Calcium lecture Flashcards
How much calcium is located in the bone?
99%
How much of the calcium in our bone is exchangeable with extracellular fluid calcium?
1%
How much of the calcium found in our blood is bound to protein? Which proteins can it bind to and what percentage binds to each protein?
50% protein bound 40%- albumin 10% globulin
Which form of calcium is biologically active in the blood? What percentage of total blood calcium does it account for?
Ionised calcium is biologically active 40% of ionsied calcium is foujd in the blood
What happens to ionised calcium levels in an acidic or alkalotic state? (respiratory)
Acidic- ionised calcium levels increase in plasma as less calcium is bound to albumin
Alkalosis- Plasma calcium levels decrease as more calcium is bound to albumin as H+ dissociates from albumin
During respiratory alkalosis caused by hyperventilation the patients lips can tingle, why does this occure?
mild hypocalcemia Small drop in calcium levels
List the 4 different mechanisms in which calcium acts as a signalling molecule
nerve and muscle automaticity muscle contraction neurotransmitter release1 endocrine/exocrine secretion
Where is most calcium found, intracellularly or extracellularly?
extracellularly
Where is most intracellular calcium found?
Mitochondria
What is the effect of hyper and hypo calcemia on action potentials in muscles and nerves?
Hypocalcemia- increases membrane permeability to sodium, therefore reducing the threshold potential for action potentials to fire in nerve and muscle Hyper- reduces the membrane potential permeability to sodium
State what happens in each of the numberd stages in this image of the cardiac action potential
4 – resting membrane, negative potential maintained by Na/K exchanger – 3 Na for 2 K
0- Opening of fast sodium channels – these channels are stabilised by extracellular calcium
1 – Early repolarisation as fast sodium channels close
2 - plateau phase: Na-Ca exchanger: Na in and calcium out, maintains positive potential
- Repolarisation – sodium and calcium channels close
What percentage of phosphate is found mineralised in bone?
85%
State the respective functions of extracellular and intracellular calcium
Intracellular- Signalling molecule for nerve and muscle automaticity; muscle contraction; neurotransmitter releas; endocrine/exocrine secretion
Extracellular- Main substrate for mineralisation of cartilage and bone
Cofactor for the enzymes of the coagulation cascadeIntracellular
Membrane excitablility
State the respective functions of extracellular and intracellular phosphate
Extracellular- Mine mineral
Intracellular- Structural
High energy bonds
Phosphorylation
How does the parathyroid cells sense and regulate calcium concentration?
Parathyroid hormone cheif cells have a calcium sensing recpetor. If calcium levels rise this will be sensed by the receptor and will turn of the release of PTH.
If calcium concentration is low the receptor is not activated and PTH release continues.
Which organ systems are targeted by the parathyroid hormone to increase the concentration of calcium and what effect does it have on each system?
Increases blood calcium concentration
- (KIDNEYS) Stimulates production of the biologically-active form of vitamin D (1,25 hydroxy vitamin D) within the kidney. Maximizes tubular reabsorption of calcium within the kidney. so So less calcium in urine. There will be increases excretion of phosphate
- (GUT) Active Vitamin D causes increased absorption of calcium (and phosphate) from the small intestine
- (BONE) Increased bone reabsorbtion of calcium and phosphate
How does the body obtain vitamin D?
Where is the Vitamin D stored?
When the vitamin D is needed what happens?
Sunlight absorbed by the skin
Fat cells
When vitamin D is needed hydroxylation occurs in the liver and kidneys turn the stored vitamin D into the active form called calcitriol
How does vitamin D increase calcium concentration in the blood? 2 methods
- facilitates the absorption of calcium from the small intestine
- enhances fluxes of calcium out of bone
Where is calcitonin made? What effect does it have on wthe body?
Made in the parafollicluar cells of the thyroid gland
Causes a reduction in the circulating levels of calcium. Secreted in responce to hypercalcemia
How does calcitonin reduce the concentration
In which biological molecules will you find phospahte?
In DNA and neucleotides
In signalling molecules such as ATP,AMP,ADP
What are the two main electrolytes which make up the bony matrix?
Calcium
Phosphate
If the kidneys are working and parathyroid hormone is acting to increase the concentration of calcium, would the concetration of phosphate be high or low? Explain why.
The concentration of phosphate will be low. This because in all the organ systems targeted by the parathyroid hormone to increase the concentration of calcium (gut, bone, kidney). The kidney is the only system which causes a reduction in the concentration of phsosphate. If the kidneys are working there action will “always win” and dominate so phosphate concentration will be low due to excretion from the kidneys as calcium is being reabsorbed in the tubules. This is becayse PTH inhibits NaPi transporters
This also applies if there is too little PTH. Calcium will fall and phosphate will rise.
