L17: Parathyroid gland: Calcium and Phosphate regulation

Question 1

What is calcium?

Answer 1

Important metal ion

Question 2

How much calcium is found in the human body? Where is it stored?

Answer 2

Adult- 1000g

99% stored in bone in form of hydroxyapatite crystals (Ca10(PO4)6(OH)2)

Question 3

How much calcium is exchanged between the bone and ECF each day?

Answer 3

300-600mg calcium exchanged between bone and ECF each day

Question 4

How much calcium do we need to eat each day?

Answer 4

1000mg

Question 5

What does the skeleton provide?

Answer 5

Structural support
Major reserve of calcium
Buffer serum levels
Releases calcium phosphate into the interstitium 
Up taking of calcium phosphate

Question 6

How does the calcium exist in the plasma?

Answer 6

50% ionised calcium–> biologically active form
10% complexed with lower molecular weight anions
40% Associated with serum protiens (albumin)

Question 7

What organs have an effect on total calcium in the body?

Answer 7

Dietary calcium approx 800-1200mg a day
Intestine absorb 500mg/day but remove 325mg= net 175mg
Bone- Calcium deposition–. 280mg/day matched by resorption
Kidney filter 10,000 mg and absorb 9825mg/day

Question 8

What is calcium needed for?

Answer 8

Bones--> builds and maintains- Hydroxyapaptite
Heart rhythm regulation 
Passage of nutrients into and out of cells 
Maintain nerve and muscle function 
Blood clotting (factor IV)
Transmission at NMJ
Intracellular signalling 
Lower blood pressure 
Activity of some enzymes
Reduces cholesterol 
Reduces some types of colon cancer

Question 9

How are calcium and phosphate regulated?

Answer 9

Three hormones

• -> Parathyroid hormone (PTH)
• -> Calcitriol (1,25(OH)2D)–> many different names
• -> Calcitonin

Question 10

What glands are they important in calcium regulation?

Answer 10

Parathyroid

Thyroid

Question 11

Where is the parathyroid gland located?

Answer 11

Posterior surface of the thyroid gland
Two pair of 2 glands
Either side of isthmus of thyroid

Question 12

Where is the thyroid gland located?

Answer 12

Anterior to trachea
3/4 cricoid cartilage down
Butterfly shaped–> 2 lobes connected by isthmus

Question 13

What is the structure of the parathyroid gland?

Answer 13

Capsule
Two cell types:
–> Chief cells –> secrete PTH
–> Oxyphil cells–> unknown function potential chief cell remenant

Question 14

Describe the structure of PTH?

Answer 14

Simple straight chain polypeptide
Pre-pro-hormone 115AA long cleaved to 84AA
No serum binding protein required for transport

Question 15

How is the synthesis of PTH regulated?

Answer 15

Synthesis regulated at transcriptional and post transcriptional level by serum calcium
PTH marginated to cell surface, held there until stimulated to be released
High Ca2+–> down regulates transcription
–> PTH produced is degraded
Low Ca2+–> up regulates transcription
Low Ca2+–> prolongues survival of mRNA–>

Released to help increase Ca2+ levels

Question 16

How long does PTH last in the plasma? What does this mean?

Answer 16

T1/2= 4 mins
Short half life–> responds quickly, fast acting
PTH cleaved in the liver
Little stored

Question 17

How does Ca2+ work on parathyroid cells to control PTH secretion?

Answer 17

Low Ca2+ in plasma–> less binding to Ca2+ receptor which is a G protein–> inhibiting the activation of PLA2 meaning PTH released
High Ca2+ in plasma–> bind to Ca2+ receptor on chief cell–> Gq activated–> PLC–> PIP2–> IP3–> increases Ca2+ into cell from ER–> activates PLA2 which inhibits PTH release

Question 18

What is the target for PTH?

Answer 18

Bone–> Increase resorption–> release Ca2+
Kidney–> Increase Ca2+ resorption
GI–> Activate Vit D and increase transceullar uptake from GI tract

Question 19

How is calcium stored within bone?

Answer 19

Hydroxyapatite crystals (Ca2+ + Pi) in collagen fibrils 
Osteoblast produce bone matrix --> mineralised by hydroxyapatite to make it hard

Question 20

How does PTH act on bone?

Answer 20

Increases Osteolysis of bone

• PTH stimulates osteoblastic cells to synthesis and secrete cytokines
• Cytokines stimulate differentiation–> osteoclast
• Osteoclasts resorb mineralised bone and release Pi (inorganic phosphate) and Ca2+ into plasma

Question 21

What does PTH do in the GI tract?

Answer 21

PTH stimulates the synthesis of Vit D (1,25(OH)2D) from vitamin D3 (cholecalciferol)

Question 22

How is Vitamin D (calcitriol) synthesised?

Answer 22

Vitamin D3–> from sunlight, food and supplements biologically inert
Liver–> Hydroxylated to 25(OH)D pre-hormone substrate
Kidney–> Hydroxylated to calcitriol 1,25(OH)2D (calcitriol)

Question 23

How does Calcitriol increase Ca2+ resorption?

