We searched Medline and PubMed for papers that were published in English from Jan 1, 1970, to June 1, 2013. We used the following search terms: “hyperparathyroidism”, “asymptomatic hyperparathyroidism”, “hyperparathyroidism and fractures”, “hyperparathyroidism and cardiovascular disease”, “subclinical hyperparathyroidism”, “normocalcaemic hyperparathyroidism”, “subclinical hypoparathyroidism”, and “normocalcaemic hypoparathyroidism”. We also searched the reference lists of articles identified
ReviewSubclinical and asymptomatic parathyroid disease: implications of emerging data
Introduction
Parathyroid hormone works with 1,25-dihydroxyvitamin D to regulate calcium homoeostasis, ensuring plasma ionised calcium concentrations are maintained within a narrow range (1·1–1·3 mmol/L, or 2·2–2·6 mmol/L after adjustment for serum albumin) for optimum functioning of many physiological processes, including neural transmission, muscle contractility, and bone metabolism.1 The calcium-sensing receptor (CaSR) on the surface of parathyroid chief cells acts as a calciostat and mediates an increase in parathyroid hormone synthesis and secretion in response to falling ionised calcium concentrations, with parathyroid hormone maintaining calcium concentrations through several mechanisms (figure).2 Calcitonin, produced by the parafollicular C cells in the thyroid, is thought to have only a minor role in calcium homoeostasis, and lowers calcium through the inhibition of osteoclasts.1
Table 1 summarises disorders of parathyroid hormone secretion and signalling. Primary hyperparathyroidism is usually characterised by hypercalcaemia with a raised parathyroid hormone concentration, although parathyroid hormone concentrations might still lie within the upper half of the normal reference range (ie, inappropriately normal), and a normocalcaemic variant also exists.3, 4 A single parathyroid adenoma is the most common cause (∼85% of cases), and although the causal mechanism is unknown, investigators have noted several low-frequency somatic mutations in tumour tissue.5 Multiple adenomas, parathyroid gland hyperplasia, and (very rarely) parathyroid carcinoma might also cause primary hyperparathyroidism. A similar pattern can also be seen in patients given a thiazide diuretic or lithium, or in tertiary hyperparathyroidism when autonomous parathyroid hormone secretion develops after longstanding secondary hyperparathyroidism (a physiological increase in parathyroid hormone due to several possible causes; panel 1). Several familial and syndromic forms of primary hyperparathyroidism also exist and are reviewed in detail elsewhere.6
The role of the CaSR is shown in familial hypercalcaemic hypocalciuria, the main differential diagnosis for primary hyperparathyroidism, in which a heterozygous inactivating mutation of CASR leads to a changed setpoint for parathyroid hormone secretion. This change leads to mild hypercalcaemia (∼2·75 mmol/L) with inappropriately normal or mildly raised parathyroid hormone concentrations, and relative hypocalciuria (urinary calcium to creatinine ratio <0·01).7 By contrast, activating mutations in CASR lead to a decreased setpoint and autosomal-dominant hypocalcaemic hypercalciuria.8
Urinary calcium excretion can be difficult to interpret in patients receiving concomitant calcium and vitamin D analogue treatment. Generally, however, patients with autosomal-dominant hypocalcaemic hypercalciuria have a higher urinary calcium excretion than do those with hypoparathyroidism, despite the loss of the calcium-conserving effects of parathyroid hormone at the renal tubule in the latter condition. The higher fractional excretion of calcium in hypoparathyroidism, compared with individuals without parathyroid disease, increases susceptibility to hypercalciuria, especially while they are receiving calcium and vitamin D replacement, although urinary calcium excretion might still be inappropriately normal or low.9 In pseudohypoparathyroidism, urinary calcium excretion usually remains low because the effects of the raised parathyroid hormone concentrations on the distal tubule are conserved, despite resistance to parathyroid hormone in the proximal tubule.9
After the introduction of automated multichannel analysers to clinical biochemistry departments in the 1970s and, more recently, the ubiquity of vitamin D testing,10 more individuals are being diagnosed with disorders of calcium metabolism at a seemingly asymptomatic stage.11 These cases are likely to include individuals with CASR mutations, mild asymptomatic hypoparathyroidism, and previously unidentified vitamin D deficiency. Mild or asymptomatic disease is perhaps most apparent in primary hyperparathyroidism, in which the severity and pattern of complications has changed in the past 30–40 years.3, 11 In this Review, we discuss the increasingly recognised and increasing range of asymptomatic parathyroid disorders. We will focus on asymptomatic primary hyperparathyroidism, discuss its natural history with respect to potential complications, and debate whether this disorder is truly asymptomatic. We will also briefly discuss the newer entities of normocalcaemic, or subclinical, primary hyperparathyroidism and hypoparathyroidism.
