[The role of calcium sensitive and vitamin D receptors in the pathogenesis of sporadic multiple parathyroid gland disease].

BACKGROUND: Sporadic multiple parathyroid gland disease is » cases of primary hyperparathyroidism (PHPT). However, a single tactic for diagnosing and operating volume in patients with this variant of PHPT has not yet been developed. One of the possible directions in the search for pathogenetically substantiated methods of diagnosis and treatment is the study of the molecular genetic features of the disease and associated clinical and laboratory factors. AIM: To study the features of the expression of calcium sensitive (CaSR) and vitamin D (VDR) receptors on the surface of parathyroid cells in primary hyperparathyroidism with solitary and multiple lesions of the parathyroid glands, as well as its changes under the influence of a decrease in the filtration function of the kidneys. MATERIALS AND METHODS: In a single center observational prospective study with retrospective data collection, there were patients who during 2019-2021. operated on for PHPT, secondary hyperparathyroidism (SHPT) and all cases of tertiary hyperparathyroidism (THPT) operated during 2014-2021. The expression of CaSR, VDR and its relationship with the main laboratory parameters, the clinical variant of hyperparathyroidism, and the morphological substrate were studied. RESULTS: The study included 69 patients: 19 with multiple and 25 with solitary PTG near PHPT, 15 with SHPT, 10 with THPT. A statistically significant decrease in the frequency of detection of normal expression of CaSR and VDR receptors occurs in any morphological variant of hyperparathyroidism and is observed in 93-60% of drugs. A decrease in the normal expression of CaSR in hyperplasia is detected statistically significantly less frequently than in adenoma (p≤0.01). The median expression intensity in adenoma was 2.5 (2:3), in hyperplasia 3.5 (3-4) (p≤0.01). The difference in the molecular mechanisms of the development of hyperparathyroidism with a predominance of a morphological substrate in the form of adenoma (PHPT with solitary adenoma) or hyperplasia (SHPT and PHPT with multiple PTG lesions) is realized in the frequency of maintaining normal CaSR expression in the PTG tissue. These mechanisms are implemented at the local level, their variability does not change under the influence of RRT. A common molecular genetic mechanism for the development of hyperparathyroidism with a predominance of a morphological substrate in the form of adenoma or hyperplasia has been found to reduce the frequency of maintaining normal VDR expression in PTG (up to 7-13%), p<0.01. This mechanism is implemented at the local level, its variability changes under the influence of RRT, reaching statistically significant differences in patients with THPT. CONCLUSION: The study demonstrates the features of changes in the expression of CaSR and VDR in PHPT with multiple lesions of the parathyroid glands. The relationship between the expression of these receptors and the clinical variant of hyperparathyroidism, the morphological substrate, the main laboratory parameters, and renal function was shown.

The Medical Benefits of Vitamin K2 on Calcium-Related Disorders.

BACKGROUND: Due to the potentially crucial role of vitamin K2 in calcium metabolism, a deficit can disrupt many mechanisms, resulting in an array of different issues, such as broken bones, stiff arteries and poor fertility. Although there has been existing research, the potential of vitamin K2 as a treatment for conditions including cerebral palsy, parathyroid disease, heart disease and gastrointestinal disease is unknown. This review discusses the biochemistry of vitamin K and the metabolism of calcium, followed by an analysis of the current literature available on vitamin K2 and its prospects. METHODS: Using public libraries including PubMed and Wiley, we searched for existing research on the metabolism and use of vitamin K2 that has been conducted in the preceding two decades. RESULTS: Data indicated that vitamin K2 had a positive impact on osteoporosis, cardiovascular disease, parathyroid disorders, cerebral palsy and sperm motility. CONCLUSION: Due to the existence of confounding variables and limitations in the quality and volume of research conducted, further investigation must be done to see whether the beneficial effects seen are reproducible and must assess the viability of vitamin K2 as treatment in isolation for these conditions.

Tissue-engineered parathyroid gland and its regulatory secretion of parathyroid hormone.

