4.3 Primary hyperparathyroidism

Primary hyperparathyroidism is no longer the severe disorder of ‘stones, bones, and groans’ described by Fuller Albright and others in the 1930s (1,2). Osteitis fibrosa cystica, with its brown tumours of the long bones, subperiosteal bone resorption, distal tapering of the clavicles and phalanges, and ‘salt-and-pepper’ appearance of erosions of the skull on radiograph is rare, and kidney stones are seen in only 20% of patients. Asymptomatic disease is the rule in the vast majority of patients, with the diagnosis commonly following the finding of hypercalcaemia on routine serum chemistry analysis (Table 4.3.1) (3–5). Primary hyperparathyroidism is due to a solitary parathyroid adenoma in 80% of patients (5). Most cases are sporadic, although some are associated with a history of neck irradiation, or prolonged use of lithium therapy for bipolar disease (6, 7). Multiple parathyroid adenomas have been reported in 2 to 4% of cases (8). Parathyroid adenomas can be discovered in many unexpected anatomic locations, including within the thyroid gland, the superior mediastinum, and within the thymus. Occasionally, the adenoma may ultimately be identified in the retroesophageal space, the pharynx, the lateral neck, and even the alimentary submucosa of the oesophagus (9). In approximately 15% of patients with primary hyperparathyroidism, all four parathyroid glands are involved. There are no clinical features that differentiate single versus multiglandular disease. In nearly one-half of cases, four-gland disease is associated with a familial hereditary syndrome, such as multiple endocrine neoplasia 1 (MEN 1) or MEN 2a.

Primary hyperparathyroidism affects individuals of all ages, although incidence peaks between the ages of 50 and 60 years. Women are affected approximately three times more commonly than men. At the time of diagnosis, most patients are asymptomatic (5). Hypertension, peptic ulcer disease, gout, or pseudogout have been described in association with the disease, but are not causally linked (except in cases of MEN). Patients often complain of weakness. Easy fatigability, depression, and intellectual weariness are seen with some regularity (see below). Despite these complaints, the physical examination is generally unremarkable, including a normal neuromuscular and neck examination in those with benign disease.

The biochemical hallmark of primary hyperparathyroidism is hypercalcaemia with elevated or inappropriately normal levels of parathyroid hormone (PTH). The disease is readily distinguished from malignancy, the other main cause of hypercalcaemia, in which PTH levels are suppressed. Rarely, a patient with malignancy will be shown to have elevated PTH levels due to ectopic secretion of PTH (10). Malignancy can also present in association with primary hyperparathyroidism. Ninety percent of patients with hypercalcaemia have primary hyperparathyroidism or malignancy. The broader differential diagnosis of hypercalcaemia is discussed in Chapter 4.2 (10).

Improved PTH assay methodology for PTH measurement, especially the immunoradiometric (IRMA) and immunochemiluminometric assays, has facilitated the diagnosis, although the ‘intact’ IRMA measures a large non-(1–84) PTH fragment in addition to biologically active PTH (11). A more specific assay detects only the full-length parathyroid hormone molecule, PTH (1–84) (12). While this assay has clear utility in uraemic patients, in whom the ‘intact’-IRMA has been shown to considerably overestimate elevations in biologically active hormone concentration (13), it is not clear whether this assay will aid in the routine diagnosis of primary hyperparathyroidism.

A small percentage of patients with primary hyperparathyroidism have PTH levels that are within the normal reference range as measured by either assay. In these patients, levels tend to be in the upper range of normal. In primary hyperparathyroidism, such values, although within the normal range, are clearly abnormal in a hypercalcaemic setting. This is even more evident in those under the age of 45 years. Because PTH levels normally rise with age, in an individual who is under 45 years old, one expects a more narrow, lower normal range (10–45 pg/ml). Thus, a PTH level of 50 pg/ml is distinctly abnormal in an individual under 45 who has hypercalcaemia. Occasionally, in either a younger or older patient, the PTH level as measured by the established IRMA, will be rather low, although not suppressed (i.e. in the 30 pg/ml range). Although these individuals require a more careful consideration of other causes of hypercalcaemia, in the end, they are also likely to have primary hyperparathyroidism because non-PTH-dependent hypercalcaemia should suppress the PTH concentration to levels that are either undetectable or at the lower limits of the reference range. Souberbielle et al. (14) have illustrated that the normal range is very much a function of whether or not the reference population is, or is not, vitamin D deficient. When vitamin D deficient individuals are excluded, the upper limit of the PTH reference interval decreases from 65 to 46 pg/ml. When vitamin D deficient individuals were excluded from the subjects used to establish a reference interval for ‘whole PTH’, the upper limit decreased from 44 to 34 ng/l.

