Endocrine control of calcium metabolism Flashcards
What is the function of calcium in the body?
neuromuscular excitability - no Ca (no Na channel blocking - more available for Na influx) causing depolarisation and hyperexcitability muscle contraction strength in bone intracellular 2nd messenger/coenzyme blood coagulation (factor IV = Ca)
Where is Ca found in the body?
found as calcium salts
mainly in bone (99%) as complex hydrated calcium salt (hydroxyapatite crystals are embedded in the bone matrix as a reservoir)
in blood: (total = 2.5mM)
- ionised Ca2+ (BIOACTIVE FORM) 50% 1.25mM
- bound to plasma proteins 45% 1.13mM
- some left as soluble salts (citrate, lactate) 5% 0.13mM
Describe Ca handling by the body
Most absorbed in the GI tract, 1000mg/24h (normal intake)
850mg lost in faeces
Ca in blood to kidneys, most reabsorbed, 150mg excreted
Hydroxyapatite crystals broken down to increase blood Ca
cells lost each day have small amounts of Ca
What 2 main hormones increase Ca ion concentration?
parathyroid hormone
1,25-dihydroxycholecalciferol (calcitriol)
What is calcitriol aka?
steroid
1,25-dihydroxy vitamin D3
What main hormone decreases Ca concentration in the blood?
calcitonin
not strong long term effect
Where are PTH and calcitonin produced?
PTH - made in 4 parathyroid glands
- initially made as pre-proPTH
- PTH is polypeptide with 84 amino acids
- binds to transmembrane G protein linked receptors to activate adenylate cyclase then PLC
Calcitonin - made in parafollicular cells between follicles of parathyroid glands
Describe the action of PTH?
- stimulates kidneys to excrete more phosphates
- increase Ca reabsorption in kidneys
- stimulates kidney 1a hydroxylase production needed to make calcitriol
- stimulates osteoclasts (reabsorb bone matrix, release of Ca from hydroxyapatite crystals into the gut)
- inhibit osteoblasts
What happens after replenishment of loss of phosphate?
loss of phosphate disturbs equilibrium
phosphate salt dissociates to compensate for excreted phosphate
calcium [] increase secondarily
What is the effect of calcitriol on small intestines?
control Ca and PO4 absorption
Describe the action of PTH in bone
- activate osteoclasts - INDIRECT
- stimulate osteoblasts DIRECT to make various osteoclast activating factors (OAFs) which move to osteoclasts to stimulate breakdown of bone matrix to release Ca
PTH BINDS DIRECTLY TO OSTEOBLASTS BUT INDIRECT EFFECT ON OSTEOCLASTS
- one OAF = RANKL that links PTH via osteoblasts to osteoclasts
= receptor activator of NFK-b
How is PTH regulated?
- PTH stimulates enzyme that causes synthesis of calcitriol to increase Ca []
- cells that produce PTH respond to Ca [] due to Ca ion receptors (receptors activated with fall in Ca)
- calcitriol also has negative feedback on PTH
- beta receptors on cells that produce PTH mean they can be stimulated by catecholamines
Describe calcitriol synthesis?
precursor = cholecalciferol (Vit D3, steroid, circulates and taken up by liver)
- diet (vitamin D2 plants/fungi, D3 meat/milk)
- sunlight (UVB works on skin, convert 7-dehydrocholesterol to cholecalciferolk)
What happens to calcitriol in the liver?
liver has 25-hydroxylase enzyme to convert cholecalciferol to 25-hydroxy-cholecalciferol (25(OH)D3) that in then stored there
circulates from liver and reaches kidneys to find 1a hydroxylase (stimulated by PTH) STORAGE FORM
1ahydroxylase converts 25-hydroxy-cholecalciferol to calcitriol (1,25 (OH)2 D3) in kidneys BIOACTIVE FORM
What are the actions of calcitriol?
