The parathyroid glands are derived developmentally from Secondary hyperparathyroidism: compensatory hypersecre-

pharyngeal pouches that also give rise to the thymus. tion of PTH in response to prolonged hypocalcemia, most
They are most commonly located in close proximity to commonly from chronic renal failure
the upper and lower poles of each thyroid lobe but may Tertiary hyperparathyroidism: persistent hypersecretion of
be found anywhere along the pathway of descent of PTH, even after the cause of prolonged hypocalcemia is
the pharyngeal pouches, including the carotid sheath, the corrected (e.g., after renal transplant)
thymus, and elsewhere in the anterior mediastinum. The
four parathyroid glands are composed of two cell types:
chief cells and oxyphil cells. Chief cells predominate; they
m in diameter, and have central,
round, uniform nuclei and light to dark pink cytoplasm. Primary hyperparathyroidism is one of the most common
Chief cells have secretory granules containing parathyroid endocrine disorders, and it is an important cause of
. Oxyphil cells and transitional oxyphils are hypercalcemia. The frequency of the various parathyroid
found throughout the normal parathyroid, either singly or lesions underlying hyperfunction is as follows:
in small clusters. They are slightly larger than the chief
cells, have acidophilic cytoplasm, and are tightly packed
with mitochondria. Glycogen granules are also present in
these cells, but secretory granules are sparse or absent. In
early infancy and childhood, the parathyroid glands are Primary hyperparathyroidism is usually a disease of
composed almost entirely of solid sheets of chief cells. adults and is more common in women than in men by a
The amount of stromal fat increases up to 25 years of age,

and then plateaus.

The function of the parathyroid glands is to regulate
calcium homeostasis. The activity of the parathyroid glands
blood. Normally, decreased levels of free calcium stimulate
the synthesis and secretion of PTH. Several metabolic func-
tions of PTH regulate serum calcium levels:
conserving free calcium
form in the kidneys, which, in turn, augments gastro-
intestinal calcium absorption
discovered incidentally on a serum electrolyte panel. Most
cases occur in the 50s or later in life.
The most common cause of primary hyperparathyroid-
ism is a solitary sporadic parathyroid adenoma (Fig. 24.24).
Most, if not all, sporadic parathyroid adenomas are mono-
clonal, consistent with a neoplastic origin. As with nodules
in goitrous thyroids, sporadic parathyroid “hyperplasia” is
also monoclonal in many instances, particularly when
associated with a persistent stimulus for parathyroid growth
(refractory secondary or tertiary parathyroidism; see later),

serum phosphate levels and further increasing calcium reactive hyperplasia and neoplasia. There are two molecular

-
tion of osteoclast progenitor cells into mature osteoclasts

The net result of these activities is to elevate the level of

free calcium, which, in turn, inhibits further PTH secretion
in a classic feedback loop.
Similar to the other endocrine organs, abnormalities of
the parathyroid glands include both hyperfunction and
hypofunction. Tumors of the parathyroid glands, in contrast
to thyroid tumors, usually come to attention because of
excessive secretion of PTH rather than mass effects.

Hyperparathyroidism is caused by elevated PTH and is

an autonomous overproduc-
tion of PTH, usually resulting from an adenoma or
hyperplasia of parathyroid tissue
defects that have an established role in the development of
sporadic adenomas:
Cyclin D1 (CCDN1) gene inversions leading to overexpres-

results in relocation of CCDN1

that it is positioned adjacent to the 5
of the
changes, a 5

parathyroid adenomas have this clonal rearrangement.

-
nisms other than CCDN1 gene inversion can lead to its
overexpression.
MEN1 mutations:
parathyroid tumors have somatic mutations of the MEN1

Germline mutations of MEN1 are also found in patients

with familial parathyroid adenomas (see later). The
spectrum of MEN1 mutations in sporadic tumors is virtu-
ally identical to that in familial parathyroid adenomas.
CDC73, which encodes a protein known
-
thyroid carcinomas, but rarely in adenomas. Germline
mutations of CDC73 lead to a rare syndrome known
as hyperparathyroidism–jaw tumor syndrome, which
includes parathyroid carcinomas and ossifying jaw tumors
as part of the disease spectrum.

