Calcium and phosphate ionsCalcium and phosphate ions
Biochemistry II
2008 (J.S.)
Biochemistry II
Lecture 11
Calcium distribution and turnover
25 mol Ca
Mineral deposits
Daily intake
about. 25 - 30 mmol / d
25 mol Ca
(rapidly exchangeable
100 mmol)
bone remodelationabout. 25 - 30 mmol / d
phosphates,
oxalates,
phytates
bone remodelation
7.5 mmol / d
rapid exchange
500 mmol / d
ICT
signaling function
ECT
2.5 mmol / l
absorption
< 15 mmol / d
500 mmol / d
signaling function
0.1 mol / l
2.5 mmol / l
total only 35 mmol
tubular resorption
secretion
up to 7 mmol / d
filtration
240 mmol / d
tubular resorption
230 mmol / d
17 – 25 mmol / d
Excretion fraction max. 5 %
decreased by PTH,
enlarged by calcitonin and
high supply of Na+17 – 25 mmol / d high supply of Na+
25 – 6 mmol / d
Blood serum calciumBlood serum calcium
The biologically active fraction is ionized Ca2+ (free Ca2+ ions).
Chemical methods (photometry, AAS) estimate
total serum calcium.total serum calcium.
Approximately one half (~ 46 %) of Ca2+ is
bound to carboxyl groups of proteins –
non-diffusible calcium.non-diffusible calcium.
A small fraction (2 - 5 - 10 %) of calcium is
bound in chelate complexes with carboxylatebound in chelate complexes with carboxylate
anions (citrate, lactate, oxalate, etc.), slightly
also with HCO3
– and phosphates –
non-ionized diffusible calciumnon-ionized diffusible calcium
(usually not taken into account).
Free Ca2+ ions - ionized calcium - areFree Ca2+ ions - ionized calcium - are
decisive for an assessment of the calcium
accessibility.
3
accessibility.
Total serum calcium S-Ca – mean value 2.5 mmol/l,
reference range 2.25 – 2.75 mmol/l .reference range 2.25 – 2.75 mmol/l .
Ionized calcium S-[Ca2+] – mean value 1.25 mmol/l,
reference range 1.0 – 1.4 mmol/l .
Conclusions deduced from the values of total calcium may be
erroneous, unless account is taken to protein (namely albumin)
concentration and abnormal pH value.concentration and abnormal pH value.
Normal total Ca concentration doesn't exclude a change in ionized Ca2+,
abnormal total Ca can be accompanied by a normal value of ionized Ca2+.
Protein-bound calcium increases if plasma protein concentration, particularly of
albumin, is high.albumin, is high.
Influence of pH can be understood as a competition for Ca2+ binding sites
between H+ and Ca2+ ions. pH value changed by 0.1 corresponds to the change in
[Ca2+] by approximately 0.02 mmol/l.[Ca2+] by approximately 0.02 mmol/l.
4
Calcium homeostasisCalcium homeostasis
– hormonal control of plasma calcium concentration
PARATHYRINPARATHYRIN
(PTH, the older name parathormone is currently taken as an improper one)
PTH consists of 84 amino acid residues (prepro-PTH 115 AA, pro-PTH 90 AA).
Biological activity is exhibited by the N-terminal sequence, the initial 28 residues.
Plasma intact PTH (1-84) – the reference range 1 - 5 pmol / l – is degradedPlasma intact PTH (1-84) – the reference range 1 - 5 pmol / l – is degraded
rapidly in the liver (half-life 3 – 5 min) by splitting off the inactive C-terminal
segments (35-84).
PTH secretion is regulated by plasma Ca2+ concentration:
hypercalcaemia inhibits the release of PTH,
secretion of PTH is stimulated in hypocalcaemia.secretion of PTH is stimulated in hypocalcaemia.
Phosphates don't have a direct influence.
