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HE four parathyroid glands, through the secretion of parathyroid hormone, regulate serum calcium concentrations and bone metabolism.1 In turn, serum calcium concentrations regulate parathyroid hormone secretion; high concentrations inhibit secretion by the parathyroid glands of parathyroid hormone and low concentrations stimulate it.2 Low or falling serum calcium concentrations act within seconds to stimulate parathyroid hormone secretion, initiated by means of a calcium-sensing receptor on the surface of the parathyroid cells.2 This receptor is a heptahelical molecule, like the receptors for light, odorants, catecholamines, and many peptide hormones.3 Parathyroid hormone secretion is 50 percent of the maximal level at a serum ionized calcium concentration of 4 mg per deciliter (1 mmol per liter); this is considered the calcium set point for parathyroid hormone secretion. A slower regulation of parathyroid hormone secretion occurs over a period of hours as a result of cellular changes in parathyroid hormone messenger RNA (mRNA). Vitamin D and its metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, acting through vitamin D receptors, decrease the level of parathyroid hormone mRNA,4 and hypocalcemia increases the level of that mRNA.5,6 The slowest regulation of parathyroid hormone secretion occurs over days or even months and reflects changes in the growth of the parathyroid glands. Metabolites of vitamin D directly inhibit the mass of parathyroid cells7; hypocalcemia stimulates the growth of parathyroid cells independently of the contrary action of vitamin D metabolites.8,9 Disruptions in these processes cause hyperparathyroidism or hypoparathyroidism.

logic activity.10 The effects of parathyroid hormone on mineral metabolism are initiated by the binding of parathyroid hormone to the type 1 parathyroid hormone receptor in the target tissues.11 Parathyroid hormone thereby regulates large calcium fluxes across bone, kidneys, and intestines1 (Fig. 1). Another parathyroid hormone receptor (type 2) has been found in the brain and the intestines. Its main ligand is a peptide different from parathyroid hormone12; the functions of this receptor are not known. Parathyroid hormone–related peptide is a distant homologue of parathyroid hormone and is not a true hormone. It is synthesized in cartilage and in many more tissues than is parathyroid hormone, and its secretion is not regulated by serum calcium.13 Its local release activates the type 1 parathyroid hormone receptor, and its affinity for this receptor is similar to that of parathyroid hormone (Fig. 1).

Parathyroid hormone is stored and secreted mainly as an 84-amino-acid peptide.1 A synthetic aminoterminal fragment, parathyroid hormone (1–34), is fully active; modifications at the amino terminal, particularly at the first two residues, can abolish its bioFrom the Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md. Address reprint requests to Dr. Marx at the National Institute of Diabetes and Digestive and Kidney Diseases, Bldg. 10, Rm. 9C-101, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1802, or at StephenM@intra.niddk. ©2000, Massachusetts Medical Society.

Measurements of serum calcium, parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D are used regularly in the diagnosis and treatment of hyperparathyroidism and hypoparathyroidism; only the measurement of serum parathyroid hormone is covered here. Serum calcium should usually be measured at the same time as serum parathyroid hormone; since the ionized fraction of serum calcium is the biologically active form, it is a more useful index of hyperparathyroidism and hypoparathyroidism than are other indexes of calcium in serum. It is therefore the preferred form of serum calcium to measure. Current assays for serum parathyroid hormone are two-site assays designed to detect both amino-terminal and carboxy-terminal epitopes of the peptide.14,15 The better assays are those that are well standardized, do not cross-react with parathyroid hormone–related peptide, and are sufficiently sensitive that normal values can be distinguished from subnormal values (Fig. 2). Parathyroid hormone molecules that are reactive in these two-site immunoassays are considered “intact,” but some have no bioactivity.14-17 For example, a loss of only six amino acids to yield parathyroid hormone (7–84) eliminates all bioactivity but does not affect the immunoreactivity measured in most or all of these assays.10 In fact, about half of the parathyroid hormone detected with these assays in the serum of patients with chronic renal disease is biologically inactive.16,17 Measurements of parathyroid hormone can help characterize parathyroid tumors. Parathyroid hormone can be measured in fluid obtained from a lesion by fine-needle aspiration (usually guided ultrasonographically) or in serum from the veins of the neck and mediastinum, catheterized selectively.18 Serum test results that can be obtained in 10 to 15 minutes allow physicians to assess the completeness of the removal
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The underlying genes that develop mutations in hyperparathyroidism have been identified only in a minority of tumors. The most important diagnostic tests for this disorder are thus measurements of serum parathyroid hormone and ionized calcium (Fig.20 Similarly.19 PRIMARY HYPERPARATHYROIDISM The Parathyroid Gland in Primary Hyperparathyroidism Most patients with primary hyperparathyroidism have high serum parathyroid hormone concentrations. Negative feedback of 1. The synthesis of parathyroid hormone (PTH) and parathyroid hormone–related peptide (PTHrP) is shown on the left.21 reflecting overgrowth from somatic or germ-line mutations in parathyroidtumor precursor cells. They help to pinpoint the molecular pathway of oncogenesis and thus help to determine possible targets for treatment . Blue arrows indicate extracellular calcium flow.25(OH)2D Endocrine mechanism PTHrP Duodenal lumen PTHrP Ca2+ Blood and other extracellular fluid Autocrine–paracrine mechanism PTH receptor Cartilage and PTHrP target cells in many other tissues Figure 1. 1864 · Decem b er 2 1 . 2). most of the parathyroid tumors are monoclonal or oligoclonal. See the text for further descriptions. The Parathyroid Axis. An excess or deficiency of parathyroid hormone may be treated either at the level of parathyroid hormone release (and the parathyroid hormone receptors) or at selected sites distal to the parathyroid hormone receptors. in multiglandular hyperparathyroidism. and even more have high serum ionized calcium concentrations. 2 0 0 0 Solitary parathyroid adenomas are monoclonal or oligoclonal tumors. and their target sites of action are shown on the right. Most also have high serum calcium concentrations. of hyperfunctioning parathyroid tissue during the operation.25-dihydroxyvitamin D is not shown.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Extracellular ionized calcium Renal tubule Calciumsensing receptor Ca2+ Parathyroid cell PTH receptor Ca2+ PTH Bone Calciumsensing receptor 1. Both act by means of the same receptor (also termed the type 1 PTH receptor).