There are a few exceptions to the rule that PTH is suppressed in all hypercalcaemic individuals who do not have primary hyperparathyroidism. These involve individuals who have a history of prolonged use of lithium or thiazide diuretics, and those with familial hypocalciuric hypercalcaemia (FHH). If the patient can be safely withdrawn from lithium or thiazide, this should be attempted. Serum calcium and PTH levels are then reassessed 3 months later. If the serum calcium and PTH levels continue to be elevated, the diagnosis of primary hyperparathyroidism is made. FHH is differentiated from primary hyperparathyroidism by: (1) family history, (2) markedly low urinary calcium excretion, and (3) the specific gene abnormality. In addition, subjects with FHH often demonstrate hypercalcaemia much earlier than patients with primary hyperparathyroidism, typically before 40 years of age.

There has been considerable controversy concerning the accuracy of this diagnosis. In many cases, the increases in PTH levels were due to measurement of inactive fragments by earlier generation PTH assays. Many other patients were vitamin D deficient, which can give the semblance of normal calcium levels when there is concomitant primary hyperparathyroidism (15). Furthermore, it is now accepted that the normal range of 25-hydroxyvitamin D is higher than previous designations. A diagnosis of normocalcaemic primary hyperparathyroidism requires that the patient has levels of 25-hydroxyvitamin D within the normal physiological range, namely above 30 ng/ml. Patients who have normal calcium levels, elevated PTH, and no causes for secondary hyperparathyroidism may represent the earliest manifestations of primary hyperparathyroidism. Several reports describing these individuals have recently been published, demonstrating that some, but not all, patients progress to overt hypercalcaemia while under observation (16, 17). Some even undergo successful parathyroid surgery with removal of a single or multiple adenomas, or hyperplastic glands. However, little is known about the natural history of patients with this variant of the disorder. The 2008 International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism designated normocalcaemic primary hyperparathyroidism, for the first time, as a recognized phenotype of the disease (18). In order to make this diagnosis, all causes of secondary hyperparathyroidism (including vitamin D deficiency, hypercalciuria, malabsorption, liver disease, renal disease, etc.) must first be eliminated.

In addition to abnormalities in serum calcium and PTH levels, there are other biochemical features typical of primary hyperparathyroidism. The serum phosphorus tends to be in the lower range of normal but frank hypophosphataemia is present in less than one-fourth of patients. Average total urinary calcium excretion is at the upper end of the normal range, with about 40% of all patients having frank hypercalciuria. Serum 25-hydroxyvitamin D levels tend to be low, as now defined by 25-hydroxyvitamin D levels below 30 ng/ml. The average serum calcium in our series is approximately 20 ng/ml. While mean values of 1,25-dihydroxyvitamin D₃ are in the high-normal range, approximately one-third of patients have frankly elevated levels of 1,25-dihydroxyvitamin D₃. This is due to parathyroid hormone-mediated conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. A mild hyperchloraemia is seen occasionally, due to the effect of PTH on renal acid–base balance. A typical biochemical profile is shown in Table 4.3.2.

Although osteitis fibrosa cystica is rarely seen today, over the past several decades we have come to understand that there is a typical picture of skeletal involvement in modern-day primary hyperparathyroidism.

Bone mineral densitometry can provide important information about the hyperparathyroid state, because the technique measures bone mass at sites containing differing amounts of cortical and cancellous bone. The known physiologic proclivity of parathyroid hormone to be catabolic at sites of cortical bone establishes the distal third of the radius, a readily accessible cortical site, as the key measurement site in this disease. Early densitometric studies in primary hyperparathyroidism revealed another physiological property of parathyroid hormone, namely to be anabolic at cancellous sites. In this regard, the lumbar spine, a predominantly cancellous bone, best demonstrates this proclivity. In primary hyperparathyroidism, bone density at the distal third of the radius is decreased, while bone density of the lumbar spine tends to be only minimally involved or even spared (19). The hip, which contains a relatively equal mixture of cortical and cancellous elements, shows bone density values intermediate between the cortical and cancellous sites (Fig. 4.3.1). In postmenopausal women, this pattern is opposite to what one typically experiences in the context of oestrogen deficiency, namely preferential loss of cancellous bone. Bone mineral density testing is important in the evaluation of all patients with primary hyperparathyroidism, because it is a key factor in clinical decision making regarding management and monitoring.

