Lecture 12 - Endocrine control of calcium metabolism Flashcards
What are the roles of calcium?
Control of NEUROMUSCULAR EXCITABILITY Muscle contraction Strength in bones Intracellular second messenger/co-enzyme Hormone/NT stimulus secretion coupling Blood coagulation (factor IV)
Where is most calcium found in the body?
Bone (99%) - as complex hydrated Ca salt Blood - present as Ca2+, some bound to protein and a little left as soluble salts
How is most calcium present in the body?
Calcium salts
What happens to glucose when it enters the body?
MOST absorbed by GI tract into blood (and some secreted back into GI) Can then pass to kidneys which regulates content of blood and returns most of the Ca back into blood, though some excreted Hydroxyapatite crystals in bone can be broken down to increase BCaL Hair, nails, dead cells also loose tiny amounts of Ca
How much Ca is taken up and how much is excreted every day?
1000mg/24h intake 850mg/24h lost as faeces 150mg/24h excreted by kidneys
What is the total value of Ca2+ in blood?
~2.5mM
How is Ca2+ in blood found?
50% - unbound (ionised) 45% - bound to plasma proteins 5% as diffusible salts
What hormones is Ca controlled by?
^ by PARATHYROID HORMONE and 1,25 dihydroxycholecalciferol OR calcitriol Decreased by Calcitonin
What are the parathyroid glands?
Usually 4 Encapsulated glands Source of PTH Made up by follicles with parafollicluar cells inbetween Parafollicular cells produce calcitonin
What is Parathyroid hormone?
Protein, so synthesised as Pre-proPTH PTH polypeptide of 84 aa
Where does PTH bind?
To transmembrane G-protein linked receptors Activate adenyl cyclase and phospholipase C as 2nd messenger
What does PTH do to the kidneys?
^ Ca2+ reabsorption ^ PO4^3- excretion ^ Calcitriol production (by ^ 1alpha OHase activity) causes in small intestine ^ Ca2+ and PO4^3- absorption
What does PTH do to the bones?
OsteoClasts stimulated OsteoBlasts inhibited Hence: ^ BONE RESORPTION
What is the equilibrium between Ca and PO4?
3Ca+2PO4 Ca3(PO4)2
What is an important enzymes in the kidneys?
1 alpha hydroxylase - involved in the synthesis of calcitriol
How does PTH increase BCaL?
What are the 3 main organs with respect to Ca2+?
Gut - where most absorbed Kidneys - where most excreted Bone - where most stored
How does PTH act on the bone?
PTH acts on the receptor present on the OSTEOBLAST, inhibiting various activities and stimulating production of Osteoclast activating factors OAFs move to osteoClasts and stimulate the breakdown of bone matrix to release Ca2+
Name an OAFs and describe its function
RANKL links PTH via osteoblasts but has an inderect effect on osteoclasts
How is PTH regulated?
Decreased plasma Ca and catecholamines (via beta receptor) stimulate parathyroid glands PTH produces calcitriol which inhibits PTH production PTH increases plasma [Ca2+], which causes negative feedback
What receptors are present on parathyroid glands that secrete PTH?
Beta receptors which can be stimulated by catecholamines to secrete PTH
How is calcitriol synthesised?
7-dehydrocholesterol in skin (+UV) and from diet form Vit D3 or cholecalciferol Then 25 (OH) D3 is synthesised in the liver and stored 1aOHase stimulated by PTH forms 1,25 (OH)2 D3, in the kidneys
What are the 2 main sources of cholecalciferol?
Diet - different vit D from diet Sunlight - UV B works on skin converting 7-dehydrocholesterol to cholecalciferol
What type of molecule is Vit D3?
Steroid, circulates around body and taken up by liver
What are the actions of calcitriol in the body?
What do osteoblasts do?
They store the calcium in the bone matrix
What does RANKL stand for?
