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DEKANLIK ONAYI
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30 7('$9ø««««««««««««««««««««««« 32 9h&87.ø/2681'$$=$/0$««««««««««« 33 1$6+ødø1ø/$d7('$9ø6ø««««««««««««« 34 4.6.2.1$6+7('$9ø6ø1'($17ø2.6ø'$1/$5««««« 35 *hd/h$17ø2.6ø'$1(7.ø<(6$+ø32/$1 )ø72g6752-(1/(5YHø=2)/$921/$5«««««««« 36 4.6.2.1.2. *(1ø67(ø1««««««««««««««««««« 37 5. GEREÇ ve YÖNTEM……… 39 5.1. DENEY HAYVANLARI……… 39 '(1(<'(.8//$1,/$1'ø<(7/(5YH+$<9$1/$5,1 %(6/(10(6ø«««««««««««««««««««««« 39 *583/$5,1'$ö,/,0,YH'(1(<6(/d$/,ù0$1,1 'ø=$<1,«««««««««««««««««««««««« 39 *(1ø67(ø1+$=,5/$10$6,YH'2=8«««««««« 40 d$/,ù0$1,1621/$1',5,/0$6,YHg51(./(5ø1 TOPLANMASI………... 40 %ø<2.ø0<$6$/$1$/ø=/(5ø1<$3,/0$6,««««« 41 +ø6723$72/2-ø.'(ö(5/(1'ø50(««««««««
Sayfa no ø67$7ø67ø.6(/$1$/ø=««««««««««««««« 42 6. BULGULAR………... 43 6.%$=$/YH'(1(<6h5(6ø1'(.ø$ö,5/,. BULGULARI……….. 43 .$5$&øö(5$ö,5/,./$5,«««««««««««« 44 %ø<2.ø0<$6$/%8/*8/$5«««««««««««« 44 6.3. SERUM TNF ALFA ve TGF-%(7$'h=(</(5ø«««« 46 /ø3ø'3(52.6ø'$6<218%8/*8/$5,……… 49 +ø6723$72/2-ø.%8/*8/$5««««««««««« 51 7$57,ù0$«««««««««««««««««««««« 56 8. KAYNAKLAR……… 63 g=*(d0øù«««««««««««««««««««««« 74
7$%/2/$5/ø67(6ø Sayfa no Tablo 1: YD÷OÕNDUDFL÷HUHQHGHQRODQIDNW|UOHU««««««« 11 7DEOR <D÷GDQ]HQJLQGL\HWLQLoHUL÷L««««««««««« 32 7DEOR1$6+KDVWDODUÕYH\DGHQH\VHOoDOÕúPDODUGD\DUDUOÕ HWNLOHULJ|VWHULOHQWHUDS|WLN\DNODúÕPODU«««««««««« 33
Tablo 4. Kontrol ve plasebo grubu ve *.YH*7JUXSODUÕQGDNL UDWODUÕQNLORWDNLELNDUDFL÷HUD÷ÕUOÕNODUÕYHEXD÷ÕUOÕNODUÕQ YFXWD÷ÕUOÕ÷ÕQDRUDQODUÕ«««««««««««««««« 43 Tablo 5. .RQWUROSODVHER*.YH*7JUXSODUÕQGDVHUXP biyokimya verileri……….. 45
Tablo 6. Serum TNF-alfa ve TGF-beta düzeyleri………... 48 7DEOR/LSLGSHURNVLGDV\RQEXOJXODUÕ3OD]PDYHNDUDFL÷HU
doku MDA düzeyleri……….
50
Tablo 8: Plasebo, GK ve GT grubu ratlarda saptanan
histopatolojik özellikler………
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plasebo ve genistein koruyucu ve tedavi edici gruptaki ratlarda DQODPOÕELUNLORND\EÕJ|zlendi…..……… 44 ùHNLO*UXSODUDUDVÕQGD$67G]H\OHUL«««««««««« 46 ùHNLO*UXSODUDUDVÕQGD$/7G]H\OHUL«««««««««« 47 ùHNLO*UXSODUDUDVÕQGDVHUXP71)-alfa düzeylerinin NDUúÕODúWÕUÕOPDVÕ«««««««««««««««««««« 48
ùHNLO*UXSODUDUDVÕQGa serum TGF-beta düzeylerinin
NDUúÕODúWÕUÕOPDVÕ««««««««««««««««««««« 49 ùHNLO*UXSODUDUDVÕQGDSOD]PD0'$GH÷HUOHULQLQ NDUúÕODúWÕUÕOPDVÕ««««««««««««««««««««« 50 ùHNLO*UXSODUDUDVÕQGDNDUDFL÷HUGRNX0'$GH÷HUOHULQLQ NDUúÕODúWÕUÕOPDVÕ«««««««««««««………. 51 ùHNLO .RQWUROJUXEXLOHSODVHERJUXEXKLVWRORMLNEXOJXODUÕQÕQ NDUúÕODúWÕUÕOPDVÕ««««««««««««««««««««« 54 ùHNLO 3ODVHERJUXEXLOH*.YH*7JUXSODUÕQÕQKLVWRORMLN EXOJXODUÕQÕQNDUúÕODúWÕUÕOPDVÕ««««««««««««««« 55
KISALTMALAR
NAYKH : 1RQDONROLN\D÷OÕNDUDFL÷HUKDVWDOÕ÷Õ NASH : Nonalkolik steatohepatit
ROS : Reaktif oksijen ürünleri MDA : Malondialdehid
HNE : Hidroksinonenal
YK : <D÷OÕNDUDFL÷HU
YZD <D÷GDQ]HQJLQGL\HW
GK : Genistein koruyucu GT : Genistein tedavi edici
TGF-beta : Transforming growth faktör beta 9.ø : Vücut kitle indeksi
AST : Asp ALT : Alanin amino transferaz
GGT : Gama glutamil transpeptidaz ALP : Alkalen fosfataz
SYA : 6HUEHVW\D÷DVLWL
CYP : Sitokrom P
1. ÖZET
Oksidatif stres nonalkolik steatohepatit (NASH) patogenezinde rol alan en önemli faktörlerden biridir. Birçok farmakolojik özelliklere sahip bir fitoöstrojen olan genisteinin (4’,5, 7-trihydoxyisoflavone) antioksidan ve anti-inflammatuvar HWNLOHUL ROGX÷X ELOLQPHNWHGLU %X oDOÕúPDGD GHQH\VHO RODUDN ROXúWXUXODQ 1$6+ PRGHOLQGHJHQLVWHLQLQNRUX\XFXUROQDUDúWÕUGÕN
48 adet erkek Sprague-Dawley rat randomize olarak dört HúLWJUXEDD\UÕOGÕ %LULQFLJUXSVDGHFHVWDQGDUWUDW\HPLDOGÕ NRQWUROJUXEX JUXS. *UXS SODVHER VHUXPIL]\RORMLN JUXEX JUXSYH¶HLVH\D÷GDQ]HQJLQGL\HW <=' DGOLELWXP RODUDNYHULOGL*UXS¶H<='¶HEDúODPDGDQELUJQ|QFHYHWPGHQH\süresince 0.2 PJNJJQGR]XQGDJHQLVWHLQVXENXWDQRODUDNX\JXODQGÕ JHQLVWHLQNRUX\XFX *. grup). Grup 4’e dördüncü haftadan sonra iki hafta 0.2 mg/kg/gün dozunda genistein VXENXWDQRODUDNX\JXODQGÕ JHQLVWHLQWHGDYL *7 JUXEX KDIWDELWWLNWHQVRQUDtüm UDWODU |OGUOG .DQ |UQHNOHUL YH NDUDFL÷HU GRNXODUÕ DOÕQGÕ $PLQRWUDQVIHUD]ODU SOD]PDYHNDUDFL÷HUPDORQGLDOGHKLG 0'$ G]H\OHUL|OoOG+LVWRSDWRORMLNRODUDN NDUDFL÷HUGHVWHDWR]EDORQODúPDGHMHQHUDV\RQXLQIODPPDV\RQ0DOORU\FLVLPFL÷LYH fibro]LVGH÷HUOHQGLULOGL
$67 YH $/7 GH÷HUOHUL S SOD]PD YH NDUDFL÷HU 0'$ YH SOD]PD TNF-DOID G]H\OHUL S VÕUDVÕ LOH SODVHER JUXEXQGD NRQWURO grubundan yüksekti. TGF-EHWD G]H\OHULQGH DQODPOÕ IDUN \RNWX +LVWRSDWRORMLN olarak steatoz, mm2 GHNL RUWDODPD LQIODPDWXYDU KFUH VD\ÕVÕ YH EDORQODúPD GHMHQHUDV\RQX SODVHER JUXEXQGD NRQWURO JUXEXQD J|UH DQODPOÕ RODUDN \NVHNWL S KHSVLQGH )LEUR]LV YH 0DOORU\ FLVPL VDSWDQPDGÕ +HP *. KHP GH *7 grubunda AST ve ALT düzeyleri (p hepsinGH SOD]PD YH NDUDFL÷HU 0'$ düzeyleri ve TNF-DOID G]H\OHUL SODVHER JUXEXQD J|UH DQODPOÕ RODUDN GúNW S
KHSVLQGH +LVWRSDWRORMLNLQFHOHPHGH*.YH*7JUXSODUÕQGDVWHDWR] VÕUDVÕLOH p<0.05 ve <0.01), mm2 deki ortalama inflamatuvar hücre sayÕVÕ KHU LNL JUXSWD S YHEDORQODúPDGHMHQHUDV\RQX KHULNLJUXSWD SODVHERJUXEXQDJ|UH DQODPOÕRODUDNGúNW
Sonuç: *oO ELU DQWLRNVLGDQ RODQ JHQLVWHLQ GHQH\VHO RODUDN 1$6+ JHOLúLPLQL belirgin olarak önlemekte, histopatolojik ve biyokimyasal düzelme ile steatohepatiti D]DOWPDNWDGÕU
Anahtar kelimeler: 1RQDONROLNVWHDWRKHSDWLW \D÷GDQ]HQJLQGL\HWRNVLGDWLIVWUHV genistein.