Parathyroid glands (PTGs) are important endocrine organs being mainly responsible for the secretion of parathyroid hormone (PTH) to regulate the balance of calcium (Ca) /phosphorus (P) ions in the body. Once PTGs get injured or removed, their resulting defect or loss of PTH secretion should disturb the level of Ca/P in blood, thus damaging other related organs (bone, kidney, etc.) and even causing death. Recently, tissue-engineered PTGs (TE-PTGs) have attracted lots of attention as a potential treatment for the related diseases of PTGs caused by hypoparathyroidism and hyperparathyroidism, including tetany, muscle cramp, nephrolithiasis, nephrocalcinosis, and osteoporosis. Although great progress has been made in the establishment of TE-PTGs with an effective strategy to integrate the key factors of cells and biomaterials, its regulatory secretion of PTH to mimic its natural rhythms in the body remains a huge challenge. This review comprehensively describes an overview of PTGs from physiology and pathology to cytobiology and tissue engineering. The state of the arts in TE-PTGs and the feasible strategies to regulate PTH secretion behaviors are highlighted to provide an important foundation for further investigation.

Pediatric parathyroid disease.

Parathyroid glands are critical for calcium and phosphate homeostasis. Parathyroid disease is relatively rare in the pediatric population, but there are some important pediatric-specific considerations and conditions. This article reviews parathyroid physiology, disorders of hyper- and hypo- function, operative management, and uniquely pediatric diagnoses such as neonatal severe hyperparathyroidism. Advances in preoperative imaging, intra-operative gland identification, and management of post-thyroidectomy hypocalcemia are also presented in detail. This article combines a review of fundamentals with recent advances in care, emphasizing pediatric-specific publications.

Hereditary Parathyroid Disease: Sometimes Pathologists Do Not Know What They Are Missing.

Parathyroid gland excision specimens are common and sometimes underestimated cases that many surgical pathologists encounter regularly. In the vast majority of cases, these will be spot diagnoses of sporadic primary parathyroid adenomas or, perhaps, hyperplasias commonly in the setting of renal failure. However, a small but significant number of parathyroid gland excisions may be due to heritable disease. In most cases, hereditary disease is suspected by the referring clinicians. Nevertheless, a subset of these are undetected which is significant, particularly in the setting of the multiple endocrine neoplasia (MEN), and the hyperparathyroidism jaw tumour (HPT-JT) syndromes. There have been recent advances in recognition of the morphological and immunohistochemical characteristics of these tumours and hyperplasias. While hereditary kindreds are over-represented at specialist referral centres, with awareness of the characteristic clinical and morphological features, the general surgical pathologist is frequently able to suggest the possibility of hereditary parathyroid disease. We therefore provide a succinct guide for pathologists to increase the recognition of hereditary parathyroid disease.

Rare PTH Gene Mutations Causing Parathyroid Disorders: A Review.

Since parathyroid hormone (PTH) was first isolated and its gene (PTH) was sequenced, only eight PTH mutations have been discovered. The C18R mutation in PTH, discovered in 1990, was the first to be reported. This autosomal dominant mutation induces endoplasmic reticulum stress and subsequent apoptosis in parathyroid cells. The next mutation, which was reported in 1992, is associated with exon skipping. The substitution of G with C in the first nucleotide of the second intron results in the exclusion of the second exon; since this exon includes the initiation codon, translation initiation is prevented. An S23P mutation and an S23X mutation at the same residue were reported in 1999 and 2012, respectively. Both mutations resulted in hypoparathyroidism. In 2008, a somatic R83X mutation was detected in a parathyroid adenoma tissue sample collected from a patient with hyperparathyroidism. In 2013, a heterozygous p.Met1_Asp6del mutation was incidentally discovered in a case-control study. Two years later, the R56C mutation was reported; this is the only reported hypoparathyroidism-causing mutation in the mature bioactive part of PTH. In 2017, another heterozygous mutation, M14K, was detected. The discovery of these eight mutations in the PTH gene has provided insights into its function and broadened our understanding of the molecular mechanisms underlying mutation progression. Further attempts to detect other such mutations will help elucidate the functions of PTH in a more sophisticated manner.

Fluorescent nanosensor for in situ detection of phosphate and alkaline phosphatase in mice with parathyroid dysfunction.

