Parathyroid Hormone and Calcium Homeostasis

What is the physiological importance of calcium? (1)

1-2 kg of Ca in the human body. 99% found in bone and teeth and hydroxyapatite crystals (structural integrity of skeleton/teeth). Concentration regulated. 0.9% EC and 0.1% IC

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What is the physiological importance of calcium? (2)

Bone growth/remodelling, blood coagulation (enzyme co-factor), muscle contraction (actin/myosin interaction), neuronal function (regulate excitability), enzyme action, exocytosis of hormones/NTs (triggered by Ca influx), IC signalling (2nd messenger)

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What are the concentrations of Ca in - serum, interstitium and intracellular?

Serum - 8.8-10.4 mg/dL (mg/100 mL). Interstitium - ~6.0 mg/dL. Intracellular 0.4-4.0 mg/dL

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What percentage of extracellular calcium is bound to plasma proteins (e.g. albumin)

~45%

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What percentage of extracellular calcium is complexed with anions (e.g. citrate, phosphate, sulfate)?

~10%

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What percentage of extracellular calcium is unbound (physiologically active)?

~45%

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Describe how an increase in Ca concentration triggers insulin secretion from beta cells when glucose induced (1)

Increase in IC glucose, causes changes in ratio of ATP levels in beta cells, ATP sensitive K channel, depolarisation of membrane, VDCC opens, Ca influx (EC Ca conc > IC Ca conc), triggers release of insulin via exocytosis

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Describe how an increase in Ca concentration triggers insulin secretion from beta cells when glucose induced (2)

Study - measure change in Ca level, expose cells to high levels of glucose, fluorescence ratio increases then decreases (graph)

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How can the role of calcium in regulation and exocytosis be determined? (1)

Use nifedipine (VDCC blocker) inhibits glucose-induced insulin secretion from human beta cells. Graph of time vs insulin secretion. Absence of nifedipine (increase insulin secretion). Presence of nifedipine (decrease in insulin secretion)

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How can the role of calcium in regulation and exocytosis be determined? (2)

Exposure of cells to high levels of glucose doesn't mean an increase in insulin (Ca plays a role in regulation)

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How does calcium act as a secondary messenger? (1)

Triggers GPCR pathways - GPR75, Gq, PLC, IP3, results in Ca influx. Ca binds to CaM (regulation of beta cell proliferation)

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How does calcium act as a secondary messenger? (2)

Study - changes in levels of CaMK4 when the cell is exposed to different glucose levels

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How is calcium homeostasis regulated?

Serum Ca is increased by two hormones - PTH and vitamin D. Regulation of Ca homeostasis using calcitonin and parathyroid hormone-related peptide

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Outline how calcium homeostasis is regulated in organs (1)

Homeostasis - normal blood Ca level of 10 mg/100 mL. Increase in Ca level (thyroid gland releases calcitonin, stimulated Ca deposition in bones, reduces Ca uptake in kidneys, return to normal level)

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Outline how calcium homeostasis is regulated in organs (2)

Fall in blood Ca (parathyroid glands releases PTH, increase Ca uptake in intestines, increase Ca uptake in kidneys/active vitamin D present, stimulate Ca release from bones, return to normal level))

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Describe the anatomy of the parathyroid glands (1)

Embedded in posterior surface of thyroid gland but are anatomically and histologically distinct from the thyroid. Usually 4 (may vary), total weight of parathyroid tissue is ~150 mg

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Describe the anatomy of the parathyroid glands (2)

Consists of oxyphil cells (unknown function) and chief cells (produce PTH)

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Describe the morphology of the parathyroid gland

Contains large amount of adipose tissue (expands in volume at puberty). PTH producing chief cells have prominent central nuclei and pale cytoplasm. Oxyphil cells appear in clusters, have dark nuclei and acidophilic cytoplasm

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Which three hormones regulate calcium homeostasis?