SI: stimulate Ca and PO4 absorption
Bone: minor effect - stimulate osteoblast activity and secondary effect of raising Ca [] in plasma
Kidney: calcitriol increase Ca reabsorption and decreases that of PO4
Describe phosphate reabsorption in the kidney
phosphate ion transporters on apical membrane
PTH inhibits this (PO4 excreted in urine)
calcitriol blocks transporter via FGF23 (molecule from osteocytes)
both inhibit PO4 reabsorption in the kidneys
What is calcitonin?
made as pre-procalcitonin
32 aa polypeptide
actis via transmembrane G protein linked receptors to AC/PLC
What are the effects of calcitonin?
inhibit osteoclast activity - decrease release of Ca from bone to blood
increase Na ion excretion which increases excretion of Ca/PO4
effects are small/short lived
What is the physiological benefit of calcitonin?
pregnancy plasma Ca raised as more ions needed for milk
also protects bone from being broken down
stimulated by increase plasma Ca []
OVERALL EFFECT = decrease plasma Ca []
What are endocrine causes of hypocalcaemia?
hypoparathyroidism (insufficient PTH)
pseudohypoparathyroidism (ass with PTH resistance)
vitamin D deficiency
What are 2 signs of hypocalcaemia?
SIGNS OF TETANY
Trousseaus sign (main d’accoucheur)
- slight pressure on arm can cause hand to contract
Chvostek’s sign
- tap facial nerve at angle of jaw and muscle contract
What are causes of hypoparathyroidism?
idiopathic
hypomagnesaemia
suppression by raised plasma [] Ca
What is pseudohypoparathyroidism?
aka allbright hereditary osteodystrophy
- target organ resistance to PTH (defective Gs proteins)
short stature, round face
low IQ
subcutaneous calcification/bone abnormalities (shorter metacarpals)
ass endocrine disorders (hypothyroidism, hypogonadism)
What are the features of hypoparathyroidism?
very abnormal 4th metacarpal
if given PTH,
normal = increase in urinary excretion of cAMP
surgical/idiopathic = normal results because target cells still sensitive to PTH
pseudo = no change due to target resistance to PTH
How to distinguish between hypoPTism, pseudo and vitamin D deficiency?
1 = high plasma PO4, low Ca and PTH 2 = low Ca, high PO4, PTH 3 = low Ca, PO4 and high PTH
Why is PTH low in hypoparathyroidism?
PTH increases excretion of phosphate and so reduces plasma []
therefore, hypoPTism = high phosphate as not PTH to stimulate excretion
Why is Ca low in pseudohypoparathyroidism?
parathyroid glands produce sufficient PTH but target organs are resistant so plasma Ca low
What is Vitamin D deficiency?
rickets/osteomalacia
decreased calcification of bone matrix causing softening of bone
bowing of bones in children, fractures in adults
elderly less likely to get sunlight (more likely to get def)
What are endocrine causes of hypercalcaemia?
primary hyperparathyroidism
tertiary hyperparathyroidism
vitamin D toxicosis
What is primary hyperparathyroidism?
tumour in parathyroid cause large increase in PTH secretion
- not regulated by normal negative feedback
- continues to produce lots of PTH leading to increased plasma Ca
What is secondary hyperparathyroidism?
some people have low plasma Ca due to renal failure
stimulates parathyroid to release PTH to maintain Ca level
What is tertiary hyperparathyroidism?
initial low chronic plasma Ca as parathyroid gland passively stimulated for long time
eventually PTH becomes autonomous and stops responding to negative feedback
increase plasma Ca level
What is associated with hypercalcaemia?
1 and 3ry hyperparathyroidism
What are the consequences of parathyroid excess?
KIDNEYS increase Ca reabsorption/PO4 excretion polyuria renal stones (Ca deposits) nephrocalcinosis increase calcitriol synthesis
GI tract
gastric acid
duodenal ulcers
BONE
bone lesions, rarefaction, fractures (breakdown of bone)
What is the feature of primary hyperparathyroidism?
clubbing of fingers