A composite nanosensor based on Zr(iv)-MOFs and PNPP was developed, and was successfully applied for the in situ fluorescence imaging of phosphate and ALP levels in mice with parathyroid dysfunction. The current work provides new ideas for further development of the diagnosis of parathyroid diseases.

Paediatric and young adult manifestations and outcomes of multiple endocrine neoplasia type 1.

CONTEXT: Multiple endocrine neoplasia 1 (MEN 1) is an autosomal dominant disease presenting as hyperplasia and neoplasia of parathyroid, pituitary and enteropancreatic tissues. Over 90% of gene carriers develop phenotypic disease by age 30 years, potentially with onset of asymptomatic disease during childhood and adolescence. OBJECTIVE: To describe the paediatric and young adult manifestations of MEN 1. DESIGN: Descriptive retrospective study of 180 patients with a common MEN1 genotype. The paediatric and young adult (age <22 years) manifestations were determined using hospital records and disease surveillance data. RESULTS: Primary hyperparathyroidism (PHPT) was identified in 42 patients (mean age 17.2 ± 3.3 years). Parathyroidectomy was performed in 16 (38.1%; mean age 17.8 ± 3.2). Four patients experienced recurrent PHPT (25%), and six (37.5%) developed permanent hypoparathyroidism. Pituitary disease was identified in 13 patients. Prolactinoma was found in nine patients (mean age 16.6 ± 2.6 years) of whom four (44.4%) had macroprolactinoma. Two patients required surgical intervention; dopamine agonists showed efficacy in six patients. Two patients with Cushing's disease were successfully treated surgically. Three patients with nonfunctioning pituitary microadenoma managed conservatively. Pancreatic neuroendocrine neoplasms (pNENs) were diagnosed in 12 patients (mean age 17.0 ± 2.6 years): three patients with insulinoma successfully resected (two resected and one exhibiting perineural invasion) and nine patients with nonfunctioning adenomas (NFAs). CONCLUSION: Pituitary adenomas, PHPT and pNENs are encountered in the paediatric and young adult MEN 1 population. Successful outcomes are typically achieved using standard medical and surgical paradigms; however, parathyroidectomy was associated with a substantial complication rate.

MANAGEMENT OF ENDOCRINE DISEASE: Unmet therapeutic, educational and scientific needs in parathyroid disorders.

PARAT, a new European Society of Endocrinology program, aims to identify unmet scientific and educational needs of parathyroid disorders, such as primary hyperparathyroidism (PHPT), including parathyroid cancer (PC), and hypoparathyroidism (HypoPT). The discussions and consensus statements from the first PARAT workshop (September 2018) are reviewed. PHPT has a high prevalence in Western communities, PHPT has a high prevalence in Western communities, yet evidence is sparse concerning the natural history and whether morbidity and long-term outcomes are related to hypercalcemia or plasma PTH concentrations, or both. Cardiovascular mortality and prevalence of low energy fractures are increased, whereas Quality of Life is decreased, although their reversibility by treatment of PHPT has not been convincingly demonstrated. PC is a rare cause of PHPT, with an increasing incidence, and international collaborative studies are required to advance knowledge of the genetic mechanisms, biomarkers for disease activity, and optimal treatments. For example, ~20% of PCs demonstrate high mutational burden, and identifying targetable DNA variations, gene amplifications and gene fusions may facilitate personalized care, such as different forms of immunotherapy or targeted therapy. HypoPT, a designated orphan disease, is associated with a high risk of symptoms and complications. Most cases are secondary to neck surgery. However, there is a need to better understand the relation between disease biomarkers and intellectual function, and to establish the role of PTH in target tissues, as these may facilitate the appropriate use of PTH substitution therapy. Management of parathyroid disorders is challenging, and PARAT has highlighted the need for international transdisciplinary scientific and educational studies in advancing in this field.

Metabolic Syndrome in Parathyroid Diseases.