PTH (polypeptide hormone, promotes increased plasma Ca). Vitamin D3 (cholesterol derivative, promotes increased plasma Ca). Calcitonin (polypeptide hormone, promotes decreased plasma Ca)

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Describe features of the parathyroid hormone (1)

Produced by parathyroid chief cells. Synthesised from pre-pro-PTH (precursor, 115 amino acids). Pre-pro-PTH cleaved to pro-PTH (90 amino acids). PTH biologically active 84 amino acid peptide (first 34aa fully active)

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Describe features of the parathyroid hormone (2)

PTH synthesised continuously. Released from parathyroid gland. Degraded. Secreted by exocytosis in response to reduced plasma Ca. Not under hypothalamic control but responds directly to changes in plasma Ca levels

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Describe features of the parathyroid hormone (3)

Detected by Ca-sensing receptors (CaSR) on the surface of chief cells

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Describe the response of the parathyroid cell to high Ca concentration in EC fluid

Activation of CaSR, activation of PLC, inhibition of AC, increased IC Ca via generation of IP3, decreased cAMP, inhibition of PTH exocytosis (PTH inhibited by increase in EC Ca). Also inhibited by vitamin D (secondary mechanism negative feedback)

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Describe the response of the parathyroid cell to low Ca concentration in EC fluid

Inhibition of CaSR, inhibition of PLC, activation of AC, decreased IC Ca (reduced generation of IP3), increased cAMP, activation of PTH exocytosis

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PTH (Chief) cells express which type of receptor?

CaSR, a GPCR (transmembrane receptor). High EC Ca inhibits PTH release. Low EC Ca stimulates PTH release. (Graph - PTH secretion decreases as the total plasma Ca conc increases)

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How does PTH act on bones? (1)

Binds to GPCR (PTH-R), activation of PTH-R, increase in cAMP, release of Ca form IC stores (increase Ca conc). Bones - PTH-R on osteoblasts (initial bone formation). Bone resorption via cytokines from osteoblasts

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What effect does PTH have on bones? (2)

Promote bone resorption (transfer of Ca from bone to blood) and increase Ca concentration

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What effect does PTH have on the kidneys?

Inhibits PO4 reabsorption (inhibits Na-PO4 co-transport in PCT), phosphaturia, less complexed Ca-PO4, increase plasma Ca, stimulates Ca reabsorption on DCT. Phosphaturia + Ca reabsorption = increase in Ca concentration

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What effect does PTH have on the small intestine?

Stimulated Ca reabsorption via activation of vitamin D. Stimulates renal 1 alpha hydroxylase - converts 25 hydroxycholecalciferol to 1,25 dihydroxycholecaliferol - stimulates intestinal Ca absorption

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Summarise the actions of PTH on the bones, kidneys and small intestine to maintain calcium homeostasis (1)

Bone (increase osteoclast activity to release Ca and PO4). Kidneys conserve Ca. Intestine absorbs Ca from diet (activation of vitamin D/increase Ca absorption)

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Summarise the actions of PTH on the bones, kidneys and small intestine to maintain calcium homeostasis (2)

Opposite effects to decrease Ca plasma levels (bone incorporates Ca, Ca excreted from diet/urine). (Increase Ca reabsorption, decrease PO4 reabsorption)

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How is vitamin D synthesised?

In skin keratinocytes from 7-dehydrocholesterol via action of UV light. Also ingested in food/absorbed into bloodstream

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Where is vitamin D metabolised?

In the liver and kidneys - activated form is 1,25(OH)2-D3 (1,25 dihydroxvitamin D3)

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What is the major site of regulation of synthesis for vitamin D?

Kidney (under control of PTH)

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1,25-(OH)2-D3 acts on which receptors?

Steroid-hormone life receptor to increase gene transcription of Ca binding protein which facilitates Ca uptake by intestinal cells

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Where is 25-dihydroxy-vitamin D3 (25-OH-D3) stored?

In the liver (storage form)

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Where is the active form of vitamin D located?

1,25-dihydroxy-vitamin D3 (1, 25-OH-D3/calcitriol) is located in kidney. (1 alpha hydroxylase, enzyme rate limiting, regulated by PTH). Conversion of 25-OH-D3 to 1,25-OH-D3/calcitriol by sequential enzymatic reactions in liver/kidney (PTH regulation)

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Describe features of the active form of vitamin D (1)

Calcitriol has a short half life (few hours). Circulates bound to specific binding proteins. Binds to nuclear receptors (VDR) - alteration gene transcription. Increase Ca transport proteins, increased Ca absorption, rapid uptake of Ca from gut

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Describe features of the active form of vitamin D (2)

Increases bone resorption and reduces urinary Ca loss at kidney

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Describe the mechanism of action for vitamin D (1)

Vitamin D binds to nuclear receptor, forms heterodimer with retinoid X receptor (RXR). Transcription and mRNS production. mRNA expression. Classical - Ca uptake, PTH synthesis, renal PO4/Ca, osteoblast/osteoclast differentiation/function

