Hypersecretion Of Parathyroid Hormone Research Articles

OR23-01 The Nonredundant Role Of Beta-Amyloid In Mediating Tonic PTH Secretion In Physiological And Pathological States

Abstract Disclosure: C. Tu: None. Z. Cheng: None. K.A. Pena: None. N. Szeto: None. J.A. Sosa: None. J. Vilardaga: None. J. Koh: None. W. Chang: None. Understanding the mechanisms driving parathyroid hormone (PTH) hypersecretion in primary hyperparathyroidism (PHPT) is essential for better management of this common endocrinopathy. Prior studies showed that reduced Ca2+-sensing receptor (CaSR) expression and the subsequent increases in heterodimerization of the CaSR with the type B γ-aminobutyric acid receptor 1 (GABAB1R) are causally linked to PTH hypersecretion in PHPT mouse models (Nat Metab 2:243-255). We further showed that expression of the putative GABAB1R ligands, amyloid precursor protein (APP) and its proteolytic product, β-amyloid (Aβ1-42), is significantly upregulated in adenomas of PHPT patients associated with vitamin D insufficiency/deficiency when compared to normal donor controls. The current study aims to delineate the actions of Aβ1-42 in promoting tonic PTH secretion and its interactions with vitamin D receptor (VDR) signaling in parathyroid glands (PTGs) in basal and PHPT states. We show that Aβ1-42 (200 nM) stimulated tonic PTH secretion in cultures of normal human PTGs without shifting the calcium/PTH secretion setpoint (Ca2+-setpoint). In contrast, conditional knockout (KO) of the App gene in the parathyroid cell (PTC) of PTCAppΔflox/Δflox mice significantly reduced serum PTH levels (KO: 64±13 pg/ml vs Control: 109±12 pg/ml; p<0.05, n=8) despite hypocalcemia, indicating hypoparathyroidism. In PTGs cultured from the PTCAppΔflox/Δflox mice, supplementation of Aβ1-42 dose-dependently (EC50=5.6 nM, p<0.001) increased PTH secretion without altering the Ca2+-setpoint. However, the stimulatory effects of Aβ1-42 on tonic PTH secretion were completely abrogated in the PTGs with concurrent deletions of App, Casr and Gabbr1 genes, supporting a direct action of Aβ1-42 on CaSR and/or GABAB1R. The latter notion is further supported by the ability of Aβ1-42 to stimulate cAMP production in cells co-expressing CaSR and GABAB1R. PTC-specific deletion of the Vdr gene in the PTCVdrΔflox/Δflox mice led to elevated serum PTH levels in vivo and increased tonic PTH secretion with unaffected Ca2+-setpoint in PTGs in vitro. Concurrent ablation of the App gene completely normalized serum PTH levels in the PTCVdrΔflox/Δflox mice and prevented PTH hypersecretion in their PTGs in culture. These findings support a critical role of the APP-derived Aβ1-42 in mediating tonic PTH secretion in the normal physiological state and suggest a new mechanism driving PTH hypersecretion in PHPT due to vitamin D deficiency. Presentation: Saturday, June 17, 2023

THU396 Digital Spatial Profiling Of Human Parathyroid Tumors Reveals Distinct Cellular And Molecular Alterations Linked To Vitamin D Deficiency

