Primary hyperparathyroidism: Clinical manifestations

INTRODUCTION — The most common clinical presentation of primary hyperparathyroidism (PHPT) is asymptomatic hypercalcemia detected by routine biochemical screening [1]. However, the presentation may be atypical and include a spectrum of disturbances in calcium homeostasis, ranging from symptomatic severe hypercalcemia (parathyroid crisis) to normocalcemic PHPT.

The clinical manifestations that are directly related to PHPT will be reviewed here. Symptoms and signs (gastrointestinal, neuromuscular, renal, and psychological) that are likely related to hypercalcemia are also discussed elsewhere (see "Clinical manifestations of hypercalcemia"). It should be recognized, however, that the distinction is to some extent arbitrary.

The clinical manifestations of the familial forms of PHPT and of parathyroid cancer, as well as the diagnosis and management of PHPT, are reviewed separately.

●(See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis".)

●(See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

●(See "Parathyroid carcinoma".)

●(See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

●(See "Primary hyperparathyroidism: Management".)

CLINICAL PRESENTATIONS — The most common clinical presentation of primary hyperparathyroidism (PHPT) in Western populations is asymptomatic PHPT. Symptomatic disease is more common in resource-limited countries, although the prevalence of asymptomatic disease has also increased in resource-limited countries, particularly in India [2-5]. Atypical presentations include normocalcemic PHPT and parathyroid crisis.

Asymptomatic primary hyperparathyroidism — Biochemical screening tests that include measurements of serum calcium currently account for the identification of at least 80 percent of patients with PHPT in Western countries [6,7]. These patients are usually asymptomatic and have mild and sometimes only intermittent hypercalcemia [8-11]. The Fifth International Workshop on Primary Hyperparathyroidism proposed two distinct categories of patients with asymptomatic PHPT based on initial presentation: those with and without evidence of target end-organ involvement on standard evaluation [1]. Standard evaluation detects subclinical manifestations that may be present in asymptomatic disease, including nephrolithiasis and vertebral fractures. This evaluation is reviewed in detail separately. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Additional evaluation to determine management'.)

In most asymptomatic patients, the mean serum calcium concentration is less than 1.0 mg/dL (0.25 mmol/L) above the upper limit of the normal range [12]. Serum calcium and parathyroid hormone (PTH) levels usually remain stable, although they may increase over time in a small subset (<5 percent) of individuals [13-15]. The natural history of asymptomatic PHPT with no end-organ damage at diagnosis is unclear. Eventually, approximately 30 percent of patients with true asymptomatic PHPT may develop clinical manifestations of PHPT, including skeletal manifestations, nephrocalcinosis, or kidney stones [13-16]. When carefully questioned, some patients with presumed asymptomatic PHPT have nonspecific symptoms, such as fatigue, weakness, anorexia, mild depression, and mild cognitive or neuromuscular dysfunction [17-21]. (See 'Manifestations by organ system' below and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

There are no specific physical findings of PHPT. Parathyroid adenomas are rarely palpable, and if a neck mass is palpated in a patient with PHPT, the diagnosis is more likely to be thyroid nodule or parathyroid carcinoma (see "Parathyroid carcinoma"). Band keratopathy (deposition of calcium phosphate in the exposed areas of the cornea) is rare and occurs only when serum calcium and phosphate concentrations are both high. A slit-lamp examination is usually needed to detect the keratopathy.

Symptomatic primary hyperparathyroidism — The classical symptoms and signs of PHPT are known as the "bones, stones, abdominal moans, and psychic groans." They reflect the combined effects of increased PTH secretion (table 1) and hypercalcemia (table 2). The abnormalities specifically associated with hyperparathyroidism are nephrolithiasis and bone disease; both are due to prolonged PTH excess [6,22]. Symptoms attributable to hypercalcemia include anorexia, nausea, constipation, polydipsia, and polyuria (table 2). Symptoms in PHPT are not necessarily related to serum calcium levels [23]; however, they seem to be more common in patients in whom hypercalcemia develops rapidly or when the hypercalcemia is moderate to severe. (See 'Parathyroid crisis' below.)