While this densitometric pattern is seen in the vast majority of patients with primary hyperparathyroidism, a small group of patients with mild disease have evidence of vertebral osteopenia at the time of presentation. In our natural history study, approximately 15% of patients had a lumbar spine Z-score of less than −1.5 at the time of diagnosis (20). Not all vertebral bone loss could be attributed to the effects of antecedent oestrogen deficiency, as half of these individuals were not postmenopausal women.

Finally, when primary hyperparathyroidism is more advanced, there will be more generalized involvement, and the lumbar spine will not appear to be protected. In this setting, when primary hyperparathyroidism is severe or more symptomatic, all bones can be extensively involved.

Both bone resorption and bone formation are increased in primary hyperparathyroidism (21). These skeletal dynamics can be measured by circulating markers of bone formation, such as bone-specific alkaline phosphatase activity, osteocalcin, and type 1 procollagen peptide. Levels are typically mildly elevated, but in many patients the more general marker, total alkaline phosphatase activity, is often within normal limits. In a small pilot study from our group, bone-specific alkaline phosphatase activity correlated with PTH levels and with bone mineral density (BMD) at the lumbar spine and femoral neck. Osteocalcin is also often increased in patients with primary hyperparathyroidism while procollagen extension peptides have not been shown to have significant predictive or clinical utility in the disease. Bone resorption markers also have potential clinical utility. Urinary hydroxyproline, once the resorption marker of choice, was frankly elevated in patients with osteitis fibrosa cystica, but is generally normal in mild, asymptomatic, primary hyperparathyroidism. The test is not used anymore as a marker of bone resorption in primary hyperparathyroidism. Hydroxypyridinium cross-links of collagen, pyridinoline, and deoxypyridinoline, on the other hand, are often elevated in primary hyperparathyroidism, and return to normal after parathyroidectomy. N- and C-terminal peptides of type I collagen are likely to have utility but they have not been studied extensively in primary hyperparathyroidism. Other markers of bone resorption have been limited also in their application to bone turnover in primary hyperparathyroidism. Studies of bone markers in the longitudinal follow-up of patients with primary hyperparathyroidism are limited, but indicate a reduction in these turnover markers following parathyroidectomy (21–23).

Analyses of percutaneous bone biopsies from patients with primary hyperparathyroidism have provided additional insight into the skeleton. (Fig. 4.3.2). Using the percutaneous bone biopsy of the iliac crest, cortical thinning is clearly seen and quantitated (24), consistent with the known effect of PTH to be catabolic at endocortical surfaces of bone. Osteoclasts are thought to erode more widely along the corticomedullary junction under the influence of PTH. Also as suggested by bone densitometry, cancellous bone volume is clearly well preserved in primary hyperparathyroidism. Cancellous bone is actually increased in primary hyperparathyroidism as compared to normal subjects (25, 26). When cancellous bone volume is compared among age- and sex-matched subjects with primary hyperparathyroidism or postmenopausal osteoporosis, cancellous bone volume is lowest in those with osteoporosis and highest in women with primary hyperparathyroidism. Preservation of cancellous bone volume even extends to comparisons with the expected losses associated with the effects of ageing on cancellous bone physiology. In primary hyperparathyroidism, there is no relationship between trabecular number or separation and age, suggesting that the actual plates and their connections were being maintained over time more effectively than one would have expected through the ageing process. Thus, primary hyperparathyroidism seems to retard the normal age-related processes leading to trabecular loss. In primary hyperparathyroidism, indices of trabecular connectivity are greater than expected, while indices of disconnectivity are decreased (26). Thus cancellous bone is preserved in primary hyperparathyroidism through the maintenance of well-connected trabecular plates.

Recent analyses of trabecular microarchitecture using newer technologies have largely been confirmatory. Using three-dimensional microCT technology, higher bone volume, higher bone surface area, higher connectivity density, and lower trabecular separation are seen in primary hyperparathyroidism (27, 28). There were also less marked age-related declines in bone volume and connectivity density as compared to controls, with no decline in bone surface area. Using the technique of backscattered electron imaging to evaluate trabecular BMD distribution in iliac crest bone biopsies (29), Roschger et al. showed reduced average mineralization density and increase in the heterogeneity of the degree of mineralization, consistent with reduced mean age of bone tissue. Studies of collagen maturity using Fourier transform infrared spectroscopy provide further support for these observations (30). Thus characteristics other than bone density are important determinants of bone strength in primary hyperparathyroidism. Together they suggest a mixed picture with regard to fracture risk. While reduced cortical bone density might argue for increased fracture risk, improved microarchitectural parameters would argue for reduced fracture risk.

