Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism

Abstract

In this narrative review, we present data gathered over four decades 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.

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

“…Gene set enrichment comparative analysis of Def-Ts and Rep-Ts suggests the possibility of alternative etiologies for these tumors and supports the notion that oxyphil cells in either context are lineal descendants of chief cells. The differential expression in parathyroid tumors of genes associated with beta-amyloid signaling reveals a potential connection between the increased amyloid burden in aging adults ( 62 , 63 ) and the heightened incidence of PHPT among older individuals ( 64 ). Collectively, these findings suggest that PHPT in vitamin D-deficient patients may be a distinct subset of the disease with an alternative etiology, tumor composition, and cellular behavior.…”

Successful parathyroidectomy improves cognition in patients with primary hyperparathyroidism: A prospective study in a tertiary medical center and comprehensive review of the literature

“…In this prospective study evaluating 18 PHPT patients for neurocognitive disorders before and 1 month after successful parathyroidectomy, a follow-up over 6 months in 13 of these patients was completed. The baseline impaired neurocognitive functions were: [1] the short-and long-term verbal memory with learning abilities assessed by RAVLT, [2] the short-and long-term visual memory, attention, planning, and working memory assessed by ROCF test, [3] visual attention, mental flexibility, and executive functioning evaluated by TMTs, and [4] complex neurocognitive functions (attention, memory, fluency, language, and visuospatial functions) assessed by ACE-III tests. This study demonstrated that successful parathyroidectomy resulted in a significant improvement in short-and long-term verbal memory and learning abilities (ACE5, RAVLT8).…”

“…Primary hyperparathyroidism (PHPT), the most frequent cause of hypercalcemia, is a common disease with 0.86% prevalence in the USA, and is more frequent in post-menopausal women (3-4/1 female-male ratio) ( 1 ), whereas in different western Europe countries the prevalence varies but a similar pattern of increased incidence specifically in postmenopausal women is observed ( 2 ) Nowadays, PHPT is usually diagnosed by laboratory routine tests in asymptomatic patients, but classic symptoms include kidney-related symptoms such as nephrolithiasis (15-20% of PHPT patients) and bone-related symptoms (<2% of PHPT patients) ( 1 , 3 ). Non-classic symptoms include muscle weakness, fatigue, rheumatological, neuromuscular manifestations, and neurocognitive and psychiatric symptoms ( 4 – 6 ).…”

Pivotal Role of Intestinal Microbiota and Intraluminal Metabolites for the Maintenance of Gut–Bone Physiology

“…Low and intermittent doses of PTH exhibit anabolic effects on bone volume and microarchitecture. In contrast, a continued hypersecretion of PTH, such as that which occurs in primary hyperparathyroidism, leads to bone resorption [ 40 , 41 ]. Acting as an opponent of PTH, calcitonin reduces calcium concentrations in the blood, for example, due to the inhibition of bone suppression or the suppression of calcium release from the bone [ 42 ].…”