Primary hyperparathyroidism
Authors: Ali Al Zahrani, Michael A Levine
Journal: The Lancet (1997)

Primary hyperparathyroidism (PHP) is a common endocrine disorder characterised by excessive secretion of parathyroid hormone (PTH) and consequent hypercalcaemia. Description of the clinical profile of PHP has changed greatly over the past three decades. There have also been advances in the understanding of the molecular pathophysiology of parathyroid neoplasia. These new insights from the clinic and laboratory have shed light on the various forms of PHP and have begun to provide a rational basis for management of the disorder. The serum calcium concentration is normally maintained within narrow limits, despite wide variations in dietary intake, the demands of the skeleton during growth, and calcium losses during pregnancy and lactation. 99% of total-body calcium is in the form of hydroxyapatite in the skeleton, and the rest is in extracellular fluids and soft tissues. In serum, about 50% of calcium is ionised at normal plasma protein concentrations, about 10% is in complexes with citrate and phosphate ions, and about 40% is protein bound. The ionised calcium is physiologically active, and the concentration is regulated by direct biological action of PTH on bone and the distal renal tubule, and indirect action on the gut by the generation of calcitriol. PTH is synthesised in the four parathyroid glands as a preprohormone (115 aminoacid residues), is converted to a prohormone (90 aminoacid residues) as it is transported across the rough endoplasmic reticulum, and is stored in secretory granules as a mature, 84-residue hormone. The rate of secretion of PTH is inversely proportional to the ambient concentration of serum ionised calcium, and is controlled mainly through interaction of extracellular calcium (and, to a lesser extent, other divalent cations) with specific calcium-sensing receptors present on the plasma membrane of the parathyroid cell. High concentrations of extracellular calcium stimulate the calcium-sensing receptors and cause a rapid, transient increase in intracellular calcium that inhibits release of PTH from the parathyroid cell. By contrast, low concentrations of serum calcium lead to increased synthesis and secretion of PTH and, over time, can result in increased parathyroid glandular mass. Fluctuations in the serum concentration of calcium cause rapid changes in PTH secretion that, within minutes, affect renal tubular reabsorption of calcium (and phosphorous) and osteoclastic bone resorption. By contrast to this short-loop feedback system, adjustments in the rate of gastrointestinal absorption of calcium via the PTHvitamin axis occur over 1–2 days, and constitute a longloop feedback system. Overall, PTH acts to raise serum calcium concentrations and to lower serum phosphorous concentrations. The integrated actions of PTH and vitamin D on the target tissues gives precise control of serum concentrations of calcium and phosphorous. PTH affects target cells in bone and kidney by binding to specific membrane receptors that are coupled by guanine-nucleotide-binding proteins (G proteins) to the signal-generating enzymes adenylyl cyclase and phospholipase C. Activation of these enzymes leads to the rapid generation of secondary messengers, including cyclic adenosine 3′;, 5′-monophosphate (cyclic AMP), inositol trisphosphate, and diacylglyerol, which stimulate activity of protein kinases A and C. These protein kinases phosphorylate specific target proteins, which in turn regulate activity of other proteins and genes that in combination bring about the physiological effects of PTH. The introduction of the multichannel autioanalyser in the early 1970s made measurement of serum calcium concentrations easier, and led to a dramatic change in clinical presentations included in the epidemiology and diagnosis of PHP. Before routine measurement of serum calcium concentration was available, PHP was thought to be an uncommon metabolic disorder that was typically associated with pronounced skeletal remodelling or nephrolithiasis.1Heath HWI Hodgson SF Kennedy MA Primary hyperparathyroidism: incidence, morbidity and potential ecnomic impact in a community.N Engl J Med. 1980; 302 (abstr).: 189-193Crossref PubMed Scopus (840) Google