Parathyroid Glands

- 4 glands on posterior surface of the lateral lobes of thyroid, each weighs about 30 gms
- 2 types of cells
o Chief (principal) cells secrete parathyroid hormone (PTH)
o Oxyphil cells – unknown function
- Developmental origins of thyroid, parathyroid, and thymus glands. Arrows show pathways of migration. Pouch III develops into
the inferior parathyroid gland and the thymus (synthesizes T cells), whereas pouch IV develops into the superior parathyroid
glands
o In DiGeorge syndrome, 3rd and 4th pharyngeal pouches fail to develop; hence patients have hypoparathyroidism
and a pure T cell deficiency with no thymic shadow
o Ex. A female neonate with DiGeorge syndrome develops severe muscle cramps and convulsions soon after birth.
Which of the following is the cause of convulsions in this neonate? Hypocalcemia
 DiGeorge syndrome is caused by a failure in the development of the third and fourth branchial pouches, resulting in agenesis or hypoplasia of the
thymus and parathyroid glands, congenital heart defects, dysmorphic facies, and a variety of other congenital anomalies. As a result of
parathyroid agenesis, patients with DiGeorge syndrome exhibit hypocalcemia, which manifests as increased neuromuscular excitability.
Symptoms range from mild tingling in the hands and feet to severe muscle cramps and convulsions.
PARATHYROID HORMONE (PTH)
- Plasma [Ca2+] is the major regulator of PTH secretion
- ↓ plasma [Ca2+] causes ↑ PTH synthesis & release
- PTH functions:
o ↑Renal tubular reabsorption of calcium
o ↑ Urinary phosphate excretion
o ↑Conversion of vitamin D to its active dihydroxy form in the kidneys
o ↑ Gastrointestinal calcium absorption
o Decreases bicarbonate reclamation in the proximal tubule
o Maintains ionized calcium level in blood
Hypercalcemia
- Asymptomatic: Primary hyperparathyroidism is the most common cause
o Serum PTH levels are inappropriately elevated for the level
- Symptomatic hypercalcemia in adults: Malignancy
o Solid tumors (Lung – Squamous cell carcinoma, breast, head and neck, and renal cancers)
o Hematologic malignancies (Multiple Myeloma and Adult T cell leukemia)
o 80% through secretion of PTH-related peptide (PTHrP), PTH levels are low to undetectable
o 20% through metastases to the bone and subsequent cytokine-induced bone resorption
- Radioimmunoassays specific for PTH and PTHrP can distinguish primary hyperparathyroidism from malignancy-
associated hypercalcemia
- PTHrP is actually a normal gene product expressed in many primitive neuroendocrine tissues and the placenta. Its major physiologic role occurs at the growth plate,
where it regulates endochondral bone development; it also mediates the epithelial-mesenchymal reaction during mammary gland formation
- Low PTH because serum calcium is high from an autonomous source, and it negatively feeds back on the normal parathyroid glands to decrease production of
endogenous PTH
- Low 1,25 Vit D because PTHrP fails to stimulate enzymatic renal conversion of vitamin D to its most active metabolite
- Ex. A 63-year-old woman had frequent headaches for 1 month. She now suddenly experiences a generalized seizure and becomes obtunded. She is taken to the
emergency department, where a physical examination reveals an irregular heart rate. Laboratory findings include serum calcium of 15.4 mg/ dL, serum phosphorus of 1.9
mg/dL, and albumin of 4.2 g/ dL. A chest radiograph shows multiple lung masses and lytic lesions of the vertebral column. Which of the following conditions best accounts
for these findings? Metastatic breast carcinoma
Symptomatic Primary Hyperparathyroidism
- “Painful Bones, Renal Stones, Abdominal Groans, and Psychic Moans”
- Bone disease and bone pain secondary to fractures of bones weakened by osteoporosis or osteitis fibrosa cystica
- Nephrolithiasis (renal stones) in 20% of newly diagnosed patients, with attendant pain and obstructive uropathy
- Chronic renal insufficiency and abnormalities in renal function lead to polyuria and secondary polydipsia
- Gastrointestinal disturbances, including constipation, nausea, peptic ulcers, pancreatitis, and gallstones
- Central nervous system alterations, including depression, lethargy, and eventually seizures
- Neuromuscular abnormalities, including weakness and fatigue
- Cardiac manifestations, including aortic or mitral valve calcifications

