原发性甲状旁腺功能亢进症的分子发病机制

原发性甲状旁腺功能亢进症（甲旁亢）的分子机制在过去的10年间取得很多新进展。散发性原发性甲旁亢的主要机制如下：（1）原癌基因cyclinD1/PRAD1过度表达。（2）pRB对cyclinD1的增殖抑制作用失活。（3）抑癌基因MEN1突变失活。（4）MEN1基因产物menin功能失活导致转化生长因子-β信号转导通路受阻。遗传性原发性甲旁亢的主要机制为：（1）多内分泌腺瘤病1型：MEN1基因突变失活。（2）多内分泌腺瘤病2a型：RET基因突变。（3）家族性低尿钙高钙血症：钙敏感受体基因杂合突变。（4）新生儿严重的甲旁亢：钙敏感受体纯合突变。另外,HRPT2基因突变可引起家族性原发性甲旁亢、甲旁亢-颚肿瘤综合征、甲状旁腺腺瘤囊性变、甲状旁腺癌。     

老年人甲状旁腺机能亢进症

老年人甲状旁腺机能亢进症济南市中心医院（２５００１３）孙金凤，宋志民甲状旁腺机能亢进症（甲旁亢）是由于甲状旁腺激素（ＰＴＨ）分泌过多，导致钙磷代谢紊乱引起的全身骨质代谢异常性疾病。其检出率为１‰，女性略高于男性，以绝经期老年妇女多见。甲旁亢病人中。以...     

甲状旁腺激素水平在早期肾脏损伤诊治中的意义

甲状旁腺激素(PTH)是调节人体钙磷代谢的主要激素之一。各种原因引起的长期低钙血症、高磷血症及低1,25-羟维生素D3血症可刺激甲状旁腺代偿性增生,PTH分泌增多,引发继发性甲状旁腺功能亢进(SHPT)。肾脏疾病患者肾功能下降,肾实质减少,出现钙磷代谢紊乱,引起PTH水平上升,升高     

原发性甲状旁腺功能亢进症诊疗指南

一定义及流行病学特征（一）定义甲状旁腺功能亢进症常分为原发性、继发性和三发性3类。原发性甲状旁腺功能亢进症（primary hyper-parathyroidism,PHPT）简称原发甲旁亢,系甲状旁腺组织原发病变致甲状旁腺激素（parathyroidhormone,PTH）分泌过多,导致的一组临床症候群,包括高钙血症、肾钙重吸收和尿磷排泄增加、肾结石、肾钙质沉着症和以皮质骨为主骨吸收增加等。病理以单个甲状旁腺腺瘤最常见,少数为甲状旁腺增生或甲状旁腺癌。     

消化系统症状为首要表现的甲状旁腺功能亢进症3例临床分析

目的探讨以消化系统症状为主要表现的甲状旁腺功能亢进症早期诊治,以降低误诊率。方法回顾性分析3例以消化系统症状为主要表现的甲状旁腺功能亢进症。结果 3例甲状旁腺功能亢进症患者血钙、尿钙、甲状旁腺激素升高,血磷水平降低。CT及放射性核素扫描99mTc-MIBI有助于定位诊断,手术治疗是目前唯一的有效措施。结论以消化系统症状为主要表现的原发性甲状旁腺功能亢进症的诊断,要重视血钙及甲状旁腺激素水平监测,达到早期诊断、早期治疗的目的。     

FHH的维生素D代谢与PHPT不同

家族性低尿钙性高血钙症(FHH)是一种显性遗传疾病,表现为终身性无症状高血钙,通常不伴有血清免疫反应甲状旁腺激素(ipTH)升高,尿钙排出相对减少。患者寿命一般正常。其临床和生化表现与原发性甲状旁腺机能亢进(PHPT)部分相同,致使许多FHH患者进行了不必要的甲状旁腺次全切除术。PHPT患者过多的PTH能刺激肾脏分泌1,25(OH)_2D_3,后者再通过刺激肠钙吸收而引     

