MEH Calcium metabolism Flashcards
What are 7 roles of calcium in the body?
Muscle contraction Nerve conduction 2nd messenger Coagulation Activation of enzymes Hormone secretion Exocytosis
What form of calcium is tightly controlled in serum?
Free ionised calcium (Ca2+)
Why does it need to be tightly controlled?
Because too high or too low levels have an effect on cells - e.g. cell membrane/contraction/uncontrolled hormones production/uncontrolled nerve firing etc
How can hypocalaemia have an effect on coagulation?
As it is factor IV so is needed in the coagulation cascade
What three hormones regulate serum calcium?
Parathyroid
Dietary Vit D
Calcitonin
What is calcitriol?
Active vitamin D
How is serum calcium carried?
half free ionised
nearly half plasma proteins
small amount bound to citrate
Where is most of the calcium stored in the body? Is this a rigid or dynamic store?
Skeleton
Dynamic
Say Ca2+ effect on blood pressure colon cancer insomnia kidney function cholesterol?
Reduction in BP, colon cancer, cholesterol
Relieves insomnia and important for normal kidney function
How much Calcium do we contain? How much stored in bones?
1000g
99%
What is calcium stored in the bones as?
Hydroxyapatite crystals
How does skeleton buffer serum levels of Ca?
Releases calcium phosphate into interstitium and takes up calcium phosphate
How is Vit D –> calcitriol?
C-1 Hydroxylation stimulated by PTH
What are 3 actions of PTH
Stimulates bone resorption and release of Ca and phosphate into blood
Stimulates increased reabsorption of Ca at the kidney
Increases vit D –> calcitriol
What are the 3 effects of dietary vit D?
Increases intestinal absorption of calcium
Increases renal absorption of calcium
Increases bone resorption
What is the role of calcitonin? Where it is secreted from?
From thyroid gland C cells
Counter effects PTH but not that important in humans
Where are the parathyroid glands? How many?
On the thyroid glands anteriorly - x 4
What are chief cells vs oxyphil cells? Which are bigger?
Chief - products PTH
Oxyphil cells - bigger - not sure of function
Which is the rapid and which is the longer term control of Ca?
Rapid - PTH 4 min half life
Long - calcitriol - 6 hour half life
how is PTH synthesised/stored?
Pre pro hormone Cleaved Secreted by chief cells Also degraded by chief cells (cleaves when serum Ca levels are high) Not really stored
How is PTH synthesis regulated (3)?
Transcriptional and post transcriptional level
- Low serum Ca2+ upregulates gene transcription (high serum does opposite opposite)
- Low serum Ca prolongs survival of mRNA
- High serum Ca stimulates cleavage by chief cells
Where is PTH that has been released into the circulation cleaved?
In the liver
How is parathyroid hormone secreted?
High Ca binds to GPR Gq
Inhibits release of PTH
and reduces transcription of PTH
Low Ca has opposite effect so increased transcription and increased release of PTH exocytosis
What are the three main target organs to PTH and its effect on them?
Bone - increased resorption to release Ca
Kidney - increased reabsorption to increase Ca
Gut - increased Vit D –> calcitriol and hence increases transcellular uptake from GI tract
What cell does PTH act on in bone?
Osteoclasts
What are 3 functions of skeleton?
Structural support
Maintaining serum Ca concentration
Haemopoiesis
What is the relevance of diseases that affect the bone in Ca serum levels?
Diseases that affect structural integrity of bone have effect on serum Ca level and vice versa
What is hydroxyapatite made up of?
Ca and phosphate
What is the relevance of hydroxyapatite in bone deposition?
Osteoblasts secrete ECM (collagen)
Mineralised by hydroxyapatite
How do osteoclasts dissolve hydroxyapatite crystals?
Produce acid micro-environment
How does PTH stimulate osteolysis? Talk through the process
1) PTH induces osteoblasts to secrete cytokines
2) Cytokines stimulate differentiation and activity in osteoclasts and protect them from apoptosis
3) PTH decreases osteoblasts activity exposing bony surface to osteoclasts
4) Increased osteoclast activity = increased bone resorption and release of Ca and phosphate into ECM
Why does phosphate have to be regulated at the kidney?
Because osteoclasts lead to release of Ca and Pi so need to regulate both Ca and Pi excretion
Pi removal prevents kidney stone formation
How is Ca excretion regulated at the kidney?
Affects tubular cells within kidney - PTH increases Ca reabsorption in
1) Ascending limb of loop of henley
2) Distal convoluted tubule
How does PTH increase absorption of Ca in the gut?
It enhances Vit D –> active calcitriol which greatly enhances absorption of calcium in intestine via transcellular route
What is the inactive Vit D called? What do you need to do to get active calcitriol?
D3 or cholecalciferol
Two hydroxylation reactions
How is vit D3 transported?
Mostly by transcalciferin only a small amount in free form
What 2 major ways do we get vit D?
Sunlight
Diet
How is vit D stored in the liver and where is it activated?
Stored for 2 weeks as inactive form (25-hydroxyvitamin D)
Activated in kidney proximal convoluted tubule
What is the half life of calcitriol?
6 hours so longer acting
What is the feedback mechanism for active calcitriol?