Reports on fracture incidence in the milder presentation of primary hyperparathyroidism seen today have been conflicting (28, 31). A definitive, prospective study is unfortunately lacking. Of the larger studies that are available, one population-based prospective analysis (17 years’ duration; 23 341 person-years) showed no increase in hip fractures in women with primary hyperparathyroidism in Sweden (32). On the other hand, the Mayo Clinic retrospective review of 407 cases of primary hyperparathyroidism over a 28-year period, 1965 to 1992, suggested an increase in fracture incidence at the vertebral spine, the distal forearm, ribs, and the pelvis (33). There was no increase in hip fractures. After multivariate analysis, age and female sex remained significant independent predictors of fracture risk. These data, however, are subject to potential ascertainment bias. Patients with primary hyperparathyroidism are typically followed more conscientiously and thus fractures at some of these sites may have been recognized by greater surveillance. Recently, Vignali, Marcocci, and their associates studied the incidence of vertebral fractures in primary hyperparathyroidism as determined by dual-energy X-ray absorptiometry-based vertebral fracture assessment (34) in 150 consecutive patients and 300 healthy women matched for age and menopausal age. Vertebral fractures were detected in more subjects with primary hyperparathyroidism (24.6%) than the control subjects (4.0%; p <0.001). Among asymptomatic primary hyperparathyroidism patients, only those who met surgical guidelines showed a higher incidence of vertebral fractures compared with controls. Thus, the matter of fracture risk in primary hyperparathyroidism remains unclear.

Although the incidence of nephrolithiasis has decreased, kidney stones remain the most common manifestation of symptomatic primary hyperparathyroidism (see Table 4.3.1), affecting 15% to 20% of all patients (35). Other renal manifestations of primary hyperparathyroidism include hypercalciuria, which is seen in approximately 40% of patients, and nephrocalcinosis, the frequency of which is unknown. It is important to note that in patients with primary hyperparathyroidism who do not have renal stone disease, there is no relationship between extent of hypercalciuria and the development of kidney stones (36).

While in the 1930s it was generally accepted that bone and stone disease did not coexist in the same patient with classic primary hyperparathyroidism (1), today there is no clear evidence for two distinct subtypes of primary hyperparathyroidism. There is no distinctive set of biochemical data for patients with stone disease (37). Urinary calcium excretion per gram of creatinine, levels of 1,25-dihydroxyvitamin D, and BMD at all sites were indistinguishable among patients with and without nephrolithiasis. Furthermore, cortical bone demineralization is as common and as extensive in those with and without nephrolithiasis (37, 38).

Over the years, primary hyperparathyroidism has been associated with complaints referable to many different organ systems. Perhaps the most common complaints have been those of weakness and easy fatigability (18). Classical primary hyperparathyroidism used to be associated with a neuromuscular syndrome, characterized by easy fatigability, symmetrical proximal muscle weakness, and type II muscle cell atrophy (39). These findings were reversible after parathyroid surgery. This disorder is rarely seen today (18).

The neuropsychiatric features of primary hyperparathyroidism remain a source of controversy today. While complaints are common, association of specific symptomatology with primary hyperparathyroidism is unclear, as are expectations for postoperative improvement (18). Although much of the available literature has been limited by design issues (lack of controls, etc.) three randomized, prospective trials have been conducted recently (41–43). Unfortunately, data from these studies do not offer clarity on specific symptoms or improvement following successful parathyroid surgery. Recent data from Walker et al. suggest that there are cognitive features of primary hyperparathyroidism, some of which do improve after parathyroidectomy (44).

Both calcium and parathyroid hormone are well known to have significant cardiovascular effects. Hyper‑calcaemia has been associated with increases in blood pressure, left ventricular hypertrophy, heart muscle contractility, and arrhythmias, as well as calcification of the myocardium, heart valves, and coronary arteries. However, the association of overt cardiovascular symptomatology with modern-day primary hyperparathyroidism is unclear. Inconsistencies in the literature on the cardiovascular manifestations of primary hyperparathyroidism relate to the fact that the clinical profile of the disease has changed. Data from cohorts with marked hypercalcaemia and hyperparathyroidism show most cardiovascular involvement

While cardiovascular mortality is increased in patients with moderate to severe primary hyperparathyroidism (45–47), the limited data on mild disease have not shown any increase in mortality (48, 49). In the Mayo Clinic study, patients whose serum calcium was in the highest quartile, and thus had levels that could not have been considered mild, had increased cardiovascular mortality (48).

Hypertension, a common feature of primary hyperparathyroidism when it is part of a MEN with phaeochromocytoma or hyperaldosteronism, has also been reported to be more prevalent in sporadic asymptomatic primary hyperparathyroidism than in appropriately matched control groups. The mechanism of this association is unknown, and the condition does not clearly remit following cure of the hyperparathyroid state (50).