钙敏感受体激活性和失活性突变所致骨矿代谢异常疾病及治疗

钙敏感受体(calcium-sensing receptor,CaSR)是感知细胞外钙离子浓度,调节甲状旁腺素分泌及尿钙重吸收,维持钙稳态的关键受体。CaSR激活性和失活性突变导致钙调定点的移动,引起相应的钙矿物质代谢异常疾病和骨代谢异常表现。本文综述CaSR突变所致疾病的发病机制、临床表现、治疗策略,通过动物实验模型阐述CaSR的病理生理功能,并探讨针对上述疾病的治疗及CaSR配体药物的研究进展。     

钙敏感受体激活性和失活性突变所致骨矿代谢异常疾病及治疗

钙敏感受体(calcium-sensing receptor,CaSR)是感知细胞外钙离子浓度,调节甲状旁腺素分泌及尿钙重吸收,维持钙稳态的关键受体。CaSR激活性和失活性突变导致钙调定点的移动,引起相应的钙矿物质代谢异常疾病和骨代谢异常表现。本文综述CaSR突变所致疾病的发病机制、临床表现、治疗策略,通过动物实验模型阐述CaSR的病理生理功能,并探讨针对上述疾病的治疗及CaSR配体药物的研究进展。     

骨质疏松的病型及预防

骨质疏松病型1.特发性（原发性）幼年型、成年型、经绝期、老年性。2.继发性（1）内分泌性,皮质醇增多症、甲状腺功能亢进症、原发性甲状旁腺功能亢进症、肢端肥大症、性腺功能低下、糖尿病等。（2）妊娠、哺乳。（3）营养性,蛋白质缺乏、维生素C（D）缺乏、低钙饮食、酒精中毒等。     

钙敏感受体激动剂:治疗甲状旁腺功能亢进症的新药物

甲状旁腺功能亢进症（甲旁亢）与甲状旁腺激素（PTH）产生过多有关，而能够有效减低PTH分泌的药物很少。钙敏感受体可以有效调节PTH的分泌，通过对其激动剂的研究发现，Ⅱ型钙敏感受体激动剂可抑制PTH分泌，有效治疗甲旁亢。目前，盐酸西那卡赛是唯一一种美国食品与药品管理局批准上市的Ⅱ型钙敏感受体激动剂，可以使轻到中度原发性甲旁亢患者血钙恢复并保持在正常范围。     

The calcium-sensing receptor and related diseases

The calcium-sensing receptor (CASR) adjusts the extracellular calcium set point regulating PTH secretion and renal calcium excretion. The receptor is expressed in several tissues and is also involved in other cellular functions such as proliferation, differentiation and other hormonal secretion. High extracellular calcium levels activate the receptor resulting in modulation of several signaling pathways depending on the target tissues. Mutations in the CASR gene can result in gain or loss of receptor function. Gain of function mutations are associated to Autossomal dominant hypocalcemia and Bartter syndrome type V, while loss of function mutations are associated to Familial hypocalciuric hypercalcemia and Neonatal severe hyperparathyroidism. More than one hundred mutations were described in this gene. In addition to calcium, the receptor also interacts with several ions and polyamines. The CASR is a potential therapeutic target to treatment of diseases including hyperparathyroidism and osteoporosis, since its interaction with pharmacological compounds results in modulation of PTH secretion.     

Pancreatitis in primary hyperparathyroidism-related hypercalcaemia is not associated with mutations in the CASR gene.

BACKGROUND: Primary hyperparathyroidism (pHPT) related hypercalcaemia is considered to represent a risk factor for the development of pancreatitis. We therefore explored whether mutations in the calcium-sensing receptor gene ( CASR) coding for the calcium-sensing receptor (CaR), an essential regulator of the calcium homeostasis in parathyroid chief cells, exist in a cohort of patients with pHPT and pancreatitis. METHODS: Among 826 patients prospectively studied between 1987 and 2002 with pHPT, 38 patients were identified with pancreatitis (4.6%). DNA was available of 25 patients (13 females and 12 males). These individuals were analysed for mutations in the CASR by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. RESULTS: None of the 25 patients with pHPT and pancreatitis carried a CASR mutation and only one had a known heterozygous polymorphism R990G. CONCLUSIONS: Pancreatitis in primary hyperparathyroidism is not associated with mutations in the CASR gene, while it remains to be determined why the polymorphisms A986S, R990G and Q1011E were less often present in that subgroup than in the normal population.     