Answer 23

GI- ↑ rate of and efficiency of mechanism of Ca2+ uptake in gut
–> Na+/Ca2+ ATPase exchanger on basolateral surface
–> Transcellular transport
–> Endocytosis and Exocytosis of Ca2+ and Ca2+CaBP complex (CaBP- calcium binding proteins)
In bone–> increase bone breakdown via osteoclast activity to release Ca2+
Kidney–> Increase resorption of Ca2+ from urine and promote excretion of phosphates

Question 24

How does PTH act on the kidney?

Answer 24

Increase Ca2+ resorption

Increase K+ excretion

Question 25

Where is calcitonin released from?

Answer 25

Thyroid gland

Specifically C cells

Question 26

When is calcitonin released?

Answer 26

Respone to increase Ca2+ levels

Question 27

What is the effect of increase Ca2+ concentration?

Answer 27

Decrease PTH–> decrease bone breakdown, increase bone building, decrease Ca2+ absorption from gut and kidney
Produce calcitonin

Question 28

What does calcitonin do?

Answer 28

Unsure of specific function

Question 29

What happens when Ca2+ regulation goes wrong?

Answer 29

Hypercalcaemia

Hypocalcaemia

Question 30

What are the symptoms of hypocalcaemia?

Answer 30

Very severe
Clinically worse
Hyper-excitabilty of NMJ
--> lower serum Ca2+--> increase Na+ entry into neurones--> depolarisation--> increase AP
Symptoms
-Paraesthaesia (pins and needles)
-Tetany (muscle spasms)
-Paralysis
-Convulsions

Question 31

What are the symptoms of hypercalcaemia?

Answer 31

Stones, Moans, Groans and Bones 
Stones--> Kidney stones
Moans--> tired, exhaustion, depressed
Groans--> Constipation, peptic ulcers, pancreatitis 
Bones--> Bone and muslce aches

Question 32

What happens in severe hypercalcaemia? What are the symptoms?

Answer 32

Serum > 3mmol/L
Polyuria–> alters the Na+ concentration gradient by inhibiting Na+/K+/2Cl- cotransporter and Na+/K+ ATPase meaning more Na+ in urine so water follows–> polyuria and dehydration
Lethargy, weakness, confusion, coma, renal failure

Question 33

How is hypercalcaemia treated?

Answer 33

Rehydration

Question 34

What is the mechanism of hypercalaemia? (How do you get it?)

Answer 34

Malignancy
- Two main mechanisms:
- 1. Haematological maligancies and those that metastasise to bone–> produce factors–> activate osteoclasts activity
- 2. Squamous tumours of lung, head, neck–> produce Parathyroid hormone related peptide (PTHrP) which acts on the parathyroid receptors
OR
Hyperparathyroidism

Question 35

How can you have a low level of PTH hormone, normal bones but still have hyperkalaemia?

Answer 35

Squamous tumour of lung, head or neck
Secrete PTHrP
Activated parathyroid hormone receptors–> increased Ca2+ resorption in kidney and GI and promote bone breakdown
Ca2+ increase, negative feedback on parathyroid gland less PTH released BUT
Ca2+ continues to rise because of tumour

Question 36

What does PTHrP do? What can it not do?

Answer 36

Mimics PTH by acting on PTH receptors

Does not increase renal C1-hydroxylase enzymes meaning it has no effect on Vit D synthesis (calcitriol)

Question 37

What cancers usually metastasise to bone?

Answer 37

Breast, lung, renal and thyroid

prostate can but doesn’t causes lesions in bone

Question 38

What are the common bony sites for metastasises?

Answer 38

Vertebrae
Pelvis
Proximal femur
Ribs 
Proximal part of humerus
Skull

Question 39

What is hyperparathyroidism? What are the different types?

Answer 39

Increased production of PTH
Primary–> 1/4 parathyroid glands develops an adenoma and secrete excessive PTH, causes serum Ca2+ to rise and phosphate to fall
Seconday–> Hyperplasia of parathyroid glands
–> usually due to Vit D deficiency–> no/low absorption from gut–> Low Ca2+ so PTH increases

Question 40

How does Ca2+ affect neuronal activity?

Answer 40

Alters the threshold for action potential development
Therefore:
Hypercalcaemia–> supression of neuronal activity
Hypocalcaemia–> excitable nerves–> increases neuronal activity

Question 41

What is one of the causes of hypocalcaemia?

Answer 41

Removal of parathyroid glands during total-thyroidectomy
Serum Ca2+ <2.10 mmol/L
Starts within 6hr of thryoidectomy
Results in tingling in mouth and fingers and tetany of muscles

Question 42

What is the difference between osteomalacia and osteoporosis?

Answer 42

Osteomalacia–> bone still there but not mineralised–> soft bones –> bendy bone
Osteoporosis–> Structurally degraded, holes in bones, but fully mineralised

Question 43

What causes osteomalacia? What does osteomalacia lead to? What are the symptoms?

Answer 43

aka Rickets in children
Vit D deficiency–> unable to mineralised bone as Ca2+ taken out of bone to increase serum levels so cannot produce hydroxyapatite
(environmental (no sun) or dietary deficiency)
Chronic renal disease–> renal osteodystrophy–> fail to maintain levels of Ca2+ in blood
Bow legs, bone pain, muscle weakness and defomity