MED ICA L PROGR ES S
Medical Progress
H YPERPARATHYROID AND
H YPOPARATHYROID D ISORDERS
STEPHEN J. MARX, M.D.
T
HE four parathyroid glands, through the secre-
tion of parathyroid hormone, regulate serum
calcium concentrations and bone metabolism.1
In turn, serum calcium concentrations regulate par-
athyroid hormone secretion; high concentrations in-
hibit secretion by the parathyroid glands of parathy-
roid hormone and low concentrations stimulate it.2
Low or falling serum calcium concentrations act with-
in seconds to stimulate parathyroid hormone secre-
tion, 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 hor-
mones.3 Parathyroid hormone secretion is 50 per-
cent of the maximal level at a serum ionized calcium
concentration of 4 mg per deciliter (1 mmol per li-
ter); this is considered the calcium set point for par-
athyroid 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-dihy-
droxyvitamin 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 se-
cretion 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 hypo-
parathyroidism.
STRUCTURE AND ACTIONS OF
PARATHYROID HORMONE
Parathyroid hormone is stored and secreted main-
ly as an 84-amino-acid peptide.1 A synthetic amino-
terminal fragment, parathyroid hormone (1–34), is
fully active; modifications at the amino terminal, par-
ticularly at the first two residues, can abolish its bio-
From 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.
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logic activity.10 The effects of parathyroid hormone on
mineral metabolism are initiated by the binding of
parathyroid hormone to the type 1 parathyroid hor-
mone receptor in the target tissues.11 Parathyroid hor-
mone thereby regulates large calcium fluxes across
bone, kidneys, and intestines1 (Fig. 1). Another par-
athyroid hormone receptor (type 2) has been found
in the brain and the intestines. Its main ligand is a pep-
tide different from parathyroid hormone12; the func-
tions of this receptor are not known.
Parathyroid hormone–related peptide is a distant
homologue of parathyroid hormone and is not a true
hormone. It is synthesized in cartilage and in many
more tissues than is parathyroid hormone, and its se-
cretion is not regulated by serum calcium.13 Its local
release activates the type 1 parathyroid hormone re-
ceptor, 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 hor-
mone, 25-hydroxyvitamin D, and 1,25-dihydroxyvi-
tamin D are used regularly in the diagnosis and treat-
ment 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 hor-
mone; 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-termi-
nal and carboxy-terminal epitopes of the peptide.14,15
The better assays are those that are well standardized,
do not cross-react with parathyroid hormone–relat-
ed peptide, and are sufficiently sensitive that normal
values can be distinguished from subnormal values
(Fig. 2). Parathyroid hormone molecules that are re-
active in these two-site immunoassays are considered
“intact,” but some have no bioactivity.14-17 For exam-
ple, a loss of only six amino acids to yield parathyroid
hormone (7–84) eliminates all bioactivity but does
not affect the immunoreactivity measured in most or
all of these assays.10 In fact, about half of the para-
thyroid hormone detected with these assays in the
serum of patients with chronic renal disease is bio-
logically 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 ultrasonograph-
ically) or in serum from the veins of the neck and
mediastinum, catheterized selectively.18 Serum test re-
sults that can be obtained in 10 to 15 minutes allow
physicians to assess the completeness of the removal
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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

Extracellular ionized 6
calcium

Renal6
tubule

Calcium-6
sensing6
Ca2+
receptor

Parathyroid cell PTH6

receptor
Ca2+

PTH Bone

Calcium-6 1,25(OH)2D
Ca2+
sensing6 Endocrine6
receptor PTHrP
mechanism6
6
Duodenal6
lumen

PTHrP Blood and other6

extracellular fluid

PTH receptor Cartilage and PTHrP6

Autocrine–paracrine6 target cells in many 6
mechanism other tissues

Figure 1. The Parathyroid Axis.

