ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد ایتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pathogenesis and etiology of primary hyperparathyroidism

Pathogenesis and etiology of primary hyperparathyroidism
Authors:
Ghada El-Hajj Fuleihan, MD, MPH
Andrew Arnold, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: Apr 25, 2022.

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]. (See "Regulation of calcium and phosphate balance".)

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, the most common clinical presentation of primary hyperparathyroidism now is asymptomatic hypercalcemia detected by routine biochemical screening (figure 2). (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 [19]. 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 [20]. In the United States, the estimated incidence of primary hyperparathyroidism between 1998 and 2010 was approximately 50 per 100,000 person-years [20,21].

Primary hyperparathyroidism can occur at any age, but the great majority of cases occur in patients over the age of 50 to 65 years [20-22]. 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 [21].

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 [23-26]. 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) [26]. 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 [27]. 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 [27] or from an atomic bomb [28]. 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 [27].

One study compared the clinical presentation and course of hyperparathyroidism in exposed (49 patients) and nonexposed (389 patients) patients [29]. 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 [30]. (See "Radiation-induced thyroid disease".)

Prior radiation exposure does not appear to increase the risk of having multigland parathyroid disease [29,31,32], nor does it preclude a minimally invasive surgical approach, particularly for hyperparathyroid patients with evidence of single gland disease and no concomitant thyroid nodules [33]. (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 [34]. However, the incidence of primary hyperparathyroidism was not increased in a prospective study of 125 patients treated with RAI for thyrotoxicosis [35]. (See "Radioiodine in the treatment of hyperthyroidism" and "Differentiated thyroid cancer: Radioiodine treatment".)

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 [36]. 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.

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 [37-40].

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) [41-43]. 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 [42-45].

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 [46]. 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 [47].

MEN1 gene — MEN1 is a classic tumor suppressor gene that contributes to cell-selective advantage through biallelic inactivation [48]. 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: Definition and 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 [49]. In two other studies, the corresponding proportions were 12 to 13 percent [50,51]. 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 [52,53]. 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 [54], and CDKI mutations/variants are found in rare patients with MEN1-like presentations of hyperparathyroidism [54,55]. 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 [56]. 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 [37,57]. CDC73 mutations are not generally a feature of typically presenting sporadic parathyroid adenomas [58] 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 [59,60]. (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 [61], vitamin D deficiency may alter the phenotypic expression of parathyroid tumors [62].

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 [63-68]; EZH2, a histone methyltransferase implicated in malignant lymphomas [69]; ZFX, encoding a DNA-binding zinc finger protein [70]; and POT1 [71].

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 [72,73].

PATHOLOGIC CONDITIONS IN PRIMARY HYPERPARATHYROIDISM — The following pathologic conditions have been found with hyperparathyroidism [74].

Adenoma — Single adenomas account for up to 80 to 90 percent of cases of primary hyperparathyroidism [75-77]. 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 [78]. 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 [76]. Subsequent smaller studies have reported more variability in the prevalence of multigland (two or more) disease, ranging from 10 to 20 percent [79-81]. 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 [82], 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 [76,77,83]. 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 [82]. 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.

CONDITIONS ASSOCIATED WITH PRIMARY HYPERPARATHYROIDISM

Familial hyperparathyroidism — Hereditary forms of hyperparathyroidism are rare [84], and the molecular basis of the various subtypes of hereditary hyperparathyroidism is well understood [56,84]. Familial hyperparathyroidism occurs in the following:

Multiple endocrine neoplasia (MEN) type 1 syndrome. (See "Multiple endocrine neoplasia type 1: Definition and genetics".)

Familial isolated hyperparathyroidism (FIHP, primary hyperparathyroidism not associated with any other endocrine or syndromic disorder).

Familial hyperparathyroidism-jaw tumor (HPT-JT) syndrome [84], previously termed familial cystic parathyroid adenomatosis [85].

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 [84], 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 [86]; 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 [56,84,87,88]. 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 [88]. 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 [89].

