CİDDİ SEKONDER HİPERPARATİROİDİ

NASIL GELİŞİR?

Doç. Dr. Ender HürMerkezefendi D.H, Manisa

PTH > 600 pg/ml;• (tüm nedenlere bağlı) mortalite artışı % 21

Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG et al. (2008) Mortality risk for dialysis with different levels •of serum calcium, phosphorus and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 52: 519–530.

PTH sentez ve salgılanması1 saat içinde;•

pre-pro-PTH (115 aa. )•pro-PTH (90 aa.) •PTH (84 aa.) •

Paratiroidlerde: •iPTH (%5-30)+C-PTH (%70-95)+N-PTH (%1)–

Hipo Ca: 1-84 PTH artar.•Hiper Ca: C-PTH (inaktif) salgılanır•

Evaluation only.Created with Aspose.PowerPoint.Copyright 2004 Aspose Pty Ltd.

PTH Salgılanması

Cell Signalling Biology - Michael J. Berridge - www.cellsignallingbiology.org - 2012

SHPT Patogenez

Elektrolitler: Ca, P–Fosfatonin: FGF23–Vit D–

CaSR–FGFR1, Klotho…–VDR–

SHPT Adaptif ? Maladaptif süreç !

SHPT Patogenez

Aktörler:•Elektrolitler: Ca, P–Fosfatonin: FGF23–Vit D–

Reseptörler:•CaSR–FGFR1, Klotho…–VDR–

Hipo Ca++

Saniye-dakika: PTH egzositozu artar•Dakika-saat: PTH degredasyonu azalır•Saat-gün: PTH gen ekspresyonu artar•Gün-hafta: Paratiroid hücrelerde proliferasyon•

Hücredışı Ca++ ve PTH

Friedman P A , and Goodman W G Am J Physiol Renal Physiol 2006;290:F975-F984

©2006 by American Physiological Society

Hiperfosfatemi

PTH sekresyonunu arttırır•PTH mRNA stabilitesini arttırarak paratiroid –hücre proliferasyonu artarHipo Ca ++ yi indükleyerek:–

 Ca ++  +  HPO4--    <-->    CaHPO4•P da küçük yükseklik, Ca++ düşürmek ve PTH’ •ı arttırmaya yetmez.KBY ileri evrelerinde Hiper P doğrudan PTH •sentez-sekresyon-hücre proliferasyonunu etkileyebilir.

Adler AJ, Ferran N, Berlyne GM. Effect of inorganic phosphate on serum ionized calcium concentration in vitro: a •reassessment of the "trade-off hypothesis". Kidney Int 1985; 28:932.Slatopolsky E, Finch J, Denda M, et al. Phosphorus restriction prevents parathyroid gland growth. High phosphorus •directly stimulates PTH secretion in vitro. J Clin Invest 1996; 97:2534.Fine A, Cox D, Fontaine B. Elevation of serum phosphate affects parathyroid hormone levels in only 50% of •hemodialysis patients, which is unrelated to changes in serum calcium. J Am Soc Nephrol 1993; 3:1947.

Naveh-Many T, J Clin Invest 1995; 96:1786.

Hiper P Tedavisi ile

GFR•(geçici) P ve Ca•PTH •

SHPT olan KBY sıçanlarda SEVELAMER•Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, Yamashita T, Wada M. Effect of manipulating serum phosphorus with phosphate binder on •

circulating PTH and FGF23 in renal failure rats. Kidney Int 69: 531–537, 2006

GFR•(geçici) P ve Ca•PTH •

SHPT olan KBY sıçanlarda SEVELAMER•Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, Yamashita T, Wada M. Effect of manipulating serum phosphorus with phosphate binder on •

circulating PTH and FGF23 in renal failure rats. Kidney Int 69: 531–537, 2006

GFR•(geçici) P ve Ca•PTH •

SHPT olan KBY sıçanlarda SEVELAMER•Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, Yamashita T, Wada M. Effect of manipulating serum phosphorus with phosphate binder on •

