NDT Advance Access originally published online on November 30, 2006
Nephrology Dialysis Transplantation 2007 22(3):696-699; doi:10.1093/ndt/gfl728
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Primary hyperparathyroidism—what the nephrologist should know—an update
Endocrine practice, Heidelberg, Germany
Correspondence and offprint requests to: Prof. Dr Med. Friedhelm Raue, Endokrinologische Gemeinschaftspraxis, Brückenstr.21, 69120 Heidelberg, Germany. Email: friedhelm.raue{at}raue-endokrinologie.de
Keywords: calcium sensing receptor; familial hypocalciuric hypercalcaemia; HRPT-2 gene; MEN-1 gene; primary hyperparathyroidism; RET-gene
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Introduction |
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 Top Introduction Calcium-sensing receptorFamilial hypocalciuric...CalcimimeticsFamilial hyperparathyroidismReferences |
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In the first 40 years, after its recognition as a clinical entity, primary hyperparathyroidism (HPT) presented as a disorder with kidney stones and bone disease. Now, HPT is often recognized as a result of biochemical screening, or as part of an evaluation for decreased bone mass [1, 2]. The diagnosis of HPT is usually made by finding an inappropriately elevated serum parathyroid hormone (PTH) concentration associated with hypercalcaemia. The current understanding of molecular mechanisms of calcium regulation by calcium-sensing receptor (CaSR) and proliferation of parathyroid cells by oncogenes (RET) and tumour suppressor genes (MEN1 gene, HRPT2 gene) has in part changed the management of HPT.
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Calcium-sensing receptor |
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TopIntroductionCalcium-sensing receptorFamilial hypocalciuric...CalcimimeticsFamilial hyperparathyroidismReferences |
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Serum ionized calcium concentrations are normally maintained within the very narrow range achieved through a tightly regulated calcium-PTH homeostatic system [3]. PTH is secreted almost instantaneously in response to very slight reductions in serum ionized calcium, which are sensed by the CaSR. The CaSR which is responsible for calcium-sensing by the parathyroid gland is a seven transmembrane-domain GTP-binding protein. There is a steep inverse sigmoidal relationship between the serum ionized calcium and PTH concentrations, with a mid-point or set-point of this function, i.e. the calcium concentration at which there is half-maximal inhibition of PTH secretion and a key determinant of the level at which calcium is ‘set’ in vivo [4]. The increase in PTH release raises the serum calcium concentration toward normal within minutes via increased bone resorption and decreased urinary calcium excretion, and within days, by increased intestinal calcium absorption mediated by increased production of calcitriol. These changes result in normalization of serum ionized calcium concentration, which then closes the system's feedback loop.
HPT is characterized by hypercalcaemia in the face of abnormally high PTH levels. The increase in PTH secretion is in part due to an elevation in the set-point, i.e. in the slope of the calcium-PTH curve, resulting in a relative non-suppressibility of PTH secretion. Although mutations of the CaSR-gene are rare in sporadic parathyroid tumours, expression of the calcium-sensing protein is reduced in parathyroid adenomas and also in secondary hyperparathyroidism of uraemia [5, 6]. PTH secretion from adenomas may be more related to the increased cell mass. Inactivating mutations in the CaSR gene are present in patients with familial hypocalciuric hypercalcaemia (FHH), a syndrome with biochemical features similar to HPT. It is important to rule out this familial calcium-sensing disorder before diagnosis of HPT is made, because patients with FHH do not benefit from parathyroid surgery.
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Familial hypocalciuric hypercalcaemia (FHH) |
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TopIntroductionCalcium-sensing receptorFamilial hypocalciuric...CalcimimeticsFamilial hyperparathyroidismReferences |
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FHH is an autosomal dominant disease with high penetrance, characterized by lifelong mild hypercalcaemia. Affected heterozygous patients typically present in childhood with the incidental discovery of hypercalcaemia, inappropriate hypocalciuria and mild-to-moderate hypermagnesaemia, as well as a normal or slightly elevated serum PTH concentration despite mild hypercalcaemia [7, 8]. The vast majority of patients with FHH are asymptomatic. The inactivating mutation of CaSR gene in FHH renders the receptor less sensitive to calcium. In the parathyroid glands, this defect means that a higher than normal serum calcium concentration is required to reduce PTH release. In the kidney, this defect leads to an increase in tubular calcium and magnesium reabsorption. The urinary calcium excretion in FHH is generally in the low-normal to reduced range. The fractional excretion of calcium (calcium clearance to creatinine clearance ratio) is often <0.01 in patients with FHH, indicating that more than 99% of the filtered calcium has been reabsorbed, despite the presence of hypercalcaemia [9]. This can be used to improve the discrimination of FHH from primary hyperparathyroidism. Although this is typical for FHH, the fractional excretion of calcium may also be low in patients with primary hyperparathyroidism, whose values often range between 0.01 and 0.05. The diagnosis of FHH, particularly its distinction from primary hyperparathyroidism, is primarily based upon the family history, laboratory findings and genetic testing. Several different mutations have been identified. Approximately 90% of the FHH kindreds investigated have been found to have unique heterozygous mutations. Most result in receptors that are either truncated or have an abnormal amino acid sequence. Both varieties result in reduced sensitivity of the receptors on the parathyroid and renal cell surface [10]. Because of the usually benign natural history and because subtotal parathyroidectomy does not cure the disorder, patients with FHH should not undergo neck exploration or any other aggressive intervention. They should not be placed on a low calcium diet.