The synthesis of parathyroid hormone (PTH) and parathyroid hormone–related 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 hor-
mone 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 con-
centrations. The most important diagnostic tests for
this disorder are thus measurements of serum para-
thyroid hormone and ionized calcium (Fig. 2).
The Parathyroid Gland in Primary Hyperparathyroidism
Solitary parathyroid adenomas are monoclonal or
oligoclonal tumors.20 Similarly, in multiglandular hy-
perparathyroidism, most of the parathyroid tumors are
monoclonal or oligoclonal,21 reflecting overgrowth
from somatic or germ-line mutations in parathyroid-
tumor precursor cells. The underlying genes that de-
velop 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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 MED IC A L PROGR ES S

10,000

Serum Parathyroid Hormone (pg/ml)

1,000
Uremic6 Primary6
hyperpara-6 hyperparathyroidism
thyroidism
100

Normal
10

Primary6 Tumor6
hyperpara-6 hypercalcemia
thyroidism
1

Lower limit6
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 do-
mains 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 hyperparathyroid-
ism (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 hy-
perparathyroidism 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 dis-
ease 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 activating mutations of the cyclin D1 gene
or more genes have mutated in parathyroid adenomas, (CCND1).20,24,39 These mutations result in the over-
reflecting a stepwise development of the adenoma.28-31 expression of the protein cyclin D1, but cyclin D1
Many of the known and unknown genes that have overexpression is even more common in parathyroid
mutated in parathyroid tumors are probably tumor- adenomas without cyclin D1 mutations.40
suppressor genes; that is to say, they contribute to the The abnormal parathyroid cells in primary (and
formation of the tumor through a sequential inacti- secondary) hyperparathyroidism have deficient sen-
vation of both copies of the gene.31-34 The multiple sitivity to inhibition by calcium; this may result in part
endocrine neoplasia type 1 gene (MEN1) is a tumor- from a deficiency of calcium-sensing receptors on par-
suppressor gene and the known gene that most of- athyroid cells.41 Deficiency of these receptors is prob-
ten has somatic mutations in both copies in parathy- ably a consequence and not a cause of neoplastic pri-
roid adenomas (in 20 percent of cases).35 Since the mary hyperparathyroidism.
calcium-sensing receptor and the vitamin D receptor
also mediate the inhibition of parathyroid-gland func- Categories and Causes of Sporadic Primary
Hyperparathyroidism
tion, it is noteworthy that no inactivating mutation
of either gene has been identified in parathyroid ad- Solitary parathyroid adenomas account for 85 per-
enomas.35-38 cent of cases of primary hyperparathyroidism; hyper-
A small minority of parathyroid adenomas have function in multiple parathyroid glands (a broad cat-

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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

Secretory6
granule
Menin
JunD
PTH

CDK 4 or 6
p53
P E2F
Cytoplasm
DNA
Cyclin3
D1
6 pRb

RET
Nucleus
G?

SHC

RRL
Calcium-sensing6 Ca2+
receptor
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. In-
activating mutations characterize tumor-suppressor–encoded 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 Jun–Fos 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 calcium-
sensing receptor in the plasma membrane, which transmits information on extracellular calcium to an unidentified guanine-nucle-
otide–binding 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 recep-
tors, 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 pa-
tients with sporadic primary hyperparathyroidism are
women; the average age at diagnosis is 55 years. The
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 se-
rum calcium. The annual incidence then fell markedly

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 MED ICA L PROGR ES S

to 8 per 100,000 in 1992, a decline in diagnoses that
may be due to the prior removal of tumors in pa-
tients whose hypercalcemia was diagnosed when they
were younger.42 During a similar period, there was
no decline in the incidence of primary hyperparathy-
roidism in Sweden.43
The factors associated with sporadic primary hy-
perparathyroidism include the external irradiation of
the neck and therapy with lithium salts.44,45 Lithium
stimulates parathyroid cells in vitro.46 Mild hyper-
parathyroidism 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 hy-
perparathyroidism caused by hyperfunction of mul-
tiple 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 fam-
ilies.38,47,48 Each syndrome raises special issues for di-
agnosis and management (Table 1).
Multiple Endocrine Neoplasia Type 1
Patients with multiple endocrine neoplasia type 1
have various combinations of parathyroid, enteropan-
creatic, anterior pituitary, and other tumors.49 By the
age of 40, patients with multiple endocrine neopla-
sia type 1 have endocrine disorders with the follow-
ing frequencies: hyperparathyroidism in 85 percent
of patients, Zollinger–Ellison syndrome in 35 percent,
prolactinoma in 25 percent, and other tumors less
often.49 Multiple endocrine neoplasia type 1 is caused
by an inactivating germ-line mutation of a tumor-
suppressor 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 nor-
mal 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-sens-
ing receptor, which result in an insensitivity of the
parathyroid cells to inhibition by serum calcium.41
The hypercalcemia persists after subtotal parathyroid-
ectomy; thus, such surgery is contraindicated. Para-
thyroid-cell hyperfunction is polyclonal and non-neo-
plastic.50 The normal urinary calcium excretion despite
hypercalcemia is an effect of the mutated calcium-
sensing receptors in the kidneys.41
Neonatal Severe Primary Hyperparathyroidism
Neonatal severe primary hyperparathyroidism is a
rare and potentially lethal disorder (Table 1). Affect-
ed neonates have a marked enlargement of all para-
thyroid 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 inac-
tivating germ-line mutations of the calcium-sensing
receptor gene.41 The effects of these mutations con-
firm the importance of the calcium-sensing receptor
in the regulation of secretion and growth of parathy-
roid cells.