Abstract Disclosure: C. Tu: None. W. Chang: None. J.A. Sosa: Advisory Board Member; Self; Novo Nordisk, AstraZeneca, Eli Lilly & Company. Grant Recipient; Self; Exelixis, Inc., Eli Lilly & Company. J. Koh: None. Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder characterized by disrupted calcium homeostasis secondary to inappropriately elevated parathyroid hormone (PTH) secretion. Low levels of serum 25-hydroxyvitamin D (25OHD) are significantly more prevalent in PHPT patients than in the general population, but the pathophysiological basis for this association remains unclear. We employed a spatially defined in situ whole-transcriptomics and selective proteomics profiling approach to compare gene expression patterns and cellular composition in parathyroid adenomas from 9 vitamin D-deficient or 34 vitamin D-replete PHPT patients with 12 eucalcemic cadaveric donor parathyroid glands as normal tissue controls. Parathyroid oxyphil cell content is markedly higher in tumors from vitamin D-deficient PHPT patients (Def-Ts) relative to tumors from vitamin D-replete PHPT patients (Rep-Ts) (47.8% vs 17.8%, respectively; p <0.0001) and normal donor parathyroid glands (7.7%). Def-Ts display increased expression of genes encoding electron transport chain (corr. coefficient=0.546), proteasomal catabolism (corr. coefficient=0.587), and oxidative phosphorylation (corr. coefficient=0.982) pathway components. In contrast, Rep-Ts are characterized by upregulation of the ras (corr. coefficient=0.632) and myc (corr. coefficient=0.811) signaling pathways, suggestive of an oncogene-driven etiology. Parathyroid oxyphil cells are comparable to chief cells at the transcriptional level, and vitamin D-status is reflected in the transcriptional profiles of both cell types in a similar manner. Among PHPT patients who did not present as vitamin D deficient, three distinct tumor transcriptional profile clusters showed a dose-dependent relationship to pre-operative 25OHD levels (p <0.0001 by ANOVA). Relative to normal tissue, the abundance of calcium sensing receptor (CaSR) protein is reduced in Def-Ts (mean protein count 253.6 vs 492.3, respectively; p=0.039 for difference), while the type B γ-aminobutyric acid receptor 1 (GABAB1R) is increased (mean protein count 114.5 vs 64.65, respectively; p=0.0099 for difference). These expression changes resulted in a vitamin D dose-dependent reduction in the ratio of CaSR to GABAB1R receptors in Def-T tumor cells (r2 = 0.218, p<0.0001), favoring the formation of calcium sensing-attenuated CaSR:GABAB1R heteromers. The abundance of the amyloid precursor protein (APP) peptide derivative Aβ1-42, a putative GABAB1R ligand, is preferentially increased in Def-Ts compared to normal tissue (mean protein count 5797 vs 4500, respectively; p=0.0318). Collectively, these findings suggest a novel mechanism where chronic vitamin D deficiency can contribute to tonic PTH hypersecretion in PHPT patients by increasing GABAB1R-mediated antagonism of CaSR activity in parathyroid adenomas. Presentation: Thursday, June 15, 2023

Brown tumor secondary to primary hyperparathyroidism. Clinical case, set-up and role of the surgeon

This work is focused on describing the most important characteristics of primary hyperparathyroidism and the bone involvement that this pathology produces, based on a clinical case of a patient attended at the Hospital de Clínicas (UDELAR) - Montevideo-Uruguay. Brown tumors (PT) are a rare abnormality of bone tissue caused by chronic hypersecretion of parathyroid hormone (PTH), the pathophysiology of which will be discussed throughout the text. They manifest clinically as tumors, which is of paramount importance since it is necessary to evaluate differential diagnoses. It frequently develops in long bones, which explains its topographic variability. The treatment of these lesions depends fundamentally on the control of hyperparathyroidism and the location of the tumor. Most of them remit when PTH levels are normalized.

Investigating Unexpected Shortening of Height of A Middle-Aged Woman: A Case Report

Osteitis fibrosa cystica (OFC) is a late sequela of untreated hyperparathyroidism caused by the autonomous secretion of parathyroid hormone (PTH). It is characterized by bone pain, skeletal deformities, and pathological fractures. OFC is caused by hypersecretion of PTH, leading to demineralization of bone and pathological fractures. We report a case of unusual presentation of OFC in a middle aged woman who noticed gradual shortening of her height within a particular period of time. Apart from height reduction, the patient had weight loss and pain in different parts of the body for over a decade. Despite being treated with analgesics and steroids initially, there was no significant improvement in her condition. Treatment history included surgical reduction of right elbow fracture and empirical anti-tubercular drug twice as there was a suspicion of disseminated tuberculosis. The patient developed lytic changes, skeletal deformities, and osteoporosis, and was diagnosed with a solitary parathyroid adenoma on the right side. Bangladesh J. Nuclear Med. 26(1): 58-61, 2023