Identification and functional characterization of novel calcium-sensing receptor mutations in familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia

Familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), and autosomal dominant hypocalcemia (ADH), in which calcium homeostasis is disordered, are associated with mutations in the calcium-sensing receptor (CASR). Six unrelated kindreds with FHH and/or NSHPT and two unrelated kindreds with ADH were studied. Direct sequence analysis of the exons of the CASR gene identified heterozygous mutations in six of the kindreds with FHH and in one of those with ADH. We performed functional analyses on the novel missense and insertion/frameshift mutants by transiently transfecting wild-type and mutant CASRs tagged with a c-Myc epitope in human embryonic kidney (HEK293) cells. All mutant receptors were expressed at a similar level to that of the wild type; however, whereas mutants R220W and A835T (the ADH mutant) were fully glycosylated and were visualized on the cell surface, glycosylation of mutants G549R and C850-851 ins/fs was impaired, resulting in reduced cell surface staining. In fura-2-loaded HEK293 cells expressing the wild-type or mutant receptors, the inactivating R220W mutant produced a significant shift to the right relative to the wild-type CASR in the cytosolic calcium response to increasing extracellular calcium concentrations and the G549R and C850-851 ins/fs mutants were without detectable activity. The activating A835T mutation resulted in a shift to the left in the cytosolic calcium response to extracellular calcium concentrations relative to the wild type. Our studies have identified novel CASR mutations that alter the function of the CASR in several different ways.     

Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population

CONTEXT: The autosomal dominantly inherited condition familial hypocalciuric hypercalcemia (FHH) is characterized by elevated plasma calcium levels, relative or absolute hypocalciuria, and normal to moderately elevated plasma PTH. The condition is difficult to distinguish clinically from primary hyperparathyroidism and is caused by inactivating mutations in the calcium sensing receptor (CASR) gene. OBJECTIVE: We sought to define the mutation spectrum of the CASR gene in a Danish FHH population and to establish genotype-phenotype relationships regarding the different mutations. DESIGN AND PARTICIPANTS: A total of 213 subjects clinically suspected to have FHH, and 121 subjects enrolled as part of a family-screening program were studied. Genotype-phenotype relationships were established in 66 mutation-positive index patients and family members. MAIN OUTCOME MEASURES: We determined CASR gene mutations, and correlating levels of plasma calcium (albumin corrected), ionized calcium (pH 7.4), and PTH were measured. RESULTS: We identified 22 different mutations in 39 FHH families. We evaluated data on circulating calcium and PTH for 11 different mutations, representing a spectrum of clinical phenotypes, ranging from calcium concentrations moderately above the upper reference limit, to calcium levels more than 20% above the upper reference limit. Furthermore, the mean plasma PTH concentration was within the normal range in eight of 11 studied mutations, but mild to moderately elevated in families with the mutations p.C582Y, p.C582F, and p.G553R. CONCLUSIONS: The present data add 19 novel mutations to the catalog of inactivating CASR mutations and illustrate a variety of biochemical phenotypes in patients with the molecular genetic diagnosis FHH.     

Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia

Parathyroid adenomas (PAs) causing primary hyperparathyroidism (PHPT) are histologically heterogeneous yet have been historically viewed as largely monotypic entities arising from clonal expansion of a single transformed progenitor. Using flow cytometric analysis of resected adenomatous parathyroid glands, we have isolated and characterized chief cells, oxyphil cells, and tumor-infiltrating lymphocytes. The parathyroid chief and oxyphil cells produce parathyroid hormone (PTH), express the calcium-sensing receptor (CASR), and mobilize intracellular calcium in response to CASR activation. Parathyroid tumor infiltrating lymphocytes are T cells by immunophenotyping. Under normocalcemic conditions, oxyphil cells produce ∼50% more PTH than do chief cells, yet display significantly greater PTH suppression and calcium flux response to elevated calcium. In contrast, CASR expression and localization are equivalent in the respective parathyroid cell populations. Analysis of tumor clonality using X-linked inactivation assays in a patient-matched series of intact tumors, preparatively isolated oxyphil and chief cells, and laser-captured microdissected PA specimens demonstrate polyclonality in 5 of 14 cases. These data demonstrate the presence of functionally distinct oxyphil and chief cells within parathyroid primary adenomas and provide evidence that primary PA can arise by both clonal and polyclonal mechanisms. The clonal differences, biochemical activity, and relative abundance of these parathyroid adenoma subpopulations likely reflect distinct mechanisms of disease in PHPT.The parathyroid glands maintain serum calcium concentration within a narrow physiological range through regulated synthesis and secretion of parathyroid hormone (PTH) (1). Parathyroid neoplasia results in inappropriate secretion of PTH by one or more glands, leading to hypercalcemia and the disease primary hyperparathyroidism (PHPT) (2). To date, research in the field has focused on histologic and molecular profiling of parathyroid tumors and the investigation of calcium sensing in dispersed cells from parathyroid tumors and normal bovine parathyroid glands. Few studies have characterized the individual cellular constituents of human parathyroid tumors, and no publications have reported live-cell functional evaluation of the different cellular subtypes observed in parathyroid tumors.Parathyroid adenomas, the most common cause of PHPT, are considered clonal proliferations of a transformed parathyroid cell that has acquired proliferative or survival advantage due to one of several genetic abnormalities including the PRAD1 translocation or mutations in the genes encoding menin, P53, and P27 (3-7). Regardless of type, most authors consider parathyroid tumors clonal (8, 9) although intratumoral heterogeneity has been observed and polyclonality of microdissected parathyroid adenomas has been reported (10, 11).Although most data support mutation-driven clonal expansion of parathyroid tumors, an alternative model for the origin of parathyroid tumors is that abnormal calcium sensing by parathyroid cells leads to abnormal secretion of PTH initially, followed by proliferation of parathyroid cells in response to chronic demand for increased PTH (12, 13). An abnormal calcium–PTH set point has been well-described in aggregate dispersed cells from parathyroid adenomas, and most reports attribute the impaired set point in these cells to decreased expression of the calcium-sensing receptor (CASR) (14, 15) or more recently to altered expression of downstream molecules linked to CASR signaling, including RhoGEF and RGS5 (16, 17). In contrast to clonal expansion following genomic tumor-initiating events, attenuated calcium responsiveness could be expected to drive polyclonal proliferation in the parathyroid gland.To investigate the composition of parathyroid tumors, we sought to characterize a series of parathyroid adenomas at the cellular and functional level. In this study, we report the isolation and characterization of chief cells, oxyphil cells, and lymphocytes present in parathyroid adenomas and histologically normal parathyroid glands from patients with PHPT. Our results show that parathyroid adenomas removed from patients with PHPT are composed of functionally and genetically distinct oxyphil and chief cells and have varying amounts of infiltrating lymphocytes. The chief and oxyphil cells within parathyroid adenomas have differing ability to respond to changes in ambient calcium and produce PTH although CASR expression is comparable between these parathyroid cell subtypes. Further, we show that a significant proportion of PHPT patients have polyclonal tumors. The relative abundance, functional behavior, and clonal origin of distinct parathyroid-cell subpopulations in parathyroid tumors likely reflect multiple alternative etiologies of PHPT.     

Identification of a novel calcium-sensing receptor gene mutation causing familial hypocalciuric hypercalcemia by single-strand conformation polymorphism analysis.

Calcium-sensing receptor gene (CASR) mutations that alter the function of the G protein coupled Ca (2+)-sensing receptor are reported in patients with familial hypocalciuric hypercalcemia (FHH), autosomal dominant hypocalcemia (ADH), and neonatal severe hyperparathyroidism (NSHPT). In search for novel disease causing mutations in the CASR gene, we screened exons 2 - 7 of the CASR gene of a family with FHH using single-strand conformation polymorphism analysis. We identified a novel CASR mutation (c.518 T > C; L173 P) in exon 4 encoding for the extracellular domain of the Ca (2+)-sensing receptor. This region seems to represent a hot spot within the CASR gene with at least 13 reported disease causing mutations thus far.     

Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: modulation of clinical severity by vitamin D status

CONTEXT: Familial hypocalciuric hypercalcemia (FHH) is a benign condition associated with heterogeneous inactivating mutations in the calcium-sensing receptor (CASR) gene. OBJECTIVE: The objective of the study was to identify and characterize a CASR mutation in a moderately hypercalcemic, hyperparathyroid individual and his family and assess the influence of vitamin D status on the clinical expression of the defect. SUBJECTS: We studied a kindred with FHH, in which the proband (a 34-yr-old male) was initially diagnosed with primary hyperparathyroidism due to frankly elevated serum PTH levels. METHODS: CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The mutant CASR was functionally characterized by transient transfection studies in kidney cells in vitro. RESULTS: A novel heterozygous mutation (F180C, TTC>TGC) in exon 4 of the CASR gene was identified. Although the mutant receptor was expressed normally at the cell surface, it was unresponsive with respect to intracellular signaling (MAPK activation) to increases in extracellular calcium concentrations. The baby daughter of the proband presented with neonatal hyperparathyroidism with markedly elevated PTH. Vitamin D supplementation of both the proband and the baby resulted in reduction of serum PTH levels to the normal range. The serum calcium level remained at a constant and moderately elevated level. CONCLUSION: The identification of a novel CASR gene mutation established the basis of the hypercalcemia in the kindred. Concomitant vitamin D deficiency modulates the severity of the presentation of FHH.     

Genetic analyses in patients with familial isolated hyperparathyroidism and hyperparathyroidism-jaw tumour syndrome

BACKGROUND: A subset of familial isolated primary hyperparathyroidism (FIHP) is a variant of hyperparathyroidism-jaw tumour syndrome (HPT-JT). AIM/PATIENTS AND METHODS: We investigated the involvement of the HRPT2, MEN1 and CASR genes in 11 provisional FIHP families and two HPT-JT families. RESULTS: Germline mutations of HRPT2 were found in two of the 11 FIHP families and one of the two HPT-JT families. One FIHP family with parathyroid carcinoma and atypical adenomas and another FIHP family with cystic parathyroid adenoma had novel frameshift mutations of 518-521del and 62-66del, respectively. In a patient with HPT-JT, a de novo germline mutation of 39delC was detected. Novel somatic HRPT2 mutations of 70-73del and 95-102del were found in two of five parathyroid tumours in a family with a 518-521del mutation. Biallelic inactivation of HRPT2 by a combination of germline and somatic mutation was confirmed in the parathyroid tumours. The finding that two families diagnosed with FIHP carried HRPT2 mutations suggests that they have occult HPT-JT. In the remaining 10 families, one family had a missense MEN1 mutation. No mutations of CASR were detected. CONCLUSION: Our results confirm the need to test for HRPT2 in FIHP families, especially those with parathyroid carcinomas, atypical adenomas or adenomas with cystic change.     

Tertiary hyperparathyroidism during high phosphate therapy of familial hypophosphatemic rickets.

We report the development of severe tertiary hyperparathyroidism in three girls treated for familial hypophosphatemic rickets and characterize parathyroid function in vivo and in vitro. All patients had been previously treated with relatively large doses of inorganic phosphorus (125 mm/day) and ergocalciferol or calcitriol for several years and had radiographic evidence of long-standing hyperparathyroidism. Even in the presence of extremely elevated PTH levels, oral phosphate lowered serum calcium levels in vivo and further stimulated PTH secretion. Profound multiglandular parathyroid hyperplasia was found in each patient at surgery. Examination of the secretory characteristics of the excised parathyroid tissue revealed that either relatively high calcium concentrations were generally needed to suppress PTH secretion or PTH secretion was not suppressible. Caution is recommended when relatively large doses of phosphate are used to treat familial hypophosphatemic rickets.