Hyperparathyroidism
- Primary hyperparathyroidism
o Autonomous overproduction of PTH
o Adenoma or Hyperplasia of parathyroid tissue
- Secondary hyperparathyroidism
o Compensatory hypersecretion of PTH in prolonged hypocalcemia
o Mostly chronic renal failure
- Tertiary hyperparathyroidism
o Persistent hypersecretion of PTH even after the cause of prolonged hypocalcemia is corrected (after renal transplant)
Primary Hyperparathyroidism
- Women to men ratio of 4:1, most frequently in postmenopausal women
- Asymptomatic in >50% of patients
- Association with MEN I and MEN IIa
- Adenoma: 85 to 95%
o Cyclin D1 gene inversions leading to overexpression of cyclin D1
o MEN1 mutations
- Primary hyperplasia (diffuse or nodular): 5 to 10%
- Parathyroid carcinoma: ~1%
- The abnormalities most directly related to hyperparathyroidism are nephrolithiasis and bone disease
- Hypercalcemia presents as fatigue, weakness, pancreatitis, metastatic calcifications, and constipation
- Localization of adenoma Technetium-99m-sestamibi radionuclide scan
- Treatment
o Surgical removal of the adenoma
o Treatment of hypercalcemia
 IV hydration with normal saline followed by IV furosemide
 Bisphosphonates
  Cinacalcet directly lowers PTH levels
 Increases the calcium-sensing receptor to extracellular calcium
- Ex. A 40-year-old woman notes lethargy, weakness, and constipation for the past 6 months. On physical examination, she is afebrile and normotensive, and her heart rate
is irregular. There is pain on palpation of the left third proximal finger. An ECG shows a prolonged QT (corrected) interval. Laboratory studies show glucose, 73 mg/dL;
creatinine, 1.2 mg/dL; calcium, 11.6 mg/dL; phosphorus, 2.1 mg/dL; total protein, 7.1g/dL; albumin, 5.3 g/dL; and alkaline phosphatase, 202 U/L. A radiograph of the left
hand shows focal expansion by a cystic lesion of the third proximal phalanx. A technicium radionuclide scan shows a 1-cm area of increased uptake in the right lateral
neck. A mutation in which of the following genes is most likely present in this woman? MEN1
- Ex. A 50-year-old woman presents with acute right flank pain of 72 hours in duration. Physical examination is unremarkable. Her temperature is 37°C (98.6°F), blood
pressure 140/85 mm Hg, and pulse 85 per minute. A CBC is normal. Urinalysis reveals hematuria and urine cultures are negative. Imaging studies show stones in the right
renal pelvis and ureter. This patient’s condition may be associated with which of the following endocrine disorders? Hyperparathyroidism
Parathyroid adenomas
- Solitary and, similar to the normal parathyroid glands
- Right inferior parathyroid gland is most often involved
- 0.5 to 5 gm, soft, tan to reddish-brown nodule with a delicate capsule
- Uniform, polygonal chief cells with small, centrally placed nuclei
- Remainder of the gland plus all other glands show atrophy
o Feedback inhibition by elevated levels of serum calcium
- Mitotic figures are rare, adipose tissue is inconspicuous
- Ex. A 40-year-old man experiences weakness and easy fatigability of 2 months’ duration. Physical examination yields no
remarkable findings. Laboratory studies show serum calcium of 11.5 mg/dL, inorganic phosphorus of 2.1 mg/dL, and serum
parathyroid hormone of 58 pg/mL, which is near the top of the reference range. A radionuclide bone scan fails to show any
areas of increased uptake. What is the most likely cause of these findings? Parathyroid adenoma
- Ex. Laboratory evaluation of the patient described in Question 20shows markedly elevated serum levels of calcium and PTH. A CT scan of the neck reveals a 3-cm mass on
the posterior surface of the right lobe of the thyroid gland. External and cross-sectional views of the surgical specimen are shown in the image. Microscopic examination
of this neck mass would most likely reveal a benign neoplasm derived from which of the following cells? Chief
o Parathyroid adenoma is the cause of 85% of all cases of primary hyperparathyroidism. The tumor arises sporadically or in
the context of multiple endocrine neoplasia (MEN-1 and MEN-2A, 20% of cases). In a small minority of cases of sporadic
adenoma, genetic analysis has identified rearrangement and overexpression of the cyclin D protooncogene. On gross
examination, a parathyroid adenoma appears as a circumscribed, reddish brown, solitary mass, measuring 1 to 3 cm in
