MED ICA L PROGR ES S

Medical Progress H YPERPARATHYROID AND H YPOPARATHYROID D ISORDERS

STEPHEN J. MARX, M.D.

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.
STRUCTURE AND ACTIONS OF PARATHYROID HORMONE

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 hormonerelated 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).
MEASUREMENT OF PARATHYROID HORMONE IN SERUM

Parathyroid hormone is stored and secreted mainly as an 84-amino-acid peptide.1 A synthetic aminoterminal fragment, parathyroid hormone (134), 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. nih.gov. 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 hormonerelated 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 (784) 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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Extracellular ionized calcium Renal tubule Calciumsensing receptor

Ca2+

Parathyroid cell

PTH receptor Ca2+ PTH Bone

Calciumsensing receptor

1,25(OH)2D Endocrine mechanism PTHrP Duodenal lumen PTHrP

Ca2+

Blood and other extracellular fluid

Autocrineparacrine mechanism

PTH receptor

Cartilage and PTHrP target cells in many other tissues

Figure 1. The Parathyroid Axis. The synthesis of parathyroid hormone (PTH) and parathyroid hormonerelated peptide (PTHrP) is shown on the left, and their target sites of action are shown on the right. Both act by means of the same receptor (also termed the type 1 PTH receptor). Negative feedback of 1,25-dihydroxyvitamin D is not shown. See the text for further descriptions. 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. Blue arrows indicate extracellular calcium flow.

of hyperfunctioning parathyroid tissue during the operation.19

PRIMARY HYPERPARATHYROIDISM

The Parathyroid Gland in Primary Hyperparathyroidism

Most patients with primary hyperparathyroidism have high serum parathyroid hormone concentrations. Most also have high serum calcium concentrations, and even more have high serum ionized calcium concentrations. The most important diagnostic tests for this disorder are thus measurements of serum parathyroid hormone and ionized calcium (Fig. 2).
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Solitary parathyroid adenomas are monoclonal or oligoclonal tumors.20 Similarly, in multiglandular hyperparathyroidism, most of the parathyroid tumors are monoclonal or oligoclonal,21 reflecting overgrowth from somatic or germ-line mutations in parathyroidtumor precursor cells. The underlying genes that develop mutations in hyperparathyroidism have been identified only in a minority of tumors. They help to pinpoint the molecular pathway of oncogenesis and thus help to determine possible targets for treatment

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10,000

Serum Parathyroid Hormone (pg/ml)

1,000
Uremic hyperparathyroidism Primary hyperparathyroidism

100

Normal

10
Primary hyperparathyroidism Tumor hypercalcemia

Lower limit of detection 6 7 8 9 10 11 12 13 14 15

Serum Calcium (mg/dl)

Figure 2. Serum Calcium and Parathyroid Hormone Concentrations in Patients with Hypercalcemia and Hypocalcemia Due to Various Causes. The diagnosis of a serious mineral disorder is usually clear, as illustrated by the nonoverlapping domains in the figure, but in the early stages of these disorders, the values for either serum calcium or parathyroid hormone may overlap with the normal ranges. The following diagnoses are not shown: familial hypocalciuric hypercalcemia (midpoint of the range for serum calcium, 11.5 mg per deciliter, and for serum parathyroid hormone, 30 pg per milliliter); neonatal severe primary hyperparathyroidism (midpoint for serum calcium, 18 mg per deciliter, and for serum parathyroid hormone, 500 pg per milliliter); hypercalciuric hypocalcemia (midpoint for serum calcium, 7 mg per deciliter, and for serum parathyroid hormone, 10 pg per milliliter); tertiary uremic hyperparathyroidism (midpoint for serum calcium, 11 mg per deciliter, and for serum parathyroid hormone, 2000 pg per milliliter); tertiary hyperparathyroidism after renal transplantation that corrected uremia (midpoint for serum calcium, 12 mg per deciliter, and for serum parathyroid hormone, 200 pg per milliliter); and adynamic bone disease with uremia (midpoint for serum calcium, 9 mg per deciliter, and for serum parathyroid hormone, 50 pg per milliliter). To convert values for serum calcium to millimoles per liter, multiply by 0.25, and to convert values for serum parathyroid hormone to picomoles per liter, multiply by 0.11.

(Fig. 3).22-27 As in other tumors, it is likely that two or more genes have mutated in parathyroid adenomas, reflecting a stepwise development of the adenoma.28-31 Many of the known and unknown genes that have mutated in parathyroid tumors are probably tumorsuppressor genes; that is to say, they contribute to the formation of the tumor through a sequential inactivation of both copies of the gene.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).35 Since the calcium-sensing receptor and the vitamin D receptor also mediate the inhibition of parathyroid-gland function, it is noteworthy that no inactivating mutation of either gene has been identified in parathyroid adenomas.35-38 A small minority of parathyroid adenomas have

activating mutations of the cyclin D1 gene (CCND1).20,24,39 These mutations result in the overexpression of the protein cyclin D1, but cyclin D1 overexpression is even more common in parathyroid adenomas without cyclin D1 mutations.40 The abnormal parathyroid cells in primary (and secondary) hyperparathyroidism have deficient sensitivity to inhibition by calcium; this may result in part from a deficiency of calcium-sensing receptors on parathyroid cells.41 Deficiency of these receptors is probably a consequence and not a cause of neoplastic primary hyperparathyroidism.
Categories and Causes of Sporadic Primary Hyperparathyroidism

Solitary parathyroid adenomas account for 85 percent of cases of primary hyperparathyroidism; hyperfunction in multiple parathyroid glands (a broad catVol ume 343 Numb e r 25