Receptor activator of nuclear factor kappa-B ligand
How does phosphate reabsorption work?
On apical membrane there are Na+/PO4^3- cotransporters PTH inhibits transporter so phosphate not reabsorbed and excreted in urine Through FGF23, calcitriol can block the transporter
What is FGF23?
Fibroblast growth factor 23
What is calcitonin?
32 aa polypeptide
How is it synthesised?
Pre-procalcitonin
How does calcitonin act?
Via transmembrane G-protein linked receptors, activating adenyl cyclase or PLC as 2nd messenger
What does Calcitonin act upon?
Works on bone, INHIBITS osteoBlast activity - decreases release of Ca into blood Affects kidneys - ^ excretion of Na+ -> Ca and PO4 ions
How long do the effects of calcitonin last?
Short-lived effects
What are the physiological benefits of clacitonin?
BCaL ^ during pregnancy, so calcitonin protects the mother’s bones from being broken down when BCaL are low
How is calcitonin regulated?
^ BCaL and gastrin stimulate parafollicular cells to release calcitonin Acts on bone and kidney and overall decreases BCaL concentration for a short time
What is hypocalcaemia?
Decreased levels of Ca in blood
What are some of the causes of hypocalcaemia?
Hypoparathyroidism (insufficient PTH) Pseudohypoparathyroidism (PTH resistance) Vit D deficiency
How can hypocalcaemia present?
Trousseau’s Sign (main d’accoucheur) Chvostek’s Sign
What is Trousseau’s sign?
When slight pressure placed on arm, the hand goes into contraction
What is Chvostek’s sign?
When facial nerve at angle of jaw is tapped, muscles contract
What is tetany?
Constant contraction due to lack of Ca, allowing Na+ into cell causing constant depolarisation
What are the causes of hypoparathyroidism?
Idiopathic Hypomagnesaemia (as Mg/Ca share channels)
Suppression by raised BCaL Tumour in parathyroid glands
What is pseudohypoparathyroidism?
AKA: Allbright Hereditary osteodystrophy Target organ resistance to PTH - due to defective G-protein
What are the features of PHoPTism?
Short stature, round face Low IQ Subcutaneous calcification and bone abnormalities (shortening of metacarpals) Endo disorders - hypothyroidism, hypogonadism
What is the difference between Idiopathic, surgical and pseudo-hypoparathyroidism?
Idiopathic and surgical still have sensitive target cells to PTH PHoPTism has target cell resistance to PTH
What happens if you are given PTH?
Normal: ^ in urinary excretion of cAMP - same for idiopathic and surgical PHoPT: no change occurs as resistant to PTH
What is the differential diagnosis of hypo- (1),pseudohypo-(2) parathyroidism and vit D deficiency (3)
Plasma Ca - 1, 2 and 3: decrease Plasma PO4 - 1 and 2: ^, 3 decrease PTH: 1: decreases, 2 and 3: ^
What diseases are caused by vitamin D deficiency?
Rickets in children, Osteomalacia in adults
What are the clinical features of vit D deficiency?
Decreased calcification of bone matrix - softening of bone Bowing of bone (kids), fractures in adults
What are the endocrine causes of hypERcalcaemia?
1ry hyperparathyroidism 3ry hyperparathyroidism Vit D toxicosis
How common is Vit D toxicosis?
Relatively uncommon, but are people who take too much vit D
What happens to the kidneys when there is an excess of PTH?
^ Ca2+ reabsorption, PO4 excretion and Calcitriol synthesis Polyuria, Renal stones (Ca deposited as stones), Nephrocalcinosis
What happens to the GIT and bone when excess PTH?
GIT: Gastric acid and duodenal ulcers Bone: lesions, rarefraction and fractures occur
What are some features of 1ry HerPTism?
Clubbing of fingers Marked periosteal bone erosion in terminal phalanges
What is the difference between primary, secondary and tertiary hyperparathyroidism?
What are the actions of PTH?