TABLE 1. CATEGORIES OF PRIMARY HYPERPARATHYROIDISM.*

MULTIPLE ENDOCRINE FAMILIAL HYPOCALCIURIC NEONATAL SEVERE PRIMARY

CHARACTERISTIC SPORADIC ADENOMA NEOPLASIA TYPE 1 HYPERCALCEMIA HYPERPARATHYROIDISM

Inheritance Not inherited Autosomal dominant Autosomal dominant Autosomal recessive

Age at onset of 55 yr 25 yr Birth Birth
hypercalcemia
Urinary calcium excretion Normal to high Normal to high Low to normal Low to normal
Serum parathyroid hormone High High Normal Very high
concentration
Parathyroid glands
No. abnormal One Multiple Multiple Multiple
Enlargement 20 times normal size 5 times normal size Minimally enlarged Very enlarged
Clonality Monoclonal or oligoclonal Monoclonal or oligoclonal Polyclonal Polyclonal
Effectiveness of 95% cured 90% cured, but many recur Surgery not indicated Total parathyroidectomy
parathyroidectomy required
Pathophysiology Stepwise acquired muta- Sequential inactivation of both Monoallelic inherited inacti- Biallelic inactivation of the
tions of certain genes, copies (first copy by inherit- vation of the calcium-sens- calcium-sensing receptor
such as MEN1, promote ance) of the MEN1 gene ing receptor gene decreases gene impairs calcium
the emergence of a leads to the growth of one or the sensing of serum calci- sensing in parathyroid
neoplastic clone more neoplastic clones in par- um by parathyroid cells and cells more than does
in parathyroid gland athyroid glands by renal tubules monoallelic inactivation

*All entries are typical for that disorder. Ranges are broad, with overlap (not shown) among categories.

