78 - Parathyroid and Ca2+ Flashcards
What % of the body’s Ca2+ is found in the bone?
99%
- Because of bone stores, it’s the most abundant cation in the body as well
What are the sx of hypocalcemia?
Muscle failure, tetany, convulsions, death
What are the sx of hypercalcemia?
Renal dysfunction, calcification of soft tissues, muscle weakness, coma
Hyperphosphatemia is rare. What’s the most common way people get it?
Severe tissue injury or “crush” injury
10x more Pi than Ca2+ in soft tissue
What is the ratio of ionized Ca2+ (free) to protein-bound Ca2+ in the serum?
50:45 (5% complexed)
What is the ratio of ionized Pi (free) to protein-bound Pi in the serum?
84:10 (6% complexed)
Because calcium is bound to it in blood, _______ is a good indicator of free Ca availability.
Albumin
What are the 2 primary mechs for Ca regulation in humans, and what is a 3rd that is probably not important?
- Parathyroid hormone (PTH)
- Vitamin D (skin, diet)
- Calcitonin - potentially not important for humans
What produces calcitonin?
Thyroid (parafollicular cells)
What amount is the typical dietary intake of Ca?
What is the net uptake?
How much is excreted in urine?
How much is excreted in feces?
1000mg
- 200mg
- 200mg
- 800mg
The kidney and bones change the levels of Ca2+ in the body’s __________________________.
Rapidly exchangeable pool
How many parathyroid glands are there, and where are they located?
4
- Located at posterior borders on lateral lobes of thyroid gland (usually embedded in capsule)
What are the parathyroid cells that synthesize PTH? (2 names)
Chief cells AKA Principle cells
Besides chief/principle cells, what other cells are found in the parathyroid gland? What are their function?
Oxyphil Cells: no known function, increase with age and chronic kidney disease
Recall: on the PTH preprohormone, what directs it to the ER?
Signal sequence/signal peptide
What part of the PTH preprohormone is biologically active?
N-terminal fragment 1-34: binds to PTH receptor
The PTH C-terminal fragment 35-84 has longer half-life than other fragments but is inactive. Therefore, what do we want to measure in the blood for best accuracy of current PTH levels?
The entire 1-84 fragment.
What is the 1/2-life of the 84AA PTH?
4 min
What is PTH-related peptide (PTHrP) and why is it important?
- Mimics PTH in bone and kidney
- produced by many tumors, resulting in hypercalcemia!
(normally, it’s very low conc and not a regulator of plasma Ca)
What are the names of the 2 PTH receptors?
Which is the primary receptor?
- PTH R1 (primary)
- PTH R2
Where are PTH R1’s located?
- Kidney
- Osteoblasts (not clasts!)
What is the 2nd msger pw of PTH R1 g-alpha-s?
What about G-alpha-q?
G-alpha-s: adenylyl cyclase/cAMP pathway
G-alpha-q: PLC/IP3/DAG
What hormones can bind PTH R1?
1-34, 1-84, and PTHrP
What binds PTH R2 and what’s its function?
1-34 only (unclear fcn)
What are the (2) net effects of PTH?
Increase plasma Ca2+, decrease plasma Pi
What do osteoblasts do?
What do osteoclasts do?
- Bone formation and mineralization (Ca and Pi taken up)
- Bone reabsorption (Ca and Pi released into circulation)
What types of SC’s are osteoblasts derived from?
Mesenchymal stem cells
What types of SC’s are osteoclasts derived from?
Hematopoetic stem cells
Which express PTH R1 receptors: osteoclasts, osteoblasts, both or neither?
Just osteoblasts (osteoclasts is indirect thru the blasts)
What cell type makes up more of the bone matrix?
Osteocytes (terminally differentiated from osteoblasts)
What 2 important factors does PTH stimulate the production of? (just name, next questions focus on them)
M-CSF and RANK Ligand (RANK-L)
What does M-CSF stand for and what does it specifically do?