circulating PTH and FGF23 in renal failure rats. Kidney Int 69: 531–537, 2006

GFR•(geçici) P ve Ca•PTH •

Paratiroid hiperplazide gerileme•

SHPT olan KBY sıçanlarda SEVELAMER•Nagano N, Miyata S, Abe M, Kobayashi N, Wakita S, Yamashita T, Wada M. Effect of manipulating serum phosphorus with phosphate binder on •

circulating PTH and FGF23 in renal failure rats. Kidney Int 69: 531–537, 2006

CaSR1993 (Brown ve ark.)•

Paratiroid •Kalsitonin salgılayan tiroid C hücreleri•Bağırsak•Kemik ve böbrek•

Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 42: 35–70, 2005.•

CaSR yapı ve fonksiyon

G-protein reseptörleri grubu “C-Ailesi”:•Metabotropik glutamat reseptörleri–GABAB–Tat reseptörleri–Feromon reseptörleri –GPRC6A (aa-divalan katyon duyarlı reseptör): –2.CaSR

Brauner-Osborne H, Wellendorph P, Jensen AA. Structure, pharmacology and therapeutic prospects of family C •G-protein coupled receptors. Curr Drug Targets 8: 169–184, 2007.Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. •Cloning and characterization of an extracellular Ca2-sensing receptor from bovine parathyroid. Nature 366: 575–580, 1993.

Hücredışı 612 aa, •7 transmembran heliks 250 aa.•Hücreiçi C-terminal 200 aa içeren.•Tfelt-Hansen J, Brown EM. The calcium-sensing receptor in normal physiology and pathophysiology: a review. Crit Rev Clin Lab Sci 42: 35–70, 2005•

Hücredışı bölgesi “venus flytrap” benzeri iki loblu motif.•

Ca++ bağlanırsa kapanır ve konformasyon değişikliği hücreiçi sinyali başlatır.•

Silve C, Petrel C, Leroy C, Bruel H, Mallet E, Rognan D, Ruat M. Delineating a Ca2 binding pocket within the venus flytrap module of the human calcium-sensing •receptor. J Biol Chem 280: 37917–37923, 2005.Hu J, Spiegel AM. Naturally occurring mutations in the extracellular Ca2-sensing receptor: implications for its structure and function. Trends Endocrinol Metab 14: •282–288, 2003.

CaSR desensitize olur mu?

Sürekli agonistlere maruz kaldığında •CaSR desensitize olabilir.

Filamin A: Desensitizasyona direnç sağlayan aktin bağlayıcı proteindir.Huang C, Miller RT. The calcium-sensing receptor and its interacting proteins. J Cell Mol Med 11: 923–934, 2007.•

CaSR’ yi bağlayan proteinlerG proteinleri –Flavin A–Caveolin-1: hücre yüzeyinde küçük girinti.–

Williams RR, Hunt SC, Hasstedt SJ, Hopkins PN, Wu LL, Berry TD, Stults BM, Barlow GK, Schumacher MC, •Lifton RP, Lalouel JM. Are there interactions and relations between genetic and environmental factors predisposing to high blood pressure? Hypertension 18: I29 –I37, 1991.

K+ kanalları: Kir4.1, Kir4.2–Reseptör aktivitesi modifiye edici protein (RAMP1, 3): –CaSR’nin hücre yüzeyine translokasyonunu sağlarE3 ubiquitin ligase dorfin: CaSR’ nin proteozomal –degredasyonunu düzenler

Huang C, Miller RT. The calcium-sensing receptor and its interacting proteins. J Cell Mol Med 11: 923–934, 2007.•

CaSR’ yi bağlayan proteinler

CaSR gen ekspresyonu upregülasyonu

Ca++•Kalsimimetikler•Vit D: Vitamin D yanıt elemanlarının •(VDRE) CaSR geninin 2 promotoru ileCanaff L, Hendy GN. Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional •responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem 277: 30337–30350, 2002.

Sitokinler (IL-1B, IL-6)•Canaff L, Zhou X, Hendy GN. The proinflammatory cytokine, interleukin-6, up-regulates calcium-sensing receptor gene transcription via Stat1/3 and •Sp1/3. J Biol Chem 283: 13586–13600, 2008.

