Update on genetic and clinical aspects of primary hyperparathyroidism

Abstract

SummaryPrimary hyperparathyroidism (pHPT) is a common endocrine disorder that predominantly affects postmenopausal women. It is mostly caused by solitary tumours within the parathyroid glands. Although the pathophysiology of pHPT is still incompletely understood, recent studies provide new clues on the development and cellular growth of tumours within the parathyroids associated with hypersecretion of parathyroid hormone and hypercalcaemia. The natural course of pHPT is rather benign. Nowadays, it has become an oligo-or asymptomatic disease often only detected by routine blood tests. These facts raise the question whether to perform parathyroidectomy on oligo-and asymptomatic patients with pHPT or whether it is possible to monitor these patients without surgery. The aim of this article is to review the literature as regards (i) the pathophysiological mechanisms that underlie parathyroid neoplasia and (ii) the defective calcium-sensing in patients with pHPT (iii) environmental and /or genetic risk factors that predispose to or promote parathyroid neoplasia, as well as (iv) alternative approaches to treat oligo-and asymptomatic patients with pHPT medically.Maintenance of a normal extracellular calcium concentration (2·2-2·6 mmol/l) depends on the integrated co-ordination of calcium fluxes with respect to intestinal tract, kidneys and bone. Changes in extracellular calcium levels are mainly regulated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (reviewed in Bushinsky & Monk, 1998). Secretion of PTH is regulated by extracellular calcium, via a G protein-coupled calcium-sensing receptor (CaR;Brown et al ., 1993). Small increments in extracellular calcium levels above normal inhibit PTH secretion. Subsequently, calcium uptake from intestine, renal reabsorption and release of calcium from bone are reduced to re-establish the normal value (see Fig. 1). If serum calcium concentration falls by only a few per cent, secretion of PTH is stimulated, and calcium uptake from the intestines, release from bone and reabsorption from the kidneys are increased (reviewed in Bushinsky & Krieger, 1992a, 1992b. In part, these effects are mediated by 1,25-dihydroxyvitamin D, whose synthesis is tightly regulated by PTH, as well as by calcium, phosphate and 1,25-dihydroxyvitamin D itself (Kumar, 1984;Breslau, 1988). In patients with primary hyperparathyroidism (pHPT), the normal regulation of PTH secretion is disrupted. In spite of increased levels of total and ionized serum calcium, its biologically active compound, hypersecretion of PTH is observed. In general, measurement of serum calcium and intact PTH (1 -84 amino acids) levels confirm the diagnosis.Newly developed PTH assays, which specifically recognize the biologically active form of the peptide (1 -84), seem to be more sensitive compared to standard immunoassays that also bind to smaller fragments of PTH (Gao et al ., 2001;Nakanishi et al ., 2001). However, these amino-terminally truncated PTH Correspondence: R. Paschke, III. Medical Department, University of Leipzig, ...

Analysis of the diagnostic presentation profile, parathyroidectomy indication and bone mineral density follow-up of Brazilian patients with primary hyperparathyroidism

“…As a consequence of the high racial admixture of our population, it is extremely difficult, if not impossible, to appropriately separate the different Brazilian ethnic groups. Calcium and vitamin D deficiencies have been related to the clinical profile of PHP (18). Moosgaard et al (19) demonstrated that vitamin D deficiency or insufficiency is a common finding in PHP patients and occurs more often than in gender-and age-matched controls.…”

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach?

“…These heritable forms are responsible for approximately 10% of primary HPT. They are usually seen in the context of syndromes, such as multiple endocrine neoplasia types 1 and 2 (MEN 1, MIM #131100 and MEN 2, MIM #171400, respectively), hyperparathyroidism-jaw tumor syndrome (HPT-JT, MIM #145001), familial benign hypocalciuric hypercalcemia (FHH, MIM #145980) and familial isolated hyperparathyroidism (FIHP, #145000) (1). FIHP is a rare autosomal dominant condition, characterized by the occurrence of familial hyperparathyroidism in the absence of other associated lesions or endocrinopathies, with a clinical and genetically heterogeneous presentation (2)(3)(4)(5)(6).…”

Parathyroid hormone-dependent hypercalcemia

“…The molecular mechanism underlying defective calcium-sensing in parathyroid tumors is still not clear. Many authors have shown that both mRNA content and protein expression of CaSR are reduced in parathyroid adenoma tissue; however, the reduction is variable and independent of investigated clinical parameters such as serum calcium and PTH concentrations or tumor mass [25,26]. It is interesting that downregulation of CaSR appears associated with increased cellular proliferation, although the precise mechanism of the association remains unknown [26].…”