What stimulates its production?
M-CSF: macrophage colony stimulating factor (production stimulated by PTH)
- Stimulates differentiation of osteoclast precursors
(key concept: *PTH stimulate of osteoclasts is indirect!)
What does RANK ligand do?
(stimulated by PTH)
- Leads to maturation of osteoclasts and bone reabsorption
What does osteoprotegerin (OPG) do?
What is its net effect?
Antagonist of RANK-L, leading to less maturation of osteoclasts (therefore less Ca is reabsorbed from bone)
What 2 hormones affect OPG, and how do they affect it?
- Estrogens stimulate OPG (v serum Ca)
- Cortisol inhibits OPG (^ serum Ca)
In the kidney, what gene does PTH stimulate?
What protein does this gene encode?
- CYP1alpha
- 1alpha-hydroxylase
What is the function of 1alpha-hydroxylase?
Converts 25(OH) Vit D -> 1,25(OH)2 Vit D (active form)
Besides stimulating CYP1alpha gene, what else does PTH do in the kidney?
Stimulates Ca reabsorption, reduces Pi reabsorption
In what segments of the kidney does PTH act to increase Ca reabsorption and decrease Pi reabsorption?
PT, TAL, DT
How do PTH act to increase Ca reabsorption in the DT, PT, and TAL?
Inserts Ca channel in apical membrane
At blood [Ca] increases, how does blood [PTH] change?
Decreases
What are the 2 mechanisms by which PTH is regulated?
- Ca-sensing receptors (CaSR)
- Vit. D
Where are CaSR’s located?
What do they bind?
Chief cells, kidney tubules, C cells
- Ca2+
Once CaSR’s bind Ca, what 2 things do they do?
Inhibit PTH synthesis at promoter level and stimulate degradation of pre-existing PTH
What types of receptors do vit D bind?
What is the name of the specific receptor?
Nuclear receptors (they are fat soluble) - VDR
What are is the direct and indirect effect of Vit D binding a VDR?
- Direct: inhibits PTH synthesis at promoter level
- Indirect: Stimulates CaSR gene TS
What’s the general term for vitamin D and other natural structural analogs?
What term specifically refers to vitamin D3 (from animal tissues)?
What about from vegetable tissues?
- Calciferol
- Cholecalciferol
- Ergocaliferol (Vitamin D2, not D3)
What is the term for 25-hydroxy-vitamin D (25-D) = 25-hydroxy-cholecalciferol (immediate precursor)?
Calcidiol
What is the term for 1,25-dihydroxy-vitamin D (1,25-D) = 1,25-dihydroxy-cholecalciferol?
Calcitriol
Vit D3 is derived from:
Cholesterol
What is the active form of vitamin D3?
1,25-dihydroxy-vitamin D or Calcitriol
How is Vit D found in the blood?
Bound to vitamin D-binding protein
What are the 2 ways we can obtain vit D?
From diet or from sunlight, requiring UV-B’s
Where is Vit D from the skin sent to be converted to its active form precursor?
What enzyme is required?
Liver
- 25 Hydroxylase (makes 25-hydroxy Vit D3)
Where is 25-hydroxy Vit D3 finally sent to be converted to its active form?
What enzyme is required?
Kidney
- 1alpha-hydroxylase
If 25-hydroxy D3 isn’t converted to 1,25(OH) vit D3, what it is instead converted to in the “inactive default pw”?
24,25(OH)2-Vit D3
W/r/t Ca and Pi levels, under what conditions would the inactive default pw be used?
- Normocalcemia, hypercalcemia
- Normophophatemia, hyperphosphatemia
(so w/hypocalcemia or hypophosphatemia, the active hormone is synthesized)
What are some dz’s that vit D deficiency is linked to?
- Multiple Sclerosis
- Asthma
- Cardiovascular disease
- Type II Diabetes mellitus
- Colorectal/breast cancer
In terms of organs, what’s the difference b/w targets of PTH and the targets of Vit D?