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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
Multiple Endocrine Neoplasia Type 2a
Multiple endocrine neoplasia type 2a is character-
ized 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 neo-
plasia type 2a is caused by an activating mutation of
the RET proto-oncogene and is inherited as an au-
tosomal dominant trait.27
Hyperparathyroidism–Jaw Tumor Syndrome
The hyperparathyroidism–jaw tumor syndrome is
rare and is characterized by hyperparathyroidism, ce-
mento-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 syn-
drome have hyperparathyroidism, and about 10 per-
cent of those have a parathyroid carcinoma. Often,
at the first presentation of hyperparathyroidism, only
one parathyroid adenoma is present, but multiple ad-
enomas can occur either simultaneously or at differ-
ent times. The disorder is caused by a mutation in
an unknown gene on chromosome 1q2452 and is in-
herited as an autosomal dominant trait.
Manifestations of Primary Hyperparathyroidism
The parathyroids are small endocrine glands, and
increases in their size or enhancements of their func-
tion have no effect on neighboring tissues. Instead,
the effects of an excessive secretion of parathyroid hor-
mone 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 sus-
pected when a patient is found on biochemical screen-
ing 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 restric-
tions on reimbursement for biochemical screening,
the proportion of newly diagnosed cases of hyper-
parathyroidism that are asymptomatic should decrease.
Currently, most patients in whom hyperparathy-
roidism is diagnosed at first appear to be asympto-
matic,54,55 but up to half of them have subtle neuro-
behavioral symptoms such as fatigue and weakness.56,57
In many of these patients, the fact that fatigue or
weakness is a symptom of hyperparathyroidism be-
comes clear only after a successful parathyroidectomy,
when the symptom resolves. About 20 percent of
patients with hyperparathyroidism have nephrolithi-
asis.55 Primary hyperparathyroidism can cause cardi-
ac calcifications and left ventricular hypertrophy; the
latter can occur in the absence of hypertension and
can be partially reversed after parathyroidectomy.58
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There is some controversy about whether any of these
changes decrease life expectancy. A recent population-
based 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, persistent-
ly high serum parathyroid hormone concentrations
have catabolic effects on bone, whereas intermittent
mild increases have anabolic effects.
On balance, the effects of mild primary hyperpara-
thyroidism 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 sex-
matched 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 in-
creased the risk of fracture in several bones, particu-
larly 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 pro-
gresses slowly, if at all. Among asymptomatic patients,
only about 25 percent have progressive disease, which
is usually manifested as a decrease in bone mass dur-
ing 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 con-
ference of the National Institutes of Health conclud-
ed 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 up-
per limit of normal, a level of urinary calcium excre-
tion of less than 400 mg (100 mmol) per day, a cre-
atinine 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 rec-
ommended for many of these patients because of the
evidence that it ameliorates neurobehavioral symp-
 MED IC A L PROGR ES S
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 par-
athyroid glands are available, including ultrasonog-
raphy 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 sur-
gical methods have become possible because imaging
can be used to detect parathyroid adenomas and can
sometimes be coupled with a rapid assay of parathy-
roid hormone during surgery.72 Such approaches can
decrease the duration of the surgery, but the rate of
success may not match that of standard parathyroid-
ectomy.73,74 When patients require repeated operation,
every effort should be made to identify abnormal
tissue preoperatively, and intraoperative testing is of-
ten 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 hyper-
parathyroidism may not undergo surgery because of
contraindications or because they decline the proce-
dure; in others, surgery may have been unsuccessful.
For these patients, several treatments directed at the
target tissues of parathyroid hormone action are avail-
able (Table 2).75 Bisphosphonates such as alendronate
and clodronate inhibit bone resorption; however, they
may be less effective in patients with hyperparathy-
roidism than in those with hypercalcemia from other
causes.76 Estrogen increases bone density in postmeno-
pausal women with hyperparathyroidism but has little
effect on serum calcium concentrations.77 A calcium-
sensing–receptor agonist acts directly on parathyroid
cells by way of the calcium-sensing receptor (and is
thus calcimimetic) in order to inhibit the secretion
of parathyroid hormone78; the further development
of drugs of this type may provide effective treatments
for primary and secondary hyperparathyroidism.79 Pa-
tients 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 hyperpara-
thyroidism change the abnormal transfer of calcium
from the serum to only one target tissue of parathy-
