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Keywords:

  • bone density;
  • hypercalcaemia;
  • parathyroid hormone;
  • primary hyperparathyroidism

Abstract.

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Primary hyperparathyroidism (PHPT) is characterized most commonly now as an asymptomatic disorder with hypercalcaemia and elevated levels of parathyroid hormone (PTH). The elevation in PTH is detected by both the standard immunoradiometric assays (IRMA) and a more recent IRMA that detects only the 1–84 full-length PTH molecule. The serum calcium concentration is usually <1 mg dL−1 above normal. Recently, another variant of PHPT (normocalcaemic PHPT) has been described in which the serum calcium is normal but the serum PTH is elevated, in the absence of any secondary cause for PTH elevation. Although usually sporadic, PHPT also occurs in inherited syndromes. Skeletal manifestations are appreciated by densitometry showing a typical pattern in which cancellous bone of the lumbar spine is reasonably well preserved whilst the cortical bone of the distal third of the radius is preferentially reduced. Although reduced in incidence, renal stones remain the most common overt complication of PHPT. Other organs are theoretical targets of PHPT such as the neurobehavioural axis and the cardiovascular system. Vitamin D looms as an important determinant of the activity of the PHPT state. The 2002 NIH Workshop on asymptomatic PHPT has led to revised guidelines to help doctors determine who is best advised to have parathyroid surgery and who can be safely followed without surgery. New information about the natural history of PHPT in those who did not undergo surgery has helped to define more precisely who is at-risk for complications. At the NIH workshop, a number of items were highlighted for further investigation such as pharmacological approaches to controlling hypercalcaemia, elevated PTH levels and maintaining bone density.


Clinical presentation

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Primary hyperparathyroidism (PHPT) is caused by excessive, incompletely regulated secretion of parathyroid hormone (PTH) from one or more of the four parathyroid glands. It is one of the most common causes of hypercalcaemia and thus should be considered in anyone with an elevated calcium concentration. It is due to a benign parathyroid adenoma in 80% of cases and multiglandular involvement in 15–20% of cases. Parathyroid cancer is exceedingly rare (0.5% of all cases). In patients who are not overtly ill, the hypercalcaemic individual is likely to have PHPT since malignancy, the other common cause of hypercalcaemia, is usually associated with features characteristic of advanced cancer.

Years ago, asymptomatic patients with PHPT were not readily apparent. The serum calcium was then generally obtained in a search to explain a constellation of signs and symptoms. Thus, most patients were symptomatic of features of either hypercalcaemia or the hyperparathyroid state. In the past 30 years, the widespread application of multichannel screening tests has changed this landscape. Now, the serum calcium is routinely obtained in patients who seek medical attention for any reason. PHPT has thus become the most common cause of hypercalcaemia and typically is detected incidentally in the course of the routine blood test. In the United States and many other developed countries, symptomatic PHPT with involvement of the skeleton (osteitis fibrosa cystica), kidneys (nephrolithiasis, nephrocalcinosis), neuromuscular dysfunction (specific muscle weakness) is the exception rather than the rule, with more than three-fourths of patients having no signs or symptoms attributable to their disease [1–3]. Women are affected more than men (3 : 1) with a peak incidence between 50 and 60 years of age. Besides the skeleton and the kidneys, PHPT is associated epidemiologically with hypertension [3–5], diabetes mellitus, peptic ulcer disease, gout or pseudogout [6, 7]. These other manifestations are not related clearly to the primary hyperparathyroid process except in the multiple endocrine neoplasia (MEN) syndromes where peptic ulcer disease (MEN1) and pheochromocytoma (MEN2) can be seen. Constitutional complaints such as weakness, easy fatigability, depression and intellectual weariness are seen with some regularity but again the relationships between these complaints and hyperparathyroidism are uncertain.

Hereditary hyperparathyroidism

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MEN1

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Primary hyperparathyroidism is the most common endocrinopathy in MEN1, reaching nearly 100% penetrance by age 50 years [8]. MEN1, however, is rare in PHPT accounting for only 2–4% of cases of PHPT [8]. In most patients with MEN1, PHPT is its first clinical manifestation surfacing typically between 20 and 30 years of age. Recognition of PHPT in a young adult can lead to discovery of a kindred with MEN1. The MEN1 gene has been implicated in parathyroid tumorigenesis both in the syndrome and in a substantial number of parathyroid tumours not associated with the MEN1 syndrome [9].