Bone disease and stone disease are the universally accepted classical manifestations of PHPT. Clinical parathyroid bone disease (osteitis fibrosa cystica) is rarely seen in the United States today (<5 percent of patients), and the incidence of nephrolithiasis has declined over the last few decades [6,22]. However, classical manifestations of PHPT are still prevalent in countries such as India and China [24-29]. As an example, in a study of 464 patients from the Indian PHPT registry (based on five tertiary referral centers from four different geographic areas) spanning from 2005 to 2015, 95 percent of patients with PHPT (mean age 41 years) were symptomatic [25]. The most common symptoms at presentation included bone pain (56 percent), renal calculi (31 percent), and weakness/fatigability (59 percent).

The geographical differences in the clinical manifestations of PHPT may be explained, at least in part, by the greater prevalence of vitamin D deficiency in some countries [5,7,30-32]. Vitamin D deficiency is common in patients with PHPT [33]. In countries where hypovitaminosis D is prevalent, PHPT may be characterized by overt, severe clinical bone and stone disease [30,31]. Individuals with vitamin D deficiency and hyperparathyroidism have more clinically significant disease, including larger adenomas, higher concentrations of PTH, increased bone turnover, and more frequent fractures [34-36].

Evaluation for and management of vitamin D deficiency in patients with PHPT are reviewed separately. (See "Primary hyperparathyroidism: Management", section on 'Concomitant vitamin D deficiency' and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Serum vitamin D'.)

Normocalcemic primary hyperparathyroidism — Patients undergoing evaluation for low bone mineral density (BMD) or other conditions may have PTH levels drawn in the absence of hypercalcemia. Normocalcemic PHPT is defined by persistently normal serum levels of total calcium (adjusted for albumin) and ionized calcium in the presence of elevated PTH levels. These findings must be evident on at least two consecutive measurements, at least one week apart, over a three- to six-month period, with exclusion of all secondary causes of PTH elevation (table 3) [1,37]. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Diagnosis'.)

This condition is challenging to characterize [1]. Its natural history is unclear, in part because studies have not consistently used rigorous diagnostic criteria, nor have they assessed patients for predefined outcomes over routine follow-up periods. Patients without an apparent secondary cause of PTH elevation may have an atypical or incipient form of PHPT [38,39]. Early in the natural history of PHPT, elevated PTH levels could precede the development of overt hypercalcemia. In such patients, the serum calcium concentration would be expected to rise above the upper limit of normal when followed over time. However, persistent normocalcemia [39,40], intermittent hypercalcemia [41,42], and progression to hypercalcemia [43-45] have all been described.

●In one prospective study of 37 patients with normocalcemic hyperparathyroidism, 41 percent developed evidence for progressive hyperparathyroid disease during a median of three years (range one to eight years) of observation [43]. However, less than 20 percent of patients became hypercalcemic during the observation period. Instead, some persistently normocalcemic patients developed other indications of progressive disease, such as kidney stones, hypercalciuria, bone loss, and fracture. Furthermore, four individuals with normal serum calcium levels had successful parathyroid surgery.

●In another study of 25 patients with normocalcemic hyperparathyroidism, five patients had nephrolithiasis [46].

●In a cross-sectional study of 47 patients with normocalcemic hyperparathyroidism, 41 patients with hypercalcemic hyperparathyroidism, and 39 matched controls, BMD and risk of moderate to severe vertebral fracture did not differ between those with normocalcemic hyperparathyroidism and controls; in contrast, patients with hypercalcemic hyperparathyroidism exhibited both reduced radius BMD and increased risk of moderate to severe vertebral fracture relative to the other two groups [47].

No data suggest that all these patients will ultimately become hypercalcemic or over what time period. In addition, since most of these patients were identified in the course of an evaluation for osteoporosis, fracture, or low BMD, they may not represent an early form of asymptomatic PHPT but could instead represent a unique phenotype of the disease. Identification of the normocalcemic patients who represent the true clinical precursor of hypercalcemic, asymptomatic PHPT would probably require population screening, which we do not recommend.

Parathyroid crisis — Parathyroid crisis is rare; the risk in a patient with known PHPT was estimated at 1 to 2 percent in two long-term studies of untreated patients with mild PHPT [48-50]. Parathyroid crisis is characterized by severe hypercalcemia, with the serum calcium concentration usually above 15 mg/dL (3.8 mmol/L) and marked symptoms of hypercalcemia: in particular, central nervous system dysfunction. In some cases, the syndrome occurs in patients with previously documented PHPT that is not severe. In others, it is the first evidence of parathyroid disease.