diameter. Microscopically, these tumors show sheets of neoplastic chief cells in a rich capillary network. A rim of normal
parathyroid tissue is usually evident outside the tumor capsule and distinguishes adenoma from parathyroid hyperplasia
Secondary Hyperparathyroidism
- Chronic hypocalcemia leads to compensatory over activity of parathyroid
o Renal failure is the most common cause
o Inadequate dietary intake of calcium
o Steatorrhea, and vitamin D deficiency
- Chronic renal insufficiency:
o ↓ phosphate excretion = hyperphosphatemia (directly depresses serum calcium levels and stimulates parathyroid gland activity)
o Loss of renal substance reduces the availability of α-1-hydroxylase necessary for the synthesis of the active form of vitamin D
 Reduces intestinal absorption of calcium
 Vitamin D has suppressive effects on parathyroid growth and PTH secretion
- Ex. A 72-year-old woman with a long history of diabetes type 2 presents with abdominal pain. Physical examination reveals neuromuscular weakness and hypertension.
Laboratory studies show markedly elevated levels of serum calcium and PTH. A surgical exploration of the patient’s neck demonstrates four symmetrically enlarged
parathyroid glands. This patient’s endocrinopathy may be caused by which of the following underlying disorders? Renal insufficiency
o Hyperparathyroidism can be primary as a result of autonomous proliferation of chief cells or may be secondary, in which case it is a compensatory
mechanism. Secondary parathyroid hyperplasia is encountered principally in patients with chronic renal failure, although the disorder also occurs in
association with vitamin D deficiency, intestinal malabsorption, Fanconi syndrome,
and renal tubular acidosis.
Parathyroid hyperplasia
- Usually associated with secondary hyperparathroidism, maybe sporadic / component of MEN syndrome
- Classically, all four glands are involved.
- Chief cell hyperplasia in a diffuse or multinodular pattern, sometimes water-clear cells (“German - wasserhelle cells”) and oncocytic cells
- Stromal fat is inconspicuous within hyperplastic glands
- Ex. A 68-year-old man has experienced increasing malaise for 3 years. Physical examination shows no remarkable findings. Laboratory findings include a serum creatinine
level of 4.9 mg/dL and urea nitrogen level of 45 mg/dL. Abdominal CT scan shows small kidneys. Which of the following endocrine glandular lesions has developed
secondary to the underlying disease in this patient? Parathyroid hyperplasia
Secondary hyperparathyroidism - clinical course
- Dominated by the inciting chronic renal failure
- Renal Osteodystrophy Not severe or prolonged, so milder skeletal abnormalities
- Calciphylaxis Vascular calcification may cause ischemic damage to skin and other organs
- Respond to dietary vitamin D supplementation, as well as phosphate binders, which decrease the prevailing hyperphosphatemia
Parathyroid carcinomas
- “Rare cause of hyperparathyroidism”
- May be circumscribed or invasive, gray-white, irregular masses
- Uniform cells resembling normal cells, in nodular or trabecular patterns
- “Invasion of surrounding tissues and metastasis are the only reliable criteria for diagnosis of malignancy”
- Local recurrence in 1/3rds, distant dissemination occurs in another third
Tertiary hyperparathyroidism
- Persistent hypersecretion of PTH even after the cause of prolonged hypocalcemia is corrected (e.g. after renal transplant)
o In a minority of patients with secondary hyperparathyroidism
o Glands become autonomous regardless of the calcium level
o Results in excessive hypercalcemia
- Parathyroidectomy may be necessary to control the hyperparathyroidism in such patients
Changes in skeletal system
- Osteoporosis
o ↓Bone mass, mainly phalanges, vertebrae and proximal femur
o Cortical bone (subperiosteal and endosteal surfaces) is affected more severely
 o Dissecting osteitis
- Brown Tumor
o Bone loss predisposes to micro-fractures and secondary hemorrhages
o Influx of macrophages and ingrowth of reparative fibrous tissue
- Osteitis Fibrosa Cystica (von-Recklinghausen disease of bone)
o ↑Osteoclast Activity + Peritrabecular Fibrosis + Cystic Brown Tumors
o Ex. A 55-year-old man who is on dialysis because of end-stage renal disease complains of pain in his jaw and left arm for 6 months.