Coronary atherosclerosis was seen in autopsy studies such as those of Roberts and Waller (51) but these individuals had very marked hypercalcaemia (16.8–27.4 mg/dl). The incidence of coronary artery disease in primary hyperparathyroidism is more likely to be present as a function of the serum calcium level. (52) The same is true of valvular and myocardial calcification (53, 54).

Left ventricular hypertrophy (LVH) is considered separately because it is itself a strong predictor of cardiovascular events and mortality. Moreover, as opposed to the indices described above, in which involvement seems to be a function of the serum calcium level, LVH has been seen across a wide range of calcium levels (55, 56). The idea has been advanced that LVH is more a function of the parathyroid hormone level than it is the serum calcium. Some studies suggest that LVH is reversible after parathyroidectomy, a finding that could have important management implications (54–57).

While marked hypercalcaemia is associated with a reduced Q–T interval, most patients with mild hypercalcaemia do not demonstrate such electrocardiographic abnormalities. Moreover, no other conduction abnormalities or arrhythmogenic potential are observed(58, 59).

The evidence implicating vascular dysfunction in primary hyperparathyroidism has out focused upon those with severe disease (60–62). However, in those with lower calcium levels, Baykan et al. also found impaired flow-mediated (endothelial) dilation that negatively correlated with calcium levels.¹⁶⁸ There is a preliminary report on endothelial dysfunction in primary hyperparathyroidism (63) and two studies that have reported increased vascular stiffness (64, 65).

Once thought to be associated with an increased incidence of peptic ulcer disease, recent studies suggest that the incidence in primary hyperparathyroidism, approximately 10%, is similar to the general population. The exception is in patients with primary hyperparathyroidism due to MEN 1, in which approximately 40% of patients have clinically apparent gastrinomas (Zollinger–Ellison syndrome). In these patients, primary hyperparathyroidism is associated with increased clinical severity of gastrinoma, and treatment of the associated primary hyperparathyroidism has been reported to ameliorate the Zollinger–Ellison syndrome (66). Despite this, current recommendations (Consensus Conference Guidelines for Therapy of MEN 1) state that the co-existence of Zollinger–Ellison syndrome does not represent sufficient indication for parathyroidectomy, since medical therapy is so successful (67).

Although hypercalcaemia can be associated with pancreatitis, the incidence of pancreatitis in patients with primary hyperparathyroidism with serum calcium levels under 12 mg/dl is not increased. The Mayo Clinic experience from 1950 to 1975 found that only 1.5% of those with primary hyperparathyroidism had coexisting pancreatitis, and alternative explanations for pancreatitis were found for several patients (68). Similarly, although pancreatitis and pregnancy may coexist in patients with primary hyperparathyroidism, there is no evidence for a causal relationship between the disorders.

Many organ systems were affected by the hyperparathyroid state in the past. Anaemia, band keratopathy, and loose teeth are no longer seen, while gout and pseudogout are rare and the nature of the association with primary hyperparathyroidism is not clear.

The availability of data on the longitudinal course of primary hyperparathyroidism with or without surgery has led to a reconsideration of the need for surgery in all patients with asymptomatic primary hyperparathyroidism. The 15-year data from the longest prospective observational trial have recently been reported by Silverberg, Bilezikian and their colleagues (69, 70).

Parathyroidectomy resulted in normalization of the serum calcium and PTH levels permanently. Postoperatively, there was a marked improvement in BMD at all sites (lumbar spine, femoral neck, and distal third radius) amounting to gains above 10%. The improvement was most rapid at the lumbar spine but all sites showed persistent gains at all sites for the 15 years of follow-up (Fig. 4.3.3). The improvements were seen in those who met and did not meet surgical criteria at study entry, confirming the salutary effect of parathyroidectomy in this regard on all patients.

In subjects who did not undergo parathyroid surgery, serum calcium remained stable for about 12 years with a tendency for the serum calcium level to rise in years 13 to 15. Other biochemical indices, such as the PTH, vitamin D metabolites, and urinary calcium, did not change for the entire 15 years of follow-up in the group as a whole. Bone density at all three sites remained stable for the first 8–10 years. However, after this period of stability, declining cortical BMD was seen at the hip and the distal third site.