The following diagnoses are not shown: familial hypocalciuric hypercalcemia (midpoint of the range for serum calcium.41 Deficiency of these receptors is probably a consequence and not a cause of neoplastic primary hyperparathyroidism. 50 pg per milliliter). that is to say. tertiary uremic hyperparathyroidism (midpoint for serum calcium. and to convert values for serum parathyroid hormone to picomoles per liter. and adynamic bone disease with uremia (midpoint for serum calcium. 2000 pg per milliliter).000 Serum Parathyroid Hormone (pg/ml) 1.20. neonatal severe primary hyperparathyroidism (midpoint for serum calcium. it is noteworthy that no inactivating mutation of either gene has been identified in parathyroid adenomas. 11. and for serum parathyroid hormone. and for serum parathyroid hormone. but cyclin D1 overexpression is even more common in parathyroid adenomas without cyclin D1 mutations. hyperfunction in multiple parathyroid glands (a broad catVol ume 343 Numb e r 25 · 1865 . (Fig.39 These mutations result in the overexpression of the protein cyclin D1.35 Since the calcium-sensing receptor and the vitamin D receptor also mediate the inhibition of parathyroid-gland function. multiply by 0. and for serum parathyroid hormone.35-38 A small minority of parathyroid adenomas have activating mutations of the cyclin D1 gene (CCND1). hypercalciuric hypocalcemia (midpoint for serum calcium. but in the early stages of these disorders. as illustrated by the nonoverlapping domains in the figure. 12 mg per deciliter.5 mg per deciliter. and for serum parathyroid hormone. reflecting a stepwise development of the adenoma. they contribute to the formation of the tumor through a sequential inactivation of both copies of the gene.22-27 As in other tumors. 11 mg per deciliter.25. 18 mg per deciliter. 30 pg per milliliter). 9 mg per deciliter. multiply by 0. Categories and Causes of Sporadic Primary Hyperparathyroidism Solitary parathyroid adenomas account for 85 percent of cases of primary hyperparathyroidism. and for serum parathyroid hormone.000 Uremic hyperparathyroidism Primary hyperparathyroidism 100 Normal 10 Primary hyperparathyroidism Tumor hypercalcemia 1 Lower limit of detection 6 7 8 9 10 11 12 13 14 15 Serum Calcium (mg/dl) Figure 2.11.28-31 Many of the known and unknown genes that have mutated in parathyroid tumors are probably tumorsuppressor genes. 7 mg per deciliter. The diagnosis of a serious mineral disorder is usually clear.40 The abnormal parathyroid cells in primary (and secondary) hyperparathyroidism have deficient sensitivity to inhibition by calcium. 500 pg per milliliter). it is likely that two or more genes have mutated in parathyroid adenomas. 200 pg per milliliter). tertiary hyperparathyroidism after renal transplantation that corrected uremia (midpoint for serum calcium. To convert values for serum calcium to millimoles per liter. 10 pg per milliliter). and for serum parathyroid hormone. Serum Calcium and Parathyroid Hormone Concentrations in Patients with Hypercalcemia and Hypocalcemia Due to Various Causes. 3).31-34 The multiple endocrine neoplasia type 1 gene (MEN1) is a tumorsuppressor gene and the known gene that most often has somatic mutations in both copies in parathyroid adenomas (in 20 percent of cases).24. this may result in part from a deficiency of calcium-sensing receptors on parathyroid cells.MED IC A L PROGR ES S 10. the values for either serum calcium or parathyroid hormone may overlap with the normal ranges.

