variation. Five most common germline variations (c.1838A>G, c.1817C>T, c.1525C>A, c.-35A>T, and c.250T>C) were observed in this study. c.-35A>T (5' untranslated region [UTR]) was associated with recurrence of PHPT (odds ratio [OR] = 5.4; p = 0.04) and subsequent detection of other endocrine tumors (OR = 13.6, p = 0.035). c.1525C>A was associated with multi glandular parathyroid tumor (OR = 13.6, p = 0.035). Align-Grantham variation and Grantham deviation (Align-GVGD), functional analysis through hidden Markov MODEL (FATHMM), and MutationTaster analysis reported the disease-specific potential of VUS and synonymous variations. Significant linkage disequilibrium was observed in c.1785G>A and c.1817C>T (r 2  = 0.3859, p = 0.0001), c.1475C>G and c.1525C>A (r 2  = 0.385, p = 0.0004), and c.1569T>C and c.1838A>G (r 2  = 0.488, p = 0.0001). The detection of MEN1 variations, especially those with disease-specific potential, can prompt early screening for other MEN1-related tumors and disease recurrence. © 2022 American Society for Bone and Mineral Research (ASBMR)., (© 2022 American Society for Bone and Mineral Research (ASBMR).)

Introduction: Primary hyperparathyroidism (PHPT) in India is mostly symptomatic with renal and skeletal complications. Evidence on mortality outcomes following parathyroidectomy from India, where the disease is predominantly symptomatic is limited., Material and Methods: This was a prospective study to evaluate mortality outcomes in the Indian PHPT registry over the past 25 years (n = 464). Pre- and postoperative parameters and mortality data were obtained from medical records and/or by verbal autopsy, a method validated by WHO for data collection in settings where several deaths are noninstitutional. Patients were divided into survivor (SG) and nonsurvivor groups (NSG) to ascertain differences in presentation and the effect of parathyroidectomy., Results: The overall mortality was 8.8% at a median follow-up of 8 years (IQR 1-13) after parathyroidectomy. Chronic kidney disease was the most common background cause of death (43.5%), followed by pancreatitis (28.2%). NSG had significantly more frequent renal dysfunction (91.9% vs 73.9%), anaemia (50 vs 16.6%) and pancreatitis (24.3 vs 6.4%). PTH (61.9 vs 38.3 pmol/l) and baseline creatinine (97.2 vs 70.7 µmol/l) were significantly higher and eGFR lower (66.7 vs 90.7 ml/min/1.73m 2 ) in the NSG than SG. By Cox proportional modelling, renal dysfunction [HR 2.88 (1.42-5.84)], anaemia [HR 2.45 (1.11-5.42)] and pancreatitis [HR 2.65 (1.24-5.66)] on univariate and renal dysfunction [HR 3.33 (1.13-9.77)] on multivariate analysis were significant for mortality. Survival curves demonstrated a significantly higher mortality with lower eGFR values., Conclusions: Nonsurvivors in PHPT had greater prevalence and more severe baseline renal dysfunction than survivors. Survival after parathyroidectomy was significantly associated with estimated glomerular filtration rate at baseline., (© 2021. The Japanese Society Bone and Mineral Research.)

Objective: Primary hyperparathyroidism (PHPT) is a common endocrine disorder in women which becomes more prevalent after menopause. In this study, we compared the demographic, clinical, and biochemical variables between premenopausal (pre-M) and postmenopausal (post-M) women with PHPT., Methods: A retrospective analysis (from 2005 to 2019) of enrolled women PHPT patients from an online Indian PHPT registry., Results: Of the women with PHPT, 232 and 122 were pre-M and post-M, respectively. The number of post-M PHPT cases registered had a 3.3-fold increase in 2015-2019 from 2005-2009 compared with only a 2.5-fold increase in pre-M cases in the same duration. The majority were symptomatic (90%), although pre-M had a higher proportion of symptomatic than post-M (92% vs 85%; P = .04). Pre-M women showed more prevalence of osteitis fibrosa cystica than post-M women (28% vs 13%; P = .03), although hypertension and gallstone disease were seen more frequently in post-M PHPT women. Pre-M women had a significantly higher median PTH (403 vs 246 pg/mL; P = .02) and median alkaline phosphatase (202 vs 145 pg/mL; P = .02) than post-M women, and vitamin D deficiency was more common in pre-M women (58% vs 45%; P = .03). Gland localization, tumor weight, and disease cure rates did not differ according to menopausal status., Conclusion: PHPT was more prevalent in pre-M women, although the number of post-M cases had significantly increased in the last 10 years. Pre-M women had generally more severe clinical and biochemical variables than post-M PHPT women., (Copyright © 2020 American Association of Clinical Endocrinologists. All rights reserved.)

