Version May 2024
INTRODUCTION — Parathyroid hormone (PTH) is one of the three major calciotropic hormones modulating calcium and phosphate homeostasis, the other two being calcitriol (1,25-dihydroxyvitamin D) and fibroblast growth factor 23 (FGF23). The minute-to-minute regulation of serum ionized calcium is exclusively regulated through PTH, maintaining the concentration of this cation within a narrow range, through stimulation of renal tubular calcium reabsorption and bone resorption. PTH secretion is, in turn, regulated by serum ionized calcium acting via an exquisitely sensitive calcium-sensing receptor (CaSR) on the surface of parathyroid cells.
Primary hyperparathyroidism is characterized by abnormal regulation of PTH secretion by calcium, resulting in hypersecretion of PTH relative to the serum calcium concentration. Experimental findings have advanced our understanding of the pathophysiology and causes of primary hyperparathyroidism. This topic will review these observations, beginning with a brief review of the basic aspects of PTH and calcium homeostasis.
Other aspects of primary hyperparathyroidism are reviewed elsewhere.
●(See "Primary hyperparathyroidism: Clinical manifestations".)
●(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
●(See "Primary hyperparathyroidism: Management".)
●(See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)
●(See "Parathyroid exploration for primary hyperparathyroidism".)
PARATHYROID HORMONE AND CALCIUM HOMEOSTASIS — Serum ionized calcium concentrations are normally maintained within the very narrow range that is required for the optimal activity of the many extracellular and intracellular processes regulated by calcium. The minute-to-minute regulation of the ionized calcium concentration is achieved through a tightly regulated calcium-parathyroid hormone (PTH) homeostatic system [1]. PTH is secreted almost instantaneously in response to very small reductions in serum ionized calcium, which are sensed by the calcium-sensing receptor (CaSR). The increase in PTH release raises the serum calcium concentration toward normal via three actions (see "Parathyroid hormone secretion and action"):
●Increased bone resorption, which occurs within minutes after PTH secretion increases.
●Increased intestinal calcium absorption mediated by increased production of calcitriol, the most active form of vitamin D, which occurs days after PTH secretion increases.
●Decreased urinary calcium excretion due to stimulation of calcium reabsorption in the distal tubule, which occurs within minutes after PTH secretion increases [2,3].
These changes result in normalization of serum ionized calcium concentrations, which then closes the system's feedback loop.
Relationship between serum PTH and ionized calcium concentrations — There is a steep, inverse, sigmoidal relationship between the serum ionized calcium and parathyroid hormone (PTH) concentrations (figure 1). The response curve is defined by the following characteristics [4]:
●The set-point, which is the calcium concentration at which there is half-maximal inhibition of PTH secretion
●The slope of the curve at the set-point
●The maximal response of PTH to hypocalcemia
●The maximal suppression of PTH by hypercalcemia
An increase in the first three or a decrease in the last can result in hypersecretion of PTH.
Primary hyperparathyroidism is characterized by abnormal regulation of PTH secretion by calcium. PTH secretion in this condition is not completely autonomous and can usually be partially inhibited by a further rise in serum calcium. If this did not occur, then patients with this disorder would have higher serum calcium concentrations than are usually found.
The increase in PTH secretion in primary hyperparathyroidism is, in part, due to an elevation in set-point. The increase in the set-point, ranging between 15 to 30 percent above that of a normal parathyroid gland, is the major determinant of the severity of the hypercalcemia [4]. There is, in addition, a variable change in the slope of the calcium-PTH curve due to relative non-suppressibility of PTH secretion [5]. The degrees of hypersecretion and non-suppressibility are a function of tumor mass and can range from none in patients with very small adenomas to considerable in patients with large ones. Both a functional change at the cellular level (a reduced number of calcium receptors on the parathyroid cell) and increased numbers of cells probably contribute to these changes in PTH secretion.
The calcium-sensing receptor — The receptor responsible for calcium sensing by the parathyroid gland has been cloned; it is a seven transmembrane-domain, guanosine triphosphate (GTP)-binding protein [6,7]. While germline inactivating mutations in this gene are commonly present in patients with familial hypocalciuric hypercalcemia (FHH), they do not appear to occur as acquired somatic mutations in sporadic parathyroid tumors [8,9]. There may be a small subset of patients with primary hyperparathyroidism and hypercalciuria, responsive to parathyroid surgery, which is due to inactivating germline mutation of the calcium-sensing receptor gene (CASR), thus expanding the phenotypic spectrum associated with CASR mutations [10,11].