Scholar PHP is now recognised as a common and often symptomless endocrine disorder with an estimated prevalence of 100 cases per 100 000 normal population. The annual incidence of PHP is 25–30 patients per 100 000,1Heath HWI Hodgson SF Kennedy MA Primary hyperparathyroidism: incidence, morbidity and potential ecnomic impact in a community.N Engl J Med. 1980; 302 (abstr).: 189-193Crossref PubMed Scopus (840) Google Scholar but studies suggest that the incidence has been declining. Of the endocrine disorders, only diabetes mellitus and hyperthyroidism occur more frequently than PHP. Although PHP can occur at any age, it is most common in the fifth and sixth decades and is unusual in children.1Heath HWI Hodgson SF Kennedy MA Primary hyperparathyroidism: incidence, morbidity and potential ecnomic impact in a community.N Engl J Med. 1980; 302 (abstr).: 189-193Crossref PubMed Scopus (840) Google Scholar The disorder is two to three times more common in women than in men, and this difference increases with age.1Heath HWI Hodgson SF Kennedy MA Primary hyperparathyroidism: incidence, morbidity and potential ecnomic impact in a community.N Engl J Med. 1980; 302 (abstr).: 189-193Crossref PubMed Scopus (840) Google Scholar A single parathyroid adenoma is the underlying pathology in more than 80% of cases. Diffuse hyperplasia of all parathyroid glands occurs in about 15–20% of patients, and may in about half of these be part of a familial syndrome (eg, multiple endocrine neoplasia syndrome type 1 or type 2a). Multiple adenomas and parathyroid cysts are uncommon, and parathyroid carcinoma is very rare (<1%). The precise cause of PHP is unknown. The occurrence of PHP in familial syndromes, as well as the increased incidence of parathyroid adenomas many years after irradiation of the head and neck,2Beard CM Heath H III O'Fallon WM Anderson JA Earle JD Melton III, LJ Therapeutic radiation and hyperparathyroidism: a case-control study in Rochester, Minn.Arch Intern Med. 1989; 149: 1887-1890Crossref PubMed Google Scholar suggested a genetic basis for parathyroid adenomas. Studies have confirmed that most, if not all, parathyroid adenomas arise from a single precursor cell that has, presumably, undergone genetic change or changes. More exciting, however, is that most forms of parathyroid hyperplasia, which may begin with a stimulus for generalised (polyclonal) parathyroid-cell proliferation, also represent monoclonal expansion. Monoclonal parathyroid tumours have been identified in parathyroid hyperplasia of multiple endocrine neoplasia syndrome type 1,3Parisien M Silverberg SJ Shane E Dempster DW Bilezikian JP Bone disease in primary hyperparathyroidism.Endocrinol Metab Clin North Am. 1990; 19: 19-34PubMed Google Scholar sporadic polyglandular parathyroid hyperplasia,4Arnold A Brown MF Urena P Gaz RD Sarfati E Drueke TB Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.J Clin Invest. 1995; 95: 2047-2053Crossref PubMed Scopus (378) Google Scholar and uraemic parathyroid hyperplasia.4Arnold A Brown MF Urena P Gaz RD Sarfati E Drueke TB Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia.J Clin Invest. 1995; 95: 2047-2053Crossref PubMed Scopus (378) Google Scholar, 5Falchetti A Bale AE Amorosi A et al.Progression of uremic hyperparathyroidism involves allelic loss on chromosome 11.J Clin Endocrinol Metab. 1993; 76: 139-144Crossref PubMed Scopus (117) Google Scholar These findings suggest, therefore, that the distinction between parathyroid adenoma and hyperplasia may be artificial, and explain why available histopathological techniques cannot distinguish between the two lesions. Chromosomal rearrangements have been identified in a small subset of parathyroid adenomas. In these tumours the 5′ regulatory region of the PTH gene, normally located on the short arm of chromosome 11 (11p15), is juxtaposed upstream of the PRAD1 oncogene located on the long arm of the same chromosome (11q13).6Rosenberg CL Kim HG Shows TB Kronenberg HM Arnold A Rearrangement and overexpression of D11S287E, a candidate oncogene on chromosome 11q13 in benign parathyroid tumors.Oncogene. 1991; 6: 449-453PubMed Google Scholar, 7Arnold A Kim HG Gaz RD et al.Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma.J Clin Invest. 