Lecture 3: Parathyroid Pathology Flashcards by Alex Miller

In early infancy and childhood, the parathyroid glands are composed almost entirely what type of cell?

Chief cells

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What are the 3 histological characteristics of the Chief Cells of the parathyroid glands?

Central round, uniform nuclei
Light pink or white cytoplasm (water-clear appearance)
Secretory granules

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Which cells of the parathyroid gland have an acidophilic cytoplasm and are tightly packed with mitochondria?

Oxyphil cells

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Which cells of the parathyroid hormone contain large amounts of cytoplasmic glycogen and secretory granules containing PTH?

Chief cells

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What are 4 specific ways PTH acts to maintain calcium homeostasis?

↑ renal tubular reabsorption of Ca²⁺
↑ conversion of Vit D —> active 1,25(OH)₂D form in kidneys
↑ urinary phosphate excretion
Augments GI calcium absorption

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Secondary hyperparathyroidism is a compensatory hypersecretion of PTH in response to prolonged hypocalcemia, most commonly in the setting of what?

Chronic renal failure

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What are 3 causes of primary hyperparathyroidism; which is most common?

Adenoma = most common
Primary hyperplasia
Parathyroid carcinoma

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Which 2 molecular defects/mutations have an established role in the development of sporadic parathyroid adenomas?

Cyclin D1 gene inversion –> overexpression of cyclin D1
MEN1 mutations

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In what 2 ways can MEN1 mutations be associated with parathyroid adenomas and which is more common?

Germline mutations causing familial MEN1 and can manifest w/ parathyroid adenomas
MORE common is sporadic parathyroid adenomas, with somatic MEN1 mutations

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Which 2 genetic syndromes are associated with familial parathyroid adenoma; what is the associated gene mutated in each?

MEN type 1 associated w/ MEN1
MEN type 2 associated w/ RET

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Familial hypocalciuric hypercalcemia is a rare disorder due to what mutation and how is it inherited?

Loss-of-function mutation in parathyroid calcium-sensing receptor gene (CASR)
Autosomal dominant

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What is the typically seen microscopically in parathyroid adenomas; what is the dominant cell type?

Uniform, polygonal CHIEF cells w/ small, centrally placed nuclei
A few nests of larger oxyphil cells are present as well

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What is “endocrine atypia” in relation to the morphology of some parathyroid adenomas?

Not uncommon to find bizarre and pleomorphic nuclei; this is not a criterion for malignancy

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What type of parathyroid adenoma may resemble a Hurthle cell tumor in the thyroid?

Oxyphil adenoma (uncommon)

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Which morphological feature of the normal parathyroid glands becomes inconspicous in adenomas and hyperplasia?

Adipose tissue

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How does parathyoid adenoma differ from hyperplasia in terms of glands involved?

Adenoma are almost always solitary, affecting one lobe
Hyperplasia almost always present in multiple glands

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What is often seen morphologically surrounding parathyroid adenomas and how does this differ from parathyroid hyperplasia?

Adenomas have a rim of compressed, normal parathyroid tissue, generally separated by a fibrous capsule
Hyperplasia does NOT have a normal rim of parathyroid tissue

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What are the only reliable criteria for diagnosis of a parathyroid carcinoma?

- Metastasis = most telltale sign!

- Invasion of surrounding tissues or vasculature

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Parathyroid carcinomas are often hard to distinguish from what?

Adenomas
Both are solitary and enclosed by fibrous capsule

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What 3 interrelated skeletal abnormalities can manifest as a result of symptomatic, untreated hyperparathyroidism?

Osteoporosis
Brown tumors
Osteitis fibrosa cystica

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The osteoporosis associated with symptomatic, untreated hyperparathyroidism preferentially involves which bones?

Phalanges + vertebrae + prox. femur

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The osteoclast activity associated with hyperparathyroidism affects what type of bone more severly?

Cortical bone (i.e., subperiosteal and endosteal surfaces)

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In untreated hyperparathyroidism, what do the osteoclasts due in medullary bone; create what appearance?

Tunnel into and dissect centrally along the length of the trabeculae
Create appearance of rail-road tracks aka dissecting osteitis

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What are the 3 hallmarks of severe hyperparathyroidism and is known as generalized osteitis fibrosa cystica (von Recklinghausen disease of bone)?

Osteoclast-driven bone destruction –> microfractures + hemorrhage
Peritrabecular fibrosis
Cystic brown tumors (STARTS as a brown tumor)

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What is the pathophysiological process underlying the development of brown tumors?

Bone loss predisposes to **microfractures** and **2'** **hemorrhages**, which elicits **influx of macrophages** and **ingrowth** of **reparative fibrous tissue** creating a **mass**

PTH-induced hypercalcemia leads to the formation of what in the urinary tract/kidneys?

- **Urinary tract stones** (nephrolithiasis) - **Nephrocalcinosis** (calcification of the renal **interstitium** and **tubules**)

The cystic brown tumors of osteitis fibrosis cystica can resemble what?

Metastatic disease

What is the most common cause of asymptomatic hypercalcemia?

Primary hyperparathyroidism

What is the most frequent cause of **symptomatic** hypercalcemia in adults?

**Malignancy** (i.e., breast, lung, head/neck and renal cancers)

Most common mechanism through which osteolytic tumors induce hypercalcemia is by secretion of what?

**PTH-related peptide (PTHrP)**

What are the levels of PTH and Ca²⁺ like in primary hyperparathyroidism?

