Sporadic Primary Hyperparathyroidism Research Articles

Operative management of primary hyperparathyroidism in Europe.

Multicentre studies have previously reported on national outcomes of surgery for primary hyperparathyroidism, but not investigated whether management and outcome are uniform among countries. This study investigated whether there are differences among European countries in operative management and outcome of surgery for primary hyperparathyroidism. Using data from Eurocrine®, a pan-European registry for endocrine surgeries, a retrospective observational cross-sectional multicentre study with 99 participating centres in 14 European countries was performed. Data on age, sex, calcium levels, operative strategy, conversion rate and rate of failed exploration were analysed for patients who underwent initial surgery for sporadic primary hyperparathyroidism. Primary outcome measures were intention to perform limited parathyroidectomy and the rate of hypercalcaemia at first follow-up. A total of 9548 patients were registered between 2015 and 2020. There were 7642 (80%, range 74.5-93.2%) females. There was intention to perform limited parathyroidectomy in 7320 of 9548 (76.7%) operations, ranging from 498 of 1007 (49.5%) to 40 of 41 (97.6%) among countries. Hypercalcaemia at first follow-up (median time to follow-up 15 days) was found in 416 of 9548 (4.4%) operations, ranging from 0 of 119 (0%) to 3 of 38 (7.9%) among countries. This study demonstrated large differences in the intention to perform limited parathyroidectomy for primary hyperparathyroidism among European countries, as well as differences in the rate of postoperative hypercalcaemia. Future studies are needed to evaluate the impact of these different healthcare practices on patient outcomes.

A pharmacoeconomic analysis from Italian guidelines for the management of sporadic primary hyperparathyroidism

A pharmacoeconomic analysis from Italian guidelines for the management of sporadic primary hyperparathyroidism

The Role of Demographic and Clinical Factors in Germline Mutation Testing for Patients with Primary Hyperparathyroidism.

Guidelines recommending genetic counseling in primary hyperparathyroidism (PHPT) vary. To further delineate current recommendations, this study examined genetic counseling referral patterns and rates of mutations in surgical patients with PHPT. A single-institution review was performed of adult patients who underwent parathyroidectomy for presumed sporadic PHPT. Genetic testing indications of hypercalcemia onset ≤ 40 years, multigland disease (MGD), family history (FHx) of PHPT, or other clinical indications suspicious for a PHPT-related endocrinopathy were examined by demographics and mutation detection rates. Genetic counseling was performed in 237 (37.9%) of 625 patients. Counseling was discussed but not performed in 121 (19.4%) patients. No evidence was noted of genetic referral discussion in the remaining 267 (42.7%). Of these groups, patients who received genetic counseling were youngest, p < 0.001 [median age 55.3 (IQR 43.2, 66.7) years]. The majority of patients with indications of age ≤ 40 years (65.7%), FHx (78.0%), and other clinical indications (70.7%) underwent genetic counseling, while most with MGD (57.0%) did not. Eight mutations were detected in 227 patients (3.5%). Mutations included: MEN1 (n = 2), CDC-73 (n = 4), and CASR (n = 2). Detection was most common in patients with FHx (4/71, 5.6%), then age ≤ 40 years (3/66, 4.5%), and other clinical indications (3/80, 3.8%). No mutations were identified in 48 patients tested solely for MGD. Most patients with onset of hypercalcemia age ≤ 40 years, positive FHx, or other clinical concerns underwent genetic counseling, while most with MGD did not. As no germline mutations were identified in patients with MGD alone, further investigation of MGD as a sole indication for genetic counseling may be warranted.

Insights into Hyperparathyroidism-Jaw Tumour Syndrome: From Endocrine Acumen to the Spectrum of CDC73 Gene and Parafibromin-Deficient Tumours.

A total of 1 out of 10 patients with primary hyperparathyroidism (PHP) presents an underlying genetic form, such as multiple endocrine neoplasia types 1, 2A, etc., as well as hyperparathyroidism-jaw tumour syndrome (HJT). We aimed to summarise the recent data, thus raising more awareness regarding HJT, from the clinical perspective of PHP in association with the challenges and pitfalls of CDC73 genetic testing and parafibromin staining. This narrative review included a sample-focused analysis from the past decade according to a PubMed search. We identified 17 original human studies (≥4 patients per article). The mean age at disease onset was between 20.8 and 39.5 years, while the largest study found that 71% of patients had HJT recognised before the age of 30. Males and females seemed to be equally affected, in contrast with sporadic PHP. PHP represented the central manifestation of HJT, occurring as the first manifestation in up to 85% of HJT cases. A biochemistry panel found a mean serum calcium level above the level of 12 mg/dL in PHP. PTH was elevated in HJT as well, with average values of at least 236.6 pg/mL. The most frequent pathological type in PHP was a parathyroid adenoma, but the incidence of a parathyroid carcinoma was much higher than in non-HJT cases (15% of all parathyroid tumours), with the diagnosis being established between the age of 15 and 37.5. In some families up to 85% of carriers suffered from a parathyroid carcinoma thus indicating that certain CDC73 pathogenic variants may harbour a higher risk. An important issue in HJT was represented by the parafibromin profile in the parathyroid tumours since in HJT both parathyroid adenomas and carcinomas might display a deficient immunoreactivity. Another frequent manifestation in HJT was ossifying fibromas of the jaw (affecting 5.4% to 50% of patients; the largest study found a prevalence of 15.4%). HJT was associated with a wide variety of kidney lesion (mostly: kidney cysts, with a prevalence of up to 75%, and renal tumours involved in 19% of patients). The risk of uterine lesions seemed increased in HJT, especially with concern to leiomyomas, adenofibromas, and adenomyosis. The underlying pathogenic mechanisms and the involvement of CDC73 pathogenic variants and parafibromin expression are yet to be explored. Currently, the heterogeneous expression of parafibromin status and, the wide spectrum of CDC73 mutations including the variety of clinical presentations in HJT, make it difficult to predict the phenotype based on the genotype. The central role of HJT-PHP is, however, the main clinical element, while the elevated risk of parathyroid carcinoma requires a special awareness.