Ectopic PTH-producing parathyroid cyst inside the thymus: a case report

BackgroundThe hallmark of hyperparathyroidism is hypersecretion of parathyroid hormone (PTH) which results in hypercalcemia and hypophosphatemia. While hypercalcemia due to malignancy is often brought about by PTH-related protein in adults, PTH-producing tumors are quite rare in clinical practice. Additionally, from the point of embryology, it is very difficult to examine ectopic PTH-producing tissue such as ectopic parathyroid glands. Furthermore, clear histopathological criteria are not present.Case presentationA 57-year-old woman was referred to our hospital for hypercalcemia. Her parathyroid hormone (PTH) level was elevated, but there were no enlarged parathyroid glands. Although 99mTc-MIBI confirmed a localized and slightly hyperfunctioning parathyroid tissue in the anterior mediastinum, it was not typical as hyperfunctioning parathyroid. We finally diagnosed her as ectopic PTH-producing cyst-like tumor with venous sampling of PTH. She underwent anterosuperior mediastinal ectopic PTH-producing cyst-like tumor resection. It is noted that intact-PTH concentration of the fluid in the cyst was very high (19,960,000 pg/mL). Based on histopathological findings, we finally diagnosed her as ectopic PTH-producing parathyroid cyst inside the thymus. After resection of anterosuperior mediastinal thymus including ectopic PTH-producing parathyroid cyst, calcium and intact-PTH levels were decreased, and this patient was discharged without any sequelae.ConclusionsWe should know the possibility of superior mediastinal ectopic PTH-producing parathyroid cyst inside the thymus among subjects with ectopic PTH-producing parathyroid glands. Particularly when the cyst is present in the superior mediastinum, it is necessary to do careful diagnosis based on not only positive but also negative findings in 99mTc-MIBI. It is noted that the patient’s bloody fluid in the cyst contained 19,960,000 pg/mL of intact-PTH, and its overflow into blood stream resulted in hyperparathyroidism and hypercalcemia. Moreover, in such cases, the diagnosis is usually confirmed after through histological examination of ectopic PTH-producing parathyroid glands. We think that it is very meaningful to let clinicians know this case.

Medical management of primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is an endocrine disorder resulting from the hyperfunction of one or more parathyroid glands, with hypersecretion of parathyroid hormone (PTH). It can be managed by parathyroidectomy (PTX) or non-surgically. Medical therapy with pharmacological agents is an alternative for those patients with asymptomatic PHPT who meet guidelines for surgery but are unable or unwilling to undergo PTX. In this review, we focus upon these non-surgical aspects of PHPT management. We emphasize the most studied and widely used pharmacological alternatives: bisphosphonates, denosumab, cinacalcet and hormone therapy, in addition to combined therapy. We also address the relevant aspects of perioperative management.

An optogenetic approach for regulating human parathyroid hormone secretion

Parathyroid hormone (PTH) plays crucial role in maintaining calcium and phosphorus homeostasis. In the progression of secondary hyperparathyroidism (SHPT), expression of calcium-sensing receptors (CaSR) in the parathyroid gland decreases, which leads to persistent hypersecretion of PTH. How to precisely manipulate PTH secretion in parathyroid tissue and underlying molecular mechanism is not clear. Here, we establish an optogenetic approach that bypasses CaSR to inhibit PTH secretion in human hyperplastic parathyroid cells. We found that optogenetic stimulation elevates intracellular calcium, inhibits both PTH synthesis and secretion in human parathyroid cells. Long-term pulsatile PTH secretion induced by light stimulation prevented hyperplastic parathyroid tissue-induced bone loss by influencing the bone remodeling in mice. The effects are mediated by light stimulation of opsin expressing parathyroid cells and other type of cells in parathyroid tissue. Our study provides a strategy to regulate release of PTH and associated bone loss of SHPT through an optogenetic approach.

Are Non-Coding RNAs Useful Biomarkers in Parathyroid Tumorigenesis?

Tumors of the parathyroid glands are common endocrine diseases almost always characterized by parathyroid hormone hypersecretion that determines the clinical manifestations of primary hyperparathyroidism, such as fatigue, kidney problems, weakness, brittle bones, and other symptoms. Most parathyroid neoplasia are benign adenomas, although rare malignant forms have been described. They are heterogeneous in terms of clinical presentation and the associated signs and symptoms overlap with those of disease and aging. Furthermore, most patients with hypercalcemia are discovered during routine blood tests for other reasons. Surgical removal is considered the main therapeutic option to cure these endocrine tumors and, therefore, innovative therapeutic approaches are actively required. Recently, a growing number of studies have suggested that alterations to the epigenetic mechanisms could play a pivotal role in parathyroid tumorigenesis. Most of the attention has been focused on non-coding RNAs (ncRNAs) (i.e., miRNAs, lncRNAs, and circRNAs) whose expression profile has been found to be deregulated in parathyroid tumors. The aim of the present paper is to give an insight into the ncRNAs involved in parathyroid tumorigenesis, which could be used in the future either as innovative diagnostic biomarkers or as therapeutic targets for the treatment of this endocrine neoplasia.

