Endocrine control of calcium metabolism Flashcards
What is the most abundant metal in the body and the 5th most abundant element?
Calcium is the most abundant metal in the human body (fifth most abundant element).
List 7 roles of calcium in the body?
- Neuromuscular excitability
- Muscle contraction
- Strength in bones
- Intracellular second messenger
- Intracellular co-enzyme
- Hormone/neurotransmitter stimulus-secretion coupling
- Blood coagulation (factor IV)
Where is most of the calcium in the body found and what form is it found in?
- Most calcium is present in the body as calcium salts
- It is mainly found in bone (99%, approx. 1kg) as complex hydrated calcium salt (hydroxyapatite crystals)
- In blood, some is present as ionized calcium (Ca2+), some bound to protein and the tiny bit left as soluble salts
- Only the free (unbound) Ca2+ is bioactive
What is the total amount of calcium in the blood?
approximately 2.5mM
What proportion of calcium in the blood in unbound (ionized), bound to plasma proteins and as diffusable salts?
Most of this calcium is present in the unbound ionised form (1.25 mM/L)
Calcium is present in the blood in DYNAMIC EQUILIBRIUM
The important component that needs to be controlled is the unbound ionised form (bioactive component)
What 4 parts of the body are involved in the calcium handling in the body and why?
GI tract - most calcium is absorbed in the GI tract
It is absorbed into the blood and some of it will get excreted in faece
Kidney- Once in the blood, the calcium can pass to the kidneys which regulates the content of the blood
A lot of the calcium passing into the kidneys will return to the blood - excretion and absorption of Ca2+into the blood
About 150 mg/24h is excreted from the kidneys per day - this maintains equilibrium
Bone- The hydroxyapatite crystals in the bone can be broken down to increase blood calcium levels - depository for calcium
Calcium is also needed for bone strength
Blood- Transport of calcium
Name two main hormones involved in increasing Ca2+ concentration?
Name the main hormone involved in decreasing calcium concentration?
Calcium Ion Regulation
TWO main hormones involved in RAISING blood calcium concentration:
PARATHYROID HORMONE (PTH)
1,25-dihydroxycholecalciferol (or CALCITRIOL)
NOTE: Calcitriol is a steroid and is also called 1,25-dihydroxy vitamin D3 Main
CALCITONIN
This doesn’t seem to have a major effect in the long run
No one really knows the importance of calcitonin
Calcitonin is NOT the main controlling influence on calcium ions
Draw a diagram showing wher PTH and Calcitonin is produced?
Parathyriod glands- Back of thyriod
How are calcium levels sensed in the body?
Where are these receptors primarily found?
The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. It is primarily expressed in the parathyroid gland and the renal tubules of the kidney. In the parathyroid gland, the calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone (PTH).[5] In the kidney it has an inhibitory effect on the reabsorption of calcium, potassium, sodium, and water depending on which segment of the tubule is being activated.
Explain how parathormone (PTH), 1,25-dihydroxycholecaciferol (calcitriol) and calcitonin are synthesised.
Initially synthesised as protein pre-proPTH
What is PTH’s mechanism of action once it has binded onto a receptor?
Binds to transmembrane G-protein linked receptors
Binding of parathormone to the G-protein linked receptor leads to activation of adenylate cyclase (with phospholipase C acting as a second messenger)
PTH is a polypeptide with 84 amino acid
Draw a diagram showing the effects of PTH in the body?
