Μεταβολισμός φωσφόρου
Σχόλια – Παραδείγματα και πολλά άλλα
Ετήσιο Μετεκπαιδευτικό Σεμινάριο
Υγρών, Ηλεκτρολυτών & Οξεοβασικής ισορροπίας
5ο Σεμινάριο
Στρογγυλό τραπέζι IV: Μεταβολισμός φωσφόρου
Προεδρείο: Δ. Γούμενος, Σ. Σπαΐα
23-24 Σεπτεμβρίου 2011
Βλάστη Κοζάνης
Σάββατο, 24 Σεπτεμβρίου 2011 10.00-11.40
Καθηγητής Γεώργιος Ι. Μπαλτόπουλος
Διευθυντής ΠανΜΕΘ ΓΝ Οι ΄Αγιοι Ανάργυροι
Μεταβολισμός φωσφόρου
Τι αναφέρθηκε;
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Φυσιολογία του ισοζυγίου του φωσφόρου (εξωγενής πρόσληψη,
απορρόφηση, απέκκριση, κατανομή). Γιαννάτος Ευάγγελος
Ορμονική ρύθμιση της ομοιοστασίας του φωσφόρου.
Οικονομίδου Δομινίκη
Υποφωσφαταιμία. Κατωπόδης Κώστας
Υπερφωσφαταιμία. Κουτρούμπας Γεώργιος
Φάρμακα και υπασβεστιαιμία ή υποφωσφαταιμία. Λιάμης
Γιώργιος
Σχόλια – Παραδείγματα και πολλά άλλα. Γ. Μπαλτόπουλος
Stellar nucleosynthesis
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Stable forms of phosphorus are produced in large
(greater than 3 solar masses) stars by fusing two oxygen
atoms together.
This requires temperatures above 1,000 megakelvins.
P4 molecule
P2 molecule
Atomic number 15
Atomic weight 30.974- 31P
Two most common isotopes: 32P and 33P (24P up to 46P)
Density 1.82 g/cm3
The four allotropic forms (white, red, black and
violet) of phosphorus
waxy white (yellow cut)
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black
Colorless, waxy white (yellow cut), scarlet (allowing a solution of white phosphorus in Carbone disulfide to evaporate in
sunlight), red (granules center left, chunk center right), violet (produced by day-long annealing of red phosphorus above 550 °C) and
black (= heating white phosphorus under high pressures 12,000 standard atmospheres)
phosphorus
Must be kept under water in pure form
Very poisonous 50mg fatal dose (white form)
Obtained from phosphate rock (apatite, Ca3(PO4)2 ) found in China, Russia, Morocco, Fl, TN, UT, ID
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red
(granules center left, chunk center right)
At current consumption rates (fertilizers, detergents, pesticides, nerve agents, matches), reserves will be depleted in the
next 50 to 100 years
Phosphorus is the sixth most abundant element in living organisms.
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Is found in every cell (Phosphate)!!
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Phosphate chemical reactions in the living cells: ≈ 2371
Η φιλοσοφική λίθος και ο φωσφόρος
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The 'squared circle' or 'squaring the
circle' is a 17th century alchemical
glyph or symbol for the creation of
the Philosopher's Stone. The
Philosopher's Stone was supposed to
be able to transmute base metals into
gold and perhaps be an elixir of life
Phosphorus - Alchemical Symbols
"The Alchymist, In Search of the Philosopher's
Stone" painted by Joseph Wright in 1717
Hennig Brand in Hamburg discovers phosphorus in 1669 from his urine.
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He called the substance he had discovered
"cold fire" because it was luminous, glowing in
the dark. White phosphorus's natural
chemiluminescence produces a rather dim
green glow
Brand sold his method to Johann Daniel Kraft
and Kunckel von Lowenstern from Dresden
for 200 thaler (=4191 $)
For further payment he also revealed his secret
to Gottfried Wilhelm Leibniz (Mr calculus!!)
