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

Primary hyperparathyroidism: Clinical manifestations

Primary hyperparathyroidism: Clinical manifestations
Authors:
Ghada El-Hajj Fuleihan, MD, MPH
Shonni J Silverberg, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: Aug 10, 2021.

INTRODUCTION — The most common clinical presentation of primary hyperparathyroidism (PHPT) is asymptomatic hypercalcemia detected by routine biochemical screening. 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, and the diagnosis and management of PHPT, are also 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 PHPT in Western populations is asymptomatic PHPT. Atypical presentations include normocalcemic PHPT and parathyroid crisis. The classical manifestations of PHPT ("bones, stones, abdominal moans, and psychic groans") are uncommon in the United States but are still prevalent in resource-limited countries [1,2]. Nevertheless, there has been an increase in the prevalence of asymptomatic disease even in resource-limited countries, particularly in India [3-5].

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 (figure 1) [6,7]. These patients are usually asymptomatic and have mild and sometimes only intermittent hypercalcemia [8-11]. 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]. In most patients, serum calcium and PTH levels remain stable, although they may increase over time in a small subset (<5 percent) of subjects [13-15]. However, with time, 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]. Thus, the differentiation between symptomatic and asymptomatic PHPT is not always clear-cut [17]. (See "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.

Normocalcemic primary hyperparathyroidism — Increasingly, patients undergoing evaluation for low bone density or other conditions may have parathyroid hormone (PTH) levels drawn in the absence of hypercalcemia. In 2009, an international panel of experts recognized this 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 have been excluded (table 1) [22,23]. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Diagnosis'.)

This condition is most challenging to characterize. Patients without an apparent secondary cause may have a "forme fruste" of PHPT [24,25]. It might be expected that early in the natural history of PHPT, elevated PTH levels would precede the development of overt hypercalcemia. In these patients, the serum calcium concentration would be expected to rise above the upper limit of normal when followed over time. However, persistent normocalcemia [25,26], intermittent hypercalcemia [27,28], and progression to hypercalcemia [29-31] 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 [29]. 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 [32].

There are no data to suggest that all these patients will ultimately become hypercalcemic, and over what time period. In addition, since most of these patients were identified in the course of an evaluation for osteoporosis, fracture, or low bone density, 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 [33-35]. 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) [36]. 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 were confused.

Sixty-nine percent had bone disease, as assessed by plain radiography or radionuclide bone scan.

Fifty-three percent had nephrolithiasis, and 50 percent had both bone disease and nephrolithiasis.

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

One-fourth of the patients were known to have had hypercalcemia 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 [37]. 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 [36].

Classical — 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 2) and hypercalcemia (table 3). The abnormalities associated with hyperparathyroidism are nephrolithiasis and bone disease; both are due to prolonged PTH excess [6,38]. Symptoms attributable to hypercalcemia include anorexia, nausea, constipation, polydipsia, and polyuria (table 3). Symptoms in PHPT are not necessarily related to serum calcium levels [39]; however, they seem to be more common in patients in whom hypercalcemia develops rapidly. (See 'Parathyroid crisis' above.)

Although 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 [6,38]. However, classical manifestations of PHPT are still prevalent in countries such as India and China [1,40-44]. 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 [41]. 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 [7,45-47]. Vitamin D deficiency is common in patients with PHPT [48]. In countries where hypovitaminosis D is prevalent, PHPT may be characterized by overt, severe clinical bone and stone disease [45,46]. 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 [49-51].

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'.)

Osteitis fibrosa cystica – The classic 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 [52]. On the other hand, bone disease remains a major problem in patients with secondary hyperparathyroidism due to chronic renal failure. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

Nephrolithiasis Nephrolithiasis is the universally accepted, classical renal manifestation of PHPT (table 4) [53]. Nephrolithiasis occurs in approximately 15 to 20 percent of patients with PHPT [6]; conversely, approximately 5 percent of patients with nephrolithiasis have hyperparathyroidism [54]. Nephrocalcinosis is less common and may represent a spectrum of the same disease process, although most studies of PHPT have not reported its frequency [53]. (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 may be intermittent and detected only by multiple measurements [8,54,55]. 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) [54].

Most stones in patients with PHPT are composed of calcium oxalate [54], 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; 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 [56-58]. 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.

The presence of subclinical nephrolithiasis in asymptomatic patients is reviewed below. (See 'Subclinical renal disease' below.)

Neuromuscular – Complaints of weakness and fatigue are common among patients with PHPT [19,59]. In classical PHPT, a neuromuscular syndrome characterized by atrophy of type II muscle fibers was seen [60]. However, that syndrome, as well as any objective evidence of myopathy or weakness, is rarely seen today [61].

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 [62]. However, these reports are limited by small sample sizes.

Neuropsychiatric – Neurobehavioral 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 [63-67]. These symptoms include lethargy, depressed mood, decreased social interaction, and cognitive dysfunction [65]. 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 [65].

