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Kidney International. Supplement May 2002Calcitriol is currently used to reduce parathyroid hormone (PTH) levels in uremic patients. However, a significant number of patients fail to respond to calcitriol... (Review)
Review
Calcitriol is currently used to reduce parathyroid hormone (PTH) levels in uremic patients. However, a significant number of patients fail to respond to calcitriol therapy. The data suggest that a poor response to calcitriol can be anticipated in patients with severe hyperparathyroidism (with a high basal PTH levels) and uncontrolled serum phosphate. The abnormal parathyroid response to calcitriol in uremic patients with severe parathyroid hyperplasia may be attributed, to a large extent, to the development of nodular hyperplasia as a result of clonal transformation from a diffuse polyclonal hyperplasia. The factors involved in the development of polyclonal parathyroid hyperplasia, at earlier stages of secondary hyperparathyroidism, appear to be the same factors that stimulate PTH secretion and synthesis: hypocalcemia, hyperphosphatemia and low serum calcitriol levels. Studies performed in vitro using parathyroid tissue from uremic patients who required parathyroidectomy demonstrate that in nodular hyperplasia there is an abnormal response to calcium and calcitriol, which suggests that there are factors intrinsic to the hyperplastic cell (such as decrease in calcium sensor receptors and vitamin D receptors) responsible for an abnormal regulation of parathyroid function. Accumulation of phosphate is a key factor in the pathogenesis of secondary hyperparathyroidism and a poor response to calcitriol treatment is associated with the failure to control the serum phosphorus. High phosphate stimulates PTH secretion as demonstrated by in vivo and in vitro studies. In addition, animal studies strongly suggest that phosphate increases parathyroid cell proliferation. There are growth-related genes potentially involved in uremic hyperparathyroidism; however, changes in the expression of these genes may be the consequence rather than the cause of parathyroid hyperplasia.
Topics: Humans; Hyperparathyroidism, Secondary; Hyperplasia; Parathyroid Glands
PubMed: 11982830
DOI: 10.1046/j.1523-1755.61.s80.26.x -
Materia Socio-medica 2023The most comon patohistological finding in primary hyperparathyroidism is adenoma of the parathyroid gland, followed by hyperplasia and the rarest is carcinoma. However,...
BACKGROUND
The most comon patohistological finding in primary hyperparathyroidism is adenoma of the parathyroid gland, followed by hyperplasia and the rarest is carcinoma. However, hyperplasia of the parathyroid glands (PTG) is most commonly found in secondary and tertiary hyperparathyroidism.
OBJECTIVE
To determine the relationship between the localization of the parathyroid glands and pathological diagnosis, as well as the prevalence of individual pathological diagnosis after surgery in patients with hyperparathyroidism.
METHODS
Analysis of retrospective-prospective database of 79 patiens who underwent parathyreoidectomy for hyperparathyroidism in the 7-year study period. Diagnostic methods were used to identify enlarged parathyroid glands as well as to determine their localization: ultrasound examination, scintigraphy and operative finding. Standard hematoxylin eosin staining was used for pathohistological diagnosis. A correlation analysis between parathyroid gland localization and pathohistological diagnosis was performed.
RESULTS
The median age of the patients were 51 age (range 20-73) and 67,1% of the patients were female. In the total number of surgically removed parathyroid glands (182), the most common pathohistological diagnosis was hyperplasia. Parathyroid adenoma was found in 21 cases. Other diagnoses (thyroid nodule / tissue, lymph node, thymus, cancer) were found in 11 cases, while a normal finding was found in 12 glands. Pathohistological diagnosis of hyperplasia and adenoma were more common in the lower parathyroid glands. Using the chi-square test, no association was found between pathohistological diagnosis and localization of enlarged parathyroid glands.
CONCLUSION
The most common pathohistological diagnosis in hyperparathyroidism was hyperplasia and was most commonly found in the inferior parathyroid glands. Adenoma as pathohistological diagnosis is also most commonly found in the lower parathyroid glands, but without statistical significance.
PubMed: 37701350
DOI: 10.5455/msm.2023.35.130-134 -
Proceedings of the National Academy of... Apr 2018The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies...