Parathyroid glands are the main regulator of body mineral metabolism through parathormone (PTH) actions on bone and kidney. Experimental evidence suggests that PTH may have non-classical target organs such as adipose tissue, arterial vascular wall, cardiac muscle cells, and adrenal cortex cells, where it may play a role in controlling body energy, blood pressure, and metabolism. Cardiometabolic features have been investigated in the wide spectrum of clinical parathyroid disorders, from hyperparathyroidism to pseudohypoparathyroidism and hypoparathyroidism. Indeed, in parathyroid disorders, besides altered PTH secretion, impaired serum calcium levels and vitamin D status occur. Both calcium and vitamin D have been shown to regulate metabolism and to be associated with cardiovascular diseases. However, despite the complexity of parathyroid disorders, features of metabolic syndrome, such as obesity, insulin resistance, and glucose intolerance, arterial blood hypertension, and dyslipidemia, are frequently diagnosed in primary and secondary hyperparathyroidism as well as in pseudohyperparathyroidism. Here, we reviewed the most consistent data highlighting challenges and providing clinical remarks.

Parathyroid Diseases and T Cells.

PURPOSE OF REVIEW: This review summarizes studies into the permissive role of T cells in the bone catabolic effects of hyperparathyroidism and parathyroid hormone (PTH). RECENT FINDINGS: Work in animals combined with recent translational studies in humans now highlight the potent amplificatory action of T cells on PTH-induced bone resorption. Mechanistic animal studies reveal a complex pathway by which PTH exploits natural self-renewal functions of CD4+ T cells, to drive TNFα production that promotes formation of IL-17A secreting Th17 T cells. TNFα and IL-17 further amplify osteoblastic receptor activator of NF-κB ligand (RANKL) production and down-modulate osteoprotegerin (OPG), establishing conditions propitious for osteoclastic bone resorption. These findings are consistent with, and add to, the traditional view of PTH-induced bone loss involving only osteoblast-lineage cells. T cells potently amplify traditional pathways and provide permissive costimulatory signals to bone marrow stromal cells, facilitating the development of an increased RANKL/OPG ratio favourable to bone resorption and bone loss.

PTH and Vitamin D.

PTH and Vitamin D are two major regulators of mineral metabolism. They play critical roles in the maintenance of calcium and phosphate homeostasis as well as the development and maintenance of bone health. PTH and Vitamin D form a tightly controlled feedback cycle, PTH being a major stimulator of vitamin D synthesis in the kidney while vitamin D exerts negative feedback on PTH secretion. The major function of PTH and major physiologic regulator is circulating ionized calcium. The effects of PTH on gut, kidney, and bone serve to maintain serum calcium within a tight range. PTH has a reciprocal effect on phosphate metabolism. In contrast, vitamin D has a stimulatory effect on both calcium and phosphate homeostasis, playing a key role in providing adequate mineral for normal bone formation. Both hormones act in concert with the more recently discovered FGF23 and klotho, hormones involved predominantly in phosphate metabolism, which also participate in this closely knit feedback circuit. Of great interest are recent studies demonstrating effects of both PTH and vitamin D on the cardiovascular system. Hyperparathyroidism and vitamin D deficiency have been implicated in a variety of cardiovascular disorders including hypertension, atherosclerosis, vascular calcification, and kidney failure. Both hormones have direct effects on the endothelium, heart, and other vascular structures. How these effects of PTH and vitamin D interface with the regulation of bone formation are the subject of intense investigation.

The effect of parathyroid hormones on hair follicle physiology: implications for treatment of chemotherapy-induced alopecia.

Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) influence hair follicles through paracrine and intracrine routes. There is significant evidence that PTH and PTHrP influence the proliferation and differentiation of hair follicle cells. The PTH/PTHrP receptor signalling plays an important role in the hair follicle cycle and may induce premature catagen-telogen transition. Transgenic mice with an overexpression or blockade (PTH/PTHrP receptor knockout mice) of PTHrP activity revealed impaired or increased hair growth, respectively. Some findings also suggest that PTHrP may additionally influence the hair cycle by inhibiting angiogenesis. Antagonists of the PTH/PTHrP receptor have been shown to stimulate proliferation of hair follicle cells and hair growth. A hair-stimulating effect of a PTH/PTHrP receptor antagonist applied topically to the skin has been observed in hairless mice, as well as in mice treated with cyclophosphamide. These data indicate that the PTH/PTHrP receptor may serve as a potential target for new (topical) hair growth-stimulating drugs, especially for chemotherapy-induced alopecia.

