By – Elizabeth H.(MD.

,)
Pathologist
 Introduction
• Four small, yellow-tan,
lentiform glands
typically abutting
posterior thyroid
capsule
– Each gland weighs ~ 30-
40 mg
– 4-6 mm long, 3-4 mm
wide, 1-2 mm thick
Developmental origins of thyroid, parathyroid, and thymus glands. Arrows
show pathways of migration.
Note how pouch III develops into the inferior parathyroid gland and the
thymus (synthesizes T cells), whereas pouch IV develops into the superior
parathyroid glands.
Chief cells are uniform small cells with
pale amphophilic to clear vacuolated
cytoplasm. The nuclei are round and small
with coarse chromatin and
inconspicuous nucleoli. These are the
functional cells of the parathyroid, which
synthesize and secrete parathyroid
hormone in response to hypocalcemia.
Oxyphil cells are altered chief cells with
abundant, granular, eosinophilic
cytoplasm. They have less secretory
activity and can be isolated or form small
nodules,
such as this focus ﬈. Smaller transitional
cells ﬊ with eosinophilic cytoplasm can be
seen as well.
• Chief cells regulate serum free (ionized) calcium via
parathyroid hormone (PTH) secretion, which
• 1. Increases bone osteoclast activity, releasing
calcium and phosphate
• 2. Increases small bowel absorption of calcium and
phosphate (indirectly by activating vitamin D)
– Synthesizes 1-α-hydroxylase in proximal tubule;
↑synthesis 1,25-(OH) D
2

• 3. Increases renal calcium reabsorption (distal

tubule) and decreases phosphate reabsorption
(proximal tubule)
• Increased serum ionized calcium levels
provide negative feedback to decrease PTH
secretion.
– PTH is stimulated by hypocalcemia and
hyperphosphatemia.
– PTH is suppressed by hypercalcemia and
hypophosphatemia.
 HYPERPARATHYROIDISM
• Two major forms
– Primary
• Autonomous, Spontaneous overproduction of PTH
– Secondary,
• typically occur as secondary phenomena
– Tertiary hyperparathyroidism.
• Glands become autonomous regardless of the calcium
level.
• Less commonly
 Primary hyperparathyroidism (HPTH)
• Excess PTH due to a disorder of the parathyroid
gland itself
• Most common nonmalignant cause of
hypercalcemia
• Occurs most frequently in postmenopausal
women
• Asymptomatic in >50% of patients
• Association with MEN I and MEN Ila
– Familial primary hyperparathyroidism
 PATHOGENESIS
• Cyclin D1 gene inversions
– Positive regulator of the cell cycle.
– Can lead to its overexpression
• MEN1 mutations
– 20% to 30% of parathyroid tumors not associated
with the MEN-1 syndrome have mutations in both
copies of the MEN1 gene
 Causes
• Adenoma (~80% of cases)
– Usually a single adenoma
– Sheets of chief cells with no intervening adipose
– Remainder of the gland plus all other glands show
atrophy.
• Hypercalcemia suppresses PTH produced from normal
tissue.
– Right inferior parathyroid gland is most often
involved.
• Morphology
– Well circumscribed,
– Soft, tan nodule, invested by a delicate capsule.
• Primary hyperplasia (~20% of cases)
– All four glands are involved.
– Usually a chief cell hyperplasia
– Clear cell hyperplasia (wasserhelle cell hyperplasia)
• Associated with markedly increased serum calcium levels
• Carcinoma (uncommon)
– Diagnosis of carcinoma based on cytologic detail is
unreliable, and invasion of surrounding tissues and
metastasis are the only definitive criteria.
 Clinical findings
Most often results in asymptomatic hypercalcemia