In a review of 48 cases of parathyroid crisis, the numbers of females and males were similar, the mean age was 55 years, and the mean serum calcium concentration was 17.5 mg/dL (4.4 mmol/L) [51]. Of the 38 patients for whom clinical information was available, the following characteristics were noted:

●Changes in mental status were common; 20 patients were comatose and the remaining 18 had confusion.

●Bone disease was present in 69 percent, as assessed by plain radiography or radionuclide bone scan.

●Nephrolithiasis was present in 53 percent, and 50 percent had both bone disease and nephrolithiasis.

●Serum PTH concentrations were, on average, 20 times the upper limit of normal.

●Hypercalcemia was evident in one-fourth of the patients at some time in the preceding 10 years.

Other clinical problems included severe abdominal pain, nausea, vomiting, peptic ulcer, and pancreatitis.

Another report compared 54 patients with parathyroid crisis with 460 patients treated at the same hospital for PHPT without hypercalcemic crisis [52]. There were more patients younger than 40 years old among those with parathyroid crisis (20 versus 5 percent).

The mechanism for the development of parathyroid crisis is not known but may be related to an intercurrent illness (often of a life-threatening nature), volume depletion, or infarction of a parathyroid adenoma [51].

MANIFESTATIONS BY ORGAN SYSTEM

●Classical manifestations – The classical manifestations of primary hyperparathyroidism (PHPT) are bone disease (bone pain, fractures, cysts, osteitis fibrosa cystica), nephrolithiasis/nephrocalcinosis, and proximal myopathy. PHPT plays an established, causal role in the development of these manifestations. Severe manifestations including osteitis fibrosa cystica and proximal myopathy are uncommon in the United States but still prevalent in resource-limited countries [26,53].

●Nonclassical manifestations – PHPT is also associated with cardiovascular, neuropsychiatric, and neuromuscular features, though a causal relationship has not been well established [1]. These associated features are also called nonclassical manifestations. (See 'Causally related symptoms and complications' below and 'Associated symptoms and complications' below.)

Causally related symptoms and complications — PHPT causes end-organ effects in bone and kidney and can also cause proximal myopathy. These effects may be clinically overt (ie, symptomatic) or subclinical and detected only on imaging or laboratory evaluation [1].

Skeletal — Although the classical bone disease osteitis fibrosa cystica is rare today, the skeleton remains a common target end-organ in PHPT.

●Osteitis fibrosa cystica – The classical manifestation of PHPT bone disease is osteitis fibrosa cystica, which is characterized clinically by bone pain and radiographically by subperiosteal bone resorption on the radial aspect of the middle phalanges (image 1), tapering of the distal clavicles (image 2), a "salt and pepper" appearance of the skull (image 3), bone cysts, and brown tumors of the long bones (image 4). Brown tumors result from excess osteoclast activity and consist of collections of osteoclasts intermixed with fibrous tissue and poorly mineralized woven bone. The brown coloration is due to hemosiderin deposition.

Osteitis fibrosa cystica is now very rare in the United States. It occurs more typically in patients with severe disease, especially those with parathyroid carcinoma [6]. In a review of 97 cases of mild PHPT, as an example, conventional radiography revealed signs of bone disease in only one patient [54]. On the other hand, bone disease remains a major problem in patients with secondary hyperparathyroidism due to chronic kidney disease. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

●Fractures – Most [55-62], but not all [63], studies demonstrate an increased risk of vertebral fractures in patients with PHPT. In a meta-analysis of 12 studies, there was an increased risk of vertebral (odds ratio [OR] 3.00, 95% CI 1.41-6.37), forearm (OR 2.36, 95% CI 1.64-3.38), and possibly hip (OR 1.27, 95% CI 0.97-1.66) fractures [62].

The largest report of hip fracture was a population-based study of over 1800 patients with PHPT in Uppsala, Sweden [64]. There was an increase in hip fracture in men but not in women. In a retrospective review of the 28-year experience at the Mayo Clinic, risks of vertebral, Colles, rib, and pelvic fractures were increased significantly, but the risk of hip fracture was increased only marginally [59].