Data from three randomized trials of surgery in mild primary hyperparathyroidism, were remarkably consistent with those from the longer observational study (41–43). The three trials are limited by their short duration. In 2004, Rao et al. reported on 53 subjects, assigned either to parathyroid surgery (n = 25) or to no surgery (n = 28) followed for at least 2 years. BMD significantly increased at the femoral neck and total hip along with normalization of the serum calcium and PTH. In those who did not undergo parathyroid surgery, there were no changes in the lumbar spine or femoral neck bone density but total hip significantly declined. Forearm BMD increased, an oddity considering the vulnerability of this site to the catabolic actions of PTH. Biochemical indices were all stable. In 2007, Bollerslev et al. reported interim results of their randomized trail of parathyroidectomy versus no surgery. In this larger study (191 patients), after surgery, biochemical indices normalized and BMD increased. In the group that did not undergo parathyroid surgery, bone mineral density did not change. Also in 2007, Ambrogini et al. reported that surgery was associated with a significant increase in bone mineral density of the lumbar spine and hip after 1 year.

Parathyroidectomy remains the only currently available option for cure of primary hyperparathyroidism. In an effort to address the need for surgery in all patients with asymptomatic primary hyperparathyroidism, there have been two conferences on the management of asymptomatic primary hyperparathyroidism and recently by a third international conference to review the most up to date information (71–73). The guidelines that emerged from the 2008 conference should be helpful to the clinician faced with the asymptomatic hyperparathyroid patient. All symptomatic patients are advised to undergo parathyroidectomy. Surgery is advised in asymptomatic patients who meet any one of the following criteria: (1) serum calcium greater than 1 mg/dl above the upper limits of normal; (2) reduction in creatinine clearance to less than 60 cc/min; (3) reduced bone density (T-score less than −2.5 at any site or the presence of a fragility fracture); (4) age less than 50 years. The updated guidelines are shown in Table 4.3.3. It is important to note that urinary calcium excretion is no longer regarded to be a guideline for surgery, because this measurement is not predictive of the risk for subsequent nephrolithiasis in subjects with primary hyperparathyroidism who have not had a kidney stone.

In the hands of an expert parathyroid surgeon, 95% of abnormal parathyroid glands will be discovered and removed at the time of initial surgery (74). However, in the patient with previous neck surgery, such high success rates are not generally achieved. Preoperative localization is extremely helpful in these cases. In addition, preoperative localization is important if a minimally invasive approach (see below) is contemplated.

Noninvasive parathyroid imaging studies include technetium Tc-99m Sestamibi, ultrasound, CT scanning, MRI, and PET scanning. Tc-99m Sestamibi is generally regarded to be the most sensitive and specific imaging modality, especially when it is combined with single photon emission computed tomography. In disease caused by a single parathyroid adenoma, sensitivity has ranged from 80 to 100% with a 5 to 10% false-positive rate. However, sestamibi scintigraphy has a poor record in the context of multiglandular disease (75). Ultrasonography is highly operator dependent (76) with experience needed to differentiate a possible parathyroid adenoma from a thyroid nodule or lymph node. Rapid spiral thin slice CT scanning of the neck and mediastinum with evaluation of axial, coronal, and sagittal views can add much to the search for elusive parathyroid tissue (77). MRI can also identify abnormal parathyroid tissue, but it is expensive and less sensitive than the other noninvasive modalities. PET with or without simultaneous CT scan is also costly and of unclear utility.

Invasive localization techniques include parathyroid aspiration and arteriography. Fine needle aspiration of a parathyroid gland, identified by any of the aforementioned modalities, can be performed and the aspirate can be analysed for PTH. This technique is not recommended for routine de novo cases, and could lead to seeding of the area with parathyroid cells (78). Arteriography and selective venous sampling for PTH may be done when the gland has not been identified by any of the techniques described. The combination of arteriography and selective venous sampling can provide both anatomical and functional localization of abnormal parathyroid tissue. This approach, however, is costly and requires an experienced interventional radiologist. It is also performed in only a few centres in the USA (79).

The four-gland parathyroid gland exploration under general or local anaesthesia, with or without preoperative localization, has long been considered the gold standard surgical approach, and led to cure in over 95% of cases. However, unilateral approaches are appealing in a disease in which only a single gland is involved (in approximately 85% of cases). The procedure of choice in many centres today is the minimally invasive parathyroidectomy (MIP) (74). Preoperative parathyroid imaging is necessary, and the procedure is directed only to the site where the abnormal parathyroid gland has been visualized. Preoperative blood is obtained for comparison of the PTH concentration with an intraoperative sample obtained after removal of the ‘abnormal’ parathyroid gland. The availability of a rapid parathyroid hormone assay in or near the operating room is necessary for this procedure. If the level falls by more than 50% following resection, into the normal range, the gland that has been removed is considered to be the sole source of overactive parathyroid tissue and the operation is terminated. If the parathyroid hormone level does not fall by more than 50%, into the normal range, the operation is extended to permit a search for other overactive parathyroid tissue. There is a small risk that a minimally invasive procedure may miss another overactive gland(s) that are suppressed in the presence of a dominant gland. In Europe, MIP is being performed with an endoscopic camera (80). Yet another variation on this theme is the use of preoperative sestamibi scanning with an intraoperative gamma probe to help locate enlarged parathyroid glands. The MIP procedure seems to be as successful as more standard approaches, in the range of 95–98%.