roid hormone action (Table 2 and Fig. 1). Most treat-
ments for hypoparathyroidism also affect the transfer
of calcium along only one of these pathways, albeit
in the opposite direction.
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Parotid
Submandibular
Thyroid
Mediastinal6
parathyroid
Heart
Figure 4. Anterior Planar Image of the Neck and Chest of a Pa-
tient with Primary Hyperparathyroidism Obtained with Techne-
tium-99m Sestamibi, Showing a Parathyroid Adenoma in the
Mediastinum.
The patient had undergone an unsuccessful parathyroid explo-
ration. The image shown was obtained two hours after the ad-
ministration of 20 mCi of the radionuclide. The lobes of the thy-
roid and the salivary glands are clearly visible. (Image courtesy
of Dr. Clara Chen.)
HYPERCALCEMIA MEDIATED BY
PARATHYROID HORMONE–RELATED
PEPTIDE
Hypercalcemia is sometimes caused by serum fac-
tors, which may be released by nonparathyroid tu-
mors, whether or not there are skeletal metastases.
Most of these tumors are malignant and secrete par-
athyroid hormone–related peptide.13 In contrast, hy-
persecretion of parathyroid hormone by a nonparathy-
roid tumor is extremely rare.
UREMIC HYPERPARATHYROIDISM
Secondary and Tertiary Hyperparathyroidism
Hypocalcemia from any cause stimulates parathy-
roid 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 hypo-
calcemia. However, in patients with chronic renal fail-
ure, secondary hyperparathyroidism often lasts longer
and is more severe than in patients with other hypo-
calcemic disorders, such as a deficiency or malabsorp-
tion of vitamin D.80 Eventually, either before or, more
often, after renal transplantation, secondary hyperpara-
thyroidism can develop into a disorder of oversecre-
tion of parathyroid hormone with hypercalcemia (ter-
tiary 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 consequent-
Vol ume 343 Numb e r 25 · 1869
 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 TREATMENT
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.
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 para-
thyroid glands that have been removed from patients
with uremia are usually overgrown with monoclonal
or oligoclonal components.22,82-84 The cause of pro-
gression from early, presumably polyclonal, secondary
hyperplasia of the parathyroid to later monoclonal or
oligoclonal tumors is poorly understood.21,80,84 Prob-
ably, some of the genes that are mutated in the par-
athyroid glands of patients with secondary or tertiary
hyperparathyroidism are different from those that are
mutated in primary hyperparathyroidism; in partic-
ular, MEN1 mutations are less frequent in the para-
thyroid glands of patients with uremia than in tumors
of patients with sporadic primary hyperparathyroid-
ism.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 fac-
tors.85,86 Some patients with chronic renal disease have
hyperparathyroid uremic bone disease, which is char-
acterized by an activation of osteoblasts and osteo-
clasts with excess bone resorption. Other patients have
an adynamic bone disease or osteomalacia. Adynam-
ic bone disease is characterized by low activity of the
bone cells, no excess accumulation of matrix, and lit-
tle parathyroid hypersecretion.86,87 Osteomalacia in
renal failure is characterized by excess accumulation
of osteoid and a minimal degree of hyperparathy-
roidism and has been associated with the accumula-
tion 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 flu-
ids.86,87 The frequency of hyperparathyroid bone dis-
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Copyright © 2000 Massachusetts Medical Society. All rights reserved.
FOR HYPERPARATHYROIDISM AND HYPOPARATHYROIDISM.
TREATMENTS FOR TREATMENTS FOR
HYPERPARATHYROIDISM HYPOPARATHYROIDISM
Parathyroidectomy Parathyroid autograft
Calcium-sensing–receptor agonist*
Blocker of type 1 receptor* Parathyroid hormone (1–34)*
Bisphosphonates
Estrogen
Blocker of vitamin D receptor* Vitamin D analogue
Calcium salts
Forced natriuresis Thiazide
Dialysis Intravenous calcium
ease among patients with uremia is similar to the fre-
quency of adynamic bone diseases.86,87
Uremic hyperparathyroid bone disease is best treat-
ed by raising serum calcium concentrations and there-
by 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 hy-
perparathyroidism is caused by hypocalcemia, which,
in turn, is caused by hyperphosphatemia and decreased
renal production of 1,25-dihydroxyvitamin D. Treat-
ment is based on raising serum calcium concentra-
tions 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 contro-
versy 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 con-
centrations,90,91 but calcitriol given orally has similar
effects.93
Severe secondary hyperparathyroidism is an im-
portant indication for parathyroidectomy in patients
with chronic renal disease who cannot be treated ad-
equately with the measures described above.94 Para-
thyroidectomy is also appropriate for some patients
with tertiary hyperparathyroidism.
After renal transplantation, secondary hyperpara-
The New England Journal of Medicine
 MED IC A L PROGR ES S
thyroidism usually regresses over a period of 1 to 10
years, but the regression may be incomplete, as re-
flected in persistently high serum parathyroid hor-
mone concentrations.95 About one third of patients
who receive renal transplants have parathyroid hor-
mone–induced 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 re-
