Μεταβολισμός φωσφόρου Σχόλια – Παραδείγματα και πολλά άλλα

1. 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

2. Μεταβολισμός φωσφόρου Τι αναφέρθηκε; • 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

3. P4 molecule P2molecule Stellar nucleosynthesis Atomic number 15 Atomic weight 30.974- 31P Two most common isotopes: 32P and 33P (24P up to 46P) Density 1.82 g/cm3 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.

4. The four allotropic forms (white, red, black and violet)of phosphorus red (granules center left, chunk center right) black waxy white (yellow cut) • Colorless, waxy white (yellow cut), scarlet (allowing a solution of white phosphorus inCarbone 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 • 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. • Is found in every cell (Phosphate)!! • Phosphate chemical reactions in the living cells: ≈2371

5. Η φιλοσοφική λίθος και ο φωσφόρος • 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

6. "The Alchymist, In Search of the Philosopher's Stone" painted by Joseph Wright in 1717 Hennig Brand in Hamburgdiscovers phosphorus in 1669from his urine. • 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

7. Evelyn de Morgan: Greek gods Phosphorus and Hesperus -Πούλια & Αυγερινός • Phosphorus (gr.Eosphoros, l. Lucifer) and Hesperus(gr.Hesperos, l. Vesper) are brothers, sons of the rosy fingered goddess of dawn, Eos (latin: Aurora). • 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). • Like the goddess Venus and the stars themselves,  Phosphorus and Hesperus are eternally young and beautiful. • 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. • 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.

8. Παραγωγή Φωσφόρου κατά Brand ??????????????? Evaporatehuman 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

9. Hydroxyapatite Phospholipids Adenosine triphosphate (ATP) and creatine phosphate (intermediate in glycolysis and oxidative phosphorylation) Nucleic acids and nucleoproteins Phosphorylation of proteins 2,3-Diphosphoglycerate (glycolysis byproduct ) Inorganic phosphate Bone structure (85% of P in body ) Structure of cell membranes Energy storage and metabolism Genetic translation (DNA) and protein synthesis (RNA) Key regulatory mechanism; activation of enzymes, cell-signaling cascade Modulates oxygen release by hemoglobin Acid-base buffer (Intracellularly and in the renal tubules where it aids in the excretion of hydrogen ions) Functions of phosphate Form Function

10. P is essential element for metabolic processesATP +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 ATP molecule is recycled 1000 to 1500 times daily, or about once every minute 80kg 72yrs BMR Harris Benedict = 1644 kcal 75kg=147.89 x 10.9=1611.65 Molecular formulaC10H16N5O13P3 Molar mass 507.18 g mol−1 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)

11. Phosphorylation- Photophosphorylation Oxidative & Photo Phosphorylation • 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. • Phosphorylation of any amino acid having a free hydroxyl group on a given protein can change the function, association, or localization of that protein. • Dephosphorylation is catalyzed by phosphatases. • 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. • Photophosphorylation uses solar energy to synthesize ATP. • Phosphorylation of sugars allows cells to accumulate sugars because the phosphate group prevents the molecules from diffusing back across their transporter.

12. Phosphate reserves • A well-fed adult in the industrialized world consumes and excretes: • 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 gor 1.1% (as 1.52 x 1025 molecules of phosphate) • 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 • this amount reflects the amount of phosphate available to soft tissue cells • Blood plasma contains orthophosphate (as HPO42-) and H2PO4- in the ratio of about 4:1.

13. PO43–:molar mass= 94.97 g/mol 0-phosphate-3D-balls.png In strongly basic conditions 1-hydrogenphosphate-3D-balls.png In weakly basic conditions 2-dihydrogenphosphate-3D-balls.png In weakly acid conditions phosphoric-acid-3D-balls.png In strongly acidic conditions

15. 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 !!!!!.

16. Phosphorus-Phosphates: Normal serum levels 0.80 to 1.45 mmol/L (2.5 to 4.5 mg/dl) Geerse et al. Critical Care 2010, 14:R147. Alternative Names: Phosphorus - serum; HPO4-2, PO4-3; Inorganic phosphate; Phosphorus blood test The serum concentration of phosphate may not reflect true phosphate stores. VARIES significantly with age!!! Mammaliam cell internal phosphate levels= 75 mEq/L. ISF =4 mEq/L

17. Phosphate metabolism and causes of hypophosphatemia Dietary P is absorbed in small intestine,excess is excreted by kidneys 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. 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 LIAMIS G, MILIONIS H, ELISAF M. Medication-induced hypophosphatemia: a review. Q J Med 2010; 103:449–459

