Primary hyperparathyroidism

Abstract

Primary hyperparathyroidism (PHPT) is a common disorder in which parathyroid hormone (PTH) is excessively secreted from one or more of the four parathyroid glands. A single benign parathyroid adenoma is the cause in most people. However, multiglandular disease is not rare and is typically seen in familial PHPT syndromes. The genetics of PHPT is usually monoclonal when a single gland is involved and polyclonal when multiglandular disease is present. The genes that have been implicated in PHPT include proto-oncogenes and tumour-suppressor genes. Hypercalcaemia is the biochemical hallmark of PHPT. Usually, the concentration of PTH is frankly increased but can remain within the normal range, which is abnormal in the setting of hypercalcaemia. Normocalcaemic PHPT, a variant in which the serum calcium level is persistently normal but PTH levels are increased in the absence of an obvious inciting stimulus, is now recognized. The clinical presentation of PHPT varies from asymptomatic disease (seen in countries where biochemical screening is routine) to classic symptomatic disease in which renal and/or skeletal complications are observed. Management guidelines have recently been revised to help the clinician to decide on the merits of a parathyroidectomy or a non-surgical course. This Primer covers these areas with particular attention to the epidemiology, clinical presentations, genetics, evaluation and guidelines for the management of PHPT.

Figure 1. Incidence of PHPT

The incidence of primary hyperparathyroidism (PHPT) in women (part a) and men (part b) as determined from a large epidemiological database from the United States. Over a 15-year period, the incidence tripled even in the setting of routine use of biochemical screening tests. Republished with permission of Endocrine Society, from Incidence and prevalence of primary hyperparathyroidism in a racially mixed population, Yeh, M. W. et al., 98, 3, 1122–1129, 2013; permission conveyed through Copyright Clearance Center, Inc.

Figure 2. Control of parathyroid hormone synthesis and secretion

In humans, the parathyroid hormone gene (PTH) is located on chromosome 11. The formation of mature PTH requires cleavage of the pre-sequences and pro-sequences (25 and 6 amino acid residues, respectively); the mature PTH peptide (84 amino acids) is packaged into secretory vesicles in the parathyroid chief cells. PTH can either be secreted by exocytosis, degraded within the secretory vesicles (producing fragments that are released in the circulation) or sequestered in a stored pool. The principal regulators of PTH secretion are extracellular ionized calcium (Ca²⁺) and 1,25-dihydroxyvitamin D (1,25(OH)₂D). Other potentially important regulators include serum phosphate and fibroblast growth factor 23 (FGF23). A rise in extracellular ionized calcium levels activates the calcium-sensing receptor (CASR), which suppresses PTH expression. In addition, PTH expression is suppressed by 1,25(OH)₂D and FGF23. FGFR1, fibroblast growth factor receptor 1; VDR, vitamin D receptor.

Figure 3. Relationship between calcium and parathyroid hormone levels in normal conditions and in PHPT

In normal conditions, the level of parathyroid hormone (PTH) secretion depends on the level of calcium, with a high level of PTH secreted when serum calcium is at the lower limit of the normal range and a low level when serum calcium is at the upper limit of the normal range. The range of normal serum calcium levels is indicated by the shaded area. The calcium set point corresponds to the concentration of calcium, which reduces PTH secretion by 50%. In primary hyperparathyroidism (PHPT), the parathyroid adenoma is relatively insensitive to the feedback suppression by calcium, and the curve is shifted to the right with an increase in the set point for serum calcium. As a consequence, PHPT is often associated with hypercalcaemia.

Figure 4. Oncogenes and tumour-suppressor genes in parathyroid tumours

a | Proto-oncogenes have a physiological role in the control of cell proliferation, differentiation and cell death. The conversion of proto-oncogenes to oncogenes (due to chromosome inversion, translocation or point mutation) causes an increased expression of its encoded protein or the synthesis of a new protein with increased function. Most oncogenes are dominant mutations; a single copy of the gene is sufficient to promote tumorigenesis. The conversion of a proto-oncogene mainly occurs in somatic cells. Its presence in a germline cell does not necessarily result in neoplastic transformation, but can increase the risk of it in the offspring. b | Tumour-suppressor genes encode proteins that normally inhibit cell proliferation and, once mutated, contribute to tumour development through their functional inactivation. Loss-of-function mutations in tumour-suppressor genes act recessively; one copy of the gene suffices to control cell proliferation. Inactivation of a tumour-suppressor gene is usually caused by point mutations or deletions, which may either be inherited in all parathyroid cells or occur somatically in a single parathyroid cell (first hit). An acquired somatic deletion or mutation of the other copy of the gene (second hit) will lead to loss of function of the related gene product.

Figure 5. Parathyroid tumorigenesis

(1) Cyclin D1 (encoded by CCND1), a regulatory subunit of cyclin-dependent kinase 4 (CDK4) and CDK6 required for progression through the G1 phase of the cell cycle, is frequently (20–40%) overexpressed in parathyroid adenomas. In a subset of these adenomas, a pericentromeric inversion of chromosome 11 places the parathyroid hormone gene (PTH) promoter sequences on 11p15 immediately upstream of CCND1. This rearrangement results in the upregulated expression of cyclin D1 upon activation of CDKs. (2) Loss-of-function mutations of MEN1 (which encodes menin) represent the main cause of multiple endocrine neoplasia type 1 (MEN1) syndrome (in up to 80% of cases), especially in the familial setting, but are also found in a subset of familial isolated hyperparathyroidism (FIHP) and in 12–35% of sporadic parathyroid adenomas. MEN1 functions as a classic tumour-suppressor gene and is frequently associated with somatic loss of heterozygosity. Menin is a component of the histone methyltransferase complex, including the histone-lysine N-methyltransferases MLL1 (encoded by KMT2A) and MLL2 (encoded by KMT2D), required for histone H3 lysine 4 trimethylation (H3K4Me) of the target genes. In physiological conditions, activation of this complex leads to the basal transcription of CDKN1B, encoding the CDK inhibitor p27 (KIP1), which stops progression of the cell cycle by inhibiting CDK complexes acting at multiple phases of the cell cycle, especially at G1-S and S-G2 checkpoints. MEN1 inactivation results in a reduction of nuclear expression levels of p27 (KIP1) and the loss of negative control of cell cycle progression. (3) CDKN1B germline mutations are the molecular cause of the MEN4 syndrome. CDKN1B is an atypical tumour-suppressor gene because biallelic inactivation is an uncommon event, suggesting that only a single inactivated copy of the gene is sufficient to lead to a diseased state (haploinsufficiency). (4) Somatic and germline inactivating CDC73 (which encodes parafibromin) mutations have been frequently identified in patients with parathyroid carcinoma. Germline CDC73 mutations are also responsible for hyperparathyroidism-jaw tumour syndrome (HPT-JT). Parafibromin binds to DNA and leads to repression of cyclin D1 and inhibition of proliferation. In case of CDC73 inactivation, parafibromin seems to associate with β-catenin, a central mediator of WNT signalling, and activates target genes (for example, MYC and CCDN1) through H3K4Me.

Figure 6. Overt bone disease in PHPT

Osteolytic lesion due to a brow n tumour of the jaw from an individual with severe primary hyperparathyroidism (PHPT; arrow; part a and part b). In addition, note the increased uptake of 99m-technetium-methyl diphosphonate on the bone scan (arrow; part c and part d).

Figure 7. Preoperation location of a parathyroid adenoma

Parathyroid adenoma in the left lower pole of the parathyroid gland is seen by 99m-technetium-sestamibi scanning (arrow). The faint outlines of the thyroid gland are also seen.