Parathyroidectomy Improves Bone Density in Women With Primary Hyperparathyroidism and Preoperative Osteopenia.

Osteoporosis and/or bone fractures are indications of parathyroidectomy in primary hyperparathyroidism (PHPT), especially in women. However, the benefit of surgery in patients with osteopenia remains unclear. To evaluate bone mineral density (BMD) and bone remodeling biomarkers changes 1 year after parathyroidectomy in women with PHPT. In the prospective, monocentric, observational prospective cohort with primary hyperparathyroidism patients (CoHPT) cohort, women operated for sporadic PHPT since 2016 with ≥1 year follow-up were included. BMD (dual-X ray absorptiometry) and bone remodeling biomarkers [cross-linked C-telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1NP), and bone-specific alkaline phosphatases] were assessed before and 1 year after parathyroidectomy. Referral center. A total of 177 women with PHPT (62.5 ± 13.3 years, 83.1% menopausal, 43.9% osteopenic, and 45.1% osteoporotic) were included. Parathyroidectomy. BMD change between before and 1 year after parathyroidectomy. Parathyroidectomy resulted in significant increase in BMD and decrease in serum bone remodeling biomarker concentrations. In the 72 patients with baseline osteopenia, mean BMD significantly increased at the lumbar spine [+0.05 g/cm2 (95% confidence interval [CI], 0.03-0.07)], the femoral neck [+0.02 g/cm2 (95% CI 0.00-0.04)], the total hip [+0.02 g/cm2 (95% CI 0.01-0.02)], and the forearm [+0.01 (95% CI 0.00-0.02)], comparable to osteoporotic patients. Among osteopenic patients, those with individual BMD gain (>0.03 g/cm2) at ≥1 site had higher preoperative serum CTX, P1NP, and urine calcium concentrations than those without improvement. Parathyroidectomy significantly improved BMD and remodeling biomarkers in women with osteopenia, thereby supporting the benefit of parathyroidectomy in these patients. Preoperative serum CTX and P1NP concentrations could be useful to predict expected BMD gain.

Heterogeneous parathyroid near-infrared autofluorescence patterns are associated with single adenomas in primary hyperparathyroidism.

Primary adenoma (PA) and multi-gland hyperplasia (MGH) account for 85% and 15% of primary hyperparathyroidism (PHPT) cases, respectively. Near-infrared autofluorescence (NIRAF) enhances intraoperative parathyroid identification. We hypothesized that PA would display a more heterogeneous NIRAF pattern compared to MGH. Patients undergoing surgery for sporadic PHPT were categorized based on the presence of PA or MGH. To quantify heterogeneity, we utilized ratios of (1) mean parathyroid gland (PG) NIRAF over background NIRAF (mean ratio), (2) minimum and (3) maximum PG NIRAF over mean PG NIRAF (minimum and maximum ratios). Additionally, a heterogeneity score was quantified using mean ratio (mean PG NIRAF over background NIRAF), and overall NIRAF (mean NIRAF of eight random 15 × 15 pixel areas). A point was assigned to ratios <0.8 or >1.2. Images were quantified by ImageJ software. Mann-Whitney test was performed for all comparisons. Of 78 patients, 63 had a single PA and 15 had MGH, totaling 102 PGs. There was no difference between their mean ratios. PA had a lower minimum ratio compared to that of MGH (0.86 ± 0.01 vs. 0.93 ± 0.01, p = 0.001) and a brighter maximum ratio (1.21 ± 0.02 vs. 1.12 ± 0.01, p = 0.0008). PA also scored higher on their heterogeneity scores compared to MGH (1.27 ± 0.23 vs. 0.33 ± 0.15, p = 0.001). Single parathyroid adenomas display a more heterogeneous autofluorescence pattern compared to that of multi-gland hyperplasia. Intraoperative characterization of PGs by real-time NIR imaging patterns may be a beneficial adjunct during parathyroid surgery.