Which condition can cause an abnormal increase in the concentration of vitamin D and how?
Granuloma dieases such as TB and sarcoid.
These produce the active form of vitamin D 1,25 Vitamine D
Which scan is used to detect abnormalities in the parathyroid gland?
Technetium-sestamibi scintigraphy
How is the parathyrioid processed and produced?
It starts off large and is broken down
PreproPTH is converted into proPTH in the rough ER. pro PTH is converted into PTH in the golgi apparatus before being stored in vesicles.
Where is the active part of the parathyroid hormone located?
N-terminal
What type of hormone is the parathyroid hormone?
Polypeptide hormone
What type of receptor is the calcium sensing receptor?
G-protein coupled receptor
List 3 actions of the calcium sensing receptor on parathyroid hormone
- Reduces PTH secretion
- Increases breakdown of stored PTH
- Suppresses transcription of PTH gene
Restrains parathyroid proliferation
Which condition is caused by an inactivating mutation of the calcium sensing receptor? What are the symptoms of this condition
Familial hypocalciuric hypercalcemia
Symptoms- chronically elevated serum calcium and reduced calcium excretion
-Elevated plasma parathyroid hormone (PTH) concentration
What is ?
What effect does activated vitamin D, phosphate and Cinacalcet have on parathyroid hormone?
A drug which mimics the effect of calcium so it allosterically activates calcium sensing receptors.
Activated vitamin D- Surpresses PTH gene trasncription
Cinacalcet- Activates the calcium sensing receptor and reduces calcium levels
Where in the kidneys is most calcium absorbed? What percentage is absorbed here and which mechanism is used?
Proximal tubueles
65%
PTH independant, paracellualr, driven by voltage gradient
Where in the kidneys are calcium receptors located? What function do they play in the control of calcium concentration?
They are located in the loop of henley
They down regulate NaK2Cl
This activtes the Ca and 3NA channel which increase calcium rebasorbtion
Where in the kidneys do loop diurectics act? Which channel do the act on and what effecr does this have on calcium concentration.
Loop of henly
Inhibits NaK2Cl
Inhibuits sodium, chloride and potassium reabsorption by competing for chloride binding site. This activates the Ca and 3NA channel
decreases calcium concentration as it is lost in urine
What percentage of
What percentage of calcium is rebasorbed in the loop of henley? Where else outside of the proxima tubules can calcium be reabsorbed? What pertentage is reabsorbed here
20%
Distale tubule (10%)
Where in the kidneys does the PTH hormone act to increase calium reabsorbtion? What are the effects of its activity?
Distal tubules
- PTH upregulates:
- TRPV calcium channels
- Calcium ATPase
- Na/Ca exchanger
What are the two main components of bone?
Collagen and Hydroxyapatite
Hydroxyapatite is composed of the mineleraisation aspects of bone- calcium + phosphate + alkaline phosphatase
Describe the function of osteoblasts. Include how they change after conducting said function
Osteoblasts produce mineral AND signal to osteoclasts to resorb bone. When mineralisation is complete they differentiate into osteocyte, encased in mineralized bone *but* maintain connections with other osteoblasts in an extended syncytium. Osteocytes have a role in sensation of bone deformation.
Parathyroid hormone can activate both bone resrbtion and bone formation. Describe the ways it can be clinically administered to encite either responce and which condition it would be used to treat?
A subcutaneouse bolus = bone formation
Treatment- osteoperosis
Continuouse infusion = bone resorbtion and increase in serum calcium.
Treatement- hypoparathyroidism
Which molecules actiavte and inhibit osteoclastogenesis? How are they regulated?
RANKL activates osteoclastogenesis and is produced by osteoblasts and mesenchymal cells.
Its production is stimulated by PTH and calcitriol
OPG: osteoprotegerin- Inhibits osteoclastogenesis. It is released by mesenchymal cells.
PTH and calcitriol downregulate OPG
Which condictions are caused by a vitamin D deficiency?
Rickets and osteomalasia (soft bones), osteoperosis (britle bones)
due to defective mineralisation
List 4 radiological findings for someone with primary hyperparathyroidism
Terminal tuft erosion (finger tip bones get fussy) and rugger jersy spine
Subperiostal erosion and brown tumour (alot of remodelling leading to a tomour like appearance)
Which hormone aids in the closure of epiphyseal plates?
What other effect does it have on the bone?
Estrogen
Inhibits bone remodelling
How is vitamin D made?
7-dehydrocholesterol is cleaved under the influence of UV radiation to previtamin D
This isomerises to vitamin D over a period of 48 hours
Why does prolonged sun exposre not cause vitamin D intoxication and hypercalcemia?