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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. Protein That Causes Parathyroid-Gland Hyperfunction When Mutated. Mutation may occur through inheritance (germ-line mutation) or postnatally (somatic mutation) in abnormal parathyroid tissue. Inactivating mutations characterize tumor-suppressorencoded proteins (menin [the product of the MEN1 tumor-suppressor gene], p53, and retinoblastoma protein [pRb]), which are shown in red. Similarly, the calcium-sensing receptor is a growth suppressor (shown in red). Activating mutations characterize proto-oncoproteins (cyclin D1 and RET) and are shown in yellow. Menin binds to JunD, a transcription factor, which dimerizes (connects) with another member of the JunFos family of transcription factors; menin thereby inhibits transcriptional activation by JunD.22 The p53 protein binds to DNA through a specific DNA response element.23 Cyclin D1 is a cell-cycle regulator that activates the catalytic units of cyclin-dependent kinases (CDK) 4 and 6.24 One substrate for phosphorylation (P) and thus blockade by CDK 4 or 6 is pRb,25 which binds to the transcription factor E2F as well as to several other transcription factors.25 Black T bars indicate binding to a specific sequence of DNA. Calcium ions probably bind to the calciumsensing receptor in the plasma membrane, which transmits information on extracellular calcium to an unidentified guanine-nucleotidebinding protein (G?) in the cytoplasm.26 The RET -encoded tyrosine kinase in the plasma membrane (RET [yellow]) is a dimer that phosphorylates Src-homology collagen (SHC) and other substrates. RET is regulated by an extracellular RET receptor attached to the membrane by its glycosylphosphatidylinositol anchor (RR-GPI [turquoise]).27 There are at least four extracellular RET receptors, each with different extracellular protein ligands (RRL). The full mechanisms by which any of these mutant proteins contribute to tumor formation are not known. Arrows show the flow of a molecule to or away from the plasma membrane.

egory that includes hyperplasia, multiple adenomas, and polyclonal hyperfunction) occurs in most of the remainder; and a few patients (less than 1 percent) have parathyroid carcinoma. About 75 percent of patients with sporadic primary hyperparathyroidism are women; the average age at diagnosis is 55 years. The
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annual incidence of primary hyperparathyroidism among postmenopausal women in Olmsted County, Minnesota, peaked at 112 per 100,000 in 1974; the high number of diagnoses in that year is attributable to the introduction of screening measurements of serum calcium. The annual incidence then fell markedly

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to 8 per 100,000 in 1992, a decline in diagnoses that may be due to the prior removal of tumors in patients whose hypercalcemia was diagnosed when they were younger.42 During a similar period, there was no decline in the incidence of primary hyperparathyroidism in Sweden.43 The factors associated with sporadic primary hyperparathyroidism include the external irradiation of the neck and therapy with lithium salts.44,45 Lithium stimulates parathyroid cells in vitro.46 Mild hyperparathyroidism occurs in approximately 5 percent of patients receiving long-term lithium therapy, and it often persists after the therapy is discontinued.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. Acquired or somatic mutation of the second MEN1 copy can give a cell the growth advantage to become a tumor.
Familial Hypocalciuric Hypercalcemia

Among the minority of patients with primary hyperparathyroidism caused by hyperfunction of multiple parathyroid glands, the disorder is inherited in about 20 percent. Any of these hereditary syndromes, such as multiple endocrine neoplasia type 1, may present as isolated hyperparathyroidism in some families.38,47,48 Each syndrome raises special issues for diagnosis and management (Table 1).
Multiple Endocrine Neoplasia Type 1

Familial hypocalciuric (or benign) hypercalcemia is characterized by lifelong hypercalcemia with normal urinary calcium excretion. It is inherited as an autosomal dominant trait (Table 1).41 It is caused by inactivating germ-line mutations of the calcium-sensing receptor, which result in an insensitivity of the parathyroid cells to inhibition by serum calcium.41 The hypercalcemia persists after subtotal parathyroidectomy; thus, such surgery is contraindicated. Parathyroid-cell hyperfunction is polyclonal and non-neoplastic.50 The normal urinary calcium excretion despite hypercalcemia is an effect of the mutated calciumsensing receptors in the kidneys.41
Neonatal Severe Primary Hyperparathyroidism

Patients with multiple endocrine neoplasia type 1 have various combinations of parathyroid, enteropancreatic, anterior pituitary, and other tumors.49 By the age of 40, patients with multiple endocrine neoplasia type 1 have endocrine disorders with the following frequencies: hyperparathyroidism in 85 percent of patients, ZollingerEllison syndrome in 35 percent, prolactinoma in 25 percent, and other tumors less often.49 Multiple endocrine neoplasia type 1 is caused

Neonatal severe primary hyperparathyroidism is a rare and potentially lethal disorder (Table 1). Affected neonates have a marked enlargement of all parathyroid glands, very high serum parathyroid hormone concentrations, and marked hypercalcemia (calcium concentration, more than 16 mg per deciliter [4 mmol per liter]). It is usually caused by homozygous inactivating germ-line mutations of the calcium-sensing receptor gene.41 The effects of these mutations confirm the importance of the calcium-sensing receptor in the regulation of secretion and growth of parathyroid cells.

TABLE 1. CATEGORIES

OF

PRIMARY HYPERPARATHYROIDISM.*
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. 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, such as MEN1, promote the emergence of a neoplastic clone in parathyroid gland

Multiple 5 times normal size Monoclonal or oligoclonal 90% cured, 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. Ranges are broad, with overlap (not shown) among categories.

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Multiple Endocrine Neoplasia Type 2a

Multiple endocrine neoplasia type 2a is characterized primarily by medullary thyroid carcinoma and pheochromocytoma.27 Primary hyperparathyroidism can occur by the age of 70 in up to 70 percent of patients and is usually mild.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.27
HyperparathyroidismJaw Tumor Syndrome

There is some controversy about whether any of these changes decrease life expectancy. A recent populationbased study found that there was no excess mortality among all patients with hyperparathyroidism, but there was excess mortality among the patients in the highest quartile for serum calcium concentrations.59
Effects on Bone

The hyperparathyroidismjaw tumor syndrome is rare and is characterized by hyperparathyroidism, cemento-ossifying fibromas of the jaw, renal cysts, Wilms tumor, and renal hamartomas.47,52,53 By the age of 40, about 80 percent of patients with this syndrome have hyperparathyroidism, and about 10 percent of those have a parathyroid carcinoma. Often, at the first presentation of hyperparathyroidism, only one parathyroid adenoma is present, but multiple adenomas can occur either simultaneously or at different times. The disorder is caused by a mutation in an unknown gene on chromosome 1q2452 and is inherited as an autosomal dominant trait.
Manifestations of Primary Hyperparathyroidism