The impact of PHPT on fracture incidence appears related not only to site-specific changes in areal bone density but also to the effect of the disease on other factors related to bone quality [22]. Excess parathyroid hormone (PTH) would induce cortical thinning due to endosteal bone resorption but would also increase periosteal apposition, thus increasing bone diameter. Decreased areal bone density would increase fracture risk, while increased bone diameter and preserved trabecular microarchitecture would protect against fractures [22]. Since fracture is not common in PHPT, prospective multicenter studies that capture site-specific fractures are needed.

●Bone mineral density – Patients with asymptomatic hyperparathyroidism may have decreased bone mineral density (BMD), in particular at more cortical sites (forearm and hip) as compared with more trabecular sites (spine) [1,65]. However, the reduction is usually small [66]. As an example, in one study of 24 patients followed for three years, only 12 percent had bone density at the hip and spine of more than 1.5 standard deviations (SD) lower than age- and sex-matched normal subjects, although 52 percent had a low score for the distal radius [67].

Randomized trials have demonstrated increased BMD following parathyroidectomy. Measurement of BMD is an essential part of the management of the disease, and BMD should be measured at the spine, hip, and distal one-third forearm sites. The degree of bone loss is reflective of the severity of hyperparathyroidism and is useful for making recommendations for parathyroid surgery or observation with monitoring. (See "Primary hyperparathyroidism: Management", section on 'Surgery versus nonsurgical management' and "Primary hyperparathyroidism: Management", section on 'Subclinical bone disease'.)

●Bone quality – In contrast to BMD, trabecular bone score (TBS) and high-resolution peripheral quantitative computed tomography (HRpQCT) reveal deterioration in indices of bone quality at the level of both cortical and trabecular bone, thus providing insights into the pathophysiology of fractures observed at the spine and peripheral sites [68-78]. TBS is readily available for clinical use in patients who have a spine dual-energy x-ray absorptiometry (DXA) BMD scan, provided the appropriate software is installed. HRpQCT is an investigational procedure.

●Bone histomorphometry – The classical histomorphometric profile of patients with hyperparathyroidism, the majority of whom have asymptomatic disease, shows thin cortices with preserved trabecular bone [79]. This profile is more pronounced in patients with concomitant vitamin D deficiency [80].

Kidney

Nephrolithiasis — Nephrolithiasis is the universally accepted, classical kidney manifestation of PHPT (table 4) [81]. Nephrolithiasis occurs in 5 to 55 percent of patients with PHPT [1,6,16,82,83]; this wide range likely reflects differences in the methods used for kidney imaging, as well as heterogeneity in PHPT severity. Conversely, approximately 5 percent of patients with nephrolithiasis have hyperparathyroidism [84]. Nephrocalcinosis is less common and may represent a spectrum of the same disease process, although most studies of PHPT have not reported its frequency [81]. (See "Nephrocalcinosis".)

Among normocalcemic patients with nephrolithiasis, PHPT should be suspected if the serum calcium concentration is in the high-normal range because the hypercalcemia of PHPT may be intermittent and detected only by multiple measurements [8,84,85]. In one series of 48 patients with nephrolithiasis and PHPT, 30 patients (63 percent) had serum calcium concentrations between 10.2 and 11 mg/dL (2.55 and 2.75 mmol/L) [84].

Most stones in patients with PHPT are composed of calcium oxalate [84], although a slightly alkaline urine may favor the precipitation of calcium phosphate stones. Contributing factors for calcium oxalate stone formation in PHPT include hypercalciuria, hyperoxaluria, hypocitraturia, hypomagnesuria, dietary risk factors (such as a low calcium intake, high oxalate intake, high animal protein intake, high sodium intake, low fluid intake), and a high serum calcitriol concentration [86-89]. The high serum calcitriol concentration, caused by PTH stimulation of renal hydroxylation of 25-hydroxyvitamin D (25[OH]D), may contribute to both hypercalciuria and stone formation. Genetic factors such as polymorphisms in calcium-sensing receptor (CaSR) gene have also been described [90].

