Transcript Document

PARATHYROID GLANDS
PARATHYROID GLANDS
Derived from the developing pharyngeal
pouches
The four glands normally lie in close
proximity to the upper and lower poles of
each thyroid lobe
10% of individuals have only two or three
glands.
In the adult, the parathyroid is a yellowbrown, ovoid encapsulated nodule weighing
approximately 35 to 40 mg.
Most of the gland is composed of chief cells.
They contain secretory granules of
parathyroid hormone (PTH).
Oxyphil cells and transitional oxyphils are
found throughout the normal parathyroid,
either singly or in small clusters.
The amount of stromal fat increases up to
age 25, reaching a maximum of
approximately 30% of the gland.
The activity of the parathyroid glands is
controlled by the level of free (ionized)
calcium in the bloodstream rather than by
trophic hormones secreted by the
hypothalamus and pituitary.
The metabolic functions of PTH in
supporting serum calcium levels can be
summarized as follows:
PTH activates osteoclasts, thereby mobilizing
calcium from bone.
It increases the renal tubular reabsorption of
calcium, thereby conserving free calcium.
It increases the conversion of vitamin D to its
active dihydroxy form in the kidneys.
It increases urinary phosphate excretion,
thereby lowering serum phosphate levels.
It augments gastrointestinal calcium absorption.
Hypercalcemia of malignancy is due to
increased bone resorption and subsequent
release of calcium.
There are two major mechanisms by
which this can occur:
(1) osteolytic metastases and local release
of cytokines
(2) release of PTH-related protein
(PTHrP).
Recently, a critical osteoclastogenic
pathway has been discovered that
involves the osteoblast cell-surface
receptor RANK (receptor activator of
nuclear factor κB), its ligand, RANKL, and
a decoy receptor for RANKL,
osteoprotegerin.
RANKL is also known as "osteoclast
differentiation factor," and by binding with
the RANK receptor, it promotes all aspects
of osteoclast function, including
proliferation, differentiation, fusion, and
activation. RANKL is secreted by tumor
cells and peritumoral stromal cells in
metastatic foci and causes osteolysis.
PTH-related protein: The most frequent
cause of hypercalcemia in nonmetastatic
solid tumors-particularly squamous cell
cancers
PTHrP-induced hypercalcemia was known
as "humoral hypercalcemia of malignancy"
to distinguish it from hypercalcemia arising
from osteolytic metastases.
Hyperparathyroidism
PRIMARY HYPERPARATHYROIDISM
Primary hyperparathyroidism is one of the most common
endocrine disorders, and it is an important cause of
hypercalcemia.
The frequency of the various parathyroid lesions underlying
the hyperfunction is as follows:
Adenoma: 75% to 80%
Primary hyperplasia (diffuse or nodular): 10% to 15%
Parathyroid carcinoma: less than 5%
Primary hyperparathyroidism is
usually a disease of adults and is
more common in women than in men
by a ratio of nearly 3:1.
In more than 95% of cases, the
disorder is caused by sporadic
parathyroid adenomas or sporadic
hyperplasia :
Cardinal features of hyperparathyroidism. With routine evaluation
of calcium levels in most patients, primary hyperparathyroidism is
often detected at a clinically silent stage. Hypercalcemia from any
other cause can also give rise to the same symptoms.
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The genetic syndromes associated with
familial primary hyperparathyroidism
include the following:
Multiple endocrine neoplasia-1 (MEN-1)
Multiple endocrine neoplasia-2 (MEN-2)
Familial hypocalciuric hypercalcemia (FHH) is
an autosomal-dominant disorder characterized
by enhanced parathyroid function due to
decreased sensitivity to extracellular calcium.
Sporadic parathyroid hyperplasia is also
monoclonal in many instances,
Morphology
Parathyroid adenomas
solitary -similar to the normal parathyroid glands,
may lie in close proximity to the thyroid gland or
in an ectopic site (e.g., the mediastinum).
The typical parathyroid adenoma averages 0.5 to
5.0 gm; is a well-circumscribed, soft, tan to
reddish-brown nodule; and is invested by a
delicate capsule
In contrast to primary hyperplasia, the glands
outside the adenoma are usually normal in size
or somewhat shrunken because of feedback
inhibition by elevations in serum calcium.
Microscopically, parathyroid adenomas are
often composed predominantly of fairly
uniform, polygonal chief cells with small,
centrally placed nuclei
Mitotic figures are rare. A rim of
compressed, non-neoplastic parathyroid
tissue, generally separated by a fibrous
capsule, is often visible at the edge of the
adenoma.