Kalsitriol ve CaSR

IL-6

CaSR aktivatörleriTip I agonist: Hücre dışı Ca++ gerekmez•

Katyonlar–+2 değerlikliler: Mg, Sr•+3 değerlikliler: La, Gd•

+ yüklü organik moleküller–Poliaminler (spermine), aminoglikozidler, •protamin, poliarginine•

Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC. Cloning and characterization of an •extracellular Ca2-sensing receptor from bovine parathyroid. Nature 366: 575–580, 1993.

Tip II : Hücre dışı Ca++ gerekir•L-aa: aromatik aa, allosterik aktivatörler –(kalsimimetikler)

Nemeth EF, Steffey ME, Hammerland LG, Hung BC, Van Wagenen BC, DelMar EG, Balandrin MF. Calcimimetics with potent and selective activity •on the parathyroid calcium receptor. Proc Natl Acad Sci USA 95: 4040–4045, 1998

CaSR aktivatörleri

Kalsilitikler

CaSR’ nin allosterik inhibitörleridir.•Trans membran bölgeye bağlanır. •(kalsimimetikler gibi)CaSR’yi inaktif konformasyonda stabilize •ederler.

Gowen M, Stroup GB, Dodds RA, James IE, Votta BJ, Smith BR, Bhatnagar PK, Lago AM, Callahan JF, DelMar EG, Miller MA, Nemeth EF, Fox •J. Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J Clin Invest 105: 1595–1604, 2000.

CaSRPTH sekresyonu-sentezi-PTH hücre proliferasyonu•

Brown EM. Anti-parathyroid and anti-calcium sensing receptor antibodies in autoimmune hypoparathyroidism. Endocrinol Metab Clin North Am 38: 437–445, 2009.

PTH gen ekspresyonunun kontrolü (transkripsiyon sonrası •mekanizmalarla)

Levi R, Ben-Dov IZ, Lavi-Moshayoff V, Dinur M, Martin D, Naveh-Many T, Silver J. Increased parathyroid hormone gene expression in secondary hyperparathyroidism of experimental uremia is reversed by calcimimetics: correlation with posttranslational modification of the trans acting factor AUF1. J Am Soc Nephrol 17: 107–112, 2006.

VDR upregülasyonu •Garfia B, Canadillas S, Canalejo A, Luque F, Siendones E, Quesada M, Almaden Y, Aguilera-Tejero E, Rodriguez M. Regulation of parathyroid vitamin D receptor •expression by extracellular calcium. J Am Soc Nephrol 13: 2945–2952, 2002.

CaSR inaktivasyonu

Ciddi PTH yüksekliği–Paratiroid hiperplazi–

Pollak MR, Chou YH, Marx SJ, Steinmann B, Cole DE, Brandi ML, Papapoulos SE, –Menko FH, Hendy GN, Brown EM. Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype. J Clin Invest 93: 1108–1112, 1994.Ho C, Conner DA, Pollak MR, Ladd DJ, Kifor O, Warren HB, Brown EM, Seidman JG, –Seidman CE. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet 11: 389–394, 1995.

SHPT Patogenez

Aktörler:•Elektrolitler: Ca, P–Fosfatonin: FGF23–Vit D–

Reseptörler:•CaSR–FGFR1, Klotho…–VDR–

FGF23Fosfat kontrolü•Osteositlerden salgılanır. •Prox.tübülde NPT2 (Na-P ko-transporter) •ekspresyonunu azaltır. 12. Kromozomdadır.•Gen mutasyonları FGF23 etkisinde artma/ •azalmasıyla sonuçlanabilir.Zadik Y, Nitzan DW (October 2011). "Tumor induced osteomalacia: A forgotten paraneoplastic syndrome?"Oral Oncol 48(2): •e9–10. doi:10.1016/j.oraloncology.2011.09.011. PMID 21985764. Jump up^ "Entrez Gene: FGF23 fibroblast growth factor 23

Fibroblast growth faktör (FGF23)

7 adet FGF •FGF23: Fosfat hemostazı “Fosfatonin”•

251 aa. polipeptid–Osteoblast ve osteositler –hipotalamus, over, testis, timüs, beyin, koroid pleksüs, kalp, paratiroid bez–