They both target kidneys and bone, but vit D targets gut as well.
What bone cells have VDRs?
Osteoblasts and osteoclasts (only osteoblasts have PTH R1s)
What are the direct effects of Vit D in bone?
Indirect effects?
- Direct: Mobilize Ca; osteoclast proliferation/differentiation
- Indirect: increases plasma Ca which promotes bone mineralization
(*breaks down old bone at the expense of making new bone)
What are the effects of vit D on the intestines?
- Increases transcellular Ca absorption at duodenum
- Stimulates Pi reabsorption at small intestine (as opposed to PTH, which excretes Pi at kidneys)
What channels are involved w/Ca xport on the luminal and basolateral sides of intestinal cells? (both are stimulated by vit D to mobilize Ca)
What does calcium bind to in cells?
- Luminal: TRPV5/6
- Basolateral: PMCA
- Calbindin
What 2 factors can feed back to negative inhibit PTH production? (slide 40, key slide)
- Active form of Vit D3
- Increased blood Ca2+ (also inhibits CYP1alpha, gene that encodes for enzyme that makes active Vit D3)
What is osteoporosis?
Reduced bone density, mainly trabecular bone
Explain the main causes of osteoporosis.
- Genetic, menopause (low estrogen which stimulates OPG), glucocorticoid therapy/chronic stress (high cortisol which inhibits OPG), low dietary Ca2+
What are tx’s for osteoporosis?
Estrogens, calcitonin, biphosphonates (inhibit bone resorption), Vitamin D
What is the difference b/w primary and secondary hyperparathyroidism?
- Primary: hyperplasia, carcinoma of parathyroid gland
- Secondary: chronic renal failure (because vitamin D is activated by the kidney, so no negative feedback?)
What are some sx of hyperparathyroidism?
Hypercalcemia, kidney stones
How would PTH be affected w/reduced vit D?
Reduced Vitamin D leads to excess PTH synthesis (lack of negative feedback)
What are the major signs/sx of hypoparathyroidism?
Hypocalcemic tetany
Chvostek sign
What is Chvostek sign?
Twitching of facial muscles in response to tapping of facial nerve
Vit D deficiency in children is called ___________, in adults it’s called ___________.
What are the major sx?
- Rickets
- Osteomalacia
- “bowing” of long bones (children); decreased bone strength
What is pseudohypoparathyroidism?
Congenital defect in G protein that associates with PTHR1 (hormone levels are nl)
- Generalized resistance to PTH, TSH, LH, and FSH
What are the signs of pseudohypoparathyroidism?
Low Ca++, high phosphate, elevated PTH, short stature
Low serum calcium and high serum phosphate are normalized by _________ infusion.
PTH
As phosphate excretion increases, tubular reabsorption of phosphate (TRP) _________.
Falls
What is elevated urinary hydroxyproline a marker of?
Enhanced bone resorption
Serum [Ca+2] normal range:
2.2-2.6 mM or 8.8-10.3 mg/100mL (mg/dL)
Serum [phosphate] normal range:
0.8-1.45 mM or 2.4-4.1 mg/100mL (mg/dL)
How would a C cell tumor (calcitonin) affect Ca2+ levels?
Doesn’t effect them
What is the therapeutic use of calcitonin?
What disease is it used to treat?
Inhibits osteoclasts, therefore decreases reabsorption of and slows bone turnover (net effect = hypocalcemic action)
- Paget disease
What is Paget disease?
- Excessive localized regions of bone resorption and reactive sclerosis.
- Very high bone turnover
- Cause is unknown.
What is calcitonin a less effective tx option that we want?
“Escape” phenomenon – rapid downregulation of calcitonin receptors cause the antiosteoclastic actions of calcitonin to diminish within a few hours (so it’s typically given locally)
Positive Chvostek sign could indicate what disease?
Hypoparathyroidism