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 [66]. 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 [68-71]. 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. These trials are reviewed in detail separately. (See "Primary hyperparathyroidism: Management", section on 'Neuropsychiatric'.)

OTHER MANIFESTATIONS

Skeletal — Although the classical bone disease osteitis fibrosa cystica is rare today, the skeleton remains very much a target organ in this disease. This is clear from studies of bone density and histomorphometry in PHPT.

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) [72]. However, the reduction is usually small [73]. 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 [74].

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'.)

Other imaging technologies – 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 [75-85]. 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 [86]. This profile is more pronounced in patients with concomitant vitamin D deficiency [87].

Fractures – Most [88-95], but not all [96], 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 [95].

The largest report of hip fracture was a population-based study of over 1800 patients with PHPT in Uppsala, Sweden [97]. 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 [92].

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 [38]. Excess 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 [38]. Since fracture is not common in PHPT, prospective multicenter studies that capture site-specific fractures are needed.

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

Asymptomatic nephrolithiasis

Hypercalciuria

Nephrocalcinosis

Chronic renal 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 below 60 mL/min/1.73 m2 [98-100]. The development of renal insufficiency in PHPT is related to the degree and duration of hypercalcemia. Mild hypercalcemia is rarely associated with renal insufficiency. In randomized trials of two to three years duration, there is little evidence that renal function deteriorates in patients with mild chronic hypercalcemia due to PHPT. (See "Primary hyperparathyroidism: Management", section on 'Biochemical abnormalities' and "Clinical manifestations of hypercalcemia", section on 'Renal insufficiency'.)

Subclinical nephrocalcinosis and nephrolithiasis are more common in patients with than without hyperparathyroidism [101,102]. In a retrospective review of 271 renal ultrasounds from patients with surgically proven, asymptomatic PHPT, the prevalence of renal 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) [103]. In a cross-sectional analyses of asymptomatic patients with PHPT, occult urolithiasis or renal calcifications (nephrolithiasis and/or nephrocalcinosis) were identified in approximately 20 percent of patients [104-106].

A contributing factor for stone formation in PHPT is hypercalciuria. Although PTH directly stimulates the distal tubular reabsorption of calcium [56], 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 [104,106]. 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 renal disease in patients with asymptomatic PHPT is reviewed separately. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Renal imaging'.)

Cardiovascular — PHPT may be associated with cardiovascular disease, including hypertension, arrhythmia, ventricular hypertrophy, and vascular and valvular calcification, as illustrated by the following findings in observational studies [107-109]:

Hypertension is common in patients with PHPT, even among those with mild disease [110-112]. The causal nature of this relationship in those without multiple endocrine neoplasia (MEN) is unclear since hypertension does not improve with cure of PHPT.

Several [113-116], but not all [117,118], 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) [119]. In addition, an indirect measure of aortic stiffness [120,121] and carotid vascular stiffness [119] 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'.)

It is uncertain if normocalcemic PHPT is also associated with cardiometabolic changes. Preliminary data suggest an association with hypertension [122,123].

The nature of cardiovascular involvement and the extent to which abnormalities improve postoperatively need to be further elucidated before a cause-and-effect relationship can be established (see "Primary hyperparathyroidism: Management", section on 'Cardiovascular'). There are no data to support routine cardiovascular evaluation in patients diagnosed with PHPT.

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'.)

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 PHPT [112,120,124,125].

Patients with PHPT appear to be heavier than age-matched controls [126]. 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 [126]. 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) [127]. (See "Primary hyperparathyroidism: Management", section on 'Cardiovascular'.)

Rheumatologic manifestations — Many rheumatologic abnormalities have been described in patients with classical symptomatic PHPT, but none of these are commonly seen in modern-day disease [128]. They include the following:

Hyperuricemia and gout.

Pseudogout with pyrophosphate crystals into the joint [129-133]. Calcification of articular cartilage (chondrocalcinosis), most commonly affecting the wrists and knees, is more commonly reported than gout itself [132,133]. 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".)

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 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 [13,57].

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 [134,135]. 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 [136]. The mechanism is unclear, but marrow fibrosis may be important [136,137]. 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 [138-141]. 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) [141]. 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 [141].

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 [142-147]. Several studies suggest a small increase in risk of death from cancer [142,144,145], even after parathyroidectomy [144,145]. 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) [143].

MORTALITY — Severe classical PHPT is associated with increased mortality, primarily due to cardiovascular disease. However, the impact of milder PHPT on cardiovascular mortality is uncertain. Excess mortality, mostly due to cardiovascular disease, has been reported in some [148-153], but not all [143,154,155], 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 [143,155-157], but not all [152] 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 [143]. 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 [155].

In some studies, the higher mortality rate declined with time from parathyroidectomy but persisted after surgical cure [142,149-151]. This suggests that the disease may cause enduring damage to the cardiovascular system. The largest study to date 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) [142]. 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 [149]. The reason for the discrepancy between the two Swedish studies is unclear.