The calcium sensor is a receptor cooperating with Gq proteins. In contradistinction to otherThe calcium sensor is a receptor cooperating with Gq proteins. In contradistinction to other
secreting cells, an increase in intracellular Ca2+ due to IP3 inhibits secretion of PTH.
High level of intact PTH is usual in primary hyperparathyroidism, the secretion is not
suppressed by hypercalcaemia.
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suppressed by hypercalcaemia.
Biological effects of PTHBiological effects of PTH
In bone,
– PTH stimulates bone resorption through differentiation and activation of– PTH stimulates bone resorption through differentiation and activation of
osteoclasts. This effect is mediated by osteoblasts that, after PTH binding,
expose one of the ODF proteins. Those proteins are recognized by the receptorsexpose one of the ODF proteins. Those proteins are recognized by the receptors
of osteoclasts and initiate the activation.
In the renal tubules,In the renal tubules,
– the Ca2+ reabsorption increases increasing so calcaemia and decreasing
calciuria (but at a high Ca2+ supply, the maximal transport capacity of the tubular
cells is exceeded and excretion of Ca2+ increases);cells is exceeded and excretion of Ca2+ increases);
– the HPO4
2– reabsorption decreases and so excretion of phosphate increases;
in hyperparathyroidism, there is also the decrease of HCO3
– reabsorption thatin hyperparathyroidism, there is also the decrease of HCO3
– reabsorption that
may be the cause of a mild hyperchloridaemic metabolic acidosis.
PTH exhibits an indirect effect on the intestinal mucosa:PTH exhibits an indirect effect on the intestinal mucosa:
– increased Ca2+ absorption results from stimulation of the 1α-hydroxylation
of calcidiol to calcitriol in the renal tubules.
6
CALCIOL (calciferol, vitamin D3)
and ercalciol (ergocalciferol of plant origin, D ) are present in the diet. In addition,and ercalciol (ergocalciferol of plant origin, D2) are present in the diet. In addition,
calciol is synthesized from 7-dehydrocholesterol in the skin due to UV irradiation.
The daily requirement for calciols is 5 – 20 g/d (200 – 800 IU/d).The daily requirement for calciols is 5 – 20 g/d (200 – 800 IU/d).
≡
The calciols are 9,10-sekosteroids, in which the ring B is opened.
Calciol (cholecalciferol, vitamin D3) Ercalciol (ergocalciferol, vitamin D2)
Most natural foods have a low content of vitamin D3. It is present in egg yolk,
butter, cow's milk, beef and pork liver, animal fat and pork skin.
The most important source of vitamin D2 is fish oil, primarily liver oil.The most important source of vitamin D2 is fish oil, primarily liver oil.
The D-provitamins, 7-dehydrocholesterol and ergosterol, are widely distributed
in the animals and plants.
7
Calciols are inactive precursors of calcitriol, a calciotropic steroid hormone.
Calciol (vit. D3) is synthesized from 7-dehydrocholesterol by photolysis thatCalciol (vit. D3) is synthesized from 7-dehydrocholesterol by photolysis that
is a cause of opening of the ring B:
Cholesterol THE LIVER CELLSCholesterol THE LIVER CELLS
7,8-Dehydrogenation
Lumisterol
Tachysterol
7-Dehydrocholesterol
Capillaries of the SKIN
An intermediate
Capillaries of the SKIN
A high-speed photolysis
λmax = 295 nm
Slow thermal conversion
An intermediate
(praevitamin)
Calciol (vit. D3)Calciol is slowly released into blood
8
and bound to serum DBP (D vit. binding protein).
The hydroxylation of calciols
C-25
1α
The LIVER CELLS
25-Hydroxylation
(monooxygenase, cyt P450)
The RENAL TUBULAR CELLS
1α-Hydroxylation
(monooxygenase, cyt P450)
Calciol
(Cholecalciferol)
Calcidiol
(25-Hydroxycholecalciferol)
Calcitriol
(1α,25-Dihydroxycholecalciferol)
A CALCIOTROPIC STEROID HORMONE
In the liver, calciol is hydroxylated to calcidiol (25-hydroxycalciol).
