Regulation of Calcium and Phosphate

Question 1

How do we get calcium in our body and why is calcium important?

What is biologically active Ca²⁺?

Why is phosphate important?

Which 2 hormones regulate Ca²⁺ and PO₄^3-?

Answer 1

Most important metal in the body, acquired via the diet - important for bone strength, muscle contraction, as a second messenger, intracellular co-enzyme, hormone/NT, blood coagulation (factor IV)

The Ca²⁺ that is not bound to other plasma proteins e.g. albumin

Part of high energy compounds e.g. ATP, makes up DNA and RNA

The same hormones - active vitamin D (calcitriol) and PTH

Question 2

What are the 3 key hormones involved in calcium regulation? Which are the 2 that are critical?

Which 2 hormones increase Ca²⁺ and where do they act?

Which hormone decreases calcium?

Answer 2

Parathyroid hormone (PTH), Vitamin D, and calcitonin - calcitonin even if removed does not cause calcium imbalance (so not necessary for calcium regulation)

Parathyroid hormone and vitamin D - act via kidney, bone and gut

Calcitonin (not critical)

Question 3

What are the 2 different sources of Vitamin D and how are they different?

Answer 3

The are different structurally as they come from 2 different places: take in via our diet - D₂ (ergocalciferol); make it through the skin using sunshine - D₃ (cholecalciferol)

Question 4

What is the name of the active form of vitamin D?

How is active Vitamin D made using sunshine / via the diet?

Answer 4

Calcitriol

1. UVB light shines on the skin
2. Precursor = 7-dehydrocholestrol, UVB triggers series of reactions to produce pre-vitamin D₃, then eventually D₃ in the skin
3. D₂ comes from the diet
4. Both, D₂ and D₃ get transported into liver
5. In the liver, the first step for the production of calcitriol = 25-hydroxylase converts D₃ and D₂ to 25(OH)cholecalciferol (inactive) by hydroxylating the 25th position
6. Travels to the kidney, where 1-alphahydroxylase acts on 25(OH)cholecalciferol, to form 1,25-(OH)₂ cholecalciferol (active form) - also known as calcitriol

So basically requires 2 hydroxylation steps overall to produce calciltriol

Question 5

How do we measure Ca²⁺ levels in a patient? And why?

What is the negative feedback from calcetriol?

Answer 5

We measure 25(OH) cholecalciferol - the inactive version, this stored vitamin D is a good marker of how much Vit D is present in a person. Calcitriol, the active version, is not measured because it is too difficult to measure, the tube must be wrapped in tin foil as it is light sensitive, etc.

Calcitriol regulates it’s own synthesis by decreasing transcription of 1-alphahydroxlase

Question 6

What does active Vitamin D / calcitriol do?

Answer 6

Acts on the kidney - increases Ca²⁺ and PO₄^3- re-absorption, less lost via urine, therefore increases in the blood. Also works in the gut to increase Ca²⁺ and PO₄^3-absorption, so more circulates in the bloodstream. Calcitriol also has positive effects on bone, stimulates e.g. increased osteoblast activity = making new bones cells, bone mineralisation, improves bone health

Question 7

What is PTH (parathyroid hormone)? Where does it come from and what precursor is it made from?

What is the relationship between serum Ca²⁺ levels and PTH?

What does PTH do?

Answer 7

{Note: PTH is all about Ca²⁺, nothing to do with thyroid hormone}

It is a peptide hormone - comes from chief cells found in the parathyroid glands, which sit at the back of the thyroid glands - made from a long precursor called pre-pro-PTH, and is chopped up (cleaved) to form PTH

PTH is inversely proportional to serum Ca²⁺ levels (amount of Ca²⁺ in circulation) - PTH decreases when Ca²⁺ increases (and vice versa)

PTH drives Ca²⁺ levels to increase, and when they do, PTH switches off

Question 8

How does PTH work to reduce Ca²⁺ levels?

What type of receptor are the calcium sensing receptors?