Although there seem to be no somatic mutations of the gene, expression of the calcium-sensing protein is reduced in parathyroid adenomas and also in uremic hyperparathyroidism [12-15] (see "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)"). In both instances, the reduction in expression of the CaSR on the surface of parathyroid cells may contribute to the increase in PTH secretion. However, PTH secretion from large adenomas may be more related to the increased cell mass since in one series, for example, there was little correlation between serum calcium concentrations and receptor expression [16]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
Inactivating heritable mutations in the CASR gene cause FHH and are also found in a small percentage of patients with familial isolated hyperparathyroidism (FIHP) (see 'Familial hyperparathyroidism' below). These mutations render the receptor (expressed in the parathyroid glands, kidneys, and other tissues) relatively insensitive to calcium [17], causing a rightward shift in the calcium-PTH curve [18] and increasing renal tubular reabsorption of calcium. It is important to distinguish this familial calcium-sensing disorder from typical primary hyperparathyroidism because parathyroid surgery is usually of no benefit in the former. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia" and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
INCIDENCE — Many years ago, clinical presentation of hyperparathyroidism was one of symptomatic renal or skeletal disease with moderate or severe hypercalcemia. However, in regions where biochemical screening is routinely performed, asymptomatic hypercalcemia is now the most common clinical presentation of primary hyperparathyroidism [19]. (See "Primary hyperparathyroidism: Clinical manifestations".)
The routine measurement of serum calcium with the widespread use of multichannel biochemical screening initially led to a marked rise in the incidence of primary hyperparathyroidism. In the local population served by the Mayo Clinic, as an example, the annual incidence rose from 16 per 100,000 person-years before 1974 (prescreening) to a peak of 112 per 100,000 person-years several years later and then declined with elimination of calcium from the automated chemistry panel [20]. There was a second peak in the incidence of primary hyperparathyroidism between 1998 and 2007 (86 per 100,000 person-years), attributed to the rise in bone density measurements and screening for osteoporosis [21]. In the United States, the estimated incidence of primary hyperparathyroidism between 1998 and 2010 was approximately 50 per 100,000 person-years [21,22].
Primary hyperparathyroidism can occur at any age, but the great majority of cases occur in patients over the age of 50 to 65 years [21-23]. Women are affected twice as often as men, probably because the increase in bone resorption that follows menopause unmasks parathyroid gland hyperactivity. In one study, the incidence of hyperparathyroidism was highest among Black individuals, followed by White, Asian, Hispanic, and other persons [22].
ETIOLOGY — A cause for primary hyperparathyroidism, such as irradiation or the rare genetic abnormalities in the multiple endocrine neoplasia (MEN) syndromes, can be identified in only a small number of patients.
Radiation exposure — A history of irradiation to the head and neck, on average 20 to 40 years before the development of hyperparathyroidism, can be obtained in some patients [24-27]. As an example, in a cohort of cleanup workers who worked at the Chernobyl nuclear power plant in 1986, primary hyperparathyroidism subsequently developed in 15 of 61 workers (odds ratio compared with prevalence in nonexposed population 63.4, 95% CI 35.7-112.5) [27]. The mean whole-body radiation exposure ranged from 0.3 to 8.7 Gy.
Hyperparathyroidism has also been reported in patients receiving radiation for benign conditions. The usual radiation dose given for benign conditions several decades ago was low; the mean dose in one study was 0.58 Gy [28]. Nevertheless, in this study of 2555 patients followed for up to 50 years, even doses as low as 0.5 Gy before age 16 years were associated with a small risk of primary hyperparathyroidism. The excess relative risk (RR) is dose dependent, being approximately 5 to 10 at 1 Gy, whether the radiation came from external X-radiation [28] or from an atomic bomb [29]. However, the probability of primary hyperparathyroidism at this degree of exposure is still quite low, being less than 1 percent at 35 years and approaching 5 percent after 50 years of follow-up [28].