egory that includes hyperplasia. and a few patients (less than 1 percent) have parathyroid carcinoma.25 Black T bars indicate binding to a specific sequence of DNA. menin thereby inhibits transcriptional activation by JunD.25 which binds to the transcription factor E2F as well as to several other transcription factors. Inactivating mutations characterize tumor-suppressor–encoded proteins (menin [the product of the MEN1 tumor-suppressor gene]. which are shown in red. a transcription factor. which dimerizes (connects) with another member of the Jun–Fos family of transcription factors. Arrows show the flow of a molecule to or away from the plasma membrane. 2 0 0 0 annual incidence of primary hyperparathyroidism among postmenopausal women in Olmsted County. and retinoblastoma protein [pRb]). About 75 percent of patients with sporadic primary hyperparathyroidism are women.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Secretory granule Menin JunD PTH CDK 4 or 6 p53 P E2F Cytoplasm Cyclin D1 DNA pRb RET Nucleus G? SHC RRL Calcium-sensing receptor RR-GPI Ca2+ Plasma membrane Figure 3. p53.26 The RET -encoded tyrosine kinase in the plasma membrane (RET [yellow]) is a dimer that phosphorylates Src-homology collagen (SHC) and other substrates. which transmits information on extracellular calcium to an unidentified guanine-nucleotide–binding protein (G?) in the cytoplasm. and polyclonal hyperfunction) occurs in most of the remainder.000 in 1974.24 One substrate for phosphorylation (P) and thus blockade by CDK 4 or 6 is pRb. the calcium-sensing receptor is a growth suppressor (shown in red). RET is regulated by an extracellular RET receptor attached to the membrane by its glycosylphosphatidylinositol anchor (RR-GPI [turquoise]). Similarly. the average age at diagnosis is 55 years. Menin binds to JunD. The 1866 · Decem b er 2 1 . the high number of diagnoses in that year is attributable to the introduction of screening measurements of serum calcium. peaked at 112 per 100. The full mechanisms by which any of these mutant proteins contribute to tumor formation are not known. multiple adenomas. Protein That Causes Parathyroid-Gland Hyperfunction When Mutated.22 The p53 protein binds to DNA through a specific DNA response element. Calcium ions probably bind to the calciumsensing receptor in the plasma membrane. The annual incidence then fell markedly .27 There are at least four extracellular RET receptors. Activating mutations characterize proto-oncoproteins (cyclin D1 and RET) and are shown in yellow.23 Cyclin D1 is a cell-cycle regulator that activates the catalytic units of cyclin-dependent kinases (CDK) 4 and 6. Minnesota. each with different extracellular protein ligands (RRL). Mutation may occur through inheritance (germ-line mutation) or postnatally (somatic mutation) in abnormal parathyroid tissue.

42 During a similar period. Any of these hereditary syndromes. which result in an insensitivity of the parathyroid cells to inhibition by serum calcium.41 Neonatal Severe Primary Hyperparathyroidism Patients with multiple endocrine neoplasia type 1 have various combinations of parathyroid. very high serum parathyroid hormone concentrations. with overlap (not shown) among categories.41 The hypercalcemia persists after subtotal parathyroidectomy.49 By the age of 40. Ranges are broad.50 The normal urinary calcium excretion despite hypercalcemia is an effect of the mutated calciumsensing receptors in the kidneys. TABLE 1.000 in 1992.46 Mild hyperparathyroidism occurs in approximately 5 percent of patients receiving long-term lithium therapy. Multiple Endocrine Neoplasia Type 1 Familial hypocalciuric (or benign) hypercalcemia is characterized by lifelong hypercalcemia with normal urinary calcium excretion. such as MEN1. Acquired or somatic mutation of the second MEN1 copy can give a cell the growth advantage to become a tumor. Vol ume 343 Numb e r 25 · 1867 . such surgery is contraindicated.47. CATEGORIES OF PRIMARY HYPERPARATHYROIDISM. Zollinger–Ellison syndrome in 35 percent.41 It is caused by inactivating germ-line mutations of the calcium-sensing receptor. and marked hypercalcemia (calcium concentration. promote the emergence of a neoplastic clone in parathyroid gland Multiple 5 times normal size Monoclonal or oligoclonal 90% cured.45 Syndromes of Hereditary Primary Hyperparathyroidism by an inactivating germ-line mutation of a tumorsuppressor gene (the MEN1 gene) that is inherited as an autosomal dominant trait.49 Multiple endocrine neoplasia type 1 is caused Neonatal severe primary hyperparathyroidism is a rare and potentially lethal disorder (Table 1). but many recur Multiple Minimally enlarged Polyclonal Surgery not indicated Sequential inactivation of both Monoallelic inherited inacticopies (first copy by inheritvation of the calcium-sensance) of the MEN1 gene ing receptor gene decreases leads to the growth of one or the sensing of serum calcimore neoplastic clones in parum by parathyroid cells and athyroid glands by renal tubules Multiple Very enlarged Polyclonal Total parathyroidectomy required Biallelic inactivation of the calcium-sensing receptor gene impairs calcium sensing in parathyroid cells more than does monoallelic inactivation *All entries are typical for that disorder. thus. anterior pituitary.48 Each syndrome raises special issues for diagnosis and management (Table 1). a decline in diagnoses that may be due to the prior removal of tumors in patients whose hypercalcemia was diagnosed when they were younger.38. prolactinoma in 25 percent. and it often persists after the therapy is discontinued. It is usually caused by homozygous inactivating