25-hydroxylation of calcidiol is inhibited by the high concentrations of calcidiol25-hydroxylation of calcidiol is inhibited by the high concentrations of calcidiol
and calcitriol (a negative feed-back control), calcitonin, and a high intake of
calcium in the diet.
In the proximal renal tubules, calcidiol is transformed by 1α-hydroxylation intoIn the proximal renal tubules, calcidiol is transformed by 1α-hydroxylation into
calcitriol (1α,25-dihydroxycalciol).
1α-hydroxylation is stimulated by PTH (in hypocalcaemia),
9
1α-hydroxylation is stimulated by PTH (in hypocalcaemia),
inhibited by high concentration of calcitriol, calcitonin, and high dietary calcium.
Calciol is transported bound to the specific protein DBP (vit, D-binding protein, the
concentration of which is less than 10 µmol/l and saturation by calciol not higher
Calciol - the blood serum concentration in the range 2.6 - 13 nmol / l .
Calcidiol is the major circulating metabolite of calciol. Its biological half-life is
concentration of which is less than 10 µmol/l and saturation by calciol not higher
than 1 – 2 %).
Calcidiol is the major circulating metabolite of calciol. Its biological half-life is
rather long, approx. 20 - 30 days.
The concentration of calcidiol in serum informs of the body calciol accessibility.The concentration of calcidiol in serum informs of the body calciol accessibility.
Seasonal variations are observed: The average concentration
during summer about 75 nmol / l (30 µg / l),
In winter about 37 nmol / l (15 µg / l, i.e. a mild deficit).In winter about 37 nmol / l (15 µg / l, i.e. a mild deficit).
Values < 20 nmol / l have to be taken as a sign of serious vitamin D deficiency.
In enormous exposition to sunlight – values up to 250 nmol / l,
Calcitriol – its biological half-life is short,
In enormous exposition to sunlight – values up to 250 nmol / l,
in hypervitaminosis D up to 1250 - 2500 nmol / l.
Calcitriol – its biological half-life is short,
serum concentration in children about 160 pmol / l,
in adults 3 - 580 pmol / l .
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in adults 3 - 580 pmol / l .
Biological effects of calcitriol:
In the enterocytes, it increases resorption of calcium into ECF in allIn the enterocytes, it increases resorption of calcium into ECF in all
three distinct steps:
- Entrance into the cell. There are no special transporters for calcium, calcitriol
induces a change in the binding of calmodulin to brush border myosininduces a change in the binding of calmodulin to brush border myosin
(it forms a complex with a special type of myosin that is bound to
membrane actin). The complex may remove calcium from the brush border
after it crosses the membrane. Changes in the phospholipid composition ofafter it crosses the membrane. Changes in the phospholipid composition of
the brush border also may explain the flux of calcium across this
membrane after calciol administration.membrane after calciol administration.
- Calcitriol induces the synthesis of cytosolic protein calbindin (CaBP,
calcium-binding protein) after a lag-period about 20 h. CaBP seems to
prevent rapid increase in Ca2+ by mediating rapid Ca2+ transport inprevent rapid increase in Ca2+ by mediating rapid Ca2+ transport in
cytoplasm.
- Calcitriol induces the synthesis of Ca2+-ATPase that removes Ca2+ from the- Calcitriol induces the synthesis of Ca -ATPase that removes Ca from the
cell into ECF.
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In bone, calcitriol controls both resorption and formation by means of
induction of the synthesis of numerous proteins in osteoblasts and
odontoblasts. The control mechanism is not yet quite clear.
The effect of calcitriol depends on the degree of osteoblast differentiation:The effect of calcitriol depends on the degree of osteoblast differentiation:
- In immature osteoblasts, calcitriol supports differentiation pathway to
mature, fully functional osteoblasts.mature, fully functional osteoblasts.
