T6: Parathyroid Hormone

Ca2+ & Phosphates are found where

main mineral in bone

name the 3 hormones that regulate Ca2+ & PO3-/4 levels

1. PTH

2. active vitamin D (1,25-dihydroxyvitamin)

3. calcitonin

Explain the Ca2+, PO3-/4, PTH interaction & homeostasis mech

(hint: affect of PTH on diff organs)

(start w/ decreased plasma Ca2+)

1. decreased plasma Ca2+

2. parathyroid gland secrete PTH

3. PTH has 3 main functions:

   1. Kidneys: stimulates Ca2+ reabsorption & PO3-/4 excretion

   2. stimulates bone resorption (dissolution of calcium phosphate crystals)

   3. vitamin D release from kidneys → stimulates intestinal absorption of Ca2+ & phosphate

4. increased Ca2+ in blood, increased phosphate excretion

5. increase Ca2+ → negative feedback

3 actions of PTH

1. converts inactive vitamin D → active vitamin D (in kidney)

2. Ca2+ reabsorption, PO3-/4 excretion in kidney

3. promotes bone resorption

PTH secreted by what cells

chief cells of parathyroid gland

another function of active vitamin D

inhibits PTH gene transcription (negative feedback mech)

state mech of how does active vitamin D inhibit PTH gene transcription

vitamin D binds to vitamin D receptor → forms heterodimer w/ RXR → VDR-RXR complex binds to DNA (at vitamin D response element on PTH gene) → inhibit PTH gene transcription

PTH synthesis mech (low Ca2+ lvl, aim = increase Ca2+)

1. Ca2+ binds to CASR

2. G-protein activated

3. downstream signalling pathway (signal sent from cytoplasm to nucleus)

4. PTH gene transcribe to PTH mRNA → PTH mRNA leaves nucleus

5. preproPTH synthesized in RER & cleaved → enters RER → becomes pro-PTH

6. pro-PTH cleaved to active PTH in golgi

7. active PTH leaves cells via exocytosis → enters blood → rise in Ca2+ lvl

explain why high Ca2+ inhibit PTH release - give mech

1. Ca2+ binds to CASR

2. activates Gq protein → phospholipase C (PLC)

3. PLC generates IP3 & DAG

   1. IP3 = releases Ca2+ from stores

   2. DAG = activate protein kinase C

4. Ca2+ + PKC = inhibit PTH secretion

how does PTH decrease phosphate reabsorption

inhibit NPT2a (sodium-phosphate) cotransporter at PCT

what happens to phosphate after decrease phosphate reabsoprtion

excreted into urine w/ HCO3-

how does PTH increase bone resorption

PTH:

• inhibits collagen synthesis in osteoblasts → decreased bone formation

• stimulates RANKL production from osteoblast → activates osteoclast → bone resorption

parathyroid disorders

cause of primary hypothyroidism (2)

parathyroidectomy, autoimmune (autoantibodies attack PTH gland)

results of primary hypoparathyroidism (3)

1. hypocalcemia (Ca2+ reabsoprtion decrease)

2. hyperphosphatemia (decreased PO3-/4 excretion)

3. bones remain strong - no bone resorption

clinical features of primary hypoparathyroidism (3)

1. …… sign

2. ….. sign

1. trousseau’s sign = hypocalcemic tetany in hand → carpopedal spasm (flexion of wrists, joints, finger extension)

2. chvostek’s sign = test: tap facial nerve around ear → twitching of face muscle

3. tetany = muscle spasms, esp. laryngeal spasm → respiratory obstruction → death

state 3 other symptoms of primary hypoparathyroidism

1. paresthesia around mouth (tingling, numbness sensation)

2. prolonged QT interval (heart takes longer than normal to reset btwn beats)

3. soft tissue calcification (high phosphate lvl → PO3-/4 binds to ca2+ → forms calcium-phosphate crystals)

state the 4 treatment options:

• PTH supplement

• high-dose vitamin D

• Ca2+ supplement

• calcitriol (active vitamin D)

primary hyperparathyroidism

• cause (3)

1. parathyroid adenoma (most common)

2. parathyroid hyperplasia

3. parathyroid carcinoma

lab results for primary hyperparathyroidism

1. increased PTH

2. increased Ca2+

3. decreased PO3-/4

state the 5 symptoms of hyperparathyroidism

stones, bones, groans, moans, fatigue overtones

in hyperparathyroidism:

explain pathogenesis of how PAINFUL BONES occurs

excess PTH secretion → increased osteoclastic bone resorption

→ increased serum Ca2+ (hypercalcemia)

