Endocrinology 8 Flashcards
Explain the importance of Ca2+ and PO4 for normal physiological processes, and describe the normal range of dietary Ca2+ and PO4- intake, distribution in the body, and excretion.
What is the range of Ca in the plasma?
Functions Ca participates in?
Which involved in blood coagulation? Bone structure? Muscle function?
Calcium: Most abundant cation Tightly regulated range in plasma (2.2 - 2.6 mM) Membrane stability and cell function Neuronal transmission Bone structure/formation Blood coagulation Muscle function Hormone secretion
Phosphate: Cellular energy metabolism (ATP) Intracellular signaling pathways Nucleic acid backbone Bone structure Enzyme activation/deactivation
What will occur in hypocalcemia? Hypercalcemia?
Hypocalcemia = muscle failure, tetany, convulsions, death
Hypercalcemia = renal dysfunction, calcification of soft tissues, muscle weakness, coma
When might hyperphosphatemia occur?
Hyperphosphatemia = result of severe tissue injury “crush”
10-fold more Pi than Ca2+ in soft tissue
Which is the more abundant in tissue? Pi or Ca2+?
Which is most abundant cation?
10-fold more Pi than Ca2+ in soft tissue
Ca- most abundant cation
How does calcium travel in plasma?
Ca in body is mostly in the bone
in plasma it is usually complexed… ionized 50 percent free, 45 percent bound to albumin, 5 percent complexed to other things (Ca-Phos. Ca-citrate)
Calcium bound to albumin - albumin levels good indicator of free calcium availability
What are the two primary regulators of calcium? (and third)
Two primary regulators of calcium :
Parathyroid hormone (PTH)
Vitamin D = Calcitriol (skin,diet)
(3rd)
Calcitonin (thyroid) *potentially not important for humans
Describe the daily calcium turnover.
Diet 1000mg
350mg absorbed, 150mg secreted
(rapidly exchangeable pool- 4000mg)
Urinary excretion-200 mg
Fetal excretion - 800mg
slide 8
Daily calcium turnover in humans. Typical dietary intake of calcium is 1000mg. The intestines absorb about half of dietary intake, but also secrete removal from the body making net uptake only ~ 200mg. Urinary excretion is about the same as GI absorption. Bone is third major organ governing calcium homeostasis.
List the primary cell types and their products in the parathyroid glands.
PARATHYROID GLAND – located on anterior surface of thyroid gland
Paired glands (4 total) located at posterior borders on lateral lobes of thyroid gland (usually embedded in capsule)
Chief Cells (also called Principal cells) – synthesize PTH
Oxyphil Cells – no known function, increase with age and chronic kidney disease
Describe the biosynthesis and receptors for PTH and explain the clinical importance of measuring the 1-84 fragment and the importance of PTHrP.
…
Describe Parathyroid hormone (PTH) synthesis.
Describe N and C terminal fragments
Half life?
Signal peptide directs processing to the ER.
Parathyroid hormone-related peptide (PTHrP) is highly homologous to PTH 1-34 AA
N-terminal fragment 1-34 biologically active – binds to PTH receptor
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
Slide 12
Describe the action of parathyroid hormone – related peptide (PTHrP).
Where does it act? What kind of action?
Concentration?
What is clinical relevance?
Mimics action of PTH in bone and kidney
Normally at very low concentrations; not a regulator of plasma Ca2+
Many tumors produce PTHrP (renal, bladder, lymphoma, head/neck) resulting in hypercalcemia
Describe the PTH receptors.
PTH 1R – primary receptor Located in osteoblasts and kidney G-protein coupled receptor Gαs ---- adenylyl cyclase/cAMP pathway Gαq ---- PLC/IP3/DAG Binds 1-34 fragment, 1-84, PTHrP
PTH 2R
physiological importance in humans unclear
Binds 1-34
Does not bind PTHrP
What are the main PTH targets and net effects?
PTH Targets – Bone and Kidney
Net Effects: Increase plasma Ca2+, decrease plasma Pi
Describe the function of osteoblasts and osteoclasts in bone remodeling.
Which are involved in bone resorption/bone reabsorption? Which express PTH receptors? What type of stem cell are each derived from?
Describe role of osteocytes.
99% body Ca2+ content is in bone
Osteoblasts –
- Bone formation and mineralization
- High expression of PTH receptors
- Derived from mesenchymal stem cells
Osteoclasts –
- Bone reabsorption
- Derived from hematopoietic stem cells
- Do not express PTH receptors
Osteocytes –
- Make up most of the bone matrix
- Terminally differentiated from osteoblasts
Describe the effect of PTH on the bone.
What does PTH stimulate in osteoblasts, osteoclasts?
How does it affect bone reabsorption?
What effect will bone degradation have?
PTH Target – Bone Remodeling
PTH stimulates macrophage colony-stimulating factor (M-CSF) in osteoblasts
M-CSF stimulates differentiation of osteoclast precursors
Key Concept
PTH stimulation of osteoclasts is indirect
PTH stimulates RANK ligand – leads to maturation of osteoclast and bone reabsorption
Bone degradation releases Ca2+ and Pi to systemic circulation.
Describe the role of osteoblasts in maintaining plasma calcium homeostasis.
Osteoblasts export Ca2+ and Pi into the extracellular space for bone mineralization
Major factor in maintaining plasma calcium homeostasis.
What is osteoprotegerin (OPG)?
What effect do estrogens and cortisol have on OPG?