Section snippets
Symptomatic versus asymptomatic primary hyperparathyroidism
Results of observational studies suggest that primary hyperparathyroidism is common. Studies from Scotland, UK,12 and Scandinavia13, 14 suggest a prevalence of about 1% in the general population, with the greatest prevalence in postmenopausal women (about 3%). These data suggest the prevalence is substantially higher than suggested by earlier studies,15, 16 and although this effect might initially have represented a catch-up effect from previously undiagnosed patients, most recent data suggest
Biochemical progression
Severe hypercalcaemia can be life-threatening. However, according to the most recent criteria, individuals with asymptomatic primary hyperparathyroidism have only mildly raised calcium—less than 0·25 mmol/L higher than the upper limit of the normal reference range (ie, about 2·85 mmol/L).24 Although studies of asymptomatic primary hyperparathyroidism have been limited by their observational nature, the risk of patients developing progressive hypercalcaemia seems to be small.12, 19
The
Prediction of adverse outcomes in primary hyperparathyroidism
Fulfilment of NIH surgical criteria at baseline did not predict clinical or biochemical progression in the Columbia University study,19 and although current guidelines do attempt to stratify patients on the basis of potential long-term risks, increasing accuracy of predictions or calculations of an individual's risk of complications would be desirable to inform clinicians of which patients would benefit most from parathyroidectomy.
Some epidemiological studies have shown an association between
Normocalcaemic primary hyperparathyroidism
Normocalcaemic primary hyperparathyroidism is defined as persistently raised parathyroid hormone concentrations with normal serum calcium concentrations, after the exclusion of causes of secondary hyperparathyroidism (panel 1).5 Until recently, studies of normocalcaemic primary hyperparathyroidism have been limited by their ability to exclude other causes of hyperparathyroidism and by potential bias from the inclusion of patients referred to specialist referral centres. Hence, although the
Subclinical hypoparathyroidism
Hypoparathyroidism (table 1) is much rarer than primary hyperparathyroidism, and most commonly results from removal or damage to the parathyroid glands or their blood supply during thyroid surgery, or from autoimmune destruction, often as part of a polyglandular autoimmune syndrome. Rarer causes include infiltration (eg, sarcoid) or congenital causes, either as part of a rare developmental syndrome such as DiGeorge's syndrome or from mutations in the gene that encodes parathyroid hormone.9, 88
Conclusion
In the past few decades, the phenotype of primary hyperparathyroidism has evolved into a disorder that is often thought of as a mild or asymptomatic disease compared with the traditional description. The prevalence of primary hyperparathyroidism has increased, especially in postmenopausal women, for reasons that are not clear. However, it is unlikely that this disorder is truly asymptomatic, as evidence suggests that subtle neuropsychological deficits and physical symptoms are attributable to
Search strategy and selection criteria
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Cited by (26)
Parathyroid Imaging
2020, Radiologic Clinics of North AmericaCitation Excerpt :The prevalence of PHPT is 1 to 7 cases per 1000 individuals, with higher incidence among female and Black individuals, and the older population.2 The highest prevalence of PHPT is among postmenopausal women and is estimated to be as high as 3%.3 Sporadic PHPT is associated with exposure to ionizing radiation in childhood and with chronic lithium use.4
Parathyroid hormone induces adipocyte lipolysis via PKA-mediated phosphorylation of hormone-sensitive lipase
2016, Cellular SignallingCitation Excerpt :The association between insulin resistance and high levels of PTH is further supported by intervention studies with parathyroidectomy, which resulted in improved insulin sensitivity and normalized blood glucose levels [6–8]. High levels of PTH are not only associated with hallmarks of diabetes, but also with cardiovascular disease, as shown in several observational studies [9–11]. Primary hyperparathyroidism is a common endocrine disorder, especially among postmenopausal women.
Primary hyperparathyroidism and vitamin D deficiency
2015, Annales d'EndocrinologieCitation Excerpt :Questions have been raised about the factors contributing to the severity and diversity of expression of the disease. Some significant factors include subject age, postmenopausal status, weight of parathyroid adenomas, the severity and time since diagnosis of parathyroid hormone overproduction, and the degree of tissue receptivity [3–6]. It has also emerged that the vitamin D (VD) load has a strong influence on the extent of intestinal calcium absorption, parathyroid hormone (PTH) levels, the effects on bones and the metabolic risk.
Brown tumor due to primary hyperparathyroidism in a familial case: a case report
2023, BMC Endocrine DisordersMorbidity Associated With Primary Hyperparathyroidism—A Population-based Study With a Subanalysis on Vitamin D
2023, Journal of Clinical Endocrinology and Metabolism