Further studies are needed to determine whether cardiovascular mortality is truly increased in patients with PHPT and whether that risk is affected by disease severity and/or timing of surgical intervention [47]. (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 5th to 6th 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 10th to 12th 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

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. (See 'Asymptomatic primary hyperparathyroidism' above.)

In 2009, an international panel of experts recognized normocalcemic PHPT as a 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 1) 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, 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.)

The classical symptoms and signs of PHPT, such as osteitis fibrosa cystica and nephrolithiasis, are due to prolonged excessive PTH secretion and hypercalcemia. Although osteitis fibrosa cystica is rarely seen in the United States and Europe, it is still prevalent in resource-limited countries. 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. (See 'Classical' above.)

Although many patients with PHPT have neuropsychologic complaints, the extent and attribution of these symptoms to PHPT in a given patient requires further elucidation. (See 'Classical' above.)

Patients with PHPT may have decreased BMD, in particular at more cortical sites (forearm and hip) as compared with more cancellous sites (spine). (See 'Skeletal' above.)

Important subclinical renal 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 'Subclinical renal disease' above.)

The nature of cardiovascular involvement and the impact of PHPT on cardiovascular mortality require further elucidation. (See 'Cardiovascular' above.)

  1. Sun B, Guo B, Wu B, et al. Characteristics, management, and outcome of primary hyperparathyroidism at a single clinical center from 2005 to 2016. Osteoporos Int 2018; 29:635.
  2. Lazaretti-Castro M. The diagnosis of primary hyperparathyroidism in developing countries remains in the past century: still with bones, stone and groans. Arch Endocrinol Metab 2020; 64:101.
  3. Yadav SK, Johri G, Bichoo RA, et al. Primary hyperparathyroidism in developing world: a systematic review on the changing clinical profile of the disease. Arch Endocrinol Metab 2020; 64:105.
  4. Arya AK, Kumari P, Bhadada SK, et al. Progressive rise in the prevalence of asymptomatic primary hyperparathyroidism in India: Data from PHPT registry. J Bone Miner Metab 2021; 39:253.
  5. Mithal A, Kaur P, Singh VP, et al. ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM EXISTS IN NORTH INDIA: RETROSPECTIVE DATA FROM 2 TERTIARY CARE CENTERS. Endocr Pract 2015; 21:581.
  6. Silverberg SJ, Bilezikian JP. Evaluation and management of primary hyperparathyroidism. J Clin Endocrinol Metab 1996; 81:2036.
  7. Silverberg SJ, Clarke BL, Peacock M, et al. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab 2014; 99:3580.
  8. Siperstein AE, Shen W, Chan AK, et al. Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery. Arch Surg 1992; 127:1157.
  9. Walker MD, Silverberg SJ. Primary hyperparathyroidism. Nat Rev Endocrinol 2018; 14:115.
  10. Cusano NE, Cipriani C, Bilezikian JP. Management of normocalcemic primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab 2018; 32:837.
  11. Silva BC, Cusano NE, Bilezikian JP. Primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab 2018; :101247.
  12. Bilezikian JP, Silverberg SJ. Clinical practice. Asymptomatic primary hyperparathyroidism. N Engl J Med 2004; 350:1746.
  13. Silverberg SJ, Shane E, Jacobs TP, et al. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999; 341:1249.
  14. Yu N, Leese GP, Smith D, Donnan PT. The natural history of treated and untreated primary hyperparathyroidism: the parathyroid epidemiology and audit research study. QJM 2011; 104:513.
  15. Rubin MR, Bilezikian JP, McMahon DJ, et al. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab 2008; 93:3462.
  16. Assadipour Y, Zhou H, Kuo EJ, et al. End-organ effects of primary hyperparathyroidism: A population-based study. Surgery 2019; 165:99.
  17. Perrier ND. Asymptomatic hyperparathyroidism: a medical misnomer? Surgery 2005; 137:127.
  18. Lundgren E, Szabo E, Ljunghall S, et al. Population based case-control study of sick leave in postmenopausal women before diagnosis of hyperparathyroidism. BMJ 1998; 317:848.