Management of patients with familial hyperparathyroidism differs from that in sporadic hyperparathyroidism because of the variability in the presentations, including [56,84]:

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 [90].

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 [56]. 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".)

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) [91].

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) [92]. 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 [93]. (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 [94-96]. 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 [97].

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 [94,98,99] (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) [99].

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 [94,100]. Lithium decreases parathyroid gland sensitivity to calcium, shifting the set-point of the calcium-PTH curve to the right [101-103].

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 [102]. Lithium is thought to exert an action downstream of the CaSR itself [104,105], although the precise mechanism by which it interferes with CaSR signaling is unknown [101,102]. (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 [99,106-108]. 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 [106].

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) [94]. It is less likely in patients receiving lithium for more than 10 years [106]. In some patients, the serum calcium concentration may not fall for one to four months after lithium is discontinued [109]. 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 [110,111]. 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 [112].

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".)

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

Primary hyperparathyroidism is characterized by abnormal regulation of parathyroid hormone (PTH) secretion by calcium. (See 'Parathyroid hormone and calcium homeostasis' above.)

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.)

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.)

  1. Brown EM. Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 1991; 71:371.
  2. Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181.
  3. Gesek FA, Friedman PA. On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells. J Clin Invest 1992; 90:749.
  4. Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983; 56:572.
  5. Brossard JH, Whittom S, Lepage R, D'Amour P. Carboxyl-terminal fragments of parathyroid hormone are not secreted preferentially in primary hyperparathyroidism as they are in other hypercalcemic conditions. J Clin Endocrinol Metab 1993; 77:413.
  6. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid. Nature 1993; 366:575.
  7. Brown EM, Pollak M, Seidman CE, et al. Calcium-ion-sensing cell-surface receptors. N Engl J Med 1995; 333:234.
  8. Hosokawa Y, Pollak MR, Brown EM, Arnold A. Mutational analysis of the extracellular Ca(2+)-sensing receptor gene in human parathyroid tumors. J Clin Endocrinol Metab 1995; 80:3107.
  9. Cetani F, Pinchera A, Pardi E, et al. No evidence for mutations in the calcium-sensing receptor gene in sporadic parathyroid adenomas. J Bone Miner Res 1999; 14:878.
  10. Carling T, Szabo E, Bai M, et al. Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 2000; 85:2042.
  11. Frank-Raue K, Leidig-Bruckner G, Haag C, et al. Inactivating calcium-sensing receptor mutations in patients with primary hyperparathyroidism. Clin Endocrinol (Oxf) 2011; 75:50.
  12. Kifor O, Moore FD Jr, Wang P, et al. Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81:1598.
  13. Gogusev J, Duchambon P, Hory B, et al. Depressed expression of calcium receptor in parathyroid gland tissue of patients with hyperparathyroidism. Kidney Int 1997; 51:328.