• Renal
– Calcium stones
– Nephrocalcinosis
• Metastatic calcification
• Causes polyuria and
renal failure
• Gastrointestinal
– Peptic ulcer disease
(PUD)
• Calcium stimulates
gastrin, which increases
gastric acid.
– Acute pancreatitis
• Calcium activates
phospholipase.
– Constipation
• Bone and joints
– Osteitis fibrosa cystica
• Cystic and hemorrhagic bone lesion
– Caused by increased osteoclastic activity
• Commonly involves the jaw
– Osteoporosis
– Chondrocalcinosis (pseudogout)
 Radiographic findings
• Subperiosteal resorption in
primary hyperparathyroidism.
The radiologic hallmark of
hyperparathyroidism is
subperiosteal bone resorption,
seen especially well on the radial
aspect of the middle phalanges of
the index and middle fingers
(solid white arrows). Here the
cortex appears shaggy and
irregular, compared to the cortex
on the opposite side of the same
bone, which is well defined. This
patient also displays two other
findings of hyperparathyroidism:
a small brown tumor (solid black
arrow) and resorption of the
terminal phalanges (acro-
osteolysis) (dotted white arrows)
 Clinical findings
• Diastolic HTN
– Due to hypercalcemia increasing smooth muscle
contraction of peripheral resistance arterioles
• Eyes
– Band keratopathy in the limbus of the eye
– Due to metastatic calcification
• Central nervous system
– Myriad of different findings—psychosis, confusion,
anxiety, coma
 Other causes of hypercalcemia
• Primary HPTH and the hypercalcemia of
malignancy account for ~80% of all cases of
hypercalcemia.
• Primary differentiating feature between these
two diagnoses is serum PTH.
– ↑PTH in former, ↓PTH in latter (whether it is due
to lytic lesions (most common) or PTH-related
peptide.)
 Secondary Hyperparathyroidism
• Excess production of PTH due to a disease process
extrinsic to the parathyroid gland
– Caused by any condition associated with a chronic
depression in the serum calcium level, because low serum
calcium leads to compensatory overactivity of the
parathyroids.
• Most common cause is chronic renal failure.
– Renal insufficiency leads to decreased phosphate excretion.
– ↑serum phosphate binds free calcium.
– ↓free calcium stimulates all four parathyroid glands.
– ↑ PTH leads to bone resorption (contributing to renal
osteodystrophy).
 Morphology
• The parathyroid glands in secondary hyperparathyroidism
are hyperplastic.
• The degree of glandular enlargement is not necessarily
symmetric.
• Microscopic
– increased number of chief cells, or water-clear cells, in a
diffuse or multinodular distribution.
– Fat cells are decreased in number
 HYPOPARATHYROIDISM
• Hypofunction of the parathyroid glands leading to
hypocalcemia
• Causes
– Autoimmune hypoparathyroidism (most common
cause)
– Previous thyroid surgery
– DiGeorge syndrome
• 3rd /4th pharyngeal pouches undeveloped;
• Hypoparathyroidism + No thymic shadow
– Hypomagnesemia
• Magnesium is a cofactor for adenylate cyclase
 Clinical findings
• Tetany is - Due to a decreased ionized calcium
level.
– Causes partial depolarization of nerves and muscle
– Lowers the threshold potential (Et)
– An action potential can be initiated with a smaller
stimulus.
– Clinical findings of tetany
• Carpopedal spasm
• Chvostek sign
A. Carpal spasm (Trousseau sign; thumb adducts into the palm) is a
manifestation of tetany, which is due to a decrease in the ionized calcium level
in blood. Its onset can be provoked by inflating a sphygmomanometer cuff to
just above the systolic pressure for at least 2 minutes. B,
Pseudohypoparathyroidism. Note the short fourth and fifth digits, producing
the classic “knuckle-knuckle-dimple-dimple” sign.
 Clinical findings
• Calcification of basal ganglia
– Due to metastatic calcification
– Increased phosphorus drives calcium into the
brain tissue.
• Cataracts, Candida infections
• 3. Laboratory findings
– Hypocalcemia, hyperphosphatemia, ↓PTH
THANK YOU!