germ-line mutations of the calcium-sensing receptor gene. Affected neonates have a marked enlargement of all parathyroid glands. and other tumors less often.MED ICA L PROGR ES S to 8 per 100.45 Lithium stimulates parathyroid cells in vitro. the disorder is inherited in about 20 percent. abnormal Enlargement Clonality Effectiveness of parathyroidectomy Pathophysiology Not inherited 55 yr Normal to high High Autosomal dominant 25 yr Normal to high High Autosomal dominant Birth Low to normal Normal Autosomal recessive Birth Low to normal Very high One 20 times normal size Monoclonal or oligoclonal 95% cured Stepwise acquired mutations of certain genes.43 The factors associated with sporadic primary hyperparathyroidism include the external irradiation of the neck and therapy with lithium salts. more than 16 mg per deciliter [4 mmol per liter]).* FAMILIAL HYPOCALCIURIC HYPERCALCEMIA NEONATAL SEVERE PRIMARY HYPERPARATHYROIDISM CHARACTERISTIC SPORADIC ADENOMA MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 Inheritance Age at onset of hypercalcemia Urinary calcium excretion Serum parathyroid hormone concentration Parathyroid glands No.44. such as multiple endocrine neoplasia type 1. It is inherited as an autosomal dominant trait (Table 1). enteropancreatic. Parathyroid-cell hyperfunction is polyclonal and non-neoplastic. patients with multiple endocrine neoplasia type 1 have endocrine disorders with the following frequencies: hyperparathyroidism in 85 percent of patients. and other tumors. Familial Hypocalciuric Hypercalcemia Among the minority of patients with primary hyperparathyroidism caused by hyperfunction of multiple parathyroid glands. may present as isolated hyperparathyroidism in some families. there was no decline in the incidence of primary hyperparathyroidism in Sweden.41 The effects of these mutations confirm the importance of the calcium-sensing receptor in the regulation of secretion and growth of parathyroid cells.

about 80 percent of patients with this syndrome have hyperparathyroidism. which is usually manifested as a decrease in bone mass during a 10-year period of follow-up. the only effective treatment. and increased rates of bone turnover. renal cysts.66 with continued increases for up to 10 years after surgery. persistently high serum parathyroid hormone concentrations have catabolic effects on bone.58 Parathyroid hormone increases the rate of bone turnover.53 By the age of 40. still. less often it is suspected because nephrolithiasis or osteopenia is present. the risk of bone fractures in patients with mild hyperparathyroidism is similar to that in matched normal subjects (one new fracture per decade).65 Successful parathyroidectomy is followed by an increase in bone mass over a period of 6 to 12 months. when the symptom resolves. Manifestations of Primary Hyperparathyroidism The parathyroids are small endocrine glands.55 but up to half of them have subtle neurobehavioral symptoms such as fatigue and weakness. Wilms’ tumor.60.6 mg per deciliter (0. Currently.63. Often. and about 10 percent of those have a parathyroid carcinoma.64 Approximately one in four patients has osteopenia (a z score lower than –2.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Multiple Endocrine Neoplasia Type 2a Multiple endocrine neoplasia type 2a is characterized primarily by medullary thyroid carcinoma and pheochromocytoma. mainly long bones) and trabecular sites (i. mainly vertebrae). On balance.47. A consensus conference of the National Institutes of Health concluded in 1990 that surgery was not routinely needed in asymptomatic patients 50 years old or older who had a serum calcium concentration 1. Among asymptomatic patients. controlled study.61 In general. primary hyperparathyroidism progresses slowly. the disorder can cause a demineralization of bone.55 Primary hyperparathyroidism can cause cardiac calcifications and left ventricular hypertrophy.63. but surgery may be recommended for many of these patients because of the evidence that it ameliorates neurobehavioral symp- 1868 · Decem b er 2 1 .62 However. About 20 percent of patients with hyperparathyroidism have nephrolithiasis. The main results are hypercalcemia. a creatinine clearance of at least 70 percent of normal.0 to 1.63. and its effects on bone may be catabolic or anabolic. With the current restrictions on reimbursement for biochemical screening. if at all. the proportion of newly diagnosed cases of hyperparathyroidism that are asymptomatic should decrease. and in the gastrointestinal tract (Fig.64 Overall.55 Thus.67 These are still reasonable guidelines. distributed variably between cortical sites (i. 1).25 to 0.40 mmol per liter) above the upper limit of normal. but there was excess mortality among the patients in the highest quartile for serum calcium concentrations. The disorder is caused by a mutation in an unknown gene on chromosome 1q2452 and is inherited as an autosomal dominant trait. the presence of hyperparathyroidism significantly increased the risk of fracture in several bones.57 In many of these patients. whereas intermittent mild increases have anabolic effects.55 Natural History and Treatment of Primary Hyperparathyroidism In most patients. but multiple adenomas can occur either simultaneously or at different times. depending on the age of the patient. in a population-based. Instead.e. cemento-ossifying fibromas of the jaw.27 Primary hyperparathyroidism can occur by the age of 70 in up to 70 percent of patients and is usually mild. a level of urinary calcium excretion of less than 400 mg (100 mmol) per day. and renal hamartomas. in the kidneys. the effects