Leibniz, also thinking as an alchemist,
mistakenly believed Brand might be able to
discover the philosophers' stone by producing
a large quantity of phophorus
Allies used phosphorus incendiary bombs in
World War II to destroy Hamburg, the place
where the "miraculous bearer of light" was first
discovered
Evelyn de Morgan: Greek gods Phosphorus
and Hesperus -Πούλια & Αυγερινός
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Phosphorus (gr. Eosphoros, l. Lucifer) and Hesperus(gr.
Hesperos, l. Vesper) are brothers, sons of the rosy
fingered goddess of dawn, Eos (latin: Aurora).
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Like the goddess Venus and the stars
themselves, Phosphorus and Hesperus are eternally
young and beautiful.
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Phosphorus is the planet Venus when it appears as the morning
star (Αυγερινός). Hesperus (Αποσπερίτης) is the planet
Venus when it appears as the evening star. The early greeks
believed these to be two distinct astronomical bodies and
assigned two distinct dieties to the planet as it appeared
respectively in the morning and evening. The later greeks
adopted the Babylonian view that the morning and evening star
were a single wandering star and associated it with the goddess
Aphrodite(l. Venus).
Only their mother Eos (Dawn) and her sister and brother, Selene
(the moon) and Helios(the Sun), shine more brightly in the
heavens.
It is Phosphorus, the bringer of light, who wakes his
mother Eos from her sleep in the depths of the sea
each morning and ushers in the dawn. It is Hesperus
who ushers in the evening at dusk. Hesperus brings all
good things home at the end of the day. He is the god
of the hearth and domestic happiness.
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One might curse Phosphorus when getting up in the morning to
go to work and bless Hesperus in the evening when returning to
the comfort of home.
Παραγωγή Φωσφόρου κατά Brand
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Evaporate human urine black residueleave
it for a few months
Then heat the residue with sand condense
the variety of gases and oils, driving off in water
The final substance to be driven off, condensing
as a white solid, is phosphorus !!!
Παραγωγή: 1100 L ούρων (60 κουβάδες
αλχημιστικά ούρα !!)  60 gr
???????????????
Functions of phosphate
Form
Function
Bone structure (85% of P in body )
Structure of cell membranes
Energy storage and metabolism
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Hydroxyapatite
Phospholipids
Adenosine triphosphate (ATP) and
creatine phosphate (intermediate in glycolysis
and oxidative phosphorylation)
Nucleic acids and nucleoproteins
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Phosphorylation of proteins
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2,3-Diphosphoglycerate (glycolysis
byproduct )
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Modulates oxygen release by
hemoglobin
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Inorganic phosphate
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Acid-base buffer (Intracellularly and in the
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Genetic translation (DNA) and protein
synthesis (RNA)
Key regulatory mechanism; activation
of enzymes, cell-signaling cascade
renal tubules where it aids in the excretion of
hydrogen ions)
P is essential element for metabolic
processes
ATP +ADP= remains fairly
constant
The human body total quantity: 0.1 mole
(about 6 x 1022 molecules). Human cells
require the hydrolysis of 100 to
150 moles (6 to 9 x 1025 molecules) of
ATP daily (50-75 kg/day).
ATP + ADP constant
ADP
Q
PO43–
80kg 72yrs BMR Harris Benedict = 1644 kcal
75kg=147.89 x 10.9=1611.65
Molecular formula
Molar mass
C10H16N5O13P3
507.18 g mol−1
ATP
ATP molecule is recycled
1000 to 1500 times daily, or
about once every minute
ATP + H2O → ADP + Pi ΔG˚ = −30.5 kJ/mol (−7.3 kcal/mol)
ATP + H2O → AMP + PPi ΔG˚ = −45.6 kJ/mol (−10.9 kcal/mol)
PhosphorylationPhotophosphorylation
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The addition of a phosphate (PO4) group to another
molecule, including any protein, is phosphorylation.
Many enzymes and receptors are switched "on" or
"off" by phosphorylation. Phosphorylation is catalyzed
by specific protein kinases.
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Phosphorylation of any amino acid having a free hydroxyl
group on a given protein can change the function,
association, or localization of that protein.