Quality of life of patients with singleand multigland parathyroid disease in sporadic primary hyperparathyroidism before and after surgical treatment

Background. In 15–25 % of cases, the cause of primary hyperparathyroidism (PHPT) is multigland parathyroid disease. The complexity of clinical and laboratory prognosis, low efficiency of imaging methods, inaccurate assessment of the radicality of the surgery are the components of the problem of this variant of the disease. Quality of life (QOL) is an important criterion for the effectiveness of surgical treatment. A study of the QOL in patients with multigland parathyroid disease in PHPT has not been previously conducted in our country. The aim of the study. To assess the quality of life of patients with single- and multigland parathyroid disease in sporadic primary hyperparathyroidism before and after parathyroidectomy (PTE). Methods. As part of a prospective observational study, the quality of life of 64 patients with PHPT before and after PTE was assessed using SF-36 (Short Form 36) questionnaire: main group (n = 13) – patients with multigland parathyroid disease; comparison group (n = 51) – patients with single-gland parathyroid disease. The quality of life indicators of the patients were compared with those in a sample of the Irkutsk region population similar in gender and age. Results. Before performing PTE, the quality of life of patients with PHPT was lower than that of the Irkutsk region population. The greatest decrease in both health components was registered in the main group. In 90 % of patients, the quality of life improved after PTE, while in the main group changes were established 1 year after the surgery, in the comparison group – 6 months after the surgery. Transient complications (laryngeal paresis) and disease outcomes (hypocalcemia, hypoparathyroidism) did not interfere with the improvement of quality of life in both groups. When persistence was detected, no significant improvement in QOL was established. Conclusion. The quality of life of patients with PHPT is significantly reduced. PTE improves the QOL of these patients, and only persistence of the disease does not allow this to be achieved. Therefore, surgical tactics aimed at reducing the frequency of persistence will achieve a decent quality of life in the majority of patients with multigland parathyroid disease in PHPT.

Do men improve their bone mineral density 1 year after parathyroidectomy for primary hyperparathyroidism? Results of a prospective study

BackgroundThe impact of parathyroidectomy on bone mineral density in men with primary hyperparathyroidism is poorly known. This study aimed to evaluate the bone mineral density and bone remodeling biomarker changes in men with primary hyperparathyroidism 1 year after parathyroidectomy. MethodsMen operated for sporadic primary hyperparathyroidism between 2016 and 2022, enrolled in a monocentric prospective cohort, were analyzed. Patients with follow-up <1 year or missing data were excluded. Bone mineral density (dual X-ray absorptiometry) was measured before and 12 months after parathyroidectomy. Bone mineral density change ≥0.03g/cm2 was deemed significant. Bone remodeling biomarkers were serum cross-linked C-telopeptide, procollagen type 1 N-terminal propeptide, and bone-specific alkaline phosphatases. ResultsForty-five men were included (mean age 58.8 ± 13.1 years). Before surgery, 49% had osteopenia, and 11% had osteoporosis. Mean serum calcium and median serum parathyroid hormone levels decreased significantly after surgery (P < .0001). One year after parathyroidectomy, the mean bone mineral density increased significantly at the lumbar spine (+0.04g/cm2 [0.01;0.70], P = .0054), femoral neck (+0.04g/cm2 [0.03;0.05], P < .0001) and total hip (+0.02g/cm2 [0.01;0.03], P = .0002). Considering significant bone mineral density gain (+1 point) and loss (–1 point) at each site, 29/45 patients (64% [95% CI 49;78]) improved. Bone remodeling biomarker concentrations significantly decreased (P < .001). ConclusionParathyroidectomy positively affects bone mineral density in men with primary hyperparathyroidism, supporting osteopenia as a surgical indication in these patients.

Therapeutic and diagnostic algorithm for preoperative prediction of sporadic multigland parathyroid disease

