9.1 Calcium metabolism Flashcards
How is most calcium stored within the body?
99% is sequested in bone in the form of hydroxyapatite crystals (Ca10(PO4)6(OH)2)
How does the skeleton affect calcium metabolism?
- major reserve of calcium
- Helps to buffer serum levels
- Releasing calcium phosphate into interstitium
- Up taking calcium phosphate
What is the normal serum calcium level?
Serum calcium 2.2-2.6mM
How is calcium within the extra cellular fluid ECF?
45% is in free ionised form of calcium (most reactive portion)
10% in the anion bound complex. (Easily accessible portion)
45% is bound to proteins (albumin) and is not easily accessible as cannot be filtered by kidney or cross membranes. Is therefore not
biologically active.
Why is it important to have healthy calcium levels?
Builds and maintains bones and teeth Regulates heart rhythm Eases insomnia Helps maintain proper nerve and muscle function Reduces blood cholesterol levels Important to normal kidney function Important for blood clotting (factor IV) and more
What 3 hormones are involved in the regulation of calcium and phosphate?
Parathyroid hormone
Calcitriol
calcitonin
Where is calcitonin produced?
In C cells in the thyroid. C cells surround the follicles. Are unusually dark.
What is the function of calcitonin?
Calcitonin lower calcium levels in serum within animals. Not very active in humans. Can give calcitonin if patient is hypercalcaemia.
Preserves maternal Skelton during pregnancy
Where is the thyroid located?
Just above the laryngeal prominence. Butterfly shaped. Parathyroid glands are dark circles in the thyroid
what cells are present in the parathyroid?
chief cells (darker, more compact) oxyphil cells (lighter, look wholly and less clearly defined)
How is parathyroid hormone regulated?
Synthesis is regulated both at transcriptional and post transcriptional levels:
• Low serum calcium up-regulates gene transcription
• High serum calcium down-regulate
• low serum calcium prolongs survival of mRNA (mechanism not known)
Where is parathyroid hormone produced?
In chief cells of the parathyroid gland.
Why is it necessary that PTH is continually produced?
As little is stored. As well as synthesising PTH, chief cells also degrade the hormone.. Cleavage of PTH in chief cells accelerated by high serum calcium levels
Where are calcium receptors located?
Calcium receptors are located on the membrane of cells.
What do high serum calcium levels trigger?
Inhibits synthesis and transcription of PTH
Inhibits cell growth
What type of receptor is the calcium receptor?
A G protein coupled receptor GPCR
Describe the mechanism by which high calcium serum levels influence PTH synthesis and secretion
- Calcium binds to the calcium GCPR receptor on chief cells.
- Binding of the calcium induces a conformational change.
- Ga subunit of the Gq coupled protein is phosphorylate and activated from GDP to GTP.
- GTP binds to membrane bound enzyme phospholipase C
- Phospholipase C is activated and goes on the cleave the membrane bound intrinsic protein PIP2
- PIP2 cleaved into IP3 and DAG
- IP3 enters into the cell and binds to the IP3/calcium channel on the membrane of the ER.
- This IP3/calcium channel opens and allows calcium to flow down ints concentration gradient into the cell.
- Secondary messengers DAG and calcium activate protein kinase C which acts to phosphorylate target proteins.
- This cascade causes PTH secretion to be inhibited and reduced PTH synthesis.
What effects does PTH have on bone?
Activates osteoclasts to release calcium and phosphate ions into the bloodstream. Increases resorption. Decreases activity of osteoblasts.
What effects does PTH have on intestine?
Activates vitamin D to calcitriol and increases calcium absorption from food.
What effects does PTH have on the kidney?
Promotes activation of vitamin D and increases calcium reabsorption. Decreases loss to urine.
How is phosphate usually found in the body?
As inorganic phosphate. This is a free phosphate ion and is not bound to esters. Denoted by Pi
what is the average dietary intake of calcium?
Dietary intake of calcium is typically 1000 mg/d, only 30% of which is absorbed
How is calcium uptake increased?
Absorption is significantly increased by Vitamin D via a transcellular uptake
How can bone diseases have consequences on calcium regulation?
Diseases in bone that affect structural integrity have consequences for serum calcium conc. Bone resorption increases serum calcium and phosphate ion levels.
How is calcium deposited in bone?
Osteoblasts lay down a collagen matrix. Hydroxyapatite crystals are deposited within the collagen fibrils and mineralises them to form bone.
How is bone reabsorbed?
Osteoclasts in the bone produce acid micro-environment that dissolved the hydroxyapatite.
How does PTH stimulate osteolysis?
1-2 hrs PTH stimulates osteolysis
• PTH induces osteoblastic cells to synthesise and secrete cytokines on cell surface
• Cytokines stimulate differentiation and activity in Osteoclasts and protect them from apoptosis
• PTH decreases Osteoblasts activity exposing bony surface to Osteoclasts
• Reabsorption of mineralized bone and release of Pi (inorganic phosphate) and Ca2+ into extracellular fluid
How is vitamin D obtained by the body?