One study compared the clinical presentation and course of hyperparathyroidism in exposed (49 patients) and nonexposed (389 patients) patients [30]. There were no clinically important differences with respect to presentation, pathology, or recurrences during six years of follow-up. However, the exposed patients had more concurrent thyroid tumors, which can make management more difficult [31]. (See "Radiation-induced thyroid disease".)
Prior radiation exposure does not appear to increase the risk of having multigland parathyroid disease [30,32,33], nor does it preclude a minimally invasive surgical approach, particularly for hyperparathyroid patients with evidence of single gland disease and no concomitant thyroid nodules [34]. (See "Parathyroid exploration for primary hyperparathyroidism".)
Radioactive iodine therapy — There are also case reports and case series that suggest an association between radioactive iodine (RAI) therapy (for the treatment of benign or malignant thyroid disease) and the subsequent development of primary hyperparathyroidism [35]. However, the incidence of primary hyperparathyroidism was not increased in a prospective study of 125 patients treated with RAI for thyrotoxicosis [36]. (See "Radioiodine in the treatment of hyperthyroidism" and "Differentiated thyroid cancer: Radioiodine treatment".)
Environmental chemicals — Environmental chemicals such as polychlorinated biphenyls (PCBs) are known endocrine disrupters and have been found in the parathyroid tissue of individuals with primary and secondary hyperparathyroidism [37]. A causal role for these chemicals in the development of hyperparathyroidism has not been established. The systemic effects of endocrine-disrupting chemicals are reviewed separately. (See "Endocrine-disrupting chemicals".)
Calcium intake — Because parathyroid hormone (PTH) is secreted almost instantaneously in response to very small reductions in serum ionized calcium, it has been hypothesized that chronically low calcium intake may increase the risk of developing primary hyperparathyroidism by causing chronic stimulation of the parathyroid gland. In one prospective cohort study, which followed over 58,000 female nurses for 22 years, primary hyperparathyroidism was diagnosed in 277 women [38]. The risk of developing primary hyperparathyroidism was inversely related to calcium intake (RR 0.56, 95% CI 0.37-0.86 for women in the group with the highest compared with lowest calcium intake). The decreased risk was significant after adjusting for age, vitamin D intake, body mass index (BMI), and race. Median total calcium intake (diet plus supplement) in the lowest to highest quintiles ranged from 522 to 1794 mg daily. Limitations of the study include potential inaccuracies in reporting calcium intake and in eliciting the diagnosis of primary hyperparathyroidism. Additional studies are warranted.
Genetic or chromosomal defects — The cells in the abnormal parathyroid tissue comprising solitary adenomas or carcinomas are usually monoclonal. A genetic cause of primary hyperparathyroidism can be identified in approximately 10 percent of patients with primary hyperparathyroidism [19].
Abnormalities in key growth-controlling genes (ie, proto-oncogenes or tumor suppressor genes) underlie the development of these parathyroid tumors. The abnormalities include gain-of-function mutations in genes such as cyclin D1/PRAD1 for sporadic tumors and RET for familial tumors or loss-of-function mutations in genes such as MEN1 or CDC73 (previous name HRPT2) for sporadic and familial tumors [39-42].
Cyclin D1/PRAD1 gene — Pericentric inversion on chromosome 11 results in a relocation of the PRAD1 (parathyroid adenoma 1) proto-oncogene so that it is juxtaposed to 5'-PTH gene promoter sequences (the gene for PTH itself is on chromosome 11) [43-45]. PRAD1 (CCND1) encodes cyclin D1, a major regulator of the cell cycle. A putative tissue-specific enhancer from the 5'-PTH gene region results in overexpression of cyclin D1. Via this and other driving mechanisms, 20 to 40 percent of sporadic parathyroid adenomas overexpress cyclin D1 [44-47].
Parathyroid cell proliferation in primary hyperparathyroidism has been hypothesized to be a consequence of a primary defect in PTH secretory control by calcium. However, transgenic mice in which cyclin D1 was overexpressed in the parathyroid glands have both excessive parathyroid cell proliferation and abnormal control of PTH secretion, suggesting that the proliferative defect is not solely a downstream consequence of the abnormal PTH-calcium relationship [48]. In this model, the excessive proliferation preceded the PTH secretory changes indicating that the primary tumorigenic/proliferative defects led to secondary dysregulation of the set-point rather than vice versa [49].