BACKGROUND: Primary hyperparathyroidism (PHPT) is a common endocrinological disease that is characterized by autonomic increased synthesis of parathyroid hormone (PTH) with elevated or upper-normal levels of blood calcium [1]. In 80–85% of cases, the cause of sporadic PHPT is an adenoma of one parathyroid gland (PTG) (sigle-gland parathyroid disease), in 20–25% — a lesion of a larger number of PTGs (hyperplasia of all glands or double adenomas — multigland parathyroid disease) [2]. The complexity of clinical and laboratory prediction, low sensitivity of imaging methods, poor assessment of the radicalness of the operation by intraoperative monitoring of intact PTH (IMiPTH) are the components of the problem of multiple lesions in PHPT. Therefore, the improvement of existing and the development of new methods for diagnosing and treating this variant of the disease are urgent tasks of modern endocrine surgery.AIM: To develop an algorithm for the diagnosis and treatment of PHPT, aimed at preoperative detection of multigland parathyroid disease.MATERIALS AND METHODS: The study was based on a study of a continuous sample of 208 patients, of which 34 with multigland parathyroid disease in PHPT, 95 with single-gland parathyroid disease in PHPT, 69 with secondary hyperparathyroidism on renal replacement therapy (RRT) with hemodialysis, and 10 with tertiary hyperparathyroidism on RRT of LT. The work was performed on the basis of clinical, laboratory, instrumental, morphological and immunohistochemical studies. The nature of the expression of the calcium-sensitive receptor and the vitamin D receptor in the studied groups was studied as a pathogenetic substantiation of the proposed algorithm [3]. Based on the study of clinical and laboratory parameters and the results of preoperative imaging methods, predictors of multigland parathyroid disease in PHPT [4,5] were established, and a method for differential diagnosis of PTG lesions in PHPT was developed [6]. In addition, the results of surgical treatment of patients with multiple PTG lesions in various clinical variants of hyperparathyroidism were studied [7]. RESULTS: The proposed algorithm is used when the diagnosis of PHPT is already established and there are indications for surgical treatment. First of all, the level of GFR (CKD-EPI) is assessed in conjunction with the results of the “gold standard” preoperative imaging methods (ultrasound and scintigraphy), with an assessment of the number of localized increased PTG and the consistency of the results of preoperative methods.At a GFR level of more than 73 ml/min/1.73 m2, an increase of only 1 PTG according to the results of 2 imaging methods, provided that they are consistent, the PHPT variant is defined as a sigle-gland parathyroid disease. If there is an inconsistency between the 2 methods of preoperative imaging, we recommend calculating the scores according to the differential diagnosis scale for multiple lesions in PHPT [6]. At a GFR level of less than 73 ml/min/1.73 m2, an increase of &gt;1 PTG according to the results of 2 imaging methods, we recommend calculating points according to the proposed scale [6].With the established variant of PHPT — sigle-gland parathyroid disease, the patient undergoes selective parathyroidectomy (PTE) with IMiPTH. When iPTH drops to reference values, the test is considered positive, and the operation ends there. If the test result is negative, a second test is required after 10 minutes. In the event that the repeated test is also negative, then the patient is shown a bilateral neck exploration (BNE) in accordance with the tactics for multigland parathyroid disease (see below).With the established variant of PHPT — multigland parathyroid disease, the following tactics are used:BNE with obligatory exploration of all four PTGs;Macroscopic assessment of the PTG found.When making a decision about 2 pathologically changed enlarged PTG, and 2 others are intact and not enlarged, a double PTE with IMiPTH is performed. If after the removal of 2 pathologically altered PTGs, the IMiPTH test is negative, then a second one is necessary after 10 minutes. In the event that the repeated test is negative, then from the 2 recognized intact ones, the least altered is determined and the scope of the operation is expanded to subtotal PTE (3.5 PTG), leaving ½ of the least altered PTG. The operation ends here.When deciding that 3 or more PTG are pathologically changed and enlarged, a subtotal PTE with IMiPTH is performed. In case of a negative IMiPTH test, the places of possible ectopic location of the PTG are examined: thyrothymic ligaments, upper thymus horns, fatty tissue along the carotid arteries. If there are no ectopically located PTGs in the indicated places, the operation is completed.CONCLUSION: The proposed treatment and diagnostic algorithm is pathogenetically substantiated, aimed at preoperative detection of multiple PTG lesions in PHPT and will improve the quality of life of this group of patients by reducing the persistence of the disease.

Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism.

Our objective was to overview the most recent data on primary hyperparathyroidism (PHP) in children and teenagers from a multidisciplinary perspective. Methods: narrative review based on full-length, English-language papers (from PubMed, between January 2020 and July 2023). Results: 48 papers (14 studies of ≥10 subjects/study, and 34 case reports/series of <10 patients/study). Study-sample-based analysis: except for one case-control study, all of the studies were retrospective, representing both multicenter (n = 5) and single-center (n = 7) studies, and cohort sizes varied from small (N = 10 to 19), to medium-sized (N = 23 to 36) and large (N = 63 to 83); in total, the reviewed studies covered 493 individuals with PHP. Case reports/series (n = 34, N = 41): the mean ages studied varied from 10.2 to 14 years in case reports, and the mean age was 17 years in case series. No clear female predominance was identified, unlike that observed in the adult population. Concerning the assessments, there were four major types of endpoints: imaging data collection, such as ultrasound, 99mTc Sestamibi, or dual-phase computed tomography (CT); gene testing/familial syndrome identification; preoperative findings; and exposure to surgical outcome/preoperative drugs, like cinacalcet, over a 2.2-year median (plus two case reports of denosumab used as an off-label calcium-lowering agent). Single-gland cases (representing 85% of sporadic cases and 19% of genetic PHP cases) showed 100% sensitivity for neck ultrasounds, with 98% concordance with 99mTc Sestamibi, as well as a 91% sensitivity for dual-phase CT, with 25% of the lesions being ectopic parathyroids (mostly mediastinal intra-thymic). Case reports included another 9/41 patients with ectopic parathyroid adenomas, 3/41 with parathyroid carcinomas, and 8/41 subjects with brown tumors. Genetic PHP (which has a prevalence of 5-26.9%) mostly involved MEN1, followed by CDC73, CASR, RET, and CDKN1B, as well as one case of VHL. Symptomatic PHP: 70-100% of all cases. Asymptomatic PHP: 60% of genetic PHP cases. Renal involvement: 10.5% of a cohort with genetic PHP, 71% of sporadic PHP cases; 50% (in a cohort with a mean age of 16.7), 29% (in a cohort with a mean age of 15.2); 0% (in infancy) to 50-62% (in teenagers). Bone anomalies: 83% of the children in one study and 62% of those in two other studies. Gastrointestinal issues: 40% of one cohort, but the data are heterogeneous. Cure rate through parathyroidectomy: 97-98%. Recurrent PHP: 2% of sporadic PHP cases and 38% of familial PHP cases. Hungry bone syndrome: maximum rate of 34-40%. Case reports identified another 7/41 subjects with the same post-parathyroidectomy condition; a potential connection with ectopic presentation or brown tumors is suggested, but there are limited data. Minimally invasive thoracoscopic approaches for ectopic tumors seemed safe. The current level of statistical evidence on pediatric PHP qualifies our study- and case-sample-based analysis (n = 48, N = 534) as one of the largest of its kind. Awareness of PHP is the key factor to benefit our young patients.