Answer 8

When there is an increase in the ECF [Ca²⁺] (extracellular fluid Ca²⁺ concentration), the Ca²⁺ binds to calcium sensing receptors on the parathyroid cells to stop PTH production - and vice versa

G-protein receptors

Question 9

On which 3 structures does PTH act on to increase serum Ca²⁺ levels?

How does PTH sitmulate action in each of these 3 areas?

What’s the difference between osteoblast and osteoclast?

Answer 9

Kidney - PTH increases serum Ca²⁺ by increasing Ca²⁺ absorption from the kidney, so less lost in the urine results in more Ca²⁺ in the bloodstream. It stimulates an increase in the excretion of PO₄^3- too. It also stimulates an increase in 1-alphahydroxylase activity, which results in a greater formation of calcitriol (active Vit. D) = indirect effects, increasing calcitriol production = more absorption of Ca²⁺ and PO₄^3- in the gut

Gut - increased calcitriol production from kidneys = more absorption of Ca²⁺ and PO₄^3- in the gut

Bone - Increases osteoclast activity = increased resorption of Ca²⁺ i.e. bone tissues broken down to release minerals such as Ca²⁺ into the blood

Both types of bone cells, but osteoBlast = Builds bone, osteoClast = Consumes bone

Question 10

Recap: Explain how PTH acts on the 3 different structures to increase plasma / serum Ca²⁺ levels?

Answer 10

Question 11

What is the mechanism of PTH action in bone?

Answer 11

osteoBlast - Build bone

osteoClast - Consume bone

PTH acts on bones, by switching blasts to clasts = when PTH binds to receptor on osteoblast, it triggers activating factors to convert the osteoblast to an osteoclast, which results in bone resorption (bone tissue broken down, releasing Ca²⁺)

Question 12

What are the negative feedback loops? (Calcitriol and PTH)

What are the 2 ways to switch off PTH production?

Answer 12

Calcitriol - acts on the enzyme that made it, decreases 1-alphahydroxylase activity so less calcitriol is produced

As Ca²⁺ falls, less binding of Ca²⁺ to the parathyroid glands, more PTH released, 3 ways PTH increases serum Ca²⁺: kidney, bone and gut

Negative feedback via Ca²⁺ and negative feedback via calcitriol:

1. Less PTH produced in response to the increase in Ca²⁺ itself, more Ca²⁺ binds to calcium sensing receptors in the PT gland, stimulates a decrease in PTH production
2. PT glands have calcetriol receptors on them, so when PTH stimulates 1-alphahydroxylase activity resulting in more calcitriol production, this is detected by the celcitriol receptors in the PT glands to decrease PTH production

Question 13

Which cells are to do with calcetonin secretion?

How critical is calcetonin in the body?

How does calcetonin act?

Answer 13

Parafollicular cells in the thyroid gland

Not very

Reduces serum Ca²⁺ levels - promotes excretion from the gut, and reducing osteoclast activity so less Ca²⁺ comsumption from the bone

Question 14

Which hormone is responsible for reabsorption of PO₄^3- in the gut?

How is serum phosphate regulated?

How does PTH work on PO₄^3-?

What is the purpose of FGF23? What are its 2 mechanisms?

Answer 14

Calcitriol

PTH and FGF23

Normally PO₄^3- is reabsorbed in the urine, unless it is reabsorbed by the Na⁺/PO₄^3- cotransporter. PTH inhibits PO₄^3- reabsorption in the kidneys by inhibiting the Na⁺/PO₄^3- cotransporter so more PO₄^3- is peed out - this lowers serum PO₄^3- levels

FGF23 is made by another type of bone cell, osteocytes, and is involved in PO₄^3- regulation. It works by inhibiting PO₄^3- reabsorption - 1. also inhibits Na⁺/PO₄^3- cotransporter in the kidney so more PO₄^3- is excreted, and 2. inhibits calcetriol production (so less PO₄^3- reabsorption from the gut)

Question 15

What is the name given to high serum Ca²⁺? And low serum Ca²⁺?