The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies for prevention and treatment of secondary hyperparathyroidism. Here we investigate the specific role of Klotho expressed in the parathyroid glands (PTGs) in mediating parathyroid hormone (PTH) and serum calcium homeostasis, as well as the potential interaction between calcium-sensing receptor (CaSR) and Klotho. We generated mouse strains with PTG-specific deletion of Klotho and CaSR and dual deletion of both genes. We show that ablating CaSR in the PTGs increases PTH synthesis, that Klotho has a pivotal role in suppressing PTH in the absence of CaSR, and that CaSR together with Klotho regulates PTH biosynthesis and PTG growth. We utilized the tdTomato gene in our mice to visualize and collect PTGs to reveal an inhibitory function of Klotho on PTG cell proliferation. Chronic hypocalcemia and ex vivo PTG culture demonstrated an independent role for Klotho in mediating PTH secretion. Moreover, we identify an interaction between PTG-expressed CaSR and Klotho. These findings reveal essential and interrelated functions for CaSR and Klotho during parathyroid hyperplasia.
Topics: Animals; Bone and Bones; Calcium; Calcium, Dietary; Female; Fibroblast Growth Factor-23; Glucuronidase; Homeostasis; Hypercalcemia; Hyperparathyroidism; Hyperplasia; Hypocalcemia; Hypophosphatemia; Immunoprecipitation; Kidney; Klotho Proteins; Male; Mice; Parathyroid Glands; Parathyroid Hormone; Protein Interaction Mapping; RNA, Messenger; Receptors, Calcium-Sensing; Receptors, G-Protein-Coupled
PubMed: 29618612
DOI: 10.1073/pnas.1717754115 -
Pathology Oncology Research : POR Jul 2012The objective of the study was to examine proliferation and apoptosis associated gene expression in the whole sequence parathyroid lesions to reveal specific features of... (Comparative Study)
Comparative Study
The objective of the study was to examine proliferation and apoptosis associated gene expression in the whole sequence parathyroid lesions to reveal specific features of carcinoma. This study was based on surgically removed parathyroid tissues, gene expression analysis was performed both at gene and protein level. First, mRNA isolation was performed from deep-frozen tissue samples, and further apoptosis pathway-specific cDNA macroarray analysis was carried out. The results were validated with real-time PCR. Subsequently, protein expression was analyzed with immunhistochemistry on Tissue Micro Array multi-blocks derived from several paraffin-embedded samples. cDNA macroarrays revealed elevated expression of both pro-apoptotic (FAS receptor, TRAIL ligand, CASPASE8, and -4) and anti-apoptotic (cIAP1, APOLLON) genes in benign proliferative lesions compared to that in normal gland. TMA studies showed overexpression of KI67, P53, SURVIVIN and APOLLON protein and failure of expression of P27, BCL2, BAX, CHROMOGRANIN-A, SYNAPTOPHYSIN, CYCLIND1, FLIP, TRAIL, CK8, CK18, CK19 in parathyroid carcinoma was detected. These alterations in gene expression of the investigated products could be used in differentiation between beningn and malignant proliferative processes of the parathyroid gland. Authors conclude that a series of alterations in gene expression such as overexpression of APOLLON, P53, KI67 and suppression of P27, BCL2, BAX lead to uncontrolled cell proliferation, but still not leading to increased apoptotic activity in parathyroid carcinoma.
Topics: Adenocarcinoma; Adenoma; Biomarkers, Tumor; Fluorescent Antibody Technique; Gene Expression Profiling; Humans; Hyperplasia; Immunoenzyme Techniques; Oligonucleotide Array Sequence Analysis; Parathyroid Glands; Parathyroid Neoplasms; RNA, Messenger; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Tissue Array Analysis
PubMed: 22198862
DOI: 10.1007/s12253-011-9483-7 -
Medicine Sep 2023We aimed to explore the value of ultrasonic elastic imaging in the diagnosis of parathyroid hyperplasia and adenoma in patients with secondary hyperparathyroidism and...