2. ABSTRACT
PREVENTIVE ROLE OF GENISTEIN IN EXPERIMENTAL NON-ALCOHOLIC STEATOHEPATITIS MODEL
Oxidative stress is one of the important factors that are playing role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Genistein (4’,5, 7-trihydoxyisoflavone), a phytoestrogen with several pharmacological features, has also antioxidant and anti-inflammatuar properties. In the present study, we evaluated preventive role of genistein in NASH model induced experimentally.
48 Sprague-Dawley rats were divided into four equal groups randomly. First group received only standart rat chow diet (control group: grup C). Group 2 (group placebo), 3 and 4 were given high fat diet (HFD) ad libitum. 0.5 ml serum physiologic injected daily to placebo group subcutaneously. 0.2 mg/kg/day genistein injected subcutaneously to group 3 (genistein prevention (GP) group) starting one day before HFD administration and during the whole experiment. After the fourth week, genistein at 0.2 mg/kg/day injected subcutaneously to the fourth group (genistein treatment (GT) group). All rats killed after six weeks. Blood samples collected and tissue samples prepared. Aminotransferases, plasma and liver malondialdehyde (MDA) levels were measured. Steatosis, ballooning degeneration, inflammation, Mallory body and fibrosis in the liver examined histopathologically.
AST and ALT levels (p for each <0.001), plasma and liver tissue MDA and plasma TNF-alpha levels (p <0.001, <0.001, <0.01, respectively) were higher in placebo group than in the control group. TGF-beta levels were comparable in the placebo and control groups. In histopthological examination, steatosis, inflammatuar cells per mm2 and balloning degeneration were significantly higher in the placebo
group than in the control group (p for each <0.001). There was no fibrosis and Mallory body. AST and ALT levels (p for each <0.05), plasma and liver tissue MDA and plasma TNF-alpha levels were significantly lower (p <0.05 for each) either in GP or in GT groups compared to the placebo group. Histopathologically, steatosis (p<0.05 and <0.01 respectively), mean number of inflammatuar cells per mm2 (p<0.01 for each) and balloning degeneration (p <0.01 for each) in GP and GT groups were significantly lower than in the placebo group.
In conclusion; genistein, a strong antioxidant agent, not only remarkably prevents the emergence of NASH, but also attenuates the existing steatohepatitis by improving the biochemical and histopathological abnormalities.
3*ø5øùYH$0$d
1RQDONROLN \D÷OÕ NDUDFL÷HU KDVWDOÕ÷Õ 1$<.+ YH EX KDVWDOÕ÷ÕQ HQ FLGGL IRUPX RODQ QRQDONROLN VWHDWRKHSDWLWLV 1$6+ ELU ]DPDQODU VÕN UDVWODQDQ IDNDW ]DUDUVÕ] ELU KDVWDOÕN RODUDN NDEXO HGLOPHVLQH UD÷PHQ JQP]GH NURQLN NDUDFL÷HU KDVWDOÕ÷ÕVLUR]YHNDUDFL÷HU \HWPH]OL÷LQHLOHUOHPHSRWDQVL\HOLWDúÕGÕ÷ÕDUWÕNoRNL\L bilinmektedir (1). Bu nedeQOH VRQ \ÕOODUGD \DSÕODQ oDOÕúPDODU KDVWDOÕ÷ÕQ SDWRIL]\RORMLVLQLDQODPD\DYHWHGDYLVLQHRGDNODQPÕúWÕU
1$6+ SDWRJHQH]L ROGXNoD NDUÕúÕN RODQ ELU KDVWDOÕNWÕU 'D\ YH -DPHV (2) WDUDIÕQGDQ RUWD\D DWÕODQ YH \D\JÕQ RODUDN NDEXO J|UHQ PRGHOH J|UH 1$6+ LNL darbeden (two-KLWPRGHO ROXúDQELUKDVWDOÕNWÕU Darbe 1 %LUoRNIDNW|UHED÷OÕRODUDN trigliseridlerin NDUDFL÷HUGH ELULPL LOH \D÷OÕ NDUDFL÷HU VWHDWR] JHOLúLPL YH EXQXQOD ELUOLNWHNDUDFL÷HULQLNLQFLGDUEHOHUHNDUúÕKDVVDVL\HWLQLQDUWÕúÕDarbe 2 øNLQFLGDUEH LOHELUOLNWHKHSDWRVLWKDVDUÕLQIODPDV\RQYHVRQXoRODUDNILEUR]LVJHOLúLPL
.DUDFL÷HUGH DúÕUÕ \D÷ ELULNLPL YH EXQD QHGHQ RODQ HWNHQOHUH NURQLN RODUDN PDUX]L\HW RNVLGDWLI VWUHV ROXúXPXQD QHGHQ ROXU 2NVLGDWLI VWUHV \D÷OÕ NDUDFL÷HU VWHWDWR] HYUHVLQGHQ 1$6+¶H LOHUOH\LúWHQ VRUXPOX WXWXODQ HQ |QHPOL IDNW|UOHUGHQ ELULRODUDNGúQOPHNWHGLUdHúLWOL1$YKH hayvan modelleri (3, 4) ve NASH’ li hastalarda (5, 6) \DSÕODQ oDOÕúPDODUGD RNVLGH SURWHLQOHULQ WLUR]LQ QLWUDV\RQX YH OLSLGOHULQ PHYFXGL\HWLQLQ J|VWHULOPHVL RNVLGDWLI VWUHVLQ 1$6+ JHOLúLPLQGH UROQH GDLULNQDHGLFLNDQÕWODUVD÷ODPÕúWÕU
5HDNWLI RNVLMHQ UQOHU 526 DUDFÕOÕ÷Õ LOH ROXúDQ OLSLG SHURNVLGDV\Rnu, 1$6+SDWRJHQH]LQGHPHUNH]LELUUROHVDKLSWLU/LSLGSHURNVLGDV\RQX PHPEUDQODUÕQ \ÕNÕPÕQD YH PDORQGLDOGHKLG 0'$ YH -hidroksinonenal (HNE) gibi reaktif PHWDEROLWOHULQDUWÕúÕQDQHGHQROXUYHE|\OHFHKFUHVHOGLVIRQNVL\RQD\RODoDU(7, 8).