Introduction: Primary hyperparathyroidism (PHPT), a third common endocrine disorder, varies from asymptomatic disease, mostly seen in the West where routine biochemical screening is practiced, to the classical symptomatic disease mostly seen in the Eastern countries. We aimed to compare the demographic, clinical, biochemical measurements in patients with asymptomatic and symptomatic PHPT from the Indian PHPT registry., Material and Methods: Data of PHPT patients from the last 25 years (1995-2019) were analyzed for demographic, clinical presentation and biochemical measurements, and compared these characteristics between asymptomatic and symptomatic PHPT patients., Results: Of the 554 patients, 54 (10%) patients had asymptomatic PHPT. There was a sharp rise in the proportion of asymptomatic PHPT patients of 3% in the first decade to 13% in the second decade of the century (p = 0.003). Patients with asymptomatic PHPT were significantly older (50 vs. 42 years; p < 0.0001) and had higher mean body mass index (27.8 vs. 23.5 kg/m 2 ; p < 0.0001) compared to the symptomatic PHPT group. In addition, asymptomatic PHPT patients had significantly lower median plasma iPTH (180 vs. 370 pg/mL; p < 0.0001), serum alkaline phosphatase (119 vs. 172 IU/L; p < 0.0001), and parathyroid adenoma weight (1.0 vs. 2.62 g; p = 0.006) compared to the symptomatic PHPT group., Conclusion: Although symptomatic PHPT is still most prevalent (> 90%) in India with higher indices of the disease and tumor weights, there is a progressive rise in the prevalence of asymptomatic PHPT patients in the last decade. Improvements in calcium and vitamin D nutrition might account for this change as in the Western series.

In patients with primary hyperparathyroidism, the size of the adenoma is a major determinant of biochemical indices, disease severity, and manner of presentation. However, the large variation in adenoma weight, both within and between populations and a steady decline in parathyroid adenoma weights over time remain largely unexplained. Based on the results in a small number of patients almost two decades ago we proposed that vitamin D nutritional status of the patient explains both the disease manifestations and much of the variation in adenoma size. Accordingly, we examined the relationship between vitamin D nutrition, as assessed by serum levels of 25-hydroxyvitamin D, and parathyroid gland weight, the best available index of disease severity, in a large number of patients (n = 440) with primary hyperparathyroidism. A significant inverse relationship was found between serum 25-hydroxyvitamin D level and log adenoma weight (r = -0.361; p < 0.001). Also, the adenoma weight was significantly related directly to serum PTH, calcium, and alkaline phosphatase as dependent variables. In patients with vitamin D deficiency (defined as serum 25-hydroxyvitamin D levels 15 ng/mL or lower), gland weight, PTH, AP, and adjusted calcium were each significantly higher than in patients with 25-hydroxyvitamin D levels of 16 ng/mL or higher, but serum 1,25-dihydroxyvitamin D levels were similar in both groups. We interpret this to mean that suboptimal vitamin D nutrition stimulates parathyroid adenoma growth by a mechanism unrelated to 1,25-dihydroxyvitamin D deficiency. We conclude that variable vitamin D nutritional status in the population may partly explain the differences in disease presentation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Accurate preoperative localization of parathyroid lesion(s) is crucial for successful surgical management of primary hyperparathyroidism (PHPT). This study was conducted to compare the effectiveness of ultrasonography (USG) of the neck, Tc-sestamibi (MIBI) imaging with or without SPECT/CT, and F-fluorocholine (FCH) PET/CT imaging in the preoperative localization of parathyroid lesions in patients with PHPT., Methods: Fifty-four consecutive patients with PHPT were included in this prospective study who underwent preoperative localization of the parathyroid lesion(s) using 3 diagnostic modalities followed by surgery. The sensitivity, positive predictive value, and accuracy of the 3 imaging procedures to accurately detect abnormal parathyroid glands were determined using histopathology as criterion standard with postoperative biochemical response confirmation., Results: F-fluorocholine PET/CT detected 52 of 54 patients and 52 of 56 lesions with histopathologically proven parathyroid adenomas on patient-based and lesion-based analysis, respectively. Preoperative USG, MIBI, and FCH PET/CT localized abnormal parathyroid gland(s) in 39 (72.2%), 43 (79.6%), and 54 (100%) patients, respectively. The sensitivity and positive predictive value were 69.3% and 87.1% for USG, 80.7% and 97.6% for MIBI, and 100% and 96.3% for FCH PET/CT. The accuracy was 62.9%, 79.6%, and 96.3% for USG, MIBI, and FCH PET/CT, respectively, in patient-wise analysis. In 6 patients with ectopic lesions, FCH PET/CT demonstrated higher sensitivity and accuracy than MIBI and USG (100% vs 66.6% and 16.7%, respectively)., Conclusions: Among the 3 imaging techniques tested simultaneously, FCH PET/CT was superior for accurate preoperative localization of parathyroid adenomas, especially for ectopic or small parathyroid lesions.