1989; 83: 2034-2040Crossref PubMed Scopus (310) Google Scholar The PRAD1 oncogene, now also known as cyclin D1, is a member of the cyclin family of regulatory proteins that control the normal cell cycle (mitosis). Placement of the coding region of PRAD1 next to the 5′ regulatory region of the PTH gene may lead to overexpression of PRAD1 in the cell cycle, which could accelerate the cell's progress through mitosis and increase proliferation of parathyroid cells. Only 5% of parathyroid adenomas contain a rearranged form of the PRAD1 gene, and do not seem to behave differently from other parathyroid adenomas. However, work with immunohistochemical techniques has shown increased expression of PRAD1 protein in the nuclei of 18% of parathyroid adenomas, which suggests that overexpression of PRAD1 may play a part in the pathogenesis of a larger proportion of parathyroid adenomas.8Hsi ED Zukerberg LR Yang WI Arnold A Cyclin D1/PRAD1 expression in parathyroid adenomas—an immunohistochemical study.J Clin Endocrinol Metab. 1996; 81: 1736-1739Crossref PubMed Scopus (187) Google Scholar Inactivation of tumour-suppressor genes is another important genetic mechanism of tumour development. Molecular analysis of parathyroid tumours has shown several chromosomal loci at which allelic loss commonly occurs, and which may contain candidate parathyroidtumour-suppressor genes: 6q (30%), 11p (27%), 15q (35%), 1p (30%), and 11q (38%).9Tahara H Smith AP Gaz RD Cryns VL Arnold A Genomic localization of novel candidate tumor suppressor gene loci in human parathyroid adenomas.Cancer Res. 1996; 56 (abstr).: 599-605PubMed Google Scholar Loss of genetic loci at 11q occurs in many sporadic parathyroid adenomas and in the majority of large parathyroid tumours in patients with multiple endocrine neoplasia syndrome type 1; typically the gene region associated with this disorder (MEN1), normally located at 11q13, is lost.10Larsson C Weber G Kvanta E et al.Isolation and mapping of polymorphic cosmid clones used for sublocalization of the multi endocrine neoplasia type 1 (MEN1) locus.Hum Genet. 1992; 89: 187-193Crossref PubMed Scopus (50) Google Scholar The autosomal dominant pattern of transmission of MEN1 is similar to inheritance of other familial neoplasia syndromes in which tumour-suppressor genes have been implicated, and suggests that the MEN1 gene may also be a tumour-suppressor gene. For example, patients with familial retinoblastoma or Li-Fraumeni syndrome have inherited gene mutations that inactivate one copy of the retinoblastoma or TP53 tumour-suppressor genes, respectively. Monoclonal tumours develop after somatic loss of the second copy of these genes, a common mechanism that leads to loss of heterozygosity at the involved locus. Although mutations in TP5311Cryns VL Rubio MP Thor AD Louis DN Arnold A p53 abnormalities in human parathyroid carcinoma.J Clin Endocrinol Metab. 1994; 78: 1320-1324Crossref PubMed Scopus (105) Google Scholar and deletion of the retinoblastoma gene12Cryns VL Thor A Xu HJ et al.Loss of the retinoblastoma tumorsuppressor gene in parathyroid carcinoma.N Engl J Med. 1994; 330: 757-761Crossref PubMed Scopus (290) Google Scholar, 13Dotzenrath C Teh BT Farnebo F et al.Allelic loss of the retinoblastoma tumor suppressor gene: a marker for aggressive parathyroid tumors?.J Clin Endocrinol Metab. 1996; 81: 3194-3196Crossref PubMed Scopus (72) Google Scholar have been reported in many parathyroid carcinomas and aggressive parathyroid tumours, these tumour-suppressor genes are not involved in parathyroid adenoma or hyperplasia.11Cryns VL Rubio MP Thor AD Louis DN Arnold A p53 abnormalities in human parathyroid carcinoma.J Clin Endocrinol Metab. 1994; 78: 1320-1324Crossref PubMed Scopus (105) Google Scholar, 12Cryns VL Thor A Xu HJ et al.Loss of the retinoblastoma tumorsuppressor gene in parathyroid carcinoma.N Engl J Med. 1994; 330: 757-761Crossref PubMed Scopus (290) Google Scholar, 14Hakim JP Levine MA Absence of p53 point mutations in parathyroid adenoma and carcinoma.J Clin Endocrinol Metab. 