- In mature osteoblasts, calcitriol induces the synthesis of osteocalcin and
(besides PTH and certain cytokines)
production of osteoclast differentiation factors (ODF) so that itproduction of osteoclast differentiation factors (ODF) so that it
also take part in maintaining of physiologic levels of Ca2+ and
phosphates in ECF.
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Osteocalcin (BGP - bone Gla-protein) is a small conservative protein
(49 AA residues) that has three γ-carboxyglutamate (Gla) centres able to(49 AA residues) that has three γ-carboxyglutamate (Gla) centres able to
bind Ca2+. Its function depends on the presence of vitamin K.
Bone contains 50 - 100 µg osteocalcin per gram of dry mineralized tissue
(more than 20 % non-collagen bone proteins).(more than 20 % non-collagen bone proteins).
Osteocalcin concentration in plasma is 5 - 10 µg / l, its biological half-life
only 4 – 5 min.only 4 – 5 min.
Osteocalcin takes part in the control of bone mineralization. It seems to
slow down mineralization of the bone matrix by binding onto collagenslow down mineralization of the bone matrix by binding onto collagen
(preventing so Ca2+ and phosphate leakage from plasma into bone), on the
other hand osteocalcin retards bone resorption in epiphysis.
Concentration of plasma osteocalcin is one of the biochemical markers ofConcentration of plasma osteocalcin is one of the biochemical markers of
bone remodelation (turnover), perharps also of osteoblast activity in
formation of organic bone matrix. In sole osteoresorption, increase information of organic bone matrix. In sole osteoresorption, increase in
osteocalcin concentration is not observed.
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CALCITONIN
is a 32 amino acid peptide secreted by the C-cells of the thyroid gland.
It is classified as a neuropeptide, because it played a role of neurotransmitter
during the evolution.during the evolution.
In humans, calcitonin is synthesized only in the thyroid gland.
Calcitonin structure differs in animal species. Rat calcitonin resembles human
one (only 2 different amino acids), the most effective calcitonin is that of salmon
(50 % homology with the human calcitonin). In the therapy of metabolic
osteopathies, the salmon, human, or the dicarba analogue of eel calcitonin are
used.used.
Plasma calcitonin about 13 - 27 pmol / l (50 - 100 ng / l),
in women over 50 years of age the values are lower (high risk of osteoporosis).in women over 50 years of age the values are lower (high risk of osteoporosis).
Secretion of calcitonin is controlled by calcaemia. The calcium sensor is of the
same kind as in parathyroid glands, but in the thyroid C-cells the increase in
intracellular Ca2+ is the signal for secretion.intracellular Ca2+ is the signal for secretion.
Procalcitonin (116 AK, calcitonin sequence in position 60-91) is split to
calcitonin and catacalcin in the C-cells and not secreted normally.calcitonin and catacalcin in the C-cells and not secreted normally.
In sepsis (not in localized infections), procalcitonin is secreted in considerable
amount (from neuroendocrine cells of the lung and intestine and mononuclear
leukocytes obviously), without an increase in calcitonin.
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Plasma procalcitonin is a reliable marker of sepsis.
Biological effects of calcitonin
Calcitonin counteracts PTH in the control of Ca metabolism.
Under normal conditions, calcitonin exhibits a limited role in calcium metabolism
control. Its effect on hypercalcaemia is not long, but acute, and it results incontrol. Its effect on hypercalcaemia is not long, but acute, and it results in
blockade of bone resorption.
No disturbance of calcium metabolism occurs following removal of the thyroid gland.
In bone, calcitonin inhibits bone resorption (if increased) by suppressing the
activity of osteoclasts and supports both synthesis of organic matrix and
mineralization of osteoid by a rapid activation of osteoblastsmineralization of osteoid by a rapid activation of osteoblasts
Calcitonin has a special role in pregnancy.
Plasma concentration increases till the end of the 2nd trimester up to the double
normal values and is maintained till the end of lactation.normal values and is maintained till the end of lactation.