Concomitant familial hypocalciuric hypercalcemia and single parathyroid adenoma: a case report

BackgroundPrimary hyperparathyroidism (PHPT) is a common endocrine disorder and the most frequent benign cause of hypercalcemia. PHPT is characterized by autonomous hypersecretion of parathyroid hormone (PTH), regardless of serum calcium levels. Familial hypocalciuric hypercalcemia (FHH) is a rare, benign syndrome only affecting the regulation of calcium metabolism. FHH is an autosomal-dominant genetic disease with high penetrance, caused by an inactivating variant in the CASR gene encoding the calcium-sensing receptor (CaSR). We present a unique case of concomitant PHPT and FHH without clinically actionable variants in MEN1.Case presentationA 47-year-old Caucasian man with severe hypercalcemia, genetic FHH, and initially normal parathyroid scintigraphy was referred for endocrine evaluation due to nonspecific symptoms. Biochemical evaluation showed elevated serum ionized calcium and PTH. The calcium–creatinine clearance ratio was low. All other biochemical measures were normal, including kidney function. Genetic evaluation was redone and confirmed FHH. A new parathyroid scintigraphy showed a significant single adenoma corresponding to the lower left gland. The patient underwent parathyroidectomy, and a parathyroid adenoma was removed. A reduced level of hypercalcemia persisted due to FHH.ConclusionsThe correct diagnosis of the underlying cause of hypercalcemia is important to ensure the right treatment. Patients with FHH should avoid operative treatment, and PHPT should be differentiated from MEN1 to determine whether surgery should include parathyroidectomy with removal of one adenoma or 3.5 hyperplastic parathyroid glands.

Aberrant Epigenetic Alteration of PAX1 Expression Contributes to Parathyroid Tumorigenesis.

Primary hyperparathyroidism (PHPT) results from the hypersecretion of parathyroid hormone from parathyroid tumors. A transcription factor, namely Paired box1 (PAX1), is active in parathyroid gland development. We aimed to study potential epigenetic-mediated mechanism of PAX1 gene in sporadic parathyroid adenomas. In parathyroid adenomas tissues, we analyzed the DNA methylation via bisulfite-specific polymerase chain reaction (BSP) and histone modifications via chromatin immunoprecipitation in regulating the differential expression of PAX1. The results showed that mRNA and protein expression of PAX1 was significantly reduced in parathyroid adenomas. Bisulfite sequencing demonstrated hypermethylation in the promoter region of PAX1 (35%; 14/40) and lower levels of histone 3 lysine 9 acetylation (H3K9ac) were observed on the promoter region of PAX1 (6-fold; P < .004) in parathyroid adenomas. Furthermore, upon treatment with a pharmacologic inhibitor, namely 5'aza-2 deoxycytidine, in rat parathyroid continuous cells, we found re-expression of PAX1 gene. Our study not only reveals expression of PAX1 is epigenetically deregulated but also paves a way for clinical and therapeutic implications in patients with PHPT.

Treatment-resistant Hypercalcemia from Ectopic PTH Hypersecretion Suspected Secondary to Disseminated Ovarian Cancer