An X-ray of the left arm reveals multiple, small bone cysts and pathologic fractures. What is the appropriate diagnosis for this
patient’s bone lesions? Osteitis fibrosa cystica
 Secondary hyperparathyroidism is a complication of chronic renal insufficiency due to renal retention of phosphate and
resulting hypocalcemia. Excess PTH causes renal osteodystrophy or, in severe cases, osteitis fibrosa cystica. The latter is
characterized by severe bone deformities and the formation of “brown tumors” of hyperparathyroidism. Patients
present with bone pain, bone cysts, pathologic fractures, and localized bone swellings (brown tumors).
- Pseudogout

Subperiosteal resorption in primary hyperparathyroidism

- Sub-periosteal resorption
o Radiologic hallmark of hyperparathyroidism
o Radial aspect of the middle phalanges of the index and middle fingers (solid white arrows)
o Cortex appears shaggy and irregular, compared to the cortex on the opposite side of the same bone, which is well defined
- 2 other findings of hyperparathyroidism
o A small brown tumor (solid black arrow)
o Resorption of the terminal phalanges (acro-osteolysis) (dotted white arrows)
Morphology
- Microscopic: increased osteoclasts with erosion of bone surfaces
- Collections of osteoclasts, reactive giant cells, and hemorrhagic debris with cystic change lead to “Brown Tumor” of
hyperparathyroidism
- von Recklinghausen disease of bone (generalized osteitis fibrosa cystica):increased bone cell activity, peritrabecular fibrosis, and
cystic brown tumors
Changes in Urinary system
- PTH-induced hypercalcemia
o Nephrolithiasis Calcium stones
o Nephrocalcinosis Metastatic calcification of the renal interstitium and tubules
 Polyuria and renal failure
- Chloride/phosphorus ratio >33
o Normal anion gap metabolic acidosis: serum chloride ↑ to counterbalance the loss of negative charges related to the
↓bicarbonate.
o In Primary Hyperparathyroidism, the increase in serum chloride from the normal anion gap metabolic acidosis plus
the decrease in serum phosphorus leads to an increase in the chloride/phosphorus ratio
o Ratio <29 excludes primary HPTH
Changes in other systems
- Metastatic calcification in other organs Stomach, lungs, myocardium, and
blood vessels
- Peptic ulcer disease (Ca+2 stimulates gastrin, ↑gastric acid)
- Acute pancreatitis (Calcium activates phospholipase)
- Diastolic hypertension due to hypercalcemia increasing smooth muscle
contraction of peripheral resistance arterioles
- Electrocardiogram shows shortening of QT interval
- Ex. A 40-year-old woman with a history of hyperparathyroidism presents with
a 2-month history of burning epigastric pain. The pain can be relieved with
antacids or food. The patient also reports a recent history of tarry stools. She
denies taking aspirin or NSAIDs. Laboratory studies show a microcytic,
hypochromic anemia (hemoglobin = 8.5 g/dL). Gastroscopy reveals a bleeding mucosal defect in the antrum. Which of the following best characterizes the pathogenesis
of epigastric pain in this patient? Increased secretion of gastrin.
o The incidence of peptic ulcer disease is increased in patients with hyperparathyroidism, possibly because hypercalcemia increases serum gastrin, thereby
stimulating gastric acid secretion. Peptic ulcers in the context of MEN-1 may be secondary to Zollinger-Ellison syndrome (i.e., gastrinoma of the endocrine
pancreas).