/LSLG SHURNVLGDV\RQXQXQ GHUHFHVL VHUEHVW \D÷ DVLWOHULQLQ PHYFXGL\HWL LOH NRUHOHGLU (9) YH VWHDWRWLN NDUDFL÷HUGH FLGGL ]DUDU YHUHFH÷LQL J|VWHUPHNWHGLU 0'$ YH +1( 1$6+¶OLKDVWDODUÕQ ¶ÕQGDVWHDWR]OXKDVWDODUODNDUúÕODúWÕUÕOGÕ÷ÕQGDRNVLGDWLIVWresin DUWWÕ÷ÕQÕJ|VWHULUELUúHNLOGHDUWPÕúRODUDNEXOXQPXúWXU(10).
1$6+ WHGDYLVL GH SDWRJHQH] oDOÕúPDODUÕQD SDUDOHO RODUDN DUDúWÕUPD VDIKDVÕQGDGÕU YH KHQ] LGHDO ELU LODo WHGDYLVL EXOXQPDPDNWDGÕU %DúODQJÕo tedavisi RODUDNKDVWDODUDNLORYHUPH|QHULOVHGHKHGHIHXODúÕOPDVÕ]RUGXUøODoWHGDYLOHULQGHQ LQVOLQGX\DUOÕOÕ÷ÕQÕDUWÕUDQDMDQODUÕQSRWDQVL\HO\DQHWNLOHULQLQGR÷XUGX÷XHQGLúHOHU KLSROLSLGHPLN LODoODUÕQ EHOLUJLQ ELU ID\GDODUÕQÕQ VDSWDQDPDPDVÕ DUDúWÕUPDFÕODUÕ DOWHUQDWLI WHGDYLOHUH \|QHOWPLúWLU $OWHUQDWLI WHGDYL LoLQGH SDWRJHQH]GHQ VRUXPOX WXWXODQ |]HOOLNOH LNLQFL GDUEHGH URO DODQ YH ILEURJHQH] JHOLúLPLQGHQ GH VRUXPOX ROGX÷XGúQOHQRNVLGDWLIVWUHVYHHQGRWRNVLQ-DUDFÕOÕVLWRNLQVDOÕQÕPÕJLELIDNW|UOHUe \|QHOLN WHGDYLOHUOH KDVWDOÕ÷ÕQ úLGGHWLQLQ D]DOWÕOPDVÕ YH\D NRUX\XFX WHGDYLOHU KHGHI DOÕQPÕúWÕU1$6+SDWRJHQH]LQGHRNVLGDWLIVWUHVLQUROQJ|VWHUHQGHOLOOHULQDUWÕúÕLOH ELUOLNWHELUoRNDQWLRNVLGDQDMDQÕQWHGDYLGHNLUROGHDUDúWÕUÕOPDNWDGÕU%HWDLQYHN-DVHWLOVLVWHLQ JLEL JOXWDW\RQ |QFOHUL LOH \DSÕODQ ED]Õ oDOÕúPDODUGD ROXPOX VRQXoODU ELOGLULOPLúWLU(11).
Birçok farmakolojik özelliklere sahip bir fitoöstrojen olan genisteinin (4’,5, 7-WULK\GR[\LVRIODYRQH NDQVHU|QOH\LFLHWNLOHULQLQ\DQÕQGDDQWL-tümör, antioksidan ve anti-LQIODPPDWXYDU HWNLOHUL ROGX÷X ELOGLULOPHNWHGLU (12, 13). Birçok hücresel VLVWHPGHE\PH\L|QOH\LFLHWNLVLROGX÷X J|VWHULOHQJHQLVWHLQLQKFUHE\PHVLQL TGF-beta-¶LQ X\DUÕ \ROODUÕQÕ PRGOH HGHUHN LQKLEH HGHELOHFH÷L |QH VUOPúWU (14) <DNÕQ ]DPDQGD \DSÕODQ LNL D\UÕ in vitro oDOÕúPDGD JHQLVWHLQLQ KHSDWLN ILEURJHQH]LVGHQVRUXPOXRODQVWHOODWKFUHOHULQSUROLIHUDV\RQXQXHWNLOHGL÷L(15, 16)
ve TGF-- DUDFÕOÕ NROODMHQ VHQWH]LQL D]DOWDUDN DQWL-ILEURWLN HWNL J|VWHUGL÷L (16) ELOGLULOPLúWLU
%X oDOÕúPDGD KHP DQWL-inflammatuvar ve antioksidan özellikleri hem de NDUDFL÷HUVWHOODWKFUHOHUL]HULQGHQHWNLJ|VWHUHUHNDQWL-ILEURWLNHWNLOHULROGX÷XLOHUL VUOHQJHQLVWHLQLQGHQH\VHORODUDNROXúWXUXODQ1$6+PRGHOLQGHNRUX\XFXUROnü DUDúWÕUPD\ÕDPDoODGÕN
*(1(/%ø/*ø/(5 <D÷OÕ.DUDFL÷HU
øON NH] \ÕOÕQGD +HULEHUW 7D\ORU WDUDIÕQGDQ DQODPOÕ PLNWDUGD DONRO kullanmayan fakat alkolik steatohepatit ile uyumlu histolojik özelliklere sahip bir YDND ELOGLULOPLúWLU %HQ]HU EDúND \D\ÕQODUGDQ VRQUD DONROH ED÷OÕ ROPD\DQ NDUDFL÷HU\D÷ODQPDVÕWHULPLLONNH] ¶GH0D\RNOLQLNWHQ/XGZLJYHDUNDGDúODUÕ WDUDIÕQGDQ WDQÕPODQPÕúWÕU \ÕOÕQGD $PHULND %LUOHúLN 'HYOHWOHULQLQ XOXVDO VD÷OÕNHQVWLWVQ\DSWÕ÷ÕNRQVHQVXVWRSODQWÕVÕLOH1$6+GkKLO\D÷OÕNDUDFL÷HU <. KDVWDOÕNODUÕQÕQ NURQLN YLUDO KHSDWLW YH DONROLN KHSDWLW LOH EHUDEHU HQGVWUL\HO OHNHOHUGH HQ VÕN UDVWODQÕODQ NDUDFL÷HU KDVWDOÕNODUÕ ROGX÷X ELOGLULOPLúWLU *HoPLúWH VHOLPVH\LUOLELUKDVWDOÕNRODUDNJ|UOHQ<.¶LQDUWÕNJQP]GHGúQOG÷NDGDU PDVXP ROPDGÕ÷Õ ELOLQPHNWHGLU <. NURQLN NDUDFL÷HU KDVWDOÕNODUÕQD YH KDWWD KHSDWRVHOOHU NDUVLQRPD\D LOHUOH\HELOPHNWHGLU +DVWDOÕ÷ÕQ PDVXP RODUDN ELOLQPHVL \DQOÕúÕQÕQ\DQÕQGD\DNÕQ]DPDQDNDGDU<.¶LQGDKDoRNUHIDKG]H\LQLQ\NVHNOL÷L YHEHUDEHULQGHDONROWNHWLPLLOHLOLúNLOLROGX÷XNDEXOHGLOPHNWH\GL .LP\DVDORODUDNVD÷OÕNOÕELUNDUDFL÷HUNXUXD÷ÕUOÕ÷ÕQÕQ\DNODúÕN–NDGDUÕ \D÷GÕUYHPLNURVNRSWDJ|UOHPH]%XPLNWDU–¶\ÕJHoWL÷LWDNGLUGHPLNURVNRSLN olaUDNNDUDFL÷HUGH\D÷ELULNLPLIDUNHGLOHELOLU%XQXQODEHUDEHUWHUPLQRORMLNRODUDN NDUDFL÷HU\D÷ODQPDVÕYH<.D\QÕGH÷LOGLU%XLNLWHULPLQD\UÕPÕú|\OH\DSÕOPDNWDGÕU +LVWRORMLN RODUDN NDUDFL÷HUGHNL KHSDWRVLWOHULQ ¶GHQ D]Õ J|UOHELOLU \D÷ GDPODFÕNODUÕiçeriyorsa buna NDUDFL÷HU\D÷ODQPDVÕH÷HUKHSDWRVLWOHUGHNLJ|UOHELOLU \D÷GDPODFÕ÷ÕLoHUL÷L¶GHQID]ODLVHEXQD<KGHQLU'L÷HUELUGH\LúOHNDUDFL÷HULQ ÕVODND÷ÕUOÕ÷ÕQDJ|UH\D÷RUDQÕ-ROGX÷XQGDEXGXUXPYKRODUDNDGODQGÕUÕOÕU (19).