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Describe the mechanism of action for vitamin D (2)

Non-classical - anti-cancer, anti-proliferative, regulation of apoptosis and angiogenesis, anti-bacterial, antigen presentation, anti-inflammatory, anti-hypertensive

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Summarie the actions of calcitriol (active form of vitamin D, 1,25-(OH)2-D3) on the bones, kidneys, and small intestine

Increase osteoclast activity to release Ca (via osteoblast paracrine effect). Kidneys conserve Ca. Intestine absorbs Ca from diet (increase Ca absorption). Opposite actions to decrease Ca levels - incorporate Ca in bone, excrete Ca in urine/diet

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Is vitamin D a vitamin? (1)

Vitamin D is not a vitamin but a steroid hormone. Vitamin is a substance that must be provided by diet (only 10% of vitamin D derived from diet, skin - 90% of vitamin D)

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Is vitamin D a vitamin? (2)

Hormone - Calcitriol is produced in the kidney/released from systemic circulation/no duct involved, acts on distant organ (epithelial cells of SI)

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Describe features of vitamin D deficiency (1)

UV light from sun rays carry far less energy in winter than in summer (only 15 mins/day of head/neck exposure in Western Europe in summer). Dietary sources of vitamin D - fish, cereal, whole grains, cheese, butter, milk

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Describe features of vitamin D deficiency (2)

Food supplementation - adding chalk-calcium carbonate to flour and vitamin D to margarine during WWI. Food laws still require supplementation of all white flour and margarine in the UK today

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Where is calcitonin synthesised and stored?

In parafollicular C-cells located between follicles in the thyroid gland

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Describe features of calcitonin and calcium homeostasis (1)

Increased plasma Ca stimulates calcitonin secretion. Inhibits osteoclast motility/inactivation, reduces bone reabsorption and reduces plasma Ca. Chronic excess of calcitonin doesn't produce hypocalcaemia

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Describe features of calcitonin and calcium homeostasis (2)

Removal of parafollicular cells doesn't cause hypercalcaemia. Role of calcitonin in Ca homeostasis is unclear (might be important for control of bone remodelling). Calcitonin used in treatment of hypercalcaemia/bone disorders (e.g. Paget's disease)

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Describe features of the thyroid gland and calcitonin

Lined by epithelial cells (principal cells) - responsible for synthesis/secretion of thyroid hormones T3/T4. C-cells (clear cells, parafollicular cells) - responsible for synthesis/secretion of calcitonin, regulates Ca homeostasis

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Describe the effects of calcitonin (1)

Peptide hormone produced by parafollicular cells of thyroid gland. Released in response to increased Ca in EC fluid (directly regulated by Ca conc, no hypothalamus/pituitary control). Opposes PTH actions - inhibits osteoclasts (release Ca from bone)

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Describe the effects of calcitonin (2)

Protective effect on bone Ca. Stimulates Ca release from kidneys. Physiological relevance is humans is unclear

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Describe the effects of calcitonin (3)

Neither thyroidectomy (calcitonin deficiency) nor thyroid tumours (excess calcitonin) has significant effect on Ca homeostasis (PTH and vitamin D3 regulation dominate)

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Describe the effects of calcitonin (4)

Used clinically in treatment of hypercalcemia in certain bone diseases in which sustained reduction of osteoclastic resorption is therapeutically advantageous

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Summarise the effects of calcitonin on the bones, kidneys and small intestine

Bones - decrease osteoclast activity to reduce Ca release. Ca excretion in urine/diet. Decrease Ca reabsorption, increase Ca excretion. Opposite effects to increase Ca levels - release Ca from bone, kidneys conserve Ca, intestines absorb Ca from diet

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What is the physiological response to hypocalcaemia? (1)

Decreased plasma Ca causes increased PTH. Mobilisation of bone Ca and PO4. Increased renal phosphate excretion and Ca retention. Increased Vit D3 synthesis. Rise in plasma Ca levels, maintenance of normal phosphate levels

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What is the physiological response to hypocalcaemia? (2)

Reduced plasma Ca, increased PTH secretion, increased breakdown of bone/reduced formation of bone, increased formation of calcitriol in kidney (increase Ca absorption), less Ca lost in urine, increased Ca absorption in gut, increased plasma Ca levels

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What is the physiological response to hypercalcaemia? (1)

Increase in plasma Ca causes decreased PTH secretion. Reduced mobilisation of bone by osteoclasts and increased formation by osteoblasts. Decreased renal Ca absorption and reduced calcitriol synthesis. Reduction in plasma Ca levels