Hypercalcemia of malignancy (HCM) can present secondary to hypersecretion of parathyroid hormone (PTH)-related protein (PTHrP) from malignant tumors, but rare cases of HCM have also been documented due to inappropriate PTH secretion from ectopic neoplasms. Here, we report an unusual case of HCM due to hypersecretion of PTH suspected secondary to a disseminated mucinous ovarian adenocarcinoma. A 45-year-old female presented with severe hypercalcemia and significant elevations in both PTH and PTHrP two weeks after total abdominal hysterectomy with bilateral salpingo-oophorectomy and suboptimal debulking of a newly discovered left ovarian mucinous adenocarcinoma with numerous metastases. Ectopic PTH secretion was highly suspected after a negative parathyroid ultrasound. Pamidronate, calcitonin, and fluid resuscitation were unable to normalize her serum calcium, resulting in the need for dialysis and subsequent continuous renal replacement therapy. Further intervention with denosumab, etelcalcetide, and cinacalcet was attempted. Serum calcium began to decline, but repeat PTH resulted greater than 2,500 pg/mL. Unfortunately, the patient died just one week into her hospital course from septic shock and multi-organ system failure. While patients with localized PTH-secreting tumors carry a good prognosis, disseminated malignancies can result in significant morbidity and mortality due to severe treatment-resistant hypercalcemia.

Treatment-Resistant Hypercalcemia Secondary to Ectopic PTH Hypersecretion From Disseminated Ovarian Cancer

Background: Hypercalcemia of malignancy (HCM) can present secondary to hypersecretion of parathyroid hormone (PTH)-related protein (PTHrP) from malignant tumors, but rare cases of HCM have also been documented due to inappropriate PTH secretion from ectopic neoplasms. Here, we report an unusual case of HCM due to hypersecretion of PTH from a disseminated mucinous ovarian adenocarcinoma. Case Presentation: A 45-year-old female presented with confusion, constipation, fatigue, and abdominal pain two weeks after total abdominal hysterectomy with bilateral salpingo-oophorectomy and suboptimal debulking of a newly discovered left ovarian mucinous adenocarcinoma with metastasis to the bladder, parametrium, vagina, right ovary, and rectosigmoid. Subsequent CT revealed numerous bilateral pulmonary nodules, hilar adenopathy, liver lesions, and abdominal adenopathy. On exam, she was tachycardic and hypertensive with diaphoresis, dry mucous membranes, respiratory distress, guarded abdominal tenderness, and altered mental status. Her labs were significant for a serum calcium of 21.7 mg/dL, creatinine of 1.93 mg/dL, ferritin of 2,379 ng/mL, leukocytosis of 21.9 bil/L, PTH of 1,061 pg/mL, and PTHrP of 29 pmol/L. Ectopic PTH secretion was highly suspected after negative parathyroid ultrasound. Pamidronate (60 mg IV), calcitonin (200 U IM), and fluid resuscitation were unable to normalize her serum calcium, resulting in the need for dialysis and subsequent continuous renal replacement therapy. Further intervention with denosumab (120 mg SQ), etelcalcetide (5 mg IV), and cinacalcet (60 mg PO) was also attempted. Serum calcium began to decline, but repeat PTH resulted greater than 2,500 pg/mL. Unfortunately, the patient died just one week into her hospital course from septic shock and multi-organ system failure. Discussion: Hypercalcemia of malignancy typically arises from tumor secretion of PTHrP, cytokine release from osteolytic metastases, or tumor production of calcitriol. In cases of hypercalcemia due to excess PTH secretion, primary parathyroid etiologies are typically considered while ectopic PTH-secreting tumors are rare. PTH staining of biopsy specimens and total body sestamibi scan may prove useful in the early detection and treatment of these tumors, but HCM offers a poor prognosis with mean survival of 2 to 3 months and in-hospital mortality of 6.8%. Currently, there are only three cases in the reported literature of ectopic PTH-induced hypercalcemia related to ovarian cancer. To our knowledge, this is the fourth reported case. Conclusion: Ectopic PTH-secreting tumors carry a poor prognosis and should be considered in cancer patients presenting with PTH-associated hypercalcemia. Biopsy staining for PTH and total body sestamibi scan may assist in the early detection of these tumors, but current treatment strategies offer suboptimal outcomes.