of an excessive secretion of parathyroid hormone are manifested chemically as abnormal fluxes of calcium and phosphate in bone. particularly the vertebrae.. hypercalciuria. there has been some controversy regarding the indications for surgery. A recent populationbased study found that there was no excess mortality among all patients with hyperparathyroidism. the effects of mild primary hyperparathyroidism on bone seem to be slightly anabolic.51 Multiple endocrine neoplasia type 2a is caused by an activating mutation of the RET proto-oncogene and is inherited as an autosomal dominant trait. and the pattern of serum concentrations of the hormone over time.54. The anticalciuric effect of thiazide drugs can raise serum calcium concentrations slightly.27 Hyperparathyroidism–Jaw Tumor Syndrome There is some controversy about whether any of these changes decrease life expectancy. at the first presentation of hyperparathyroidism.and sexmatched mean) in cortical or trabecular bone.56..59 Effects on Bone The hyperparathyroidism–jaw tumor syndrome is rare and is characterized by hyperparathyroidism. the skeletal site.55. Primary hyperparathyroidism is usually first suspected when a patient is found on biochemical screening to have hypercalcemia. “z” refers to the number of standard deviations from an age. the fact that fatigue or weakness is a symptom of hyperparathyroidism becomes clear only after a successful parathyroidectomy. thereby uncovering occult hyperparathyroidism. only one parathyroid adenoma is present. the latter can occur in the absence of hypertension and can be partially reversed after parathyroidectomy.e. only about 25 percent have progressive disease. and increases in their size or enhancements of their function have no effect on neighboring tissues. or a z score higher than –2 for bone mass.52. 2 0 0 0 . most patients in whom hyperparathyroidism is diagnosed at first appear to be asymptomatic.

The lobes of the thyroid and the salivary glands are clearly visible. This secondary hyperparathyroidism usually resolves with the treatment of the underlying cause of hypocalcemia. Such patients should be advised to avoid dehydration and to keep their calcium intake at or below 1000 mg per day. creatinine. The Parathyroid Gland in Uremia Hypercalcemia in patients with uremia who have tertiary hyperparathyroidism might reflect an excess of nearly normal parathyroid cells with a consequentVol ume 343 Numb e r 25 · 1869 . surgery may have been unsuccessful. (Image courtesy of Dr. in patients with chronic renal failure. every effort should be made to identify abnormal tissue preoperatively. whether or not there are skeletal metastases. such as a deficiency or malabsorption of vitamin D.79 Patients with primary hyperparathyroidism who have severe symptomatic hypercalcemia should be treated with intravenous saline. Clara Chen. 1).73. Some patients with more severe primary hyperparathyroidism may not undergo surgery because of contraindications or because they decline the procedure. furosemide.57 Surgery is not only an effective but also a safe treatment for primary hyperparathyroidism. and intraoperative testing is often included as well. even in patients who are more than 70 years old.MED IC A L PROGR ES S toms that may be hard to detect. several treatments directed at the target tissues of parathyroid hormone action are available (Table 2). Showing a Parathyroid Adenoma in the Mediastinum.69-71 Rapid assays for measuring serum parathyroid hormone during surgery are also available. as discussed above.77 A calciumsensing–receptor agonist acts directly on parathyroid cells by way of the calcium-sensing receptor (and is thus calcimimetic) in order to inhibit the secretion of parathyroid hormone78. and cortical and trabecular bone density at 12-month intervals. secondary hyperparathyroidism can develop into a disorder of oversecretion of parathyroid hormone with hypercalcemia (tertiary hyperparathyroidism). Anterior Planar Image of the Neck and Chest of a Patient with Primary Hyperparathyroidism Obtained with Technetium-99m Sestamibi. including ultrasonography and imaging with technetium-99m sestamibi before or during surgery (Fig. Most treatments for hypoparathyroidism also affect the transfer of calcium along only one of these pathways. and in some cases dialysis.13 In contrast. UREMIC HYPERPARATHYROIDISM Secondary and Tertiary Hyperparathyroidism Hypocalcemia from any cause stimulates parathyroid hormone secretion. Most of these tumors are malignant and secrete parathyroid hormone–related peptide. The patient had undergone an unsuccessful parathyroid exploration. in others. secondary hyperparathyroidism often lasts longer and is more severe than in patients with other hypocalcemic disorders. but the rate of success may not match that of standard parathyroidectomy. however. The image shown was obtained two hours after the administration of 20 mCi of the radionuclide.80 Eventually. the further development of drugs of this type may provide effective treatments for primary and secondary hyperparathyroidism. which may be released by nonparathyroid tumors. and chronic hypocalcemia also stimulates the growth of the parathyroid glands. but these are not used routinely. and parathyroid hormone should be measured at 6-to-12-month intervals. For these patients.68 Several methods for characterizing overactive parathyroid glands are available.74 When patients require repeated operation.75 Most of these treatments for primary hyperparathyroidism change the abnormal transfer of calcium from the serum to only one target tissue of parathyroid hormone action (Table 2 