Brief info on calcium:

  • Calcium is important for many physiologic processes
  • Neurons are very sensitive with changes in Ca2+ ion concentration
    • 0.1%: in ECF
    • 1%: in cells
    • 98.9%: stored in bones & teeth
  • Most abundant cation in the body
  • Calcium in plasma is present in 3 forms:
    • protein bound form (can’t diffuse capillary membrane)
    • ionized form (can diffuse capillary membrane)
      • physiologically active
    • complex form (complex with anions)

Functions of calcium

  • Structural integrity & metabolism of bone
    • bone growth & remodelling
    • tooth formation
  • Synaptic transmission
    • presynaptic ending, calcium enters –> neurotransmitter exits
  • Control of excitability of nerve & muscle cells
    • stabilization of membrane potentials
      • by modulation of permeability to Na+ & K+
    • Excitation-contraction coupling in muscle
    • exocytosis for endocrine & exocrine glands)
  • Coenzyme function
    • haemostatis & complement systems (blood clotting)
  • Regulation of transmembrane ion transport
    • Bidirectional calcium transport
      • in ER, sarcoplasmic reticulum, mitochondria
  • Cell motibility
  • 2nd messenger in intracellular signal transduction pathways

Calcium homeostasis

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This is a summarised representation of calcium homeostasis.

An increase in Ca2+ in blood, Calcitonin will be secreted from parathyroid gland and stimulate

  • Ca2+ deposition in bone (storage)
  • Ca2+ reabsorption in kidney decreases

A decrease in Ca2+ in blood, PTH will be secreted from parathyroid gland and stimulate

  • Ca2+ release by bone
  • Ca2+ reabsortion in kidney increases
  • Kidney releases active Vitamin D
    • Increases Ca2+ uptake in intestine

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Calcium regulation involves

  • 3 tissues
    • bone
    • intestine
    • kidney
  • 3 hormones
    • Parathyroid
    • calcitonin
    • activated Vit D3
  • 3 cells
    • osteoblasts
    • osteocytes
    • osteroclasts

Regulation of calcium

  • Intestinal absorption (vit D dependent)
    • duodenum
    • proximal jejunum
  • Renal tubular reabsorption & excretion
  • Exchange of calcium between plasma & bone
    • bone remodelling

Calcium absorption

Calcium absorption occurs in the small intestine by

  • Active transport
    • Duodenum & proximal jejunum
  • Diffusion
    • Ileum

Once absorbed, intracellular transport involves carrier proteins, intestinal calcium-binding protein & cytosolic calcium-binding protein.

Active transport

Across the basolateral membrane

  • Mg2+ – Ca2+ – ATPase
    • Primary active transport
  • Ca2+/NA+ exchanger
    • Secondary active transport

Vitamin D3/Calcitriol/1,25 dihydroxyvitamin D3

  • regulates amount of cytosolic calcium binding protein
  • activates the active transport systems

Parathyroid hormone

  • increases small intestinal absorption
    • by enhancing 25-OH D-1 hydroxylase activity & calcitriol synthesis

Renal excretion

  • 10% ingested calcium will be excreted in the urine
  • Ionized & complex forms only can be filtered in the glomerulus
    • 70% reabsorbed in proximal tubule
      • transcelluar absorption via calcium channels (down electrochemical gradient)
      • calcium extrusion across basolateral membrane/active transport (against electrochemical gradient)
      • Paracellular absorption
        • across tight junctions (Between epithelial cells)
    • 20% reabsorbed in the LOH
    • 9% reabsorbed in he distal tubule
      • transcellular absorption through voltage sensitive Ca2+ channels (activated by PTH)
    • 1% excreted in urine