It is further isomerised to luminosterol and tachysterol
pigmentation limits the UV penetration
What does vitamin D bind to in circulation?
Albumin and vitamin D binding protein
What is the active form of vitamin D, what is it produced from? Where is it converted into this form and which enzyme catalyzes this conversion?
25 (OH)D to 1,25(OH)D
Proximal tubules
p450 enzyme- 1-alpha hydroxylase
Where are vitamin D receptors located? What is the negative feedback inhibition which occurs when vitamin D binds to its receptor?
Nucleus and brain
VDR inhibits the action of 1α hydroxylase, therefore reducing the amount of activated vitamin D able to bind to the VDR.
What upregulates and down regulates 1α hydroxylase activity?
Upregulation- Parathyroid hormone
Downregulation- Vitamin D receptor activation
Which immune cell can produce vitmain D? What does it use it from?
In which conditions will you find macrophages producing vitamin D? What can this lead to?
Activated Macrophages
Increases its cytotoxicity
TB and sacoid granulomata.
This is why these conditsions can lead to hypercalcemia
Vitamin D production is not regulated
What is the main role of Calcitriol?
Increases gut calcium and phosphate absorption
Which other factors apart from calcitriol determine calcium absorbtion?
Presence of bile salts, free fatty acids, dietry fiber and gastric acidity
Which drug inhibits calcium uptake?
Proton pump inhibitors - omeprazol
List the 3 routes which can be used by Vitamin D to cross enterocytes?
transcellular, paracellular and vesicular routes
What effect does vitamin D have on the parathyroid, bone, phosphate and amino acids?
- Parathyroid: modest reduction in PTH transcription
- Bone: reduces expression of type 1 collagen; increases levels of osteocalcin & RANKL; facilitates osteoclast differentiation
- Increases phosphate absorption from the gut AND increases levels of FGF23 to remove it via renal excretion
- Increases amino acid uptake: deficiency à myopathy
In cushings syndrome can cause myopathy and low bone desnity, how does it accomplish this?
Cushings syndrome is caued by excess glucocorticoids. Glucocorticoid reduces the expression of the vitamin D receptor. Not enough vitamin D can lead to defective mineralisation.
What is FGF 23? What is its function?
a phosphatonin - hormone that reduces serum phosphate levels
There are 2 main medical conditions which can lead to an excess of FGF23, what are they? What is the effect of excess FGF23
A tumour which secretes too much FGF23 (paraneoplastic FGF23) resulting in Tumour induced osteomalacia
- An autosomal dominant activating muation of FGF23. This can lead to too little phosphate causing rickets (hypophosphataemic rickets)
Which condition is caused by low levels of FGF23?
Familial tumoral calcinosis
condition characterized by an increase in the levels of phosphate in the blood (hyperphosphatemia) and abnormal deposits of phosphate and calcium (calcinosis) in the body’s tissues.
What is the physiological role of parathyroid hormone related pepetide? Whcih pathological condiatio can it cause?
Lactation -
Hypercalcemia of malignancy
What pathological condition can calcitonin cause?
Medullary thyroid cancer
What is the primary and secondary cause of hyperthyroidism?
Primary- Parathyroid adenoma, carcinoma and hyperplasia
Secondary- Physiological compensation for hypocalcemia or Vitamin D deficiency
What are the symptoms of hyperparathyroidism?
Polyuria and polydipsia
Kidney stones
Osteoporosis
Mood disorder
Which diagnostic tests would you use for someone with suspected hyperparathyroidism?
a) Serum calcium and PTH
a) 24 hr urine calcium (will bebhigh)
a) Urine calcium creatinine excretion index (used to rule out FHH- Familial hypocalciuric hypercalcemia)
a) Renal ultrasound- looks for signs of nephrocalcinosis, which is an indication for surgical treatment
DXA scan- looks for osteoporosis,
Thyoid localisation using a ultrasound and a sestaMIBI scan
Signs and symptoms of hypocalcemia
Convulsions
Confusion
Tetany
Tachyarrhythmia
List 4 causes of hypoparathyroidism
•Hypoparathyroidism
–Iatrogenic
–Autoimmune
–Genetic
- Vitamin D deficiency
- Chronic kidney disease
- PTH resistance
How is hypothyroidism treated? Acutly and chronically
Acutely- IV or oral calcium replacement
alfacalcidol (1,25 vitamin D3) orally – this will increase gut absorption of calcium. However, the lack of PTH means that calcium will continue to be lost from the kidneys at a high rate.
continuous subcutaneous infusions of PTH, given via an insulin pump.
How can a high and a low PTH lead to kidney stones?
Kicndey stones from high PTH- urine calcium which crysilises can cause kidneys stones
Low pTH- reduced ability to rebasorbe calcium from unine so urine calcium is high