The parathyroids are small endocrine glands, and increases in their size or enhancements of their function have no effect on neighboring tissues. Instead, the effects of an excessive secretion of parathyroid hormone are manifested chemically as abnormal fluxes of calcium and phosphate in bone, in the kidneys, and in the gastrointestinal tract (Fig. 1). The main results are hypercalcemia, hypercalciuria, and increased rates of bone turnover. Primary hyperparathyroidism is usually first suspected when a patient is found on biochemical screening to have hypercalcemia; less often it is suspected because nephrolithiasis or osteopenia is present. The anticalciuric effect of thiazide drugs can raise serum calcium concentrations slightly, thereby uncovering occult hyperparathyroidism. With the current restrictions on reimbursement for biochemical screening, the proportion of newly diagnosed cases of hyperparathyroidism that are asymptomatic should decrease. Currently, most patients in whom hyperparathyroidism is diagnosed at first appear to be asymptomatic,54,55 but up to half of them have subtle neurobehavioral symptoms such as fatigue and weakness.56,57 In many of these patients, the fact that fatigue or weakness is a symptom of hyperparathyroidism becomes clear only after a successful parathyroidectomy, when the symptom resolves. About 20 percent of patients with hyperparathyroidism have nephrolithiasis.55 Primary hyperparathyroidism can cause cardiac calcifications and left ventricular hypertrophy; the latter can occur in the absence of hypertension and can be partially reversed after parathyroidectomy.58

Parathyroid hormone increases the rate of bone turnover, and its effects on bone may be catabolic or anabolic, depending on the age of the patient, the skeletal site, and the pattern of serum concentrations of the hormone over time.60,61 In general, persistently high serum parathyroid hormone concentrations have catabolic effects on bone, whereas intermittent mild increases have anabolic effects. On balance, the effects of mild primary hyperparathyroidism on bone seem to be slightly anabolic.62 However, the disorder can cause a demineralization of bone, distributed variably between cortical sites (i.e., mainly long bones) and trabecular sites (i.e., mainly vertebrae).63,64 Approximately one in four patients has osteopenia (a z score lower than 2; z refers to the number of standard deviations from an age- and sexmatched mean) in cortical or trabecular bone.63,64 Overall, the risk of bone fractures in patients with mild hyperparathyroidism is similar to that in matched normal subjects (one new fracture per decade); still, the presence of hyperparathyroidism significantly increased the risk of fracture in several bones, particularly the vertebrae, in a population-based, controlled study.65 Successful parathyroidectomy is followed by an increase in bone mass over a period of 6 to 12 months,55,63,66 with continued increases for up to 10 years after surgery.55
Natural History and Treatment of Primary Hyperparathyroidism

In most patients, primary hyperparathyroidism progresses slowly, if at all. Among asymptomatic patients, only about 25 percent have progressive disease, which is usually manifested as a decrease in bone mass during a 10-year period of follow-up.55 Thus, there has been some controversy regarding the indications for surgery, the only effective treatment. 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 1.0 to 1.6 mg per deciliter (0.25 to 0.40 mmol per liter) above the upper limit of normal, a level of urinary calcium excretion of less than 400 mg (100 mmol) per day, a creatinine clearance of at least 70 percent of normal, or a z score higher than 2 for bone mass.67 These are still reasonable guidelines, but surgery may be recommended for many of these patients because of the evidence that it ameliorates neurobehavioral symp-

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toms that may be hard to detect.56,57 Surgery is not only an effective but also a safe treatment for primary hyperparathyroidism, even in patients who are more than 70 years old.68 Several methods for characterizing overactive parathyroid glands are available, including ultrasonography and imaging with technetium-99m sestamibi before or during surgery (Fig. 4), but these are not used routinely.69-71 Rapid assays for measuring serum parathyroid hormone during surgery are also available, as discussed above. 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.72 Such approaches can decrease the duration of the surgery, but the rate of success may not match that of standard parathyroidectomy.73,74 When patients require repeated operation, every effort should be made to identify abnormal tissue preoperatively, and intraoperative testing is often included as well.18,19 Patients who do not undergo surgery should be evaluated clinically, and serum calcium, creatinine, and parathyroid hormone should be measured at 6-to-12-month intervals, and cortical and trabecular bone density at 12-month intervals. Such patients should be advised to avoid dehydration and to keep their calcium intake at or below 1000 mg per day. Some patients with more severe primary hyperparathyroidism may not undergo surgery because of contraindications or because they decline the procedure; in others, surgery may have been unsuccessful. For these patients, several treatments directed at the target tissues of parathyroid hormone action are available (Table 2).75 Bisphosphonates such as alendronate and clodronate inhibit bone resorption; however, they may be less effective in patients with hyperparathyroidism than in those with hypercalcemia from other causes.76 Estrogen increases bone density in postmenopausal women with hyperparathyroidism but has little effect on serum calcium concentrations.77 A calciumsensingreceptor 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; the further development of drugs of this type may provide effective treatments for primary and secondary hyperparathyroidism.79 Patients with primary hyperparathyroidism who have severe symptomatic hypercalcemia should be treated with intravenous saline, a bisphosphonate, furosemide, and in some cases dialysis.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. 1). Most treatments for hypoparathyroidism also affect the transfer of calcium along only one of these pathways, albeit in the opposite direction.

Parotid Submandibular Thyroid

Mediastinal parathyroid Heart

Figure 4. Anterior Planar Image of the Neck and Chest of a Patient with Primary Hyperparathyroidism Obtained with Technetium-99m Sestamibi, Showing a Parathyroid Adenoma in the Mediastinum. The patient had undergone an unsuccessful parathyroid exploration. The image shown was obtained two hours after the administration of 20 mCi of the radionuclide. The lobes of the thyroid and the salivary glands are clearly visible. (Image courtesy of Dr. Clara Chen.)

HYPERCALCEMIA MEDIATED BY PARATHYROID HORMONERELATED PEPTIDE

Hypercalcemia is sometimes caused by serum factors, which may be released by nonparathyroid tumors, whether or not there are skeletal metastases. Most of these tumors are malignant and secrete parathyroid hormonerelated peptide.13 In contrast, hypersecretion of parathyroid hormone by a nonparathyroid tumor is extremely rare.
UREMIC HYPERPARATHYROIDISM
Secondary and Tertiary Hyperparathyroidism

Hypocalcemia from any cause stimulates parathyroid hormone secretion, and chronic hypocalcemia also stimulates the growth of the parathyroid glands. This secondary hyperparathyroidism usually resolves with the treatment of the underlying cause of hypocalcemia. However, in patients with chronic renal failure, secondary hyperparathyroidism often lasts longer and is more severe than in patients with other hypocalcemic disorders, such as a deficiency or malabsorption of vitamin D.80 Eventually, either before or, more often, after renal transplantation, secondary hyperparathyroidism can develop into a disorder of oversecretion of parathyroid hormone with hypercalcemia (tertiary hyperparathyroidism).
The Parathyroid Gland in Uremia

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TABLE 2. TREATMENTS

FOR

HYPERPARATHYROIDISM

AND

HYPOPARATHYROIDISM.
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.