SAT180 Comparison Between Sporadic Primary Hyperparathyroidism And Multiple Endocrine Neoplasia Type 1 (MEN1)-Associated Primary Hyperparathyroidism: A Retrospective Analysis Of The Indian PHPT Registry

Abstract Disclosure: S. Bhadada: None. A.M. Chakraborty: None. P. Kumari: None. R. Pal: None. A. Sood: None. D. Dahiya: None. S.D. Rao: None. Introduction: Multiple endocrine neoplasia type 1 (MEN1)-associated tumours are located in parathyroid, pituitary and pancreatoduodenal locations. Though heterogenous, the most consistent presentation of MEN1 is primary hyperparathyroidism (PHPT) seen in almost 100% of cases. Comparisons between sporadic and MEN1 PHPT patients are sparse in the literature. Objective: To retrospectively compare the demography, clinical manifestations, management, and outcome of sporadic PHPT and MEN1-associated PHPT patients. Design and setting: A registry-based (www.indianphptregistry.com) retrospective cohort study from a tertiary care hospital in North India. Methods and patients: The medical records and clinical data of sporadic PHPT patients and MEN1-associated PHPT patients registered in the Indian PHPT registry were analysed. Result: A total of 616 PHPT patients have been registered in the electronic registry, 72 of whom (11.68%) were MEN1-associated PHPT. The mean age of sporadic PHPT patients was 43.4 ± 14.3, whereas MEN1-associated PHPT was 35.8 ± 13.5 years (p&amp;lt;0.05). Among MEN1-associated PHPT cases, 66 (90%) were index cases at the time of presentation, and the rest were detected on family screening. For both sporadic PHPT and MEN1-associated PHPT, the most common presenting symptom was bone pain, followed by renal stone disease. Sporadic PHPT and MEN1 PHPT both had comparable mean calcium (11.9 ± 1.5 vs 11.9 ± 1.6 mg/dl), mean phosphate (2.7 ± 1 vs 2.58 ± 0.7 mg/dl), median PTH (314; IQR 161-984 pg/ml vs 292; IQR 180-818 pg/ml) level at presentation. Median 25-hydroxyvitamin D level was 19.3; IQR 10.4-30.4 ng/dl, and 15; IQR 8.1 – 25.1 ng/dl (p&amp;lt;0.05) for sporadic PHPT and MEN1-associated PHPT respectively. Multiglandular disease was common in MEN1-associated PHPT (40.2%) compared to sporadic cases (3%). Median tumour weight was higher in sporadic cases (2.5; IQR 0.8- 7.3 gm) compared to MEN1 cases (1.9; IQR 1.08 – 4.05 gm). Ultrasound neck and Sesta-MIBI concordance rate among sporadic cases was 57%, whereas MEN1 cases were 70.8%. Median post-surgery decline in PTH and calcium was more in the case of sporadic PHPT in comparison to MEN1-associated PHPT 84.81% vs 46.7% and 23.4% vs 16.59 % respectively (p&amp;lt;0.05). Discussion: MEN1-associated PHPT patients presented at an earlier age than sporadic cases. There was no statistical difference in PTH, calcium or phosphate levels between the two cohorts, but 25-hydroxyvitamin D levels were lower in MEN1-associated PHPT. Localisation was better in the case of the MEN-1 cohort as per as the Sesta-MIBI and USG concordance was concerned. Postoperative fall of PTH and calcium was more in sporadic cases than in MEN1 cases. Presentation: Saturday, June 17, 2023

SAT178 EZH2 Upregulation And Lysine 27 Trimethylation at Histone 3 Is Associated With Severe Sporadic Primary Hyperparathyroidism