We aimed to explore the value of ultrasonic elastic imaging in the diagnosis of parathyroid hyperplasia and adenoma in patients with secondary hyperparathyroidism and provide more evidence for clinical treatment. Forty patients who were on dialysis and underwent parathyroid surgery were selected All patients underwent routine ultrasound, ultrasound elasticity examination and blood biochemical examination before surgery, including calcium, phosphorus, parathyroid hormone (PTH), etc. According to postoperative results, adenoma group and hyperplasia group were divided into 2 groups. Receiver operating characteristic curve was drawn to evaluate the diagnostic efficacy and combined diagnostic efficacy of each index. The PTH levels significantly differed between the adenoma and hyperplasia groups (P < .001). The volume and blood flow grades significantly differed between the adenoma and hyperplasia groups (P < .001) The minimum of the adenoma group was 14.62 ± 6.79 kPa, mean was 19.42 ± 6.29 kPa, and maximum was 24.25 ± 6.35 kPa which were significantly different from those in the hyperplasia group (P < .05). The combinations of more than 6 indicators in the diagnosis of parathyroid adenoma resulted in an area under the curve of 0.892 (P < .001), and the sensitivity and specificity were 78.9% and 97.4%, respectively. Shear wave elastography can be used as an effective tool to distinguish secondary parathyroid hyperplasia from adenoma. When combined with PTH, conventional ultrasound blood flow grading and volume measurement, it has higher diagnostic efficacy.
Topics: Humans; Diagnosis, Differential; Elasticity Imaging Techniques; Hyperplasia; Renal Dialysis; Hyperparathyroidism, Primary; Parathyroid Hormone; Adenoma
PubMed: 37713846
DOI: 10.1097/MD.0000000000035079 -
World Journal of Surgical Oncology Jan 2021Primary hyperparathyroidism is an endocrine pathology that affects calcium metabolism. Patients with primary hyperparathyroidism have high concentrations of serum...
BACKGROUND
Primary hyperparathyroidism is an endocrine pathology that affects calcium metabolism. Patients with primary hyperparathyroidism have high concentrations of serum calcium or high concentrations of parathyroid hormone, or incorrect parathyroid hormone levels for serum calcium values. Primary hyperparathyroidism is due to the presence of an adenoma/single-gland disease in 80-85%. Multiple gland disease or hyperplasia accounts for 10-15% of cases of primary hyperparathyroidism. Atypical parathyroid adenoma and parathyroid carcinoma are both responsible for about 1.2-1.3% and 1% or less of primary hyperparathyroidism, respectively.
METHODS
We performed a retrospective cohort study and enrolled 117 patients with primary hyperparathyroidism undergoing minimally invasive parathyroidectomy. Histological and immunohistochemical examination showed that 107 patients (91.5%) were diagnosed with typical adenoma (group A), while 10 patients (8.5%) were diagnosed with atypical parathyroid adenoma (group B). None of the patients were affected by parathyroid carcinoma.
RESULTS
Significant statistical differences were found in histological and immunohistochemical parameters as pseudocapsular invasion (p < 0.001), bands of fibrosis (p < 0.001), pronounced trabecular growth (p < 0.001), mitotic rates of > 1/10 high-power fields (HPFs) (p < 0.001), nuclear pleomorphism (p = 0.036), thick capsule (p < 0.001), Ki-67+ > 4% (p < 0.001), galectin-3 + (p = 0.002), and protein gene product (PGP) 9.5 + (p = 0.038).
CONCLUSIONS
Atypical parathyroid adenoma is a tumor that has characteristics both of typical adenoma and parathyroid carcinoma. The diagnosis is reached by excluding with strict methods the presence of malignancy criteria. Atypical parathyroid adenoma compared to typical adenoma showed significant clinical, hematochemical, histological, and immunohistochemical differences. We did not find any disease relapse in the 10 patients with atypical parathyroid adenoma during 60 months of follow-up time.