4.1.1. Ya÷OÕ.DUDFL÷HULQ2OXúXPX
<D÷OÕ NDUDFL÷HU ELUoRN PHNDQL]PD\OD ROXúPDNWDGÕU %HOOL EDúOÕ RODUDN G|UW PHNDQL]PDLOHROXúDELOLU
a) 7ULJOLVHULGOHUYH\D÷DVLWOHULQLQEHVLQ\ROXLOHDOÕQPDVÕ %HVLQOHUGHNL\D÷ SRUWDOYHQNDQÕQGDúLORPLNURQODULOHNDUDFL÷HUHWDúÕQÕU1|WUDO\D÷ODUÕQELUNÕVPÕLVH WULJOLVHULGOHU YH VHUEHVW \D÷ DVLWOHUL RODUDN GHSRODQGÕNODUÕ \D÷ GRNXVXQD XODúÕUODU 'DKDVRQUDHVWHUOHQPHPLú\D÷DVLWOHULRODUDNNDUDFL÷HUHXODúDELOLUOHU
E +HSDWRVLWOHUGHVHUEHVW\D÷DVLGLVHQWH]LQGHDUWPDYH\DKFUH\HDOÕQDQ \D÷DVLWOHULQLQRNVLGDV\RQXQGDD]DOPD. Her ikisi de hücrede trigliserid birikmesine yol açar.
c) 7ULJOLVHULGOHULQ KHSDWRVLWOHUGHQ GÕúDUÕ WDúÕQPDVÕQGD ER]XOPD. Trigliseridler kolesterol, fosfolipidler ve apo-SURWHLQOHUOH ELUOLNWH GÕúDUÕ WDúÕQÕU TDúÕ\ÕFÕSURWHLQOHULQVHQWH]LER]XOGX÷XQGDWULJOLVHULGOHUKFUHLoHULVLQGHNDOÕU
d) .DUERQKLGUDWID]ODOÕ÷Õ +FUHGHWULJOLVHULGOHUHG|QúWUOHELOLUYHEXUDGD depolanabilir (20).
<D÷OÕ.DUDFL÷HU(SLGHPL\RORMLVL
<D÷OÕ NDUDFL÷HU VÕN UDVWODQÕODQ ELU GXUXP ROPDVÕQD NDUúÕQ JHQHO SRSXODV\RQGDNL SUHYDODQVÕ EHOOL GH÷LOGLU +LVWRSDWRORML LOH HOGH HGLOHQ VRQXoODU VHoLOPLú KDVWD SRSXODV\RQX ROGX÷X LoLQ JHQHOOHQHPHPHNWHGLU .DUDFL÷HU KLVWRORMLVL ROPDGDQ ODERUDWXYDU YH J|UQWOHPH \|QWHPOHUL LOH \DSÕODQ oDOÕúPalarda ise YK’e QHGHQ RODQ ELUoRN KDVWDOÕN D\ÕUW HGLOHPH] YH KDWDOÕ VRQXo HOGH HGLOLU +LVWRORML HQ NHVLQ VRQXFX YHUPHNOH EHUDEHU KLoELU LQFHOHPH WHN EDúÕQD <. SUHYDODQVÕQÕ EHOLUOHPHGH JYHQLOLU GH÷LOGLU øQFHOHQHQ SRSXODV\RQXQ VRV\DO \DSÕVÕ GD epidemiyoloMLN VRQXoODUÕ |QHPOL RUDQGD HWNLOHPHNWHGLU <D÷OÕ NDUDFL÷HU VÕNOÕ÷Õ -DSRQ\DYHøWDO\D¶GD\DSÕODQoDOÕúPDODUDJ|UHLOHDUDVÕQGDGH÷LúPHNWHGLUYH
RUWDODPD RODUDN ¶WU %X JHQLú DUDOÕ÷ÕQ VHEHEL GQ\DGDNL IDUNOÕ SRSXODV\RQODUGÕUYHSRSXODV\RQODUÕQIDUNOÕVRV\RHNRQRPLNGXUXPODUÕGÕU
&LQVL\HW NRQXVXQGD GD VRQXoODU IDUNOÕOÕN DU] HWPHNWHGLU gQFHOHUL <.¶LQ NDGÕQ YH HUNHN FLQVL\HWWH HúLW VÕNOÕNWD ROGX÷X ELOGLULOPHNWH\GL 8OWDVRQRJUDIL LOH \DSÕODQ \HQL oDOÕúPDODUGD LVH -DSRQODU IDUNOÕ VRQXoODU ELOGLUPHNWHGLU $úÕUÕ NLORVX YH\D KLSHUWULJOLVHULGHPLVL ROPD\DQ NLúLOHUGH <. HUNHNOHUGH NDGÕQODUD J|UH DQODPOÕ RODUDNGDKDVÕNWÕU
8OWUDVRQRJUDILLOH\DSÕODQoDOÕúPDODUGDoRFXNODUGDGD<.¶HGúNVÕNOÕNWDGD olsa (%1.8- UDVWODQPDNWDGÕU)DNDWHQVÕNJ|UOPH\DúÕ- \DúODUÕDUDVÕQGDGÕU (24).