Parathyroidectomy Calcium-sensingreceptor agonist* Blocker of type 1 receptor* Bisphosphonates Estrogen Blocker of vitamin D receptor* Forced natriuresis Dialysis

Parathyroid autograft Parathyroid hormone (134)*

Vitamin D analogue Calcium salts Thiazide Intravenous calcium

ly high and nonsuppressible base-line secretion of parathyroid hormone; in fact, however, it most often reflects the secretory dysfunction of autonomously functioning parathyroid cells.21,80,81 Overactive parathyroid glands that have been removed from patients with uremia are usually overgrown with monoclonal or oligoclonal components.22,82-84 The cause of progression from early, presumably polyclonal, secondary hyperplasia of the parathyroid to later monoclonal or oligoclonal tumors is poorly understood.21,80,84 Probably, 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; in particular, MEN1 mutations are less frequent in the parathyroid glands of patients with uremia than in tumors of patients with sporadic primary hyperparathyroidism.82,83
Bone Disease in Patients with Chronic Renal Disease and Hyperparathyroidism

ease among patients with uremia is similar to the frequency of adynamic bone diseases.86,87 Uremic hyperparathyroid bone disease is best treated by raising serum calcium concentrations and thereby decreasing parathyroid hormone secretion. The cause of adynamic bone disease is not known, and there is no specific treatment.88,89
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.85,86 Some patients with chronic renal disease have hyperparathyroid uremic bone disease, which is characterized by an activation of osteoblasts and osteoclasts with excess bone resorption. Other patients have an adynamic bone disease or osteomalacia. Adynamic bone disease is characterized by low activity of the bone cells, no excess accumulation of matrix, and little parathyroid hypersecretion.86,87 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. This disorder has become less common as a result of the minimization of use of products with high concentrations of aluminum, such as are found in some antacids and dialysis fluids.86,87 The frequency of hyperparathyroid bone dis1870
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In patients with chronic renal failure, secondary hyperparathyroidism is caused by hypocalcemia, which, in turn, is caused by hyperphosphatemia and decreased renal production of 1,25-dihydroxyvitamin D. Treatment is based on raising serum calcium concentrations by the oral administration of calcium salts; these salts also ameliorate hyperphosphatemia by chelating phosphate in the intestines. Additional measures for treating hypocalcemia include raising the calcium concentration in the dialysis fluid and administering some form of vitamin D. When treatment is initiated early, severe secondary hyperparathyroidism can be prevented or at least delayed. There is some controversy regarding the most appropriate dosage, type, and route of administration of vitamin D or vitamin D analogue90,91 and the most appropriate phosphate binder for these patients.92 1,25-Dihydroxyvitamin D3 (calcitriol) has sometimes been given intravenously in pulsed doses in the hope of inhibiting parathyroid hormone secretion without raising serum calcium concentrations,90,91 but calcitriol given orally has similar effects.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.94 Parathyroidectomy is also appropriate for some patients with tertiary hyperparathyroidism. After renal transplantation, secondary hyperpara-

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thyroidism usually regresses over a period of 1 to 10 years, but the regression may be incomplete, as reflected in persistently high serum parathyroid hormone concentrations.95 About one third of patients who receive renal transplants have parathyroid hormoneinduced hypercalcemia postoperatively that, depending on its magnitude and duration, can present a threat to the renal graft and to other functions. The hypercalcemia usually subsides within months or at most a few years, but 1 to 3 percent of patients require parathyroidectomy an average of three years after renal transplantation because of persistent hypercalcemia.96
HYPOPARATHYROIDISM

diasisectodermal dystrophy syndrome.100 The hypoparathyroidism, like other manifestations of the syndrome, occurs during childhood; for this reason and because of such associated abnormalities as hypoadrenalism and intestinal malabsorption, the hypoparathyroidism may be difficult to treat. 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.101
Defects in the Parathyroid Hormone Molecule

Hypoparathyroidism can cause hypocalcemia with consequent paresthesias, muscle spasms (i.e., tetany), and seizures, especially when it occurs rapidly. In contrast, chronic hypoparathyroidism generally causes hypocalcemia so gradually that the only symptom may be visual impairment from cataracts caused by years of hypoparathyroidism.
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.102
Defective Regulation of Parathyroid Hormone Secretion

Like hyperparathyroidism, hypoparathyroidism is diagnosed on the basis of measurements of serum calcium and parathyroid hormone (Fig. 2).14,15 The causes of hypoparathyroidism are diverse, representing disruptions of one or more of the steps in the development and maintenance of parathyroid hormone secretion.
Damage to the Parathyroid Glands from Surgery

Hypocalcemia and hypercalciuria are the chief features of autosomal dominant hypercalciuric hypocalcemia, which is caused by activating mutations of the parathyroid and renal calcium-sensing receptor. These mutations cause excessive calcium-induced inhibition of parathyroid hormone secretion. The hypocalcemia is usually mild and asymptomatic. When it is mild, it should be treated cautiously, if at all, because raising serum calcium concentrations further increases urinary calcium excretion and may cause nephrocalcinosis.41,103
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.
Developmental Defects in the Parathyroid Glands

Agenesis of the parathyroid glands occurs in infants with the DiGeorge syndrome (and the closely related velocardiofacial syndrome). The manifestations of these syndromes include incomplete development in the branchial arches, resulting in varying degrees of parathyroid and thymic hypoplasia, conotruncal cardiac defects, facial malformations, and learning disability. Both syndromes are associated with rearrangements and microdeletions affecting an unknown gene or genes on the short arm of chromosome 22.97 Any resultant defect should be treated, depending on its severity.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.99
Autoimmune Hypoparathyroidism

Hypoparathyroidism is a prominent component of autoimmune polyglandular syndrome type 1, also known as autoimmune polyendocrinopathycandi-