Subclinical kidney disease — Important subclinical kidney manifestations of PHPT include (table 4):

●Asymptomatic nephrolithiasis

●Hypercalciuria

●Nephrocalcinosis

●Chronic kidney insufficiency

●Abnormalities in renal tubular function (in particular, decreased concentrating ability)

Up to 20 percent of patients with asymptomatic PHPT have an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m² [91-93]. The development of kidney insufficiency in PHPT is related to the degree and duration of hypercalcemia. Mild hypercalcemia is rarely associated with kidney insufficiency. In randomized trials of two to three years duration, there is little evidence that kidney function deteriorates in patients with mild chronic hypercalcemia due to PHPT. (See "Clinical manifestations of hypercalcemia", section on 'Kidney insufficiency' and "Primary hyperparathyroidism: Management", section on 'Biochemical abnormalities'.)

Subclinical nephrocalcinosis and nephrolithiasis are more common in patients with than without hyperparathyroidism [94,95]. In a retrospective review of 271 renal ultrasounds from patients with surgically proven, asymptomatic PHPT, the prevalence of kidney stones on ultrasound performed within six months prior to surgery was significantly higher than in age-matched subjects who had renal ultrasounds for other reasons (7 versus 1.6 percent) [96]. In a cross-sectional analyses of asymptomatic patients with PHPT, occult urolithiasis or kidney calcifications (nephrolithiasis and/or nephrocalcinosis) were identified in approximately 20 percent of patients [82,97,98].

Hypercalciuria is a contributing factor for stone formation in PHPT. Although PTH directly stimulates the distal tubular reabsorption of calcium [86], this effect is overshadowed by the increase in filtered calcium due to hypercalcemia, leading to increased urinary calcium excretion in 35 to 40 percent of patients with PHPT. In the cross-sectional analysis described above, occult urolithiasis was associated with higher urinary calcium excretion; however, there was no biochemical index that accurately predicted occult stones [82,97]. This is likely due to the limited precision of a 24-hour urine calcium collection and to the complexity of factors that determine stone formation. Urinary calcium concentration is only one of at least six urinary risk factors that determine the urine saturation of the calcium salts that lead to calcium stone formation.

Evaluation for subclinical kidney disease in patients with asymptomatic PHPT is reviewed separately. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Kidney imaging'.)

Neuromuscular (proximal myopathy) — In classical PHPT, a neuromuscular syndrome characterized by atrophy of type II muscle fibers was seen [99]. However, that syndrome, as well as any objective evidence of myopathy or weakness, is rarely seen today [100].

Associated symptoms and complications — Observational and cross-sectional studies show associations between PHPT and neuromuscular, cardiovascular, and neuropsychiatric abnormalities. These have been described in the different PHPT phenotypes, but a causal relationship has not been established. These associated symptoms and complications are also referred to as nonclassical manifestations of PHPT [1].

Neuropsychiatric — Neuropsychiatric symptoms have been recognized in patients with PHPT for almost seven decades and appear to be more prevalent in patients with PHPT than in the general population [101-105]. These symptoms include lethargy, depressed mood, decreased social interaction, and cognitive dysfunction [103]. The exact prevalence of such abnormalities is not well defined due to the lack of rigorous assessment for symptoms in many studies, the small size of the studies, and the wide variations in the instruments used to assess such disturbances [103].

As an example, in a case-control study comparing 39 postmenopausal women with mild PHPT with 89 postmenopausal controls without PHPT, symptom scores for depression and anxiety were higher, and performance on tests of verbal memory and nonverbal abstraction was worse in women with PHPT [104]. After parathyroidectomy, depressive symptoms, nonverbal abstraction, and some aspects of verbal memory significantly improved.

Since 2002, four randomized clinical trials have been published, assessing the effect of parathyroidectomy versus nonintervention in mild PHPT on, among other things, neuropsychiatric symptoms [106-109]. Although limited differences were shown by some, as a whole, these trials do not show a consistent and convincing clinically significant improvement in the various domains examined [1]. These trials are reviewed in detail separately. (See "Primary hyperparathyroidism: Management", section on 'Nonclassic end organ effects'.)

Cardiovascular — PHPT may be associated with cardiovascular diseases, including hypertension, arrhythmia, ventricular hypertrophy, and vascular and valvular calcification, as illustrated by the following findings in observational studies [110-112]:

●Hypertension is common in patients with PHPT, even among those with mild disease [113-115]. In a large database of over 37,000 inpatients from the National Inpatient Sample, the diagnosis of PHPT was associated with a 30 percent increase in the risk of hypertension [116]. However, no evidence supports the resolution of hypertension after parathyroidectomy [1]. The causal nature of this relationship in patients without multiple endocrine neoplasia (MEN) is therefore unlikely.