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Dephosphorylation is catalyzed by phosphatases.
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Oxidative phosphorylation is the process of oxidizing nutrients to produce
adenosine triphosphate (ATP). Substrate-level phosphorylation forms ATP by
the direct transfer of a phosphate group to adenosine diphosphate (ADP)
from a reactive intermediate.
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Photophosphorylation uses solar energy to synthesize ATP.
Phosphate reserves
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A well-fed adult in the industrialized world consumes and
excretes:
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1-3 g of phosphorus per day in the form of phosphate (2-6 x 1022
molecules).
Phosphorus in a "standard man" of 70 kg : 780 g or 1.1% (as
1.52 x 1025 molecules of phosphate)
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1.4 g/kg (98 g, 1.9 x 1024 molecules of phosphate) are present in soft
tissue
675 gr (1.33 x 1025 molecules of phosphate) in mineralized tissue
such as bone and teeth
0.1% of body phosphate (about 2 x 1022 molecules) circulates in the
blood
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this amount reflects the amount of phosphate available to soft tissue cells
Blood plasma contains orthophosphate (as HPO42-) and H2PO4in the ratio of about 4:1.
PO43– : molar mass= 94.97 g/mol
0-phosphate-3D-balls.png
In strongly basic conditions
2-dihydrogenphosphate-3D-balls.png
In weakly acid conditions
1-hydrogenphosphate-3D-balls.png
In weakly basic conditions
phosphoric-acid-3D-balls.png
In strongly acidic conditions
Πάρτε μια αγελάδα
About 1,000,000 tones of elemental phosphorus is produced annually.
In 2000, the global population produced 3 million tones of phosphorus from urine
and faeces alone !!!!!.
Phosphorus-Phosphates: Normal
serum levels
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0.80 to 1.45 mmol/L (2.5 to 4.5 mg/dl)
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Geerse et al. Critical Care 2010, 14:R147.
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Alternative Names: Phosphorus - serum; HPO4-2, PO4-3; Inorganic
phosphate; Phosphorus blood test
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The serum concentration of phosphate may not reflect true phosphate stores.
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VARIES significantly with age!!!
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Mammaliam cell internal phosphate levels= 75 mEq/L. ISF =4 mEq/L
AGE
PHOSPHORUS
0–5 day
4.8–8.2 mg/dL
1–3 yr
3.8–6.5 mg/dL
4–11 yr
3.7–5.6 mg/dL
12–15 yr
2.9–5.4 mg/dL
16–19 yr
2.7–4.7 mg/dL
Phosphate metabolism and causes of
hypophosphatemia
Dietary P is absorbed in
small intestine, excess
is excreted by kidneys
Geerse et al. Critical Care 2010, 14:R147
PTH =↓ renal resorption of phos
Calcitriol (1,25 Vit D) ↑ intestinal absorption of
phos and helps renal resorption of phos.
Absorption of phosphate can be blocked by
aluminum-, calcium-, and magnesium-containing
antacids.
Gaasbeek A, Meinders AE. Hypophosphatemia: An update on its etiology and treatment
The American Journal of Medicine 2005; 118: 1094-1101
LIAMIS G, MILIONIS H, ELISAF M. Medication-induced hypophosphatemia: a review. Q J Med 2010; 103:449–459
Prevalence and/or incidence of hypophosphatemia
Up to 5% of hospitalized pts may have S. PO4 less than 2.5mg%.
In alcoholics, 30-50% have been reported.
Geerse et al. Critical Care 2010, 14:R147
Reported incidence of
hypophosphatemia
Gaasbeek A, Meinders AE. Hypophosphatemia: An update on its etiology and treatment
The American Journal of Medicine 2005; 118: 1094-1101
DIAGNOSIS OF
HYPOPHOSPHATEMIA
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History & S. PO4
24 hr urine collection
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Urine phosphate excretion
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If renal P wasting in not the cause of hypophosphatemia
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DD of hypoP with low FEPO4
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Daily P excretion should be<100mg/d. FEPO4 <5% normally
 Calculation: FEPO4=(U PO4 * Pcr) * 100/ P PO4* Ucr
Increased cellular uptake
Chronic diarrhea
Causes of high PO4 excretion-Renal PO4 wasting
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Hyperparathyroidism
Proximal renal tubular defect.
