21 +24 physiology

• Calcium


  An essential intracellular signaling molecule and also plays a variety of extracellular functions

  
• Components of the system that maintains calcium homeostasis

  • Cell types that sense changes in extracellular calcium and release calcium-regulating hormones
  • Targets of these hormones, including the kidneys, bones, and intestine, that respond with changes in calcium mobilization, excretion, or uptake

  
• Hormones primarily concerned with the regulation of calcium homeostasis

  • Parathyroid hormone (PTH)
  • 1,25-Dihydroxycholecalciferol
  • Calcitonin

  
• Parathyroid hormone (PTH)


  Its main action is to mobilize calcium from bone and increase urinary phosphate excretion

  
• 1,25-Dihydroxycholecalciferol


  Its primary action is to increase calcium absorption from the intestine

  
• Calcitonin


  A calcium-lowering hormone that inhibits bone resorption
• Phosphate homeostasis is likewise critical to normal body function, particularly given its inclusion in adenosine triphosphate (ATP), its role as a biological buffer, and its role as a modifier of proteins, thereby altering their functions
• Many of the systems that regulate calcium homeostasis also contribute to that of phosphate, albeit sometimes in a reciprocal manner

  
• Calcium in the body


  The body of a young adult human contains about 1100 g (27.5 moles) of calcium, with 99% in the skeleton

  
• Plasma calcium


  Normally at a concentration of around 10 mg/dL (5 mEq/L, 2.5 mmol/L), partly bound to protein and partly diffusible

  
• Free, ionized calcium (Ca2+)


  A vital second messenger and is necessary for blood coagulation, muscle contraction, and nerve function

  
• A decrease in extracellular Ca2+ exerts a net excitatory effect on nerve and muscle cells in vivo, resulting in hypocalcemic tetany
• The extent of Ca2+ binding by plasma proteins is proportional to the plasma protein level, and other electrolytes and pH also affect the free Ca2+ level
• Calcium in bone


  • A readily exchangeable reservoir and a much larger pool of stable calcium that is only slowly exchangeable
• Regulation of plasma Ca2+


  1. Movement of about 500 mmol of Ca2+ per day into and out of the readily exchangeable pool in the bone

  2. Ca2+ interchange between plasma and the stable pool of bone calcium is only about 7.5 mmol/d

  
• Regulation of Ca2+ absorption from the intestine

  Controlled by 1,25-dihydroxycholecalciferol

  
• Reabsorption of filtered Ca2+ in the kidneys

  98–99% of the filtered Ca2+ is reabsorbed, with 60% in the proximal tubules and the remainder in the ascending limb of the loop of Henle and the distal tubule
• Distal tubular reabsorption of Ca2+


  Regulated by PTH

  
• Phosphate


  Found in ATP, cyclic adenosine monophosphate (cAMP), 2,3-diphosphoglycerate, many proteins, and other vital compounds in the body

  
• Total body phosphorus


  500–800 g (16.1–25.8 moles), with 85–90% in the skeleton
• Total plasma phosphorus


  About 12 mg/dL, with two-thirds in organic compounds and the remaining inorganic phosphorus (Pi) mostly in PO43–, HPO42–, and H2PO4–
• The amount of phosphorus normally entering bone is about 3 mg (97 μmol)/kg/d, with an equal amount leaving via reabsorption
• Reabsorption of filtered Pi in the kidneys


  85–90% of the filtered Pi is reabsorbed, with active transport in the proximal tubule involving two related sodium-dependent Pi cotransporters, NaPi-IIa and NaPi-IIc
• NaPi-IIa


  Powerfully inhibited by PTH, causing its internalization and degradation and thus a reduction in renal Pi reabsorption

  
• Absorption of Pi in the duodenum and small intestine

  Many stimuli that increase Ca2+ absorption, including 1,25-dihydroxycholecalciferol, also increase Pi absorption
• Vitamin D


  A group of closely related sterols produced by the action of ultraviolet light on certain provitamins

  
• Vitamin D3 (cholecalciferol)

  Produced in the skin of mammals from 7-dehydrocholesterol by the action of sunlight

  
• Metabolism of vitamin D3


  1. Converted to 25-hydroxycholecalciferol (calcidiol, 25-OHD3) in the liver

  2. Converted to 1,25-dihydroxycholecalciferol (calcitriol, 1,25-(OH)2D3) in the cells of the proximal tubules of the kidneys

  
• 1,25-Dihydroxycholecalciferol


  Also made in the placenta, in keratinocytes in the skin, and in macrophages

  
• Normal plasma levels


  25-hydroxycholecalciferol: about 30 ng/mL

  1,25-dihydroxycholecalciferol: about 0.03 ng/mL (approximately 100 pmol/L)
• Actions of 1,25-dihydroxycholecalciferol


  Increases Ca2+ absorption from the intestine, facilitates Ca2+ reabsorption in the kidneys (proximal tubules), increases the synthetic activity of osteoblasts, and is necessary for normal calcification of matrix

  
• Regulation of 1,25-dihydroxycholecalciferol synthesis


  1. Formation catalyzed by the renal 1α-hydroxylase, regulated in a feedback manner by plasma Ca2+ and PO43+

  2. Expression of 1α-hydroxylase stimulated by PTH and inhibited by high plasma PO43– levels

  3. Direct negative feedback effect of 1,25-dihydroxycholecalciferol on 1α-hydroxylase, positive feedback action on 24,25-dihydroxycholecalciferol formation, and direct action on the parathyroid gland to inhibit PTH expression

  
• Parathyroid glands


  • Humans usually have four parathyroid glands: two embedded in the superior poles of the thyroid and two in its inferior poles
  • Each parathyroid gland is a richly vascularized disk, about 3 × 6 × 2 mm, containing two distinct types of cells: abundant chief cells that synthesize and secrete PTH, and less abundant and larger oxyphil cells

  
• Synthesis and metabolism of PTH


  • PTH is a linear polypeptide with 84 amino acid residues, synthesized as part of a larger molecule containing 115 amino acid residues (preproPTH)
  • The normal plasma level of intact PTH is 10–55 pg/mL, with a half-life of approximately 10 min

  
• Actions of PTH


  Increases bone resorption and mobilizes Ca2+, increases phosphate excretion in the urine, increases reabsorption of Ca2+ in the distal tubules, and increases the formation of 1,25-dihydroxycholecalciferol

  
• Regulation of PTH secretion

  1. Circulating Ca2+ acts directly on the parathyroid glands in a negative feedback manner

  2. 1,25-Dihydroxycholecalciferol acts directly on the parathyroid glands to decrease preproPTH mRNA

  3. Increased plasma phosphate stimulates PTH secretion by lowering plasma levels of free Ca2+ and inhibiting the formation of 1,25-dihydroxycholecalciferol

  4. Magnesium is required to maintain normal parathyroid secretory responses

  
• Calcitonin


  A Ca2+-lowering hormone produced by the parafollicular cells of the thyroid gland
• Regulation of calcitonin secretion


  1. Secretion is increased when the thyroid gland is exposed to a plasma calcium level of approximately 9.5 mg/dL

  2. β-Adrenergic agonists, dopamine, and estrogens also stimulate calcitonin secretion

  3. Gastrin, cholecystokinin (CCK), glucagon, and secretin have also been reported to stimulate calcitonin secretion, with gastrin being the most potent stimulus
• Parathyroid


  Secretory responses. Impaired PTH release along with diminished target organ responses to PTH account for the hypocalcemia that occasionally occurs in magnesium deficiency.

  
• Calcitonin


  A Ca2+-lowering hormone