  14. Cetani F, Picone A, Cerrai P, et al. Parathyroid expression of calcium-sensing receptor protein and in vivo parathyroid hormone-Ca(2+) set-point in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2000; 85:4789.
  15. Sengul Aycicek G, Aydogan BI, Sahin M, et al. Clinical Impact of p27Kip1 and CaSR Expression on Primary Hyperparathyroidism. Endocr Pathol 2018; 29:250.
  16. Farnebo F, Enberg U, Grimelius L, et al. Tumor-specific decreased expression of calcium sensing receptor messenger ribonucleic acid in sporadic primary hyperparathyroidism. J Clin Endocrinol Metab 1997; 82:3481.
  17. Pollak MR, Brown EM, Chou YH, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993; 75:1297.
  18. Khosla S, Ebeling PR, Firek AF, et al. Calcium infusion suggests a "set-point" abnormality of parathyroid gland function in familial benign hypercalcemia and more complex disturbances in primary hyperparathyroidism. J Clin Endocrinol Metab 1993; 76:715.
  19. Wermers RA, Khosla S, Atkinson EJ, et al. Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993-2001: an update on the changing epidemiology of the disease. J Bone Miner Res 2006; 21:171.
  20. Griebeler ML, Kearns AE, Ryu E, et al. Secular trends in the incidence of primary hyperparathyroidism over five decades (1965-2010). Bone 2015; 73:1.
  21. Yeh MW, Ituarte PH, Zhou HC, et al. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab 2013; 98:1122.
  22. Abood A, Vestergaard P. Increasing incidence of primary hyperparathyroidism in Denmark. Dan Med J 2013; 60:A4567.
  23. Beard CM, Heath H 3rd, O'Fallon WM, et al. Therapeutic radiation and hyperparathyroidism. A case-control study in Rochester, Minn. Arch Intern Med 1989; 149:1887.
  24. Tisell LE, Hansson G, Lindberg S, Ragnhult I. Hyperparathyroidism in persons treated with X-rays for tuberculous cervical adenitis. Cancer 1977; 40:846.
  25. McMullen T, Bodie G, Gill A, et al. Hyperparathyroidism after irradiation for childhood malignancy. Int J Radiat Oncol Biol Phys 2009; 73:1164.
  26. Boehm BO, Rosinger S, Belyi D, Dietrich JW. The parathyroid as a target for radiation damage. N Engl J Med 2011; 365:676.
  27. Schneider AB, Gierlowski TC, Shore-Freedman E, et al. Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995; 80:254.
  28. Fujiwara S, Sposto R, Ezaki H, et al. Hyperparathyroidism among atomic bomb survivors in Hiroshima. Radiat Res 1992; 130:372.
  29. Tezelman S, Rodriguez JM, Shen W, et al. Primary hyperparathyroidism in patients who have received radiation therapy and in patients who have not received radiation therapy. J Am Coll Surg 1995; 180:81.
  30. Wilson SD, Doffek KM, Wang TS, et al. Primary hyperparathyroidism with a history of head and neck irradiation: the consequences of associated thyroid tumors. Surgery 2011; 150:869.
  31. Woll M, Sippel RS, Chen H. Does previous head and neck irradiation increase the chance of multigland disease in patients with hyperparathyroidism? Ann Surg Oncol 2011; 18:2240.
  32. Ippolito G, Palazzo FF, Sebag F, Henry JF. Long-term follow-up after parathyroidectomy for radiation-induced hyperparathyroidism. Surgery 2007; 142:819.
  33. Rahbari R, Sansano IG, Elaraj DM, et al. Prior head and neck radiation exposure is not a contraindication to minimally invasive parathyroidectomy. J Am Coll Surg 2010; 210:942.
  34. Colaço SM, Si M, Reiff E, Clark OH. Hyperparathyroidism after radioactive iodine therapy. Am J Surg 2007; 194:323.
  35. Fjälling M, Dackenberg A, Hedman I, Tisell LE. An evaluation of the risk of developing hyperparathyroidism after 131I treatment for thyrotoxicosis. Acta Chir Scand 1983; 149:681.
  36. Paik JM, Curhan GC, Taylor EN. Calcium intake and risk of primary hyperparathyroidism in women: prospective cohort study. BMJ 2012; 345:e6390.
  37. Shattuck TM, Välimäki S, Obara T, et al. Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 2003; 349:1722.