Liu S, Zhou J, Tang W, Jiang X, Rowe DW, Quarles LD: Pathogenic role of Fgf 23 in Hyp mice. Am J Physiol Endocrinol Metab 2006, 291, –E38–E49

Serumda (t1/2: 58 dakika)•biyolojik aktif: intact FGF23 –İnaktif C-terminal FGF23–

FGF23 Sentezi, salgılanma ve yapısı

Komaba, H. & Fukagawa, M. (2012) The role of FGF23 in CKD—with or without KlothoNat. Rev. Nephrol. doi:10.1038/nrneph.2012.116

FGF reseptörleri:•FGFR1,2,3 ve 4•Hücre içi domain: Tirozin kinaz •aktiviteHücre dışı domain: Ig benzeri yapıda •(D1-D3)Powers CJ, McLeskey SW, Wellstein A: Fibroblast growth factors, their receptors and signaling. Endocr Relat •Cancer 2000, 7, 165–197.Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell 2000, 103, 2211–2225.•

FGF23 •Heparan sülfat’a afinitesi düşüktür. •Kan dolaşımında bulunabilir •Sistemik fonksiyonlar yerine getirebilir.•Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert TA, Zhang F, •Linhardt RJ, Yu X, White KE, Inagaki T, Kliewer SA, Yamamoto M, Kurosu H, Ogawa Y, Kuo-o M, Lanske B, Razzaque MS, Mohammadi M: Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Moll Cell Biol 2007, 27, 3417–3428.

Diğer FGF’ler: Heparan sülfat’a afinitesi yüksek. •Hücre membranları tarafından yakalanır ve •tutulur. Bu yüzden sadece parakrin etkileri vardır. Yamashita T: Structural and biochemical properties of fibroblast growth factor 23. Ther Apher Dial 2005, 9, •313–318.

FGF-19

FGF-23

FGF-19

FGF-19

FGF-23

FGF-19

FGF-1

Goetz R, Molecular insights •into the klotho-dependent, endocrine mode of action of •fibroblast growth factor 19

subfamily members. Moll Cell Biol 2007, 27, 3417–3428.

FGF19•Kolesterol-7-α-OHlase (CYPA1) (safra asit –sentezi hız kısıtlayıcı basamak ta inhibisyonCrestani M, Sadeghpour A, Stroup D, Galli G, Chiang JY: Transcriptional activation of the cholesterol 7α-hydroxylase gene (CYP7A) by nuclear hormone –receptors. J Lipid Res 1998, 39, 2192–2200.

FGF21•Trigliseridleri düşürür–Adipositlerde insüline bağımlı “glukoz uptake”i –artırır.Kharitonenkov A, Shiyanova T, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, –Gromada J, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB: FGF-21 as a novel metabolic regulator. J Clin Invest 2005, 115, 1627–1635.

FGF23•

FGF23 ü Nötralize etmekAnti-FGF23 Antikor

Akut:•Vit D artışı, –PTH süpresyonu–

Hasegawa H, et al. Direct evidence for a causative role –of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. Kidney Int. 2010;78(10):975–980.

Yamazaki Y, et al. Anti-FGF23 neutralizing antibodies –show the physiological role and structural features of FGF23. J Bone Miner Res. 2008; 23(9):1509–1518.

Kronik:•KBY progresyonuna –etkisizKardiyak –parametrelere etkisizShalhoub V, et al. FGF23 neutralization improves –chronic kidney disease–associated hyperparathyroidism yet increases mortality. J Clin Invest. 2012; 122(7):2543–2553.

Fosfat toksisite–Zoccali C, et al. Phosphate may promote CKD –progression and attenuate renoprotective effect of ACE inhibition. J Am Soc Nephrol. 2011;22(10):1923–1930.

FGF23 kardiyomyopati–

YOKLUĞUNDA:•Kısa yaşam•Kısırlık•Arterioskleroz•Ciltte atrofi •Osteoporoz •Amfizem •Beta-glucosidase enzim dizilimi ile benzer kodlar •taşır.Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, •Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997 Nov 6;390(6655):45-51. PubMed PMID: 9363890.