Objective: Urolithiasis may be the only presenting manifestation of primary hyperparathyroidism (PHPT), and early detection of PHPT in such patients may prevent future urolithiasis and other PHPT complications. This study was performed to study the prevalence and predictors of PHPT in patients presenting with urolithiasis., Methods: Consecutive patients presenting with urolithiasis were evaluated for clinical and biochemical manifestations of PHPT with serum and urine calcium (Ca), serum intact parathyroid hormone and 25 (OH) vitamin D. We then compared the clinical and biochemical characteristics of PHPT patients presenting with urolithiasis (group A) and without (group B)., Results: During the 3-year study period, 381 patients with urolithiasis were seen with a mean age of 38.5 ± 13.9 years. Nineteen of the 381 (5%) patients had histologically proven PHPT (group A). Four patients in group A (21%) and 8 in group B (2%) had nephrocalcinosis (P<.0001), multiple stones (≥3), calcific pancreatitis, and neuropsychiatric manifestations were more common in group A (P<.0001). Presence of multiple or bilateral stones, and recurrent stone episodes predicted PHPT (odds ratio [OR]: 3.06, confidence interval [CI]: 0.87, 0.7)., Conclusion: One out of every 20 patients with urolithiasis had PHPT, which is higher than the prevalence of PHPT in general population. The presence of nephrocalcinosis and multiple, bilateral, and recurrent stone disease increased the risk of PHPT among stone formers., Abbreviations: Ca = calcium; CI = confidence interval; iPTH = intact parathyroid hormone; nPHPT = normocalcemic PHPT; OR = odds ratio; PHPT = primary hyperparathyroidism.