1994; 78 (abstr).: 103-106Crossref PubMed Scopus (40) Google Scholar Inactivation of tumour-suppressor genes may contribute to the abnormal proliferation of parathyroid cells, but it does not explain the primary pathophysiological hallmark of PHP, which is an apparent reduction in the ability of extracellular calcium to suppress PTH secretion. Therefore, studies have focused on possible mutations in the genes that encode the calcium-sensing receptor as a possible explanation for the defective sensitivity of parathyroid adenomas to calcium. Excessive parathyroid function occurs in patients with familial (benign) hypocalciuric hypercalcaemia, an autosomal dominant disorder in which decreased ability of calcium to suppress PTH secretion is due to heterozygous germline mutations that inactivate the calcium-sensing-receptor gene.15Pollak MR Chou YH Marx SJ et al.Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism: effects of mutant gene dosage on phenotype.J Clin Invest. 1994; 93: 1108-1112Crossref PubMed Scopus (236) Google Scholar Similar homozygous mutations are found in patients with severe neonatal hyperparathyroidism,15Pollak MR Chou YH Marx SJ et al.Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism: effects of mutant gene dosage on phenotype.J Clin Invest. 1994; 93: 1108-1112Crossref PubMed Scopus (236) Google Scholar a life-threatening hypercalcaemic disorder in which parathyroid hyperplasia occurs. Although somatic mutations of the gene for the calcium-sensing receptor have not been found in sporadic parathyroid tumours16Thompson DB Samowitz WS Odelberg S Davis RK Szabo J Heath H III Genetic abnormalities in sporadic parathyroid adenomas: loss of heterozygosity for chromosome 3q markers flanking the calcium receptor locus.J Clin Endocrinol Metab. 1995; 80: 3377-3380Crossref PubMed Google Scholar, 17Hosokawa Y Pollak MR Brown EM Arnold A Mutational analysis of the extracellular Ca(2+)-sensing receptor gene in human parathyroid tumors.J Clin Endocrtinol Metab. 1995; 80: 3107-3110PubMed Google Scholar expression of the receptor is greatly reduced on both parathyroid adenomas18Kifor O Moore Jr, FD Wang P et al.Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism.J Clin Endocrinol Metab. 1996; 81: 1598-1606Crossref PubMed Google Scholar and hyperplastic parathyroid glands in patients with uraemic hyperparathyroidism18Kifor O Moore Jr, FD Wang P et al.Reduced immunostaining for the extracellular Ca2+-sensing receptor in primary and uremic secondary hyperparathyroidism.J Clin Endocrinol Metab. 1996; 81: 1598-1606Crossref PubMed Google Scholar or multiple endocrine neoplasia syndrome type 1.19Carling T Rastad J Ridefelt P et al.Hyperparathyroidism of multiple endocrine neoplasia type 1: candidate gene and parathyroid calcium sensing protein expression.Surgery. 1995; 118: 924-930Summary Full Text PDF PubMed Scopus (11) Google Scholar Other studies have examined a role for defective vitamin D regulation of PTH gene expression in the development of parathyroid neoplasia. A molecular study of the polymorphic gene that encodes the vitamin D receptor found that patients with PHP are more likely than normal postmenopausal women to have the bb genotype,20Carling T Kindmark A Hellman P et al.Vitamin D receptor genotypes in primary hyperparathyroidism.Nat Med. 1995; 1: 130911Crossref Scopus (188) Google Scholar and, therefore, have two copies of a vitamin-D-receptor allele that has been associated wth decreased expression. PHP is most often diagnosed after the unexpected discovery of hypercalcaemia in a symptom-free patient. When PHP does cause symptoms, the skeleton and kidneys are the main organs affected. Other organ systems can be affected, however, and gastrointestinal, neuromuscular, and psychiatric symptoms are well-recognised, although uncommon, features of PHP. The symptoms and signs of PHP are, in part, related to the degree of hypercalcaemia and, accordingly, a few patients may present with acute onset of severe hypercalcaemia, which is a life-threatening condition and called hyperparathyroid crisis. Patients with multiple endocrine neoplasia syndromes often have additional clinical features that are related to the involvement of other endocrine tissues (eg, pituitary prolactinoma or pancreatic gastrinoma). Hyperparathyroidism affects mainly cortical bone with sparing of the cancellous bone.21Parisien M Mellish RW Silverberg SJ et al.Maintenance of cancellous bone connectivity in primary hyperparathyroidism: trabecular strut analysis.J Bone Miner Res. 1992; 7: 