Calcium metabolism Flashcards
Calcium; Endocrine control of calcium; Phosphate; Hyperparathyroidism
What are the physiological functions of calcium?
Muscle contraction Bone strength Intracellular messenger and co-enzyme blood coagulation hormone/neurotransmitter stimulus-secretion coupling
How is calcium stored?
Mostly as salts
99% in blone as complex hydrated Ca2+ salt
Less in blood as ionised calcium and attached to proteins
Only free Ca2+ is bioactive - 50% unbound in blood, 45% to plasma proteins and 5% as diffusable salts
How is calcium regulated?
Parathyroid hormone and calcitrol increases Ca2+
Calcitonin from parafollicular cells of thyroid decreases Ca2+
Homeostasis dependent on osteoclast:osteoblast ratio
-increased osteoclast activity = increased Ca2+ and (PO4)3- into blood
-Increased osteoblast activity = formation of calcium salts in bone
How is calcium regulated in the parathyroid gland?
same receptors as in kidneys and GI
G-protein coupled receptors have transmembrane domains and an external binding site
Ligand binding changes G protein conformation to allow G subunit intracellular mechanism
When calcium high receptor suppresses PTH release as regulation not needed
When calcium low G protein receptors lead to parathyroid hormone release
What causes increased osteoblast activity?
Low concentration of PTH, High calcitonin and low calcitrol
What causes increased osteoclast activity and increased intestinal/renal Ca2+ absorption?
High PTH, Low calcitonin, high calcitrol
How is hypocalcaemia identifiable?
Tetany due to Na+ entering cells more easily and increasing the likelihood of an action potential
Trousseau’s sign - BP cuff stops blood flow and hand starts to contract
What are principle causes of hypocalcaemia?
Hypoparathyroidism - decreased PTH secretion
-idiopathic or due to hypomagnesaemia
-suppressed by raised blood Ca2+
Pseudohypoparathyroidism - target organ resistance to PTH
-Defective Gs protein
- Low IQ, short staturem subcutaneous calcification
Vitamin D deficiency
- rickets in children and osteomalacia in adults
-decreased calcification of bone matrix=bone softening (kids) fractures (adults)
What are the main causes of hypercalcaemia?
endocrine 1°/2°/3° hyperparathyroidism
Vitamin D toxicosis - high intake
What is the role of PTH?
preservation of plasma calcium concentration at the expense of bone
What is the role of calcitrol?
Promotes laying of calcium/phosphate salts in bone
What is the role of calcitonin?
Limited effect to protect bone
How is PTH produced?
Pre-proPTH cleaved to 84aa PTH
How is calcitrol produced?
VitD3 sourced from diet and conversion from cholesterol in skin under UV light
Hydroxylated twice in kidneys
How is calcitonin produced?
Pre-procalcitonin cleaved to produce calcitonin
What is the method of action of PTH?
Binds to transmembrane G protein linked receptors
activates adenyl cyclase and phospholipase C
What is the method of action of calcitrol?
Increases bone osteoblast activity and calcium/phosphate absorption in the kidneys
increase levels for bile salts
What is the method of action of calcitonin?
Inhibits osteoclast activity
Stops bone breakdown
Increases kidney’s secretion of calcium
How is PTH regulated?
Decreased plasma conc of Ca2+ increases PTH secretion
Increase in plasma conc of Ca2+ produces -ve feedback via sensing receptor
Inhibited by VitD/Ca2+
Stimulated by catecholamines
How is calcitrol regulated?
Inhibited by FGF23
Stimulated by high Ca2+
How is calcitonin regulated?
Gastrin from stomach increases calcitonin
XS acid results from high circulating Ca2+
What are the effects of PTH in the kidneys?
increase in phosphate excretion and Ca2+ reabsorption
Stimulates 1α hydroxylase to synthesise active form of VitD3 which acts on small intestine to increase Ca2+ and PO43- absorption
What are the effects of PTH in bones?
Binds to the PTH receptors on osteoblasts to stimulate release of osteoclast activating factors
These bind to osteoclast receptors to cause bone resorption
What are the effects of PTH in blood?
Increases circulating Ca2+ levels for contraction and signalling
How does PTH regulate phosphate reabsorption?
Stimulates kidneys to increase phosphate excretion but also stimulates SI to increase phosphate absorption
How does fibroblast growth factor 23 regulate phosphate reabsorption?
VitD3 stimulates phosphate absorption, but if to high then FGF23 stimulated so more Na+ and phosphate enters urine
How does calcitrol regulate phosphate reabsorption?
Stimulates FGF23 in high phosphate concentration
negatively feeds back on calcitrol
What hormones control phosphate reabsorption?
PTH
FGF23
Calcitrol
What is 1° hyperparathyroidism caused by?
Parathyroid adenoma produces XS PTH
not regulated by increased Ca2+
What is 2° hyperparathyroidism caused by?
Parathyroid glands secrete XS PTH in response to chronically low plasma Ca2+
Often seen in kidney failure
What is 3° hyperparathyroidism caused by?
Began as 2°
PTH levels got so high that glands became hyperplastic
Underlying deficiency rectified, but autonomous parathyroid glands no longer -vely regulated by plasma Ca2+