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The parathyroid glands & it’s hormones

image

  • 4 parathyroid glands
    • 2 superior 2 inferior
  • behind the thyroid gland
  • macroscopic appearance: dark drown fat
  • removal of 2 parathyroid glands will not cause any abnormalities, but removal of 3  or more will cause transient hypoparathyroidism
  • Cells
    • Chief cells: secrete most of the PTH
    • Oxyphil cells

image

image

Parathyroid hormone

  • Maintains the plasma ionized  calcium level
    • calcium sensing receptor are located on the parathyroid cell surface
    • detects the serum calcium concentration & determine the set point for the serum PTH concentration
  • Mg2+ required for PTH release & to perform it’s effects on target tissues
  • PTH binds to plasma membrane G-protein coupled receptors on target cells (bone & kidney)
  • PTH levels follow a diurnal circadian pattern

Structure

  • Biological activity confined to the NH2-terminal 34 amino acid sequence
  • no disulphide linkages
  • Encoded on chromosone 11
  • Circulating half life : 2-4 minutes only

Bone cells

  • osteoblast: bone formation
  • osteoclast: bone resorption/ breakdown

Actions of PTH

  • Bone
    • releases Ca2+ from bone
      • Bone resorption
      • Direct effect of osteroblasts which then stimulates osteocla
        sts
      • transports calcium from bone to ECF (increase in serum calcium level)
    • phases
      • Rapid phase: begins in minutes and increases progressively for several hours, results from activation of already existing bone cells (osteocytes) to promote calcium & phosphate absorption
        • osteoblasts & osteocytes have receptors for PTH
        • PTH stimulate calcium pump at the bone fluid side of the osteocytic membrane
        • calcium pump transfers calcium ions into the ECF
      • Slower phase: several days/ weeks to become fully developed. Results from proliferation of osteoclasts, followed by greatly increased osteoclastic reabsorption of the bone
        • Activation of osteoclasts by PTH
        • Activation of osteoblasts & osteocytes send 2ndary signals to osteoclasts for bone resorpsion
    • Osteoclastic osteolysis
      • increased osteoclastic size & no.
      • increased osteoclastic collagenase & lysosomal enzyme activity
      • increased osteoclastic acid phosphatase, carbonic anhydrase, lactic acid, and citric acid concentration
      • increased bone resorption
      • mobilization of Ca+, Mg2+ and inorganic phosphate
    • Increased osteoblastic number
      • also has bone formation effect, but less than resorptive effect
    • Increased collagen synthesis
      • for osteoid
    • Increased alkaline phosphatase activity
      • for resorption process
    • Increase local growth factors
      • IGF & transforming factors

 

  • GIT
    • Increase calcium uptake
      • Acts synergistically with vit D
      • indirect action thru vitamin D (induce a calcium-binding protein in the duodenal & jejunal mucosa)
    • Increase absorption of phosphate
      • Acts synergistically with vit D

 

  • Kidney
    • Increase reabsorption of calcium
    • Increase urinary excretion of phosphate
    • Reduces tubular reabsorption of phosphate
    • Formation of Vit D3
      • acts on intestine
    • Decrease Na+ and bicarbonate reabsorption from the proximal tubule

Calcitonin

image

  • effects opposite to PTH (decrease plasma calcium concentration)
  • from parafollicular cells/C cells
  • Effect of calcitonin in children is much greater

Actions of calcitonin

  • Decrease absorptive activities of the osteoclasts & osteolysis
  • Deposition of calcium in the bone salts
  • Prolong & decrease formation of new osteoclasts
  • minor effect on kidney
    • excretion of calcium, natrium & phosphate
    • inhibit tubular reabsorption
    • decrease synthesis of vit D3
      • by inhibiting renal 1 alpha-hydroxylase activity
  • Inhibit gastric motility & secretion
  • Inhibit absorption in intestine
  • Used to treat for osteoporosis as well (decrease resorption)

Activated Vitamin D3

  • also known as 1,25-dihydroxycholecalciferol (1,25-DHCC)/calcitriol
  • is formed in the skin as a result of UV rays
    • increase sunlight, increase Vit D

Synthesis

  • Cholecalciferol is converted to 25-hydroxycholecalciferol in the liver
  • converted to 1,25-dihydrocholecalciferol in proximal tubule (requires PTH)