MEN2

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The prevalence of PHPT in MEN2A-affected individuals is much less than its prevalence in MEN1. Figures in MEN2A vary between 20 and 30%. The highest frequency is associated with any codon 634 mutation of the RET gene [10]. Most cases of PHPT in MEN2A are associated with fewer clinical manifestations than are typically observed in MEN1.

Hyperparathyroidism-jaw tumour syndrome

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This is a rare syndrome in which ossifying jaw tumours are seen in association with PHPT [10]. Renal cysts and other lesions can be present. Similar to most of the familial syndromes, hyperparathyroidism is present in young adulthood with a penetrance that approaches 80%. Parathyroid cancer has been reported in up to 15% of cases [11].

Familial isolated hyperparathyroidism

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In this syndrome, PHPT exists amongst kindreds but no other endocrine glands are overtly involved. It is likely that this hereditary form of PHPT is due to several different syndromes including occult MEN1 and MEN2.

Familial hypocalciuric hypercalcaemia

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This disorder can be confused with isolated, sporadic PHPT. Its differentiating features are noted under differential diagnosis of hypercalcaemia.

Neonatal severe primary hyperparathyroidism

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In this rare, but life-threatening presentation, neonates are gravely ill with marked hypercalcaemia, very high PTH levels, hypotonia and respiratory distress. It is generally due to the presence of homozygotic expression of the abnormal, calcium receptor gene.

Pathology

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The single, benign parathyroid adenoma is by far the most common lesion found in patients with PHPT, occurring in 80% of patients [1]. Multiple parathyroid adenomas have been reported in 2–4% of cases. In approximately 15% of patients with PHPT, all four parathyroid glands are involved in a process characterized histologically by hyperplasia. In MEN1 or MEN2A, the patient is likely to harbour multiple, overactive glands. It is not clear whether the histological distinction is based upon a true difference in pathophysiology (adenoma versus hyperplasia) since patients with multiply overactive glands in the MEN syndromes can harbour clonal tumours and can demonstrate overactive glands that differ markedly in size. It is of historical interest that the MEN syndrome was first described by Wermer [113] in the early 1950s as a condition of ‘adenomatosis’– a term that might describe the process more accurately than ‘hyperplasia’.

Differential diagnosis of hypercalcaemia

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The differential diagnosis is very straightforward although there are many causes of hypercalcaemia. In PHPT, immunoradiometric assays (IRMA) detect PTH levels that are either frankly elevated or in the upper range of normal. In malignancy, the other most common cause of hypercalcaemia, the IRMA will not detect PTH, even if the cause of the hypercalcaemia in malignancy is PTH-related protein (PTHrP). Recently, an IRMA for PTH that measures the biologically active, full-length molecule [PTH(1–84)] has been introduced [12, 13]. The assay differs from the assay that has been in common use for years by not detecting a large moiety terminally truncated at the amino-terminal end of PTH. This large peptide, which is likely to be PTH(7–84), circulates in normal subjects and in subjects with PHPT. It may constitute up to 50% of the circulating species of PTH. Whether this newer assay that does not detect PTH(7–84) will be shown to be more useful as a diagnostic tool in PHPT than the IRMA that has been used now for over 15 years remains to be seen [14, 15].

In young individuals with PHPT, the IRMA for PTH may show levels that are closer to the middle range of normal, not in the upper range of normal or frankly elevated above the typical normal range of 10–65 pg mL−1. In individuals under 45 years of age, the normal range of PTH is actually lower because PTH levels increase with age. The normal reference range does not make this distinction. A PTH level of 50 pg mL−1 in an individual under 45 who has hypercalcaemia is distinctly abnormal since the reference range for the standard IRMA for PTH is closer to 10–45 pg mL−1 than 10–65 pg mL−1 in younger subjects (G. Segre, personal communication). In familial hypocalciuric hypercalcaemia (FHH), the PTH can also be consistent with typical PHPT, but it is distinguished from typical PHPT by (i) family history, (ii) onset of hypercalcaemia early in life, (iii) exceedingly low urinary calcium excretion, and (iv) a specific gene abnormality.