The main treatments available for patients with acute or chronic hypoparathyroidism are calcium salts, vitamin D or vitamin D analogues, and drugs that increase renal tubular reabsorption of calcium (i.e., thiazides) (Table 2). The parathyroid hormonedependent renal production of 1,25-dihydroxyvitamin D is deficient in all hypoparathyroid states. Therefore, therapy with a vitamin D analogue is used to ensure that there is a steady serum concentration of an active vitamin D analogue. If parathyroid hormone is absent or nonfunctional, its hypocalciuric action cannot occur; therefore, raising the serum calcium concentration may cause hypercalciuria, nephrolithiasis, and renal damage. Patients in whom hypocalcemia develops suddenly for example, after neck surgery are best treated with intravenous calcium and with oral or intravenous calcitriol. Those with chronic hypocalcemia should be treated with oral calcium and either calcitriol or vitamin D. Patients in whom the efficacy of treatment may vary, such as those with autoimmune polyglandular syndrome type 1, are best treated with vitamin D analogues that have a short half-life. Calcitriol raises serum calcium concentrations within one or two days after treatment begins, and its action dissipates
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equally rapidly; the action of vitamin D begins and dissipates over a period of two to four weeks.
Parathyroid-Tissue Transplantation or Parathyroid Hormone

ited as an autosomal recessive trait. The growth plates show accelerated calcification and a near-absence of proliferating chondrocytes.
Defects of the Stimulatory Guanine-NucleotideBinding Protein

Transplantation of parathyroid tissue is appealing but rarely possible. A parathyroid allograft would require immunosuppression and so would be more dangerous than the disease it was meant to treat. Parathyroid autografts are sometimes placed in the forearm and can consist of either fresh parathyroid tissue or parathyroid tissue removed earlier and cryopreserved. The indication for a parathyroid autograft is a high likelihood of postoperative hypoparathyroidism. As many as half of these grafts fail, and among those that survive and function, the potential for late autograft-mediated recurrences of hyperparathyroidism is substantial, since the parathyroid tissue used for the graft was abnormal.84,94 Patients with hypoparathyroidism have been treated successfully with synthetic human parathyroid hormone (134) given subcutaneously once daily.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. However, synthetic human parathyroid hormone (134) is not currently available.
GENETIC DISORDERS OF PARATHYROID HORMONE ACTION

Parathyroid hormone signaling in cells is mediated by the type 1 parathyroid hormone receptor, which then acts on a stimulatory guanine-nucleotidebinding (Gs) protein, which is composed of three subunits (a, b, and g). The Gsa subunit (encoded by the GNAS1 gene) mediates cyclic AMP stimulation by parathyroid hormone and by several other peptide hormones, including thyrotropin.26
Pseudohypoparathyroidism Type 1a

Pseudohypoparathyroidism type 1a is characterized by short stature and other skeletal abnormalities, which are known collectively as Albrights hereditary osteodystrophy, as well as hypocalcemia and high serum concentrations of parathyroid hormone. It is caused by inactivating mutations in the a subunit of Gs 26 and is inherited as an autosomal dominant trait. Many patients with pseudohypoparathyroidism type 1a have resistance not only to parathyroid hormone but also to thyrotropin.
Pseudo-pseudohypoparathyroidism

Hereditary defects in parathyroid hormone action are rare but informative. Each confirms the role of an important signaling molecule. To some extent, these states mimic disorders of parathyroid hormone excess or deficiency.
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.11,13
Jansens Chondrodystrophy

Pseudo-pseudohypoparathyroidism occurs in families with pseudohypoparathyroidism type 1a. It consists of a combination of inactivating mutations of GNAS1 and Albrights osteodystrophy without the resistance to multiple hormones that characterizes pseudohypoparathyroidism. The hormone resistance is suppressed when the mutated GNAS1 gene is inherited from the father (i.e., paternal imprinting, or suppression, of the mutant copy occurs in selected tissues).107,108
Pseudohypoparathyroidism Type 1b

Jansens chondrodystrophy is characterized by short limbs, mild hypercalcemia, and low serum parathyroid hormone concentrations. It is caused by activating mutations of the type 1 parathyroid hormone receptor105 and is inherited as an autosomal dominant trait. It is associated with increased proliferation and delayed maturation of chondrocytes, which may weaken the growth plates, thereby causing the short limbs.
Blomstrands Chondrodystrophy

Pseudohypoparathyroidism type 1b is characterized by isolated resistance to parathyroid hormone without the accompanying Albrights osteodystrophy. It is associated with defective methylation within GNAS1, which is most likely caused by a mutation in or near GNAS1.109 Hypocalcemia in patients with pseudohypoparathyroidism type 1a or 1b should be treated in the same way as it is in patients with true hypoparathyroidism.
CONCLUSIONS

Blomstrands chondrodystrophy is characterized by growth impairment, primarily in the form of short limbs. It has been lethal prenatally, and therefore the regulation of serum calcium has not been evaluated in vivo. It is caused by inactivating mutations of the type 1 parathyroid hormone receptor106 and is inher1872
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Despite a confusing disease nomenclature that is a remnant of past eras, substantial insight has been gained into many disorders of the parathyroid axis. With the advent of reliable and specific assays for parathyroid hormone, the diagnosis of parathyroid dysfunction has become much easier. Treatments are generally satisfactory and are logically related to the defects