ZeusGod of the sky,

lightning, thunder, law, order, justice

Themis "divine law"

Klothospinning the thread of

human life.

Klotho protein:Yaşlanmayı baskılar•Kuro-o M, Matsumara Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, •Iida A, Shiraki-lida T, Nishikawa S, Nagai R, Nabeshima Y: Mutation of the mouse klotho gene leads to a syndrome resembling aging. Nature 1997, 390, 45–51.

FGF23-FGF23R bağlanmasını ko-reseptör fonksiyonu •göstererek stabilize eder.Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T: Klotho converts canonical FGF receptor into a specific receptor for FDF23. Nature 2006, 444, 770–774.•

Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kro-o M: Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem 2006, 281, 6120–6123. •

Böbrek, paratiroid, pituiter, choroid plexus.•

FGF23 etkinliği için gereklidir.•

SDBY’de Klotho-bağımlı and Klotho-bağımsız FGF23 etkileri

Komaba, H. & Fukagawa, M. (2012) The role of FGF23 in CKD—with or without Klotho Nat. Rev. Nephrol. doi:10.1038/nrneph.2012.116

Klotho protein tipleri:•Soluble (Çözünen)–Transmembran –

FGF23 “çözünen tip”in salgılanmasını •arttırır.“Çözünen Klotho” Na/Pi IIa kanal •aktivitesini azaltır. (FGF23’den bağımsız

olarak):::::FosfatüriHu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Razzaque MS, Rosenblatt KP, Baum •MG, Kuro-o M, Moe OW: Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J. 2010, 24, 3438–3450.

The fibroblast growth factor (FGF)-23 receptor. In light blue, FGF receptor type-1 (FGFR-1). In dark blue, left-sided membrane-bound Klotho; right-sided soluble, shed Klotho. The red hexagon depicts FGF-23. FGF-23 signal transduction is established when Klotho and FGFR-1 colocalize (left side). It is unknown whether signal transduction can occur by soluble Klotho (right side). In the kidney, signaling leads to downregulation of CYP27B1 and retrieval of phosphate transporters in the proximal tubule (figure provided by J Hoenderop, Department of Physiology, University Medical Center Nijmegen, The Netherlands).

Fibroblast growth factor-23 and Klotho in chronic kidney diseaseMarc G Vervloet and Tobias E Larsson

Paratiroid hiperplazinin gelişmesi

Paratiroid hiperplazinin gelişmesi

Paratiroid hiperplazinin gelişmesi

Paratiroid hiperplazinin gelişmesi

SHPT Patogenez

Aktörler:•Elektrolitler: Ca, P–Fosfatonin: FGF23–Vit D–

Reseptörler:•CaSR–FGFR1, Klotho…–VDR–

Vitamin D reseptör (VDR).

Brown A J et al. Am J Physiol Renal Physiol 1999;277:F157-F175

©1999 by American Physiological Society

VDR ve 1,25(OH)2D3.

Brown A J et al. Am J Physiol Renal Physiol 1999;277:F157-F175

©1999 by American Physiological Society

VDR

Paratiroid hücrelerinde•Kalsitiriol bağlandığında paratiroid hücre –proliferasyonunu inhibe eder

PTH geninde Vit D yanıt elementi •(VDRE) bulunur.

Kasitriol bağlandığında PTH gen –ekspresyonunu ve dolayısıyla sentezini inhibe eder.

Naveh-Many T, Friedlaender MM, Mayer H, Silver J. Calcium regulates parathyroid hormone messenger ribonucleic acid (mRNA), but not –calcitonin mRNA in vivo in the rat. Dominant role of 1,25-dihydroxyvitamin D. Endocrinology 1989; 125:275.

Ca düzeyi ve VDR

Peptidyl-prolyl cis-trans isomerase,NİMA interacting-1 (Pin 1), K-homology splicing regulatory protein (KSRP) e bağlanarak fosforilasyonu engeller sonuçta PTH/RNA degredasyonu artar

Pin 1 olmayan •sıçanlarda serum Ca++ ve P seviyesinden bağımsız SHPT görülür.

Ciddi SHPT-Masif yumuşak doku kalsifikasyonları

POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2013; 123 (4)

Teşekkürler •