MEN1 gene — MEN1 is a classic tumor suppressor gene that contributes to cell-selective advantage through biallelic inactivation [50]. The MEN1 gene was identified by positional cloning as the major source of predisposing germline mutations in familial MEN1 (see "Multiple endocrine neoplasia type 1: Genetics"). It is also an important contributor to sporadic nonfamilial parathyroid adenomas through its acquired/somatic mutation.
One report of sporadic parathyroid tumors found a somatic inactivating mutation in the MEN1 gene in 4 of 24 (16 percent) subjects with true sporadic tumors, and all of the tumors with this mutation had no expression of the wild-type allele [51]. In two other studies, the corresponding proportions were 12 to 13 percent [52,53]. The mechanism by which the MEN1 gene product, a protein termed menin, functions normally and in tumorigenesis remains an active area of investigation.
CDKN1B and other CDKI genes — CDKN1B encodes the p27 cyclin-dependent kinase inhibitor (CDKI), and both somatic and germline mutations/variants in this and other CDKI genes are present at low frequency in sporadic parathyroid adenomas [54,55]. Not only are these genes linked to the cell cycle control pathway that includes cyclin D1, an established parathyroid oncogene, but CDKN1B mutation causes hyperparathyroidism in an animal model [56], and CDKI mutations/variants are found in rare patients with MEN1-like presentations of hyperparathyroidism [56,57]. Importantly, the CDKI findings suggest that low-penetrance genetic variants, insufficiently robust to cause obvious familial clustering, can predispose to sporadic, typical presentations of solitary parathyroid adenoma.
CDC73/HRPT2 gene — Germline-inactivating CDC73 (HRPT2) mutations have been described in a type of familial hyperparathyroidism, the hyperparathyroidism-jaw tumor (HPT-JT) syndrome, that is associated with an increased risk of parathyroid cancer [58]. In addition, both somatic and germline mutations of this gene have been reported in patients with sporadic parathyroid carcinoma. The presence of germline mutations in some of these individuals suggests that they may have the HPT-JT syndrome or a phenotypic variant [39,59]. CDC73 mutations are not generally a feature of typically presenting sporadic parathyroid adenomas [60] but can, of course, be present in adenomas associated with HPT-JT syndrome. (See "Parathyroid carcinoma".)
RET gene — Tumor-specific mutations similar to those in MEN2A or 2B (ie, gain-of-function RET mutations) are rarely, if ever, found in sporadic primary hyperparathyroidism. As an example, none of the known mutations occurred in 34 sporadic adenomas in one report [61,62]. (See "Classification and genetics of multiple endocrine neoplasia type 2".)
Vitamin D receptor gene — The vitamin D receptor (VDR) gene is a natural candidate for inactivation in parathyroid adenomas because of the well-established action of 1,25-dihydroxyvitamin D to inhibit proliferation of parathyroid cells in culture. While inactivating mutations of the VDR gene do not seem to play a primary role in parathyroid gland tumorigenesis [63], vitamin D deficiency may alter the phenotypic expression of parathyroid tumors [64].
Other candidate genes — A few genes have been reported to rarely harbor somatic mutations in sporadic parathyroid adenomas; they have not yet been shown to drive hyperparathyroidism in experimental/model systems. These include: CTNNB1 (b-catenin) in the Wnt signaling pathway, which has been implicated in the development of several neoplasms including breast, prostate, colon, pancreas, stomach, adrenal, and liver [65-70]; EZH2, a histone methyltransferase implicated in malignant lymphomas [71]; ZFX, encoding a DNA-binding zinc finger protein [72]; and POT1 [73].
Ectopic PTH gene expression — Several cases of ectopic parathyroid hormone (PTH) production by nonparathyroid malignant neoplasms have been reported; tumor cell expression of the PTH gene and tumoral production of PTH was directly demonstrated in very few [74,75].