Familial syndromes are a distant second to sporadic

parathyroid adenomas as causes of primary hyperparathy-
roidism. The genetic syndromes associated with familial
parathyroid adenomas
(discussed in further detail later), as well as familial hypo-
calciuric hypercalcemia, a rare autosomal dominant disorder
caused by loss-of-function mutations in the parathyroid
calcium-sensing receptor ( ) gene, which results in
decreased sensitivity to extracellular calcium.
associated with the classic clinical manifestations of primary
hyperparathyroidism.
Asymptomatic hyperparathyroidism. Because serum calcium
levels are routinely assessed, most patients with primary
hyperparathyroidism are diagnosed incidentally. In fact,
primary hyperparathyroidism is the most common cause
of asymptomatic hypercalcemia. Hence, many of the
classic manifestations, particularly those referable to bone
and renal disease, are now seen infrequently in clinical
practice. Among other causes of hypercalcemia (Table
24.5), malignancy stands out as the most frequent cause
of symptomatic hypercalcemia in adults, and must be
excluded by appropriate clinical and laboratory investiga-
tions. As discussed in Chapter 7, hypercalcemia can occur
with solid tumors, such as lung, breast, head and neck,
and renal cancers, and with hematologic malignancies,
notably multiple myeloma. The most common mechanism

hypercalcemia is by secretion of PTH-related peptide

(PTHrP), which (like PTH) induces osteoclastic bone

hypercalcemia through metastases to the bone and

subsequent cytokine-induced bone resorption. In individu-
als with primary hyperparathyroidism, serum PTH levels
are inappropriately elevated for the level of serum calcium,
whereas PTH levels are low to undetectable in hyper-
calcemia caused by nonparathyroid diseases (see Table

are available and can be useful in distinguishing primary

hyperparathyroidism and malignancy-associated hyper-
calcemia. Other laboratory alterations referable to PTH
excess include hypophosphatemia and increased urinary
excretion of both calcium and phosphate. Secondary renal
disease may in turn lead to phosphate retention, “normal-

Symptomatic primary hyperparathyroidism. The signs and

effects of increased PTH secretion and hypercalcemia.

Primary hyperparathyroidism is associated with “painful
bones, renal stones, abdominal groans, and psychic
moans.” The constellation of symptoms includes the
following:
 Bone disease and bone pain secondary to fractures of
cystica
Nephrolithiasis
patients, with attendant pain and obstructive uropathy.
function lead to polyuria and secondary polydipsia.
Gastrointestinal disturbances, including constipation,
nausea, peptic ulcers, pancreatitis, and gallstones
Central nervous system alterations, including depres-
Neuromuscular abnormalities, including weakness
and fatigue
Cardiac manifestations, including aortic or mitral valve
The abnormalities most directly related to hyperpara-
thyroidism are nephrolithiasis and bone disease, whereas
those attributable to hypercalcemia include fatigue, weakness,
Secondary hyperparathyroidism is caused by any condition
that gives rise to chronic hypocalcemia, which, in turn,
leads to compensatory overactivity of the parathyroid
glands. Renal failure is by far the most common cause of
secondary hyperparathyroidism, although several other
diseases, including inadequate dietary intake of calcium,
disorder. The mechanisms by which chronic renal failure
induces secondary hyperparathyroidism are complex and
with decreased phosphate excretion, which, in turn, results
in hyperphosphatemia. The elevated serum phosphate levels
directly depress serum calcium levels and thereby stimulate
parathyroid gland activity. In addition, loss of renal substance
reduces the availability of -hydroxylase, which is necessary
for the synthesis of the active form of vitamin D, leading
in turn to reduced intestinal absorption of calcium (Chapter
hyperparathyroidism in renal failure.
The clinical features of secondary hyperparathyroidism are
usually dominated by the inciting chronic renal failure.
Secondary hyperparathyroidism is usually not as severe or
as prolonged as primary hyperparathyroidism, hence the
skeletal abnormalities (referred to as renal osteodystrophy)
tend to be milder. Control of the hyperparathyroidism allows
-
-
cant ischemic damage to skin and other organs, a process
referred to as calciphylaxis. Patients with secondary hyper-
parathyroidism often respond to dietary vitamin D supple-
mentation as well as phosphate binders, which decrease
the prevailing hyperphosphatemia.
In a minority of patients, parathyroid activity may become
autonomous and excessive, with resultant hypercalcemia, a
process termed tertiary hyperparathyroidism. Parathyroidec-
tomy may be necessary to control the hyperparathyroidism
in such patients.
Hypoparathyroidism is far less common than is hyperpara-
thyroidism. Acquired hypoparathyroidism is almost always
an inadvertent consequence of surgery; in addition, there
are several genetic causes of hypoparathyroidism.
Surgically induced hypoparathyroidism occurs with inad-
vertent removal of all parathyroid glands during thy-
roidectomy, excision of parathyroid glands in the mistaken
belief that they are lymph nodes during radical neck
dissection for some form of malignant disease, or removal
of too large a proportion of parathyroid tissue in the
treatment of primary hyperparathyroidism.
Autoimmune hypoparathyroidism is often associated with
chronic mucocutaneous candidiasis and primary adrenal
caused by mutations in the
gene. The syndrome typically presents in childhood with
the onset of candidiasis, followed several years later by
this chapter.