*|UOG÷ JLEL <. SUHYDODQVÕ \Dú FLQVL\HW EHVOHQPH WDU]Õ YFXW NLWOH LQGHNVL 9.ø LODoNXOODQÕPÕYHWRNVLQOHUOHWHPDVDJ|UHGH÷LúNHQOLNJ|VWHUPHNWHGLU YK için en önemli risk faktörleri obezite, alkol tüketimi ve insülin direncidir. .RQWUROOHUGH<.SUHYDODQVÕLOHDUDVÕQGDLNHQEXRUDQDONROLNOHUGH¶\D DúÕUÕ NLOROXODUGD ¶\D REH] DONROLNOHUGH LVH ¶H \NVHOPHNWHGLU Bu VRQXoODUGDJ|VWHUPHNWHGLUNLREH]LWHDONRONXOODQÕPÕQDJ|UH<.JHOLúLPLLoLQGDKD JoOELULOLúNLJ|VWHUPHNWHGLU
<D÷OÕ.DUDFL÷HU(W\RORMLVL
<D÷PHWDEROL]PDVÕQGDNDUDFL÷HUEDUVDNODUNDQYHSHULIHULN\D÷GRNXVXJLEL GH÷LúLN RUJDQODU DUDVÕQGDNL LOLúNLOHU ]LQFLUL EHVLQ DOÕPÕ NDUDFL÷HU YH EDUVDN PXNR]DVÕQÕQYH\DKRUPRQPHWDEROL]PDVÕQÕQVHQWH]\HWHQH÷LJLELoHúLWOLIRQNVL\RQODU DUDVÕQGD NDUPDúÕN ELU LOLúNL YDUGÕU %XQODUGD PH\GDQD JHOHELOHFHN ER]XNOXNODU NDUDFL÷HU \D÷ PLNWDUÕQGD GH÷LúLNOLNOHUH QHGHQ RODELOLU YH <. JHOLúLPLQH ]HPLQ KD]ÕUOD\DELOLU
7DEOR <D÷OÕNDUDFL÷HUHQHGHQRODQIDNW|UOHU
%HVOHQPH\HED÷OÕQHGHQOHU $úÕUÕEHVOHQPHDGLSR]LWDV\HWHUVL]EHVOHQPH 0DOQWULV\RQ KÕ]OÕNLORND\EÕYE DONROWRWDOSDUHQWHUDOEHVOHQPH
Jejuno-ileal by-pass, mide by-SDVVÕJDVWULNEDQGDM
0HWDEROL]PDER]XNOXNODUÕ Tip 2 diyabetes mellitus, hiperlipidemi, abetalipoproteinemi, *DODNWR]HPLJOLNRJHQH]IUXNWR]LQWROHUDQVÕYE Reye sendromu Gut .URQLNKDVWDOÕNODU øQIODPDWXYDUEDUVDNKDVWDOÕNODUÕ :LOVRQKDVWDOÕ÷Õ .URQLNVD÷NDOS\HWPH]OL÷L Kistik fibrozis
Enfeksiyonlar: Kronik hepatit C, fulminan virüs hepatiti, HIV enfeksiyonu, tüberküloz, kronik osteomiyelit
.DUDFL÷HU UH]HNVL\RQX YH\D WUDQVSODQDWDV\RQX VRQUDVÕQGD NDUDFL÷HU\HWHUVL]OL÷L
Endokrinopatiler: &XVKLQJKDVWDOÕ÷ÕPLNV|GHPDNURPHJDOL
øODoODUWRNVLQOHU Amiodaron, tamoksifen, glukokortikoidler, sentetik östrojenler, metotreksat, tetrasiklin, salisilât, valproik asit, virostatikler
$UVHQLNNXUúXQWHWUDNORUNDUERQ mantar zehirlemesi vb. Hamilelik: +LSHUHPH]LVJUDYLGDUXPJHEHOL÷LQDNXW\D÷OÕNDUDFL÷HUL
0XKWHPHOQHGHQOHULQoHúLWOLOL÷L<.¶GHWP\OHQRQ-spesifik bir tablonun söz NRQXVX ROGX÷XQX YH <.¶LQ NHQGL EDúÕQD EHOLUOL ELU QHGHQH ED÷ODQDPD\DFD÷ÕQÕ YH D\UÕFD NHQGL EDúÕQD ELU KDVWDOÕN GH÷HUL WDúÕPDGÕ÷ÕQÕ J|VWHUPHNWHGLU $OWWD \DWDQ KDVWDOÕNYH\DQHGHQLQJLGHULOPHVL\OHNDUDFL÷HUGHGHSRODQDQ\D÷NRPSOLNDV\RQVX]ELU úHNLOGHND\EROXU)DNDW<.WHNEDúÕQDKHUKDQJLELUULVNWDúÕPDVDGDFLGGLIRUPXRODQ 1$6+ JHOLúLPL LoLQ ROPD]VD ROPD] NRúXOGXU %X QHGHQOH <. WDPDPÕ\OD ]DUDUVÕ] RODUDN NDEXO HGLOPHPHOLGLU YH <.¶GHQ úSKHOHQLOHQ ROJXODU GHWD\OÕ RODUDN LQFHOHQPHOLYHJHUHNOLWHWNLNOHU\DSÕOÕSX\JXQ|QOHPOHUDOÕQPDOÕGÕU
4.2. Nonalkolik steatohepatit
.DUDFL÷HUGH DQODPOÕ PLNWDUGD DONRO WNHWLPL ROPDGÕ÷ÕQGD NDUDFL÷HUGH \D÷OÕ GH÷LúLNOLNOHU ROPDVÕQD 1$<.+ GHQPHNWHGLU 1$<.+¶ÕQÕQ KLVWRORMLN VSHNWUXPX ROGXNoDJHQLúWLU*HQHOOLNOHVHOLPVH\LUOLKDILINDUDFL÷HU \D÷ODQPDVÕQGDQSURJUHVLI fibrozis ve siroza ilerleyebilen formu olanVWHDWRKHSDWLWH \D÷ODQPDYHKHSDWRVHOOHU LQIODPDV\RQ YH KDVDUÕQ ELUOLNWHOL÷L NDGDU GH÷LúLN IRUPODUÕ PHYFXWWXU 1$<.+¶Õ nedene yönelik olarak primer veya sekonder olabilir (26). Metabolik sendromun |]HOOLNOHULQLQ HúOLN HWWL÷L YH GL÷HU QHGHQOHULQ EXOXQPDGÕ÷Õ WLSH SULPHU 1$<.+¶Õ denmektedir. Sekonder nedenler Tablo 1’de J|VWHULOPLúWLU 3ULPHU YH VHNRQGHU 1$<.+¶ÕQÕQ ELULELULQGHQ D\ÕUW HGLOPHVL |QHPOLGLU dQN SDWRJHQH]OHUL YH SURJQR]ODUÕELUELUOHULQGHQIDUNOÕGÕUYHVHNRQGHUWLSWHSURJQR]GDKDN|WGU
NASH1$<.+¶ÕQÕQNOLQLNIRUPODUÕQGDQELULGLUYHHQFLGGLVH\LUOLRODQÕGÕU Psödoalkolik hepatit, diyabetik hepatit, metabolik steatohepatit, steatonekroz, alkol EHQ]HULKHSDWLWJLELELUoRNIDUNOÕWHULP1$6+LOHHúDQODPOÕRODUDNWDQÕPODQPÕúYH NXOODQÕOPÕúWÕU 1$6+ WDQÕPÕ LoLQ XOXVODUDUDVÕ ELU X]ODúÕ WRSODQWÕVÕ ROPDVD GD \DNÕQ ]DPDQGD\DSÕODQoDOÕúPDODUGD1$6+WDQÕVÕQÕ\DSDUNHQúXNULWHUOHUNXOODQÕOPDNWDGÕU (18, 27, 28).
a) Histoloji:.DUDFL÷HUEL\RSVLVLQGHRUWDLOHúLGGHWOLGHUHFHGHPDNURYH]LNOHU \D÷OÕ GHMHQHUDV\RQ LOH ELUOLNWH OREXOHU YH\D SRUWDO LQIODPDV\RQ ROPDVÕ %LUOLNWH Mallory cismi, fibrozis ve siroz olabilir veya olmayabilir.
1$6+¶LQ KLVWRORMLN WDQÕPODQPDVÕQGD GD IDUNOÕOÕNODU ROPDVÕQD NDUúÕQ VWHDWRKHSDWLWHHNRODUDNKHSDWRVLWOHUGHEDORQODúPDGHjenerasyon, fibrozis ve Mallori FLVPL1$6+WDQÕVÕQGDJHQHOOLNOHDUDQPDNWDGÕU
<DNÕQ ]DPDQGD 0DWWHRQL YH DUNDGDúODUÕ 1$<.+¶ ÕQÕ NDWHJRUL]H HGHQ ELU oDOÕúPD\DSPÕúODUGÕU %XQDJ|UH1$<.+¶ÕG|UWDOWWLSHD\UÕOPÕúWÕU
7LS 6DGHFH\D÷ODQPDQÕQROPDVÕ
TLS <D÷ODQPDQÕQ\DQÕQGDLQIODPDV\RQXQEXOXQPDVÕ 7LS <D÷ODQPDYHEDORQODúPDGHMHQHUDV\RQXROPDVÕ
7LS <D÷ODQPDYHILEUR]LVYHYH\D0DOORU\FLVLPFLNOHULQLQEXOXQPDVÕ %XQODUGDQVDGHFHWLSYH¶QLOHULNDUDFL÷HUKDVWDOÕ÷ÕQDLOHUOHGL÷LJ|VWHULOPLúWir.