Κλινικές εκδηλώσεις
Geerse et al. Critical Care 2010, 14:R147
Gaasbeek A, Meinders AE. Hypophosphatemia: An
update on its etiology and treatment
The American Journal of Medicine 2005; 118: 1094-1101
Treatment
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Intravenous therapy (severe deficiency or cannot tolerate oral)
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Sodium phosphate or potassium phosphate
Choice based on K+ level
Starting doses are 0.08–0.16 mmol/kg over 6 hr.
The oral preparations of phosphorus are available with various ratios of
sodium and potassium. Oral maintenance doses are 2–3 mmol/kg/day in
divided doses. (cause diarrhea)
Increasing dietary phosphorus is the only intervention needed in infants with
inadequate intake.
Certain diseases require specific therapy.
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Nutritional vitamin D deficiency
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Vitamin D supplementation, not phosphorus, is the principal therapy
X-linked hypophosphatemic rickets
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Combination of 1,25-dihydroxyvitamin D and oral phosphorus.
Intravenous treatment of hypophosphatemia
Geerse et al. Critical Care 2010, 14:R147
CRRT : Phosphate and Magnesium
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Hypophosphatemia and Hypomagnesiemia
occur in almost all patients on CRRT for ≥ 48
hours.
Management:
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Routinely supplement patients with IV PO4 and
MgSO4 on regular basis:
Sodium phosphate 20 mmol in 250 mls IV fluid over 3-4
hours q 8-12 hours
 Magnesium sulphate 2 gm IV q 8-12 H,
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Phosphate Control in
ESRD
Average daily intake of phosphorous
=
1000mg
Approximately 50% absorbed
=
500mg
Dialysis removes around
Daily net positive balance
300mg
=
+200mg
Therefore oral phosphate binders needed to reduce
phosphate absorption by at least 200mg
Practice Case 1
A 15-year-old girl is admitted to your facility with severe anorexia
nervosa and amenorrhea. She weighs 35 kg and is 160 cm tall.
She has bradycardia and orthostatic hypotension. You plan to
stabilize her medically and begin nasogastric tube feeding.
Of the following, the electrolyte abnormality that is MOST likely to
occur during the first week of her treatment is
A. hypercalcemia
B. hyperphosphatemia
C. hypocalcemia
D. hyponatremia
E. hypophosphatemia
Practice Case 2
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A 56 yrs ♂. Referred from another hospital with H/o LOC  treated
for CVA , intubated because of respiratory distress and low GCS (7/15).
On regaining conscious, he was confused and developed fever with
restlessness. Right 3rd nerve Palsy, was able to move all 4 limbs. Paucity
of movements and Babinski on right side. Right pupil: 3mm, Left
pupil:2mm
CT scan Head : Small Area of bleed in left occipito-temporal region with
mild surrounding edema. Infarcts in right side of midbrain and pons
Type 2DM-6 yrs, HTN-6 yrs, CAD & CABG (2004).
Chronic smoker & chronic alcoholic(150g/d for >30 years)
P:92 b/m. BP : 142/80 mmHg. Echo : EF : 35 %, hypokinesia of LV
segments.
Investigations upon admission
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Urea : 51 mg%
Cr :1.1 mg%
Na+ : 140 meq/l
K+ : 3.4 meq/l
Hb :13 g%
Tc
: 8,800 cells/c.mm.
ABG : mild respiratory alkalosis
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Urine analysis
1 + proteinuria
2-4 RBC’s & WBC’ s
Continued
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Over 48 hours the sensorium improved marginally, but
over next 12 hours deteriorated markedly without any
apparent reason.