and Fig.19 Patients who do not undergo surgery should be evaluated clinically. they may be less effective in patients with hyperparathyroidism than in those with hypercalcemia from other causes. and serum calcium. more often. either before or.76 Estrogen increases bone density in postmenopausal women with hyperparathyroidism but has little effect on serum calcium concentrations.72 Such approaches can decrease the duration of the surgery. albeit in the opposite direction. However. So-called minimally invasive surgical methods have become possible because imaging can be used to detect parathyroid adenomas and can sometimes be coupled with a rapid assay of parathyroid hormone during surgery. hypersecretion of parathyroid hormone by a nonparathyroid tumor is extremely rare.56.18. after renal transplantation.) HYPERCALCEMIA MEDIATED BY PARATHYROID HORMONE–RELATED PEPTIDE Hypercalcemia is sometimes caused by serum factors.75 Bisphosphonates such as alendronate and clodronate inhibit bone resorption. 4). a bisphosphonate. Parotid Submandibular Thyroid Mediastinal parathyroid Heart Figure 4.

87 The frequency of hyperparathyroid bone dis1870 · Dec em b er 2 1 . TREATMENTS FOR HYPOPARATHYROIDISM PROCESS AFFECTED BY TREATMENT TREATMENTS FOR HYPERPARATHYROIDISM Secretion of parathyroid hormone by parathyroid gland Activation of receptor for parathyroid hormone Release of calcium from bone Uptake of calcium from gut Excretion of calcium in urine Exchange with extracorporeal calcium pool *This treatment is not currently available. When treatment is initiated early. and there is no specific treatment. There is some controversy regarding the most appropriate dosage.83 Bone Disease in Patients with Chronic Renal Disease and Hyperparathyroidism ease among patients with uremia is similar to the frequency of adynamic bone diseases. secondary hyperparathyroidism is caused by hypocalcemia. it most often reflects the secretory dysfunction of autonomously functioning parathyroid cells. secondary hyperplasia of the parathyroid to later monoclonal or oligoclonal tumors is poorly understood.25-Dihydroxyvitamin D3 (calcitriol) has sometimes been given intravenously in pulsed doses in the hope of inhibiting parathyroid hormone secretion without raising serum calcium concentrations.84 Probably.81 Overactive parathyroid glands that have been removed from patients with uremia are usually overgrown with monoclonal or oligoclonal components.21. presumably polyclonal.88. TREATMENTS FOR HYPERPARATHYROIDISM AND HYPOPARATHYROIDISM.21.85. however.86.22. such as are found in some antacids and dialysis fluids.92 1. Treatment is based on raising serum calcium concentrations by the oral administration of calcium salts. and little parathyroid hypersecretion.90.91 but calcitriol given orally has similar effects.89 Treatment of Hyperparathyroidism in Patients with Chronic Renal Diseases Bone disease in patients with chronic renal disease is caused by both hyperparathyroidism and other factors. secondary hyperpara- . some of the genes that are mutated in the parathyroid glands of patients with secondary or tertiary hyperparathyroidism are different from those that are mutated in primary hyperparathyroidism. which.93 Severe secondary hyperparathyroidism is an important indication for parathyroidectomy in patients with chronic renal disease who cannot be treated adequately with the measures described above. This disorder has become less common as a result of the minimization of use of products with high concentrations of aluminum. in fact. After renal transplantation. type.91 and the most appropriate phosphate binder for these patients. severe secondary hyperparathyroidism can be prevented or at least delayed. Additional measures for treating hypocalcemia include raising the calcium concentration in the dialysis fluid and administering some form of vitamin D.86. 2 0 0 0 In patients with chronic renal failure.82-84 The cause of progression from early.80. is caused by hyperphosphatemia and decreased renal production of 1. in particular. in turn. Other patients have an adynamic bone disease or osteomalacia. The cause of adynamic bone disease is not known.87 Uremic hyperparathyroid bone disease is best treated by raising serum calcium concentrations and thereby decreasing parathyroid hormone secretion.82. Parathyroidectomy Calcium-sensing–receptor agonist* Blocker of type 1 receptor* Bisphosphonates Estrogen Blocker of vitamin D receptor* Forced natriuresis Dialysis Parathyroid autograft Parathyroid hormone (1–34)* Vitamin D analogue Calcium salts Thiazide Intravenous calcium ly high and nonsuppressible base-line secretion of parathyroid hormone.86 Some patients with chronic renal disease have hyperparathyroid uremic bone disease. and route of administration of vitamin D or vitamin D analogue90. MEN1 mutations are less frequent in the parathyroid glands of patients with uremia than in tumors of patients with sporadic primary hyperparathyroidism. which is characterized by an activation of osteoblasts and osteoclasts with excess bone resorption.94 Parathyroidectomy is also appropriate for some patients with tertiary hyperparathyroidism. these salts also ameliorate hyperphosphatemia by chelating phosphate in the intestines.87 Osteomalacia in renal failure is characterized by excess accumulation of osteoid and a minimal degree of hyperparathyroidism and has been associated with the accumulation of aluminum in bone.25-dihydroxyvitamin D. no excess accumulation of matrix. Adynamic bone disease is characterized by low activity of the bone cells.86.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 2.80.

