Endocrinology: Physiology - Calcium homeostasis Flashcards
Which three hormones regulate calcium homeostasis and how do they work (in brief)?
- Parathyroid hormone: mobilises Ca2+ from bone, increases urinary phosphate excretion
- 1,25-dihydroxycolecalciferol: increases Ca2+ absorption from gut
- Calcitonin: inhibits bone resorption
How much calcium in grams is in the body of a young adult? What % of this is stored in bone?
1100g
99% stored in bone
What is the normal plasma level of calcium? What of this is protein-bound vs diffusible?
Normal level 2.5nmol/L (10ug/dL)
~46% protein-bound, ~54% diffusible
Calcium is predominantly bound to which plasma protein for transport?
Albumin
What are the three main functions of free ionised calcium as a second messenger?
- Coagulation
- Muscle contraction
- Nerve function
What is the effect of decreased extracellular calcium on nerve and muscle function?
Excitatory effect
Causes hypocalcaemic tetany
How does death occur as a result of hypocalcaemic tetany?
Due to laryngospasm and fatal asphyxia
Why are clotting abnormalities generally not seen with severe hypocalcaemia?
Fatal tetany would occur before calcium sufficiently decreased to significantly disturb clotting
What are the two forms of calcium storage in bone and what is the significance of this with regards to calcium homeostasis?
- Readily exchangeable reservoir: 500mmol/day moved in and out from this reservoir to maintain plasma Ca2+
- Larger pool of stable calcium (slowly exchangeable): bone remodelling, only 7.5mmol exchanged per day
Describe the process of calcium absorption for the GIT. What hormone regulates this process?
Ca2+ absorbed across brush border membrane via TRPV6 and sequestered with Calbindin-D
Transported across basolateral membrane into bloodstream either via Na+/Ca2+ exchanger (NCXI) or Ca2+-dependent ATPase
Process regulated by 1,25-dihydroxycolecalciferol
Describe how calcium is filtered and excreted by the kidneys. What hormone regulates this process?
Freely filtered, 98-99% reabsorbed in tubules
Of this: 60% reabsorbed in proximal tubule, remainder in ascending limb of loop of Henle and in distal tubule
In distal tubule reabsorption occurs via TRPV5 (expression regulated by PTH)
What is the normal intake of dietary calcium?
25mmol
How much calcium is normally excreted in urine vs faeces?
Urine: 2.5mmol
Faeces: 22.5mmol
What is the normal free ionised calcium level?
1.18
How much calcium in grams is in the body of a young adult? What % of this is stored in bone?
500-800g
85-90% in bone
What is the normal plasma level of phosphorus? What proportion of this is incorporated in organic compounds vs existing as inorganic forms of phosphorus?
12mg/dL
2/3 organic compounds
1/3 inorganic phosphorus [PO4(3-), HPO4(2-), H2PO4-]
How many mg (or umol) of phosphorus per kg per day leave and re-enter bone?
3mg/kg/day or 97umol/kg/day
Describe the renal filtration and excretion of phosphorus. What hormone regulates this process?
Pi filtered in glomeruli with 85-90% tubular reabsorption
Reabsorption mostly occurs as active transport via two related sodium-dependent Pi cotransporters in the proximal tubule
PTF inhibits one of these cotransporters to increase urinary phosphorus excretion
Describe the absorption of phosphorus from the GIT. What hormone regulates this process?
Absorbed in duodenum and small intestine via a combination of active transport and passive diffusion
Many of the stimuli which increase Ca2+ absorption in the GIT also increase Pi absorption (including 1,25-dihydroxycolecalciferol)
What are the D vitamins?