CONDITIONS ASSOCIATED WITH PRIMARY HYPERPARATHYROIDISM
Familial hyperparathyroidism — Hereditary forms of hyperparathyroidism are rare [19,76], and the molecular basis of the various subtypes of hereditary hyperparathyroidism is well understood [58,76]. Familial hyperparathyroidism occurs in the following:
●Multiple endocrine neoplasia (MEN) type 1 syndrome. (See "Multiple endocrine neoplasia type 1: Genetics".)
●Familial isolated hyperparathyroidism (FIHP, primary hyperparathyroidism not associated with any other endocrine or syndromic disorder) [19].
●Familial hyperparathyroidism-jaw tumor (HPT-JT) syndrome [76], previously termed familial cystic parathyroid adenomatosis [77].
●Multiple endocrine neoplasia type 2A (MEN2A). (See "Classification and genetics of multiple endocrine neoplasia type 2".)
Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism are also forms of familial hyperparathyroidism [76], but because of the dual defect in calcium sensing at the parathyroid gland and kidney, these syndromes are discussed separately. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
The term MEN5 has been proposed for kindreds/patients with germline MAX gene mutations and pheochromocytoma/paraganglioma plus other endocrine tumors, primarily pituitary adenoma [78]; primary hyperparathyroidism has been reported in a small subset of such cases, even fewer with surgically proven parathyroid tumors. With the available evidence, we feel it is premature to consider "MEN5" as a familial hyperparathyroid syndrome but this certainly warrants further investigation.
FIHP is rare and, in most instances, its genetic basis appears to be distinct from that in MEN type 1 or 2, FHH, or HPT-JT [58,76,79,80]. However, a minority of kindreds with apparently isolated hyperparathyroidism have predisposing mutations in either MEN1, calcium-sensing receptor (CASR), or HRPT2 (CDC73), or may have evidence of other syndromic diagnoses [80]. In the latter study, five of 36 kindreds had inactivating mutations of the CASR gene and other features similar to FHH, and three had the HPT-JT syndrome. None of the kindreds had MEN1 syndrome.
Patients presenting with apparently sporadic primary hyperparathyroidism at younger ages may be at increased risk for having a familial form of hyperparathyroidism. In a study of 86 patients (age <45 years) with clinically nonsyndromic primary hyperparathyroidism, the results of genetic testing showed germline mutations in susceptibility genes in eight (9.3 percent) subjects: four with MEN1, three with CASR, and one with HRPT2 [81].
Management of patients with familial hyperparathyroidism differs from that in sporadic hyperparathyroidism because of the variability in the presentations, including [58,76]:
●Penetrance
●Delay in onset of symptoms
●Severity of hypercalcemia
●Propensity to parathyroid cancer (HPT-JT syndrome)
●Feasibility and accuracy in assessment of carrier status
●High recurrence rate post-parathyroidectomy
In one series of 16 patients with familial primary hyperparathyroidism, almost one-half had severe hypercalcemia (>15 mg/dL [3.8 mmol/L]), one-third presented in parathyroid crisis, and 75 percent had multiple abnormal parathyroid glands [82].
DNA testing can play a role in the diagnosis or management of the familial hyperparathyroid syndromes, but the issues are complex and need to be considered on an individual basis [58]. RET mutation testing is mandatory in MEN2 for prevention of metastatic medullary thyroid carcinoma, and periodic surveillance that may include biochemical monitoring and imaging for associated tumors is advised in MEN1 and 2, as well as in HPT-JT syndrome. Subtotal parathyroidectomy, at times with autografting and cryopreservation, are recommended in MEN1 and 2. The role of CDC73/HRPT2 mutation testing, biochemical surveillance, and surgical management related to HPT-JT syndrome is discussed separately. (See "Parathyroid carcinoma".)
The role of genetic testing in the diagnostic evaluation of primary hyperparathyroidism is reviewed separately. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Role of genetic testing'.)
Thiazide therapy — Thiazide diuretics reduce urinary calcium excretion and therefore can cause possible transient mild hypercalcemia (up to 11.5 mg/dL [2.9 mmol/L]) (see "Etiology of hypercalcemia"). In addition, thiazide therapy can unmask underlying primary hyperparathyroidism. Primary hyperparathyroidism is more likely when hypercalcemia persists after drug withdrawal or when the initial serum calcium value is above 12 mg/dL (3 mmol/L) [83].