18. Prevalence and/or incidence of hypophosphatemia 2.8-100% 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

19. Reported incidence of hypophosphatemia 0.2-100% Gaasbeek A, Meinders AE. Hypophosphatemia: An update on its etiology and treatment The American Journal of Medicine 2005; 118: 1094-1101

20. DIAGNOSIS OF HYPOPHOSPHATEMIA • History & S. PO4 • 24 hr urine collection • Urine phosphate excretion • If renal P wasting in not the cause of hypophosphatemia • Daily P excretion should be<100mg/d. FEPO4 <5% normally • Calculation: FEPO4=(U PO4 * Pcr) * 100/ P PO4* Ucr • DD of hypoP with low FEPO4 • Increased cellular uptake • Chronic diarrhea • Causes of high PO4 excretion-Renal PO4 wasting • Hyperparathyroidism • Proximal renal tubular defect.

21. Κλινικές εκδηλώσεις Gaasbeek A, Meinders AE. Hypophosphatemia: An update on its etiology and treatment The American Journal of Medicine 2005; 118: 1094-1101 Geerse et al. Critical Care 2010, 14:R147

22. Treatment • Intravenous therapy (severe deficiency or cannot tolerate oral) • 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. • Nutritional vitamin D deficiency • Vitamin D supplementation, not phosphorus, is the principal therapy • X-linked hypophosphatemic rickets • Combination of 1,25-dihydroxyvitamin D and oral phosphorus.

23. Intravenous treatment of hypophosphatemia 0.2-0.6 mmol/kgbw or 20-40mmol Geerse et al. Critical Care 2010, 14:R147

24. CRRT : Phosphate and Magnesium • Hypophosphatemia and Hypomagnesiemia occur in almost all patients on CRRT for ≥ 48 hours. • Management: • 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,

25. Phosphate Control in ESRD Average daily intake of phosphorous = 1000mg Approximately 50% absorbed = 500mg Dialysis removes around 300mg Daily net positive balance = +200mg Therefore oral phosphate binders needed to reduce phosphate absorption by at least 200mg

26. 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

27. Practice Case 2 • 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.

28. 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 Urine analysis 1 + proteinuria 2-4 RBC’s & WBC’ s Investigations upon admission

29. Continued • 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%) • 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)

30. Pt’s Hypophosphatemia treatment • 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

31. The happy end !! • Subsequent day,his sensorium worsened with 1 episode of seizure .But his PO4 was 2.4 mg%. • MRI Brain revealed increase in the size of intracranial bleed with fresh infarcts in PCA territory. • 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). • CONDITION ON DISCHARGE • Alert, conscious • Ptosis of RE • Mild residual right hemiparesis • He was able to walk and eat by himself

32. Practice Case 3 • 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) • GCS 11T, καταστολή, εμπύρετος 38οC • 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.

33. Νέο Σηπτικό shock Glucophos 20-40mmol Νέο Σηπτικό shock MSOF CVVHDF 11Τ 3Τ 77ημέρες στη ΜΕΘ Σηπτικό shock • 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

34. Μερικοί χρήσιμοι υπολογισμοί Calculation: FE PO4=(U PO4 * Pcr) * 100/ P PO4* Ucr PCr (mg%) UPO4 (mg%) UCr (mg%) PPO4 (mg%) CVVHDF 0.7 2.8 0.4 3 Λειτουργία Νεφρών 1.3 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 351mg Fractional Excretion of PO4(FENa) = (1.3PCr * 0.9 U PO4 ) / (3.5P PO4 x 4.6UCr) %=7.26%

35. Hyperphosphatemia:Clinical Manifestations • Hypocalcemia • Tissue deposition of calcium-phosphorus salt • Inhibition of 1,25-dihydroxyvitamin D production • Decreased bone resorption. • Symptomatic hypocalcemia is most likely when • phosphorus increases rapidly • diseases predisposing to hypocalcemia are present • chronic renal failure • rhabdomyolysis). • Systemic calcification • 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.

36. Diagnostic Testing • 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 • Check potassium, uric acid, calcium, LDH, bilirubin, and CPK • If mild hyperphosphatemia and sign hypocalcemia • check serum PTH level • Distinguishes between hypoparathyroidism and pseudohypoparathyroidism.

37. 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 • 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. • 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 • only an adjunct to dietary restriction and phosphorus binders • dialysis is not efficient enough to keep up with normal dietary intake.

38. 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

39. Συμπεράσματα • 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 Ευχαριστώ για την προσοχή σας