Oxyphil cell metaplasia in the parathyroids is characterized by somatic mitochondrial DNA mutations in NADH dehydrogenase genes and cytochrome c oxidase activity-impairing genes.

Oxyphil cell transformation of epithelial cells due to the accumulation of mitochondria occurs often during cellular aging. To understand the pathogenic mechanisms, we studied mitochondrial DNA (mtDNA) alterations in the three cell types of the parathyroids using multiplex real-time PCR and next-generation sequencing. mtDNA was analyzed from cytochrome c oxidase (COX)-positive and COX-negative areas of 19 parathyroids. Mitochondria-rich pre-oxyphil/oxyphil cells were more prone to develop COX defects than the mitochondria-poor clear chief cells (P < 0.001). mtDNA increased approximately 2.5-fold from clear chief to oxyphil cells. In COX deficiency, the increase was even more pronounced, and COX-negative oxyphil cells had approximately two times more mtDNA than COX-positive oxyphil cells (P < 0.001), illustrating the influence of COX deficiency on mtDNA biosynthesis, probably as a consequence of insufficient ATP synthesis. Next-generation sequencing revealed a broad spectrum of putative pathogenic mtDNA point mutations affecting NADH dehydrogenase and COX genes as well as regulatory elements of mtDNA. NADH dehydrogenase gene mutations preferentially accumulated in COX-positive pre-oxyphil/oxyphil cells and, therefore, could be essential for inducing oxyphil cell transformation by increasing mtDNA/mitochondrial biogenesis. In contrast, COX-negative cells predominantly harbored mutations in the MT-CO1 and MT-CO3 genes and in regulatory mtDNA elements, but only rarely NADH dehydrogenase mutations. Thus, multiple hits in NADH dehydrogenase and COX activity-impairing genes represent the molecular basis of oxyphil cell transformation in the parathyroids.

[New Developments in CKD-MBD. Cell Biology of parathyroid in CKD].

Parathyroid monitors the calcium concentration in blood by signals from calcium-sensing receptors, adjusts secretion of parathyroid hormone to keep constant calcium concentration in the body. Although parathyroid parenchymal cells consist of chief cells which secrete PTH, and oxyphil cells which are rich in mitochondria, all hardly perform mitotic proliferation in normal status. However, in CKD, PTH hypersecretion and hyperplasia are started by hyperphosphatemia, hypocalcemia, and activated-vitamin-D deficiency, and the secondary hyperparathyroidism develops. While treatment with cinacalcet hydrochloride salt induced apoptosis into the parathyroid cell, a possibility of promoting the transdifferentiation to oxyphil cells from chief cells was suggested. The specific accumulation to the parathyroid of an oncotropic photosensitizer suggests the possibility of photodynamic diagnosis and treatment of hyperparathyroidism.

[Bilateral neck exploration with intraoperative iPTH assay in patients not eligible for minimally invasive parathyroidectomy]. / Obustronna eksploracja szyi ze sródoperacyjnym monitoringiem stezenia parathormonu u chorych niekwalifikujacych sie do maloinwazyjnej paratyreoidektomii.