S. Ca2+ :8.2 mg%
S. PO4- :1.1 mg%, coincided with the time in
deterioration in sensorium. The test report was not
given attention for 12 hours (Repeat Sr PO4: 1.3 mg%)
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24 hrs urine Ca2+ : 101 mg/day
24 hrs urine PO4 : 891 mg/day( upto 1400mg is normal)
FEPO4 was : 25 %.(expected was close to 0)
25 OH VIT D : 25.5 ng/l (7.6-75)
S. iPTH : 73 pg/ml (10-69)
Pt’s Hypophosphatemia treatment
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We treated with IV potassium phosphate: 5ml in
250ml of NS over 6 hrs on day 1 & 2.
Next day his S. PO4 was 2.1mg%
We also noticed that his sensorium had improved
significantly.
Continued on oral sodium phosphate
The happy end !!
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Subsequent day,his sensorium worsened with 1 episode of seizure .But his PO4 was
2.4 mg%.
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MRI Brain revealed increase in the size of intracranial bleed with fresh infarcts in PCA
territory.
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He was treated with anticonvulants, antiedema measures and antibiotics in suspicion
of sepsis.
On day 5, his PO4 level was built to 4.2mg%, at which point NaPO4 was
discontinued. His azotemia resolved.
He remained ventilator dependent for 19 days, developed VAP (resolved).
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CONDITION ON DISCHARGE
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Alert, conscious
Ptosis of RE
Mild residual right hemiparesis
He was able to walk and eat by himself
Practice Case 3
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67 yrs ♀.
Προηγούμενο ιστορικό: Παχυσαρκία, Κύφωση, Κάπνισμα (½ πακ/ημέρα), άπνοια του
ύπνου, υπέρταση (micardis 1/2x1), ΧΑΠ, ΣΔ ( glucophage 1x2, solosa 1x1), ΝΦΔ (
xanax 0,25x2)
Προγραμματισμένη επέμβαση για κοιλιοκοίλη (29/6/11) σε ιδιωτική κλινική 
μεταφορά σε ΜΑΦ λόγω ΜΤΧ ΟΑΑ (υποξαιμία) διασωλήνωση – εισαγωγή σε ΜΕΘ
(1/7/11) μεταφορά στην ΠΑΝ ΜΕΘ (4/7/11)
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GCS 11T, καταστολή, εμπύρετος 38ο C
Αιμοδυναμική αστάθεια υπό νοραδρεναλίνη 15 γ/λεπτό
ΗΚΓ- φλεβόκομβος, RBBB
Αναπνευστική ανεπάρκεια υπό ΜΥΑ, FiO2 0.9-1.0, PEEP 10
Βρογχόσπασμος, μείωση αναπν. ψιθυρίσματος αριστερά
Α/Α θώρακος - πυκνοατελεκτασία αριστερά
Διούρηση μειωμένη υπό lasix
Κοιλία – εντερικοί ήχοι υπάρχουν, φέρει 2 παροχετεύσεις
Διακομιδή από ιδιωτική κλινική 4 ημέρες μετά από Προγραμματισμένη επέμβαση για
κοιλιοκοίλη (29/6/11), για αναπνευστική ανεπάρκεια/λοίμωξη του
αναπνευστικού/σηπτικό shock.
77 ημέρες στη ΜΕΘ
Νέο Σηπτικό shock
Glucophos 20-40mmol
Σηπτικό Νέο Σηπτικό shock
shock
12
MSOF
CVVHDF
10
8
Ca
PO43
6
Mg
11Τ
4
2
3Τ
04
.0
7
10 .1 1
.0
7
15 .1 1
.0
7.
20 1 1
.0
7
23 .1 1
.0
7
27 .1 1
.0
7
01 .1 1
.0
8
06 .1 1
.0
8.
09 1 1
.0
8
12 .1 1
.0
8
15 .1 1
.0
8
18 .1 1
.0
8.
1
21 1
.8
.1
24 1
.8
.1
1
27
.8
1
30 1
.8
.1
1
2.
9.
11
5.
9.
11
8.
9.