Hyperparathyroidism
- Asymptomatic: Primary hyperparathyroidism is the most common cause
o Serum PTH levels are inappropriately elevated for the level
- Symptomatic hypercalcemia in adults: Malignancy
o Both solid tumors (lung, breast, head and neck, and renal cancers)and with hematologic malignancies (multiple myeloma)
o PTH levels are low to undetectable
o Most common mechanism: secretion of PTH-related peptide (PTHrP)
- Radioimmunoassays specific for PTH and PTHrP can distinguish primary hyperparathyroidism and malignancy-associated hypercalcemia
- Hypophosphatemia and ↑ urinary excretion of calcium and phosphate
- Normal anion gap metabolic acidosis
o Due to decreased proximal tubule reclamation of bicarbonate
o Type II renal tubular acidosis
- Chloride/phosphorus ratio >33
o In a normal anion gap metabolic acidosis, serum chloride is increased to counterbalance the loss of negative charges related to the decrease in bicarbonate.
o In Primary Hyperparathyroidism, the increase in serum chloride from the normal anion gap metabolic acidosis plus the decrease in serum phosphorus leads to
an increase in the chloride/phosphorus ratio
o Ratio <29 excludes primary HPTH
- Decreased serum 1,25-(OH)2D
o ↓synthesis of 1-α-hydroxylase in the proximal renal tubule
o Protective effect so that serum calcium is not too high
- Electrocardiogram shows shortening of QT interval
Hypoparathyroidism
- Surgically induced hypoparathyroidism
o Inadvertent removal of all parathyroid glands during thyroidectomy
o Mistakenly excising parathyroid glands as lymph nodes during radical neck dissection
o Removing too much parathyroid tissue in the treatment of primary hyperparathyroidism
o Ex. A 47-year-old woman noticed a lump in her neck 1 week ago. On physical examination, there is a 2-cm nodule in the right lobe of the thyroid gland. A fine-
needle aspiration biopsy is performed, and microscopic examination of the specimen shows cells consistent with a follicular neoplasm. She undergoes a
subtotal thyroidectomy. Which of the following laboratory tests should be performed on this patient in the immediate postoperative period? Calcium
 Inadvertent removal of or damage to the parathyroid glands during thyroid surgery can cause hypocalcemia secondary to hypoparathyroidism.
This is the most common cause of hypoparathyroidism
o Ex. A 45-year-old woman complains of tingling in her hands and feet, 24 hours after surgery to remove a thyroid follicular carcinoma. Her symptoms rapidly
progress to severe muscle cramps, laryngeal stridor, and convulsions. Which of the following laboratory findings would be expected in this patient prior to
treatment? Decreased serum calcium and decreased PTH.