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in the parathyroid gland or to their expression in the target organs. Controversies persist, however, particularly about the treatment of primary hyperparathyroidism.
REFERENCES
1. Jppner H, Gardella TJ, Brown EM, Kronenberg HM, Potts JT Jr. Parathyroid hormone and parathyroid hormone-related peptide in the regulation of calcium homeostasis and bone development. In: DeGroot LJ, ed. Endocrinology. 4th ed. Philadelphia: W.B. Saunders (in press). 2. Brown EM, Vassilev PM, Quinn S, Hebert SC. G-protein-coupled, extracellular Ca2+-sensing receptor: a versatile regulator of diverse cellular functions. Vitam Horm 1999;55:1-71. 3. Marchese A, George SR, Kolakowski LF, Lynch KR, ODowd BF. Novel GPCRs and their endogenous ligands: expanding the boundaries of physiology and pharmacology. Trends Pharmacol Sci 1999;20:370-5. [Erratum, Trends Pharmacol Sci 1999;20:447.] 4. Demay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response to 1,25dihydroxyvitamin D3. Proc Natl Acad Sci U S A 1992;89:8097-101. 5. Moallem E, Kilav R, Silver J, Naveh-Many T. RNA-protein binding and post-transcriptional regulation of parathyroid hormone gene expression by calcium and phosphate. J Biol Chem 1998;273:5253-9. 6. Chung U, Igarashi T, Nishishita T, et al. The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium. J Biol Chem 1996;271:8593-8. 7. Naveh-Many T, Rahamimov R, Livni N, Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats: the effects of calcium, phosphate, and vitamin D. J Clin Invest 1995;96:1786-93. 8. Li YC, Amling M, Pirro AE, et al. Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocrinology 1998;139:4391-6. 9. Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev 1999;20:156-88. 10. Chorev M, Alexander JM, Rosenblatt M. Interactions of parathyroid hormone and parathyroid homonerelated protein with their receptors. In: Bilezikian JP, Levine MA, Marcus R, eds. The parathyroids: basic and clinical concepts. 2nd ed. San Diego, Calif.: Academic Press (in press). 11. Juppner H. Receptors for parathyroid hormone and parathyroid hormone-related peptide: exploration of their biological importance. Bone 1999;25:87-90. 12. Usdin TB, Hoare SRJ, Wang T, Mezey E, Kowalak JA. TIP39: a new neuropeptide and PTH2-receptor agonist from hypothalamus. Nat Neurosci 1999;2:941-3. 13. Strewler GJ. The physiology of parathyroid hormonerelated protein. N Engl J Med 2000;342:177-85. 14. Kao PC, van Heerden JA, Grant CS, Klee GG, Khosla S. Clinical performance of parathyroid hormone immunometric assays. Mayo Clin Proc 1992;67:637-45. 15. Michelangeli VP, Heyma P, Colman PG, Ebeling PR. Evaluation of a new, rapid and automated immunochemiluminometric assay for the measurement of serum intact parathyroid hormone. Ann Clin Biochem 1997; 34:97-103. 16. Lepage R, Roy L, Brossard JH, et al. A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clin Chem 1998;44: 805-9. 17. John MR, Goodman WG, Gao P, Cantor TL, Salusky IB, Juppner H. A novel immunoradiometric assay detects full-length human PTH but not amino-terminally truncated fragments: implications for PTH measurements in renal failure. J Clin Endocrinol Metab 1999;84:4287-90. 18. Jaskowiak N, Norton JA, Alexander HR, et al. A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma. Ann Surg 1996;224:308-20. 19. Irvin GL III, Molinari AS, Figueroa C, Carneiro DM. Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Ann Surg 1999;229:874-8. 20. Arnold A. Molecular basis of primary hyperparathyroidism. In: Bilezikian JP, Levine MA, Marcus R, eds. The parathyroids: basic and clinical concepts. 2nd ed. San Diego, Calif.: Academic Press (in press). 21. Arnold 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;95:2047-53. 22. Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the

AP1 transcription factor JunD and represses JunD-activated transcription. Cell 1999;96:143-52. 23. Malkin D. Li-Fraumeni syndrome. In: Scriver CR, Beaudet A, Sly WS, Valle D, Vogelstein B, eds. The metabolic and molecular bases of inherited disease. 8th ed. Vol. X. New York: McGraw-Hill (in press). 24. Pestell RG, Albanese C, Reutens AT, Segall JE, Lee RJ, Arnold A. The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. Endocr Rev 1999;20:501-34. 25. Masciullo V, Khalili K, Giordano A. The Rb family of cell cycle regulatory factors: clinical implications. Int J Oncol 2000;17:897-902. 26. Spiegel AM. Mutations in G proteins and G protein-coupled receptors in endocrine disease. J Clin Endocrinol Metab 1996;81:2434-42. 27. Hoff AO, Cote GJ, Gagel RF. Multiple endocrine neoplasias. Annu Rev Physiol 2000;62:377-411. 28. Tahara 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;56:599-605. 29. Farnebo F, Kytola S, Teh BT, et al. Alternative genetic pathways in parathyroid tumorigenesis. J Clin Endocrinol Metab 1999;84:3775-80. 30. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996;87:159-70. 31. Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol 1996;122:135-40. 32. Cryns VL, Thor A, Xu H-J, et al. Loss of the retinoblastoma tumorsuppressor gene in parathyroid carcinoma. N Engl J Med 1994;330:75761. 33. Cryns VL, Rubio MP, Thor AD, Louis DN, Arnold A. p53 Abnormalities in human parathyroid carcinoma. J Clin Endocrinol Metab 1994; 78:1320-4. 34. Agarwal SK, Schrock E, Kester MB, et al. Comparative genome hybridization analysis of human parathyroid tumors. Cancer Genet Cytogenet 1998;106:30-6. 35. Heppner C, Kester MB, Agarwal SK, et al. Somatic mutation of the MEN1 gene in parathyroid tumours. Nat Genet 1997;16:375-8. 36. Hosokawa Y, Pollak MR, Brown EM, Arnold A. Mutational analysis of the extracellular Ca(2+)-sensing receptor gene in human parathyroid tumors. J Clin Endocrinol Metab 1995;80:3107-10. 37. Brown SB, Brierley TT, Palanisamy N, et al. Vitamin D receptor as a candidate tumor-suppressor gene in severe hyperparathyroidism of uremia. J Clin Endocrinol Metab 2000;85:868-72. 38. Carling T, Szabo E, Bai M, et al. Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 2000;85:2042-7. 39. Motokura T, Bloom T, Kim HG, et al. A novel cyclin encoded by a bcl1-linked candidate oncogene. Nature 1991;350:512-5. 40. Hsi ED, Zukerberg LF, Yang WI, Arnold A. Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study. J Clin Endocrinol Metab 1996;81:1736-9. 41. Brown EM, Pollak M, Hebert SC. The extracellular calcium-sensing receptor: its role in health and disease. Annu Rev Med 1998;49:15-29. 42. Wermers RA, Khosla S, Atkinson EJ, Hodgson SF, OFallon WM, Melton LJ III. The rise and fall of primary hyperparathyroidism: a population-based study in Rochester, Minnesota, 1965-1992. Ann Intern Med 1997;126:433-40. 43. Lundgren E, Rastad J, Thurfjell E, Akerstrom G, Ljunghall S. Population-based screening for primary hyperparathyroidism with serum calcium and parathyroid hormone values in menopausal women. Surgery 1997; 121:287-94. 44. Schneider AB, Gierlowski TC, Shore-Freedman E, Stovall M, Ron E, Lubin J. Dose-response relationships for radiation-induced hyperparathyroidism. J Clin Endocrinol Metab 1995;80:254-7. 45. Bendz H, Sjodin I, Toss G, Berglund K. Hyperparathyroidism and long-term lithium therapy a cross-sectional study and the effect of lithium withdrawal. J Intern Med 1996;240:357-65. 46. Brown EM. Lithium induces abnormal calcium-regulated PTH release in dispersed bovine parathyroid cells. J Clin Endocrinol Metab 1981;52: 1046-8. 47. Teh BT, Farnebo F, Twigg S, et al. Familial isolated hyperparathyroidism maps to the hyperparathyroidism-jaw tumor locus in 1q21-q32 in a subset of families. J Clin Endocrinol Metab 1998;83:2114-20. 48. Kassem M, Kruse TA, Wong FK, Larsson C, Teh BT. Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia type 1 in a large Danish pedigree. J Clin Endocrinol Metab 2000;85:165-7. 49. Marx SJ, Spiegel AM, Skarulis MC, Doppman JL, Collins FS, Liotta LA. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 1998;129:484-94. 50. Marx SJ. Contrasting paradigms for hereditary hyperfunction of endocrine cells. J Clin Endocrinol Metab 1999;84:3001-9. 51. Schuffenecker I, Virally-Monod M, Brohet R, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia

Vol ume 343

Numb e r 25

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The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

type 2A families with mutations at codon 634 of the RET proto-oncogene. J Clin Endocrinol Metab 1998;83:487-91. 52. Szabo J, Heath B, Hill VM, et al. Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31. Am J Hum Genet 1995;56:944-50. 53. Williamson C, Cavaco BM, Jauch A, et al. Mapping the gene causing hereditary primary hyperparathyroidism in a Portuguese kindred to chromosome 1q22-q31. J Bone Miner Res 1999;14:230-9. [Erratum, J Bone Miner Res 1999;14:1472.] 54. Bilezikian JP, Silverberg SJ, Gartenberg F, et al. Clinical presentation of primary hyperparathyroidism. In: Bilezikian JP, Levine MA, Marcus R, eds. The parathyroids: basic and clinical concepts. 2nd ed. San Diego, Calif.: Academic Press (in press). 55. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999;341:1249-55. [Erratum, N Engl J Med 2000; 342:144.] 56. Chan AK, Duh QY, Katz MH, Siperstein AE, Clark OH. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy: a case-control study. Ann Surg 1995;222:402-14. 57. Burney RE, Jones KR, Christy B, Thompson NW. Health status improvement after surgical correction of primary hyperparathyroidism in patients with high and low preoperative calcium levels. Surgery 1999;125: 608-14. 58. Steffenelli T, Abela C, Frank H, et al. Cardiac abnormalities in patients with primary hyperparathyroidism: implications for follow-up. J Clin Endocrinol Metab 1997;82:106-12. 59. Wermers RA, Khosla S, Atkinson EJ, et al. Survival after diagnosis of hyperparathyroidism: a population-based study. Am J Med 1998;104:11522. 60. Ishizuya T, Yokose S, Hori M, et al. Parathyroid hormone exerts disparate effects on osteoblastic differentiation depending on exposure time in rat osteoblastic cells. J Clin Invest 1997;99:2961-70. 61. Schiller PC, DIppolito G, Roos BA, Howard GA. Anabolic or catabolic responses of MC3T3-E1 osteoblastic cells to parathyroid hormone depend on time and duration of treatment. J Bone Miner Res 1999;14: 1504-12. 62. Dempster DW, Parisien M, Silverberg SJ, et al. On the mechanism of cancellous bone preservation in postmenopausal women with mild primary hyperparathyroidism. J Clin Endocrinol Metab 1999;84:1562-6. 63. Abdelhadi M, Nordenstrom J. Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism. J Clin Endocrinol Metab 1998;83:3845-51. 64. Silverberg SJ, Locker FG, Bilezikian JP. Vertebral osteopenia: a new indication for surgery in primary hyperparathyroidism. J Clin Endocrinol Metab 1996;81:4007-12. 65. Khosla S, Melton LJ III, Wermers RA, Crowson CS, OFallon WM, Riggs BL. Primary hyperparathyroidism and the risk of fracture: a population-based study. J Bone Miner Res 1999;14:1700-7. 66. Christiansen P, Steiniche T, Brixen K, et al. Primary hyperparathyroidism: effect of parathyroidectomy on regional bone mineral density in Danish patients: a three-year follow-up study. Bone 1999;25:589-95. 67. NIH conference: diagnosis and management of asymptomatic primary hyperparathyroidism: Consensus Development Conference statement. Ann Intern Med 1991;114:593-7. 68. Chen H, Parkerson S, Udelsman R. Parathyroidectomy in the elderly: do the benefits outweigh the risks? World J Surg 1998;22:531-6. 69. Pattou F, Torres G, Mondragon-Sanchez A, et al. Correlation of parathyroid scanning and anatomy in 261 unselected patients with sporadic primary hyperparathyroidism. Surgery 1999;126:1123-31. 70. Wei JP, Burke GJ. Cost utility of routine imaging with Tc-99m-sestamibi in primary hyperparathyroidism before initial surgery. Am Surg 1997; 63:1097-100. 71. Shawker TH, Avila N, Premkumar A, Bradford MH, Doppman JL. Ultrasound evaluation of primary hyperparathyroidism. Ultrasound Q 2000;16:73-87. 72. Norman J, Chheda H, Farrell C. Minimally invasive parathyroidectomy for primary hyperparathyroidism: decreasing operative time and potential complications while improving cosmetic results. Am Surg 1998;64:391-5. 73. Ryan JA Jr, Lee F. Effectiveness and safety of 100 consecutive parathyroidectomies. Am J Surg 1997;173:441-4. 74. Low RA, Katz AD. Parathyroidectomy via bilateral cervical exploration: a retrospective review of 866 cases. Head Neck 1998;20:583-7. 75. Stock JL, Marcus R. Medical management of primary hyperparathyroidism. In: Bilezikian JP, Levine MA, Marcus R, eds. The parathyroids: basic and clinical concepts. 2nd ed. San Diego, Calif.: Academic Press (in press). 76. Brown DL, Robbins R. Developments in the therapeutic applications of bisphosphonates. J Clin Pharmacol 1999;39:651-60. 77. Grey AB, Stapleton JP, Evans MC, Tatnell MA, Reid IR. Effect of hor-