E $ONRO NXOODQÕPÕ %LULQFL EDVDPDN VD÷OÕN NXUXOXúX KHNLPOHUL ODERUDWXDU WHVWOHUL YH\D DLOH \DNÕQODUÕQÕQ GR÷UXODPDVÕ LOH LKPDO HGLOHELOLU GHUHFHGH HWDQRO NXOODQÕPÕ
*QP]GH LKPDO HGLOHELOLU DONRO GR]X KHQ] WDP DQODPÕ\OD WDQÕPODQPDPÕúWÕU$ONRONXOODQÕPÕQÕQGÕúODQPDVÕLoLQKLVWRORMLNLQFHOHPHYHoHúLWOL ODERUDWXDU WHVWOHUL NXOODQÕOPDNWDGÕU +LVWRORMLN RODUDN 1$6+¶WH QNOHHU YDNXROD]LV\RQ YH VWHDWR]LV DONROLN VWHDWRKHSDWLWH J|UH GDKD úLGGHWOL\NHQ SHULSRUWDO fibrozis, Mallory cisimcikleri ve safra kanal proliferasyonu alkolik steatohepatitte GDKDVÕNWÕU$ONROLNVWHWDRKHSDWLWWHKLVWRORMLNúLGGHWLQGHUHFHVLQLQGDKDID]ODROGX÷X ELOGLULOPHNOHEHUDEHUEXLNLNOLQLNGXUXPXVDGHFHKLVWRORML\HGD\DQDUDND\ÕUWHWPHN PPNQGH÷LOGLU
Ayaktan hastalarda rutin biyokimyasal testler ve klinik ile de NASH ile DONROLNVWHDWRKHSDWLWD\ÕUÕPÕ\DSPDN]RUGXU$úÕUÕDONRONXOODQÕPÕQÕJ|VWHUPHNLoLQ birçok belirteç (mitokondriyel aspartat aminotransferaz (AST), ortalama eritrosit partikül hacmi, gama glutamil transpeptidaz (GGT) karbonhidrat eksik transferin ve $67$/7 RUDQÕ JLEL NXOODQÕOPDVÕQD UD÷PHQ desile transferinin total transferine RUDQÕDúÕUÕDONRODOÕPÕLoLQHQL\LJ|VWHUJHGLU Henüz ne tek ne de kombine olarak hiçbir laboratuvar göstergesi alkol alGÕ÷ÕQÕLQNkUHGHQKDVWDODUGD JUDPÕQ DOWÕQGDDONRODOÕPÕQÕEHOLUOHPHGH\DUGÕPFÕGH÷LOGLU
F (úOLNHGHQKDVWDOÕNODU 'L÷HUDNWLINDUDFL÷HUKDVWDOÕNODUÕQÕQROPDPDVÕ 1$<.+¶ÕWDQÕVÕNRQXOPDGDQ|QFH<.¶HQHGHQRODELOHFHNVHNRQGHUQHGHQOHU GÕúODQPDOÕGÕU%XQODUÕQLoHULVLQGHHQ|QHPOLOHUL :LOVRQKDVWDOÕ÷ÕNRUWLNRVWHURLGLOH WHGDYLHGLOHQRWRLPPQ NDUDFL÷HUKDVWDOÕ÷Õ JDODNWR]HPLPHWRWUHNVDWWRNVLVLWHVLYH hepatit C enfeksiyonudur (29)
4.2.1 NASH epidemiyolojisi
1$<.+¶ÕQÕQJHUoHNLQVLGDQVÕYHSUHYDODQVÕELOLQPHPHNOHEHUDEHU\DNODúÕN RODUDN1$<.+¶ÕQJHQHOWRSOXPXQ¶VLQGH1$6+¶LQLVH¶QGHJ|UOG÷ ELOGLULOPHNWHGLU 7P \Dú JUXSODUÕQGD J|UOHQ <.¶LQ SUHYDODQVÕ YFXW NLORVXQXQ DUWPDVÕ\OD DUWÕú J|VWHUPHNWHGLU 1RUPDO NLOROX NLúLOHUGH J|UOPH VÕNOÕ÷Õ %10-15 iken obezlerde bu oran %70-¶H oÕNPDNWDGÕU <DNÕQ ]DPDQGD \D\ÕQODQDQ ELU GHUOHPHGH GH 1$<.+¶ ÕQ HQ VÕN RODUDN GL\DEHWLNOHUGH YH REH]OHUGH J|UOG÷ YH PRUELG RODUDN REH] RODQ GL\DEHWLNOHULQ KHPHQ KHSVLQGHPHYFXWROGX÷Xbildirilmektedir (26). 1$6+J|UOPHVÕNOÕ÷ÕLVHREH]OHUGH úLGGHWOL REH] GL\DEHWOLOHUGH LVH GLU %XQXQ \DQÕQGD QRUPDO NLOROX NLúLOHUGH GH GDKD GúN VÕNOÕNWD ROPDNOD EHUDEHU 1$6+¶H UDVWODQPDNWDGÕU (32, 34).
+HUQHNDGDU \ÕOÕQGDQ|QFHNL\D\ÕQODUGD1$6+¶LQJHQHOOLNOHNDGÕQODUGD (%53- J|UOG÷ELOGLULOVHGH , GDKD\DNÕQ]DPDQODUGD\DSÕODQoDOÕúPDODU 1$6+¶LQKHULNLFLQVWHGHHúLWVÕNOÕNWDJ|UOG÷QELOGLUPLúOHUGLU
4.2.3. Klinik belirtiler ve laboratuvar bulgulDUÕ
Klinik belirtiler: %LUoRN GL÷HU NURQLN NDUDFL÷HU KDVWDOÕ÷ÕQGD ROGX÷X JLEL
1$<.+¶ÕDVHPSWRPDWLNWLU.DUDFL÷HUKDVWDOÕ÷Õ\DEDúNDQHGHQOHUGHQGROD\Õ\DSÕODQ LQFHOHPHOHUGH \D GD UXWLQ ODERUDWXDU WHWNLNOHULQGH UDVWODQWÕVDO RODUDN RUWD\D oÕNDU Birçok asempWRPDWLN KDVWDGD DODQLQ DPLQRWUDQVIHUD] $/7 \NVHNOL÷L DQWLKLSHUOLSLGHPLN LODo NXOODQDODUGD KHSDWLN SDQHOLQ PRQLWRUL]DV\RQX HVQDVÕQGD VDSWDQÕU %D]HQ úSKHOL VDIUD NHVHVL WDúÕ DUDúWÕUÕOÕUNHQ $/7 \NVHOL÷L VDSWDQÕU 1$<.+¶Õ YLUDO KHSDWLW % YH & JLEL NURQLN KDVWDOÕ÷ÕQÕQ ELOLQHQ GL÷HU QHGHQOHU GÕúODQGÕNWDQVRQUDDoÕNODQDPD\DQSHUVLVWDQ$/7\NVHNOL÷LQLQHQVÕNQHGHQLGLU
6HPSWRPODUROXúWX÷XQGDJHQHOOLNOHQRQVSHVLILNWLU+DOVL]OLNPXKWHPHOHQHQ VÕNELOGLULOHQVHPSWRPGXUIDNDWKLVWRORMLNOH]\RQXQúLGGHWLLOHNRUHOHGH÷LOGLU 'L÷HU VÕN ELU úLND\HW LVH NDUDFL÷HULQ EXOXQGX÷X VD÷ VW NDGUDQGD NQW ELU D÷UÕ UDKDWVÕ]OÕN KLVVL ROPDVÕGÕU .oN ELU KDVWD JUXEXQGD GDKD FLGGL NDUDFL÷HU KDVWDOÕ÷ÕQÕQ EXOJXODUÕ RODQ NDúÕQWÕ EXODQWÕ YH NXVPD J|UOHELOLU +DWWD ileri G|QHPOHUGHVDUÕOÕNDVLWJLELNURQLNNDUDFL÷HUKDVWDOÕ÷ÕQD|]JEHOLUWLYHEXOJXODUGD RUWD\DoÕNDELOLU
Fizik muayene: NASH için herhangi bir patognomonik bir belirti yoktur.