  19. Lundgren E, Ljunghall S, Akerström G, et al. Case-control study on symptoms and signs of "asymptomatic" primary hyperparathyroidism. Surgery 1998; 124:980.
  20. Chan AK, Duh QY, Katz MH, et al. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case-control study. Ann Surg 1995; 222:402.
  21. Trombetti A, Christ ER, Henzen C, et al. Clinical presentation and management of patients with primary hyperparathyroidism of the Swiss Primary Hyperparathyroidism Cohort: a focus on neuro-behavioral and cognitive symptoms. J Endocrinol Invest 2016; 39:567.
  22. Silverberg SJ, Lewiecki EM, Mosekilde L, et al. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009; 94:351.
  23. Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin Endocrinol Metab 2014; 99:3570.
  24. Silverberg SJ, Bilezikian JP. "Incipient" primary hyperparathyroidism: a "forme fruste" of an old disease. J Clin Endocrinol Metab 2003; 88:5348.
  25. Tordjman KM, Greenman Y, Osher E, et al. Characterization of normocalcemic primary hyperparathyroidism. Am J Med 2004; 117:861.
  26. Ayturk S, Gursoy A, Bascil Tutuncu N, et al. Changes in insulin sensitivity and glucose and bone metabolism over time in patients with asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab 2006; 91:4260.
  27. Schini M, Jacques RM, Oakes E, et al. Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History. J Clin Endocrinol Metab 2020; 105.
  28. Šiprová H, Fryšák Z, Souček M. PRIMARY HYPERPARATHYROIDISM, WITH A FOCUS ON MANAGEMENT OF THE NORMOCALCEMIC FORM: TO TREAT OR NOT TO TREAT? Endocr Pract 2016; 22:294.
  29. Lowe H, McMahon DJ, Rubin MR, et al. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab 2007; 92:3001.
  30. Diri H, Unluhizarci K, Kelestimur F. Investigation of glucose intolerance in patients with normocalcemic primary hyperparathyroidism: 4-year follow-up. Endocrine 2014; 47:971.
  31. Cusano NE, Maalouf NM, Wang PY, et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab 2013; 98:2734.
  32. Lemos ALP, Andrade SRL, Pontes LLH, et al. High Rate of Occult Urolithiasis in Normocalcemic Primary Hyperparathyroidism. Kidney Blood Press Res 2019; 44:1189.
  33. Corlew DS, Bryda SL, Bradley EL 3rd, DiGirolamo M. Observations on the course of untreated primary hyperparathyroidism. Surgery 1985; 98:1064.
  34. Scholz DA, Purnell DC. Asymptomatic primary hyperparathyroidism. 10-year prospective study. Mayo Clin Proc 1981; 56:473.
  35. Ahmad S, Kuraganti G, Steenkamp D. Hypercalcemic crisis: a clinical review. Am J Med 2015; 128:239.
  36. Fitzpatrick LA, Bilezikian JP. Acute primary hyperparathyroidism. Am J Med 1987; 82:275.
  37. Bondeson AG, Bondeson L, Thompson NW. Clinicopathological peculiarities in parathyroid disease with hypercalcaemic crisis. Eur J Surg 1993; 159:613.
  38. Bilezikian JP, Brandi ML, Rubin M, Silverberg SJ. Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features. J Intern Med 2005; 257:6.
  39. Harrison BJ, Wheeler MH. Asymptomatic primary hyperparathyroidism. World J Surg 1991; 15:724.
  40. Gopal RA, Acharya SV, Bandgar T, et al. Clinical profile of primary hyperparathyroidism from western India: a single center experience. J Postgrad Med 2010; 56:79.
  41. Bhadada SK, Arya AK, Mukhopadhyay S, et al. Primary hyperparathyroidism: insights from the Indian PHPT registry. J Bone Miner Metab 2017.
  42. Makay Ö, Özçınar B, Şimşek T, et al. Regional Clinical and Biochemical Differences among Patients with Primary Hyperparathyroidism. Balkan Med J 2017; 34:28.
  43. Yadav SK, Mishra SK, Mishra A, et al. Changing Profile of Primary Hyperparathyroidism Over Two and Half Decades: A Study in Tertiary Referral Center of North India. World J Surg 2018; 42:2732.
  44. Yao XA, Wei BJ, Jiang T, Chang H. The characteristics of clinical changes in primary hyperparathyroidism in Chinese patients. J Bone Miner Metab 2019; 37:336.
  45. Bilezikian JP, Meng X, Shi Y, Silverberg SJ. Primary hyperparathyroidism in women: a tale of two cities--New York and Beijing. Int J Fertil Womens Med 2000; 45:158.
  46. Mishra SK, Agarwal G, Kar DK, et al. Unique clinical characteristics of primary hyperparathyroidism in India. Br J Surg 2001; 88:708.
  47. 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.