Calcitonin primarily supports formation of calcium deposits in the bones of mother
(formation of stores for the foetus), later on the effect is diminished due to
increased secretion of PTH (increasing the calcium accessibility to the foetus).increased secretion of PTH (increasing the calcium accessibility to the foetus).
In the renal tubules, calcitonin inhibits reabsorption of Ca2+ and phosphates
increasing their excretion in this way.increasing their excretion in this way.
In the GIT, it inhibits the secretion of HCl, pepsin, and pancreatic enzymes.
Calcitonin has an analgetic effect, it alleviates bone pain in the course of metabolic
osteopathies or bone metastases.
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osteopathies or bone metastases.
Hypercalcaemia
Mild hypercalcaemia (< 3 mmol/l) usually don´t have clinical symptoms.
Defects of renal tubular functions, particularly polyuria, may occur.
Hypercalcaemia > 3.5 - 4 mmol/l is a serious menace.
If hypercalcaemia is chronic, renal functions are impaired,If hypercalcaemia is chronic, renal functions are impaired,
soft tissue calcifications and renal tract stones develop.
In turn, chronic renal failure in chronic hypercalcaemiaIn turn, chronic renal failure in chronic hypercalcaemia
disturbs calcium homeostasis:
Decrease in GFR to about one third is the cause of phosphate retention and
hyperphosphataemia, FE(Ca) increases, calcium loss follows, calcidiol ishyperphosphataemia, FE(Ca) increases, calcium loss follows, calcidiol is
hydroxylated insufficiently, and intestinal calcium resorption diminished
The consequence is hypocalcaemia that induces secondary hyperparathyroidism.The consequence is hypocalcaemia that induces secondary hyperparathyroidism.
The most usual cause of hypercalcaemia (in about 90 %) is
primary hyperparathyroidism, the second most frequent being malignant disease.primary hyperparathyroidism, the second most frequent being malignant disease.
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Primary hyperparathyroidism is usually caused by a solitary adenoma.
It is detected mostly (up to 50 %) as calcium urolithiasis or nephrocalcinosis, polyuria,It is detected mostly (up to 50 %) as calcium urolithiasis or nephrocalcinosis, polyuria,
osteopathy (osteodystrophy, pathological bone fractures), etc.
The diagnosis is supported by hypophosphataemia resulting from phosphate losses,
and mild metabolic acidosis from losses of HCO – . Increased PTH is conclusive.
Malignancy-related hypercalcaemia
– osteolytic metastases of solid tumours (lung, breast, kidney) resorb bone either
and mild metabolic acidosis from losses of HCO3
– . Increased PTH is conclusive.
– osteolytic metastases of solid tumours (lung, breast, kidney) resorb bone either
directly, or (breast carcinoma) activate osteoclasts by means of local release of
humoral factors.
– multiple myeloma (and some lymphomas)– multiple myeloma (and some lymphomas)
– tumours producing PTHrP (namely squamous cell carcinomas of the bronchus).
Other causes of hypercalcaemia:
Calciol intoxication in excessive intake of calciol (e.g. long-lasting treatment of
hypoparathyroidism, calciol overdose is released from the adipose tissue slowly,hypoparathyroidism, calciol overdose is released from the adipose tissue slowly,
in the course of several weeks) or when calcitriol is used (immediate effect,
a narrow therapeutic range).
Long-lasting immobilization intensifies osteoresorption, namely in teenagersLong-lasting immobilization intensifies osteoresorption, namely in teenagers
due to high bone turnover. A complete immobilization can cause about 30 % loss
of bone minerals.
17
of bone minerals.
HypocalcaemiaHypocalcaemia
Clinical symptoms appear when total calcium is lower than approx. 1.9 mmol / l
(ionized Ca lower than 0.9 – 1.0 mmol / l).(ionized Ca lower than 0.9 – 1.0 mmol / l).