SECONDARY HYPERPARATHYROIDISM AMONG END-STAGE RENAL DISEASE PATIENTS

Objectives: The study aims to determine the incidence of secondary hyperparathyroidism (SHPT) in chronic kidney disease patients, the correlation between creatinine, parathyroid hormone (PTH) and phosphate, and calcium in renal disease.&#x0D; Methods: A retrospective cross-sectional study was performed, a total of 100 hemodialysis patients’ reports were analyzed from January 2019 to December 2019, at Hebron Governmental Hospital, in Hebron, Palestine. The patients’ data were collected, including creatinine level, calcium, and phosphorus in addition to PTH concentrations. Twenty-five healthy persons with normal kidney function were also included in the study as a control for comparison. Statistical Package for the Social Sciences version 22 was used to analyze the data. T-test and Pearson’s tests were used to study the results. R (Pearson’s test) was used to determine the correlation between creatinine, PTH, phosphate, and calcium.&#x0D; Results: The mean values of serum of creatinine, phosphate, calcium, and PTH were determined for both patients and the control. Levels of PTH were significantly higher in kidney failure patients and positively correlated with creatinine and phosphate. However, levels of PTH were significantly negatively correlated with calcium. All patients included in the study have very high levels of PTH PTH. This increase might be due to many factors that contributed to the hypersecretion of PTH. The correlations between these predisposing factors of SHPT are explained.&#x0D; Conclusion: The study showed that SHPT is common among patients with end-stage renal disease. The most complications of SHPT are mineral and bone metabolism disorders and cardiovascular diseases. Thus, early detection and treatment of SHPT may control these complications.

18F-Fluorocholine PET/CT, Tc-99m-MIBI and TC-99m-MDP SPECT/CT in Tertiary Hyperparathyroidism with Renal Osteodystrophy.

Tertiary hyperparathyroidism (HPT) is a metabolic disorder characterized by the semi-autonomous hypersecretion of parathyroid hormone (PTH), leading to hypercalcemia. It can be the end result of persistent secondary hyperparathyroidism and is most commonly observed in patients with long-standing chronic kidney disease (CKD) and often after renal transplantation. Untreated HPT can lead to progressive bone disease, fibrocystic osteitis, and soft-tissue calcifications, along with other severe complications. In the 2009 Kidney Disease Improving Global Outcomes (KDIGO) guidelines, CKD-Mineral and Bone Disorder (CKD-MBD) is used to describe the broader clinical syndrome encompassing mineral, bone, and calcific cardiovascular abnormalities that develop as a complication of CKD. We report a 62-year-old female with a severe HPT evolved from advanced chronic kidney disease (stage 5D, KDIGO). Patient was evaluated with multimodality nuclear medicine functional imaging to assess hyperfunctioning parathyroid glands and bone lesions. Tc-99m-methoxyisobutylisonitrile (MIBI) dual-phase scintigraphy, Tc-99m-methylenediphosphonate (MDP) bone scan and 18F-Fluorocholine positron emission tomography/computed tomography (18F-FCH PET/CT) were performed before surgery.

Effects of PTH and PTH Hypersecretion on Bone: a Clinical Perspective.

Hyperparathyroidism may be due to an autonomous hypersecretion of parathyroid hormone (PTH) or occurs in response to a number of physiological stimuli. A number of recent findings have provided new insights into the importance of the calcium-parathyroid-vitamin D axis to bone in normal physiology and pathological conditions. PTH is known to affect bone microarchitecture with different effects on cortical and trabecular bone compartments. In trabecular bone, PTH may exert anabolic effects, whereas PTH promotes bone resorption in cortical bone. Vertebral fractures are prevalent in primary hyperparathyroidism (PHPT), and patients seem to fracture at higher values of bone mineral density (BMD) than patients with osteoporosis. This may be explained by changes in bone microarchitecture, which cannot be detected by measuring BMD. Even in mild PHPT, bone seems to benefit from parathyroidectomy. In secondary hyperparathyroidism, bone seems much more susceptible to fracture with insufficient levels of vitamin D compared with a replete vitamin status. If elevated PTH levels cannot be explained by conditions known to cause secondary hyperparathyroidism, the condition is termed normocalcemic PHPT, which also has been associated with an increased risk of fractures. Hyperparathyroidism is harmful to bone, which is why it is of importance to normalize PTH levels either by parathyroidectomy in PHPT or by counteracting conditions known to increase PTH in secondary hyperparathyroidism.