  38. Westin G, Björklund P, Akerström G. Molecular genetics of parathyroid disease. World J Surg 2009; 33:2224.
  39. Costa-Guda J, Arnold A. Hyperparathyroidism. In: Genetics of Bone Biology and Skeletal Disease, 2nd ed, Thakker R, Whyte M, Eisman J, Igarashi T (Eds), Elsevier, Cambridge, MA 2017. p.599.
  40. Arnold A, Agarwal SK, Thakker RV. Familial States of Primary Hyperparathyroidism. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 9th ed, Bikezikian JP (Ed), Wiley-Blackwell, Hoboken, NJ 2018. p.629.
  41. Arnold A, Kim HG, Gaz RD, et al. Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma. J Clin Invest 1989; 83:2034.
  42. Hsi ED, Zukerberg LR, Yang WI, Arnold A. Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab 1996; 81:1736.
  43. Rosenberg CL, Kim HG, Shows TB, et al. Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors. Oncogene 1991; 6:449.
  44. Hemmer S, Wasenius VM, Haglund C, et al. Deletion of 11q23 and cyclin D1 overexpression are frequent aberrations in parathyroid adenomas. Am J Pathol 2001; 158:1355.
  45. Vasef MA, Brynes RK, Sturm M, et al. Expression of cyclin D1 in parathyroid carcinomas, adenomas, and hyperplasias: a paraffin immunohistochemical study. Mod Pathol 1999; 12:412.
  46. Imanishi Y, Hosokawa Y, Yoshimoto K, et al. Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. J Clin Invest 2001; 107:1093.
  47. Mallya SM, Gallagher JJ, Wild YK, et al. Abnormal parathyroid cell proliferation precedes biochemical abnormalities in a mouse model of primary hyperparathyroidism. Mol Endocrinol 2005; 19:2603.
  48. Agarwal SK, Kester MB, Debelenko LV, et al. Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet 1997; 6:1169.
  49. Heppner C, Kester MB, Agarwal SK, et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet 1997; 16:375.
  50. Carling T, Correa P, Hessman O, et al. Parathyroid MEN1 gene mutations in relation to clinical characteristics of nonfamilial primary hyperparathyroidism. J Clin Endocrinol Metab 1998; 83:2960.
  51. Farnebo F, Teh BT, Kytölä S, et al. Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 1998; 83:2627.
  52. Costa-Guda J, Marinoni I, Molatore S, et al. Somatic mutation and germline sequence abnormalities in CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas. J Clin Endocrinol Metab 2011; 96:E701.
  53. Costa-Guda J, Soong CP, Parekh VI, et al. Germline and somatic mutations in cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic parathyroid adenomas. Horm Cancer 2013; 4:301.
  54. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Natl Acad Sci U S A 2006; 103:15558.
  55. Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab 2009; 94:1826.
  56. Falchetti A, Marini F, Giusti F, et al. DNA-based test: when and why to apply it to primary hyperparathyroidism clinical phenotypes. J Intern Med 2009; 266:69.
  57. Cetani F, Pardi E, Borsari S, et al. Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors. J Clin Endocrinol Metab 2004; 89:5583.
  58. Krebs LJ, Shattuck TM, Arnold A. HRPT2 mutational analysis of typical sporadic parathyroid adenomas. J Clin Endocrinol Metab 2005; 90:5015.
  59. Pausova Z, Soliman E, Amizuka N, et al. Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 1996; 81:2711.
  60. Padberg BC, Schröder S, Jochum W, et al. Absence of RET proto-oncogene point mutations in sporadic hyperplastic and neoplastic lesions of the parathyroid gland. Am J Pathol 1995; 147:1600.
  61. Samander EH, Arnold A. Mutational analysis of the vitamin D receptor does not support its candidacy as a tumor suppressor gene in parathyroid adenomas. J Clin Endocrinol Metab 2006; 91:5019.
  62. Rao DS, Honasoge M, Divine GW, et al. Effect of vitamin D nutrition on parathyroid adenoma weight: pathogenetic and clinical implications. J Clin Endocrinol Metab 2000; 85:1054.
  63. Björklund P, Lindberg D, Akerström G, Westin G. Stabilizing mutation of CTNNB1/beta-catenin and protein accumulation analyzed in a large series of parathyroid tumors of Swedish patients. Mol Cancer 2008; 7:53.