  48. Boudou P, Ibrahim F, Cormier C, et al. A very high incidence of low 25 hydroxy-vitamin D serum concentration in a French population of patients with primary hyperparathyroidism. J Endocrinol Invest 2006; 29:511.
  49. 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.
  50. Silverberg SJ, Shane E, Dempster DW, Bilezikian JP. The effects of vitamin D insufficiency in patients with primary hyperparathyroidism. Am J Med 1999; 107:561.
  51. Kandil E, Tufaro AP, Carson KA, et al. Correlation of plasma 25-hydroxyvitamin D levels with severity of primary hyperparathyroidism and likelihood of parathyroid adenoma localization on sestamibi scan. Arch Otolaryngol Head Neck Surg 2008; 134:1071.
  52. Bilezikian JP, Silverberg SJ, Shane E, et al. Characterization and evaluation of asymptomatic primary hyperparathyroidism. J Bone Miner Res 1991; 6 Suppl 2:S85.
  53. Peacock M. Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum. J Bone Miner Res 2002; 17 Suppl 2:N87.
  54. Parks J, Coe F, Favus M. Hyperparathyroidism in nephrolithiasis. Arch Intern Med 1980; 140:1479.
  55. Yendt ER, Gagne RJ. Detection of primary hyperparathyroidism, with special reference to its occurrence in hypercalciuric females with "normal" or borderline serum calcium. Can Med Assoc J 1968; 98:331.
  56. 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.
  57. Broadus AE, Horst RL, Lang R, et al. The importance of circulating 1,25-dihydroxyvitamin D in the pathogenesis of hypercalciuria and renal-stone formation in primary hyperparathyroidism. N Engl J Med 1980; 302:421.
  58. Silverberg SJ, Shane E, Jacobs TP, et al. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med 1990; 89:327.
  59. Mallette LE, Bilezikian JP, Heath DA, Aurbach GD. Primary hyperparathyroidism: clinical and biochemical features. Medicine (Baltimore) 1974; 53:127.
  60. Patten BM, Bilezikian JP, Mallette LE, et al. Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 1974; 80:182.
  61. Turken SA, Cafferty M, Silverberg SJ, et al. Neuromuscular involvement in mild, asymptomatic primary hyperparathyroidism. Am J Med 1989; 87:553.
  62. Chou FF, Sheen-Chen SM, Leong CP. Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995; 117:18.
  63. McAllion SJ, Paterson CR. Psychiatric morbidity in primary hyperparathyroidism. Postgrad Med J 1989; 65:628.
  64. Joborn C, Hetta J, Johansson H, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988; 12:476.
  65. Coker LH, Rorie K, Cantley L, et al. Primary hyperparathyroidism, cognition, and health-related quality of life. Ann Surg 2005; 242:642.
  66. Walker MD, McMahon DJ, Inabnet WB, et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab 2009; 94:1951.
  67. Chiodini I, Cairoli E, Palmieri S, et al. Non classical complications of primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab 2018; 32:805.
  68. Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab 2007; 92:1687.
  69. Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab 2007; 92:3114.
  70. Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab 2004; 89:5415.
  71. Pretorius M, Lundstam K, Hellström M, et al. Effects of Parathyroidectomy on Quality of Life: 10 Years of Data From a Prospective Randomized Controlled Trial on Primary Hyperparathyroidism (the SIPH-Study). J Bone Miner Res 2021; 36:3.
  72. Silverberg SJ, Shane E, de la Cruz L, et al. Skeletal disease in primary hyperparathyroidism. J Bone Miner Res 1989; 4:283.
  73. Christiansen P, Steiniche T, Brixen K, et al. Primary hyperparathyroidism: biochemical markers and bone mineral density at multiple skeletal sites in Danish patients. Bone 1997; 21:93.
  74. Abdelhadi M, Nordenström J. Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism. J Clin Endocrinol Metab 1998; 83:3845.
  75. Hansen S, Beck Jensen JE, Rasmussen L, et al. Effects on bone geometry, density, and microarchitecture in the distal radius but not the tibia in women with primary hyperparathyroidism: A case-control study using HR-pQCT. J Bone Miner Res 2010; 25:1941.
  76. Stein EM, Silva BC, Boutroy S, et al. Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women. J Bone Miner Res 2013; 28:1029.
  77. Vu TD, Wang XF, Wang Q, et al. New insights into the effects of primary hyperparathyroidism on the cortical and trabecular compartments of bone. Bone 2013; 55:57.
  78. Silva BC, Boutroy S, Zhang C, et al. Trabecular bone score (TBS)--a novel method to evaluate bone microarchitectural texture in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 2013; 98:1963.