Include kidneys, bone and small intestine
Remeber calcuim is in a dynamic equilibrium with calcium phosphate
PTH stimulates the kidneys to excrete more phosphates- in urine
People used to think that as PTH causes the loss of free phosphates from the kidneys, the equation is no longer in equilibrium so the phosphate salt will dissociate to make amends for the phosphate that has been excreted and so calcium concentration increases secondarily to the replenishment of phosphate levels
We have since found out that PTH actually has direct effects on the calcium in the kidneys
The OVERALL effect is an increase in calcium reabsorption
PTH has another important effect in the kidneys: stimulates the synthesis of 1a HYDROXYLASE
1a Hydroxylase is involved in the synthesis of calcitriol
Calcitriol has an important effect on the small intestines: controls the absorption of calcium and phosphate (increases absorption)
PTH also has an effect on bone:
Stimulates osteoclasts - causes resorption of the bone matrix and release of calcium from hydroxyapatite crystals into the gut
Inhibits osteoblasts
THIS ALL LEADS TO AN INCREASE IN BLOOD CALCIUM CONCENTRATION
In the intestine, via kidney, PTH enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D activation occurs in the kidney. PTH up-regulates 25-hydroxyvitamin D3 1-alpha-hydroxylase, the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). This activated form of vitamin D increases the absorption of calcium (as Ca2+ ions) by the intestine via calbindin.
However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, absorption of both calcium and phosphate is mediated by an increase in activated vitamin D. The absorption of phosphate is not as dependent on vitamin D as is that of calcium. The end result of PTH release is a small net drop in the serum concentration of phosphate.
PTH increases the activity of 1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of vitamin D, in the kidney.
Draw a diagram showing the effect of PTH on blood [Ca2+]?
Include in the diagram kidneys, bone and small intestine
What are the effects of PTH on bone?
Osteoclasts are activated by PTH but NOT directly
PTH works on osteoblasts and inhibits various activities
However, PTH stimulates osteoblasts to produce various OSTEOCLAST ACTIVATING FACTORS (OAFs)
OAFs move to the osteoclasts and stimulates the breakdown of bone matrix to RELEASE CALCIUM
One of the OAFs is called RANKL which links PTH via the osteoblasts to the main target which are the osteoclasts
REMEMBER: PTH binds directly to osteoblasts but has an INDIRECT effect on OSTEOCLASTS
What does PTH cause Osteoblasts to do?
However, PTH stimulates osteoblasts to produce various OSTEOCLAST ACTIVATING FACTORS (OAFs)
OAFs move to the osteoclasts and stimulates the breakdown of bone matrix to RELEASE CALCIUM
One of the OAFs is called RANKL which links PTH via the osteoblasts to the main target which are the osteoclasts
REMEMBER: PTH binds directly to osteoblasts but has an INDIRECT effect on OSTEOCLASTS
How do OSTEOCLAST ACTIVATING FACTORS (OAFs) work?
Osteoclasts are activated by PTH but NOT directly
PTH works on osteoblasts and inhibits various activities
However, PTH stimulates osteoblasts to produce various OSTEOCLAST ACTIVATING FACTORS (OAFs)
OAFs move to the osteoclasts and stimulates the breakdown of bone matrix to RELEASE CALCIUM
One of the OAFs is called RANKL which links PTH via the osteoblasts to the main target which are the osteoclasts
REMEMBER: PTH binds directly to osteoblasts but has an INDIRECT effect on OSTEOCLASTS
An osteoclast (from the Greek words for “bone” (ὀστέον), and “broken” (κλαστός)) is a type of bone cell that breaks down bone tissue.
Draw a diagram showing how PTH is regulated?
Overall effect of PTH: raise calcium ion concentration
PTH stimulates an enzyme that leads to the synthesis of calcitriol
Increased synthesis of calcitriol also leads to increased plasma calcium concentration
The cells in the parathyroid gland which produce PTH respond to changes in plasma calcium concentration - they have calcium ion receptors
These receptors are activated whenever there is a fall plasma calcium concentration
Calcitriol also has a negative feedback effect on PTH
There are Beta Receptors on the cells that produce PTH so they can be stimulated by catecholamines to secrete PTH
What effect does catecholamines have on PTHs secretion?
What type of receptors are found in the parathyroid glands?
