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FHB - Endocrine & Reproductive > Lecture 8 (75) : Parathyroid > Flashcards

Lecture 8 (75) : Parathyroid Flashcards

1
Q

State the general functions of Calcium. (8)

What range is it tightly regulated in?

mM and mg/dL

A
  1. Most abundant cation

2.Tightly regulated range in plasma (2.2 - 2.6 mM)
(or 8.8 - 10.3 mg/dL)

  1. Membrane stability and cell function
  2. Neuronal transmission
  3. Bone structure/formation
  4. Blood coagulation
  5. Muscle function
  6. Hormone secretion
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2
Q

State the general functions of Phosphate. (8)

What range is it typically found it?
mM and mg/dL

A
  1. Cellular energy metabolism (ATP)
  2. Intracellular signaling pathways
  3. Nucleic acid backbone
  4. Bone structure
  5. Enzyme activation/deactivation
  6. 8 1.45 mM or 2.4 - 4.1 mg/dL
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3
Q

What is the main affect of HYPERPHOSPHATEMIA?

A

Hyperphosphatemia:
- result of severe tissue injury “crush”

-10-fold more Pi than Ca2+ in soft tissue

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4
Q

Most calcium is free or protein bound?

Most phosphate?

What is a good indicator of free calcium availability?

A

both are FREE

  1. Calcium bound to albumin -

albumin levels good indicator of free calcium availability

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5
Q

What are the 4 main affects of HYPOCALCEMIA?

HYPERCALCEMIA?(4)

A

Hypocalcemia:

  1. muscle failure
  2. tetany
  3. convulsions
  4. death

tetany = depolarization threshold is lower = EASIER TO DEPOLARIZE when less calcium in Extracellular space

Hypercalcemia:

  1. renal dysfunction
  2. calcification of soft tissues
  3. muscle weakness
  4. coma
  • RENAL dysfunction
  • kidney overwhelmed and cannot filter the calcium deposits in the soft tissues!!
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6
Q

What are the 2 primary regulators of Calcium?

What is the 3rd, but potentially not important for humans?

A

Two primary regulators of calcium :

  1. Parathyroid hormone (PTH)
  2. Vitamin D = Calcitriol (skin,diet)
  3. Calcitonin (thyroid) *potentially not important
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7
Q

What are the 2 primary cell types in the Parathyroid Gland?
(what is their function)

Where is it located?

A
  1. Chief Cells (also called Principal cells) – synthesize PTH
  2. Oxyphil Cells – no known function, increase with age and chronic kidney disease
    - Paired glands (4 total) located at posterior borders on lateral lobes of thyroid gland (usually embedded in capsule)
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8
Q

What directs processing to the ER?

______ is highly homologous to PTH 1-34 AA.

What is the only active portion of PTH?

A
  1. Signal Peptide
  2. PTHrP is highly homologous
  3. Only N terminal 1-34 is ACTIVE - binds to PTH receptor
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9
Q

What fragment of PTH has a longer half life?

What portion is clinically important with a half life of 4 min?

A

C-terminal fragment 35-84 has longer half-life than other fragments – inactive

Intact 1-84 fragment: half-life of 4 min. Clinically important measurement
- need full PTH to measure how much PTH is in the blood

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10
Q

_______Mimics action of PTH in bone and kidney.

Normally at very low concentrations; not a regulator of _____ .

Many tumors produce it (renal, bladder, lymphoma, head/neck) resulting in _____

A
  1. PTH rP
  2. plasma Ca2+
  3. hypercalcemia.
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11
Q

Are PTH and PTHrP structurally similar?

What are they similar in?

A

NO

Equal binding to PTH–> activate the same receptor equally well

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12
Q

What is the primary PTh receptor?

Where is it located? (2)

What type of receptor? (2 subdivisions)

Which fragment of PTh does it bind?

Does it bind both PTH and PTHrp?

A
  1. PTH 1R – primary receptor
  2. Located in osteoblasts and kidney (bone & kidney - where PTH acts)
  3. G-protein coupled receptor
    a) Gαs —- adenylyl cyclase/cAMP pathway
    b) Gαq —- PLC/IP3/DAG
  4. Binds 1-34 fragment, 1-84, PTHrP
  5. binds both PTH & PTHrP
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13
Q

What is the role of PTH 2R?

A

physiological importance in humans unclear

Binds 1-34

Does not bind PTHrP

  • BUT can be a therapeutic target
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14
Q

What are the net affects of PTH?