Hypocalcaemia is accompanied by typical neuromuscular manifestations –
paresthesiae, increased neuromuscular excitability and tetany (carpopedalparesthesiae, increased neuromuscular excitability and tetany (carpopedal
spasms up to a state of spontaneous tonic muscular contraction).
Spurious hypocalcaemia due to hypoalbuminaemia or haemodilution should beSpurious hypocalcaemia due to hypoalbuminaemia or haemodilution should be
excluded primarily.
18
The most common causes of hypocalcaemia:The most common causes of hypocalcaemia:
Alkalosis – hyperventilation (artificial, hysteric reaction), too rapid infusion of HCO3
–.
Acute complexation – multiple blood transfusions (citrate or EDTA form complexes
with Ca2+);
Reduced parathyroid hormone action – rare primary hypoparathyroidism,
– secondary hypoparathyroidism – surgery on the neck is the most common
with Ca2+);
– secondary hypoparathyroidism – surgery on the neck is the most common
form (destruction of the glands or transient ischemia).
Insufficient supply of calcium, impairment of intestinal calcium absorption,Insufficient supply of calcium, impairment of intestinal calcium absorption,
failure to produce calcitriol:
– inadequate dietary intake of calcium or calciol,
– limited exposure to sunlight (this sometimes occurs in elderly subjects,– limited exposure to sunlight (this sometimes occurs in elderly subjects,
high sensitivity in immigrants from Asian tropical zones),
– malabsorption of liposoluble compounds (diseases of pancreas, insufficient bile
production, intestinal by-pass),production, intestinal by-pass),
– chronic renal failure (insufficient 1α-hydroxylation of calcidiol).
In adults, insufficient calcium intake results in osteomalacia (bands ofIn adults, insufficient calcium intake results in osteomalacia (bands of
decalcification, affecting particularly the pelvis, femur, and scapula),
in children in rickets (rachitis, skeletal deformities and muscle weakness).
19
in children in rickets (rachitis, skeletal deformities and muscle weakness).
Urinary calcium excretion dU-Ca or fU-Ca / creatinine ratio
Calciuria increases in – high monosaccharide intake,
– deficits of Mg and phosphates, and
is not a basal test – calciuria occurs usually in all hypercalcaemias.
– deficits of Mg and phosphates, and
– in starving.
Hypercalciuria – excretion > 7.5 mmol / d (300 mg / d) in men,Hypercalciuria – excretion > 7.5 mmol / d (300 mg / d) in men,
> 6.2 mmol / d (250 mg / d) in women
is the natural consequence of all hypercalcaemias.
(but it may also occur at normal calcium levels or in hypocalcaemia).(but it may also occur at normal calcium levels or in hypocalcaemia).
– Primary hyperparathyroidism
– "Idiopathic" hypercalciurias (at normal calcaemia, inherited?), either– "Idiopathic" hypercalciurias (at normal calcaemia, inherited?), either
a hyperabsorptive type or a renal type
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Phosphate distribution and turnover Mineral deposits
Daily intake
about. 30 - 80 mmol / d
15 - 25 mol PO4
3Mineral
deposits
(80 – 85 % total P)
about. 30 - 80 mmol / d
exchange
8 - 15 mmol / dAl3+ and
calcium
ICT (15 – 19 % of total content)
1 mmol / l inorg. phosphate
ECT (total only 55 mmol)
1.0 mmol / l inorg. phosphate
absorption
15 - 55 mmol / d 1 mmol / l inorg. phosphate
100 mmol / l organic esters
filtration
1.0 mmol / l inorg. phosphate
2.5 mmol / l phosphate esters
tubular reabsorption
15 - 55 mmol / d
filtration
> 130 - 200 mmol / d
tubular reabsorption
> 110 - 150 mmol / d
Excretion fraction < 25 %
10 – 40 mmol / d
Excretion fraction < 25 %
(children < 15 %)
increased by PTH or calcitonin
10 – 40 mmol / d
2113 – 40 mmol / d
Phosphate homeostasis
is maintained by urinary excretion of phosphateis maintained by urinary excretion of phosphate
that depends on reabsorption of phosphate in renal tubules.