How does high extracellular Ca²⁺ affect the NS?

How does low extracellular Ca²⁺ affect the NS?

Answer 15

Hypercalcaemia = high serum Ca²⁺, hypocalcaemia = low serum Ca²⁺

Lots of Ca²⁺ in the way, so Ca²⁺ blocks Na⁺ influx - less Na⁺ can get in across the cell membrane = less membrane excitability

Enables greater Na+ influx = more membrane excitability (more opportunity for Na+ to get across membrane)

Question 16

What are the signs and symptoms of hypocalcaemia?

What is the mneumonic for this to help remember these symptoms?

What serum levels should be monitored after a thyroidectomy?

What is Chvostek’s sign and how to test for Chvostek’s sign?

Answer 16

The increased NS excitability can lead to: arrythmias, convulsions / seizures, parasthesia (pins and needles), tetany (contracting muscles that afterwards cannot relax)

CATs go numb (convulsions, arrythmias, tetany - parasthesia)

After the thyroid gland surgery, monitor Ca²⁺ levels incase PTGs have been damaged

Twitching of the facial muscles (usually due to neuromuscular irritability due to hypocalcaemia) - tested for by tapping the facial nerve found under the zygomatic arch (cheekbone) - postive result = twitching

Question 17

What is Trouseau’s sign? How can this be tested for clinically?

Answer 17

Also a sign of hypocalcaemia: shows tetany - irritable membranes = muscle contracts but cannot relax muscles

Inflation of BP cuff for several minutes, which induces carpopedal spasms (tetany)

Question 18

What are the causes of hypocalcaemia?

Answer 18

Causes are likely to be due to poor regulation of serum Ca²⁺ levels, e.g.

Low PTH levels = hypoparathyroidism, which can arise from: damaged neck from surgery, autoimmune destruction of the PT gland or thyroid etc., Mg deficiency (needed for PTH to work), congenital i.e. born with in (agenesis, rare)

or Vitamin D deficiency

Both leading to low serum Ca2⁺ levels

Question 19

What are some causes of Vitamin D deficiency? Use the diagram to find areas in the pathway for calcitriol production and action that could be damaged to stop Ca²⁺ regulation

Answer 19

Lack of UVB light, lack of D₂ in diet, issues with asorption in the gut e.g. coeliac disease, liver disease (first hydroxylation step cannot take place), renal disease (2nd hydroxylation step cannot take place), Vitamin D receptor defects (v. rare)

Question 20

What are some consequences of Vitamin D deficiency?

Answer 20

Lack of bone mineralisation, which in children = bendy bones (rickets) due to lack of ability to support growing weight

In adults = osteomalacia (increased risk of fractures), proximal myopathy (unhappy muscles = muscle weakness)

Question 21

What are the signs and symptoms of hypercalcaemia?

Mneumonic?

Answer 21

High ECF [Ca²⁺] results in reduced neuronal excitability = atonal muscles (floppy muscles, not of regular strength)

Stones - renal effects include kidney stones and renal colic (a pain as a result of expelling a calcium kidney stone via urethra)

Abdominal moans - high Ca²⁺ can make a person feel very sick and therefore can have strong GI effects, such as nausea, heartburn, constipation (due to gut becoming an atonal muscle), predispose to pancreatitis

Psychic groans - negative brain function effects / CNS effects, such as fatigue, depression, impaired concentration, low mood, can result in a coma (w/ v. high Ca²⁺)

Stones, abdominal moans, and psychic groans

Question 22

What are the causes of hypercalcaemia?

Answer 22

Usually a result of poor Ca²⁺ regulation - so an issue with calcitriol or PTH

Primary hyperparathyroidism = too much PTH production, usually due to PT gland adenoma (tumour) = negative feedback loop non-functioning

Malignancy = bone metastases = osteoclasts switched on permanently, so more bone broken down to produce Ca²⁺

Some cancers may release molecules that mimic PTH, such as PTH related peptide = acts on PTH receptors

Vitamin D excess (v. rare)