In a population-based study of residents of Olmsted County, Minnesota, the annual age- and sex-adjusted incidence of thiazide-associated hypercalcemia was 12.2 per 100,000 person-years (95% CI 10.6-13.8) [84]. Hypercalcemia was identified (mostly in women [86.4 percent]) a mean of 5.2 years after initiating thiazides, and it persisted in 71 percent of patients who discontinued the thiazide. Among all patients with thiazide-associated hypercalcemia, 24 percent were subsequently diagnosed with primary hyperparathyroidism. The mean maximum serum calcium in these patients was 10.85 mg/dL (2.71 mmol/L). Patients diagnosed with hyperparathyroidism had higher average serum calcium (10.9 versus 10.7 mg/dL [2.72 versus 2.67 mmol/L] in the overall cohort). A greater proportion of patients with than without a formal diagnosis of primary hyperparathyroidism had serum calcium >11 mg/dL (26 versus 10 percent). Severe hypercalcemia was uncommon.
Although the best management strategy in patients with thiazide-induced primary hyperparathyroidism is unclear, asymptomatic patients with unequivocal biochemical evidence of hyperparathyroidism weeks after thiazide discontinuation are best managed as patients with thiazide-unrelated, asymptomatic primary hyperparathyroidism [85,86]. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)
Lithium therapy — Lithium increases serum total and ionized calcium and intact parathyroid hormone (PTH) levels within weeks, but these remain within the normal range in most subjects [87-89]. Nevertheless, even though hypercalcemia may not be present, lithium can induce a continued defect in calcium-PTH regulation; normocalcemic patients can have a slightly raised serum PTH concentration and an increase in mean parathyroid gland volume [90].
Although estimates vary widely, approximately 10 to 20 percent of patients taking lithium develop hypercalcemia and hypocalciuria, and a smaller percentage have high serum PTH concentrations [87,91,92] (see "Etiology of hypercalcemia"). In a retrospective case-control study of Swedish individuals (313 patients with bipolar disorder treated with and 137 not treated with lithium) and 102 randomly selected controls, the prevalence of hypercalcemia was higher in patients with bipolar disease who were taking lithium (26 percent versus 1.4 percent in those not taking lithium and 2.9 percent of the control population) [92].
Lithium also increases the serum magnesium and decreases urinary calcium and magnesium concentrations, findings reminiscent of familial benign hypocalciuric hypercalcemia, a syndrome caused by inactivation mutations in the CASR [87,93]. Lithium decreases parathyroid gland sensitivity to calcium, shifting the set-point of the calcium-PTH curve to the right [94-96].
In one study of lithium-treated patients, the value for the set-point of the serum ionized calcium concentrations was 1.26 mmol/L, as compared with 1.21 mmol/L in normal subjects [95]. Lithium is thought to exert an action downstream of the CaSR itself [97,98], although the precise mechanism by which it interferes with CaSR signaling is unknown [94,95]. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
Whereas altered calcium sensing would be anticipated to result in four-gland hyperplasia in patients with lithium-induced hyperparathyroidism, equal or greater numbers of adenomas than hyperplasias have been reported [92,99-101]. The median duration of lithium therapy in patients with adenomas was two years, whereas it was 12 years in those with four-gland hyperplasia. It is possible that lithium unmasks adenomas in patients with preexisting parathyroid lesions within a few years of starting therapy or induces parathyroid hyperplasia with more chronic use [99].
If the lithium can be stopped without exacerbating the psychiatric condition, the hypercalcemia may resolve. Normalization of serum calcium is more likely to occur one to four weeks post-lithium withdrawal in patients with a relatively short duration of lithium use (less than a few years) [87]. It is less likely in patients receiving lithium for more than 10 years [99]. In some patients, the serum calcium concentration may not fall for one to four months after lithium is discontinued [102]. Other probable predictors of calcium normalization include the underlying parathyroid gland pathology and mass and the use of other drugs that may also affect calcium metabolism, such as thiazide diuretics.
The effect of mild, lithium-induced hyperparathyroidism on the skeleton is unclear. Two longitudinal studies of a total of 21 patients suggested significant bone mineral loss in the forearm after a short period (three to six months) of lithium therapy [103,104]. However, these findings were not confirmed in a cross-sectional study of bone mineral density in the spine and the hip in 25 lithium-treated and 25 control patients [105].
