Disorders of the Parathyroid Gland

Question 1

MOA of chief cells

Answer 1

have secretory granules containing parathyroid hormone (PTH)

Question 2

MOA of oxyphil cells

Answer 2

found throughout the normal parathyroid either singly or in small clusters. They are slightly larger than the chief cells, have acidophilic cytoplasm, and
are tightly packed with mitochondria

Question 3

third pharyngeal pouch forms the

Answer 3

inferior parathyroid gland

Question 4

fourth pharyngeal pouch forms the

Answer 4

superior PTH gland

Question 5

pathogenesis of CASR gene calcium in homeostasis

Answer 5

Decrease in extracellular calcium concentration
extracellular fluids (ECF) ——>
diminishes the activity CaSR parathyroid
Release of PTH——–>
PTH acts on kidney and bone to increase renal and
bone Ca2+ resorption + favors vitamin D synthesis
in kidney.——–>
Vitamin D promotes Ca2+ absorption in small
intestine.———->
These effects contribute altogether to return
extracellular Ca2+ levels to the normal level, thus
activating the CaSR and inhibiting release of PTH.

Question 6

list 4 effects of PTH

Answer 6

• Increased renal tubular reabsorption of calcium
• Increased urinary phosphate excretion,
• Increased conversion of vitamin D to its active
  dihydroxy form in the kidneys,
• Enhanced osteoclastic activity

Question 7

what is the role of fibroblastic growth factor 23 (FGF 23)

Answer 7

FGF 23
* Phosphaturic hormone
* Reduces expression of sodium phosphate
cotransporters in kidney PCT
* reducing 1,25 dihydroxy Vit D levels

Question 8

what is the role of fibroblastic growth factor 23 (FGF 23)

Answer 8

FGF 23
* Phosphaturic hormone
* Reduces expression of sodium phosphate
cotransporters in kidney PCT
* reducing 1,25 dihydroxy Vit D levels

Question 9

what is the function of RANKL (receptor activator of nuclear factor κB ligand)

Answer 9

Membrane-bound protein of osteoblasts that stimulates osteoclasts by interacting with RANK
Ensures fusion and differentiation into activated osteoclasts and prevents their apoptosis

Question 10

what is the function of RANK

Answer 10

receptor on osteoclasts and osteoclast precursors, for interaction with osteoblasts

Question 11

what is the function of Osteoprotegerin (OPG)

Answer 11

A regulatory protein secreted by osteoblasts that binds RANKL
Inhibits RANK-RANKL interaction, leading to decreased osteoclast activity.

Question 12

__________ :
-Secreted by osteoblasts
-Promotes the proliferation of osteoclast precursor cells
-Simultaneous binding and fusion of ______and RANKL on the surface of precursor osteoclasts on the synovium→ differentiation of precursor osteoclasts into osteoclasts

Answer 12

M-CSF(macrophage colony-stimulating factor)

Question 13

Interaction of membrane bound or soluble _______with RANK ____________ cells induces their differentiation and activation into mature osteoclasts.

Answer 13

RANKL , RANK-expressing osteoclast precursor cells

Question 14

vitamin D3, prostaglandin E2 (PGE2), parathyroid hormone (PTH) and several cytokines - (TNFα) and
interleukin (IL)-1, -11 and -17. induced ___________ expression

Answer 14

RANKL expression by osteocytes and osteoblasts

Question 15

Expression of the decoy receptor osteoprotegerin (OPG) is induced by :

Answer 15

17-β oestradiol,
IL-4
TGF-β

Question 16

OPG ___________ with RANK/RANKL interaction thereby _________bone degradation

Answer 16

interferes, inhibition

Question 17

list 3 inducers of RANKL expression

Answer 17

progesterone
PTH
calcitriol (vit. D3)

Question 18

estrogen, induces the expression of the _______

Answer 18

decoy receptor OPG

Question 19

____________ important cause of hypercalcemia.

Answer 19

Primary hyperparathyroidism

Question 20

• Adults, more common in women than men 4 : 1.
  !Adenoma: 85% to 95%:

primary or secondary hyperPTH

Answer 20

1º hyper-PTH

Question 21

pathogenesis of PRIMARY HYPERPARATHYROIDISM

Answer 21

Excess production of PTH → Hypercalcemia

Question 22

Clinically silent – cause of hypercalcemia

Answer 22

Primary hyperparathyroidism

Question 23

Clinically apparent – causes of hypercalcemia

Answer 23

Cancer – PTH like polypeptide + Osteolytic bone metastasis

Question 24

Persistent hyperplasia in long standing secondary
hyperparathyroidism even with correction