Group of closely related sterols produced by action of UV light on certain provitamins
Describe the metabolism of the D vitamins
In skin:
7-dehydrocholesterol converted to previtamin D3 by the action of sunlight (rapid)
Previtamin D3 converted to vitamin D3 (colecalciferol; slower)
Vitamin D3 transported via vitamin D binding protein (DBP) to liver
In liver:
Vitamin D3 converted to 25-hydroxycolecalciferol (calcidiol) via 25-hydroxylase
In kidney:
Calcidiol converted to 24,25-dihydroxycolecalciferol (less active metabolite) via 24-hydroxylase, and to 1,25-dihydroxycolecalciferol (calcitriol) via 1a-hydroxylase
In what other three cells/tissues is 1,25-dihydroxycolecalciferol produced?
Placenta
Keratinocytes in skin
Macrophages
Outline six mechanisms of 1,25-dihydroxycolecalciferol in maintaining calcium homestasis
- Increased calbindin-D to increase absorption from GIT
- Increased Ca+-dependent ATPase to increase absorption from GIT
- Increased TRPV6 to increase absorption from GIT
- Increased TRP5 to increase renal tubular reabsorption and decrease excretion
- Stimulates osteoblast activity
- Essential for normal calcification of bone matrix
Describe how 1,25-dihydroxycolecalciferol regulates its own production
Inhibits 1a-hydroxylase
Promotes production of less active 24,25-dihydroxycolecalciferol
Negative feedback to parathyroid gland
What is the effect of PTH on 1,25-dihydroxycolecalciferol?
Stimulates expression of 1a-hydroxylase to increase production
How do plasma levels of Ca2+ and PO4(3-) regulate 1,25-dihydroxycolecalciferol production?
Effect of Ca2+ mediated via PTH (low Ca2+ stimulates PTH release, PTH increases production of 1,25-dihydroxycolecalciferol)
PO4(3-) directly inhibits 1a-hydroxylase to reduce production of 1,25-dihydroxycolecalciferol
Describe the homeostatic response to low plasma calcium levels
Low plasma calcium levels stimulates parathyroid gland to release PTH
PTH acts on:
1. Kidneys: to increase Ca2+ reabsorption (reducing urinary excretion), and to increase 1,25-dihydroxycolecalciferol formation (thereby also increasing GIT absorption)
2. Bone: to increase resorptionW
What are the two cell types of the parathyroid glands and their functions?
- Chief cells: secrete PTH
- Oxyphil cells: unknown function
What is the normal plasma PTH level and what is its half-life?
Normal level 10-55pg/mL
t1/2 = 10mins
Describe the metabolism and excretion of PTH
Metabolised by Kuppfer cells in liver
Excreted by kidneys
What are the three main actions of PTH and how are these achieved?
- Increased plasma Ca2+ via:
- Direct action on bone, increasing resorption
- Increased 1,25-dihydroxycolecalciferol formation (to increase GIT absorption and renal tubular reabsorption)
- Increased reabsorption in distal tubules - Decreased plasma PO4(3-):
- Phosphaturic action via decreased expression of Na+-dependent cotransporter for PO4(3-) reabsorption in proximal tubule - Longterm stimulates both osteoblasts and osteoclasts (variable net effect but usually anabolic)
Why does hyperparathyroidism cause hypercalciuria?
Increased load overwhelms effect of hyperPTH on tubular reabsorption
Describe the three mechanisms of PTH regulation
- Circulating Ca2+ acts via CaSR on parathyroid gland to reduce PTH secretion
- 1,25-dihydroxycolecalciferol acts directly on parathyroid gland to decrease preproPTH mRNA
- Increased PO4(3-) stimulates release indirectly via reduction in Ca2+ and 1,25-dihydroxycolecalciferol
What electrolyte is required for normal parathyroid function?
Mg2+
Where is calcitonin produced?
By parafollicular (clear or C cells) in the thyroid gland
List eight factors which stimulate calcitonin secretion
- Increased plasma Ca2+
- B-agonists
- Dopamine
- Oestrogens
- Gastrin
- CCK
- Secretin
- Glucagon
What is the clinical significance of gastrin as a potent stimulus for calcitonin release?
Elevated calcitonin seen in Zollinger-Ellison syndrome and pernicious anaemia (not a significant contributor to calcitonin levels in normal function)
What are the effects of calcitonin on Ca2+ and PO4(3-)?