  79. Eller-Vainicher C, Filopanti M, Palmieri S, et al. Bone quality, as measured by trabecular bone score, in patients with primary hyperparathyroidism. Eur J Endocrinol 2013; 169:155.
  80. Romagnoli E, Cipriani C, Nofroni I, et al. "Trabecular Bone Score" (TBS): an indirect measure of bone micro-architecture in postmenopausal patients with primary hyperparathyroidism. Bone 2013; 53:154.
  81. Muñoz-Torres M, Manzanares Córdova R, García-Martín A, et al. Usefulness of Trabecular Bone Score (TBS) to Identify Bone Fragility in Patients with Primary Hyperparathyroidism. J Clin Densitom 2019; 22:162.
  82. Tay YD, Cusano NE, Rubin MR, et al. Trabecular Bone Score in Obese and Nonobese Subjects With Primary Hyperparathyroidism Before and After Parathyroidectomy. J Clin Endocrinol Metab 2018; 103:1512.
  83. Grigorie D, Coles D, Sucaliuc A. TRABECULAR BONE SCORE (TBS) HAS A POOR DISCRIMINATIVE POWER FOR VERTEBRAL FRACTURES IN 153 ROMANIAN PATIENTS WITH PRIMARY HYPERPARATHYROIDISM. Acta Endocrinol (Buchar) 2018; 14:208.
  84. Hong AR, Lee JH, Kim JH, et al. Effect of Endogenous Parathyroid Hormone on Bone Geometry and Skeletal Microarchitecture. Calcif Tissue Int 2019; 104:382.
  85. Wang W, Nie M, Jiang Y, et al. Impaired geometry, volumetric density, and microstructure of cortical and trabecular bone assessed by HR-pQCT in both sporadic and MEN1-related primary hyperparathyroidism. Osteoporos Int 2020; 31:165.
  86. Parisien M, Mellish RW, Silverberg SJ, et al. Maintenance of cancellous bone connectivity in primary hyperparathyroidism: trabecular strut analysis. J Bone Miner Res 1992; 7:913.
  87. Stein EM, Dempster DW, Udesky J, et al. Vitamin D deficiency influences histomorphometric features of bone in primary hyperparathyroidism. Bone 2011; 48:557.
  88. De Geronimo S, Romagnoli E, Diacinti D, et al. The risk of fractures in postmenopausal women with primary hyperparathyroidism. Eur J Endocrinol 2006; 155:415.
  89. Dauphine RT, Riggs BL, Scholz DA. Back pain and vertebral crush fractures: an unemphasized mode of presentation for primary hyperparathyroidism. Ann Intern Med 1975; 83:365.
  90. Kenny AM, MacGillivray DC, Pilbeam CC, et al. Fracture incidence in postmenopausal women with primary hyperparathyroidism. Surgery 1995; 118:109.
  91. Melton LJ 3rd, Atkinson EJ, O'Fallon WM, Heath H 3rd. Risk of age-related fractures in patients with primary hyperparathyroidism. Arch Intern Med 1992; 152:2269.
  92. Khosla S, Melton LJ 3rd, Wermers RA, et al. Primary hyperparathyroidism and the risk of fracture: a population-based study. J Bone Miner Res 1999; 14:1700.
  93. Khosla S, Melton J 3rd. Fracture risk in primary hyperparathyroidism. J Bone Miner Res 2002; 17 Suppl 2:N103.
  94. Vignali E, Viccica G, Diacinti D, et al. Morphometric vertebral fractures in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab 2009; 94:2306.
  95. Ejlsmark-Svensson H, Rolighed L, Harsløf T, Rejnmark L. Risk of fractures in primary hyperparathyroidism: a systematic review and meta-analysis. Osteoporos Int 2021; 32:1053.
  96. Wilson RJ, Rao S, Ellis B, et al. Mild asymptomatic primary hyperparathyroidism is not a risk factor for vertebral fractures. Ann Intern Med 1988; 109:959.
  97. Larsson K, Ljunghall S, Krusemo UB, et al. The risk of hip fractures in patients with primary hyperparathyroidism: a population-based cohort study with a follow-up of 19 years. J Intern Med 1993; 234:585.
  98. Tassone F, Gianotti L, Emmolo I, et al. Glomerular filtration rate and parathyroid hormone secretion in primary hyperparathyroidism. J Clin Endocrinol Metab 2009; 94:4458.
  99. Belli M, Martin RM, Brescia MDG, et al. Acute and long-term kidney function after parathyroidectomy for primary hyperparathyroidism. PLoS One 2020; 15:e0244162.
  100. Cipriani C, Bilezikian JP. Non-surgical management of primary hyperparathyroidism in the aging population. Maturitas 2020; 136:49.
  101. Cassibba S, Pellegrino M, Gianotti L, et al. Silent renal stones in primary hyperparathyroidism: prevalence and clinical features. Endocr Pract 2014; 20:1137.
  102. Rejnmark L, Vestergaard P, Mosekilde L. Nephrolithiasis and renal calcifications in primary hyperparathyroidism. J Clin Endocrinol Metab 2011; 96:2377.
  103. Suh JM, Cronan JJ, Monchik JM. Primary hyperparathyroidism: is there an increased prevalence of renal stone disease? AJR Am J Roentgenol 2008; 191:908.