Calcium and phosphate increased

Requires parathyroidectomy

Answer 24

teritary hyper-PTH

Question 25

Compensatory hyperplasia of all parathyroids because of prolonged hypocalcemia - CKD or Vit D def Calcium levels low / normal

Answer 25

secondary hyperparathyroidism

Question 26

Primary Hyperparathyroidism is most common in adults or children women or men 4:1 ratio adenoma 85-95%

Answer 26

ADULTS , WOMEN

Question 27

list 3 genetic abnormalities in primary hyperparathyroidism

Answer 27

1. Cyclin D1 gene rearrangements – overexpressed in 40% parathyroid adenoma Cyclin D1 – normal cell cycle regulator, gene located at 11q Inversion Chr 11 repositions this gene adjacent to PTH gene located at 11p drives abnormal expression of Cyclin D1 in PTH producing cells 2. MEN mutations: MEN-1,MEN-2a ( parathyroid tumors) 3. Familial hypocalciuric hypercalcemia (CASR inactivating mutations)

Question 28

determine diiagnosis: -rare autosomal dominant condition. -(CASR inactivating mutations) decreasing sensitivity to extracellular calcium leading high PTH levels.

Answer 28

Familial hypocalciuric hypercalcemia (FHH)

Question 29

diagnosis of FHH

Answer 29

* asymptomatic hypercalcemic patient with a family history of hypercalcemia, * asymptomatic hypercalcemia before the age of 40 years * serum calcium values from first-degree relatives in the absence of family history.

Question 30

FHH patient typically have electrolyte imbalances of:

Answer 30

* mild hypercalcemia * hypocalciuria * hypermagnesemia * hypophosphatemia.

Question 30

FHH patient typically have electrolyte imbalances of:

Answer 30

* mild hypercalcemia * hypocalciuria * hypermagnesemia * hypophosphatemia.

Question 31

Increased PTH secretion despite increased Serum Calcium = Hypercalcemia is seen in?

Answer 31

in parathyroid ; reuced CASR function

Question 32

Increased calcium reabsorption despite increased Serum Calcium = Hypercalcemia & Hypocalciuria is seen in?

Answer 32

in kidney; reduced CASR function

Question 33

Determine Diagnosis:

Answer 33

* 24 hours urinary calcium excretion is less than 100 mg/24 hours. * Ca/Cr excretion ratio is low. (0.020 or less)- should be tested for CaSR gene mutations. * Serum Magnesium is in the upper-normal range or mildly elevated

Question 34

Morphologic findings in Primary hyperparathyroidism: parathyroid adenoma GROSS:

Answer 34

* solitary nodule confined to single gland; * other glands normal/shrunken (feedback inhibition by calcium) * well-circumscribed – delicate capsule * soft, tan to reddish-brown * 0.5-5g

Question 35

Morphologic findings in Primary hyperparathyroidism: parathyroid adenoma Microscopically:

Answer 35

* fairly uniform, polygonal chief cells with small, centrally placed nuclei- endocrine atypia * Absence of adipose tissue that is seen in normal parathyroid.

Question 36

Morphologic findings in Primary hyperparathyroidism: parathyroid HYPERPLASIA:

Answer 36

All 4 glands involved - asymmetry (together not >1g) Chief cell predominant- nodular / diffuse Fat may be inconspicuous

Question 37

Morphologic findings in Primary hyperparathyroidism: parathyroid CARCINOMAS:

Answer 37

involves one parathyroid circumscribed lesions / clearly invasive neoplasms Gross: * gray-white, irregular masses weighing up to 10g Microscopy * dense, fibrous capsule * cells usually are uniform and resemble normal parathyroid cells nodular or trabecular patterns. * Diagnosis of carcinoma based on cytologic detail is unreliable, invasion of surrounding tissues and metastasis are the only definitive criteria

Question 38

bones marrow contains fibrous tissue accompanied by foci of hemorrhage and cyst formation