Occasionally, patients with PHPT will have normal serum calcium levels. They are discovered when a PTH level is obtained. These subjects are to be distinguished from patients with typical PHPT in whom the serum calcium is occasionally normal but generally elevated. When patients who have persistently normal serum calcium levels are discovered to have elevated PTH levels, all the known secondary causes for secondary hyperparathyroidism must be ruled out. This includes ensuring that they are vitamin D sufficient (i.e. 25-hydroxyvitamin D levels are >20 ng mL−1). These patients may represent the earliest manifestations of PHPT [16]. An explanation for why this entity is being recognized today may reside in the fact that currently, many endocrinologists and other osteoporosis specialists evaluate the skeletal status of women at-risk for osteoporosis not only with determination of bone density but also with calciotropic hormone measurements. That these patients should exist is not surprising, as clinical manifestations of PHPT are already present when the disorder is commonly diagnosed with hypercalcaemia [17, 18]. In fact, when patients are first discovered with hypercalcaemia, the hyperparathyroid process is already established with selective reductions in bone density (see below). One would expect, therefore, the earliest phase of this disease to be characterized by elevated PTH levels in the absence of hypercalcaemia. During this clinically silent period, the patient would not come to medical attention because the serum calcium is normal.

Skeletal manifestations

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Although classic radiological bone disease of PHPT is rarely seen today in the United States, with more sensitive techniques, it has become clear that skeletal involvement in mild primary hyperparathyrodism is actually quite common. The most common site to see evidence for skeletal effects is the distal third of the radius [19, 20], a site of cortical bone. The lumbar spine bone density, a site that is composed mostly of cancellous bone, is only minimally reduced. The hip region, containing a relatively equal admixture of cortical and cancellous elements, shows bone density intermediate between the cortical and cancellous sites. In postmenopausal women, the same pattern is observed [19]. In patients with oestrogen deficiency as a result of the menopause, the site affected first is the lumbar spine because cancellous bone is most sensitive to reductions in oestrogen. Relatively well-preserved density at the lumbar spine suggests that PHPT helps to protect postmenopausal women from bone loss because of oestrogen deficiency.

This densitometric profile is not always seen in PHPT. Some patients will have vertebral osteopenia at the time of presentation as was demonstrated in approximately 15% of our cohort of patients [21]. When PHPT is more advanced, involvement will be more generalized and the entire skeleton can be involved.

Histomorphometric analysis of the bone biopsy in PHPT shows cortical thinning, maintenance of cancellous bone volume, and a very dynamic process associated with accelerated bone remodelling [22, 23]. Other features emphasize the point that the cortical bone compartment is at-risk in PHPT, with good maintenance of cancellous bone volume. The biopsy studies have also shown that trabecular indices show greater connectivity than expected. Even the expected age-dependent loss of cancellous bone is not seen in PHPT [22, 24–26].

Based upon the densitometric data, it might be expected that the cortical skeleton would be at greater risk for fracture than the cancellous skeleton. Dauphine et al. [27], however, suggested that back pain and vertebral crush fractures can be a presenting feature of PHPT. Since the report of Dauphine et al. [27], reports on fracture incidence have been conflicting, with some studies showing an increase and other studies showing no increase in incidence of vertebral fractures [28–31]. The retrospective review of a 28-year Mayo Clinic experience concluded that overall fracture risk was increased at all sites except the hip [32]. These data, however, are subject to potential ascertainment bias by virtue of the possible special attention accorded these patients who are perceived to be at greater fracture risk and therefore are more likely to have more testing after complaints-like back pain. Densitometric data were not provided in the Mayo Clinic report so it was not possible to relate bone density to fracture incidence at any site.

Expectations of fracture incidence in PHPT have to take into account other effects of PTH to affect the skeleton besides a change in bone mineral density. If bone density were the only factor to consider, the distal forearm, for example, would be expected to be at the greatest risk for fracture. But, bone density is only one of several important qualities of bone, all of which are influential in the overall assessment of fracture risk. Bone size, for example, influences fracture risk. From the clinical trials of PTH in the treatment of osteoporosis as well as in observations of PHPT per se, it is likely that bone size is affected by PTH. Cortical thinning, through PTH-mediated endosteal resorption, is compensated by PTH-mediated periosteal apposition, leading to bone that may be increased in cross-sectional diameter. Bone size can be assessed noninvasively by quantitative computerized tomography. This increase in bone size helps to provide biomechanical protection, even if bone density is reduced. Thus, in PHPT, two dynamics tend to vie with each other: cortical thinning favours an increase fracture risk whilst increased bone size favours a reduction in fracture risk. Additionally, microarchitecture that is generally preserved in patients with PHPT might be another protective factor. These considerations emphasize the need for prospective studies of site-specific fracture incidence in PHPT [33–35].