Parathyroid adenomas are almost always solitary lesions. Technetium-99msestamibi radionuclide scan demonstrates an area of increased uptake
corresponding to the left inferior parathyroid gland (arrow). This patient had
a parathyroid adenoma. Preoperative scintigraphy is useful in localizing and
distinguishing adenomas from parathyroid hyperplasia, where more than
one gland would demonstrate increased uptake.
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Parathyroid adenoma. A, Solitary chief cell parathyroid adenoma (lowpower photomicrograph) revealing clear delineation from the residual gland
below.
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© 2005 Elsevier
Parathyroid adenoma. B, High-power detail of a chief cell parathyroid
adenoma. There is some slight variation in nuclear size but no anaplasia
and some slight tendency to follicular formation.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 20 February 2006 11:38 PM)
© 2005 Elsevier
Primary hyperplasia
Sporadically or as a component of MEN
syndrome.
Classically all four glands are involved, there is
frequently asymmetry with apparent sparing of
one or two glands, making the distinction
between hyperplasia and adenoma difficult.
The combined weight of all glands rarely
exceeds 1.0 gm and is often less.
Microscopically, the most common pattern seen
is that of chief cell hyperplasia, which may
involve the glands in a diffuse or multinodular
pattern.
Parathyroid carcinomas
Circumscribed lesions that are difficult to
distinguish from adenomas, or they may
be clearly invasive neoplasms.
These tumors enlarge one parathyroid
gland and consist of gray-white, irregular
masses that sometimes exceed 10 gm in
weight.
The cells of parathyroid carcinomas are usually
uniform and resemble normal parathyroid cells.
They are arrayed in nodular or trabecular
patterns with a dense, fibrous capsule enclosing
the mass.
diagnosis of carcinoma based on cytologic
detail is unreliable, and invasion of
surrounding tissues and metastasis are the
only reliable criteria of malignancy.
Local recurrence occurs in one third of cases,
and more distant dissemination occurs in
another third.
Skeletal changes include prominence of
osteoclasts, which, in turn, erode bone matrix
and mobilize calcium salts, particularly in the
metaphyses of long tubular bones
In more severe cases, the cortex is grossly
thinned, and the marrow contains increased
amounts of fibrous tissue accompanied by foci of
hemorrhage and cyst formation (osteitis fibrosa
cystica).
Aggregates of osteoclasts, reactive giant cells,
and hemorrhagic debris occasionally form
masses that may be mistaken for neoplasms
(brown tumors of hyperparathyroidism).
PTH-induced hypercalcemia favors
formation of urinary tract stones
(nephrolithiasis) as well as calcification of
the renal interstitium and tubules
(nephrocalcinosis).
Metastatic calcification secondary to
hypercalcemia may also be seen in other
sites, including the stomach, lungs,
myocardium, and blood vessels.
Clinical Course.
Primary hyperparathyroidism presents in
one of two general ways:
(1) It may be asymptomatic and be
identified after a routine chemistry profile,
(2) Patients may have the classic clinical
manifestations of primary
hyperparathyroidism
Raised PTH
Decreased PTH
Hyperparathyro
idism
Primary
(adenoma >
hyperplasia)*
Secondary†
Tertiary†
Familial
hypocalciuric
hypercalcemia
Hypercalcemia of
malignancy
Osteolytic metastases
(RANKL-mediated)
PTH-rP-mediated
Vitamin D toxicity
Immobilization
Thiazide diuretics
Granulomatous disease
(sarcoidosis)
Primary hyperparathyroidism is the most
common cause of hyper-calcemia overall.
Malignancy is the most common cause of
symptomatic hypercalcemia.
Primary hyperparathyroidism and
malignancy account for nearly 90% of
cases of hypercalcemia.
Secondary and tertiary
hyperparathyroidism are most commonly
associated with progressive renal failure.
Asymptomatic Hyperparathyroidism
Because serum calcium levels are routinely
assessed in the work-up of most patients who
need blood tests for unrelated conditions,
clinically silent hyperparathyroidism is often
detected early.
The most common manifestation of primary
hyperparathyroidism is an increase in the level of
serum ionized calcium; in fact, primary
hyperparathyroidism is the most common cause
of asymptomatic hypercalcemia.
Symptomatic Primary Hyperparathyroidism
The signs and symptoms of hyperparathyroidism reflect the
combined effects of increased PTH secretion and
hypercalcemia. The symptomatic presentation involves a
diversity of clinical manifestations:
Bone disease includes bone pain secondary to fractures of
bones weakened by osteoporosis or osteitis fibrosa cystica.
Nephrolithiasis (renal stones) occurs in 20% of newly
diagnosed patients, with attendant pain and obstructive
uropathy. Chronic renal insufficiency and a variety of
abnormalities in renal function are found, including polyuria
and secondary polydipsia.