913-919Crossref PubMed Scopus (135) Google Scholar The classic bone disease of hyperparathyroidism, osteitis fibrosa cystica (figure 1), is rarely seen today. Subperiosteal resorption, often present at the radial aspects of the middle phalanges, is the most sensitive radiological sign of severe parathyroid bone disease. Additional features may include resorption of the distal phalanges, distal tapering of the clavicles, and a "salt and pepper" appearance of the skull. Locally destructive lesions, such as bone cysts and "brown tumours", occur only in more advanced stages of hyperparathyroid bone disease. Although overt bone disease has become unusual, studies by dual-energy X-ray absorptiometry or bone histomorphometry have shown that bone density is reduced in regions of cortical bone but is normal in areas of cancellous bone (eg, the spine) in patients with mild PHP, the reverse of effects in postmenopausal women. Bone mineral density in the cancellous bone of the spine is, however, reduced in a small subset of patients with PHP, which is more typical of the pattern of postmenopausal osteoporosis,22Silverberg SJ Locker FG Bilezikian JP Vertebral osteopenia: a new indication for surgery in primary hyperparathyroidism.J Clin Endocrinol Metab. 1996; 81: 4007-4012Crossref PubMed Scopus (169) Google Scholar and implies a loss of the protective, anabolic effect of PTH on cancellous bone. Sensitive assays for biochemical markers of bone metabolism have expanded the description of bone disease in patients with mild PHP. Markers of bone formation (bone-specific alkaline phosphatase and osteocalcin), as well as markers of bone resorption (deoxypyridinoline and N-telopeptide), are generally present in increased concentrations in PHP.23Garnero P Gineyts E Riou JP Delmas PD Assessment of bone resorption with a new marker of collagen degradation in patients with metabolic bone disease.J Clin Endocrinol Metab. 1994; 79: 780-785Crossref PubMed Scopus (198) Google Scholar, 24Seibel MJ Gartenberg F Silverberg SJ Ratcliffe A Robins SP Bilezikian JP Urinary hydroxypyridinium cross-links of collagen in primary hyperparathyroidism.J Clin Endocrinol Metab. 1992; 74: 481-486Crossref PubMed Scopus (106) Google Scholar The occurrence of nephrolithiasis in PHP has decreased greatly because more symptom-free patients are discovered through routine biochemical testing. Early studies of PHP had reported that 40% of patients had renal calculi, but this proportion has since decreased to 15–20%. Nevertheless, nephrolithiasis appears to be the most common complication of PHP, and the occurrence of PHP among all patients who develop stones is about 5%. Screening of all patients who develop stones for PHP, particularly women, in whom isolated nephrolithiasis is less common, is, therefore, reasonable. Nephrocalcinosis, which appears radiologically as a diffuse deposition of calcium and phosphate throughout the kidneys, can also occur in patients with PHP and may be associated with stones. Hypercalciuria (24 h urine calcium excretion >250 mg for women, and >300 mg for men) occurs in about 40% of patients with PHP and has been implicated in the pathogenesis of nephrolithiasis. The degree of hypercalciuria exceeds the degree of hypercalcaemia in many cases. Patients with PHP commonly complain of becoming tired easily. Some patients have proximal muscle weakness that primarily affects the lower extremities and is associated with neuropathic atrophy of type-2 muscle fibres.25Patten BM Bilezikian JP Mallette LE Prince A King Engle W Aurbach GD The neuromuscular disease of hyperparathyroidism.Ann Intern Med. 1974; 80 (abstr).: 182-193Crossref PubMed Scopus (215) Google Scholar Other patients have symptoms that constitute a poorly characterised neuropsychiatric syndrome, from decreased attentiveness and ability to concentrate to severe depression. It is unclear to what extent these symptoms are related to hypercalcaemia or PHP. Hypercalcaemia is the biochemical hallmark of PHP and is an essential diagnostic criterion. Hypercalcaemia may be mild or even intermittent in some patients. The ionised serum calcium may be raised in some patients who have normal concentrations of total serum calcium. The serum phosphate concentration is usually in the low or low/normal range