Abstract Disclosure: P. Kumari: None. A.K. Arya: None. D. Dahiya: None. N. Sachdeva: None. J. Kaur: None. U.N. Saikia: None. S. Bhadada: None. S.D. Rao: None. Introduction: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that regulates gene activity through histone modifications of lysine (K) at H3 histone and has a crucial role in tumor development. However, the level of methylation at H3 histone and its association with EZH2 expression in sporadic primary hyperparathyroidism (PHPT) are not known. This study was designed to investigate how global levels of histone methylation were associated with altered expression of EZH2 in promoting parathyroid tumorigenesis. Methodology: A total of 30 parathyroid tumors (15 non-severe, 15 severe, and 5 normal parathyroid tissues) were collected during 2020-2021. The global histone methylation of major methylation sites at lysine (K) K4, K9, K27, K36, and K79 was evaluated from blood and tissue samples using a calorimetric ELISA (H3 global modification kit, Epegentek, USA). Gene and protein expression of EZH2 were performed by quantitative real-time PCR and immunohistochemistry respectively. Histone methylation and expression data were correlated with indices of disease severity. Results: We found that the global levels of H3K27me1 and me3 were significantly upregulated, whereas, H3K4me3 and H3K36me2 were significantly downregulated in tumors from patients with severe PHPT compared to tumors from non-severe PHPT and controls. Moreover, H3K27me3 showed the highest upregulation (8-fold) in severe PHPT. Additionally, EZH2 gene expression was significantly upregulated in severe PHPT [Mean ± S.E; (9.1 ± 1.6 vs. 1.2 ± 0.3, p = 0.005), but not in non-severe (4.2 ± 2.7 vs. 1.2 ± 0.3, p = 0.4) PHPT, compared to normal parathyroid tissues. Furthermore, the protein expression was also consistent with the gene expression, with 86% (n= 13/15) nuclear positivity for EZH2 in tumors from severe PHPT and 40% (6 of 15) in tumors from non-severe PHPT compared to normal parathyroid tissue (negative staining). Correlation analysis revealed that EZH2 gene expression is positively related with S.Ca (r = 0.44, p = 0.003), PTH (r = 0.59, p = 0.000), tumor weight (r = 0.455, p = 0.002), EZH2 protein expression (r = 0.7, p = 0.000), and Ki67 proliferative marker (r = 0.66, p = 0.002). Conclusions: Increased global trimethylation of K27 at histone 3 (H3K27me3) was associated with increased EZH2 expression in sporadic PHPT and was predictive of a more severe clinical phenotype. Sources of research support: (ICMR), New Delhi Extramural Research Grant 2020. Presentation: Saturday, June 17, 2023

Trabecular Bone Score as a More Sensitive Tool to Evaluate Bone Involvement in MEN1-related Primary Hyperparathyroidism.

The skeletal involvement of multiple endocrine neoplasia type 1-related primary hyperparathyroidism (MHPT) is not exactly the same as that of sporadic primary hyperparathyroidism (SHPT). Trabecular bone score (TBS) as a texture parameter has been reported to reflect trabecular bone damage. This study aimed to compare the clinical characteristics, especially the skeletal involvement, between patients with MHPT and SHPT. The clinical characteristics were retrospectively collected in 120 patients with MHPT and compared with 360 patients with SHPT in the same period. Dual-energy X-ray absorptiometry were conducted in some patients with MHPT, in whom bone mineral density (BMD) and calculated TBS derived from lumbar spine dual-energy X-ray absorptiometry images were compared with those of patients with SHPT. Although the duration of disease in the MHPT group was longer, the age at hospital visit was significantly lower than that in the SHPT group (43.5 [interquartile range, 31.5-52.0] vs 52.0 [interquartile range, 40.5-61.0], P < .001). The proportion of skeletal involvement in the MHPT group was significantly lower. However, in the subgroup of MHPT cases (n = 86) with data of BMD, there was no significant difference in skeletal involvement from SHPT cases matched for gender and age. Although the BMD and TBS in the lumbar spines of patients with MHPT were lower than those of patients with SHPT (BMD: 0.91 ± 0.18 g/cm2 vs 1.01 ± 0.17 g/cm2; TBS: 1.22 ± 0.14 vs 1.29 ± 0.11, P < .001). According to TBS, among 34 patients with MHPT with normal BMD, 15 patients had bone microstructure damage. The cancellous bone microarchitecture was more severely damaged in patients with MHPT according to TBS, which suggested that TBS could be a sensitive supplemental index in addition to BMD to identify bone-involvement risk in patients with MHPT.

Older Patients With Asymptomatic Primary Hyperparathyroidism: Should Criteria for Surgery Be Expanded?