Gastrointestinal disturbances include constipation, nausea,
peptic ulcers, pancreatitis, and gallstones.
Central nervous system alterations include depression,
lethargy, and eventually seizures.
Neuromuscular abnormalities include complaints of
weakness and fatigue.
Cardiac manifestations include aortic or mitral valve
calcifications (or both).
SECONDARY
HYPERPARATHYROIDISM
Secondary hyperparathyroidism is caused by any
condition associated with a chronic depression in
the serum calcium level because low serum
calcium leads to compensatory overactivity of the
parathyroid glands.
Renal failure is by far the most common cause of
secondary hyperparathyroidism, although a
number of other diseases, including inadequate
dietary intake of calcium, steatorrhea, and
vitamin D deficiency, may also cause this
disorder.
Morphology:
The parathyroid glands in secondary
hyperparathyroidism are hyperplastic.
As in the case of primary hyperplasia, the degree of
glandular enlargement is not necessarily symmetric.
Microscopically, the hyperplastic glands contain an
increased number of chief cells, or cells with more
abundant, clear cytoplasm (so-called water-clear cells)
in a diffuse or multinodular distribution.
Fat cells are decreased in number.
Bone changes similar to those seen in primary
hyperparathyroidism may also be present.
Metastatic calcification may be seen in many
tissues, including lungs, heart, stomach, and blood
vessels.
Clinical Course
The clinical features of secondary
hyperparathyroidism are usually
dominated by those associated with
chronic renal failure.
Bone abnormalities (renal osteodystrophy)
and other changes associated with PTH
excess are, in general, less severe than
are those seen in primary
hyperparathyroidism.
In a minority of patients, parathyroid
activity may become autonomous and
excessive, with resultant hypercalcemia, a
process that is sometimes termed tertiary
hyperparathyroidism. Parathyroidectomy
may be necessary to control the
hyperparathyroidism in such patients.
Hypoparathyroidism
Hypoparathyroidism is far less common than
is hyperparathyroidism. There are many
possible causes of deficient PTH secretion
resulting in hypoparathyroidism:
Surgically induced hypoparathyroidism
occurs with inadvertent removal of all the
parathyroid glands during thyroidectomy,
excision of the parathyroid glands in the
mistaken
Congenital absence of all glands, as in certain
developmental abnormalities, such as thymic
aplasia and cardiac defects (22q11.2 syndrome)
Familial hypoparathyroidism is often associated
with chronic mucocutaneous candidiasis and
primary adrenal insufficiency; this syndrome is
known as autoimmune polyendocrine syndrome
type 1 (APS1) and is caused by mutations in the
autoimmune regulator (AIRE) gene.
İdiopathic hypoparathyroidism most likely
represents an autoimmune disease with isolated
atrophy of the glands.
The major clinical manifestations of
hypoparathyroidism are referable to
hypocalcemia and are related to the
severity and chronicity of the
hypocalcemia.
The hallmark of hypocalcemia is tetany,
which is characterized by
neuromuscular irritability
Mental status changes can include
emotional instability, anxiety and
depression, confusional states,
hallucinations, and frank psychosis.
Intracranial manifestations include calcifications
of the basal ganglia, parkinsonian-like
movement disorders
Ocular disease results in calcification of the lens
leading to cataract formation.
Cardiovascular manifestations include a
conduction defect, which produces a
characteristic prolongation of the QT interval in
the electrocardiogram.
Dental abnormalities occur when hypocalcemia
is present during early development. These
findings are highly characteristic of
hypoparathyroidism and include dental
hypoplasia, failure of eruption, defective enamel
and root
Pseudohypoparathyroidism
Hypoparathyroidism occurs because of endorgan resistance to the actions of PTH.
Serum PTH levels are normal or elevated.
Central to the understanding of PTH resistance
are two key concepts: (1) G-proteins, principally
Gs, mediate the cellular actions of PTH on bone
and kidney, and (2) GNAS1 is a selectively
imprinted gene, with tissue-specific patterns of
imprinting
Two types of pseudohypoparathyroidism have
been identified depending on the parent of origin
of the mutant allele:
1-Pseudohypoparathyroidism type 1A is
associated with multihormone resistance and
Albright hereditary osteodystrophy (AHO), a
syndrome characterized by skeletal and
developmental defects. Patients with AHO often
have short stature, obesity, short metacarpal and
metatarsal bones, and variable mental deficits.
The multihormone resistance involves three
hormones (PTH, TSH, and LH/FSH),
2-Pseudopseudohypoparathyroidism: In
this disorder, the mutation is inherited on
the paternal allele, and it is characterized
by AHO without accompanying
multihormonal resistance. As a result,
serum calcium, phosphate and PTH levels
are normal.