depending on its magnitude and duration. therefore. if at all. but 1 to 3 percent of patients require parathyroidectomy an average of three years after renal transplantation because of persistent hypercalcemia.96 HYPOPARATHYROIDISM diasis–ectodermal dystrophy syndrome. Patients in whom hypocalcemia develops suddenly — for example. but the regression may be incomplete.e.98 Isolated agenesis of the parathyroid glands in one family has been attributed to a recessive deletion in the gene on chromosome 6 that normally encodes a transcription factor. Diagnosis and Causes A few cases of familial hypoparathyroidism have been described in which the cause was a mutation in the gene for parathyroid hormone that resulted in the synthesis of a defective parathyroid hormone molecule and undetectable amounts of parathyroid hormone in serum. because raising serum calcium concentrations further increases urinary calcium excretion and may cause nephrocalcinosis.25-dihydroxyvitamin D is deficient in all hypoparathyroid states.100 The hypoparathyroidism. In contrast. and its action dissipates Vol ume 343 Numb e r 25 · 1871 .. muscle spasms (i.95 About one third of patients who receive renal transplants have parathyroid hormone–induced hypercalcemia postoperatively that. and seizures. the hypoparathyroidism may be difficult to treat. representing disruptions of one or more of the steps in the development and maintenance of parathyroid hormone secretion. Developmental Defects in the Parathyroid Glands Agenesis of the parathyroid glands occurs in infants with the DiGeorge syndrome (and the closely related velocardiofacial syndrome). such as those with autoimmune polyglandular syndrome type 1. depending on its severity. If parathyroid hormone is absent or nonfunctional. conotruncal cardiac defects.. after neck surgery — are best treated with intravenous calcium and with oral or intravenous calcitriol. Both syndromes are associated with rearrangements and microdeletions affecting an unknown gene or genes on the short arm of chromosome 22. for this reason and because of such associated abnormalities as hypoadrenalism and intestinal malabsorption. Patients in whom the efficacy of treatment may vary.MED IC A L PROGR ES S thyroidism usually regresses over a period of 1 to 10 years.99 Autoimmune Hypoparathyroidism Hypoparathyroidism is a prominent component of autoimmune polyglandular syndrome type 1. Calcitriol raises serum calcium concentrations within one or two days after treatment begins. and learning disability. occurs during childhood. hypoparathyroidism is diagnosed on the basis of measurements of serum calcium and parathyroid hormone (Fig. Damage to the Parathyroid Glands from Surgery Hypocalcemia and hypercalciuria are the chief features of autosomal dominant hypercalciuric hypocalcemia. like other manifestations of the syndrome. and renal damage. therapy with a vitamin D analogue is used to ensure that there is a steady serum concentration of an active vitamin D analogue. also known as autoimmune polyendocrinopathy–candi- The main treatments available for patients with acute or chronic hypoparathyroidism are calcium salts. chronic hypoparathyroidism generally causes hypocalcemia so gradually that the only symptom may be visual impairment from cataracts caused by years of hypoparathyroidism.41. The manifestations of these syndromes include incomplete development in the branchial arches. tetany).14. 2). it should be treated cautiously. especially when it occurs rapidly. Those with chronic hypocalcemia should be treated with oral calcium and either calcitriol or vitamin D.101 Defects in the Parathyroid Hormone Molecule Hypoparathyroidism can cause hypocalcemia with consequent paresthesias.102 Defective Regulation of Parathyroid Hormone Secretion Like hyperparathyroidism.97 Any resultant defect should be treated. as reflected in persistently high serum parathyroid hormone concentrations. facial malformations. can present a threat to the renal graft and to other functions. which is caused by activating mutations of the parathyroid and renal calcium-sensing receptor. thiazides) (Table 2). are best treated with vitamin D analogues that have a short half-life. resulting in varying degrees of parathyroid and thymic hypoplasia. The parathyroid hormone–dependent renal production of 1. The syndrome is inherited as an autosomal recessive trait and is caused by mutations in an autoimmune regulator gene (AIRE ) with a known sequence but an unknown function. When it is mild.15 The causes of hypoparathyroidism are diverse. nephrolithiasis. The hypocalcemia is usually mild and asymptomatic. and drugs that increase renal tubular reabsorption of calcium (i. raising the serum calcium concentration may cause hypercalciuria. vitamin D or vitamin D analogues. Therefore. its hypocalciuric action cannot occur.e. These mutations cause excessive calcium-induced inhibition of parathyroid hormone secretion.103 TREATMENT OF HYPOPARATHYROIDISM Calcium and Vitamin D Analogues Injury to or removal of the parathyroid glands during neck surgery is the most common cause of acute or chronic hypoparathyroidism. The hypercalcemia usually subsides within months or at most a few years.