→ decreased phosphate (lost in urine → renal phosphate wasting)

bone manifestations in primary hyperparathyroidism

1. mild case =

2. severe case =

→ name the condition arising in severe case

mild case = increased osteoclast activity balanced by osteoblast

severe case = excessive bone resorption (exceeds bone formation)→ bone mass decrease

→ condition = osteitis fibrosa cystica

state the 3 clinical features of osteitis fibrosa cystica

1. bone cysts (due to giant cell osteoclast tumors)

2. punched-out lesions - on radiograph

3. multiple fractures after minor trauma

explain the ‘stones’ symptom in primary hyperparathyroidism

1. stones where?

2. pathogenesis of how its formed

3. give the condition name

1. renal stones

2. PTH increase → more calcium absorbed in kidneys → too much of this overwhelms kidney → hypercalciuria → Ca2+ in urine crystallizes → forms stones

3. nephrolithiasis

complications of renal stones (3)

1. nephrolithiasis (kidney stones)

2. Ca2+-PO3-/4 stones & calcium oxalate stones

3. alkaline urine (bone resorption releases alkaline phosphate buffer)

state the 4 symptoms of ‘abdominal groans’

nausea, constipating, peptic ulcer, abdominal pain

state the 2 symptoms of psychic moans

depression, confusion

what is fatigue overtones

generalized weakness & fatigue

apart from the ‘ones symptoms of primary hyperparathyroidism, what is another symptom present?

anorexia

PTH crisis / PTH poisoning

• state the calcium lvl

• pathogenesis =

• a condition present =

• how severe is it

• Ca2+ > 17mg/dL

• super high Ca2+ → metastatic calcification = calcium accumulates in soft tissues, vital organs

  • calcium-phosphate crystals deposit in lungs, kidneys, stomach, mucosa, thyroid, arteries

• hyperphosphatemia (kidney pung → less phosphate excretion → more phosphate in blood)

secondary hyperparathyrodism

• lab

• common triggers (2)

• lab = decreased Ca2+ → negative feedback: increased PTH

• common triggers:

  • vitamin D deficiency

  • CKD → decrease vitamin D production

2 diseases that arise from secondary hyperparathyrodism

osteomalacia (adults)

rickets (children)

osteomalacia & rickets

• give definition + affects what part of bone

• state the pathogenesis of how each condition occurs

• osteomalacia = defective bone mineralization in adults → affects bone matrix

• rickets = defective bone mineralization in children → affects growth plates

pathogenesis:

• high PTH → increased bone resorption → weakened bones

complication of severe case rickets

respiratory muscle spasm → risk of death

induction of bone loss by PTH

→ state mechanism

PTH binds to osteoblat → increases RANKL release → RANKL binds to receptors in osteoclast precursors → activates osteoclast: bone resorption occurs

what happens to bone mineral density in primary hyperparathyroidism

BMD decrease → bone loss

bone densitometry

• normal score =

• osteopenia (bone mass lower than normal but not servere) =

• osteoporosis =

• normal = T score btwn +1 & -1

• osteopenia = T score btwn -1 & -2.5

• osteoporosis = T score < -2.5

state the 6 common causes of osteoporosis

1. physical inactivity

2. malnutrition

3. vitamin C deficiency

4. post-menopausal estrogen deficiency

5. old age

6. cushing’s syndrome

give mech of how physical inactivity causes osteoporosis

physical inactivity → reduced mechanical stress → reduced bone formation (bone resorption > formation)

give mech of how malnutrition causes osteoporosis

protein intake low → less bone matrix (osteoid) formation

give mech of how vitamin C deficiency causes osteoporosis

vitamin C deficient → impared collagen synthesis → defective osteoid production

give mech of how post-menopausal estrogen deficiency causes osteoporosis

estrogen inhibits osteoclasts → less estrogen = more bone resorption

give mech of how old age causes osteoporosis

old age = reduced growth hormones & anabolic activity + impaired osteoblast function → less matrix deposition

give mech of how cushing’s syndrome causes osteoporosis

prolonged exposure to cortisol → increase PTH → increase bone resorption

state the markers for bone resorption (3)

NTX, CTX (collagen degradation products), TARCP (enzyme)

state the 3 markers for bone formation

osteocalcin (matrix proteins), PICP & PINP (propeptide), enzyme (total alkaline phosphatase)

what happens after parathyroidectomy of several years

BMD increase, bone turn over marker decreases → less osteoporosis