After surgery, serum calcium and PTH levels normalize and urinary calcium excretion falls by as much as 50%. Postoperative hypocalcaemia (‘hungry bone syndrome’) is now rare. Occasionally, postoperative hypocalcaemia still occurs, especially if preoperative bone turnover markers are elevated. Although typically the early postoperative course is not complicated by symptomatic hypocalcaemia, it is important that patients be instructed to take calcium supplementation following parathyroidectomy.

There are new guidelines for monitoring those patients who are not going to have parathyroid surgery (Table 4.3.4). This includes annual measurements of the serum calcium concentration, a calculated creatinine clearance, and regular monitoring of bone mineral density. In addition, patients should be instructed to remain well hydrated and to avoid thiazide diuretics and prolonged immobilization. Dietary calcium intake in patients can safely be liberalized to 1000 mg/day if 1,25-dihydroxyvitamin D₃ levels are not increased, but should be more tightly controlled if 1,25-dihydroxyvitamin D levels are elevated.

The 2008 Workshop on Primary Hyperparathyroidism concluded that there is no drug for which there are sufficient data to recommend its use in patients with this disorder (81). Drugs that are sometimes used in patients with primary hyperparathyroidism are reviewed in this section.

While oral phosphate can lower the serum calcium by up to 1 mg/dl this drug is no longer used in primary hyperparathyroidism due to its limited gastrointestinal tolerance, possible further increase in PTH levels, and the possibility of soft tissue calcifications after long-term use.

Serum calcium reductions of 0.5 to 1.0 mg/dl in postmenopausal women with primary hyperparathyroidism who receive oestrogen replacement therapy is generally seen, while PTH is unchanged (82–84). Studies of BMD in oestrogen-treated patients with primary hyperparathyroidism have documented an increase in BMD at the femoral neck and lumbar spine (85). Data on raloxifene, a selective oestrogen receptor modulator, in primary hyperparathyroidism are limited. In a short-term (8-week) trial of 18 postmenopausal women, raloxifene (60 mg/day) was associated with a statistically significant although small (0.5 mg/dl) reduction in the serum calcium concentration and in markers of bone turnover (86). No long-term data or data on bone density are available.

By reducing bone turnover, bisphosphonates could be beneficial in primary hyperparathyroidism. The most extensive data are available with alendronate. With alendronate (87–89) bone mineral density of the lumbar spine and hip regions increases and bone turnover markers decline. A bisphosphonate such as alendronate could be useful in patients with low bone density in whom parathyroid surgery is not an option.

Targeted medical therapy for primary hyperparathyroidism is inhibition of the synthesis and secretion of PTH from the parathyroid glands. Calcimimetics that bind to the parathyroid cell calcium-sensing receptor and inhibit PTH secretion would be an example of targeted therapy. The calcimimetic, phenylalkylamine (R)-N(3-methoxy-α-phenylethyl)-3-(2-chlorophenyl)-1-propylamine (R-568), has been shown to inhibit PTH secretion in postmenopausal women with primary hyperparathyroidism (90). A second-generation calcimimetic, cinacalcet, has been the subject of recent more extensive investigation in primary hyperparathyroidism. The studies, conducted by Peacock, Shoback, Bilezikian, and their colleagues indicate that this drug can reduce the serum calcium concentration to normal in primary hyperparathyroidism (Fig. 4.3.4) (91,92). Despite normalization of the serum calcium concentration, PTH levels fell but did not return to normal, and BMD did not change, even after 3  years of cinacalet. Marcocci et al. have recently shown that cinacalcet is effective in subjects with intractable primary hyperparathyroidism (93). Silverberg et al. have shown that cinacalcet reduces calcium levels effectively in inoperable parathyroid carcinoma (94).