- Body makes vitamin D when exposed to the sun
- Cheese, butter, margarine, fortified milk, fish and fortified cereals are food sources of vitamin D
How is calcitriol formed?
- Vitamin D3 (cholecalciferol) required to synthesise 25(OH)D . Vitamin D3 mostly provided by UVB.
- 25(OH)D is produced in the liver.
- 1,25(OH)2D (calcitriol) is produced predominantly in the kidney from 25(OH)D
Where is vitamin D3 formed?
Formed in the skin when exposed to UVB
Where is calcitonin produced?
Thyroid by C cells that surround follicles in thyroid.
What are follicles in the thyroid?
Follicles are are large circular structures with thyroglobulin stored in the colloid of the follicle.
Describe the feedback loop of HIGH serum calcium on PTH secretion.
high plasma calcium levels inhibit PTH secretion by the parathyroid gland.
Low PTH secretion results in low calcitriol production and low calcium reabsorption in the kidneys.
Low PTH secretion result in decreased osteoclast activity and increased osteoblast activity in bone.
As less calcium is absorbed from diet and more calcium is stored as hydroxyapatite crystals in bone, there is a decrease in plasma calcium levels.
Describe the feedback loop of LOW serum calcium on PTH secretion
low plasma calcium levels stimulate PTH secretion by the parathyroid gland.
high PTH secretion results in high calcitriol production and high calcium reabsorption in the kidneys.
Low PTH secretion result in increased osteoclast activity and decreased osteoblast activity in bone.
As more calcium is absorbed from diet and less calcium is stored as hydroxyapatite crystals in bone, there is a increase in plasma calcium levels.
Describe the clinical consequences of chronic hypercalcaemia?
Stones, moans, groans and bones. kidney stones (renal calculi) depression abdominal pain muscle aches kidney damage/renal failure constipation dehydration tiredness polyuria ( leading to dehydration, exacerbating the hypercalcaemia) lethargy weakness confusion coma
Describe the clinical consequences of hypocalcaemia
hyper-excitability of NMJ Lower serum calcium, causes increase Na+ entry into neurones, leading to depolarisation and increase likelihood of AP. • pins and needles • tetany (muscle spasms) • paralysis • convulsions
What hormone is likely to be released if calcium levels are too high
calcitonin
What high is serum calcium in hypercalcaemia?
greater than 3.0mmol/L
What is the common aetiology of hypercalcaemia?
malignant osteolytic bone metastasis
multiple myeloma
Common cancers that metastasise to bone causing lytic lesions and hypercalcemia (Breast, Lung, Renal, Thyroid, Prostate)
Where are common sites for bone metastasis?
vertebrae, pelvis, femur, ribs, humerus, skull
What is primary hyperparathyroidism?
One of the 4 parathyroid glands develops an adenoma and secretes excessive parathyroid hormone.
This causes serum calcium to rise and serum phosphate to fall as kidney increases excretion of phosphate.
What is secondary hyperparathyroidism?
All 4 parathyroid glands become hyperplastic.
• This is seen in patients with Vitamin D deficiency (Vitamin D Deficiency means that their calcium absorption is low resulting in low serum
calcium levels, that then causes PTH levels to rise)
• Vitamin D deficiency can be dietary/environmental
• or seen in chronic renal failure due to failure of the 25 hydroxylation of Vitamin D
What are the symptoms of hyperparathyroidism?
Stones – kidney stones. Also polyuria due to
impaired sodium and water reabsorption
Moans – tired, exhausted, depressed
Groans – constipation, peptic ulcers, pancreatitis
Bones – bone and muscle aches
How does disturbances to calcium serum levels affect the nervous system?
Calcium raises the threshold for nerve membrane
depolarisation and therefore the development of an action potential:
• Hypercalcemia leads to supression of neuronal activity – lethargy, confusion, coma
• Hypocalcemia leads to ‘excitable’ nerves – tingling, muscle tetany and even epilepsy
What is the aetiology of symptomatic hypocalcaemia?
Seen mostly in post total-thyroidectomy patients (because of inadvertent
removal/ischaemia of parathyroid glands)
what are the sensory symptoms of hypocalcaemia?
tingling around the mouth and fingers
what are the motor symptoms of hypercalcaemia
tetany (involuntary contraction) of muscles carpopedal spasm (involuntary contractions in hands and feet)
Describe the structure of bone in a patient with osteomalacia?
normal bone structure, just under-mineralised. Bones are soft
Describe the structure of bone in a patient with osteoporosis
Structurally degraded bone with many holes. bones are fully mineralised but more brittle.
What causes osteomalacia?
Caused by vitamin D deficiency. Cannot mineralise the bone causing it to be softer. Not absorbing the calcium across the gut as vitamin D is required for absorption.
what is rickets?
Osteomalacia in children. may be caused by dietary / environmental factors, chronic renal disease.
what are the symptoms of osteomalacia in adults?
bone pain, muscle weakness, deformity