Patients with primary hyperparathyroidism (PHPT) can present with variable signs, symptoms, and end-organ effects. Clinical practice guidelines influence referral for consideration of parathyroidectomy. This study compared the demographic, biochemical, and symptom profile and examine indications for surgery in patients older than 50 years who underwent parathyroidectomy to determine how changes to current guidelines may affect recommendations for parathyroidectomy. A retrospective review was conducted of patients age 50 years or older who underwent initial parathyroidectomy for sporadic PHPT from 2012 to 2020. Patients were classified by indications for surgery per guideline criteria (classic, asymptomatic, and no criteria met) and age group (AG): 50 to 59 years; 60 to 69 years; 70 years or older. Patients were treated at a high-volume tertiary medical center by endocrine surgeons. Of 1182 patients, 367 (31%) classic and 660 (56%) asymptomatic patients met the criteria for surgery. The most common indications for surgery were extent of hypercalcemia (51%), osteoporosis (28%), and nephrolithiasis (27%). Of the 155 (13%) patients who did not meet the criteria, neurocognitive symptoms (AG1: 88% vs AG2: 81% vs AG3: 70%; P = .14) and osteopenia (AG1: 53% vs AG2: 68% vs AG3: 68%; P = .43) were frequently observed regardless of patient age. If the age threshold of younger than 50 years was expanded to 60, 65, or 70 years, an additional 61 (5%), 99 (8%), and 124 (10%) patients in the entire cohort would have met the guideline criteria for surgery, respectively. Expanding current guidelines for PHPT to include a broader age range, osteopenia, and neurocognitive symptoms may allow for earlier surgical referral and evaluation for definitive treatment.

Genetic and clinical screening for hereditary primary hyperparathyroidism in a large Chinese cohort: a single-center study.

Primary hyperparathyroidism (PHPT) includes sporadic PHPT and hereditary PHPT. However, until now, there have been no exact data on the proportion and composition of hereditary PHPT in the Chinese PHPT population. This study aimed to clarify the proportion and composition of hereditary PHPT in patients at a large academic center in Beijing, China, and to analyze genotype-phenotype characteristics. A total of 394 newly diagnosed Han PHPT patients who consented to genetic screening were enrolled. Targeted next-generation sequencing (T-NGS) (including for MEN1, RET, CDKN1B, CaSR, HRPT2/CDC73, GNA11, AP2S1, GCM2), combined with MEN1-multiplex ligation-dependent probe amplification (MLPA) and CDC73-MLPA, was used for genetic screening. Diagnosis of hereditary PHPT was based on clinical manifestations, family history, and genetic screening. Thirty-seven pathogenic (P)/likely pathogenic (LP) variants were detected in 41 patients via T-NGS, and three patients carried long-range deletions of MEN1 or CDC73 detected by MLPA, with a variant detection rate of 11.2% (44/394). In total, 30 patients were clinically diagnosed with MEN1. Combined with genetic and clinical screening, the rate of hereditary PHPT in this study was 18.8% (74/394). For purposes of comparison, the rate of unequivocal nonhereditary PHPT was 66.5% (262/394); 14.7% (58/394) did not exhibit the clinical features of hereditary PHPT but carried variants of uncertain clinical significance and so could not be clearly categorized. Both the age at hospital visit (43.6 ± 14.0 versus 53.7 ± 14.9 years) and age at onset (35.4 ± 13.8 versus 50.6 ± 14.8 years) in the hereditary group (n = 74) were significantly lower than those in the nonhereditary group (n = 262). Higher levels of ionized calcium and serum β-CTX were observed in the hereditary group; proportions of parathyroid hyperplasia and multigland involvement were also higher. In addition to multigland disease and positive family history, it is recommended that patients with an age of onset less than 38 should be screened for hereditary forms. © 2023 American Society for Bone and Mineral Research (ASBMR).

Operative success is achieved regardless of ioPTH criterion used during focused parathyroidectomy for sporadic primary hyperparathyroidism

BackgroundFocused parathyroidectomy (F-PTX) guided by intraoperative parathormone (ioPTH) monitoring may result in higher operative failure rates from missed multiglandular disease (MGD) in patients with sporadic primary hyperparathyroidism (spHPT) when ioPTH levels do not reach normal range. MethodsA retrospective review included 690 patients with spHPT who underwent F-PTX and ioPTH monitoring were divided into 2 groups: >50% ioPTH decrease to normal range, and >50% ioPTH decrease to above normal range. Operative success, recurrence, bilateral/unilateral neck exploration (BNE/UNE), MGD were evaluated. Results533 patients demonstrated >50% ioPTH decrease to normal range, and 157 patients >50% ioPTH decrease to above normal range. There were no differences in operative success 99% vs. 97%, recurrence 2.5% vs. 5%, BNE 12% vs. 11%, UNE 4% vs. 5%, or MGD 4% vs. 4%, (p > 0.05) with 46 months mean follow-up. ConclusionsThere were no differences in operative success, failure, BNE, UNE or MGD regardless of ioPTH criterion used for F-PTX.

Variant Tyr 394Ser in the GCM2 Gene Is Rare in a Cohort of Ashkenazi Jews With Primary Hyperparathyroidism.