- **↑ PTH + ↑Ca²⁺** - When Ca²⁺ levels are ↑, levels of PTH should be ↓ due to **negative feedback**

Other than Ca²⁺ and PTH, what other lab values can point to PTH excess?

- **Hypo**phosphatemia - ↑ urinary **excretion** of both **calcium** and **phosphate**

What are 5 GI manifestations which may result from increased PTH secretion and hypercalcemia (aka 1' hyperparathyroidism)?

- **Constipation** - Nausea - **Peptic ulcers** - **Pancreatitis** - **Gallstones**

What are 3 CNS alterations which may result from increased PTH secretion and hypercalcemia (aka 1' hyperparathyroidism)?

- **Depression** - **Lethargy** - Eventually **seizures**

What are 2 neuromuscular abnormalities which may result from increased PTH secretion and hypercalcemia (aka 1' hyperparathyroidism)?

- **Weakness** - **Fatigue**

What are 2 cardiac manifestations which may result from increased PTH secretion and hypercalcemia (aka 1' hyperparathyroidism)?

- **Aortic calcification** - **Mitral calcification** - Or **BOTH**

Nephrolithiasis and bone disease are abnormalities most directly related to what in the setting of primary hyperparathyroidism?

↑↑↑ PTH (hyperparathyroidism)

Fatigue, weakness, pancreatitis, metastatic calcifications, and constipation are abnormalities most directly attributable to what in the setting of primary hyperparathyroidism?

Hypercalcemia

What is the most common cause of secondary hyperparathyroidism and list 3 other causes?

- **Renal failure** = most common - **Inadequate dietary intake of Ca²⁺** - **Steatorrhea** (malabsorption of ADEK) - **Vit D deficiency**

What are 5 causes of hypercalcemia which are associated with ↓ [PTH]?

- Hypercalcemia of malignancy - Vit D toxicity - Immobilization - Thiazide diuretics - Granulomatous disease (sarcoidosis)

What is the morphology of the parathyroid glands in secondary hyperparathyroidism?

Are **hyperplastic** as a result of **reactive hyperplasia**

The skeletal abnormalities of secondary hyperparathyroidism are usually not as severe or as prolonged as primary hyperparathyroidism and are known as what?

Renal osteodystrophy

Renal osteodystrophy associated w/ secondary hyperparathyroidism may be seen as what "sign" on imaging?

"**Rugger Jersey Sign"**

What is Calciphylaxis in the setting of secondary hyperparathyroidism?

**Extensive calcification** and **occlusion** of **blood vessels** w/ resultant **ischemia**

Vitamin D mediated causes of humoral hypercalcemia of malignancy are seen with what type of tumors?

Lymphomas

Local osteolytic hypercalcemia due to the release of calcium as a result of osteoclastic bone resorption is associated with what 2 types of tumors?

- Breast carcinoma - Myeloma

Acquired hypoparathyroidism is almost always a consequence of what?

Surgery

Autoimmune hypoparathyroidism is often associated with what underlying condition?

Auto-immune polyendocrine insufficiency syndrome type 1 (APS1)

Auto-immune polyendocrine insufficiency syndrome type 1 (APS1) is due to mutations in what gene?

Autoimmune regulator (***AIRE****)* gene

When does Auto-immune polyendocrine insufficiency syndrome type 1 (APS1) typically present and what are the manifestations of this disease?

- During **childhood** w/ onset of **candidiasis** - Followed several years later by **hypoparathyroidism** - Then **adrenal insufficiency** during **adolescence**

Autosomal-dominant hypoparathyroidism is caused by gain-of-function mutations in which gene?

**Calcium-sensing receptor (*CASR) gene***

Inappropriate CASR activity in autosomal-dominant hypoparathyroidism leads to what serum and urine calcium levels?

**HYPO**calcemia and **HYPER**calciuria

Familial isolated hypoparathyroidism (FIH) can be inherited via AD or AR patterns; how does each differ and which mutation is seen?

- **AD** = due to mutation in gene encoding **PTH precursor peptide**, which impairs its processing to the mature hormone - **AR** = due to loss-of-function mutations in the transcription factor gene ***glial cells missing-2 (GCM2)***, essential for parathyroid development

Congenital absence of parathyroid glands can occur in conjunction with what?

- Thymic aplasia - Cardiovascular defects - Part of 22q11 deletion syndrome (i.e., DiGeorge Syndrome)

What is the hallmark of hypocalcemia?

Tetany (aka neuromuscular irritability)

What are 3 intracranial manifestations which may result from chronic hypocalcemia?

- **Calcifications** of the **basal ganglia** - **Parkinsonian-like** movement disorders - **↑ ICP** ---\> **papilledema**

What are 2 disease manifestations of the eye which may occur in the setting of hypocalcemia?

- **Calcification** of the **lens** - **Cataract** formation

What is a cardiovascular manifestation of hypocalcemia?

**Conduction defect** --\> **prolongation** of the **QT interval** on ECG

What is the pathophysiology of Pseudohypoparathyroidism?

Due to **end-organ resistance** to the actions of **PTH**

Due to PTH acting through a GPCR, one form of Pseudohypoparathyroidism also shows resistance to what other hormones?

**TSH** and **FSH/LH**

What are the serum levels of PTH, calcium, and phosphate like in Pseudohypoparathyroidism?

- **Normal** or ↑ **PTH** - **HYPOcalcemia** - **HYPERphosphatemia**

Which condition presents with hypocalcemia despite a high serum PTH?

Pseudohypoparathyroidism

Lecture 3: Parathyroid Pathology Flashcards

(62 cards)