●Several [117-120], but not all [121,122], observational studies have reported an association between PHPT and left ventricular hypertrophy and diastolic dysfunction.

●Mean carotid intima-media thickness (IMT) was significantly higher in patients with mild PHPT compared with controls (0.96 versus 0.91 mm) [123]. In addition, an indirect measure of aortic stiffness [124,125] and carotid vascular stiffness [123] were associated with extent of PTH elevation, suggesting that vessel stiffness may be related to the severity of hyperparathyroidism. In adult populations, there is a moderate, graded, positive relationship between carotid IMT and the presence of coronary atherosclerosis. (See "Overview of possible risk factors for cardiovascular disease", section on 'Arterial intima-media thickness'.)

A systematic review of studies on the cardiovascular manifestations of PHPT found no consistent evidence from randomized trials that parathyroidectomy reduces cardiovascular events or risk factors [1,126,127]. The extent to which abnormalities improve postoperatively needs to be further elucidated before any causal relationships can be established. No data support routine cardiovascular evaluation in patients diagnosed with PHPT.

It is uncertain if normocalcemic PHPT is also associated with cardiometabolic changes. Preliminary data suggest an association with hypertension [128,129].

The only proven association between PHPT and cardiovascular disease is in patients with PHPT as part of multiple endocrine neoplasia type 2 (MEN2) with pheochromocytoma. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Pheochromocytoma'.)

Neuromuscular (nonspecific symptoms) — Weakness, muscle cramps, paresthesias, and fatigue are nonspecific neuromuscular symptoms commonly reported by patients with PHPT [19,130]. Some of these symptoms may be due to hypercalcemia, as they have been reported in non-PTH-mediated hypercalcemic states. Hypophosphatemia and hypovitaminosis D also may be contributory factors [105]. In some more severely affected patients, neuromuscular symptoms may improve after cure. In one report, muscle strength and fine motor movement increased four weeks after parathyroidectomy in all nine patients with PHPT but not in a control group who underwent surgery for nodular goiter [131]. However, these reports are limited by small sample sizes. Overall, data are insufficient to demonstrate a direct, causal association between PHPT and nonspecific neuromuscular symptoms [1].

OTHER LABORATORY FINDINGS — In addition to abnormalities in serum calcium and parathyroid hormone (PTH), other laboratory findings may include the following:

Hypophosphatemia — In most patients with mild primary hyperparathyroidism (PHPT), phosphate levels are not frankly low but are instead in the lower half of the normal range. In some patients with more severe disease, serum phosphate concentrations are low because PTH inhibits the proximal tubular reabsorption of phosphate, leading to increased phosphate excretion. The decrease in reabsorption is due to reduced activity of the sodium-phosphate cotransporter in the luminal membrane, so that entry of filtered phosphate into the tubular cells, and therefore its return to the systemic circulation, are decreased. (See "Hypophosphatemia: Causes of hypophosphatemia", section on 'Primary and secondary hyperparathyroidism'.)

1,25-dihydroxyvitamin D — Patients with PHPT convert more 25-hydroxyvitamin D (25[OH]D; calcidiol) to 1,25-dihydroxyvitamin D (calcitriol) than normal individuals. Serum concentrations of 1,25-dihydroxyvitamin D may therefore be at upper limits of normal or elevated [13,87].

Magnesium balance — Renal tubular reabsorption of magnesium is stimulated by PTH but inhibited by hypercalcemia. The effects of the hypercalcemia on magnesium excretion may be mediated via calcium-sensing receptors in the thick ascending loop of Henle. Overall, magnesium excretion tends to be slightly increased, and a few patients have mild hypomagnesemia. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

Acid-base balance — High concentrations of PTH inhibit proximal tubular bicarbonate reabsorption, which tends to cause a mild metabolic acidosis. However, this effect is usually counterbalanced by the alkali liberated as a result of increases in bone resorption and in tubular reabsorption of bicarbonate caused by hypercalcemia [132,133]. Thus, metabolic acidosis is unusual in PHPT unless serum PTH concentrations are very high or the patient has coexistent renal insufficiency.