C-1 hydroxylation is under negative feedback to serum calcium levels - elevated Ca prevents C1 hydroxylation
How do we know calcitonin doesn’t have that much of a role in humans? When might it?
Because thyroidectomy doesn’t have a marked effect on Ca levels
Maybe in pregnancy to protect maternal skeleton
How can calcitonin be used clinically?
TO lower serum Ca in cases of hypercalcaemia - is rapid acting
What are the symptoms of hypocalcaemia?
Hyperexcitibility of NMJ Tetany (muscle spasms) Pins and needles Paralysis Convulsions
What are the symptoms of chronic hypercalcaemia?
STONES - kidney damage and renal calculi - stones
MOANS - tiredness/depression
GROANS - abdominal pains/constipation/dehydration
Why is the fact Ca is a coagulant relevant in taking blood tests in medicine?
Need to add chelating agent to prevent blood samples from clotting
EDTA
How about if giving transfusions?
Citrate chelates Ca in transfused blood so over about 5 units need to give IV Ca2+ otherwise prevents natural coagulation and could lead to bleeding
What is adjusted serum Ca level on a blood test?
Adjusted for albumin level
What is the one cancer that causes osteoblastic metastases? Do these increase serum Ca?
Prostate cancer
No doesnt
What are four common osteolytic metastases?
Breast
Lung
Kidney
Thyroid
What other primary may cause increased serum Ca?
Multiple myeloma
Where are more than 90% of bone mets found and why (6)
Vertebrae Pelvis Prox part of femur Ribs Prox part of humerus Skull
Due to microenvironment of marrow - particularly active and good blood supply
What are the primary and secondary causes of hyperparathyroidism?
Primary - one of 4 PT glands - develops adenoma and secretes PTH - causes serum Ca to rise and serum phosphate to fall
Secondary - all 4 PT glands. Due to vit D déficience - can either be due to diet/environmental or chronic renal failure
Why does an adenoma secreting PTH lead to raised serum Ca and fall in phosphate serum?
As main action of PTH is at kidney - reabsorption of Ca and excretion of Phosphate
Why can renal failure lead to vit D deficiency?
As this is where the 25 hydroxylation of via D occurs
What is the main clinical feature of via D deficient hyperparathyroidism? What are two reasons for it?
BONE PAIN
Osteomalacia - painful bones due to increased resorption in an attempt to increase serum Ca levels
Renal osteodystrophy - bone abnormalities due to chronic renal failure
If your patient has a low serum phosphate what is the cause of the hyperparathyroidism?
Primary - due to adenoma secreting PTH
can also have no change in serum phosphate but only cause of low serum phosphate
Why would hyperparathyroidism (hypercalcaemia) lead to polyuria?
Due to impaired Na and water reabsorption
Can patients be asymptomatic with hyperparathyroidism?
Yes
Why do bone metastases lead to increased serum Ca without a change in PTH?
Because Ca is being released by osteoclastic action on bone
Which type of Cancer is the odd one out and causes osteoblastic action on bone mets?
Prostate
What why does primary hyperparathyroidism lead to increased Ca but decreased Pi and increased PTH?
Tumour secreting excess PTH so excess serum Ca levels
Decreased Pi due to action of PTH at kidney that excretes Pi while reabsorbing Ca
Why does secondary hyperparathyroidism lead to reduced serum Ca but increased PTH with no change in Pi?
Because the cause of increased serum Ca is not due to PTH it is due to Vit D deficiency so reduced Ca absorption in the gut and therefore PTH is stimulated from parathyroids hence increased level.
How does hypercalcaemia lead to lethargy, confusion, coma, and hypocalcaemia lead to excitable nerves - tingling, tetany, epilepsy?
Because EC Ca raises the threshold for neuronal AP (more negative inside).
So hypercalcaemia will lead to suppression of neuronal activity and hypo will lead to increased neuronal activity
If someone is in a coma - what might you need to consider as a reversible cause? Especially if malignant hypercalcaemia (it may not be a terminal event)
Hypercalcaemia - over 3mmol/l can cause coma
How can polyuria add to hypercalcaemia?
Further dehydrates and therefore adding to Ca conc
Someone post thyroidectomy has hypocalcaemia what might have happened? At what Ca level will symptoms be felt?
Accidentally removed/injured the parathyroid glands
Below 2.10mmol/l Ca
Why would neuronal symptoms of Ca be around the mouth and fingers in particular?
Because of the large representation of these areas sensually in the brain
What kind of tetany can you see with hypocalcaemia? Why flexed?
Carpopedal spasm
As flexors are stronger than extensors in wrist and fingers
What is a major danger of hypocalcaemia? What is it called?
Chvostek’s sign
Tetany of laryngeal muscle tetany - needs treating quickly
How is osteomalacia different to osteoporosis? What can osteomalacia lead to in children?
Osteoporosis mineral:matrix normal
Osteomalacia mineral:matrix reduced as less mineral being made/being broken down
Can lead to ricketts in children soft bones prone to bending
What is the cause of osteomalacia?
Vit D deficiency
What are risk factors for osteoporosis?
Post menopausal women Low BMI Long term steroids Heavy drinking Smoking Inactivity
What kind of fractures are common in osteoporosis?
Hip
Wrist
Vertebral crush
