calcium metabolism

calcium

· body contains 1000 g calcium

· 99% in skeleton

· 1% in plasma

Serum calcium

· normal serum concentration is 2.5 mmol/l

· about half is diffusible

· mostly ionised as Ca++

· rest bound to HCO3-, citrate etc.

· about half is protein-bound

· mostly to albumin

· some to globulin

· free ionised calcium is necessary for

· coagulation

· muscle contraction

· nerve function

· irritability and contractility of

· nerve and smooth & skeletal muscle inversely proportional to Ca++

· cardiac muscle directly proportional to Ca++

Hypocalcaemia

· decrease in extracellular Ca ++

· effect is

· hypertonicity

· hyperreflexia

· convulsions

· death in diastole

· Chvostek's sign

· quick contraction of ipsilateral facial muscles elicited by tapping over facial nerve at angle of jaw

· Trousseau's sign

· spasm of muscles of upper extremity with flexion of wrist and thumb and extension of fingers

· may be produced by occluding circulation for few minutes with blood pressure cuff

Hypercalcaemia

· increase in extracellular Ca++

· effect is

· hypotonicity

· hyporeflexia

· obtundation and coma

· death in systole

Protein-bound plasma calcium

· must know plasma protein level when evaluating total plasma calcium

· extent of Ca++ binding by plasma proteins affected by plasma protein level

· can measure ionised calcium and estimate total plasma calcium by taking plasma protein level into account

pH

· serum pH affects Ca++ level

· alkaline pH means that plasma proteins are more ionised

· more Ca++ binding occurs

· free ionised plasma Ca++ level decreases

· thus tetany occurs at higher total Ca++ levels with alkaline pH

· eg. hyperventilation

Intracellular calcium

· concentration much less than serum level

· ratio of extracellular:intracellular Ca++ is 10⁴:1

· reservoirs of Ca++ exist in mitochondria and endoplasmic reticulum

· extracellular Ca++ regulates cell function by calcium messenger system

· related to cAMP messenger system

· calmodulin is intracellular calcium receptor

· calcium-binding proteins transport Ca++ across cell membrane

· calbindin and cholecalcin

Bone calcium

· two forms

· 99% is large pool of stable calcium that is only slowly exchangable

· 1% is readily exchangable

· two homeostatic systems affecting calcium in bone

· system that regulates plasma calcium affects exchangable reservoir (500 mmol/day moves in and out)

· bone resorption and deposition regulates stable pool (7.5 mmol/d moves in and out)

Kidneys

· large amount of Ca++ filtered in kidneys

· 250 mmol

· 99% of filtered calcium resorbed

· 60% occurs in proximal tubules

· 40% occurs in distal tubules (and ascending loop of Henle)

· resorption in proximal tubules regulated by 1,25-vit D

· resorption in distal tubules regulated by parathyroid hormone

Gastrointestinal tract

· Ca++ actively transported out of intestine by system in brush border of epithelial cells

· at distal duodenum and proximal jejunum

· process regulated by 1,25-vit D

· when Ca++ intake high, absorption decreases

· active transport mechanism becomes saturated

· 1,25-vit D levels decrease

· calcium absorption decreased by

· substances that form insoluble salts with Ca++

· alkalis which favour formation of insoluble calcium salts

· insoluble salts formed by

· chelating agents (oxalate, phytate)

· excessive phosphate (dietary excess)

· free fatty acids (biliary disease, chronic bowel disease)

phosphorus

· phosphorus metabolism not as finely regulated

· 90% of total body phosphorus in skeleton

· remainder in extracellular fluids

· as inorganic phosphate ions

· intolved in generation and transfer or energy

· phosphorus absorbed in duodenum and small intestine

· by active transport and passive diffusion

· linearly related to dietary intake

· inhibited by excess calcium and aluminium

· 90% of phosphorus filtered in kidneys reabsorbed

· most by active transport in proximal tubule

· inhibited by PTH

· main control mechanism for phsophate is renal

· low Ca++ leads to increased PTH release

· leads to decreased tubular resorption of phosphate

· result is decreased serum phosphate and phosphate diuresis

regulation of calcium

Uptake

· three components regulate Ca++ uptake

· 1,25-D enhances mRNA to synthesise transport proteins

· increased intracellular phosphate turns off transport

· PTH enhances 1,25-D synthesis in kidneys

· absorption will occur if

· sufficient dietary calcium

· no excess of chelating and solubility-inhibiting factors

· sufficient 1,25-D and PTH

Serum level

· three factors regulate serum Ca++

· renal filtration

· tubular reabsorption

· formation and resorption of bone

vitamin d

Chemistry

· group of fat-soluble sterols

· two forms

Vitamin D₃

· cholecalciferol

· naturally occurring form

· provitamin D₃ (7-dehydroxycholesterol) produced in liver

· provit D₃ converted to vit D₃ in skin by action of sunlight

· 15 min exposure needed to provide daily requirement (10 mg)