  104. Tay YD, Liu M, Bandeira L, et al. Occult urolithiasis in asymptomatic primary hyperparathyroidism. Endocr Res 2018; 43:106.
  105. Cipriani C, Biamonte F, Costa AG, et al. Prevalence of kidney stones and vertebral fractures in primary hyperparathyroidism using imaging technology. J Clin Endocrinol Metab 2015; 100:1309.
  106. Ejlsmark-Svensson H, Bislev LS, Rolighed L, et al. Predictors of Renal Function and Calcifications in Primary Hyperparathyroidism: A Nested Case-Control Study. J Clin Endocrinol Metab 2018; 103:3574.
  107. Iwata S, Walker MD, Di Tullio MR, et al. Aortic valve calcification in mild primary hyperparathyroidism. J Clin Endocrinol Metab 2012; 97:132.
  108. Walker MD, Silverberg SJ. Cardiovascular aspects of primary hyperparathyroidism. J Endocrinol Invest 2008; 31:925.
  109. Roberts WC, Waller BF. Effect of chronic hypercalcemia on the heart. An analysis of 18 necropsy patients. Am J Med 1981; 71:371.
  110. Lind L, Hvarfner A, Palmér M, et al. Hypertension in primary hyperparathyroidism in relation to histopathology. Eur J Surg 1991; 157:457.
  111. Lind L, Ljunghall S. Pre-operative evaluation of risk factors for complications in patients with primary hyperparathyroidism. Eur J Clin Invest 1995; 25:955.
  112. Lind L, Jacobsson S, Palmér M, et al. Cardiovascular risk factors in primary hyperparathyroidism: a 15-year follow-up of operated and unoperated cases. J Intern Med 1991; 230:29.
  113. Stefenelli T, Abela C, Frank H, et al. Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up. J Clin Endocrinol Metab 1997; 82:106.
  114. Näppi S, Saha H, Virtanen V, et al. Left ventricular structure and function in primary hyperparathyroidism before and after parathyroidectomy. Cardiology 2000; 93:229.
  115. Nilsson IL, Aberg J, Rastad J, Lind L. Left ventricular systolic and diastolic function and exercise testing in primary hyperparathyroidism-effects of parathyroidectomy. Surgery 2000; 128:895.
  116. Piovesan A, Molineri N, Casasso F, et al. Left ventricular hypertrophy in primary hyperparathyroidism. Effects of successful parathyroidectomy. Clin Endocrinol (Oxf) 1999; 50:321.
  117. Barletta G, De Feo ML, Del Bene R, et al. Cardiovascular effects of parathyroid hormone: a study in healthy subjects and normotensive patients with mild primary hyperparathyroidism. J Clin Endocrinol Metab 2000; 85:1815.
  118. Walker MD, Fleischer JB, Di Tullio MR, et al. Cardiac structure and diastolic function in mild primary hyperparathyroidism. J Clin Endocrinol Metab 2010; 95:2172.
  119. Walker MD, Fleischer J, Rundek T, et al. Carotid vascular abnormalities in primary hyperparathyroidism. J Clin Endocrinol Metab 2009; 94:3849.
  120. Smith JC, Page MD, John R, et al. Augmentation of central arterial pressure in mild primary hyperparathyroidism. J Clin Endocrinol Metab 2000; 85:3515.
  121. Rubin MR, Maurer MS, McMahon DJ, et al. Arterial stiffness in mild primary hyperparathyroidism. J Clin Endocrinol Metab 2005; 90:3326.
  122. Yener Ozturk F, Erol S, Canat MM, et al. Patients with normocalcemic primary hyperparathyroidism may have similar metabolic profile as hypercalcemic patients. Endocr J 2016; 63:111.
  123. Chen G, Xue Y, Zhang Q, et al. Is Normocalcemic Primary Hyperparathyroidism Harmful or Harmless? J Clin Endocrinol Metab 2015; 100:2420.
  124. Procopio M, Magro G, Cesario F, et al. The oral glucose tolerance test reveals a high frequency of both impaired glucose tolerance and undiagnosed Type 2 diabetes mellitus in primary hyperparathyroidism. Diabet Med 2002; 19:958.
  125. Valdemarsson S, Lindblom P, Bergenfelz A. Metabolic abnormalities related to cardiovascular risk in primary hyperparathyroidism: effects of surgical treatment. J Intern Med 1998; 244:241.
  126. Bolland MJ, Grey AB, Gamble GD, Reid IR. Association between primary hyperparathyroidism and increased body weight: a meta-analysis. J Clin Endocrinol Metab 2005; 90:1525.
  127. Bollerslev J, Rosen T, Mollerup CL, et al. Effect of surgery on cardiovascular risk factors in mild primary hyperparathyroidism. J Clin Endocrinol Metab 2009; 94:2255.
  128. Rubin MR, Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism: Rheumatologic manifestations and bone disease. In: Bone Disease in Rheumatology, Maricic M, Gluck OS (Eds), Lippincott Williams & Wilkins, Philadelphia 2005. p.190.