quire parathyroidectomy an average of three years af-
ter renal transplantation because of persistent hyper-
calcemia.96
HYPOPARATHYROIDISM
Hypoparathyroidism can cause hypocalcemia with
consequent paresthesias, muscle spasms (i.e., tetany),
and seizures, especially when it occurs rapidly. In con-
trast, chronic hypoparathyroidism generally causes hy-
pocalcemia 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, represent-
ing disruptions of one or more of the steps in the
development and maintenance of parathyroid hor-
mone secretion.
Damage to the Parathyroid Glands from Surgery
Injury to or removal of the parathyroid glands dur-
ing 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 in-
fants 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 dis-
ability. Both syndromes are associated with rearrange-
ments 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 de-
letion 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 polyendocrinopathy–candi-
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Copyright © 2000 Massachusetts Medical Society. All rights reserved.
diasis–ectodermal dystrophy syndrome.100 The hypo-
parathyroidism, like other manifestations of the syn-
drome, occurs during childhood; for this reason and
because of such associated abnormalities as hypoadre-
nalism and intestinal malabsorption, the hypoparathy-
roidism may be difficult to treat. The syndrome is in-
herited 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 mole-
cule and undetectable amounts of parathyroid hor-
mone in serum.102
Defective Regulation of Parathyroid Hormone Secretion
Hypocalcemia and hypercalciuria are the chief fea-
tures of autosomal dominant hypercalciuric hypocal-
cemia, 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 rais-
ing serum calcium concentrations further increases
urinary calcium excretion and may cause nephrocal-
cinosis.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., thi-
azides) (Table 2). The parathyroid hormone–depend-
ent renal production of 1,25-dihydroxyvitamin D is
deficient in all hypoparathyroid states. Therefore, ther-
apy with a vitamin D analogue is used to ensure that
there is a steady serum concentration of an active vi-
tamin D analogue. If parathyroid hormone is absent
or nonfunctional, its hypocalciuric action cannot oc-
cur; therefore, raising the serum calcium concentra-
tion 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 polyglan-
dular 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
Vol ume 343 Numb e r 25 · 1871
 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 re-
quire immunosuppression and so would be more dan-
gerous than the disease it was meant to treat. Parathy-
roid 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 auto-
graft-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 hor-
mone (1–34) given subcutaneously once daily.104 The
increase in urinary calcium excretion in these patients
was smaller than that which occurs in patients treat-
ed with calcium and calcitriol or vitamin D. Howev-
er, synthetic human parathyroid hormone (1–34) 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 sim-
ilar effect on bone growth.11,13
Jansen’s Chondrodystrophy
Jansen’s chondrodystrophy is characterized by short
limbs, mild hypercalcemia, and low serum parathyroid
hormone concentrations. It is caused by activating mu-
tations 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.
Blomstrand’s Chondrodystrophy
Blomstrand’s 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 inher-
1872 · Dec em b er 2 1 , 2 0 0 0
The New England Journal of Medicine
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Copyright © 2000 Massachusetts Medical Society. All rights reserved.
ited as an autosomal recessive trait. The growth plates
show accelerated calcification and a near-absence of
proliferating chondrocytes.
Defects of the Stimulatory Guanine-Nucleotide–Binding
Protein
Parathyroid hormone signaling in cells is mediated
by the type 1 parathyroid hormone receptor, which
then acts on a stimulatory guanine-nucleotide–bind-
ing (Gs) protein, which is composed of three sub-
units (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 Albright’s hereditary osteo-
dystrophy, 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 pa-
tients with pseudohypoparathyroidism type 1a have
resistance not only to parathyroid hormone but also
to thyrotropin.
Pseudo-pseudohypoparathyroidism
Pseudo-pseudohypoparathyroidism occurs in fam-
ilies with pseudohypoparathyroidism type 1a. It con-
sists of a combination of inactivating mutations of
GNAS1 and Albright’s osteodystrophy without the
resistance to multiple hormones that characterizes
pseudohypoparathyroidism. The hormone resistance
is suppressed when the mutated GNAS1 gene is in-
herited 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 with-
out the accompanying Albright’s 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 pseudohypoparathy-
roidism 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 par-
athyroid hormone, the diagnosis of parathyroid dys-
function has become much easier. Treatments are gen-
erally satisfactory and are logically related to the defects
 MED IC A L PROGR ES S
in the parathyroid gland or to their expression in the
target organs. Controversies persist, however, particu-
larly about the treatment of primary hyperparathy-
roidism.
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