  64. Costa-Guda J, Arnold A. Absence of stabilizing mutations of beta-catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas. J Clin Endocrinol Metab 2007; 92:1564.
  65. Cetani F, Pardi E, Banti C, et al. Beta-catenin activation is not involved in sporadic parathyroid carcinomas and adenomas. Endocr Relat Cancer 2010; 17:1.
  66. Haglund F, Andreasson A, Nilsson IL, et al. Lack of S37A CTNNB1/β-catenin mutations in a Swedish cohort of 98 parathyroid adenomas. Clin Endocrinol (Oxf) 2010; 73:552.
  67. Guarnieri V, Baorda F, Battista C, et al. A rare S33C mutation of CTNNB1 encoding β-catenin in a parathyroid adenoma found in an Italian primary hyperparathyroid cohort. Endocrine 2012; 41:152.
  68. Starker LF, Fonseca AL, Akerström G, et al. Evidence of a stabilizing mutation of β-catenin encoded by CTNNB1 exon 3 in a large series of sporadic parathyroid adenomas. Endocrine 2012; 42:612.
  69. Cromer MK, Starker LF, Choi M, et al. Identification of somatic mutations in parathyroid tumors using whole-exome sequencing. J Clin Endocrinol Metab 2012; 97:E1774.
  70. Soong CP, Arnold A. Recurrent ZFX mutations in human sporadic parathyroid adenomas. Oncoscience 2014; 1:360.
  71. Newey PJ, Nesbit MA, Rimmer AJ, et al. Whole-exome sequencing studies of nonhereditary (sporadic) parathyroid adenomas. J Clin Endocrinol Metab 2012; 97:E1995.
  72. Nussbaum SR, Gaz RD, Arnold A. Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. N Engl J Med 1990; 323:1324.
  73. VanHouten JN, Yu N, Rimm D, et al. Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene. J Clin Endocrinol Metab 2006; 91:580.
  74. Salti GI, Fedorak I, Yashiro T, et al. Continuing evolution in the operative management of primary hyperparathyroidism. Arch Surg 1992; 127:831.
  75. Bartsch D, Nies C, Hasse C, et al. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. Br J Surg 1995; 82:926.
  76. Ruda JM, Hollenbeak CS, Stack BC Jr. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg 2005; 132:359.
  77. Udelsman R. Six hundred fifty-six consecutive explorations for primary hyperparathyroidism. Ann Surg 2002; 235:665.
  78. Maret A, Bourdeau I, Ding C, et al. Expression of GCMB by intrathymic parathyroid hormone-secreting adenomas indicates their parathyroid cell origin. J Clin Endocrinol Metab 2004; 89:8.
  79. Kebebew E, Hwang J, Reiff E, et al. Predictors of single-gland vs multigland parathyroid disease in primary hyperparathyroidism: a simple and accurate scoring model. Arch Surg 2006; 141:777.
  80. Barczyński M, Bränström R, Dionigi G, Mihai R. Sporadic multiple parathyroid gland disease--a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg 2015; 400:887.
  81. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg 2016; 151:959.
  82. Erickson LA, Mete O, Juhlin CC, et al. Overview of the 2022 WHO Classification of Parathyroid Tumors. Endocr Pathol 2022; 33:64.
  83. Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA. Parathyroid carcinoma: clinical and pathologic features in 43 patients. Medicine (Baltimore) 1992; 71:197.
  84. Marx SJ, Simonds WF, Agarwal SK, et al. Hyperparathyroidism in hereditary syndromes: special expressions and special managements. J Bone Miner Res 2002; 17 Suppl 2:N37.
  85. Mallette LE, Malini S, Rappaport MP, Kirkland JL. Familial cystic parathyroid adenomatosis. Ann Intern Med 1987; 107:54.
  86. Seabrook AJ, Harris JE, Velosa SB, et al. Multiple Endocrine Tumors Associated with Germline MAX Mutations: Multiple Endocrine Neoplasia Type 5? J Clin Endocrinol Metab 2021; 106:1163.
  87. Simonds WF, Robbins CM, Agarwal SK, et al. Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome. J Clin Endocrinol Metab 2004; 89:96.
  88. Simonds WF, James-Newton LA, Agarwal SK, et al. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002; 81:1.