Renal involvement

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Renal stone disease was more common amongst subjects with PHPT in the 1970s and 1980s [36, 37] than in the past two decades [38]. Although the incidence of nephrolithiasis is much less common than its incidence in the classic, older presentation of PHPT, kidney stones remain the most common manifestation of PHPT. Estimates in recent studies place the incidence of kidney stones at 15–20% of all patients [39]. Other renal manifestations of PHPT include hypercalciuria, which is seen in approximately 40% of patients, and nephrocalcinosis, the frequency of which is unknown. Interestingly, urinary calcium excretion per gram of creatinine is indistinguishable amongst patients with and without nephrolithiasis. Moreover, cortical bone loss is as common in those with and without nephrolithiasis [38, 40], an argument against the historical notion that patients tend to have either bone or stone disease.

Other organ involvement

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Neurological and cognitive signs or symptoms

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Perhaps the most common nonspecific complaints amongst patients with PHPT are those of weakness and easy fatigability [41]. The nature of these complaints does not represent a manifestation of a more distinct neuromuscular syndrome, characterized years ago by type II muscle cell atrophy [42, 43]. In the milder, less symptomatic form of the disease that is common today, this specific neuromuscular disorder is rarely seen [44]. Nevertheless, the nonspecific complaints of patients in this regard are noteworthy. Patients often report some degree of constitutional, behavioural and/or psychiatric symptomatology and, in some studies, such symptoms have been documented by psychometric testing [45]. Reports exist in which there is apparent improvement after successful parathyroid surgery [46–50] whilst others have not been able to document changes postoperatively [50–52]. This issue remains unsettled.

Cardiovascular manifestations

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Interest in the effect of PHPT on cardiovascular function is rooted in pathophysiological observations of hypercalcaemia in which hypertension, left ventricular hypertrophy and arrhythmias are common [53–56]. The association of overt cardiovascular symptomatology with modern day PHPT is unclear. An exception is in the setting of MEN when pheochromocytoma or hyperaldosteronism is present. Otherwise, with respect to the hypertension, cure of the hyperparathyroid state does not change the patient's blood pressure or its ease of control. Other aspects of cardiovascular function in PHPT have tended to associate involvement with severity of disease [56, 57]. Whether cardiovascular manifestations will be demonstrable with the use of highly sensitive measurements of cardiovascular function in mild asymptomatic PHPT and, if present, whether they are reversible with successful parathyroid surgery are areas in which more study is needed [58–62].

Gastrointestinal manifestations

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The 10% incidence of peptic ulcer disease in PHPT matches its presence in the general population. In MEN1, however, an increased incidence of peptic ulcer disease is seen in patients with PHPT because approximately 40% of patients have clinically apparent gastrinomas. In those patients, PHPT is associated with increased clinical severity of gastrinoma, because hypercalcaemia contributes to increase gastrin secretion from neuroendocrine tumour [63] and treatment of the associated PHPT has been reported to decrease gastrin in these patients [64, 65]. With successful direct medical therapy for gastrinoma, these patients do not necessarily have to undergo parathyroidectomy for this reason alone [66].

Although hypercalcaemia can be responsible for the development of acute pancreatitis, most large series do not confirm an increased incidence of pancreatitis in PHPT. An older experience from the Mayo Clinic, from 1950 to 1975, reported only a 1.5% incidence of pancreatitis in PHPT [67].

Vitamin D in primary hyperparathyroidism

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In countries where biochemical screening tests are not routinely employed, more classic presentations of PHPT overtly involving the skeleton and the kidneys are described [68–70]. Lack of routine screening tests in these countries helps to explain these findings but it is not an adequate explanation by itself. In these countries, vitamin D deficiency is also common, an observation that fits with the proposal made years ago by Lumb and Stanbury that PHPT is worse in the presence of vitamin D deficiency [71]. Even in mild, asymptomatic PHPT, we have shown that low 25-hydroxyvitamin D levels are associated with increased indices of disease activity [72]. With the emergence of vitamin D deficiency as a growing problem in developed countries, it is conceivable that PHPT will become once again a more symptomatic disease throughout the world.

