PARATHYROID

List the causes of hyperparathyroidism and hypoparathyroidism List the symptoms of hypercalcemia and hypocalcemia Be able to interpret parathyroid hormone levels and describe what they mean for the patient Robbins 735-738

NORMAL PARATHYROID
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NORMAL PARATHYROID DEVELOPMENT

Usually four glands located close to the upper and lower poles of the thyroid Develop from 3rd and 4th pharyngeal pouches Thymus also develops from the third pouch NORMAL PARATHYROID LOCATION o Upper glands more consistent in location, could be along carotid sheath or in the retropharyngeal or retroesophageal space o The lower glands may be found near or within the thymus gland in the superior mediastinum NORMAL PARATHYROID COMPOSITION

CHIEF CELLS: chiefly composed of chief cells (water clear cells)

Functionally active

Light to dark pink on H&E; small with clear cytoplasm Contain secretory granules of parathyroid hormone (PTH)

OXYPHIL CELLS (ONCOCYTES): functionally inactive

Larger than chief cells with acidophilic cytoplasm (pink) Lots of mitochondria, few secretory granules
Analogous to the Hurthle cells/oncocytes of the parathyroid: these are large, granular, and metabolically inactive (do not secrete PTH)

FAT: (~35%) increase with age

IMAGE: Can see small blue chief cells that compose the majority of the parathyroid. Large plump, pink oxyphil cells are scattered throughout with fat infiltrating through the gland.

PTH HORMONE

CALCIUM HOMEOSTASIS

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Activity controlled by serum Ca+ rather than the pituitary Decreased Ca triggers the synthesis and secretion of PTH

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PTH increases serum CA by acting at targets in the bone, kidney, and GI tract Activates osteoclasts serum Ca and HPO4+: chews up the bone to increase serum calcium levels renal tubular reabsorption of Ca+ conversion vitamin D active form in kidneys (enhances Ca and HPO4 absorption in gut) urinary phosphate excretion (prevents mineralization of calcium phosphate in bone) Augments GI Ca+ absorption NET result = increased level of free calcium (inhibits further PTH secretion)

MECHANISMS OF PTH ACTION

HYPERCALCEMIA
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Hyperparathyroidism is the most common cause of asymptomatic hypercalcemia

Also: diuretics, immobilization, sarcoidosis can cause hypercalcemia

Malignancy (bone mets, paraneoplastic syndromes) is the most common cause of clinically apparent hypercalcemia
Two mechanisms o Osteolytic metastasis: lytic lesions chew up bone Ca release o PTH-related protein: effects the gut and bone, stimulating similar action as PTH

HYPERPARATHYROIDISM

Most hyperparathyroidism is asymptomatic! ***KNOW!!! o We care if this is asymptomatic because hyperparathyroidism can indicate Chronic renal failure Vascular calcification resulting in calciphylaxis Increased fracture risk
Due to autonomous secretion of PTH that is not controlled by serum calcium levels Most cases are asymptomatic due to sporadic PT adenoma or sporadic hyperplasia in more than 95% of cases CLINICAL FEATURES OF SYMPTOMATIC HYPERCALCEMIA o Painful bones, renal stones, abdominal groans, and psychic moans o Skeletal: osteomalacia and fractures (Ca+ depleted in skeleton) o Kidney: kidney stones, polyuria and polydipsia o GI: constipation, nausea, peptic ulcers (Ca+ in serum pepsin formation), Pancreatitis, gallstones o CNS: depression, lethargy, and seizures o Neuromuscular: weakness and fatigue o Cardiac: aortic and mitral valve calcification

PRIMARY HYPERPARATHYROIDISM: high PTH resulting in high serum Ca2+ ***KNOW!!!

1. PRIMARY HYPERPARATYROIDISM-FAMILAL o MULTIPLE ENDOCRINE NEOPLASIA-1 (MEN-1)

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MULTIPLE ENDOCRINE NEOPLASIA-2 (MEN-2)

Chromosome 11q13 Tumor suppressor gene MEN1 is inactivated (dont need to know any mutations/chromosome specifics for exam) Chromosome 10q Mutations are activated in the tyrosine kinase receptor RET (dont need to know any mutations/chromosome specifics for exam) Autosomal dominant Chromosome 3q (dont need to know any mutations/chromosome specifics for exam) Parathyroid function enhanced due to decreased sensitivity to calcium (inactivating mutation of calcium-sensing

FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH)

receptor gene)

There are high levels of Ca+ but the receptors cant sense this and parathyroid continues to secrete more PTH

2. PRIMARY PARATHYROID ADENOMA (familial and sporadic)- 75-80%

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Solitary lesions defined by well circumscribed capsule with atrophy of normal glands since these secrete excess PTH; defined histologically by hypercellular bland sheets of cell with little fat (distinguish from follicular thyroid lesions because TTF negative) Usually solitary (confined to a single gland!) Well circumscribed, soft, thinly encapsulated
Other glands are normal or shrunken sporadic PT tumors due to cyclin D1 gene inversions or MEN1 gene mutations Usually weighs 0.5-5.0 grams HISTOLOGY Hypercellular Little or no fat Architectural patterns: nested, trabecular, follicular (can mimic follicular lesion)

endocrine atypia is common but is NOT a sign of malignancy

IMAGE: Histology. Can see adenoma is composed mostly of chief cells with few nests of oxyphil cells, with very little fat, and compression of normal glands. Schematic. Shows that this involves only 1 gland and the rest atrophy.