Justification of a combined study of the parathyroid and adrenal glands in patients with primary hyperparathyroidism

Primary hyperparathyroidism (PHPT) is an endocrine disease caused by tumor or hyperplastic changes in one or more parathyroid glands, which leads to unregulated hypersecretion of parathyroid hormone, hypercalcemia, and a number of pathological changes in target organs, especially in bones and kidneys. PHPT in most cases is sporadic and occurs of a single parathyroid adenoma (PTA), in 1—18 % of cases, PHPT can be associated with type 1 multiple endocrine neoplasia syndrome (MEN1) and be familial. Classic MEN1 consists of hyperplasia or a tumor of the parathyroid gland, a pancreatic tumor, and a tumor of the anterior pituitary gland. Asymptomatic adrenal tumors (AT) can be detected in 20—40 % of patients with MEN1. In 10 % of cases, AT show hormonal activity. Objective — to develop and implement a modified diagnostic algorithm for the simultaneous topical diagnosis of pathologically altered parathyroid gland and visualization of adrenal glands,to analyze of the results and to identify hormone-active AT. Materials and methods. 86 (100 %) patients were included in the study group. The age of the patients is from 24 to 82 years (mean (57.5 ± 1.4) years), among them women — 82 (95.3%), men — 4 (4.7 %). The level of parathyroid hormone (PTH) ranged from 11.10 to 2186.20 pg/ml Mean total serum calcium was (2.81 ± 0.02) mmol/l, ionized calcium (1.44 ± 0.01) mmol/l, phosphorus (0.88 ± 0.02) pg/ml, vitamin D (34.11 ± 1.85) nmol/l. All patients underwent computed tomography. To fulfill the purpose of our research, the standard scanning protocol for PHPT was modified. Results and discussion. As a result of the study, altered parathyroid glands were found in all 86 patients, which were the cause of hormonal changes. Also, in 25 (29.1 %) cases, a combination of adenomas/parathyroid hyperplasia with AT was diagnosed. In 22 (88.0 %) cases, there were radiological signs of unilateral benign lesions of adrenal cortex. In 5 (20.0 %) of 25 patients, hormone-active AT were detected. Conclusions. Using the modified CT protocol, adrenal tumors were detected in patients with PHPT in 29.1 % of cases (5.8 % hormone-active). The characteristic radiological patterns of changes in the adrenal glands help get closer to the morphological diagnosis, which guides the endocrinologist for prescribing appropriate additional laboratory tests.

PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism.

Molecular mechanisms mediating tonic secretion of parathyroid hormone (PTH) in response to hypocalcemia and hyperparathyroidism (HPT) are unclear. Here we demonstrate increased heterocomplex formation between the calcium-sensing receptor (CaSR) and metabotropic GABAB1 receptor (GABAB1R) in hyperplastic parathyroid glands (PTGs) of patients with primary and secondary HPT. Targeted ablation of GABAB1R or glutamic acid decarboxylase 1 and 2 in PTGs produces hypocalcemia and hypoparathyroidism and prevents PTH hypersecretion in PTGs cultured from mouse models of hereditary HPT and dietary calcium-deficiency. Co-binding of CaSR/GABAB1R complex by baclofen and high extracellular calcium blocks the coupling of heterotrimeric G-proteins to homomeric CaSRs in cultured cells and promotes PTH secretion in cultured mouse PTGs. These results combined with the ability of PTG to synthesize GABA support a critical autocrine action of GABA/GABAB1R in mediating tonic PTH secretion of PTGs and ascribe aberrant activities of CaSR/GABAB1R heteromer to HPT.

Parathyroidectomy in Chronic Haemodialysis in the Nephrology and Haemodialysis Department at the University Hospital Center of Point G in Bamako, Mali