A
  1. Increase plasma Ca2+

2. Decrease plasma Pi

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15
Q

Osteoblasts:

  1. What is their function?
  2. High expression of _____
  3. Derived from what type of stem cells?
A
  1. Bone formation and mineralization
  • extrude calcium & phosphate from inside bone where they are stored into EXTRACELLULAR space
  • nucleation = hardening bone
  1. High expression of PTH receptors
  2. Derived from mesenchymal stem cells
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16
Q

Osteoclasts:

  1. Function
  2. Derived from?
  3. Express/do not express PTH receptors?

Osteocytes:

  1. Function
  2. Terminally differentiated from____.
A

Osteoclasts:
1. Bone reabsorption

  1. Derived from hematopoietic stem cells
  2. Do not express PTH receptors

Osteocytes:
1. Make up most of the bone matrix

  1. Terminally differentiated from osteoblasts
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17
Q

PTH stimulates _____ in osteoblasts which stimulates the differential of osteoclast precursors.

PTH stimulation of osteoclasts is direct or indirect?

PTH also stimulates _____ which leads to the maturation of osteoclast & bone reabsorption.

A
  1. M - CSF

(Macrophage colony stimulating factor)

  1. INDIRECT
  2. RANK ligand
    - Bone degradation releases Ca2+ and Pi to systemic circulation
18
Q

Osteoblasts export Ca2+ and Pi where and for what purpose?

It is the major factor maintaining what?

A
  1. into extracellular space for bone mineralization

2. Major factor in maintaining plasma calcium homeostasis.

19
Q

What is the antagonist of RANK ligand?

What stimulate and what inhibits it?

How is this related to osteoporosis and stress?

A

Osteoprotegerin (OPG) antagonist of RANK ligand.

Estrogens stimulate and Cortisol inhibits OPG

-pre-menopausal protected from osteoporosis due to HIGH ESTROGEN
post = excessive RANK stimulation of RANK ligand!!!

  • stress = more cortisol released –> increased bone resorption
20
Q

What is the function of PTH in the kidney?

What gene does it stimulate?

Which enzyme does it encode and what does this convert?

It also stimulates _____ insertion onto apiece membrane of what part of the nephron?

A

Stimulates CYP1α –

encodes 1α-hydroxylase which converts active form of Vitamin D

Stimulates Ca2+ channel insertion in apical membrane of DISTAL tubule (Thick ASCENDING LIMB)

  • phosphate reabsorption is mostly blocked at Proximal Tubule
21
Q

What is the primary regulator of PTH?

A

Plasma calcium concentration!!!!

22
Q

PTH REGULATION:

Where are Calcium - Sensing Receptors (CaSR) located? (3)

What do they bind?

What do they inhibit?

What do they degrade?

A
  1. Located in
    - chief cells
    - kidney tubules
    - C cells (of thyroid)
  2. Binds ionized (free) Ca2+
  3. Inhibits PTH synthesis at promoter level

Stimulates degradation of preformed PTH

23
Q

Vitamin D binds ____.

What is its DIRECT affect on PTH?

INDIRECT affect?

A

Binds nuclear receptor - VDR

  1. DIRECT: Inhibits PTH synthesis at PROMOTER level (like CaSR)
  2. INDIRECT: Stimulates CaSR gene transcription
24
Q

State the calcium type responsible for the following functions:

  1. Vitamin D2 – dietary from vegetables - NOT FROM CHOLESTEROL
  2. general term for vitamin D and other natural structural analogs.
  3. 1,25-dihydroxy-vitamin D (1,25-D) = 1,25-dihydroxy-cholecalciferol (this is the active form)
  4. specifically refers to vitamin D3 (from animal tissues). - derived from cholesterol
  5. 25-hydroxy-vitamin D (25-D) = 25-hydroxy-cholecalciferol (immediate precursor)
A
  1. Ergocaliferol
  2. Calciferol
  3. *Calcitriol = calcifitriol
  4. Cholecaciferol
  5. Calcidiol = calcifidiol
    - BINDS RECEPTOR + high abundance compared to active form - plays a role in mediating calcium homeostasis
25
Q

Vitamin D synthesis:

  1. Derived from?
  2. What type of receptor?
    3 Active form?
  3. Bound in plasma or not? If yes, to what?
A
  1. Derived from cholesterol – steroid hormone
  2. Nuclear Receptor = VDR
  3. Active form = 1,25-dihydroxycholecalciferol
  4. Bound in plasma to vitamin D-binding protein
26
Q

How is Vitamin D transported to the LIVER? (2 ways)

What happens in the liver?

Where is it converted to the active form? What enzyme does it require for this?

A
  1. Chylomicrons via lymphatics
  2. Portal Vein
    - in the liver it is converted to 25-OH- D3

by 25-Hydroxylase

  1. KIDNEY –> by 1 alpha-hydroxylase
27
Q

What is Vitamin D said to have pleotropic effects?

A

Deficiency linked to:

  1. Multiple Sclerosis
  2. Asthma
  3. Cardiovascular disease
  4. Type II Diabetes mellitus
  5. Colorectal/breast cancer
28
Q

What are the 3 targets of Vitamin D?