Topics: Adenoma; Humans; Parathyroid Glands; Parathyroid Hormone; Parathyroid Neoplasms; Parathyroidectomy; Prognosis; Retrospective Studies
PubMed: 33472651
DOI: 10.1186/s12957-021-02123-7 -
Sisli Etfal Hastanesi Tip Bulteni 2019Primary hyperparathyroidism (pHPT) is characterized by an increase in the levels of PTH and Ca, or one of these (Ca, PTH) as a result of a dysregulation of calcium (Ca)... (Review)
Review
Primary hyperparathyroidism (pHPT) is characterized by an increase in the levels of PTH and Ca, or one of these (Ca, PTH) as a result of a dysregulation of calcium (Ca) metabolism due to inappropriate excess parathyroid hormone (PTH) autonomously produced from one or more than one parathyroid glands. Ninety to 95% of pHPT is a sporadic type, which is not associated with the familial history and other endocrine organ tumors, and 5-10% of it is hereditary. While 80-85% of pHPT arises from a single parathyroid adenoma, 4-5% is caused by a double adenoma, 10-15% by multigland hyperplasia and less than 1% by parathyroid cancer. The diagnosis of pHPT is reached biochemically. The only curative treatment of pHPT is surgery. The choice of surgery in pHPT may vary depending on whether the patient has hereditary HPT or thyroid disease requiring surgical treatment, preoperative localization studies and the findings in these studies, the possibilities of using intraoperative PTH and the preference of the surgeon. The preoperatively determined surgical strategy can be revised according to intraoperative findings in case of need to achieve excellent results. The two main approaches in the surgical treatment of pHPT are BNE (bilateral neck exploration) and MIP (minimal invasive parathyroidectomy). Although BNE is a consistently valid option that has excellent results in the surgical treatment of pHPT and is considered the gold standard, MIP is the ideal approach in selected patients with clinically and radiologically considered a single-gland disease. Negative imaging is not a contraindication for parathyroid surgery and is not a criterion for the presence or absence of surgical indication. Although both methods are safe and effective in the surgical treatment of sporadic pHPT, there is still controversy regarding the effectiveness of both methods. Surgical intervention should establish the risk-benefit balance well, minimize the risk of persistent and recurrent disease and provide the highest cure rate without increasing the risk of complications. Complication rates are higher in the secondary surgery, thus in secondary procedures, selective surgery should be performed under guidance of an imaging modality. The surgical strategy should be determined to achieve maximum cure with minimum dissection and minimal morbidity. In this study, we aimed to determine the type of surgical treatment and pHPT patients suitable for the surgical treatment.
PubMed: 32377085
DOI: 10.14744/SEMB.2019.56873 -
Journal of the American Society of... Feb 2008Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary...
Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF-alpha is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-alpha, the progression of growth, and the reduction of VDR. Increased TGF-alpha/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-beta, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein-beta transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF-alpha activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.
Topics: Animals; CCAAT-Enhancer-Binding Protein-beta; Calcitriol; Carcinoma, Squamous Cell; Cell Line, Tumor; Disease Models, Animal; Drug Resistance; ErbB Receptors; Erlotinib Hydrochloride; Female; Genes, Reporter; Humans; Hyperparathyroidism, Secondary; Hyperplasia; Protein Kinase Inhibitors; Quinazolines; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Renal Insufficiency, Chronic; Transforming Growth Factor alpha
PubMed: 18216322
DOI: 10.1681/ASN.2007040406 -
Nature Communications Feb 2022Parathyroid hormone (PTH) plays crucial role in maintaining calcium and phosphorus homeostasis. In the progression of secondary hyperparathyroidism (SHPT), expression of...
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.
Topics: Bone and Bones; Calcium; Homeostasis; Humans; Hyperparathyroidism; Hyperparathyroidism, Secondary; Hyperplasia; Optogenetics; Parathyroid Glands; Parathyroid Hormone; Receptors, Calcium-Sensing
PubMed: 35140213
DOI: 10.1038/s41467-022-28472-9 -
Kidney International Feb 2010Over the past few years there have been considerable advances in our understanding of the physiological regulation of mineral homeostasis. One of the most important... (Review)
Review
Over the past few years there have been considerable advances in our understanding of the physiological regulation of mineral homeostasis. One of the most important breakthroughs is the identification of fibroblastic growth factor 23 (FGF23) and its role as a key regulator of phosphate and 1,25-dihydroxyvitamin D metabolism. FGF23 exerts its biological functions by binding to its cognate receptor in the presence of Klotho as a cofactor. FGF23 principally acts on the kidney to induce urinary phosphate excretion and suppresses 1,25-dihydroxyvitamin D synthesis, thereby indirectly modulating parathyroid hormone secretion. FGF23 also acts directly on the parathyroid to decrease parathyroid hormone synthesis and secretion. In patients with chronic kidney disease, FGF23 levels increase progressively to compensate for phosphate retention, but these elevated FGF23 levels fail to suppress the secretion of parathyroid hormone, particularly in the setting of uremia. Recent data suggest that this parathyroid resistance to FGF23 may be caused by decreased expression of Klotho-FGFR1 complex in hyperplastic parathyroid glands. This review summarizes recent insights into the role of FGF23 in mineral homeostasis and discusses the involvement of its direct and indirect interaction with the parathyroid gland, particularly focusing on the pathophysiology of secondary hyperparathyroidism in chronic kidney disease.
Topics: Animals; Chronic Disease; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperplasia; Kidney Diseases; Parathyroid Glands; Parathyroid Hormone; Uremia
PubMed: 20010546
DOI: 10.1038/ki.2009.466