Calcium Homeostasis

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

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

• 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

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

• 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.

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: Trousseau sign of latent tetany

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

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: 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

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