In view of the uncertainty of the effect of lithium on bone, we recommend periodic measurement of bone mineral density of the forearm in younger patients (<45 years) and of the spine and hip in older patients who have persistent hypercalcemia. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women".)
PATHOLOGIC CONDITIONS IN PRIMARY HYPERPARATHYROIDISM — The following pathologic conditions have been found with hyperparathyroidism [106].
Adenoma — Single adenomas account for up to 80 to 90 percent of cases of primary hyperparathyroidism [107-109]. Most adenomas consist of parathyroid chief cells. They are usually encapsulated, and 50 percent are surrounded by a rim of normal parathyroid tissue. Some adenomas, however, are composed of oxyphil cells. These adenomas are usually larger than chief cell adenomas.
Parathyroid hormone (PTH)-secreting adenomas are occasionally located in the thymus gland. These tumors express a parathyroid-specific gene, GCM2, unlike normal human thymus, which expresses neither PTH nor GCM2 [110]. This observation suggests that these tumors are derived from parathyroid cells that migrated during embryogenesis.
Multiglandular hyperplasia — In a systematic review of 215 studies including 20,225 patients, multiple-gland (three or more) hyperplasia accounted for approximately 6 percent of cases of primary hyperparathyroidism and double adenomas for approximately 4 percent [108]. Subsequent smaller studies have reported more variability in the prevalence of multigland (two or more) disease, ranging from 10 to 20 percent [111-113]. The glands are usually composed of chief cells. Clear cell hyperplasia is very rare and is the only form in which the upper glands are larger than the lower ones. In the 2022 World Health Organization (WHO) classification of parathyroid tumors [114], the term "multiglandular parathyroid disease" is preferred over "hyperplasia" to accommodate the finding of clonal proliferative expansions in multiple parathyroid glands in some cases.
Carcinoma — Parathyroid carcinomas account for no more than 1 to 2 percent of cases of primary hyperparathyroidism [108,109,115]. The diagnosis of carcinoma requires at least one of the following: local/extracapsular invasion of contiguous structures (although WHO criteria include vascular invasion even if within the gland or capsule), intraneural or lymphatic invasion, or distant metastases [114]. While not sufficient for diagnosis, characteristic histopathologic changes in parathyroid carcinoma include fibrous trabeculae, mitotic figures, and capsular invasion. (See "Parathyroid carcinoma".)
Parathyroid tumors with such features but that do not fulfill strict criteria for malignancy have been termed atypical parathyroid adenomas or atypical parathyroid tumors.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary hyperparathyroidism".)
SUMMARY
●Parathyroid hormone and calcium homeostasis – Serum ionized calcium concentrations are normally maintained within a very narrow range by a tightly regulated calcium-parathyroid hormone (PTH) homeostatic system. PTH is secreted almost instantaneously in response to very small reductions in serum ionized calcium, sensed by the calcium-sensing receptor (CaSR). Primary hyperparathyroidism is characterized by abnormal regulation of PTH secretion by calcium. (See 'Parathyroid hormone and calcium homeostasis' above.)
●Etiology – A cause for primary hyperparathyroidism, such as irradiation or the rare familial genetic abnormalities, can be identified in only a small number of patients. (See 'Etiology' above.)
Abnormalities in key growth-controlling genes (ie, proto-oncogenes or tumor suppressor genes) underlie the development of parathyroid tumors, which may occur sporadically or in familial patterns. The underlying genetic abnormalities include gain-of-function changes in genes such as cyclin D1/PRAD1 for sporadic tumors and RET for familial tumors or loss-of-function mutations in genes such as MEN1 or CDC73 for sporadic and familial tumors. (See 'Genetic or chromosomal defects' above.)
●Pathologic conditions in primary hyperparathyroidism – Single adenomas account for approximately 80 to 90 percent of cases of primary hyperparathyroidism. Multiple-gland disease with two or more abnormal glands accounts for approximately 10 to 20 percent and parathyroid carcinoma for less than 1 percent of cases of primary hyperparathyroidism. (See 'Pathologic conditions in primary hyperparathyroidism' above.)
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