  129. Pappu R, Jabbour SA, Regianto AM, Reginato AJ. Musculoskeletal manifestations of primary hyperparathyroidism. Clin Rheumatol 2016; 35:3081.
  130. Helliwell M. [Rheumatic symptoms in primary hyperparathyroidism]. Postgrad Med J 1983; 59:236.
  131. Bilezikian JP, Connor TB, Aptekar R, et al. Pseudogout after parathyroidectomy. Lancet 1973; 1:445.
  132. Rynes RI, Merzig EG. Calcium pyrophosphate crystal deposition disease and hyperparathyroidism: a controlled, prospective study. J Rheumatol 1978; 5:460.
  133. Alexander GM, Dieppe PA, Doherty M, Scott DG. Pyrophosphate arthropathy: a study of metabolic associations and laboratory data. Ann Rheum Dis 1982; 41:377.
  134. Hulter HN, Peterson JC. Acid-base homeostasis during chronic PTH excess in humans. Kidney Int 1985; 28:187.
  135. Sutton RA, Wong NL, Dirks JH. Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney. Kidney Int 1979; 15:520.
  136. Boxer M, Ellman L, Geller R, Wang CA. Anemia in primary hyperparathyroidism. Arch Intern Med 1977; 137:588.
  137. Meytes D, Bogin E, Ma A, et al. Effect of parathyroid hormone on erythropoiesis. J Clin Invest 1981; 67:1263.
  138. Johansson H, Werner I. Letter: Dysproteinemia, malignancy, and hyperparathyroidism. Ann Intern Med 1975; 83:121.
  139. Mundis RJ, Kyle RA. Primary hyperparathyroidism and monoclonal gammopathy of undetermined significance. Am J Clin Pathol 1982; 77:619.
  140. Rao DS, Antonelli R, Kane KR, et al. Primary hyperparathyroidism and monoclonal gammopathy. Henry Ford Hosp Med J 1991; 39:41.
  141. Arnulf B, Bengoufa D, Sarfati E, et al. Prevalence of monoclonal gammopathy in patients with primary hyperparathyroidism: a prospective study. Arch Intern Med 2002; 162:464.
  142. Nilsson IL, Yin L, Lundgren E, et al. Clinical presentation of primary hyperparathyroidism in Europe--nationwide cohort analysis on mortality from nonmalignant causes. J Bone Miner Res 2002; 17 Suppl 2:N68.
  143. Wermers RA, Khosla S, Atkinson EJ, et al. Survival after the diagnosis of hyperparathyroidism: a population-based study. Am J Med 1998; 104:115.
  144. Palmér M, Adami HO, Krusemo UB, Ljunghall S. Increased risk of malignant diseases after surgery for primary hyperparathyroidism. A nationwide cohort study. Am J Epidemiol 1988; 127:1031.
  145. Pickard AL, Gridley G, Mellemkjae L, et al. Hyperparathyroidism and subsequent cancer risk in Denmark. Cancer 2002; 95:1611.
  146. Michels KB, Xue F, Brandt L, Ekbom A. Hyperparathyroidism and subsequent incidence of breast cancer. Int J Cancer 2004; 110:449.
  147. Tanaka Y. Primary hyperparathyroidism with breast carcinoma. Breast Cancer 2010; 17:265.
  148. Palmer M, Adami HO, Bergström R, et al. Survival and renal function in untreated hypercalcaemia. Population-based cohort study with 14 years of follow-up. Lancet 1987; 1:59.
  149. Hedbäck G, Odén A. Increased risk of death from primary hyperparathyroidism--an update. Eur J Clin Invest 1998; 28:271.
  150. Hedbäck G, Tisell LE, Bengtsson BA, et al. Premature death in patients operated on for primary hyperparathyroidism. World J Surg 1990; 14:829.
  151. Palmér M, Adami HO, Bergström R, et al. Mortality after surgery for primary hyperparathyroidism: a follow-up of 441 patients operated on from 1956 to 1979. Surgery 1987; 102:1.
  152. Clifton-Bligh PB, Nery ML, Supramaniam R, et al. Mortality associated with primary hyperparathyroidism. Bone 2015; 74:121.
  153. Yu N, Donnan PT, Leese GP. A record linkage study of outcomes in patients with mild primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study (PEARS). Clin Endocrinol (Oxf) 2011; 75:169.
  154. Söreide JA, van Heerden JA, Grant CS, et al. Survival after surgical treatment for primary hyperparathyroidism. Surgery 1997; 122:1117.
  155. Wermers RA, Griebeler ML, Thapa P, et al. Survival in primary hyperparathyroidism over five decades (1965-2010) a population-based retrospective study. Bone 2021; 152:116099.
  156. Reid LJ, Muthukrishnan B, Patel D, et al. Predictors of Nephrolithiasis, Osteoporosis, and Mortality in Primary Hyperparathyroidism. J Clin Endocrinol Metab 2019; 104:3692.
  157. Yu N, Leese GP, Donnan PT. What predicts adverse outcomes in untreated primary hyperparathyroidism? The Parathyroid Epidemiology and Audit Research Study (PEARS). Clin Endocrinol (Oxf) 2013; 79:27.
Topic 2031 Version 21.0

References