L5: endocrinology of calcium homeostasis Flashcards
How does calcium exist in the body?
- exists as hydroxyapatite crystals within the bones (99%) and teeth
- intracellular calcium concentration is normally held at about 0.1micromol/L (very low)
- extracellular (plasma) concentration is 2.2-2.6mmol/L. This is under hormonal control.
- in the blood 50% is bound to plasma proteins or in inorganic complexes.
- the concentration of free calcium ions (ionised) is around 1.4mmol/L. Responsible for physiological effects and under hormonal control.
(Min 4 flow diagram)
Important roles of calcium
- major component of bones, teeth and connective tissue
- calcification of bone occurs with formation of hydroxyapatite crystals
- central role in blood clotting
- second messenger
- muscle contraction
- calcium required for nerve transmission at NMJ
Main sources of calcium
7: 30
- majority are dietary - green leafy vegetables, salmon and sardines, dairy
- some secreted into blood, some intestines or some in urine
- bone
What 3 hormones regulate plasma calcium?
Parathyroid hormone (PTH), vitamin D, calcitonin
What 3 things do hormones act on to regulate plasma calcium?
Bone, kidney, intestine
What other ion is the regulation of calcium closely associated with?
Phosphate
Relationship between parathyroid hormone and calcium
Inverse relationship. As blood ionised calcium increases, serum PTH decreases. Graph at 10:50.
Where is the parathyroid gland and what does it regulate?
Consists of 4 glands embedded in posterior surface of thyroid tissue.
Regulates the calcium and phosphate levels.
When do parathyroid glands secrete PTH?
PTH secreted in response to:
- low ionised calcium
- high phosphate
What happens to the parathyroid glands if the thyroid gland is destroyed?
Parathyroid glands can be removed and once the thyroid tissue is removed, they can be embedded back into the neck to continue their role.
What cells is PTH secreted from and when?
Chief cells of the parathyroid gland respond directly to change in plasma calcium level and secrete PTH. When calcium is low PTH is secreted. When calcium is high PTH is inhibited. Short-term regulation of calcium.
How to chief cells respond to low ECF calcium concentration?
- chief cells have G-protein coupled receptors that are calcium sensing receptors and when calcium is available in the blood, it inhibits the receptor.
- as calcium depletes in the blood, the receptor is activated.
- PTH is prestored in the cells for rapid release.
- if chronic hypocalcemia, then Ca receptors stimulate PTH synthesis.
Chief cell properties
Highly vascularised so that PTH can be directly secreted into the blood
What does PTH do - rapid mobilisation of calcium?
PTH travels to the bone and acts on osteocyte membrane to release calcium and phosphates into the blood.
What are the two forms that calcium exist as in the bone?
Calcium is bound to phosphates in bone (slow release). Calcium is bound to phosphates in interstitial fluid around bone (rapid release).
What does PTH do - slow mobilisation of calcium?
- PTH does not directly stimulate osteoclasts (bone destroying cells)
- PTH receptors on osteoblasts (bone forming cells)
- release of RANK-L from osteoblasts stimulates activity of osteoclasts by binding to RANK
- osteoclasts destroy bone collagen
- levels of hydroxyproline are high when bone breaks down a lot. Hydroxyproline is an amino acid that has calcium phosphate deposits.
Bone resorption and formation
21:20
Bone resorption:
Once osteoclasts are active, they attach onto the bone, secrete H+ ions to create an acidic environment, seal this off and destroy the bone to release calcium phosphate, destroys collagen, and brings about hydroxyproline (sometimes used as a marker in the blood of bone destruction).
Bone formation:
Osteoblasts reform bone.
How is free calcium formed? (since it is bound to phosphate when resorbed from bone)
PCT - phosphate reabsorption
DCT - calcium reabsorption
PTH blocks the sodium phosphate co-transporters
Phosphate reabsorption
In the PCT cells:
- PTH will inhibit the sodium/phosphate co-transporter.
- so PTH will stop the kidney from absorbing phosphate.
- so blood phosphates will decrease and urine phosphates will increase.