· converted in liver and kidney to active form

Vitamin D₂

· ergocalciferol

· injested in diet

· occurs naturally in cod liver oil

· added to milk

· similar activation and actions as vit D₃

Activation

· vit D₃ converted to 25-hydroxycholecalciferol (25-D) in liver

· enzyme is 25-hydroxylase

· Mg++ required as cofactor

· 25-D converted to 1,25-dihydroxycholecalciferol (1,25-D) in proximal tubules of kidney

· enzyme is 1-alpha-hydroxylase

· activated by PTH

· inactive 24,25-dihydroxycholecalciferol (24,25-D) also produced

· normally much more 24,25-D made

· production of 1,25-D favoured by low Ca++, low PO₄- or high PTH

· production of 24,25-D favoured by high Ca++, highPO₄-- or low PTH

Actions of 1,25-D

· increases intestinal absorption of Ca++

· induces production of calcium-binding protein responsible for active calcium transport

· facilitates resorption of Ca++ by kidneys

· acts on proximal tubules

· mobilises Ca++ from bone

· increases number and activity of osteoclasts

· probably acts on osteoblast which then influences osteoclast

Regulation of synthesis

· formation of 25-D not stringently regulated

· formation of 1,25-D regulated by plasma Ca++ and PO₄---

· 1,25-D leads to increased plasma Ca++ and PO₄--- levels

· increased Ca++ and PO4--- lead to decreased 1,25-D production in kidneys

· increased Ca++ and 1,25-D3 lead to decreased PTH secretion which decreases production of 1,25-D

· increased 1,25-D leads to decreased 1-alpha-hydroxylase

· increased 1,25-D leads to increased production of 24,25-D

parathyroid glands

· usually 4 parathyroid glands embedded in thyroid

· each contains chief cells and oxyphil cells

· parathyroid hormone (PTH) is synthesised by chief cells

Actions OF PTH

· acts directly on bone to increase bone resorption and mobilise Ca++

· increases reasorption of Ca++ in distal tubules

· increases formation of 1,25-D

· increases phosphate excretion in urine by decreasing resorption of phosphate in proximal tubules

Regulation

· Ca++ acts directly on parathyroid glands to decrease secretion of PTH in negative feedback fashion

· 1,25-D acts directly on parathyroid glands to decrease secretion of PTH in negative feedback fashion

· increased PO₄-- stimulates PTH secretion by

· lowering plasma Ca++

· inhibiting formation of 1,25-D

calcitonin

· polypeptide secreted by clear cells (parafollicular cells, C cells) in thyroid

· exact role uncertain

· calcitonin secreted when thyroid perfused with Ca++

· causes quiescence of osteoclasts and thus decreases plasma Ca++

· also increases excretion of Ca++ in urine

· total thyroidectomy does not affect plasma Ca++ if parathyroid glands preserved

other hormones

Glucocorticoids

· lower plasma Ca++

· inhibit osteoblast formation and activity

· decrease absorption of Ca++ and PO4--- from intestine by anti-vit D action

· increase renal excretion of Ca++ and PO4---

· cause osteoporosis over long periods

· secondary hyperparathyroidism as a consequence of decreased Ca++

· increases osteoclastic bone resorption

Growth hormone

· increases Ca++ excretion in urine

· increases Ca++ absorption from intestine

· resultant positive balance

Thyroid hormones

· act directly on osteoclastic bone resorption

· precise mode of action unknown

· may cause hypercalcaemia, hypercalcuria and osteoporosis

Oestrogens

· prevent osteoporosis

· by direct effect on osteoblasts

Insulin

· increases bone formation

· significant bone loss in untreated diabetes

alterations in homeostasis

Hypocalcaemia

· response to low Ca++ is increased synthesis and release of PTH

· causes increased production of 1,25-D

· together cause

· increased absorption of Ca++ in gut

· increased tubular resorption of Ca++ in kidneys

· enhanced degradation of bone by release of mineral from hydroxyapatite

· enhanced destruction of bone by osteoclasts

· causes of hypocalcaemia

· hypoparathyroidism

· pseudohypoparathyroidism

· vitamin D deficiency

· hypoalbuminaemia

· hypomagnesaemia

Hypercalcaemia

· calcitonin released by C cells of thyroid

· response to hypercalcaemia insufficient to markedly lower serum Ca++

· causes of hypercalcaemia

· hyperthyroidism (primary and tertiary)

· neoplasms (metastases, multiple myeloma)

· disuse osteopaenia

· Paget’s disease with immobilisation

· sarcoidosis and tuberculosis

· vitamin D intoxication

Nutritional deficiency

· daily requirements are

· 750 mg for adult male

· 1000 mg for premenopausal female

· 1500 mg for postmenopausal female

· 1500 mg for pregnant female

· 2000 mg for lactating female

Summary

PTH

increases Ca++

· mobilises Ca++ from bone

· increases renal Ca++ reabsorption

· increases production of 1,25-D3

1,25-D3

increases Ca++

· increases Ca++ absorption from intestine

· mobilises Ca++ from bone

· increases renal Ca++ reabsorption

Calcitonin

decreases Ca++

· inhibits bone reabsorption

· increases Ca++ in urine