Anemia — Patients with severe PHPT may have a normochromic, normocytic anemia that responds to parathyroidectomy [134]. The mechanism is unclear, but marrow fibrosis may be important [134,135]. In patients with mild disease, anemia should not be attributed to coexisting PHPT.

Monoclonal gammopathy — There may be an association between PHPT and monoclonal gammopathy, although data are conflicting. While the prevalence of monoclonal gammopathy in the general adult population is approximately 1 percent, estimates in patients with PHPT have ranged from 1 to 10 percent [136-139]. This may be an association limited to those with severe disease. As an example, the highest prevalence (10 percent) was reported in a prospective study of 100 cases with severe PHPT (median calcium of 12 mg/dL and PTH levels of 200 pg/mL), compared with 2 to 3 percent in two control groups (age- and sex-matched) [139]. Of the 10 patients with monoclonal gammopathy, two were discovered to have multiple myeloma.

There are also several single-case reports of concomitant PHPT and multiple myeloma. Whether this truly represents an increased prevalence of this comorbidity remains unknown [139].

ASSOCIATED CONDITIONS

Body weight and abnormalities in glucose metabolism — A higher than normal frequency of impaired glucose tolerance and type 2 diabetes have been reported in some, but not all, studies of primary hyperparathyroidism (PHPT) [115,124,140,141].

Patients with PHPT appear to be heavier than age-matched controls [142]. In a meta-analysis of 13 studies of PHPT, subjects with PHPT were on average 3.3 kg heavier than controls, and body mass index (BMI), in the four studies that reported it, was 1.1 kg/m² higher than controls [142]. The increased body weight may contribute to the association of PHPT with cardiovascular disease, hypertension, and glucose intolerance. In one trial, BMI did not change after parathyroidectomy (versus observation) [143].

Rheumatologic conditions — Many rheumatologic abnormalities have been described in patients with classical symptomatic PHPT, but none of these are commonly seen in modern-day disease [144]. They include the following:

●Hyperuricemia and gout.

●Pseudogout with pyrophosphate crystals into the joint [145-149]. Calcification of articular cartilage (chondrocalcinosis), most commonly affecting the wrists and knees, is more commonly reported than gout itself [148,149]. Pseudogout may also be seen soon after parathyroidectomy. The mechanism for this is unclear. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

Cancer — There are conflicting data on whether PHPT is more common in patients with cancer and/or whether it is associated with an increased risk of cancer [150-155]. Several studies suggest a small increase in risk of death from cancer [150,152,153], even after parathyroidectomy [152,153]. In contrast, cancer-related mortality was lower than expected in an unselected cohort of patients with PHPT in the community (many of whom did not undergo surgery) [151].

MORTALITY — Severe classical primary hyperparathyroidism (PHPT) is associated with increased mortality, primarily due to cardiovascular disease. However, the impact of milder PHPT on cardiovascular mortality is uncertain [37,156]. Excess mortality, mostly due to cardiovascular disease, has been reported in some [157-162], but not all [151,163,164], studies of patients with milder forms of PHPT (relative risk [RR] ranging from 1.2 to 2.0). Studies of European populations tend to report increased mortality, whereas those from the United States do not. One explanation for the incongruent mortality data is that more patients in the United States studies had mild disease with lower serum calcium levels (mean calcium 10.9 mg/dL [2.7 mmol/L]) and fewer symptoms than patients in the European studies, where average calcium levels were significantly higher. In some [151,164-166], but not all [161] studies, higher serum calcium levels were associated with increased mortality. As an example, in a multivariate analysis of the Rochester study, higher calcium levels (≥11.2 mg/dL [2.8 to mmol/L]) were associated with worse survival [151]. In an updated report from the same group, patients with a serum calcium (≥10.8 mg/dL [2.7 to mmol/L]) had increased mortality [164].

