Parathyroid gland physiology

Section: Endocrine Sub-section: Parathyroid

Calcium Transport

• Transported in the blood
  • Bound to plasma proteins (45%; largely Albumin)
  • Bound to small anions such as phosphate or citrate (15%)
  • Free ionized state (40%)
• Normal range of ionized Ca2+ is 4.6 to 5.2 mg/dL
• Total serum Ca2+ concentrations range from 8.5 to 10.2 mg/dL
• Calcium levels are maintained within the very narrow range required for optimal activity of intracellular and extracellular processes
  • Hormone secretion
  • Muscle contraction
  • Synaptic/Nerve function
  • Coagulation cascade
• If fluctuation of protein concentration, total calcium levels vary significantly, but ionized calcium remains relatively stable
  • E.g. volume overload, chronic illness, or malnutrition, serum protein is often reduced
  • Low serum protein leads to a low total plasma calcium level; however, ionized calcium remains within normal limits
    • Pseudohypocalcemia
• Changes in pH alter the equilibrium between calcium and albumin
  • Acidosis reduces calcium binding to albumin
  • Alkalosis enhances binding and can cause symptoms
  • When significant shifts in pH, measure ionized calcium for accurate assessment of calcium status

Calcium Homeostasis

• Main regulators are
  • PTH
  • Vitamin D
  • Calcitonin
• Main target organs of these are
  • Bone
  • Kidneys
  • Gut

Parathyroid Hormone

• Secreted by Parathyroid Chief Cells in response to decreased serum (extracellular) Ca2+
  • Plasma ½ life of 4.5 mins
• Exerts action on target organs by binding to:
  • PTH1R (Parathyroid 1 receptor)
    • Heavily expressed in bone (osteoblasts) and kidney
    • Also present in breast, skin, heart and pancreas
    • Recognises PTH and PTHrP
  • PTH2R (Parathyroid 2 receptor)
    • Heavily expressed in GIT, CVS and CNS (rarely present on bone and kidneys)
    • Selectively binds PTH only

PTH Effects

• Kidneys
  • Increased Ca2+ resorption from distal tubule
  • Increased Phosphate and Bicarb excretion
  • Increased renal synthesis of Calcitriol: 1,25-dihydroxyvitamin D3
    • Stimulates synthesis of 1α-Hydroxylase in Proximal tubules
  • Results in increased GIT Ca2+ and Phosphate absorption
• Bone
  • Works in 2 phases
    • Early, mobilises readily available Ca2+ stores - osteoblasts
    • Later, indirectly stimulates bone resorption (Ca2+ and Phosphate release) - osteoclasts
  • PTH1R on osteoblasts
    • No PTH receptor on osteoclasts, but osteoclasts indirectly stimulated as action coupled to osteoblasts (by RANK ligand)
  • Intermittent PTH stimulation causes bone deposition, chronic high PTH stimulation causes bone resorption
• Net effect
  • Increases Serum Ca2+ and decreases Phosphate (if kidneys functioning)

Vitamin D

• Overview
  • Initially in inactive forms
    • Ergocalciferol (Vit D2) - from diet
    • Cholecalciferol (Vit D3) - from sunlight
  • Converted to Calcidiol (25-hydoxyvitamin D3) by hepatic enzyme 25-hydroxylase
  • Calcidiol travels in circulation to kidneys and converted to Calcitriol (1,25-hydroxyvitamin D) which is the active form by 1α-Hydroxylase
• Absorption/Synthesis
  • Fat soluble vitamin (makes steroid hormone)
    • Can have deficiency if fat malabsorption syndrome
  • Most synthesised by UV light at the skin
  • Small amount from diet
    • Very few foods naturally contain Vit D
      • Except fatty fish livers
    • Most dietary Vit D from fortified foods and supplements
  • Initially in inactive forms
    • Ergocalciferol (Vit D2) - from diet
    • Cholecalciferol (Vit D3) - from sunlight
• Calcidiol (25-hydoxyvitamin D3)
  • Vit D2 and Vit D3 from gut and skin circulate to liver
  • Hepatic enzyme 25-hydroxylase places hydroxyl group at 25 position of Vit D molecule
    • Makes 25-hydroxyvitamin D (Calcidiol)
      • Main circulating form of Vit D
      • T1/2 is 2-3 weeks
      • Has mild activity at bone and intestine
      • < 1% as potent as Calcitriol
• Calcitriol (1,25-hydroxyvitamin D)
  • Calcidiol travels in circulation to kidneys
    • Taken up into Proximal Tubule cells
  • 1α-Hydroxylase converts Calcidiol into 1,25-hydroxyvitamin D (Calcitriol)
    • Most active form of Vit D
    • T1/2 ~ 4-6 hours
  • Calcitriol effects
    • Most important: Promotes enterocyte differentiation and intestinal absorption of Ca2+
    • Also stimulates intestinal phosphate absorption
    • Suppression of PTH (negative feedback)
    • Regulation of osteoblast function
    • Permissively allowing PTH-induced osteoclast activation and bone resorption
    • Decreased renal excretion of Ca2+ and phosphate
• 1α-Hydroxylase
  • Converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D
    • Mostly in the Proximal Tubule cells of the kidney
    • Also present at extra-renal sites
      • GIT, skin, vasculature, mammary epithelial cells, osteoblasts, and osteoclasts
      • Most commonly seen extra-renal calcitriol synthesis is in granulomatous disease (e.g. Sarcoid)
        • Get PTH independent extra-renal calcitriol synthesis
        • Results in hypercalcaemia and hypercalciuria
  • Regulated by
    • Increased PTH, due to low Ca2+ (stimulates)
    • Low phosphate (stimulate)
    • FGF-23 (inhibits)

Calcitonin

• 32 amino acid polypeptide secreted by parafollicular C cells
  • Located superolaterally in each thyroid lobe
  • Increased peripheral levels of Ca2+ stimulate calcitonin release
    • Ca2+ infusion, gastrin/pentagastrin, ETOH can do this
• Major effect (“tones down calcium”)
  • Acts on the surface receptors of osteoclasts
  • Directly inhibits Ca2+ release from bone
  • Decreases peripheral serum Ca2+ levels
• Minor Effect
  • Inhibits renal tubular reabsorption of Ca2+ and phosphate
  • Allows them to be excreted in the urine
• In normal physiology, calcitonin has minor role
  • E.g. Medullary Thyroid Ca has calcitonin excess but has little alteration in peripheral Ca2+ metabolism
  • E.g. Post-thyroidectomy: Low calcitonin doesn’t require Ca2+ supplementation
• Sensitive markers from primary or recurrent Medullary Thyroid Ca