A

3 targets:
Bone
Gut
Kidney

29
Q

What are the DIRECT affects of Vitamin D on bone?

INDIRECT?

A
  1. Direct:
    Mobilize Ca2+ from bone

Osteoblasts and osteoclasts have VDRs

Vitamin D stimulates osteoclast proliferation/differentiation (NEW bone formation)

  1. Indirect:

Increases plasma Ca2+ which promotes bone mineralization
- primary role is BONE FORMATION by braking down OLD bone to make NEW bone

30
Q

What are the DIRECT affects of Vitamin D on INTESTINE?

3 for Calcium & 1 affect for Phosphate

A
  1. Increases transcellular Ca2+ absorption in duodenum
    - by increasing TRYP5 channels
    - increasing cal binding
    - increasing Ca-ATPase
  2. Stimulates Pi reabsorption from small intestine
31
Q

Describe the process of Calcium Homeostasis.

A
  1. Low blood calcium sensed:
  2. increase PTH (CaSR in chief cells)
  3. Long term: stimulate CYPa to convert inactive to active Vitamin D
  4. Short turn: increase bone turnover by osteoclast
  5. increase calcium reabsorption and phosphate excretion of kidney (fast)
  6. NEGATIVE FEEDBACK on PTH
    a) shut off the promoter b) more CaSR (sensing receptors)
32
Q

Clinical Disorders:

HYPERPARATHYROIDISM:

  1. Primary problem
    1b. Secondary
  2. Causes
  3. How is it related to Vitamin D?
A

Primary: hyperplasia, carcinoma of parathyroid gland
Hypercalcemia, kidney stones

1b. Secondary:
- due to chronic renal failure (no Vitamin D activated = too much PTH synthesis since vitamin D not inhibiting)

Reduced Vitamin D leads to excess PTH synthesis

33
Q

Clinical Disorders:

Osteoporosis:

  1. Main problem
  2. Causes
  3. Treatment
A
  1. Reduced bone density – mainly trabecular bone***
  2. Causes: genetic, menopause (low estrogen – loss of OPG),
  • glucocorticoid therapy/chronic stress,
  • low dietary Ca2+
  1. Treatment:
    - estrogens
    - calcitonin
    - biphosphonates (inhibit bone resorption)
    - Vitamin D
34
Q

Clinical Disorders:

HYPOPARATHYROIDISM:

  1. Main problem
  2. What is a symptom? What is this called?

Rickets (children)/Osteomalacia (adults)

  1. Main problem
  2. Symptoms (2)
A
  1. Hypocalcemic tetany (reducing threshold for depolarization)
  2. Chvostek sign: twitching of facial muscles in response to tapping of facial nerve
  3. Unmineralized bone due to Vitamin D deficiency
  4. “bowing” of long bones (children)
    & Decreased bone strength
35
Q

Clinical Disorders:

Pseudohypoparathyroidism
Congenital defect where?

Generalized resistance to what? (4)

Clinical signs? (4)

A
  1. G protein that associates with PTHR1
  2. PTH, TSH, LH, and FSH
3. Clinical signs: 
low Ca++, 
high phosphate, 
elevated PTH
 short stature

** no issue with thyroid gland itself**

36
Q

Tubular reabsorption of phosphate (TRP) _____ as phosphate excretion increases.

Urinary hydroxyproline shows what?

A

DECREASES

enhanced bone resorption

37
Q

Calcitonin:

32 -amino acid peptide produced in the ______ of what gland?

possible function?

Why is the normal physiological importance unclear?

A
  1. C-cells of thyroid gland.
  2. Inhibits calcium reabsorption in bone?
3. 
 Complete thyroidectomy (with parathyroids left intact) does not alter NORMAL physiological range of Ca2+.
  1. C-cell tumors – extremely high calcitonin – does not affect Ca2+ levels.
38
Q

What is the therapeutic use of Calcitonin?

What is the net affect?

What is it used to treat?

A
  1. inhibits osteoclast reabsorption of and slows bone turnover
  2. net effect:
    hypocalcemic action
  3. Used to treat Paget disease: (one part of bone resorped too quickly)
39
Q

What is Paget Disease?

A

excessive localized regions of bone resorption and reactive sclerosis.

Very high bone turnover
Cause is unknown.

40
Q

What is the ESCAPE phenomenon in regards to Calcitonin treatment?

A

“Escape” phenomenon – rapid downregulation of calcitonin receptors cause the antiosteoclastic actions of calcitonin to diminish within a few hours making this a less effective treatment option.

  • receptors for CALCITONIN downregulate = NOT A LONG TERM FORM OF TREATMENT (have to stop and start)

FHB - Endocrine & Reproductive (17 decks)

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