*Osteoprotegerin (OPG) antagonist of RANK ligand.
Estrogens stimulate and Cortisol inhibits OPG
Describe PTH effect on the kidney.
Stimulates CYP1alpha – encodes 1alpha-hydroxylase which converts active form of Vitamin D
Stimulates Ca2+ channel insertion in apical membrane of distal tubule
Describe the regulation PTH and the role of the calcium-sensing receptor.
Where is the Calcium sensing receptor located?
What does it inhibit? What does it stimulate?
Graph slide 26
Calcium-sensing receptor (CaSR)
Located in chief cells, kidney tubules, C cells
Binds ionized Ca2+
Inhibits PTH synthesis at promoter level
Stimulates degradation of preformed PTH
Describe PTH regulation as it relates to Vitamin D.
Vitamin D
Binds nuclear receptor - VDR
Inhibits PTH synthesis at promoter level
Stimulates CaSR gene transcription – indirect regulation of PTH
Identify the sources of Vitamin D and diagram its biosynthetic pathway.
Slide 32-33
Describe the following (Vitamin D nomenclature)
Calciferol
Cholecaciferol
Calcidiol
Calcitriol
Ergocaliferol
Calciferol = general term for vitamin D and other natural structural analogs.
Cholecaciferol = specifically refers to vitamin D3 (from animal tissues).
Calcidiol = calcifidiol = 25-hydroxy-vitamin D (25-D) = 25-hydroxy-cholecalciferol (immediate precursor)
*Calcitriol = calcifitriol = 1,25-dihydroxy-vitamin D (1,25-D) = 1,25-dihydroxy-cholecalciferol (this is the active form)
Ergocaliferol = Vitamin D2 – dietary from vegetables
Describe Vitamin D synthesis.
From what is it derived?
Receptor?
Active form?
How does it travel in the plasma?
Derived from cholesterol – steroid hormone
Nuclear Receptor = VDR
Active form = 1,25-dihydroxycholecalciferol
Bound in plasma to vitamin D-binding protein
Describe factors regulating conversion of 25-D to 1,25(OH)2-D by CYP1α or inactive 24,25(OH)2-D by CYP24.
Slide 33
Explain how Ca2+ and PO4 is regulated by PTH and vitamin D.
…
Describe the pleiotropic effects of Vitamin D.
Deficiency linked to:
Multiple Sclerosis Asthma Cardiovascular disease Type II Diabetes mellitus Colorectal/breast cancer
Describe Vitamin D targets (direct and indirect if applicable).
Slide 36
Bone: Direct: -Mobilize Ca2+ from bone -Osteoblasts and osteoclasts have VDRs -Vitamin D stimulates osteoclast proliferation/differentiation
Indirect:
-Increases plasma Ca2+ which promotes bone mineralization
Intestine:
- Increases transcellular Ca2+ absorption in duodenum
- Stimulates Pi reabsorption from small intestine
Describe how calcium is transported across the cell.
Slide 39
Draw a flow chart for calcium homeostasis.
Slide 40
Describe osteoporosis.
What happens?
Causes?
Treatment?
Osteoporosis
Reduced bone density – mainly trabecular bone
Causes: genetic, menopause (low estrogen), glucocorticoid therapy/chronic stress, low dietary Ca2+
Treatment: estrogens, calcitonin, biphosphonates (inhibit bone resorption), Vitamin D
Describe hyperparathyroidism.
Primary and Secondary.
Hyperparathyroidism
Primary: hyperplasia, carcinoma of parathyroid gland
Hypercalcemia, kidney stones
Secondary: due to chronic renal failure
Reduced Vitamin D leads to excess PTH synthesis
Describe the consequences of under production of PTH and vitamin D.
Give 2 examples.
Hypoparathyroidism
Hypocalcemic tetany
Chvostek sign: twitching of facial muscles in response to tapping of facial nerve
Rickets (children)/Osteomalacia (adults)
Unmineralized bone due to Vitamin D deficiency
“bowing” of long bones (children)
Decreased bone strength
Describe Pseudohypoparathyroidism. What is it?
What are clinical signs?
Pseudohypoparathyroidism
Congenital defect in G protein that associates with PTHR1
Generalized resistance to PTH, TSH, LH, and FSH
Clinical signs: low Ca++, high phosphate, elevated PTH, short stature
How does PTH infusion affect low serum Ca and high serum phosphate?
How does tubular reabsorption of phosphate change as phosphate excretion increases?
What does urinary hydroxyproline indicate?
Low serum calcium and high serum phosphate are normalized by the PTH infusion
Tubular reabsorption of phosphate (TRP) falls as phosphate excretion increases.
Urinary hydroxyproline = enhanced bone resorption
Describe the source and role of calcitonin in calcium regulation.
How many aa?
Physiological purpose?
32-amino acid peptide produced in the C-cells of thyroid gland.
Inhibits calcium reabsorption in bone?
Normal physiological importance is unclear – Complete thyroidectomy (with parathyroids left intact) does not alter normal physiological range of Ca2+. C-cell tumors – extremely high calcitonin – does not affect Ca2+ levels.
Describe therapeutic use of calcitonin.
What can calcitonin be used to treat?
What is the “escape” phenomenon?
Therapeutic use: inhibits osteoclast reabsorption of and slows bone turnover (net effect = hypocalcemic action).
Used to treat Paget disease:
Excessive localized regions of bone resorption and reactive sclerosis.
Very high bone turnover
Cause is unknown.
“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.
