Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism

Abstract

In this narrative review, we present data gathered over four decades (1980-2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1-MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Keywords: CALCIUM SENSING RECEPTOR; FAMILIAL PHPT; GENETIC TESTS; PARATHYROID HORMONE; PRIMARY HYPERPARATHYROIDISM.

Fig. 1

Potential role of altered parathyroid CaSR expression in the pathogenesis of PHPT. Epigenetic modification of the CASR promoter region in parathyroid adenomas may be mediated by mutations affecting oncogenes and tumor‐suppressor genes, which in turn cause reduced CaSR protein expression.^{( 71 )} Reduced parathyroid CaSR expression may decrease the number of functioning CaSR homodimers at the cell‐surface, which will impair CaSR signal transduction and lead to increased PTH secretion. Reduced numbers of CaSR homodimers may also cause the CaSR to form heterodimers with the parathyroid‐expressed GABA_B1 receptor (GABA_B1R). Such CaSR‐GABA_B1R heterodimers are postulated to inhibit signaling from CaSR homodimers,^{( 175 )} thereby further increasing PTH secretion and parathyroid gland proliferation.