1
11 1
.9
.1
14 1
.9
.1
17 1
.9
.1
1
0
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34/77 (44.1 %) ημέρες: Φυσιολογικός φωσφόρος
6/77 (7.8 %) ημέρες: Υπεφωσφαταιμία
27/77 (35.1 %) ημέρες: Υποφωσφαταιμία
10/77 (12,9%) ημέρες: Δεν μετρήθηκε
CREATININE
Μερικοί χρήσιμοι υπολογισμοί
Calculation: FE PO4=(U PO4 * Pcr) * 100/ P PO4* Ucr
CVVHDF
PCr (mg%)
0.7
Λειτουργία Νεφρών 1.3
UPO4 (mg%)
2.8
UCr (mg%) PPO4 (mg%)
0.4
3
0.9
4.6
3.5
Με φίλτρο 1347.34 mg
Fractional Excretion of PO4 (FEPO4) = (0.7PCr * 2.8U PO4 ) /(3P PO4 x 0.4UCr) %=163,33%
Με δικη της διούρηση 351 mg
Fractional Excretion of PO4(FENa) = (1.3PCr * 0.9 U PO4 ) / (3.5P PO4 x 4.6UCr) %=7.26%
Hyperphosphatemia:
Clinical Manifestations
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Hypocalcemia
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Tissue deposition of calcium-phosphorus salt
Inhibition of 1,25-dihydroxyvitamin D production
Decreased bone resorption.
Symptomatic hypocalcemia is most likely when
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phosphorus increases rapidly
diseases predisposing to hypocalcemia are present
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chronic renal failure
rhabdomyolysis).
Systemic calcification
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Solubility of phosphorus and calcium in the plasma is exceeded.
Inflamed conjunctiva- foreign body feeling, erythema, and injection. (BOBBY)
Hypoxia from pulmonary calcification
Renal failure from nephrocalcinosis.
Diagnostic Testing
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Assess renal function: Bun and creatinine.
Focus history on intake of phosphorus and the presence
of chronic disease.
If suspect rhabdomyolysis, tumor lysis, or hemolysis
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Check potassium, uric acid, calcium, LDH, bilirubin, and CPK
If mild hyperphosphatemia and sign hypocalcemia
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check serum PTH level
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Distinguishes between hypoparathyroidism and
pseudohypoparathyroidism.
Treatment
Depends on its severity and etiology.
 Dietary phosphorus restriction- in mild hyperphosphatemia
 Intravenous fluids- enhance renal excretion if kidney function is
intact.
 Oral phosphorus binder- in significant hyperphosphatemia
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Prevents absorption of dietary phos
Removes phos from the body by binding what is normally secreted and
absorbed by GI tract
Binders containing aluminum hydroxide or use calcium carbonate if also
hypocalcemic.
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Aluminum-containing binders NOT used in CRF because of aluminum toxicity.
Esp if taking oral citrate, which ↑ gastrointestinal absorption of aluminum.
Preservation of renal function-high urine flow permits continued
excretion
Dialysis directly removes phosphorus from the blood in ESRD
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only an adjunct to dietary restriction and phosphorus binders
dialysis is not efficient enough to keep up with normal dietary intake.
Phosphate removal by dialysis – difficult!
•
Phosphate is mostly found intracellularly
•
Has a large sphere of hydration
•
Cleared rapidly from serum in first 2 hours of HD
•
Rebounds significantly at 3 - 4 hours post – HD
•
Consequently slightly better clearance by PD
•
Excellent clearance by daily home HD
Συμπεράσματα
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Η υπερφωσφαταιμία και υποφωσφαταιμία
Δεν είναι σπάνιες σε μια ΜΕΘ
Είναι αντιμετωπίσιμες οντότητες
Δεν μπορούμε να πούμε ποια είναι η συμμετοχή τους
στην νοσηρότητα και θνητότητα
Στις ΜΕΘ πάντα υπάρχει η πιθανότητα να βρεις ένα
περιστατικό που να τα λέει όλα!!!

Το πείραμα το κάνει η φύση και εμείς αξιοποιούμε τα
αποτελέσματα