mone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism: a randomized, controlled trial. Ann Intern Med 1996;125:360-8. 78. Silverberg SJ, Bone HG III, Marriott TB, et al. Short-term inhibition of parathyroid hormone secretion by a calcium-receptor agonist in patients with primary hyperparathyroidism. N Engl J Med 1997;337:1506-10. 79. Antonsen JE, Sherrard DJ, Andress DL. A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure: rapid communication. Kidney Int 1998;53:223-7. 80. Parfitt AM. The hyperparathyroidism of chronic renal failure: a disorder of growth. Kidney Int 1997;52:3-9. 81. Malberti F, Farina M, Imbasciati E. The PTH-calcium curve and the set point of calcium in primary and secondary hyperparathyroidism. Nephrol Dial Transplant 1999;14:2398-406. 82. Shan L, Nakamura Y, Murakami M, et al. Clonal emergence in uremic parathyroid hyperplasia is not related to MEN1 gene abnormality. Jpn J Cancer Res 1999;90:965-9. 83. Imanishi Y, Tahara H, Salusky I, et al. MEN1 gene mutations in refractory hyperparathyroidism of uremia. J Bone Miner Res 1999;14:Suppl 1:S446. abstract. 84. Horandner HH, Neyer U, Gruber U, et al. Pathomorphology of parathyroid autografts. Nieren Hochdruckkrankheiten 1997;26:319-27. 85. Solal M-EC, Sebert J-L, Boudailliez B, et al. Comparison of intact, midregion, and carboxy terminal assays of parathyroid hormone for the diagnosis of bone disease in hemodialyzed patients. J Clin Endocrinol Metab 1991;73:516-24. 86. Sherrard DJ, Hercz G, Pei Y, et al. The spectrum of bone disease in end-stage renal failure an evolving disorder. Kidney Int 1993;43:43642. 87. Mucsi I, Hercz G. Relative hypoparathyroidism and adynamic bone disease. Am J Med Sci 1999;317:405-9. 88. Wang M, Hercz G, Sherrard DJ, Maloney NA, Segre GV, Pei Y. Relationship between intact 1-84 parathyroid hormone and bone histomorphometric parameters in dialysis patients without aluminum toxicity. Am J Kidney Dis 1995;26:836-44. 89. Hampl H, Steinmuller T, Frohling P, et al. Long-term results of total parathyroidectomy without autotransplantation in patients with and without renal failure. Miner Electrolyte Metab 1999;25:161-70. 90. Hasnain M, Hauncher C, Pegoraro AA, Arruda JAL, Dunea G. Suppression of hyperparathyroidism by calcitriol therapy. ASAIO J 1999;45: 424-7. 91. Bacchini G, Fabrizi F, Pontoriero G, Marcelli D, Filippo SD, Locatelli F. Pulse oral versus intravenous calcitriol therapy in chronic hemodialysis patients: a prospective and randomized study. Nephron 1997;77:267-72. [Erratum, Nephron 1998;79:509.] 92. Loghman-Adham M. Phosphate binders for control of phosphate retention in chronic renal failure. Pediatr Nephrol 1999;13:701-8. 93. Indridason OS, Quarles LD. Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. Kidney Int 2000;57: 282-92. 94. Tominaga Y. Surgical management of secondary hyperparathyroidism in uremia. Am J Med Sci 1999;317:390-7. 95. Torres A, Rodriguez AP, Concepcion MT, et al. Parathyroid function in long-term renal transplant patients: importance of pre-transplant PTH concentrations. Nephrol Dial Transplant 1998;13:Suppl 3:94-7. 96. Kerby JD, Rue LW, Blair H, Hudson S, Sellers MT, Diethelm AG. Operative treatment of tertiary hyperparathyroidism: a single-center experience. Ann Surg 1998;227:878-86. 97. Novelli A, Sabani M, Caiola A, et al. Diagnosis of DiGeorge and Williams syndromes using FISH analysis of peripheral blood smears. Mol Cell Probes 1999;13:303-7. 98. Markert ML, Boeck A, Hale LP, et al. Transplantation of thymus tissue in complete DiGeorge syndrome. N Engl J Med 1999;341:1180-9. 99. Ding C, Buckingham B, Levine MA. Neonatal hypoparathyroidism attributable to homozygous partial deletion of the human glial cell missing gene-B. In: Program and abstracts of the 82nd Annual Meeting of the Endocrine Society, Toronto, June 2124, 2000. Bethesda, Md.: Endocrine Society Press, 2000:409. abstract. 100. Ahonen P, Myllrniemi S, Sipil I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathycandidiasisectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322:1829-36. 101. Bjorses P, Halonen M, Palvimo JJ, et al. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am J Hum Genet 2000;66:378-92. 102. Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S. A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroidism. J Clin Endocrinol Metab 1999;84:3792-6. 103. Pearce SHS, Williamson C, Kifor O, et al. A familial syndrome of hy-

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pocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med 1996;335:1115-22. 104. Winer KK, Yanovski JA, Cutler GB Jr. Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA 1996;276:631-6. 105. Schipani E, Langman CB, Parfitt AM, et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormonerelated peptide in Jansens metaphyseal chondrodysplasia. N Engl J Med 1996;335: 708-14. 106. Zhang P, Jobert AS, Couvineau A, Silve C. A homozygous inactivating mutation in the parathyroid hormone/parathyroid hormone-related

peptide receptor causing Blomstrand chondrodysplasia. J Clin Endocrinol Metab 1998;83:3365-8. 107. Davies SJ, Hughes HE. Imprinting in Albrights hereditary osteodystrophy. J Med Genet 1993;30:101-3. 108. Yu SH, Yu DW, Lee E, et al. Variable and tissue-specific hormone resistance in heterotrimeric Gs protein alpha subunit (Gsalpha) knockout mice is due to tissue-specific imprinting of the Gsalpha gene. Proc Natl Acad Sci U S A 1998;95:8715-20. 109. Liu J, Litman D, Rosenberg MJ, Yu S, Biesecker LG, Weinstein LS. A GNAS1 imprinting defect in pseudohypoparathyroidism type IB. J Clin Invest 2000;106:1167-74.

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