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FGF23

FGF23. in hypophosphatemic states. lessons learnt from a unique patient. Gabriele Haeusler , MD Medical University of Vienna Austria. Vasile-Joan B, born 1990 Healthy until age 13 years Muscle weakness Bone pain Severely disabled at age 15 years. 16 yrs

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FGF23

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  1. FGF23 in hypophosphatemicstates lessonslearntfrom a uniquepatient • Gabriele Haeusler, MD • Medical University of Vienna • Austria

  2. Vasile-Joan B, born 1990 Healthyuntilage 13 years Muscleweakness Bonepain Severelydisabledatage 15 years 16 yrs Laboratory findings: Alkalinephosphatase1652 U/L (<200) Serum phosphate0,31-0,55mmol/l (>0,9) Serum calcium 2,44 mmol/l (>2,25) PTH 39,8 pg/ml (15-60) 25-OHVitD 67,8nmol/l (>50) 1,25-OH2VitD 9pg/ml (>25) Photograph shownwithpermisiionofpatient/family Height 148 cm (<<3rd Pct) Puberty: Tanner V

  3. Rickets/ osteomalacia= Defect in mineralization Mineralization: Deposition ofhydroxyapatiteCa10(Po4)6 OH 2 withincollagen-I fibers

  4. bone Intracellularspace PTH serumphosphate FGF-23 Vit-D reabsorption absorption Mineralization Bonedevelopment Skeletalintegrity Componentof DNA,RNA Energysource (ATP) intestine kidney

  5. Bhattacharyya N et al Trends EndocrinolMetab 23: 610-618 (2012) Farrow E & White K NatRevNephrol 6:207-217 (2010) Jüppner-H et al J BoneMiner Res 25: 2091—2097 (2010) Sapir-Kohen & Livshits IBMS BoneKEy 8: 286-300 (2011)

  6. Urakawa et al, Nature 2006 Kurosi et al,JBiolChem 2006 Weinman, J BiolChem 2011 Baum et al, KidnInt 2005 Shimada et al JBMR 2004 JCI 2004 Farrow, E. G. & White, K. E.(2010) Recent advances in renal phosphate handling Nat. Rev. Nephrol. doi:10.1038/nrneph.2010.17

  7. Figure 1 FGF23 regulatory systems in phosphate metabolism Farrow, E. G. & White, K. E.(2010) Recent advances in renal phosphate handling Nat. Rev. Nephrol. doi:10.1038/nrneph.2010.17 Sapir-Kohen et al, IBMR BoneKEy 2011

  8. Osteocytes 90-95% of all bonecells Actasmechanosensors Communicators Orchestrators (boneremodelling) Regulators ofcalciumand phosphatehomeostasis FGF-23 not highlyexpressed in OC underphysiologicalconditions But excessiveexpression in hypophosphatemicpatientsand CKD FGF-23 productionbyosteocytes Bonewald& Wacker, PediatrNephrol 2013

  9. Figure 1 FGF23 regulatory systems in phosphate metabolism Farrow, E. G. & White, K. E.(2010) Recent advances in renal phosphate handling Nat. Rev. Nephrol. doi:10.1038/nrneph.2010.17 Sapir-Kohen et al, IBMR BoneKEy 2011

  10. Bhattacharyya N et al, Trends Endocrinology & Metabolism 2012

  11. Bhattacharyya N et al, Trends Endocrinology & Metabolism 2012

  12. Acquiredforms Recognition of a phosphaturicfactor in 1959 byPrader et al Shimada T et al Cloningandcharacterizationof FGF-23 as a causativefactoroftumor-inducedosteomalacia PNAS 98: 6500, 2001 Tumor inducedrickets <20 cases Tumor inducedosteomalacia (TIO) > 300 cases Folpe 2004, Chong 2011

  13. TIO- Diagnosis/ Detection Histopathologicalentity (Folpeet al, 2004) PMTMCT phosphaturicmesenchymaltumormixedconnectivetissuevariant Variety of bone sites, size <1-14 cm Detection rate about 50% ( MRI) High resolution techniques (HR-MRI) Somatostatinreceptorimaging (Scintigraphy 111 In-octreotide)

  14. 68-Gallium DOTATOC PET HE, 1:25 mixed connective tissue type JCEM 95; 4511-4517 (2010)

  15. Serum FGF23 Komaba, H. & Fukagawa, M. Nat Rev Nephrol(2012)

  16. surgery Immunohistochemistry FGF23 Oral Calcium 1-2g/d HE, 1:25 mixed connective tissue type JCEM 95; 4511-4517 (2010)

  17. Photograph shownwithpermisiionofpatient/family

  18. JCEM 95; 4511-4517 (2010)

  19. The porcine model forgrowthplateresearch Piglets 4-6 weeks Histo/cDNA Database Manual extraction total growth plates Whole explant culture Collagenase digestion Laser microdisection Density gradient centrifugation Monolayer culture 3D culture

  20. Immunehistochemistry FGF23Pig, 4 weeks Phalanx 10x 25x

  21. Raimann et al, Conn Tiss 2012

  22. Summary FGF-23 is a centralregulatorofphosphatemetabolism FGF-23 isinvolved in hypophosphatemicrickets, bothhereditaryandacquired FGF-23 isthefactorresponsibleforrenalphosphatewasting in patientswith TIO The sourceof FGF-23 isbone, where FGF-23 isproducedbybonecellsunder physiological, andmuchmoreabundand, in pathologicalstates In TIO, therapyconsistsofsurgicalremovalofthetumor, which, ifcomplete, results in healingandcompleterecovery In hereditaryformsofhypophosphatemicrickets, therapyconsistsof oral phosphateand 1-25 OHD untilnewtherapeuticagendsareavailable

  23. Thankyouforyourattention

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