3. PRIMARY PARATHYROID HYPERPLASIA (familial and sporadic)- 10-15%

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Involves all 4 glands so that all 4 glands are larger than normal size ; component of MEN syndrome Sporadic or component of MEN syndrome All 4 glands involved although there may be asymmetry
Combined weight of all 4 glands usually <1 g Histologically identical to an adenoma (difficult to distinguish), but tends to be multiglandular

4. PARATHYROID CARCINOMA- <5%

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Adherent lesion involving 1 gland and is defined by irregularly shaped dense fibrous capsule and bands with defining histological features being invasion of surrounding tissue or metastasis One gland involved Gray-white and irregularly shaped with dense fibrous capsule and intervening fibrous bands Often described as adherent by surgeons
Can exceed 10 g of weight Cells dont necessarily look malignant Atypia is not criterion as it may be present in adenomas (so called endocrine atypia) Only reliable criteria for malignancy are: Invasion of surrounding tissue Metastasis

IMAGE: Can see carcinoma infiltrating into fat. The normal parathyroid is well circumscribed with sharply defined border, but here can see fibrous bands and nests of cells that will penetrate in stellate fashion into the surrounding fat.

SECONDARY HYPERPARATHYROIDISM: high PTH in response to low serum Ca+ ***KNOW!!!!

1. CHRONIC RENAL FAILURE!!!
o o This is the most common cause of secondary hyperparathyroidism Dialysis associated with chronic renal failure leads to loss of Calcium and decreased Phosphate excretion and the body tries to compensate and stimulate the parathyroid gland to make more PTH Also can be because of diet low in calcium, vitamin D deficiency, or steatorrhea PTH glands will be hyperplastic and often contain chief cells with more abundant clear cytoplasm ( water-clear cells) bone changes and met calcifications (if damages blood vessels, then calciphylaxis) may also be seen if PT activity becomes autonomous and excessive, with resultant hypercalcemia = tertiary hyperparathyroidism

HYPOPARATHYROIDISM

Far less common than hyperparathyroidism

IATROGENIC (SURGICAL REMOVAL, DURING THYROID SURGERY)

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Parathyroid glands sit right behind the thyroid so they can be removed during thyroid surgery inadvertently Very rare, usually not asked about

CONGENITAL ABSENCE (22Q11.2 SYNDROME) FAMILIAL HYPOPARATHYROIDISM

Autoimmune polyendocrine syndrome type 1 (APS1): due to a defect in the AIRE gene (autoimmune destruction of parathyroid)
chronic fungal infections (esp Candida) Likely autoimmune disease targeting CASR receptor (Ca+ sensing receptor) on parathyroid, preventing release of PTH

IDIOPATHIC HYPOPARATHYROIDISM
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CLINICAL MANIFESTATIONS
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Unlike hyperparathyroidism, hypothyroidism will tend to be symptomatic Hypocalcemia Tetany

Circum-oral and/or extremity numbness or tingling, carpopedal spasm If severe, laryngospasms and general seizures Trousseau sign (carpal spasm induced by blood pressure cuff) Chvostek: tapping facial nerve results in twitch of eyes, mouth, or nose Mental status changes: anxiety, depression, psychosis Intracranial manifestations: calcifications of basal ganglia, Parkinson-like movement disorder, increased ICP Cardiovascular manifestations: long QT Dental abnormalities: the teeth demineralize

PSEUDOHYPOPARATHYROIDISM

End organ resistance to the actions of PTH Serum PTH levels normal or elevated but the calcium will be low Has to do with G proteins and genetic imprinting (differential methylation of paternal or maternal aleles) o If maternal allele is mutated = Pseudohypoparathyroidism Type 1A o If paternal allele is mutated = Pseudopseudohypoparathyroidism
o o Due to mutation in the maternal allele Results in multihormone resistance + Albright hereditary osteodystrophy (ADO) AHO: short stature, obesity, short metacarpal and metatarsal bones and variable mental deficits Results in hypocalcemia, hyperphosphatemia, and elevated PTH Due to mutation in paternal allele Get AHO WITHOUT multihormone resistance This means that calcium and PTH levels are normal

2. PSEUDOHYPOPARATHYROIDSIM TYPE 1A

3. PSEUDOPSEUDOHYPOPARATHYROIDISM
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REVIEW

Adenoma (C): high PTH because adenoma secretes PTH and the calcium levels also increase Hypercalcemia of malignancy (A): high calcium because the bone is being destroyed and PTH decreases Hyperplasia (C): just like adenoma; increased PTH and increased Ca+ levels Secondary hyperparathyroidism (chronic renal failure) (E): the calcium levels decrease because of calcium loss
through dialysis physiological response of increased PTH Hypoparathyroidism- from surgery (B): leads to decreased PTH and decreased Ca+

Pseudohypoparathyroidism Type 1A (AHO + multihormone resistance, maternal allele) (E): leads to resistance
of end organs, meaning body is trying to overcome this resistance so high PTH but low serum calcium Pseudopseudohypoparathyroidism (Normal): there are normal levels because there is no multihormone resistance