Introduction: Secondary hyperparathyroidism is a common complication in chronic hemodialysis patients. It is characterized by hypersecretion of parathormone by the parathyroid glands to maintain phosphocalcium homeostasis in response to hypocalcemia, lowering of 1.25 dihydroxy vitamin D3 and hyperphosphatemia. Objective: To analyze the results of parathyroidectomy (PTX) in cases of secondary hyperparathyroidism (HPTS), report the post-operative course and early and late complications. Patients and Methods: We conducted a retrospective study of ten (10) patients with chronic renal failure operated on at the CHU of Point G over a 32-month period, from January 1, 2016 to August 31, 2019. We analyzed the clinical, biological, radiological and histological parameters of the thyroid glands. Results: We have collected 33 cases of secondary hyperparathyroidism. Ten (10) patients met the inclusion criteria. They were 45 years old on average, seven (7) women and three (3) men, in dialysis for an average of 6.8 years before parathyroidectomy. Half of the initial kidney disease was of vascular origin (HTA). No cases of diabetic nephropathy were identified. Symptoms were in order of frequency: bone pain (60%), paresthesia (50%), functional impotence of the lower limbs (50%). Radiological signs included demineralisation (5 out of 6 cases) and brown tumour associated with a fracture (1 out of 6 cases). The most frequent indication for parathyroidectomy (100%) was persistence despite treatment of a serum PTH concentration above 1000 pg/ml. Subtotal PTX (7/8) was performed after cervical ultrasound in all patients. Histological analysis of the parathyroid glands showed adenoma (60%) and hyperplasia in 40% of cases. The evolution was marked by a progressive reduction of the parathormone level over twelve (12) months, without achieving normalization. This could be related to sub-dialysis (generator failure with reduction of dialysis time). There were no cases of complications or mortality. Conclusion: Parathyroidectomy is an effective treatment to curb hypersecretion of parathyroid hormone. Despite this satisfactory result, the management of phosphocalcic abnormalities in renal failure remains an ongoing concern.

289O - Spectrum of mitochondrial genomic variation in parathyroid neoplasms by ultra-deep targeted DNA sequencing

BackgroundParathyroid neoplasms are characterized with hypersecretion of parathyroid hormone and potentially exhibit disruption of metabolic pathways. Mitochondria are essential for energy homeostasis and mitochondrial DNA (mtDNA) abnormalities are related to multiple types of malignancies. However, the status of mtDNA mutation and copy number variations in parathyroid carcinoma (PC) is not well known. MethodsUltra-deep targeted sequencing of mitochondrial genome was performed using tissues of 12 PCs and 12 parathyroid adenomas (PAs). Germline variants and somatic mutations in the mitochondrial genome were scanned and analysed in comparison with clinical features. The relative copy number of mtDNA in PCs and PAs was determined via quantitative real-time polymerase chain reaction. ResultsA total of 528 germline variants and 16 somatic mutations were identified in 24 samples of parathyroid neoplasms. All 62 non-synonymous germline variants in coding sequence (CDS) were predicted to be of low pathogenicity in PA and PC samples. Five somatic mutations with high pathogenicity in CDSs were identified in 4 (33.3%, 4/12) PC samples and 1 PA sample (8.3%, 1/12). A somatic mutation in a CDS was correlated with high mtDNA copy number in parathyroid neoplasm (p = 0.004), CDC73 gene mutation (p = 0.017) and PC recurrence (p = 0.024). More C-19 genotypes in the D310 region were found in PA than in the PC samples (3.5% vs 1.9%, p = 0.045). ConclusionsMore somatic CDS mutations with high pathogenicity were identified in PC than in PA. A high mtDNA copy number was found in parathyroid neoplasms with somatic CDS mutations and in PCs with CDC73 mutations and recurrence. Legal entity responsible for the studyThe authors. FundingThis work was supported by the Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS-I2M) (2017-I2M-1-001), Peking Union Medical College Innovative Team Development Program, the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32014) and the 2016 Peking Union Medical College Hospital Science Foundation for Junior Faculty (pumch-2016.2.7). DisclosureAll authors have declared no conflicts of interest.

Diabetes mellitus, chronic pancreatitis and primary hyperparathyroidism: is there a connection?

Hyperparathyroidism is a relatively frequent condition characterized by hypersecretion of parathyroid hormone. There are several forms of primary hyperparathyroidism. Each form affects its target region. In the visceral form, nephrocalcinosis, nephrolithiasis and peptic and duodenal ulcers are common. The pancreas is also a target organ. This article describes a clinical case of a patient with diabetes mellitus and previously treated primary hyperparathyroidism. The patient was admitted to the hospital due to poor glycaemic control. During the hospitalization, diabetes mellitus developed as a consequence of frequent relapses of chronic pancreatitis (outcome of the visceral form of primary hyperparathyroidism and severe hypertriglyceridemia). Glycaemic control was achieved after treatment of acute pancreatitis and insulin administration. This clinical case is an example of the impact of previous primary hyperparathyroidism (even after radical treatment and remission) on the development of a multi-faceted comorbidity.