Calcium reabsorption (DCT)
At the DCT cells:
- PTH increases calcium ATPase activity
- PTH increases the sodium/calcium exchange protein
- so more calcium will leave the DCT cells and enter the interstitium and thus the blood. This creates a gradient so calcium diffuses from the lumen into the cells.
- this increases blood calcium and lowers urine calcium.
Sources of vitamin D
- > 90% vitamin D is produced when skin is exposed to sunlight. Sunlight converts 7-dehydrocholesterol to cholecalciferol
- few foods contain vitamin D naturally but can be fortified: vitamin D3 in dairy, oily fish and liver; vitamin D2 in yeast, fungi, added to margarines.
The role of PTH in vitamin D
- vitamin D3 (cholecalciferol) is produced in the skin by action UV light on 7-dehydrocholesterol
- vitamin D3 is activated to calcitriol (1,25-dihydroxyvitamin D3) after 2 successive hydroxylations in the liver and kidney:
• vitamin D3 is bound by a specific globulin and transported to the liver where it is converted to 25dihydroxyvitaminD3 by 25 hydroxylase
• in the kidney proximal tubule, this is converted to 1,25(OH)2D3 by the enzyme 1(alpha)-hydroxylase - transcription of 1(alpha)-hydroxylase is increase by PTH
Actions of 1,25(OH)2D3
- long-term regulation of calcium (cf PTH)
- acts on nuclear receptors (VDR - vitamin D receptor) in the intestinal mucosa
- increases synthesis of calcium binding protein (calbindin) in intestinal cells.
- calbindin increases calcium (and phosphate) absorption
- facilitates remodelling of bone - stimulates osteoblasts to reform bone
- high levels of vit D will have negative feedback on the chief cells causing lower PTH secretion
Where is calcitonin secreted from?
Parafollicular cells/C cells in the thyroid gland
What does calcitonin do?
- released when calcium levels are high
- binds to receptors in the bone
- acts to inhibit bone resorption - returns plasma calcium level to normal. Helps lay bone down - stimulates osteoblasts, pulling calcium out of the blood.
How important is calcitonin?
Not essential to life. Post thyroidectomy has shown no calcium problems. Physiological relevance is unknown.
Negative feedback response flowchart in response to hypercalemia and hypocalemia.
36:30
Disorders of hypercalcaemia
Causes:
- Hyperparathyroidism (oversecretion of PTH)
- Malignancy
- Others - less common
Results in kidney stones, constipation, dehydration, kidney damage, tiredness, depression
Primary hyperparathyroidism
- primary parathyroid adenoma
- treatment is parathyroidectomy (only one removed)
- restore CFV after excessive urine loss
Disorders of hypocalcaemia
Regulation of calcium is dependent on adequate calcium in the diet. Otherwise the body will maintain serum calcium at the cost of bone.
Physiological response to hypocalcaemia = increased PTH, breakdown of bone to release calcium
Causes: vitamin D deficiency, PTH deficiency, renal disease, PTH resistance, vitamin D resistance (rare)
PTH deficiency
Hypoparathyroidism is rare but can be caused by the removal of parathyroid glands. Causes life-threatening hypocalcaemia (death when respiratory muscles affected) also hyperphosphataemia.
Vitamin D deficiency
Causes: poor diet, lack of sunlight, chronic renal failure (since kidney cannot activate vitamin D so nothing to aid absorption of diet calcium)
Consequence - bone is sacrificed to maintain plasma calcium levels leading to rickets in children and osteomalacia (soft bones) in adults.
Treatment - vitamin D replacement through diet (not sunlight as this can cause skin cancer)
What do people present with if they are hypocalcaemic?
Results in hyperexcitability of the NMJ - causing pins and needles, tetany spasm, paralysis, convulsions. If drops beneath certain levels it can cause fatal laryngospasm - asphyxiation - death. In NMJ activity, normal calcium levels inhibit sodiums firing ability but this is removed when calcium is low, causing hyperexcitability of the NMJ.
Test by Chvostek’s sign - touching just beneath the eye will cause uncontrolled twitching. Test by Trousseau’s sign - blood pressure cuff pumped on arm will cause hand spasms.
What does parathyroidectomy result in?
Parathyroidectomy results in hypocalcaemic tetany and death due to asphyxia if untreated, so parathyroids are essential for life.