BACKGROUND AND AIMS: Bilateral neck exploration (BNE) is the preferred surgical technique in patients with primary hyperparathyroidism (pHPT) not eligible for minimally invasive parathyroidectomy (MIP). The aim of this study was to assess indications for BNE in the era of MIP, including short-term outcomes of surgery with intraoperative intact parathyroid hormone (iPTH) monitoring added-value. METHODS: Data of 155 patients with pHPT qualified for BNE with intraoperative iPTH monitoring and treated in 2003-2012 were retrospectively analysed. All patients underwent biochemical and imaging testing in the preoperative work-up. The following endpoints were analysed in this study: indications for BNE, short-term outcomes of surgery, and intraoperative iPTH monitoring added-value. RESULTS: Indications for BNE were: negative preoperative imaging in 65 (41.9%) patients, concomitant goitre necessitating surgical removal in 51 (32.9%) patients, MEN 1 syndrome in 17 (11.0%) patients, lithium treatment in 12 (7.7%) patients, lacking consent for MIP in 5 (3.2%) patients, and MEN 2A syndrome in 5 (3.2%) patients. The extent of parathyroidectomy was a solitary parathyroid adenoma removal in 97 (62,6%) patients, subtotal parathyroidectomy in 41 (26.4%) patients, and double-parathyroid adenoma removal in 17 (11,0%) patients. Use of intraoperative iPTH monitoring influenced on the extent of parathyroid tissue resection in 16(10.3%) patients. Normalised total serum calcium values were observed in 154 (99.4%) patients during a 6-month follow-up. CONCLUSIONS: BNE in patients with pHPT is the preferred surgical technique in the following circumstances: a suspicion of multiglandular parathyroid disease (MEN 1 or 2A syndrome, familial hyperparathyroidism, lithium therapy), a negative preoperative imaging, in patients not consenting for MIP, and in cases with concomitant goitre necessitating surgical treatment. Use of intraoperative iPTH monitoring influences on the extent of parathyroid tissue resection in one often patients, hence assuring the highest quality of surgical treatment.

[Rare abnormalities of parathyroid gland function and parathyroid hormone receptor action]. / Rzadkie zaburzenia funkcji przytarczyc i dzialania receptorowego parathormonu.

The parathyroid glands, located near or within the posterior surface of the thyroid gland and secreting parathyroid hormone, are essential organs for the regulation of calcium and phosphate metabolism. As they are necessary to sustain life and maintain homeostasis, undetected or misdiagnosed parathyroid disorders may pose a significant threat to health outcomes, as their presence may increase morbidity and mortality in affected individuals. The clinical picture of some disorders associated with abnormal parathyroid hormone secretion and receptor action is sometimes complicated by coexisting abnormalities, and in these cases establishing the correct diagnosis is challenging. The remarkable progress of recent years in the area of hormonal assessment, imaging procedures and molecular biology, has resulted in a great improvement in the identification, differentiation and treatment of various parathyroid disorders and has made it possible to identify several new clinical entities. In this paper, we discuss the present state-of-art on the etiopathogenesis, clinical manifestations, diagnosis and treatment of chosen rare abnormalities of parathyroid gland function and parathyroid hormone receptor action.

Utility of birefringent crystal identification by polarized light microscopy in distinguishing thyroid from parathyroid tissue on intraoperative frozen sections.

Differentiating parathyroid with pseudofollicular architecture from thyroid tissue can be challenging on intraoperative frozen sections. Birefringent calcium oxalate crystals are present in colloid of normal thyroid follicles, whereas crystals are rare in parathyroid tissue. It has been suggested that crystal identification using polarized microscopy could aid in distinguishing thyroid from parathyroid tissue on frozen sections when other ancillary studies are not available. However, the actual clinical utility of crystal detection on frozen sections has not been assessed. We reviewed all deferred or discrepant parathyroid versus thyroid intraoperative frozen section diagnoses over a 12.5-year period (17 cases). For comparison, we also reviewed 20 cases each of hypercellular parathyroid glands with pseudofollicular architecture, follicular adenomas, follicular carcinomas, follicular variant of papillary thyroid carcinomas, and nodular hyperplasias with a microfollicular pattern. These are diagnoses that could be difficult to differentiate tissue of origin (thyroid vs. parathyroid) on frozen section biopsies. Crystals were more common in thyroid (60/80) than in parathyroid (2/20) microfollicular/pseudofollicular lesions (75% vs. 10%, P<0.001). In 9 of 12 cases (75%) for which the frozen section was interpreted as or favored to be parathyroid but permanent sections showed only thyroid tissue, identification of crystals on the actual frozen section slides would have aided interpretation. This included 1 case of papillary thyroid carcinoma that was reimplanted into the patient's neck after a frozen section misdiagnosis of "parathyroid tissue" was made. We recommend examination of difficult follicular patterned parathyroid frozen sections by polarizing microscopy and deferring the diagnosis if crystals are found.