  89. Starker LF, Akerström T, Long WD, et al. Frequent germ-line mutations of the MEN1, CASR, and HRPT2/CDC73 genes in young patients with clinically non-familial primary hyperparathyroidism. Horm Cancer 2012; 3:44.
  90. Huang SM, Duh QY, Shaver J, et al. Familial hyperparathyroidism without multiple endocrine neoplasia. World J Surg 1997; 21:22.
  91. Christensson T, Hellström K, Wengle B. Hypercalcemia and primary hyperparathyroidism. Prevalence in patients receiving thiazides as detected in a health screen. Arch Intern Med 1977; 137:1138.
  92. Griebeler ML, Kearns AE, Ryu E, et al. Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades. J Clin Endocrinol Metab 2016; 101:1166.
  93. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab 2014; 99:3561.
  94. Mallette LE, Eichhorn E. Effects of lithium carbonate on human calcium metabolism. Arch Intern Med 1986; 146:770.
  95. Mak TW, Shek CC, Chow CC, et al. Effects of lithium therapy on bone mineral metabolism: a two-year prospective longitudinal study. J Clin Endocrinol Metab 1998; 83:3857.
  96. McKnight RF, Adida M, Budge K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012; 379:721.
  97. Mallette LE, Khouri K, Zengotita H, et al. Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume. J Clin Endocrinol Metab 1989; 68:654.
  98. Lehmann SW, Lee J. Lithium-associated hypercalcemia and hyperparathyroidism in the elderly: what do we know? J Affect Disord 2013; 146:151.
  99. Meehan AD, Udumyan R, Kardell M, et al. Lithium-Associated Hypercalcemia: Pathophysiology, Prevalence, Management. World J Surg 2018; 42:415.
  100. El-Hajj Fuleihan G, Brown EM, Heath H III. The Familial Benign Hypocalciuric Hypercalcemic Syndromes. In: Principles of Bone Biology, Bilezikian JP, Raisz LG, Rodan GA (Eds), Academic Press, San Diego 1996.
  101. Brown EM. Lithium induces abnormal calcium-regulated PTH release in dispersed bovine parathyroid cells. J Clin Endocrinol Metab 1981; 52:1046.
  102. Haden ST, Stoll AL, McCormick S, et al. Alterations in parathyroid dynamics in lithium-treated subjects. J Clin Endocrinol Metab 1997; 82:2844.
  103. McHenry CR, Lee K. Lithium therapy and disorders of the parathyroid glands. Endocr Pract 1996; 2:103.
  104. Racke F, McHenry CR, Wentworth D. Lithium-induced alterations in parathyroid cell function: insight into the pathogenesis of lithium-associated hyperparathyroidism. Am J Surg 1994; 168:462.
  105. McHenry CR, Stenger DB, Racke F. Investigation of calcium-induced hydrolysis of phosphoinositides in normal and lithium-treated parathyroid cells. Am J Surg 1995; 170:484.
  106. Nordenström J, Strigård K, Perbeck L, et al. Hyperparathyroidism associated with treatment of manic-depressive disorders by lithium. Eur J Surg 1992; 158:207.
  107. Järhult J, Ander S, Asking B, et al. Long-term results of surgery for lithium-associated hyperparathyroidism. Br J Surg 2010; 97:1680.
  108. Awad SS, Miskulin J, Thompson N. Parathyroid adenomas versus four-gland hyperplasia as the cause of primary hyperparathyroidism in patients with prolonged lithium therapy. World J Surg 2003; 27:486.
  109. Bendz H, Sjödin I, Toss G, Berglund K. Hyperparathyroidism and long-term lithium therapy--a cross-sectional study and the effect of lithium withdrawal. J Intern Med 1996; 240:357.
  110. Plenge P, Rafaelsen OJ. Lithium effects on calcium, magnesium and phosphate in man: effects on balance, bone mineral content, faecal and urinary excretion. Acta Psychiatr Scand 1982; 66:361.
  111. Christiansen C, Baastrup PC, Transbøl I. Development of 'primary' hyperparathyroidism during lithium therapy: longitudinal study. Neuropsychobiology 1980; 6:280.
  112. Nordenström J, Elvius M, Bågedahl-Strindlund M, et al. Biochemical hyperparathyroidism and bone mineral status in patients treated long-term with lithium. Metabolism 1994; 43:1563.
Topic 2038 Version 22.0

References