because of depressed renal-tubular reabsorption. A mild hyperchloraemic (chloride >103 mmol/L) metabolic acidosis is common. Other biochemical features of PHP include increased circulating concentrations of 1,25-dihydroxyvitamin D, increased urinary excretion of nephrogenous cyclic AMP, and decreased tubular reabsorption of phosphate. Several formulae that use serum concentrations of calcium, phosphate, chloride, albumin, or alkaline phosphatase have been devised to distinguish between PHP and other causes of hypercalcaemia. None of these algorithms is, however, entirely satisfactory. PHP and malignant disorders account for more than 90% of cases of hypercalcaemia. The availability of highly sensitive and specific immunometric assays for intact PTH (1–84) has greatly simplified the diagnosis of PHP and makes extensive diagnostic investigation unnecessary in most cases. Use of immunoassays for intact PTH and PTH-related protein, the humoral mediator of malignancy-associated hypercalcaemia, further refines the distinction between these two disorders. Circulating PTH is high in PHP, and low or undetectable in malignancyassociated hypercalcaemia. Conversely, PTH-related protein is high in most patients with malignancy-associated hypercalcaemia and undetectable in PHP. As the epitope specificity and sensitivity of the new assays for PTH-related protein vary widely, clinicians who rely upon measurement of PTH-related protein in the differential diagnosis of hypercalcaemia must be aware of the immunochemical and clinical performance characteristics of the specific assay they use. Several additional caveats are worth mentioning. First, concentrations of PTH-related protein will not be increased in all cancer patients with raised serum calcium concentrations, particularly those in whom hypercalcaemia is due to osteolytic metastases or multiple myeloma. In these patients, additional testing (eg, serum protein electrophoresis, haemogram, endoscopy, and imaging studies) will be needed to identify the cancer. Second, serum concentrations of PTH-related protein can be raised in patients who do not have a malignant tumour; for example, concentrations of C-terminal PTH-related protein are increased in patients who are pregnant or who have renal insufficiency. With few exceptions, other non-parathyroid causes of hypercalcaemia are accompanied by low serum concentrations of PTH. Chronic treatment with lithium may produce hypercalcaemia that is associated with high serum PTH,26Mallette LE Khouri K Zengotita H Hollis BW Malini S Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume.J Clin Endocrinol Metab. 1989; 68: 654-660Crossref PubMed Scopus (90) Google Scholar a clinical picture indistinguishable from PHP. Discontinuation of lithium therapy, if possible, may be necessary to show the correct diagnosis. Familial hypocalciuric hypercalcaemia must always be considered in patients with symptomless hypercalcaemia. These patients are characteristically healthy, despite hypercalcaemia since the first decade of life; they have hypocalciuria, and serum concentrations of PTH are usually, but not always, normal. During the prescreening era, PHP was typically diagnosed only when symptoms occurred, and parathyroid surgery was commonly used. The proportion of symptom-free patients diagnosed with PHP has, however, increased since the introduction of the multichannel autoanalyser,1Heath HWI Hodgson SF Kennedy MA Primary hyperparathyroidism: incidence, morbidity and potential ecnomic impact in a community.N Engl J Med. 1980; 302 (abstr).: 189-193Crossref PubMed Scopus (840) Google Scholar and with this change new questions about the management of these patients have arisen. Surgery, with its attendant risks, for all patients now seems unwise when many will have no features of metabolic bone or stone disease. On the other hand, long-term data about the potential adverse effects of PHP without symptoms are lacking. These issues and others were considered by a National Institutes of Health Consensus Development Conference in 1991, which produced a set of guidelines about the advisability of surgery for PHP.27Potts Jr, JT Fradkin JE Aurbach GD Bilezikian JP Raisz LG Proceedings of the NIH Consensus Development Conference on Diagnosis and Management