Neonatal primary hyperparathyroidism is a rare form of primary hyperparathyroidism caused by homozygous inactivation of the calcium-sensing receptor (95). When present in a heterozygous form, it is a benign hypercalcaemic state, known as familial hypocalciuric hypercalcaemia (FHH). However, in the homozygous, neonatal form, hypercalcaemia is severe and the outcome is fatal unless it is recognized early. The treatment of choice is early subtotal parathyroidectomy to remove the majority of hyperplastic parathyroid tissue.

Complications of primary hyperparathyroidism in pregnancy impact on the fetus and neonate, and include spontaneous abortion, low birth weight, supravalvular aortic stenosis, and neonatal tetany (96). Tetany occurs due to fetal parathyroid gland suppression by high levels of maternal calcium, which readily crosses the placenta during pregnancy. These infants have functional hypoparathyroidism after birth, and can develop hypocalcaemia and tetany in the first few days of life. Today, with most pregnant patients presenting with only mild hypercalcaemia, an individualized approach to the management is advised. Many of those with very mild disease can be followed safely, with successful neonatal outcomes without surgery. However, parathyroidectomy during the second trimester remains the traditional recommendation for this condition.

Known variously as parathyroid crisis, parathyroid poisoning, parathyroid intoxication, and parathyroid storm, acute primary hyperparathyroidism describes an episode of life-threatening hypercalcaemia in a patient with primary hyperparathyroidism (97). Clinical manifestations are associated with severe hypercalcaemia, and may include nephrocalcinosis or nephrolithiasis, subperiosteal bone resorption, and altered mental state. Laboratory evaluation is remarkable for very high serum calcium levels and PTH elevations to approximately 20 times normal. A history of persistent mild hypercalcaemia has been reported in 25% of patients. Intercurrent severe medical illness with immobilization may precipitate acute primary hyperparathyroidism (i.e. stroke, myocardial infarction, etc.). Early diagnosis, with aggressive medical management followed by surgical cure, is essential for a successful outcome.

Parathyroid carcinoma accounts for less than 0.5% of cases of primary hyperparathyroidism (98, 99) and is not associated with a malignant degeneration of previously benign parathyroid adenomas. The disease does not tend to have a bulk tumour effect, spreading slowly in the neck and causing symptoms related to hypercalcaemia. Metastatic disease is a late finding, with lung (40%), liver (10%), and lymph node (30%) involvement seen most commonly. There is no female predominance and serum calcium and PTH are far higher than are seen in benign disease. Nephrolithiasis or nephrocalcinosis is seen in up to 60% of patients, while overt radiological evidence of skeletal involvement is seen in 35 to 90% of patients. A palpable neck mass is reported in 30 to 76% of patients with parathyroid cancer.

Parathyroid carcinoma has also been reported in hereditary syndromes of hyperparathyroidism, (100–102) particularly in hyperparathyroidism-jaw tumour syndrome, a rare autosomal disorder, in which as many as 15% of patients will have malignant parathyroid disease. Parathyroid carcinoma has also been reported in familial isolated hyperparathyroidism. Recently, parathyroid carcinoma, as defined pathologically, has been reported in MEN 1 syndrome and with somatic MEN1 mutations (103, 104). Only one case of parathyroid carcinoma has been reported in the MEN 2A syndrome (105).

Parathyroid carcinomas from 10 of 15 (66%) patients with sporadic parathyroid cancer carried a mutation in the HRPT2 gene. The HRPT2 gene that encodes for the parafibromin protein has been shown to be mutated in a substantial number of patients with parathyroid cancer, as reviewed by Marcoccci et al. (98).

Surgery is the only effective therapy currently available for this disease. The greatest chance for cure occurs with the first operation. Once the disease recurs, cure is unlikely, although the disease may smoulder for many years thereafter. The tumour is not radiosensitive, although there are isolated reports of tumour regression with localized radiation therapy. Traditional chemotherapeutic agents have not been useful. When metastasis occurs, isolated removal is an option, although never curative. Chemotherapy has had a very limited role in this disease. Bradwell and Harvey have attempted an immunotherapeutic approach by injecting a patient who had severe hypercalcaemia due to parathyroid cancer with immunogenic PTH. Coincident with a rise in antibody titre to PTH, previous refractory hypercalcaemia fell impressively (106). A more recent report provided evidence of antitumour effect in a single case of PTH immunization in metastatic parathyroid cancer (107). Recent attention has been focused instead on control of hypercalcaemia. Intravenous bisphosphonates treat severe hypercalcaemia, but do not have a lasting effect. The calcimimetic agents hold promise for offering calcium-lowering effects on an outpatient basis (108). Cinacalcet has been shown to have utility in the management of parathyroid cancer (94) and has been approved by the US Food and Drug Administration for the treatment of hypercalcaemia in patients with parathyroid cancer.