Increase Secretion
There are Beta Receptors on the cells that produce PTH so they can be stimulated by catecholamines to secrete PTH
Draw a diagram showing the synthesis of 1,25 (OH)2 VITAMIN D3 (DIHYDROXY- CHOLECALCIFEROL, or CALCITRIOL)
Calcitriol Synthesis
Calcitriol is the other hormone, other than PTH, which causes an increase in plasma calcium concentration
The precursor is CHOLECALCIFEROL
Cholecalciferol has TWO main sources:
Diet
Different types of vitamin D come from the diet (Vitamin D2 = plants and fungi/ Vitamin D3 = meat/milk)
Sunlight
UV B works on the skin
UV B converts 7-dehydrocholesterol to cholecalciferol
REMEMBER THESE TWO IMPORTANT SOURCES OF CHOLECALCIFEROL: DIET and SUNLIGHT
Cholecalciferol is Vitamin D3
Vitamin D3 is a steroid which circulates around the body and is taken up by the liver
The liver has an enzyme called 25-hydroxylase which converts cholecalciferol to 25-hydroxy-cholecalciferol which is then stored in the liver
25-hydroxy-cholecalciferol is stored in the liver but then circulates from the liver and reaches the kidneys where you find 1a hydroxylase (which is stimulated by PTH)
1a hydroxylase is responsible for the conversion of 25-hydroxy-cholecalciferol to 1,25-dihydroxy-cholecalciferol (calcitriol)
What are the actions of Calcitriol?
Main action is on the SMALL INTESTINE: stimulates calcium and phosphate absorption (through separate pathways)
It has minor effect on bone - it stimulates osteoblast activity (secondary effect of raising the plasma calcium concentration - by raising the calcium level in the blood, the calcium is there to be stored (e.g. in the bone))
Kidneys - calcitriol increases calcium reabsorption and phosphate reabsorption
State how PTH effects phosphate reabsorption in kidney cells?
State how Calcitriol effects phosphate reabsorption in kidney cells?
Draw a diagram
On the apical membrane there are transporters for the phosphate ions
PTH inhibits this transporter so phosphate will NOT be reabsorbed so it will be excreted in the urine
Calcitriol also has an effect on phosphate reabsorption
Through the FGF23 (fibroblast growth factor 23 (from osteocytes)) molecule, calcitriol can block the phosphate transporter
So PTH and Calcitriol (via FGF23) inhibit phosphate reabsorption in the kidneys
Fibroblast growth factor 23 or FGF23 is a protein that in humans is encoded by the FGF23gene.[5] FGF23 is a member of the fibroblast growth factor (FGF) family which is responsible for phosphate and vitamin D metabolism
Fibroblast growth factor 23 (FGF-23) is a phosphaturic hormone produced in bone
What type of receptor does calcitonin act on and what happens when it binds to that receptor?
Synthesised as pre-procalcitonin
Calcitonin is a 32 amino acid polypeptide
Calcitonin acts via transmembrane G-protein linked receptors
Activation of adenyl cyclase or phospholipase C as second messenger systems
State the effects of calcitonin?
State how it effects bone and kidney
What substance causes calcitonin levels to increase?
Calcitonin works on bone and inhibits osteoclast activity - thus decreasing the release of calcium from bone into the blood
Calcitonin also affects the kidneys: increases the excretion of sodium ions which, in turn, an increase in the urinary excretion of calcium and phosphate ions
The effects of calcitonin are relatively small and short-lived
Physiological benefit:
Plasma calcium levels are raised in PREGNANCY when you need more calcium ions (e.g. in milk)
Calcitonin protects the bone from being broken down to provide calcium
Calcitonin is stimulated by an increase in plasma calcium concentration and its overall effect is to decrease plasma calcium ion concentration
Draw a diagram showing the regulation and effects of calcitonin?
Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility.
list 3 ENDOCRINE CAUSES OF HYPOCALCAEMIA?
Hypoparathyroidism (insufficient PTH)
Pseudohypoparathyroidism (associated with resistance to PTH)
Vitamin D Deficiency
What are the two signs of hypocalcaemia?