of Asymptomatic Primary Hyperparathyroidism.J Bone Miner Res. 1991; 6 (abstr).: S1-S165Google Scholar Surgery is generally recommended for patients if the total serum calcium concentration is more than 1 mg/dL (0·250 mmol/L) above the upper limit of normal range; if there is evidence of overt bone disease (eg, osteitis fibrosa cystica) or if cortical bone mineral density is more than 2 SD below the adjusted mean for age, and sex; if there is reduced renal function, stone disease (nephrolithiasis or nephrocalcinosis), or significant hypercalciuria (>400 mg [9·98 mmoles] per day); and if there has been an episode of acute PHP. Last, patients who are young (<50 years) should be considered for surgery even in the absence of other indications, since younger patients will have PHP for longer than older people and, therefore, have a greater theoretical risk of complications. Although only about 20% of patients with PHP have symptoms at presentation, these guidelines will identify an additional 30–40% of symptom-free patients who are candidates for surgery. Therefore, about 50% of patients with PHP will meet criteria for surgery. When done by an experienced parathyroid surgeon, parathyroidectomy is curative in more than 90% of cases. Not unexpectedly, success rates are lower when less experienced surgeons do the exploration, particularly in cases of multiple gland disease or cancer. Surgical complications are unusual, but include hypoparathyroidism and injury to the recurrent laryngeal nerve with attendant vocal cord dysfunction. Most patients experience mild and transient postoperative hypocalcaemia, but those with extensive skeletal disease can develop protracted hypocalcaemia that is due to remineralisation of "hungry bones". Preoperative localisation investigations such as ultrasonography, computed tomography, magnetic resonance imaging, and scintigraphy, are generally not indicated for patients who have not had parathyroid surgery previously. These techniques have an overall sensitivity of 60–70% and a false-positive rate of 12–15%—statistics that are far less favourable than the surgical success rate of 90–95% in initial operations. Moreover, no well-controlled studies have shown that these techniques lead to either reduced operating time or improved surgical success. On the other hand, preoperative localisation studies greatly increase the success rate of surgery in patients who have previously undergone an unsuccessful parathyroid exploration. Of the non-invasive localisation investigations, technetiumsestamibi scintigraphy with single photon emission computed tomography imaging seems to be the most promising new technique (figure 2).28Hindie E Melliere D Simon D Perlemuler L Galle P Primary hyperparathyroidism: is technetium99-sestamibi/iodine123 subtraction scanning the best procedure to locate enlarged glands before surgery?.J Clin Endocrinol Metab. 1995; 80: 302-307Crossref PubMed Google Scholar However, since all the non-invasive localisation techniques have shortcomings, two positive tests are usually required for accurate and reliable localisation. When computed tomography or ultrasound shows a suspicious lesion that is not confirmed by a second non-invasive technique, direct fine-needle aspiration of the lesion to measure PTH concentrations will often eliminate the need to proceed to invasive localisation techniques. Often localisation will not be achieved by non-invasive techniques, and invasive investigations, such as parathyroid arteriography or selective venous sampling for PTH, will be necessary. These investigations require experience and close collaboration between radiologist, endocrinologist, and surgeon, and, therefore, patients who need these studies should be referred to specialised centres. One important benefit of successful parathyroid surgery is an improvement in bone density. Dual energy X-ray absorptiometry has shown increases in bone density at several skeletal sites in the 4 years after surgery. These changes were more striking in regions containing cancellous bone (lumbar spine and femoral neck) than in sites of cortical bone (distal radius), and were even observed in postmenopausal women with PHP.22Silverberg SJ Locker FG Bilezikian JP Vertebral osteopenia: a new indication for surgery in primary hyperparathyroidism.J Clin Endocrinol Metab. 