Mortality in primary hyperparathyroidism

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Several European studies have confirmed higher mortality rates in PHPT [73, 74] whilst studies from the United States have not confirmed this impression [75]. Indeed, cardiovascular death rates were reduced in this American population. An explanation for this finding may be the change in clinical profile to a largely asymptomatic disease in which hypercalcaemia is less severe. Consistent with this idea, the degree of hypercalcaemia was found to be an independent predictor of mortality, especially the upper quartile of serum calcium concentrations [75]. Improved survival rates could be due, therefore, to lesser degrees of hypercalcaemia in PHPT. On the contrary, detailed population studies of the scope of the European reports have not yet been undertaken in this country so that there may be methodological issues that help to explain the differences in mortality rates between Europe and the United States.

Therapy

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Successful parathyroidectomy cures PHPT. As the disease profile has changed, questions have been raised concerning the advisability of surgery in all patients, with particular focus upon the asymptomatic ones. If one considers the point that many patients with PHPT are known to have the disease only because an incidental serum calcium determination was obtained, is it possible that they would have never had the disease called to their attention if it were not for the blood test? Are there some patients for whom the natural history of PHPT is benign? If some asymptomatic patients have a benign natural history, then it would be safe not to operate on them. On the contrary, asymptomatic patients may be associated with levels of hypercalcaemia or hypercalciuria that are associated with future concerns. Similarly, if bone mineral density measurements are low, at any site, they may be at risk for fractures. In these patients, surgery might be the wiser option although they are asymptomatic.

These issues have been addressed at two NIH conferences, one held in 1990 [76] and more recently in 2002 [77]. The conference in 2002 was held because the guidelines for surgery emanating from the conference held 12 years before were felt to be in need of revision in light of new knowledge about key issues that had become evident since. All symptomatic patients are still advised to undergo parathyroidectomy. Surgery is also advised in asymptomatic patients who meet any one of the following criteria: (i) serum calcium >1 mg dL−1 above the upper limits of normal; (ii) marked hypercalciuria (>400 mg day−1) or reduction in creatinine clearance by more than 30% below age- and sex- matched reference values; (iii) markedly reduced bone density (T-score < −2.5) at any site; (iv) age <50 years. A comparison between the older guidelines and the newer guidelines is provided in Table 1.

Table 1.  A comparison of new and old guidelines for surgery in asymptomatic primary hyperparathyroidism (from references [77,78])
MeasurementGuidelines, 1990Guidelines, 2002
Serum calcium (above normal, mg dL−1)1–1.61.0
24-hour urinary calcium (mg)>400>400
Creatinine clearanceReduced by 30%Reduced by 30%
Bone mineral densityZ-score < −2.0 (forearm)T-score < −2.5 (any site)
Age<50<50

Management of primary hyperparathyroidism in the familial hyperparathyroid states

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The general consensus is that when PHPT occurs in the setting of MEN1 and MEN2A, surgery is indicated, but experts differ about the timing of the parathyroid surgery and what operation to perform (see article by Udelsman). Since the disease becomes apparent in early adulthood, and there are concerns about the consequences of lifelong hypercalcaemia [78], surgery would certainly seem appropriate when the disease presents itself. Similarly, in the hyperparathyroid-jaw tumour syndrome, surgery for hyperparathyroidism is indicated. Since there is an appreciable incidence of parathyroid cancer in this syndrome, surgical management should be appropriately aggressive. In FHH, surgery is not indicated. In neonatal severe PHPT, on the other hand, emergency surgery can be lifesaving. In general, therefore, with the exception of FHH, most experts feel that parathyroid surgery is indicated when PHPT presents in the context of a familial syndrome. The guidelines considered by the Workshop on Asymptomatic Primary Hyperparathyroidism, are thus not directly applicable to these special situations.

