MEDICAL PROGRESS

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

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.

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

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
Vo l u m e 3 4 3

Nu m b e r 2 5

1863

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

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

Extracellular ionized 6
calcium
Renal6
tubule
Calcium-6
sensing6
receptor

Ca2+

PTH6
receptor

Parathyroid cell

Ca2+
Bone

PTH

Calcium-6
sensing6
receptor

1,25(OH)2D
Endocrine6
mechanism6
6

Ca2+

PTHrP
Duodenal6
lumen
Blood and other6
extracellular fluid

PTHrP

Autocrineparacrine6
mechanism

PTH receptor

Cartilage and PTHrP6

target cells in many 6
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

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).
1864

The Parathyroid Gland in Primary Hyperparathyroidism

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

De c e m b e r 2 1 , 2 0 0 0

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

MEDICAL PROGRESS

Serum Parathyroid Hormone (pg/ml)

10,000

1,000
Uremic6
hyperpara-6
thyroidism

Primary6
hyperparathyroidism

100

Normal

10
Tumor6
hypercalcemia

Primary6
hyperpara-6
thyroidism

Lower limit6
of detection
6

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 catVo l u m e 3 4 3

Nu m b e r 2 5

1865

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

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

Secretory6
granule
Menin
JunD
PTH
CDK 4 or 6

p53
E2F

Cytoplasm

DNA
Cyclin3
D1

pRb

RET

Nucleus
G?
SHC

RRL
Calcium-sensing6
receptor

Ca2+

RR-GPI

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
1866

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

De c e m b e r 2 1 , 2 0 0 0

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

MEDICAL PROGRESS

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

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

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

TABLE 1. CATEGORIES

OF

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

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

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.

PRIMARY HYPERPARATHYROIDISM.*

MULTIPLE ENDOCRINE
NEOPLASIA TYPE 1

FAMILIAL HYPOCALCIURIC
HYPERCALCEMIA

NEONATAL SEVERE PRIMARY

HYPERPARATHYROIDISM

CHARACTERISTIC

SPORADIC ADENOMA

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

Autosomal dominant
25 yr

Autosomal dominant
Birth

Autosomal recessive
Birth

Normal to high
High

Normal to high
High

Low to normal
Normal

Low to normal
Very high

One
20 times normal size
Monoclonal or oligoclonal
95% cured

Multiple
5 times normal size
Monoclonal or oligoclonal
90% cured, but many recur

Multiple
Minimally enlarged
Polyclonal
Surgery not indicated

Stepwise acquired mutations of certain genes,

such as MEN1, promote
the emergence of a
neoplastic clone
in parathyroid gland

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.

Vo l u m e 3 4 3

Nu m b e r 2 5

1867

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

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.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

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

1868

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

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-

De c e m b e r 2 1 , 2 0 0 0

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

MEDICAL PROGRESS

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

Mediastinal6
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

Hypercalcemia in patients with uremia who have

tertiary hyperparathyroidism might reflect an excess
of nearly normal parathyroid cells with a consequentVo l u m e 3 4 3

Nu m b e r 2 5

1869

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

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

TABLE 2. TREATMENTS

PROCESS AFFECTED

BY

FOR

HYPERPARATHYROIDISM

HYPOPARATHYROIDISM.

TREATMENTS FOR
HYPERPARATHYROIDISM

TREATMENT

Secretion of parathyroid hormone by parathyroid gland

AND

Uptake of calcium from gut

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

Excretion of calcium in urine

Exchange with extracorporeal calcium pool

Forced natriuresis
Dialysis

Activation of receptor for parathyroid hormone

Release of calcium from bone

TREATMENTS FOR
HYPOPARATHYROIDISM

Parathyroid autograft
Parathyroid hormone (134)*

Vitamin D analogue
Calcium salts
Thiazide
Intravenous calcium

*This treatment is not currently available.

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

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

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

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-

De c e m b e r 2 1 , 2 0 0 0

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

MEDICAL PROGRESS

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

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

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

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-

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

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

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

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
Vo l u m e 3 4 3

Nu m b e r 2 5

1871

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

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

equally rapidly; the action of vitamin D begins and

dissipates over a period of two to four weeks.
Parathyroid-Tissue Transplantation or Parathyroid
Hormone

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

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

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

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

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

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

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

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

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

De c e m b e r 2 1 , 2 0 0 0

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

MEDICAL PROGRESS

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

Vo l u m e 3 4 3

Nu m b e r 2 5

1873

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

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-

1874

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-

De c e m b e r 2 1 , 2 0 0 0

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

MEDICAL PROGRESS

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.

Vo l u m e 3 4 3

Nu m b e r 2 5

1875

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

New England Journal of Medicine

CORRECTION

Hyperparathyroid and Hypoparathyroid Disorders

Hyperparathyroid and Hypoparathyroid Disorders . On page 1865, in
Figure 2, the domain on the lower left-hand side of the figure should
have been labeled ``Primary hypoparathyroidism, not ``Primary hyperparathyroidism, as printed. The corrected figure appears below.

N Engl J Med 2001;344:240-a

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.

New England Journal of Medicine

CORRECTION

Hyperparathyroid and Hypoparathyroid Disorders

Hyperparathyroid and Hypoparathyroid Disorders . On page 1871,
the sentence that begins 12 lines from the bottom of the left-hand
column should have read, ``Both syndromes are associated with rearrangements and microdeletions affecting an unknown gene or genes
on the long arm of chromosome 22, not ``on the short arm of chromosome 22, as printed.

N Engl J Med 2001;344:696-a

Downloaded from www.nejm.org on June 28, 2010 . Copyright 2000 Massachusetts Medical Society. All rights reserved.