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What is the physiological response to hypercalcaemia? (2)

Increased plasma Ca, reduced PTH secretion, reduced breakdown of bone/increased formation of bone, reduced formation of calcitriol in kidneys/reduced Ca absorption, excess Ca lost in urine, less Ca uptake from gut, reduced plasma Ca levels

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Describe features of calcium related pathologies - hypocalcaemia (1)

Vit D deficiency (lack of sunlight/dietary sources), chronic renal failure (reduced hydroxylation of vit D), pseudohypoparathyroidism (tissue resistance to PTH), iatrogenic (damaged/removed during thyroid surgery)

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Describe features of calcium related pathologies - hypocalcaemia (2)

Autoimmune disorders (auto-antibodies destroy tissue)

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Describe features of calcium related pathologies - hypercalcaemia

Excess plasma Ca. Kidney-calcification (stones). Depression (regulation of NTs). Abdominal pains (constipation)

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What is PTH-deficient hypoparathyroidism?

Reduced/absent synthesis pf PTH. Due to removal of excessive parathyroid tissue during thyroid surgery (results in bone resorption and hypocalcaemia)

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What is PTH-ineffective hypoparathyroidism?

Synthesis of biologically inactive PTH (results in bone resorption and hypocalcaemia)

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What are the symptoms of hypocalcaemia?

Tetanic muscle contractions (spasms laryngeal muscle/stridor). Seizures (brain). Cardiac effect (repolarisation delayed/prolonged QT interval). Cataract (protein accumulation). Dry/flaky skin/brittle nails. Tetany in hand (Trousseau/latent tetany)

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What is a carpopedal spasm?

Adduction of the thumb over the palm, followed by flexion of metacarpophalengeal joints (fingers together), adduction of hyperex-tended fingers, flexion of wrist and elbow joints (similar effects in joints of feet)

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What is a Chvostek sign?

Hypocalcaemia causes a Chvostek sign. Twitching of lip at corner of mouth to spasm of all facial muscles (depends on severity of hypocalcaemia)

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What is osteomalacia?

Softening of bones (defective bone mineralisation). Adults-partial fractures (bone pain, looser appearance on X-ray examination). Children-elongation/distoration in chrondrocytes in growth region of cartilage (reduced/absent calcification/rickets)

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What causes rickets?

Associated with severe dietary restriction of Ca. Common in malnourished children in development countries

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What is osteoporosis?

Brittle/fragile bones (fractures from minimal trauma). Hormonal changes (oestrogen, testosterone, thyroid hormones). Deficiency of Ca or Vit D. Long-term use of corticosteroid medications

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Describe features of PTH disorders (excess) (1)

Caused by adenoma or hyperplasia (more common in women). Chronically elevated plasma PTH causes hypercalcaemia (low PO4). Depression of NS (flow reflex, depression), decreased appetite/anorexia/constipation/vomiting

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Describe features of PTH disorders (excess) (2)

Bones - osteitis fibrosa/arthritis, cystic area in bone, may contain fibrous tissue, marrow fibrosis. Stones - calcium phosphate crystals throughout the body, kidney stones (deposit in kidney)

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Describe features of Jansen's metaphyseal chrondrodysplasia

Rare activating mutation of PTH receptor. Hypercalcaemia/hypophosphotemia, short-limbed dwarfism. Delayed irregular ossification. Generalised symmetric shortening of long bone. Deeply cupped metaphyseal ends of long bone. Ossified shafts of long bone

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Describe features of 1,25-(OH)2-D3 deficiency (1)

Lack of UV, dietary insufficiency, genetic mutations. Excess osteoid (demineralised bone) - lack of repression of osteoblastic collagen synthesis. Children - rickets/deformed bones. Adults - osteomalacia/soft bones

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Describe features of 1,25-(OH)2-D3 deficiency (2)

More common in children of Asian, African-Caribbean and Middle Eastern origin. Premature babies at risk, babies exclusively breastfed for longer than 6 months may be at risk

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Describe features of hypercalcaemia

Excess plasma Ca. Tests - increased PTH, increased serum Ca, most hypercalcaemic patients have overtly elevated PTH/Ca

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What are the causes of hyperparathyroidism?

Adenoma (unreponsive to negative feedback). Hyperplasia. Carcinoma

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Parathyroid Hormone and Calcium Homeostasis

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