State how you would cause the patients to show these signs?
Hypocalcaemia
Hypocalcaemia can be shown in TWO ways:
Trousseau’s Sign (main d’accoucheur)
Put slight pressure on the arm and the hand can go into contraction
Chvostek’s Sign
Tap the facial nerve at the angle of the jaw you get the muscles to contract
These are both forms of TETANY
Tetany is the bad news associated with hypocalcaemia
What is PSEUDOHYPOPARATHYROIDISM
What is psuefohypoparathyroidism also known as?
•Also known as
ALLBRIGHT HEREDITARY OSTEODYSTROPHY
target organ resistance to PTH (multiple underlying causes). Believed due to defective Gs protein (needed to increase cAMP intracellularly in response to PTH receptor activation
List 4 features of psuedohypoparathyroidism?
•Features include
– particular physical appearance (short stature, round face)
– low IQ
– subcutaneous calcification and various bone abnormalities (e.g. shortening of metacarpals)
– associated endocrine disorders (e.g. hypothyroidism, hypogonadism).
Pseudohypoparathyroidism
There is a very abnormal 4th metacarpal
If you give someone PTH, you get an increase in urinary excretion of cAMP - this is what you’d expect in a normal person
In people with idiopathic hypoparathyroidism and surgical hypoparathyroidism you get normal results because their target cells are still sensitive to PTH
Pseudohypoparathyroidism you get no change because of target resistance to PTH
What is Vitamen D deficiency known as in children and what is it known as in adults?
- Rickets in children
- Osteomalacia in adults
What are the clinical features of Vitamen D deficiency?
•Clinical feature is the decreased calcification of bone matrix resulting in softening of bone
® bowing of bones in children
® fractures in adults
How would you differentiate between
- HYPOPARATHYROIDISM
- PSEUDO- HYPOPARATHYROIDISM
- VITAMIN D DEFICIENCY
Hint: PTH, Plasma Ca2+, Plasma P04
In the kidneys, PTH increases the excretion of phosphate thereby reducing the blood plasma concentration so in hypoparathyroidism you get an increase in plasma phosphate concentration because PTH isn’t stimulating the excretion of phosphate from the kidneys
Pseudohypoparathyroidism - the parathyroid glands are producing sufficient PTH so PTH levels are normal but the target organs are resistant to PTH and hence plasma calcium ion concentration is low
Vitamin D Deficiency - phosphate levels are low, plasma calcium concentration is normal and PTH is normal
List 3 ENDOCRINE CAUSES OF HYPERCALCAEMIA
Primary Hyperparathyroidism
Tertiary Hyperparathyroidism
Vitamin D Toxicosis
What is Primary Hyperparathyroidism?
State what conditio can cause this?
Primary Hyperparathyroidism - a tumour in the parathyroid causes a large increase in PTH secretion
Because it is a tumour it is unlikely to be regulated by the normal negative feedback - it will continue to produce large amounts of PTH leading to an increased plasma calcium ion concentration
What is secondary hyperparathyroidism?
State what condition can cause this?
Secondary Hyperparathyroidism
Some people have low plasma calcium concentration for a variety of other reasons such as renal failure
Renail failure leads to loss of calcium in the urine which will stimulate the parathyroid to release PTH which will do its best to maintain the plasma calcium ion level
What is tertiary hyperparathyroidism?
Tertiary Hyperparathyroidism
Initial chronic low plasma calcium ion concentration
The parathyroid gland is being massively stimulated for a long time
Eventually, the PTH becomes autonomous and it stops responding to the negative feedback
This is similar to primary hyperparathyroidism as it causes an increased plasma calcium ion level
PRIMARY and TERTIARY hyperparathyroidism are associated with HYPERCALCAEMIA
Sate what causes primary, secondary and tertairy hyperparathyroidism?
How does hyperparathyroidism effect your fingers?
What effect does excess parathyroidehormone have on kidneys, GI tract and Bone?