Long-term results of surgery for hyperparathyroidism

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The surgical success rate in patients with PHPT because of MEN1 is similar to the results of surgery in sporadic disease, about 95%. The operation in MEN, however, requires subtotal parathyroidectomy or total parathyroidectomy with a fresh parathyroid autograft to the forearm [79, 80]. The recurrence rate after successful surgery is different from the sporadic form of the disease in which most patients are permanently cured. There is a 50% recurrence rate 8–12 years after successful subtotal parathyroidectomy in MEN1 [81]. Moreover, local expressions of increased parathyroid activity can appear at the site of transplanted parathyroid tissue in the forearm [82, 83]. To prevent late recurrence, an alternative to be considered is total parathyroidectomy with the subsequent lifelong need for treatment with calcium and vitamin D. Reluctance to embark upon this approach is related to difficulty establishing stable, normal levels of calcium in these subjects who have become completely hypoparathyroid. The availability of synthetic PTH analogues, although not indicated for this condition, might signal an opportunity for better calcaemic control.

Vague or constitutional symptoms may or may not improve after surgery, whilst hypertension and peptic ulcer disease, if present, are unlikely to remit (excepting the setting of the gastrinoma). Surgery is of clear benefit in reducing the incidence of recurrent nephrolithiasis [84]. After surgery, there is a 90% reduction in the incidence of stones amongst stone formers with PHPT. Surgery also leads to an improvement in bone mineral density in patients with PHPT [85]. Over a 10-year period, parathyroidectomy is associated with a 10–12% improvement in bone density at the lumbar spine and femoral neck. Postmenopausal women show a similar pattern of increased cancellous bone density. Most of the gains are seen within the first 3–4 years after successful parathyroid surgery. The mechanism by which bone density increases following parathyroid surgery is likely to be related to remineralization of the remodelling space. Other potential explanations for the postoperative increase in bone density include the possibilities that normal pulsatility and amplitude of the secretory patterns of PTH are restored. Smaller gains in bone density are seen at cortical sites after parathyroid surgery.

The capacity of the skeleton to restore itself is seen dramatically in young patients with severe PHPT. Kulak et al. [86] reported two patients with osteitis fibrosa cystica who experienced increases in bone density that ranged from 260 to 430% 3–4 years following surgery. More recently, similar observations have been made by Tritos and Hartzband [87] and by DiGregorio [88].

Long-term results of conservative follow-up in primary hyperparathyroidism

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In patients with asymptomatic PHPT for whom there are no medical contraindications, surgery is always an appropriate course to follow. However, the published guidelines by the expert Panel at the recent NIH Workshop acknowledge that many patients with asymptomatic PHPT can be followed safely without parathyroid surgery if they do not meet any guideline for surgery [77]. In the United States, about 40–50% of patients with PHPT will fit into this category in which no surgical guideline is met. Data are now available on these patients with mild PHPT who have been followed for up to 10 years without surgery or specific medical therapy [17, 89, 90]. Over this period of time, all serum and urine biochemical parameters were stable. Similarly, in the majority of patients, bone mineral density was unchanged after 10 years. When these data for the group as a whole are analysed further, it is clear that some patients who are followed without surgery will show changes and thus acquire criteria for surgery. In about 25% of these patients followed without surgery over 10 years, guidelines were met by virtue of an increasing serum or urinary calcium or declining bone mineral density.

General measures

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The Panel that convened after the 2002 Workshop on Asymptomatic Primary Hypeparathyroidism recommended a plan for monitoring patients who are not to undergo parathyroid surgery (Table 2). In patients who are going to be followed without surgery, serum calcium should be obtained every 6 months, whilst it is not necessary to monitor the urinary calcium excretion on a regular basis. Bone densitometry should be repeated annually at all three sites, the lumbar spine, the hip and the distal one-third radius site. Patients are instructed to maintain adequate hydration and to avoid thiazide diuretics. Prolonged immobilization, which can increase hypercalcaemia and hypercalciuria, is to be avoided, if at all possible.

Table 2.  A comparison of new and old management guidelines for patients with asymptomatic primary hyperparathyroidism (PHPT) who do not undergo parathyroid surgery (from references [77,78])
MeasurementOlder guidelinesNewer guidelines
  1. aThese tests are recommended for baseline assessment.