 The most common cause of hypoparathyroidism is surgical resection of the parathyroids as a complication of thyroidectomy. Of patients
undergoing surgery for primary hyperparathyroidism, 1% develop irreversible hypoparathyroidism. The symptoms of hypoparathyroidism relate
to hypocalcemia, which causes increased neuromuscular excitability. This is reflected in symptoms that range from mild tingling in the hands and
feet to severe muscle cramps, laryngeal stridor, and convulsions
- Autoimmune hypoparathyroidism
o Associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency {Autoimmune Polyendocrine Syndrome type 1 (APS1)}
o Mutations in the autoimmune regulator (AIRE) gene
- Autosomal-dominant hypoparathyroidism
o Gain-of-function mutations in the calcium-sensing receptor (CASR) gene
o Inappropriate CASR activity suppresses PTH hypocalcemia, hypercalciuria
- Familial isolated hypoparathyroidism (FIH) - rare condition
o Autosomal-dominant FIH: mutation in the gene encoding PTH precursor peptide, which impairs its processing to the mature hormone
o Autosomal-recessive FIH: loss-of-function mutations in the transcription factor gene glial cells missing-2 (GCM2), essential for development of parathyroid
- Congenital absence of parathyroid glands
o In conjunction with other malformations, such as thymic aplasia and cardiovascular defects, or as a component of the 22q11 deletion syndrome
- Hypomagnesemia
o Most common pathologic cause of hypocalcemia in hospital
o Diarrhea, aminoglycosides, diuretics, alcohol
o Magnesium is a cofactor for adenylate cyclase and cAMP is required for PTH activation and secretion
- Tetany
o ↓ Serum ionized calcium causes increased excitability of nerves
o Comes closer to the resting membrane potential (Em)
o ↑membrane permeability to Na leads to ↑action potentials which causes tetanic contractions of peripheral muscle
o Circumoral numbness or paresthesias (tingling) of the distal extremities and carpopedal spasm, to life-threatening laryngospasm and generalized seizures
o Chvostek sign and Trousseau sign
 Chvostek sign (abnormal spasm of the facial muscles in response to light taps on the facial nerve)
 Trousseau sign (an abnormal carpopedal spasm induced by inflating a sphygmomanometer cuff on the upper arm to a pressure exceeding systolic
blood pressure for 2 minutes)
- Clinical Features
o Mental status changes
 Emotional instability, anxiety, depression, confusion, hallucinations, psychosis
o Intracranial manifestations
 Calcifications of the basal ganglia, parkinsonian-like movement disorders and ↑ intracranial pressure with papilledema
o Ocular disease - calcification of the lens and cataract formation
o CVS: prolongation of the QT interval in the ECG
o Dental abnormalities – dental hypoplasia, failure of eruption, defective enamel and root formation, abraded carious teeth
- Treatment
o PTH replacement therapy is not effective (short-term action of PTH, tendency to form antibodies against PTH)
o High doses of vitamin D3 (Calcitriol) and calcium intake
o Teriparatide (recombinant PTH)
Pseudohypoparathyroidism
- Autosomal dominant disease
- End-organ resistance to PTH (includes its ability to synthesize 1-α-hydroxylase in the proximal tubule)
- Serum PTH levels are normal or elevated with Hypocalcemia
- Mental retardation, basal ganglia calcification, short fourth and fifth metacarpals (“knuckle-knuckle-dimple-dimple”sign)
- Hypocalcemia, normal to ↑PTH, normal 25-(OH)D, ↓1,25-(OH)2D; ↓serum calcium, ↑ S phosphorus
- In one form of pseudohypoparathyroidism, there is end-organ resistance to TSH and FSH/LH as well as PTH
o PTH resistance is the most obvious clinical manifestation
o TSH resistance is generally mild
o LH/FSH resistance - hypergonadotropic hypogonadism in females
- All of these hormones signal via G-protein–coupled receptors, and the disorder results from genetic defects in components of this pathway that are shared across
endocrine tissues
- Ex. A 15-year-old boy with Albright hereditary osteodystrophy is rushed to the emergency room with severe muscle cramps and convulsions. The child has a history of
mental retardation. Laboratory studies reveal hypocalcemia and elevated blood levels of PTH. Which of the following distinguishes this patient’s endocrinopathy from
hypoparathyroidism seen in DiGeorge syndrome? End-organ unresponsiveness to PTH.
o Pseudohypoparathyroidism designates a group of hereditary conditions in which hypocalcemia is caused by target organ insensitivity to PTH. The defect in
these patients has been traced to mutations in a gene whose product couples hormone receptors to the stimulation of adenylyl cyclase. Consequently, in the
renal tubular epithelium, the production of cAMP in response to PTH is impaired, and inadequate resorption of calcium from the glomerular fi ltrate ensues.
These patients demonstrate a characteristic phenotype (Albright hereditary osteodystrophy), including short stature, obesity, mental retardation,
subcutaneous calcification, and a number of congenital anomalies of bone