In some studies, the higher mortality rate declined with time from parathyroidectomy but persisted after surgical cure [150,158-160]. This suggests that the disease may cause enduring damage to the cardiovascular system. The largest study on this subject was conducted on 10,995 Swedish patients with PHPT who underwent parathyroidectomy between 1958 and 1997 (identified through the Cancer and Causes of Death Registries) [150]. Mortality, primarily cardiovascular, was increased after surgery (standard mortality ratio of 1.2, 95% 1.19-1.27) in the overall group and persisted up to 15 years post-parathyroidectomy. It was noted in both sexes and all age groups. However, in the subset of 6386 patients operated on between 1985 and 1997, there was no increase in mortality. Possible speculations for the decreased mortality in the latter subset include a milder clinical presentation or earlier surgical intervention. Surprisingly, a previously published Swedish study conducted on 4461 patients operated in the same period, between 1987 and 1994, and using the same national Swedish registries, observed an increased mortality (RR 1.7 for males and 1.85 for females), compared with age-, sex-matched controls [158]. The reason for the discrepancy between the two Swedish studies is unclear.

Global registries are needed to accurately define the impact of PHPT on mortality, including cardiovascular and cancer mortality [1]. Such registries also would help identify predictors of mortality, which may include age, severity and chronicity of disease, and timing of surgical intervention [1,37,156]. (See "Primary hyperparathyroidism: Management".)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Primary hyperparathyroidism (The Basics)")

●Beyond the Basics topic (see "Patient education: Primary hyperparathyroidism (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical presentations

•Asymptomatic primary hyperparathyroidism – The most common clinical presentation of primary hyperparathyroidism (PHPT) in Western populations is asymptomatic hypercalcemia detected by routine biochemical screening. The serum parathyroid hormone (PTH) concentration is either frankly elevated or within the normal range but inappropriately elevated given the patient's hypercalcemia. Asymptomatic patients may have subclinical manifestations of PHPT (eg, asymptomatic nephrolithiasis and/or vertebral fractures) on initial evaluation. (See 'Asymptomatic primary hyperparathyroidism' above.)

•Symptomatic primary hyperparathyroidism – The classical symptoms and signs of PHPT are known as the "bones, stones, abdominal moans, and psychic groans." They reflect the combined effects of increased PTH secretion (table 1) and hypercalcemia (table 2) and include bone disease, kidney stones, anorexia, nausea, constipation, polydipsia, and polyuria (table 2). (See 'Symptomatic primary hyperparathyroidism' above.)

•Normocalcemic primary hyperparathyroidism – Normocalcemic PHPT describes the phenotype of PHPT in which PTH levels are consistently elevated but serum total and ionized calcium levels are normal, and all secondary causes for hyperparathyroidism (table 3) are excluded. Patients with normocalcemic hyperparathyroidism typically come to medical attention in the setting of an evaluation for low bone mineral density (BMD). (See 'Normocalcemic primary hyperparathyroidism' above.)

•Parathyroid crisis – Parathyroid crisis, which is rare, is characterized by severe hypercalcemia, with the serum calcium concentration usually above 15 mg/dL (3.8 mmol/L) and marked symptoms of hypercalcemia (in particular, central nervous system dysfunction). (See 'Parathyroid crisis' above.)

●End-organ manifestations – End-organ effects of PHPT may be present in patients with either symptomatic or asymptomatic disease. (See 'Manifestations by organ system' above.)

•Causally-related symptoms and complications – PHPT causes end-organ effects in bone and kidney and can also cause proximal myopathy. These effects may be clinically overt, or subclinical and detected only on imaging or laboratory evaluation. (See 'Causally related symptoms and complications' above.)

-Skeletal – Patients with PHPT may have decreased BMD, in particular at more cortical sites (forearm and hip) as compared with more cancellous sites (spine), and increased risk of fractures. Osteitis fibrosa cystica is rare in resource-rich countries but is still found in resource-limited countries. (See 'Skeletal' above.)

-Kidney – Nephrolithiasis is the universally accepted, classical kidney manifestation of PHPT. Important subclinical kidney manifestations of PHPT include asymptomatic nephrolithiasis, hypercalciuria, nephrocalcinosis, chronic renal insufficiency, and several abnormalities in renal tubular function: in particular, decreased concentrating ability (table 4). (See 'Kidney' above.)

•Associated symptoms and complications – Observational and cross-sectional studies show associations between PHPT and cardiovascular, neuropsychiatric, and neuromuscular abnormalities, but causal relationships have not been clearly established. These associated symptoms and complications are referred to as nonclassical manifestations of PHPT. (See 'Associated symptoms and complications' above.)