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., Competing Interests: AA Khan is on the advisory board for Amgen, Eli Lilly, and Merck; has research grants from NPS, Amgen, and Merck; and has received lecture fees from Amgen, Eli Lilly, Warner Chilcott, and Merck; D Hanley has received funding for grants from Amgen, Eli Lilly, Merck, and Novartis; has received funding for lectures from Amgen Eli Lilly and Novartis; and is on the membership board for Amgen, Eli Lilly, Merck, and Novartis; R Rizzoli received consultancy and lecture fees from Amgen, Eli Lilly, MSD, Danone, and Servier; L Rejnmark received consultancy and lecture fees from NPS Pharmaceuticals, Amgen, Eli Lilly, and Novo Nordic; RV Thakker is a chairman of Astra-Zeneca Stratified Medicine Panel and has received lecture and consultancy fees from Novartis, Eli Lilly, AstraZeneca, and Ipsen; S Kaiser has received consultancy fees from Amgen and Eli Lilly and has received lecture fees from Amgen, Eli Lilly, Merck, and NRS; L Mosekilde has received funds for the development of educational presentations; DS Rao is on the advisory board for Diasorin Inc., has received consultancy fees from NPS Pharmaceuticals, has received grants from NIAMS, and has received funding for lectures from Eli Lilly; M Lewiecki has received research grant support from Amgen, Merck, and Eli Lilly and has received consultancy fees from Amgen, Eli Lilly, Merck, Radius Health, AgNovos Healthcare, Theranova, and Alexion; R Eastell received grants, lecture fees, and travel expenses from Amgen, AstraZeneca, IDS, Eli Lilly, Merck, Novartis, Roche, Alexion, Otsuka, IBMS, and Warner Chilcott; KS Davison has received honorarium for lectures from Novartis, Merck, Amgen, and Eli Lilly; and ML Brandi has received consultancy fees and grant funding from Amgen, Eli Lilly, MSD, Novartis, Roche, and Servier. Funding This work was supported by the Calcium Disorders Clinic, McMaster University Hamilton, Ontario, Canada.

Purpose: The pathogenesis of parathyroid tumours is only partially understood. A direct approach using proteomics could be a promising tool to increase our understanding of parathyroid tumorigenesis. The aim of the study was to investigate differentially expressed proteins to explore the underlying molecular basis of the disease and identify potential target proteins responsible for the genesis of adenoma., Methods: Proteins were extracted from adenomatous and normal parathyroid tissues. Differentially expressed proteins were separated by two-dimensional gel electrophoresis (2-D) and identified by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. Statistical analysis was performed using spss 10.01 software., Results: Comparative analysis of the 2-D profiles of proteins isolated from adenomatous and normal parathyroid tissues showed 15 differentially expressed proteins, of which 11 were overexpressed. The characterized proteins were associated with diverse cellular functions including regulation of cell organization, programmed cell death, transcription and signal transduction., Conclusion: The differentially expressed proteins in parathyroid adenomas may potentially serve as new targets to investigate the mechanisms of parathyroid adenoma transformation., (© 2014 John Wiley & Sons Ltd.)

Background: To explore underlying molecular mechanisms in the pathogenesis of symptomatic sporadic primary hyperparathyroidism (PHPT)., Materials and Methods: Forty-one parathyroid adenomas from patients with symptomatic PHPT and ten normal parathyroid glands either from patients with PHPT (n=3) or from euthyroid patients without PHPT during thyroid surgery (n=7) were analyzed for vitamin D receptor (VDR), calcium-sensing receptor (CASR), cyclin D1 (CD1), and parathyroid hormone (PTH) expressions. The protein expressions were assessed semiquantitatively by immunohistochemistry, based on percentage of positive cells and staining intensity, and confirmed by quantitative real-time PCR., Results: Immunohistochemistry revealed significant reductions in VDR (both nuclear and cytoplasmic) and CASR expressions and significant increases in CD1 and PTH expressions in adenomatous compared with normal parathyroid tissue. Consistent with immunohistochemistry findings, both VDR and CASR mRNAs were reduced by 0.36- and 0.45-fold change (P<0.001) and CD1 and PTH mRNAs were increased by 9.4- and 17.4-fold change respectively (P<0.001) in adenomatous parathyroid tissue. PTH mRNA correlated with plasma PTH (r=0.864; P<0.001), but not with adenoma weight, while CD1 mRNA correlated with adenoma weight (r=0.715; P<0.001). There were no correlations between VDR and CASR mRNA levels and serum Ca, plasma intact PTH, or 25-hydroxyvitamin D levels. In addition, there was no relationship between the decreases in VDR and CASR mRNA expressions and the increases in PTH and CD1 mRNA expressions., Conclusions: The expression of both VDR and CASR are reduced in symptomatic PHPT in Asian Indians. In addition, CD1 expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth and differential clinical expression of PHPT.