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Calcimimetics |
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TopIntroductionCalcium-sensing receptorFamilial hypocalciuric...CalcimimeticsFamilial hyperparathyroidismReferences |
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The CaSR can be considered a low-affinity receptor, responding to relatively high concentrations of calcium exceeding 1 mmol/l. The limited selectivity of the receptor is responsible for its activation by numerous divalent or trivalent cations in addition to calcium, such as magnesium, gadolinium, aluminium and lanthanum, and by other polycationic compounds such as neomycin, spermine and numerous amino acids [11]. New substances, calcimimetics, have been developed to modulate the CaSR; one of these is AMG 073, called cinacalcet, which can decrease PTH secretion from the parathyroids. This substance is completely inactive in the absence of extracellular calcium; it does not interact directly with the calcium binding site of the CaSR, but with a different site of the molecule. Interaction of the calcimimetics with the receptor causes conformational changes of the receptor molecule and increases the calcium sensitivity of the receptor, so-called allosteric modulation. Cinacalcet can lower the PTH concentration in primary and secondary hyperparathyroidism. Cinacalcet is a powerful compound in reducing PTH in patients with poorly controlled secondary hyperparathyroidism; it may be also used in primary hyperparathyroidism, especially in patients with parathyroid carcinoma when an operation has failed [12].
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Familial hyperparathyroidism |
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TopIntroductionCalcium-sensing receptorFamilial hypocalciuric...CalcimimeticsFamilial hyperparathyroidismReferences |
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More important for the increased PTH secretion in HPT is the increase in the number of parathyroid cells forming parathyroid hyperplasia, parathyroid adenoma or carcinoma induced by activation of oncogenes or inactivation of tumour suppressor genes. This could be shown in the rare hereditary forms of hyperparathyroidism, where the molecular basis of the various subtypes are well understood [13]. Probably the most common cause of this rare form of hyperparathyroidism are the multiple endocrine neoplasia (MEN) type 1 or 2 syndromes. It can also occur as familial isolated HPT or in the familial hyperparathyroidism-jaw tumour syndrome (HPT-JT), as familial HPT is not associated with any other endocrine disorder [14]. Familial hyperparathyroidism may be the result of multiple abnormal parathyroid glands, hyperplasia of all four glands or multiple adenomas. Germline abnormalities in key growth-controlling genes, proto-oncogenes or tumour suppressor genes underlie the development of familial HPT and are also found as somatic mutations in sporadic parathyroid tumours. The abnormalities include gain-of-function in genes such as RET proto-oncogene (MEN-2 gene) or loss-of-function mutations in genes such as MEN-1 and the HRPT-2 gene (HPT-JT-syndrome).
RET-gene
Germline mutations in the RET proto-oncogene are found in 98% of patients with MEN-2, a syndrome characterized by the occurrence of medullary thyroid carcinoma, pheochromocytoma and parathyroid tumours. Primary hyperparathyroidism occurs in 10–25% of MEN-2 gene carriers [15]. Medullary thyroid carcinoma precedes the occurrence of primary hyperparathyroidism often seen in codon 634 mutations, usually manifesting after the third decade of life [16]. Hyperparathyroidism develops slowly, is usually mild and clinical features do not differ from those seen in mild sporadic hyperparathyroidism [17]. Pathological findings show chief cell hyperplasia involving multiple glands. Annual measurement of serum calcium concentration in gene carriers is probably adequate for screening purposes. Tumour-specific mutations similar to those in MEN-2 syndrome (i.e. gain-of-function RET mutations) are rarely, if ever, found as somatic mutations in sporadic primary hyperparathyroidism [18].
MEN-1 gene
MEN-1 gene is a classic tumour suppressor gene that contributes to cell-selective survival through bi-allelic inactivation (loss of heterozygosity). In MEN-1 syndrome, HPT is the first manifestation and the leading disorder in 90% of MEN-1 patients. Enteropancreatic and pituitary tumours are found less frequently. Germline mutations in the MEN-1 gene are found in 95% of patients with MEN-1 syndrome [16, 19]. A loss of sequences at the same locus on chromosome 11 (11q13) has been found in approximately one-fourth of adenomas from patients with sporadic primary hyperparathyroidism, suggesting that the same gene might be involved [20].
HRPT-2 gene
Germ-line HRPT-2 mutations (located on chromosome 1q24-q32) have been described in the HPT-JT syndrome that is associated with an increased risk of parathyroid cancer [14]. The bone lesions characteristic of HPT-JT are ossifying fibromas of the mandible and/or maxilla, although they may occur elsewhere in the skeleton. In addition, renal lesions have been described, including Wilms’ tumours, hamartomas and polycystic disease [21]. Somatic mutations of this gene and loss of heterozygosity have been reported in patients with sporadic parathyroid carcinoma, indicating that the gene was likely to be a tumour suppressor [22].
The molecular basis for HPT has been further elucidated by the detection of inactivating germline mutations in the CaSR gene in familial hypocalciuric hypercalcaemia syndrome and in the RET-, MEN-1 and HRPT-2 genes in the familial forms of HPT. Although rare, diagnosis of the hereditary variants have important clinical implications: FHH patients should not be operated on, while in patients with MEN-1, MEN-2 and HPT-JT all parathyroid glands should be explored and operated on as hyperplasia or multiple adenomas are often found. DNA-mutation analysis allows identification of gene carriers, pre-symptomatic diagnosis and treatment of syndrome-related lesions, which should lead to improved survival and quality of life.
Conflict of interest statement. None declared.
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References |
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[Abstract/Free Full Text]
Accepted in revised form: 6.11.06
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