Parathyroid Disease

Specific aims:

  • Characterize the molecular epidemiology important in the development of primary hyperparathyroidism.
  • Identify the molecular genetic aberrations contributing to the development of parathyroid tumors.
  • Clinical and genetic characterization of familial hyperparathyroidism.

Hyperparathyroidism (HPT), regardless of underlying etiology, is characterized by parathyroid gland hypercellularity and parathyroid hormone (PTH) hypersecretion which causes hypercalcemia. Primary HPT of non-familial origin can be attributed to a benign, single adenoma in 80-85% of cases, to multiglandular parathyroid enlargement (hyperplasia) in 15-20%, whereas parathyroid carcinoma is exceptionally rare occurring in less than 1% of patients1.

Parathyroid hyperplasia also may occur due to known underlying factors, most often renal failure, and the disorder is then termed secondary HPT. The relative hypocalcemia, hyperphosphatemia and active vitamin D (1,25(OH)2D3;calcitriol) deficiency in these patients cause hyperproliferation of all the parathyroid glands.

Primary HPT is common and extensive health-screening examinations, mainly from Scandinavia, suggest a prevalence of up to 2.1% in postmenopausal women. Some studies, however, have noted a reduced incidence of primary HPT after the initial peak which coincided with the introduction of serum calcium screening in the 1970s. Age, female gender and previous irradiation to the neck are established risk factors for primary HPT. Although primary HPT in the vast majority of cases occur sporadically, it may be part of familial disorders with a high penetrance of the disease, such as multiple endocrine neoplasia type 1 (MEN 1), MEN 2A, the HPT-jaw tumor syndrome, familial isolated hyperparathyroidism (FIHPT), familial hypocalciuric hypercalcemia (FHH), and neonatal severe HPT (NSHPT). The management of primary HPT in such kindreds typically differs from sporadic primary HPT and it is advisable that such patients are managed at centers with significant experience with diagnosis, management and operative treatment of endocrine tumor susceptibility disorders.

Table. Inherited forms of hyperparathyroidism

Disorder
Inheritance
Responsible Gene
Chromosomal location
HPT*
Associated tumors*
MEN 1a
AD
MEN1
11q13
High penetrance (~ 90 %), MultiglandularPituitary, EPT
MEN2a
AD
RET
10q21
Low penetrance (20%) Multiglandular/AdenomaMTC, pheo
chromo
cytoma
HPT-JT
AD
HRPT2
1q21-q32
Cystic parathyroid tumors, Increased risk of carcinomaJaw tumors, renal lesions
FIHPTb
AD
n.i.
1q21-q32
Adenoma/multi-glandular
-
AD
MEN1
11q13
-
FHHc
AD
CaR
3q13-21
Normal to mild hyperplasia
-
AD
n.i.
19p13.3
-
AD
n.i.
19q13
-
ADMH
AD
CaR
3q13-21
Multiglandular/Adenoma
-
NSHPT
AR
CaR
3q13-21
Markedly hyperplastic
-

Hyperparathyroid disease has two major characteristics: increased parathyroid cell proliferation and calcium insensitive hypersecretion of PTH. Under normal circumstances, a homeostatic system exists for the maintenance of a tightly regulated ionized calcium concentration (within 1.1-1.3 mM). The parathyroid glands sense fluctuations in the extracellular calcium concentrations by a calcium sensing receptor (CaR) mechanism responding with rapid changes in the secretion of PTH. PTH increases serum calcium levels via enhanced bone resorbtion and renal calcium reabsorption, as well as stimulation of the synthesis of active 1,25(OH)2D3, thereby enhancing intestinal calcium absorption. 1,25(OH)2D3, via its receptor VDR, acts as an important negative feedback regulator of calcium homeostasis by inhibiting PTH gene transcription and hormone secretion.

The regulation of parathyroid cell proliferation is mediated mainly by 1,25(OH)2D3,calcium and phosphate, and low calcium and 1,25(OH)2D3 stimulates proliferation. A relatively calcium-insensitive hypersecretion of PTH accompanies primary HPT. The secretory derangement of primary HPT is associated both with a right-shifted EC50 and an inability to maximally suppress PTH secretion. Both the VDR and CaR show a reduced parathyroid cell expression in primary and secondary HPT, and is likely to contribute to impaired regulation of both parathyroid cell proliferation and PTH secretion. However, considering the lack of somatic mutations in these genes, it is likely that the down regulation of these receptors is secondary rather than the cause of HPT. Genetic polymorphisms in the VDR gene have been associated with the risk of developing primary HPT, most likely due to reduced parathyroid expression of VDR in patients with the baT haplotype.

Tumorigenetic studies have so far identified genetic alterations in the PRAD1/Cyclin D1 oncogene, the tumor suppressor genes MEN1, as well as the recently cloned HRPT2 as pathogenically important for development of parathyroid adenomas. Alteration of the Rb tumor suppressor has been identified particularly in parathyroid carcinomas, and adenomas with an aggressive phenotype.Hypercalcemia of HPT is associated with a variety of signs and symptoms including nephrolithiasis, nephrocalcinosis, and bone disease (both osteopenia and osteporosis). Additionally, a number of “non-traditional” abnormalities have been demonstrated in recent studies, including decreased cognitive function, lethargy, musculoskeletal impairment, hypertension, phenotype IV lipoprotenemia, and increased cardiovascular morbidity and mortality.

Despite recent advances in the understanding of the pathophysiology and molecular genetics of hyperparathyroidism, a number of important scientific questions remain.