Filtration of free Pi (about 90 %) is complete, from which 50 – 70 % is reabsorbedFiltration of free Pi (about 90 %) is complete, from which 50 – 70 % is reabsorbed
in the proximal tubule (specific active co-transport with Na+, inhibited by PTH), about
10 – 20 % in the distal parts of the nephron.
Of the 240 mmol of phosphate filtered daily, about 85 % (80 – 97 %) is reabsorbed.
Excretion fraction EF(phosphate) – in adults less than 20 %,
in children less than 15 %.in children less than 15 %.
Increased phosphate excretion (decrease in tubular phosphate reabsorption)
is caused by PTH and calcitonin,is caused by PTH and calcitonin,
– by acidosis (hyperphosphataemia, protons excreted as H2PO4
–),
– and indirectly (through hypocalcaemia that stimulates PTH secretion)
by alkalosis or increased ECF volume.by alkalosis or increased ECF volume.
Retention (decreased excretion) of phosphate (increased tubular phosphate
reabsorption) is causedreabsorption) is caused
– by somatotropin (decrease in ECF volume) and corticosteroids,
– to a lesser degree, by calcitriol and phosphate deficiency.
22
Fasting serum inorganic phosphate in adults 0.8 – 1.3 mmol / l,Fasting serum inorganic phosphate in adults 0.8 – 1.3 mmol / l,
in children 1.6 – 2.2 mmol / l.
Plasma concentration is 0.06 – 0.10 mmol/l lower than that of serum due to the
release of intracellular phosphate from platelets and erythrocytes during clotting:release of intracellular phosphate from platelets and erythrocytes during clotting:
(serum should be separated from the coagulum without delay).
In healthy adults, there is a marked diurnal variation (range 12 – 22 %) inIn healthy adults, there is a marked diurnal variation (range 12 – 22 %) in
phosphataemia – the lowest being in the morning and the highest during the
night (this variation is abolished by fasting).
Postprandially, phosphate concentration tends to decrease presumably becausePostprandially, phosphate concentration tends to decrease presumably because
of insulin release (anabolic action of insulin). Therefore, samples for serum
phosphate estimation should be taken in the fasting state in the morning.
Great and rapid changes in serum phosphate concentration may have
their causes in the shifts of phosphates between ICF and ECF that
depend on the nutritional status (the energy charge of the cells).depend on the nutritional status (the energy charge of the cells).
Urinary phosphate excretion
depends considerably on dietary intake of phosphates.depends considerably on dietary intake of phosphates.
At the average daily intake of phosphate (about 50 mmol/d),
dU-Pi is in the range 13 - 29 mmol / d in healthy adults.
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Measurements of tubular phosphate reabsorption are importantMeasurements of tubular phosphate reabsorption are important
in assessing parathyroid function (diagnosis of primary hyperparathyroidism
and other hypophosphataemias).
The threshold phosphate concentration is thought to be the best parameter
– the theoretical phosphate concentration in glomerular filtrate (equal to plasma)
below which all phosphate is reabsorbed and above which phosphate is excreted in urine:below which all phosphate is reabsorbed and above which phosphate is excreted in urine:
the ratio of maximal tubular reabsorption to glomerular filtration rate
TmP / GFR (normal range 0.74 – 1.2 mmol / l ).
It can be easily determined using fasting urinary and serum concentrations of phosphate and
creatinine and the Walton's nomogram.
In primary hyperparathyroidism, TmP/GFR is considerably lower than 0.6 mmol/l, and higherIn primary hyperparathyroidism, TmP/GFR is considerably lower than 0.6 mmol/l, and higher
than 1.2 mmol/l in hypoparathyroidism.
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Hyperphosphataemia
Even a mild form (> 1.6 mmol/l) is a rare finding among hospital patients (1.5 %).