Serum calciumSemiannuallySemiannually
24-h urinary calciumAnnuallyNot recommendeda
Creatinine clearanceAnnuallyNot recommendeda
Serum creatinineAnnuallyAnnually
Bone densityAnnuallyAnnually
Abdominal X-rayAnnuallyNot recommendeda

Diet

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Conventional wisdom suggests that patients should limit their dietary calcium intake because of the hypercalcaemia. The counter argument, however, suggests that low calcium diets could lead to further increases in PTH levels as they do in normal individuals [91–93]. Given the fact that patients with PHPT maintain some sensitivity to ambient calcium concentrations, although the sensitivity is impaired, diets restricted in calcium could fuel processes associated with abnormal production of PTH. The logic of this argument could extend to diets enriched in calcium that could be expected to suppress PTH levels in PHPT, as shown by Insogna et al. [94]. Levels of 1,25-dihyroxyvitamin D have to be taken into account in this discussion, since patients with PHPT typically have concentrations that are at or above the upper limit of normal. The data of Locker et al. [95] are of interest, in this regard. In subjects with elevated levels of 1,25-dihydroxyvitamin D3, high calcium diets were associated with worsening hypercalciuria. This observation suggests that dietary calcium intake in patients can be liberalized to 1000 mg day−1 if 1,25-dihydroxyvitamin D3 levels are not increased, but should be more tightly controlled if 1,25-dihydroxyvitamin D levels are elevated. However, diets restricted in calcium are probably not advisable unless the patient has high 1,25-dihydroxyvitamin D levels and/or hypercalciuria and cannot under parathyroid surgery.

Pharmacological approaches

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Oestrogens and SERMs.

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Although the beneficial effects of oestrogen therapy in PHPT are now well founded in the literature [96–99], risks associated with oestrogen use have been well publicized recently [100]. In addition, for PHPT, the amount of oestrogen required is higher than most women can tolerate, although some positive studies have utilized lower doses [101]. Nevertheless, amongst postmenopausal women who are not candidates for surgery or refuse this option, and will agree to take oestrogen, it remains a reasonable option. The SERM, raloxifene, is a potential alternative to oestrogen. In a short-term, 8-week trial of 18 postmenopausal women, raloxifene (60 mg day−1) reduced the serum calcium by 0.5 mg dL−1 along with reduction in markers of bone turnover [102].

Bisphosphonates.

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The conceptual basis for expecting that bisphosphonates would be useful in PHPT is evident. By reducing bone turnover, without affecting PTH secretion directly, bisphosphonates could reduce serum and urinary calcium levels. Early studies with the first generation bisphosphonates, etidronate and clodronate, however, were disappointing [103, 104]. The experience with alendronate has been more encouraging. Two well-controlled doubled-blinded randomized-clinical trials, following several open label studies [105, 106], have been conducted [107, 108]. Alendronate leads to substantial gains in lumbar spine and hipbone density. Calcium and PTH levels do not change. The only experience with risedronate, another bisphosphonate, was an acute, 7-day study of 19 patients with PHPT in which the serum and urinary calcium fell significantly [109].

Calcimimetics.

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A drug that inhibits that processes associated with the synthesis and secretion of PTH would be the most specific approach to PHPT. Molecules that interact with the calcium-sensing receptor on the parathyroid cell offer this approach [110]. These molecules alter the affinity of calcium, leading to facilitation of the message stimulated by the interaction between calcium and the receptor. The first calcimimetic, (R)-N(3-methoxy-α-phenylethyl)-3-(2-chlorophenyl)-1-propylamine (R-568) [111] has been supplanted by cinacalcet, a second generation ligand [112]. Cinacalcet normalizes the serum calcium in most patients with mild hyperparathyroidism. Interestingly, the PTH concentration falls but not to normal levels. These data suggest that a drug of this type may become a useful alternative to parathyroidectomy in patients with PHPT.

In March 2004, the American Food and Drug Administration approved this calcimimetic for the treatment of hypercalcaemia in patients with parathyroid cancer or in patients on dialysis with secondary hyperparathyroidism but it has not yet been approved for PHPT.

Conclusion

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As experience with asymptomatic PHPT has grown over the past three decades, newer data have suggested new concepts in pathophysiology, evaluation and management of this common disorder. Sporadic PHPT should be distinguished from the disorder when it appears as part of the MEN syndromes. Newer knowledge about the natural history of asymptomatic PHPT, along with new approaches to parathyroid surgery, has led to new guidelines for surgical and medical management.

Conflict of interest statement

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No conflict of interest was declared.

References

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  • 1
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