2EH]LWH IL]LN PXD\HQHGH HQ VÕN UDVWODQDQ EXOJXGXU YH oDOÕúPDODUÕQ -100’ünde PHYFXWWXU .DUDFL÷HUKDVWDOÕ÷ÕQDGDLUHQVÕNEXOJXLVHKHSDWRPHJDOLGLUYH oDOÕúPDODUGD¶\HNDGDURODQELUVÕNOÕNWDELOGLULOPHNWHGLU
+DVWDODUÕQ D] NÕVPÕQGD NURQLN NDUDFL÷HU KDVWDOÕ÷ÕQD DLW EXOJXODU RODELOLU bunlardan daHQVÕNRODQODUÕVSLGHUQHYLYHSDOPDUHULWHPGLU øOHUOHPLúKDVWDOÕNWD VDUÕOÕN|GHPYHSRUWDOKLSHUWDQVL\RQEXOJXODUÕRODELOLU.DUDFL÷HUKDVWDOÕ÷ÕLOHUOHGLNoH NDV HULPHVL JHOLúHELOLU IDNDW |GHP YH |QFHGHQ PHYFXW RODQ REH]LWH EXQX maskeleyeblir.
LaboUDWXYDUER]XNOXNODUÕ
+DVWDQH SRSXODV\RQODUÕQGDNL 1$6+ KDVWDODUÕQGD \DSÕODQ oDOÕúPDODUGD 27, 35) oR÷XROJXGD -90) anormal aminotrasferaz aktiviteleri mevcuttur. Enzim \NVHOPHVLQLQGHUHFHVL EHOLUJLQGH÷LOGLUYH JHQHOOLNOHQRUPDOLQVWVÕQÕUÕQÕQELU ila G|UWNDWÕDUDVÕQGDGÕU$/7GH÷HUOHULELUoRNGXUXPGD$67GH÷HUOHULQGHQ\NVHNROVD GD $67 ED]HQ |]HOOLNOH GH VLUR] YDUOÕ÷ÕQGD $/7 VHYL\HVLQGHQ \NVHN RODELOLU $PD$67$/7RUDQÕKHPHQKLoELU]DPDQ¶GHQE\NGH÷LOGLU$/7 seviyesinin \NVHOGL÷LKDVWDODUGDEX\NVHNOLNJHQHOOLNOHSHUVLVWDQROPDNODEHUDEHU GH÷HUOHUGH GDOJDODQPDODU J|UOHELOLU 'DKD D] VÕNOÕNWD LVH $/7 VHYL\HOHUL GDLPL RODUDNQRUPDOG]H\GHNDODELOLU$/7GH÷HUOHULVWHDWR]XQYH\DILEUR]LVLQGHUHFHVLLOH NRUHOH GH÷LOGLU 0). GGT düzeyleri de artabilir. Alkalen fosfataz seviyeleri JHQHOOLNOH QRUPDO G]H\OHUGH VH\UHWPHNOH EHUDEHU QRUPDOLQ VW VÕQÕUÕQÕQ LNL NDWÕQD NDGDUDUWÕúJ|VWHUHELOLU
6LUR]YH\DNDUDFL÷HU\HWPH]OL÷LJHOLúHQHNDGDUKHSDWLNIRQNVL\RQHONDSDVLWe QRUPDO VÕQÕUODUGD VH\UHGHU 'L\DEHWLNOHUGH GL\DEHWLN QHIURSDWL QHGHQL\OH SURWHLQUL YH KLSRDOEPLQHPL JHOLúHELOLU %LUoRN VHULGH KDVWDODUÕQ -15’nde antinükleer DQWLNRUSR]LWLIWLU YHLOHUOHPLúILEUR]LVLOHLOLúNLOLROGX÷XEXOXQPXúWXU HasWDODUÕQ \DNODúÕN -¶VLQGH GL\DEHW YH\D JOXNR] WROHUDQV ER]XNOX÷X -¶QLQGHLVHDoOÕNOLSLGSURILOLQGHKLSHUWULJOLVHULGHPLPHYFXWWXU
4.2.4. TANI
Görüntüleme: 8OWUDVRQRJUDIL ELOJLVD\DUOÕ WRPRJUDIL %7 YH PDJQHWLN
rezonans gib görüntüOHPH \|QWHPOHUL NDUDFL÷HUGHNL RUWD YH úLGGHWOL \D÷OÕ GH÷LúLNOLNOHUL EHOLUOHPHGH JYHQLOLUGLU 8OWUDVRQGD KHSDWLN \D÷ GDODN YH E|EUHN NRUWHNVLQLQ GDKD D] RODQ HNRMHQLWHVLQH J|UH DUWPÕú HNRMHQLWH\H QHGHQ ROXU
.RQWUDVWVÕ]%7LQFHOHPHVLQGH\D÷OÕNDUDFL÷HUKLpodens ve dalaktan daha koyu olarak belirir.
%DVLW VWHDWR]LV YH 1$6+¶L KLoELU J|UQWOHPH \|QWHPL D\ÕUW HGHPH] 8OWUDVRQRJUDILQLQ\D÷OÕNDUDFL÷HULEHOLUOHPHGHGX\DUOÕOÕ÷ÕYH|]JOO÷9.øDUWWÕNoD D]DOPDNWDGÕUEXQHGHQOHGX\DUOÕOÕ÷Õ LOHDUDVÕQGD|]JOO÷LVHLOH DUDVÕQGD GH÷LúPHNWHGLU *|UQWOHPH \|QWHPOHULQLQ GX\DUOÕOÕ÷Õ \D÷OÕ LQILOWUDV\RQXQ GHUHFHVL LOH DUWPDNWDGÕU YH HQ D] VWHDWR]LV ROPDVÕ J|UQWOHPH yöntemleri ile tespit için optimaldir (45).
.DUDFL÷HU EL\RSVLVL: .DUDFL÷HU EL\RSVLVL YH KLVWRORMLVL 1$6+ WDQÕVÕQD J|WUHQ HQ |QHPOL WDQÕ \|QWHPOHULGLU dRN VD\ÕGD NLP\DVDO ILEUR]LV J|VWHUJHVL NXOODQÕOPDVÕQD UD÷PHQ ILEUR]LV YH VLUR] WDQÕVÕ LoLQ úLPGL\H NDGDU \DUGÕPFÕ ROPDPÕúWÕU(YUHOHPHLoLQVDGHFHNDUDFL÷HULQKLVWRORMLNLQFHOHPHVLDQODPOÕGÕU
1$<.+LoLQWDQÕGDDOWÕQVWDQGDUWVWHDWR]LVLQNDUDFL÷HUEL\RSVLVLLOHWH\LGLYH DONRO JLEL GL÷HU QHGHQOHULQ NOLQLN RODUDN GÕúODQPDVÕ VRQUDVÕQGD NOLQLNRSDWRORMLN NRUHODV\RQXQVD÷ODQPDVÕGÕU)DNDWDONROLNNDUDFL÷HUKDVWDOÕ÷ÕYH1$<.+¶ÕEHQ]HU KLVWRORMLN EXOJXODUD VDKLS ROGX÷X LoLQ NDUDFL÷HU EL\RSVLVL \DUGÕPÕ\OD D\ÕUÕP \DSÕODPD] $ONROLN YH QRQDONROLN \D÷OÕ NDUDFL÷HU KDVWDOÕ÷ÕQÕ D\ÕUPDN LoLQ JHUHNOL RODQDONRODOÕPÕVÕQÕUÕLoLQFXW-RIIGH÷HULEHOOLGH÷LOGLU)DNDWJHQHOOLNOHNDGÕQODrda 20 JUDPJQHUNHNOHUGHJUDPJQDONRODOÕPÕVÕQÕURODUDNNXOODQÕOPDNWDGÕU
.DUDFL÷HU +LVWRORMLVL 1$6+ WDQÕVÕ NOLQLN DoÕGDQ NHVLQOL÷H VDKLS ROPDGÕ÷ÕQGDQ KLVWRORMLN EXOJX JHUHNOLGLU 1$<.+¶Õ WDQÕVÕ LoLQ PLQLPXP RODUDN D÷ÕUOÕ÷ÕQ -10’u kadar steatozis gereklidir. Steatozis genellikle makroveziküler ROPDNODEHUDEHUPLNURYH]LNOHUGDPODFÕNODULOHNDUÕúÕNRODELOLU
1$6+¶L EDVLW VWHDWR]LVGHQ D\ÕUPDN LoLQ JHUHNOL RODQ KLVWRORMLN |]HOOLNOHU oHOLúNLOLGLUYHOLWHUDWUGHIDUNOÕOÕNODUPHYFXWWXU
<DNÕQ]DPDQGD \DSÕODQ ELUNRQIHUDQVWD 1$6+ ]RQH¶GHEDVNÕQRODQ PDNURYH]LNOHU \D÷ODQPD LOH NRPELQH RODUDN KHSDWRVLWOHUGH EDORQODúPD GHMHQHUDV\RQX YH PLNVW WLSWH LQIODPDWXYDU LQILOWUDW RODUDN WDQÕPODQPÕúWÕU YH genellikle karakteristik perisinüzoidal ve periselüler fibrozis ile beraberdir.
