Calcium Homeostasis I

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Calcium Homeostasis I

• Dr. Sumbul Fatma

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Introduction

• Calcium has a lot of cellular and tissue effects
  involving contractile machinery, structural
  roles, enzymatic reactions etc
• All these effects depend upon the blood calcium
  to be within normal limits

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Calcium Distribution

• 99 is part of bone and 1 is present in blood
  and ECF
• Calcium distribution in blood
• - 45 circulates as free calcium ions
• referred to as ionized calcium
• - 40 is bound to protein (albumin)
• - 15 is bound to anions such as bicarbonate,
  citrate, phosphate, and lactate
• (conc. of these anions can change dramatically
  during surgery or critical care and therefore,
  ionized calcium cannot be reliably calculated
  from total calcium measurements)

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Ionized calcium

• It is important to maintain ionized calcium
  because decreased ionized calcium
• - impairs myocardial function, and can also
  cause
• - neuromuscular irritability, which may become
  apparent as irregular muscle spasms, called
  tetany

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Samples for calcium measurement

• Sample- Blood and Urine
• Total Calcium- Serum or lithium heparin plasma
• Ionized Calcium
• - anaerobic collection
• - heparinized whole blood preferred
• - serum from sealed evacuated blood collection
  tubes

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Heparin for ionized calcium

• No liquid heparin should be used as most heparin
  anticoagulants (sodium/lithium) partially bind to
  calcium and lower ionized calcium concentrations.
  e.g. 25 IU/mL heparin decreases calcium
  concentration by 3
• Dry heparin products titrated with small amounts
  of calcium or zinc ions or with small amounts of
  heparin in an inert puff that essentially
  eliminates the interference by calcium should be
  used

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Urine for calcium analysis

• Urine
• - Accurately timed collection
• - Urine should be acidified with 6M HCl with
  1ml HCl per 100mL of urine

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Total Calcium determination

• Dyes are used that form a complex with calcium.
  Prior to dye binding the sample is acidified so
  that calcium is released from its protein
  carriers and complexes
• e.g. ortho-cresolphthalein complexone (CPC) or
  arsenzo III dye
• Atomic Absorption Spectrophotometer (AAS) is
  used as the reference method for whole blood
  analysis

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Ionized Calcium determination

• Commercial analyzers use Ion selective electrodes
  (ISEs) for calcium measurement. These systems may
  use membranes impregnated with special molecules
  that selectively but reversibly bind calcium
  ions. As calcium ions bind to these membranes an
  electric potential develops across the membrane
  that is proportional to the ionized calcium
  concentration

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Total Calcium versus ionized calcium

• During surgery, the patients may receive large
  amounts of citrate, bicarbonate, calcium salts or
  fluids, the greatest discrepancies between total
  and ionized calcium concentration may be seen
  during these times.
• Consequently, ionized calcium measurements are
  the calcium measurements of greater clinical
  value

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Reference Ranges
Total Calcium (serum, plasma)
Child 2.20-2.70 mmol/L (8.8-10.8 mg/dL)
Adult 2.15-2.50 mmol/L (8.6-10.0 mg/dL)

Ionized Calcium (serum)
Neonate 1.20-1.48 mmol/L (4.8-5.9 mg/dL)
Child 1.20-1.38 mmol/L (4.8-5.5 mg/dL)
Adult 1.16-1.32 mmol/L (4.6-5.3 mg/dL)
Urine (24-hour) 2.50-7.15 mmol/day (100-300 mg/day), varies with diet
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Regulation of calcium

• Three hormones regulate serum calcium by altering
  their secretion rate in response to changes in
  ionized calcium
• 1. Parathyroid hormone (PTH)
• 2. Vitamin D, and
• 3. Calcitonin

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Parathyroid hormone (PTH)

• A decrease in ionized calcium leads to increase
  in PTH secretion and it is decreased with an
  increase in calcium concentration
• PTH exerts three major effects on both bone and
  kidney
• 1. In bone, PTH activates bone resorption, a
  process in which activated osteoclasts breakdown
  bone and subsequently release calcium into the
  extracellular fluid
• 2. In Kidneys, PTH conserves calcium by
  increasing tubular reabsorption of calcium ions
• 3. PTH also stimulates renal production of
  active Vitamin D

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Vitamin D synthesis

• Vitamin D in reality is a hormone and is a
  metabolic product of the cholesterol biosynthetic
  pathway
• Vitamin D3, a cholecalciferol is synthesized de
  novo by the exposure of skin to sunlight that
  converts 7-dehydrocholesterol to vit D3
• Vitamin D3 is then converted in liver, to
  25-hydroxycholecalciferol (25-OH- D3) by the
  enzyme 25-hydroxylase - still an inactive form
• 25-OH- D3 is the blood test used to assess
  adequacy of vitD stores in the body
• In the kidney, renal 1 a-hydroxylase hydrolyses
  25-OH- D3 to form 1,25-dihydroxycholecalciferol
  (1,25-OH2- D3) the biologically active form
  (PTH stimulates this enzyme)

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Vitamin D from diet

• Vitamin D is relatively rare in most typical
  foods
• The only common dietary source of vitamin D are
  multivitamins , supplements and vitamin D
  fortified milk
• Cod liver oil is also a source of vitamin D

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Vitamin D regulation

• Vitamin D receptor (VDR) is a nuclear receptor
  that carries out physiologic regulation by
  directing transcription of specific vitamin D
  responsive genes

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Vitamin D regulation

• Stimulates osteoblasts to release cytokines to
  influence osteoclasts to mobilize bone calcium-
  bone resorption
• In small intestinal epithelial cells, vitamin D
  upregulates expression of numerous genes that
  stimulate transepithelial calcium transport from
  the intestinal lumen into the blood. The site of
  maximal absorption is duodenum
• Blood calcium feeds back to parathyroid tissue
  and affects synthesis and secretion of PTH
• Also, vitamin D-VDR complex down-regulates PTH
  expression

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Calcitonin

• It is not secreted during normal regulation of
  the ionized calcium in blood
• Increased concentration of calcium in blood leads
  to secretion of calcitonin from the medullary
  cells of thyroid gland
• It lowers calcium by inhibiting the action of PTH
  and vitamin D

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Organs involved in calcium homeostasis

• Calcium is in constant flux entering and leaving
  the blood pool
• The principal organs involved in this flux are
• - small intestine
• - bone
• - kidney

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Gastrointestinal tract

• All calcium that enters the body arrives via GI
  absorption
• Normal vitamin D availability is required for
  optimal calcium absorption (doubles the calcium
  absorption)
• Dietary phosphate can bind dietary calcium in the
  intestinal lumen and precipitate as insoluble
  calcium phosphate preventing the absorption of
  both
• A diet high in phosphate (e.g. junk food diet or
  high consumption of dark soda pops) tend to
  inhibit calcium absorption

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Renal

• The real net loss of calcium from the body occurs
  via the kidneys in urine
• Kidneys reabsorb the calcium in the tubules and
  also excrete the calcium in urine depending upon
  the total filtered load

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Bone

• Chief reservoir of calcium in the body
• It can serve to remove calcium from the blood to
  be stored in bone and release calcium stored in
  bone to the blood

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falling
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Summary

• Calcium homeostasis is a complex balance between
  into blood and out of blood factors , which
  reflects integrated endocrine and organ
  physiology
• Any disturbance in this balance results in
  alterations in calcium metabolism that can lead
  to various medical conditions

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References

• Clinical Chemistry by Bishop, Fody and Schoeff
• Chapters- 13 and 21