Answer 38

(osteitis fibrosa cystica- Brown tumor of hyperparathroidism)

Question 39

clinical features of 1º hyperPTH

Answer 39

-painful bones ( abnormal remodeling, osteolysis & fractures) -renal stones ( renal colic) -abdominal groans ( hypercalcemia induced ileus, constipation, pancreatitis, peptic ulcer) -psychic moans ( malaise, fatigue, depression)

Question 40

lab diagnosis for 1º hyper-PTH

Answer 40

* Elevated serum Calcium and PTH D/D: Paraneoplastic syndrome (e.g., squamous cell cancer of the lung) and Renal cell carcinoma distinguishing factors: serum PTH levels will be low due to negative feedback

Question 41

what is the renal pathogenesis for secondary hyper-PTH

Answer 41

renal insufficiency --> Reduced α 1 hydroxylase --> Reduced synthesis of active Vit D--> Reduced Calcium absorption in GIT - chronic hypocalcemia ---> Parathyroid stimulation --->PTH

Question 42

describe the gross morphology of 2º hyperparathyroidism

Answer 42

glandular enlargement

Question 43

describe the microscopic morphology of 2º hyperparathyroidism

Answer 43

hyperplastic glands with increased water clear chief cells, fat decreased Metastatic calcification in various tissues. Vascular calcification – ischemic damage to skin and other organs. Bone: as seen in primary hyperparathyroidism

Question 44

what are the 5 main lab dx. for 2º hyperparathyroidism

Answer 44

➢Hypocalcemia* ➢Hyperphosphatemia * ➢Increased PTH levels ➢Decreased Vit D ➢Increased ALP

Question 45

Disorder : Primary hyperparathyroidism Serum calcium Serum PTH Serum phosphorus Serum 1,25(OH)2

Answer 45

Increased Increased Decreased Increased

Question 46

Disorder: secondary hyperparathyroidism (renal vit D. Def) Serum calcium Serum PTH Serum phosphorus Serum 1,25(OH)2

Answer 46

Decreased Increased Increased Decreased

Question 47

Disorder: malignancy induced hypercalemia Serum calcium Serum PTH Serum phosphorus Serum 1,25(OH)2

Answer 47

Increased Decreased Normal Decreased

Question 48

Disorder: hypoparathyroidism Serum calcium Serum PTH Serum phosphorus Serum 1,25(OH)2

Answer 48

decreased decreased increased decreased

Question 49

what are 4 main causes for hypoparathyroidism

Answer 49

* Acquired - inadvertent consequence of surgery of thyroid / neck dissection Autoimmune hypoparathyroidism- assc. w/ APS1 * Autosomal-dominant hypoparathyroidism is caused by gain-of-function mutations in the calcium-sensing receptor (CASR) gene. * Congenital absence of parathyroid glands: Associated malformations like thymic aplasia and cardiovascular defects, or as a component of the 22q11 deletion syndrome – DiGeorge Syndrome - hypomagnesemia

Question 50

determine dx: * Defective response in renal tubule to PTH ( PTH resistance) * Due to defects in G protein receptor Type IA ( Albrights hereditary osteodystrophy) * May be associated with end organ resistance to TSH/ FSH/LH

Answer 50

Pseudohypoparathyroidism

Question 51

lab findings for pseudohypoparathyroidism

Answer 51

* Increased PTH * Hypocalcemia * Hyperphosphatemia * increased Alkaline phosphatase

Question 52

what are to signs for neuromuscular irrirabilty

Answer 52

* Chvostek sign: twitch of the facial muscles that occurs when gently tapping an individual's cheek, in front of the ear Trousseau sign - carpopedal spasm

Question 53

ACUTE clinical features for hypo-PTH

Answer 53

Acute- surgical ablation * neuromuscular irritability : tingling, muscle spasms, facial grimacing and sustained carpopedal spasm (tetany) - chvostek sign - trousseau sign - cardiac arrythmas - increased ICP & seixures

Question 54

CHRONIC clinical features for hypo-PTH

Answer 54

Cataract, calcifications of the basal ganglia, dental abnormalities * Mental status changes - emotional instability

Question 55

Disorder: pseudohypoparathyroidism Serum calcium Serum PTH Serum phosphorus Serum 1,25(OH)2

Answer 55

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