which are known collectively as Albright’s hereditary osteodystrophy. GENETIC DISORDERS OF PARATHYROID HORMONE ACTION Parathyroid hormone signaling in cells is mediated by the type 1 parathyroid hormone receptor. The hormone resistance is suppressed when the mutated GNAS1 gene is inherited from the father (i.26 Pseudohypoparathyroidism Type 1a Pseudohypoparathyroidism type 1a is characterized by short stature and other skeletal abnormalities. 2 0 0 0 Despite a confusing disease nomenclature that is a remnant of past eras. which is composed of three subunits (a. the action of vitamin D begins and dissipates over a period of two to four weeks. and g). Many patients with pseudohypoparathyroidism type 1a have resistance not only to parathyroid hormone but also to thyrotropin. paternal imprinting. including thyrotropin. It is caused by activating mutations of the type 1 parathyroid hormone receptor105 and is inherited as an autosomal dominant trait. It consists of a combination of inactivating mutations of GNAS1 and Albright’s osteodystrophy without the resistance to multiple hormones that characterizes pseudohypoparathyroidism. which may weaken the growth plates. since the parathyroid tissue used for the graft was abnormal. However. It is associated with defective methylation within GNAS1. It is associated with increased proliferation and delayed maturation of chondrocytes.. these states mimic disorders of parathyroid hormone excess or deficiency.11. A parathyroid allograft would require immunosuppression and so would be more dangerous than the disease it was meant to treat. It is caused by inactivating mutations in the a subunit of Gs 26 and is inherited as an autosomal dominant trait. or suppression. and among those that survive and function. which is most likely caused by a mutation in or near GNAS1. The growth plates show accelerated calcification and a near-absence of proliferating chondrocytes. The Gsa subunit (encoded by the GNAS1 gene) mediates cyclic AMP stimulation by parathyroid hormone and by several other peptide hormones. As many as half of these grafts fail. The indication for a parathyroid autograft is a high likelihood of postoperative hypoparathyroidism. synthetic human parathyroid hormone (1–34) is not currently available.109 Hypocalcemia in patients with pseudohypoparathyroidism type 1a or 1b should be treated in the same way as it is in patients with true hypoparathyroidism. Parathyroid-Tissue Transplantation or Parathyroid Hormone ited as an autosomal recessive trait.107.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne equally rapidly.104 The increase in urinary calcium excretion in these patients was smaller than that which occurs in patients treated with calcium and calcitriol or vitamin D. of the mutant copy occurs in selected tissues). It has been lethal prenatally.84. as well as hypocalcemia and high serum concentrations of parathyroid hormone. and low serum parathyroid hormone concentrations. b.108 Pseudohypoparathyroidism Type 1b Jansen’s chondrodystrophy is characterized by short limbs. Pseudo-pseudohypoparathyroidism Hereditary defects in parathyroid hormone action are rare but informative. CONCLUSIONS Blomstrand’s chondrodystrophy is characterized by growth impairment. Each confirms the role of an important signaling molecule. Treatments are generally satisfactory and are logically related to the defects . It is caused by inactivating mutations of the type 1 parathyroid hormone receptor106 and is inher1872 · Dec em b er 2 1 . the diagnosis of parathyroid dysfunction has become much easier. With the advent of reliable and specific assays for parathyroid hormone. mild hypercalcemia. thereby causing the short limbs. To some extent. the potential for late autograft-mediated recurrences of hyperparathyroidism is substantial. substantial insight has been gained into many disorders of the parathyroid axis.13 Jansen’s Chondrodystrophy Pseudo-pseudohypoparathyroidism occurs in families with pseudohypoparathyroidism type 1a. Blomstrand’s Chondrodystrophy Pseudohypoparathyroidism type 1b is characterized by isolated resistance to parathyroid hormone without the accompanying Albright’s osteodystrophy.e. primarily in the form of short limbs.94 Patients with hypoparathyroidism have been treated successfully with synthetic human parathyroid hormone (1–34) given subcutaneously once daily. and therefore the regulation of serum calcium has not been evaluated in vivo. Defects of the Stimulatory Guanine-Nucleotide–Binding Protein Transplantation of parathyroid tissue is appealing but rarely possible. Parathyroid autografts are sometimes placed in the forearm and can consist of either fresh parathyroid tissue or parathyroid tissue removed earlier and cryopreserved. which then acts on a stimulatory guanine-nucleotide–binding (Gs) protein. Defects of the Type 1 Parathyroid Hormone Receptor Two defects with opposite effects on the type 1 parathyroid hormone receptor have a surprisingly similar effect on bone growth.

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