L17: Parathyroid gland: Calcium and Phosphate regulation Flashcards
What is calcium?
Important metal ion
How much calcium is found in the human body? Where is it stored?
Adult- 1000g
99% stored in bone in form of hydroxyapatite crystals (Ca10(PO4)6(OH)2)
How much calcium is exchanged between the bone and ECF each day?
300-600mg calcium exchanged between bone and ECF each day
How much calcium do we need to eat each day?
1000mg
What does the skeleton provide?
Structural support Major reserve of calcium Buffer serum levels Releases calcium phosphate into the interstitium Up taking of calcium phosphate
How does the calcium exist in the plasma?
50% ionised calcium–> biologically active form
10% complexed with lower molecular weight anions
40% Associated with serum protiens (albumin)
What organs have an effect on total calcium in the body?
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
What is calcium needed for?
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
How are calcium and phosphate regulated?
Three hormones
- -> Parathyroid hormone (PTH)
- -> Calcitriol (1,25(OH)2D)–> many different names
- -> Calcitonin
What glands are they important in calcium regulation?
Parathyroid
Thyroid
Where is the parathyroid gland located?
Posterior surface of the thyroid gland
Two pair of 2 glands
Either side of isthmus of thyroid
Where is the thyroid gland located?
Anterior to trachea
3/4 cricoid cartilage down
Butterfly shaped–> 2 lobes connected by isthmus
What is the structure of the parathyroid gland?
Capsule
Two cell types:
–> Chief cells –> secrete PTH
–> Oxyphil cells–> unknown function potential chief cell remenant
Describe the structure of PTH?
Simple straight chain polypeptide
Pre-pro-hormone 115AA long cleaved to 84AA
No serum binding protein required for transport
How is the synthesis of PTH regulated?
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
How long does PTH last in the plasma? What does this mean?
T1/2= 4 mins
Short half life–> responds quickly, fast acting
PTH cleaved in the liver
Little stored
How does Ca2+ work on parathyroid cells to control PTH secretion?
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
What is the target for PTH?
Bone–> Increase resorption–> release Ca2+
Kidney–> Increase Ca2+ resorption
GI–> Activate Vit D and increase transceullar uptake from GI tract
How is calcium stored within bone?
Hydroxyapatite crystals (Ca2+ + Pi) in collagen fibrils Osteoblast produce bone matrix --> mineralised by hydroxyapatite to make it hard
How does PTH act on bone?
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
What does PTH do in the GI tract?
PTH stimulates the synthesis of Vit D (1,25(OH)2D) from vitamin D3 (cholecalciferol)
How is Vitamin D (calcitriol) synthesised?
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)
How does Calcitriol increase Ca2+ resorption?
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
How does PTH act on the kidney?
Increase Ca2+ resorption
Increase K+ excretion
Where is calcitonin released from?
Thyroid gland
Specifically C cells
When is calcitonin released?
Respone to increase Ca2+ levels
What is the effect of increase Ca2+ concentration?
Decrease PTH–> decrease bone breakdown, increase bone building, decrease Ca2+ absorption from gut and kidney
Produce calcitonin
What does calcitonin do?
Unsure of specific function
What happens when Ca2+ regulation goes wrong?
Hypercalcaemia
Hypocalcaemia
What are the symptoms of hypocalcaemia?
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
What are the symptoms of hypercalcaemia?
Stones, Moans, Groans and Bones Stones--> Kidney stones Moans--> tired, exhaustion, depressed Groans--> Constipation, peptic ulcers, pancreatitis Bones--> Bone and muslce aches
What happens in severe hypercalcaemia? What are the symptoms?
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
How is hypercalcaemia treated?
Rehydration
What is the mechanism of hypercalaemia? (How do you get it?)
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
How can you have a low level of PTH hormone, normal bones but still have hyperkalaemia?
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
What does PTHrP do? What can it not do?
Mimics PTH by acting on PTH receptors
Does not increase renal C1-hydroxylase enzymes meaning it has no effect on Vit D synthesis (calcitriol)
What cancers usually metastasise to bone?
Breast, lung, renal and thyroid
prostate can but doesn’t causes lesions in bone
What are the common bony sites for metastasises?
Vertebrae Pelvis Proximal femur Ribs Proximal part of humerus Skull
What is hyperparathyroidism? What are the different types?
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
How does Ca2+ affect neuronal activity?
Alters the threshold for action potential development
Therefore:
Hypercalcaemia–> supression of neuronal activity
Hypocalcaemia–> excitable nerves–> increases neuronal activity
What is one of the causes of hypocalcaemia?
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
What is the difference between osteomalacia and osteoporosis?
Osteomalacia–> bone still there but not mineralised–> soft bones –> bendy bone
Osteoporosis–> Structurally degraded, holes in bones, but fully mineralised
What causes osteomalacia? What does osteomalacia lead to? What are the symptoms?
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