Decrease Ca2+ by directly inhibiting bone resorption and by increasing urinary excretion
Decrease PO4(3-)
What is the physiological significance of calcitonin?
Unclear: no syndrome attributable to its deficiency or excess
May have a role in skeletal development (higher levels in children), in preventing postprandial hypercalciaemia (released in response to gastric hormones), or in preventing bone loss during pregnancy
What is the effect of glucocorticoids on calcium homeostasis?
Inhibits osteoclasts to decrease plasma Ca2+
Over long periods can cause osteoporosis due to decreased bone formation (inhibits protein synthesis in osteoblasts) and increase bone resorption (due to feedback of initial low Ca2+ increasing PTH secretion), decreased Ca2+ and PO4(3-) absorption from GIT and increased urinary excretion
What is the effect of growth hormone on calcium homeostasis?
Increases Ca2+ absorption from GIT
Also increases urinary excretion of Ca2+
However absorption > excretion so net increase in Ca2+
What is the effect of insulin on calcium homeostasis?
Increases bone formation (bone loss seen in untreated diabetes)
What is the effect of oestrogens on calcium homeostasis?
Protect against osteoporosis by inhibiting stimulatory cytokines acting on osteoclasts
What is the effect of thyroid hormones on calcium homeostasis?
Cause hypercalcaemia and hypercalciuria
May cause osteoporosis
Three functions of bone
- Ca2+ and PO4(3-) homeostasis
- Protection of vital organs
- Permits locomotion and supports loads against gravity
What is bone?
Specialised connective tissue composed of collagen framework embedded with Ca2+ and PO4(3-) salts, particularly hydroxyapatites [Ca10(PO4)6(OH)2]
Describe the structure of bone, making reference to the two different types of bone and their relative proportions
Outer cortical bone (80%) with inner trabecular (20%)
Describe the differences between cortical and trabecular bone
Cortical: low surface-to-volume ratio, cells lie in lacunae, receives nutrients from Haversian canals/systems via canaliculi
Trabecular: high surface-to-volume ratio, made of spicules/plates, nutrients diffuse from ECF
What type of collagen predominates in bone?
> 90% type I
Describe the process of normal bone growth
Epiphyses at ends of bone separated from shaft by plate of actively proliferating cartilage called the epiphyseal plate
Growth ceases after epiphyseal closure: cartilage stopes secreting, becomes hypertrophic and releases VEGF to induce vascularisation and ossification
What is the width of the epiphyseal plate proportional to? What hormones affect it?
Rate of growth
Affected by HGH and IGF-1
What is the difference between endochondral and intramembranous ossification?
Endochondral: bones modelled in cartilage and transformed to bone via ossification (majority)
Intramembranous: bone formed directly from mesenchymal cells (clavicles, mandibles, and certain bones of face/skull)
What cells are responsible for bone formation vs resorption, and what are their origins?
Bone formation: osteoblasts, modified fibroblasts
Bone resorption: osteoclasts, member of monocyte family
Briefly describe how osteoclasts break down bone
Bind via integrins to create “sealing zone”
Proton pumps acidify area, functions similar to lysosome
How do monocytes differentiate to osteoclasts?
In response to simultaneous RANK/RANKL pairing and M-CSF
How long does the cycle of bone remodelling take?
100 days
What is the % yearly Ca2+ turnover in an adult vs infant?
Adult: 18%
Infant: 100%
What is osteopetrosis?
Disease caused by unopposed osteoblast activity
Results in increased bone density, neurologic defects due to foraminal narrowing, haematologic abnormalities due to marrow crowding
What causes osteoporosis? Which type of bone is preferentially affected?
Relative excess of osteoclast function
Trabecular bone lost more rapidly as it is more metabolically active
What are two signs seen in hypocalcaemic tetany?
- Chvostek sign: facial muscle contraction caused by tapping facial nerve at angle of jaw
- Trosseau sign: muscular spasm causing flexion of wrist and thumb with extension of fingers