1996; 81: 4007-4012Crossref PubMed Scopus (169) Google Scholar, 29Silverberg SJ Gartenberg F Jacobs TP et al.Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism.J Clin Endocrinol Metab. 1995; 80: 729-734Crossref PubMed Scopus (229) Google Scholar Patients with symptomless PHP who do not meet criteria for surgery can be treated conservatively. Regular reassessment is essential to detect complications that would justify prompt referral for surgery. There is little biochemical progression or continued loss of bone density in many patients who are followed without treatment,30Silverberg SJ Gartenberg F Jacobs TP et al.Longitudinal measurements of bone density and biochemical indices in untreated primary hyperparathyroidism.J Clin Endocrinol Metab. 1995; 80: 723-728Crossref PubMed Google Scholar which suggests that the natural history of mild PHP can be benign. Recommendations for medical surveillance include measurement of serum calcium every 6 months, and measurement of urinary calcium and creatinine every 12 months. Although bone density seems to remain stable in patients with mild PHP,22Silverberg SJ Locker FG Bilezikian JP Vertebral osteopenia: a new indication for surgery in primary hyperparathyroidism.J Clin Endocrinol Metab. 1996; 81: 4007-4012Crossref PubMed Scopus (169) Google Scholar, 29Silverberg SJ Gartenberg F Jacobs TP et al.Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism.J Clin Endocrinol Metab. 1995; 80: 729-734Crossref PubMed Scopus (229) Google Scholar without specific guildelines it seems prudent to monitor bone mineral density (including the distal radius, an important site of cortical bone) in symptom-free patients at intervals of 1–3 years. Medical managment is also appropriate for patients who have symptoms but are unfit for surgery, refuse surgery, or have inoperable parathyroid cancer. Urgent medical treatment of hypercalcaemia is often necessary to stabilise patients before surgery. Several general guidelines can be recommended to all patients with hypercalcaemia who will be followed medically. Patients should be instructed to avoid diuretics, particularly thiazides, and to drink plenty of fluids. Ambulation should be encouraged. An appropriate dietary intake of calcium has not been determined. A high calcium intake could, theoretically, aggravate hypercalcaemia, whereas a low intake might stimulate further secretion of PTH. Until more information is available, patients should moderate their dietary calcium intake and avoid calcium or vitamin D supplements. Safe and effective therapeutic agents are still lacking for the chronic medical treatment of PHP. Oral phosphate supplements can lower serum calcium concentrations by about 0·5–1·0 mg/dL (0·125–0·250 mmol/L) and can greatly reduce urinary calcium excretion. Oestrogen therapy has been advocated for treatment of bone density loss in postmenopausal women with PHP. Oestrogen inhibits PTH-mediated bone resorption and produces modest decreases in serum and urine calcium concentrations, but PTH concentrations are generally not affected. Other agents, such as the bisphosphonates and calcitonin, are effective in the acute management of hypercalcaemia, but seem to be of little benefit in the longterm treatment of PHP. Novel therapeutic agents for PHP are now being developed, however. The most promising of these drugs are the calcimimetic compounds that target calcium-sensing receptors present on the parathyroid cell. These agents increase the sensitivity of the receptor to activation by extracellular calcium,31Nemeth EF Ca2+ receptor-dependent regulation and cellular functions.News Physiol Sci. 1995; 10: 1-5Google Scholar and are currently under clinical trial as a treatment for hyperparathyroidism. For the clinician, definition of the evolving natural history of PHP will facilitate development of the best management strategies, particularly for patients who have no symptoms. For the scientist, clarification of the molecular basis of PHP will enable earlier detection of PHP and multiple endocrine neoplasia syndrome type 1. The discovery of the calcium-sensing receptor provides not only insights into pathophysiology of PHP but also the promise of new treatments for hyperparathyroidism.