Calcium automatically converts 25 DHCC to 1,25 DHCC. At higher calcium concentrations, activated D3 (1,25-DHCC) is converted to 24,25 DHCC.

image

Actions of Vit D3

  • Increase intestinal calcium absorption
    • increase calcium binding protein in the intestine
      • brush border
    • rapid phase: via increased Na/Ca exchange activity
    • slow phase: via increased synthesis of calcium binding protein (calbindins)
  • Increase phosphate absorption
  • Increase calcium & phosphate reabsoption in kidneys
  • Increase calcium transporters thru cellular membranes in bone
    • increases bone resorption
    • In smaller quantities, Vit D promotes bone calcification

Other non-classical actions, read up Calcium homeostasis lecture notes.

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Hypoparathyroidism (Insufficient PTH)

  • Decreased bone resorption & osteocytic activity
  • Decrease calcium in ECF (hypocalcemia)
    • Increased neuromuscular excitavility
    • Na+ channel remain open, Na+ enters myocytes and cause increased excitability –>
      • tetanic muscle contractions
      • spasm of laryngeal muscle (laryngeal stridor)
      • seizures (brain)
      • Cardiac effect (repolarization is delayed with prolonged QT interval)
      • *Cataract (protein accumulation)
      • Dry & flaky skin
      • Brittle nails
      • tetany in the hand (Trousseau sign of latent tetany)
      • Chvostek sign

image

Image: Trousseau sign of latent tetany

  • carpopedal spasm
  • sometimes hidden, seen suddenly when inflate BP cuff (decrease blood flow)

image

Image: Chvostek sign

Pseudo hypoparathyroidism

  • Target organs (bone, kidney & intestine) receptors are resistant to PTH
  • Congenital defect in the G protein
    • associated with PTHR1
  • Plasma Ca2+ low
  • Plasma phosphate high
  • Basic phosphatase activity is high

Primary hyperparathyroidism

  • Excess PTH –> hypercalcemia, low phospahe
    • Tumour, adnoma or hyperplasia
    • Ectopic tumour in mediastinum
  • More common in woman
  • Large cystic area in bone, may contain fibrous tissue
  • Marrow fibrosis
  • Bone disease: osteitis fibrosa cystica
  • Metabolic acidosis (effect on renal tubule H+ reabsorption)
  • Increased alkalline phosphatase (from osteoblasts, due to increased osteoblastic activity)

image

Image: Osteitis fibrosa cystica

Hypercalcemia with hyperparathyroidism (not very important)

MOANS, GROANS, BONES, STONES

  • Psychic moans
    • Depression of nervous system
    • slow reflex
    • depression
  • Abdominal Groans
    • Decreased appetite, anorexia, constipation, vomiting
  • Bones
    • Osteitis fibrosa/arthritis
  • Parathyroid poisoning & metastatic calcification
    • Calcium phosphate crystals throughout body
    • Kidney stones (deposit in kidney)
  • Shortened QT interval

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Hypercalcemia can also be due to thiazide diuretics.

Secondary hyperparathyroidism

  • As a compensation for hypocalcemia
    • Increase in PTH –> hyperparathyroidism

Tertiery hyperparathyroidism

  • After prolonged 2ndary hyperparathyroidism
    • 2ndary hyperparathyroidism no longer responsive to treatment
  • PTH related peptide (PTH-rp)
    • binds to PTH receptor
    • actions similar to PTH –> results in hypercalcemia
    • PTH levels: low/undetected
    • Produced by cancers
    • Useful for: bone development, mammary gland development, lactation and tooth eruption
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Terri is obsessed with making medical school as painless as possible. She studies and compiles medical school notes in a concise, easy-to-understand format. She also enjoys reading contributions by others. She is an investor in sustainability projects. Her ideal weekend is wine tasting and experimenting on bread-making. She has yet to master the art of Sourdough baking.

2 COMMENTS

  1. Can someone please give me a refrence on the information on homeostasis of calcium in the blood, as i would love to use this information for my assignment but i cant unless i have the proper information on who wrote this information. Thanks

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