Various genes have been associated with familial and sporadic primary hyperparathyroidism (PHPT), including activating mutations of the glial cells missing transcription factor 2 (GCM2) gene. The aim of this study was to assess the prevalence of the GCM2 p.Tyr394Ser variant in the Jerusalem Ashkenazi Jewish (AJ) population with PHPT, and to conclude whether routine genetic testing is justified. The blood of 40 self-reported AJ patients with PHPT and 200 AJ controls was tested for the GCM2 p.Tyr394Ser variant. Demographic and medical information was extracted from the patients' charts and evaluated accordingly. Two (5%) PHPT patients and 3 (1.5%) controls were heterozygotes for the tested variant. Our patients were mostly (87.5%) sporadic cases. One of the heterozygote patients had familial PHPT; the other had 2 parathyroid adenomas, and the levels of his blood and urinary calcium were extremely high. Our results suggest that in AJ patients with sporadic, single-gland PHPT, the likelihood of the tested variant is low and genetic testing should be limited to those with familial PHPT or multiglandular disease.

Long-term Recurrence Rates After Surgery in Primary Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia, yet long-term (5- and 10-year) recurrence rates after curative surgery have been unclear. To perform the first systematic review and meta-analysis investigating the long-term recurrence rates of sporadic PHPT after successful parathyroidectomy. A comprehensive search of multiple databases (including PubMed, EMBASE, Cochrane, EBSCO-CINHAL, EMBASE, Ovid, Scopus, and Google Scholar) was performed from each database's inception to January 18, 2023. Observational studies reporting at least 5 years of follow-up data after surgical resection were included. Two reviewers independently screened articles for relevance. Of 5769 articles initially identified, 242 were examined in full-text review and 34 were deemed eligible for inclusion. Two authors independently performed data extraction and study appraisal, using the National Institutes of Health study quality assessment tools. Of 30 658 participants, 350 patients (1.1%) experienced recurrence after resection. A meta-analysis of proportions was performed to obtain the pooled recurrence rates. The pooled estimate for overall recurrence rate was 1.56% (95% CI 0.96-2.28%; I2 = 91%). The pooled estimates for 5- and 10-year recurrence rate after resection were 0.23% (0.04-0.53%, 19 studies; I2 = 66%) and 1.03% (0.45-1.80%, 14 studies; I2 = 89%), respectively. Sensitivity analyses did not find a statistically significant difference when adjusting for study size, diagnosis, or surgical approach. Approximately 1.56% of sporadic PHPT patients eventually develop recurrence following parathyroidectomy. The initial diagnosis and procedure type does not influence recurrence rates. Consistent long-term follow-up is warranted to help identify recurrent disease.

Surgery for Sporadic Primary Hyperparathyroidism: Evolution over the Last Twenty Years in a Monocentric Setting.

The sporadic parathyroid pathology of surgical interest is primarily limited to lesions that are the cause of hormonal hyperfunction (primary hyperparathyroidism). In recent years, parathyroid surgery has evolved significantly, and numerous minimally invasive parathyroidectomy techniques have been developed. In this study, we describe a single-center and well-documented case series of sporadic primary hyperparathyroidism, surgically treated by a single operator in the Endocrine Surgery Unit of the Surgical Clinic of the University of Florence-Careggi University Hospital, recorded and updated in a dedicated database that embraces the entire evolutionary timeframe of parathyroid surgery. From January 2000 to May 2020, 504 patients with a clinical and instrumental diagnosis of hyperparathyroidism were included in the study. The patients were divided into two groups, based on the application of intraoperative parathyroid hormone (ioPTH). The analysis shows that the use of ioPTH with the rapid method could be ineffective in helping surgeons in primary operations, especially when ultrasound and scintiscan are concordant. The advantages obtained by not using intraoperative PTH are not only economic. In fact, our data shows shorter operating and general anesthesia times and hospital stays, having an important impact on patient biological commitment. Furthermore, the significant reduction in operating time makes it possible to almost triple the volume of activity in the same unit of time available, with an undeniable advantage for the reduction of waiting lists. In recent years, minimally invasive approaches have allowed surgeons to reach the best compromise between invasiveness and aesthetic results.

Localization diagnostics and operative strategy for the first intervention in sporadic primary hyperparathyroidism

Primary hyperparathyroidism (pHPT) is afrequent endocrine disease, the incidence of which is clearly increasing. In addition to the classical symptoms of bone pain, osteoporosis and renal calculi, nonspecific complaints, such as listlessness and exhaustion, anxiety states and depressive symptoms also often occur. The diagnosis is simple and is carried out by determination of calcium and parathormone (PTH) serum levels. The majority of parathyroid adenomas can be localized by ultrasound and Tc-99m-MIBI scintigraphy. The indications for surgery can normally already be identified by the laboratory biochemical detection. Surgery is the only curative treatment of pHPT and is normally successful. In addition to bilateral exploration, a focused parathyroidectomy can be planned. The success of surgery can be intraoperatively documented by the determination of intraoperative Quick PTH (IOPTH).