Consequences – Acute hyperphosphataemia can lead to hypocalcaemia.
In chronic hyperphosphataemia, the low production of calcitriol may lead toIn chronic hyperphosphataemia, the low production of calcitriol may lead to
bone changes (osteomalacia or rickets) or to soft tissue calcification in
myocardium, lungs, and the liver.
Artificial (spurious) hyperphosphataemia may result from haemolysis due to the release of
intracellular phosphate from red blood cells and platelets.
Causes of hyperphosphataemiaCauses of hyperphosphataemia
Reduced urinary excretion
– Renal failure accounts for more than 90 % in hospital patients; retention of
phosphate occurs when the GFR falls below 20–30 % of normal and may be a causephosphate occurs when the GFR falls below 20–30 % of normal and may be a cause
of secondary hyperparathyroidism.
– Hypoparathyroidism – increased tubular phosphate reabsorption.– Hypoparathyroidism – increased tubular phosphate reabsorption.
Excess phosphate administration to patients on parenteral and enteral nutrition,
also in sucklings nourished with undiluted cow's milk.
Shift of intracellular phosphate into the ECF is seen inShift of intracellular phosphate into the ECF is seen in
– hypercatabolic states and in metabolic acidosis (untreated lactic acidosis and
diabetic ketoacidosis) due to increased ATP breakdown and tissue hypoxia,
25
diabetic ketoacidosis) due to increased ATP breakdown and tissue hypoxia,
– excessive haemolysis.
Hypophosphataemia
is much more frequent than hyperphosphataemia.is much more frequent than hyperphosphataemia.
Mild and moderate hypophosphataemia (0.6 - 0.8 mmol / l)
is quite common in hospital patients (14 – 39 %, namely in acutely ill, malnourished, or with
diabetic ketoacidosis), but it is rather exceptional in out-patients (incidence 0.9 %).diabetic ketoacidosis), but it is rather exceptional in out-patients (incidence 0.9 %).
In moderate hypophosphataemia of long duration, skeletal changes
(i.e., rickets or osteomalacia) are the only consistent abnormalities.
Severe hypophosphataemia ( in particular <<<< 0.3 mmol / l) is rare,
but if it is of at least four days duration, important consequences may be seen:
haemolysis due to decreased 2,3-BPG and ATP in erythrocytes,haemolysis due to decreased 2,3-BPG and ATP in erythrocytes,
muscular weakness that may result in respiratory failure,
impaired cardiac contractility and nervous system disorders.
Hypophosphataemia does not always indicate intracellular phosphate
deficiency, phosphate depletion may be present with normal or even increased
phosphataemia.phosphataemia.
26
The most common causes of hypophosphataemia:
Haemodilution – water retention, parenteral nutrition.
Reduced absorption
– Low dietary intake is an unusual cause (strict vegetarians) as phosphate– Low dietary intake is an unusual cause (strict vegetarians) as phosphate
occurs widely in foods,
– oral phosphate-binding agents (Al3+-containing or other antacids in excessive
quantities),
– diarrhoea or long-lasting vomiting,
– malabsorption.
Increased uptake of phosphate into cells
– Administration of glucose (both intravenous and enteral) or hyperalimentation
leads to increased insulin concentration, increased formation of phosphorylated
– malabsorption.
leads to increased insulin concentration, increased formation of phosphorylated
intermediates leads to the shift of phosphate into the cells. Life-threatening
hypophosphataemia may occur in rapid realimentation of starved patientshypophosphataemia may occur in rapid realimentation of starved patients
("refeeding syndrome"), treatment of diabetic ketoacidosis, alcoholics during
alcohol withdrawal and glucose refeeding.
Increased phosphate eliminationIncreased phosphate elimination
– Decreased renal tubular reabsorption due to high PTH secretion in
hyperparathyroidism, rickets and osteomalacia.
– Haemodialysis.
27
– Haemodialysis.