Histolojik olarak NASH üç formda görülebilir (47).
a) øQDNWLI 1$6+ øOHUOHPH\HQ IRUP +LVWRORMLN RODUDN KDILI LQIODPDV\RQ \D÷ODQPDYH\DLQIODPDV\RQVX]\D÷ODQPDL]OHQLU
b) Subfulminan NASH: Çok seyrek görülür. Potansiyel olarak fataldir. $ONROLNVWHDWRKHSDWLWWHQD\ÕUÕPÕ]RUGXU
c) .URQLN 1$6+ .OLQLV\HQOHULQ 1$6+ RODUDN DGODQGÕUGÕNODUÕ NURQLN RODQ IRUPGXU<DYDúLOHUOHU+DVWDOÕNX]XQVUHGXUDNOD\DELOLUVRQUD\LQH\DYDú LOHUOHPHJ|VWHUHELOLU$WDNODUúHNOLQGHJLGLúJ|VWHUebilir, fokal infiltratlar ROXúWXUDELOLUYHED÷GRNXVXOLIOHULELULNHELOLU<ÕOODUVRQUDVLUR]DG|QúU
NASH’ te saptanan tipik histolojik bulgular: makroveziküler, mikroveziküler
YH\D PLNVW WLSWH \D÷ODQPD KHSDWRVLWOHUGH EDORQODúPD PLNVW KFUHOL LQIODPasyon, lobüler hepatit, tek hücre veya fokal nekrozlar, periselüler ve perisinüzoidal fibrozis (chicken wire fibrozis), santral ven çevresinde tel örgüsü fibrozisi (chicken wire
fibrozis)VDQWUDODODQODUDUDVÕQGDSHULSRUWDODODQGDQGL÷HULQHX]DQDQILEU|]septalar,
NDUDFL÷HU\DSÕVÕQÕQWP\OHGH÷LúPHVL VLUR] YHGDKDVH\UHNRODUDNWDVLGHUR]LV 6HQWULOREXOHU LQIODPDV\RQ YH ILEUR]LVLQ EXOXQPDPDVÕ NDUDFL÷HUGH \D÷ODQPDQÕQROPDPDVÕKDOÕQGHEDúNDWDQÕGúQOPHOLGLU
4.2.5. Grade ve Stageleme
$QODPOÕSDUDQNLPSDUDPHWUHOHULQLQ\DUÕNDQWLWDWLIRODUDNGH÷HUOHQGLULOPHVLQH JUDGHOHPH GHUHFHOHQGLUPH GHQLU (YUHOHQGLUPH VWDJLQJ LVH NDUDFL÷HU SDUHQNLP KDVDUÕVRQXFXQGDJHOLúHQ\DSÕVDOGH÷LúLPOHULQGH÷HUOHQGLULOPHVLGLU+LVWRORMLNJUDGH
steatohepatit lezyonunun aktivitesini gösterirken, evre fibrozisin derecesini \DQVÕWPDNWDGÕU
1$6+¶LQNOLQLNJLGLúLGH÷LúNHQOLN J|VWHUPHNWHGLU.OLQLNRODUDN|QHPOLELU EXOJX ROPDGDQ D÷ÕU LOHUOH\LFL ELU JLGLú J|VWHUHELOLU %X QHGHQOH KDVWDOÕN WDEORVX PRUIRORMLN NULWHUOHUOH WDQÕPODQPDOÕGÕU )DUNOÕ DUDúWÕUPDFÕODUÕQ EXOJXODUÕQÕ NDUúÕODúWÕUÕODELOLU NÕOPDN DPDFÕ\OD KLVWRORMLN YHULOHU VWDQGDUGL]H HGLOPHOLGLU %X QHGHQOHELUGHUHFHOHQGLUPHYHHYUHOHQGLUPHVLVWHPLROXúWXUXOPDOÕGÕU
1$6+ LoLQ %UXQW YH DUDNDGDúODUÕ ELU JUDGH YH HYUHOeme sistemi |QHUPLúOHUGLU %X VLVWHPH J|UH JUDGH LoLQ EXOJX NXOODQPÕúODUGÕU KHSDWLN PDNURYH]LNOHUVWHDWR]LVKHSDWRVHOOHUEDORQODúPDLQWUD-asinar inflamasyon, portal trakt inflamasyonu, Mallory hyaleni, asidofil cisimcikler, glikojen nükleusu, lipogUDQORPODUYHKHSDWRVHOOHUGHPLULQGH÷HUOHQGLULOPHVL%XQODUÕQKHSVLD\UÕD\UÕ VNRUODQPDNWDGÕU 1$6+¶WH JUDGH VÕIÕU \RNWXU dQN 1$6+ PRUIRORLN GH÷HUOHQGLUPH ROPDGDQ RQX WDQÕPOD\DFDN ELU VHURORMLN WHVWL EXOXQPD\DQ klinikopatolojik bir antitedir.
FibUR]LV LoLQ o SDUDPHWUH VNRUODQPDNWDGÕU SHULVLQ]RLGDO ILEUR]LV SRUWDO ILEUR]LV YH N|SUOHúPH ILEUR]LVL %XQODUD GD\DQDUDNWDQ QHNURLQIODPDWXYDU DNWLYLWH KDILI RUWD YH úLGGHWOL RODUDN HYUHOHQPHNWHGLU +DVWDOÕN HYUHOHQPHVL GH ILEUR]LVLQ derecesine göre 1’GHQ¶HNDGDUVÕQÕIODQGÕUÕOPÕúWÕU
%UXQW YH DUNDGDúODUÕ WDUDIÕQGDQ ¶GD 1$6+ LoLQ |QHULOHQ EX \DUÕ NDQWLWDWLI GH÷HUOHQGLUPH VLVWHPL 1$<.+¶ÕQÕQ LoHULVLQH DOGÕ÷Õ NOLQLN VSHNWUXPXQ WDPDPÕQÕGH÷HUOHQGLUPHGHNXOODQÕODPDPDNWDGÕUdRN\DNÕQ]DPDQGD1$SH Klinik $UDúWÕUPDQHWZRUNXWDUDIÕQGDQ\HQLELUKLVWRORMLNGH÷HUOHQGLUPH\|QWHPLJHOLúWLULOGL %X VLVWHPGH NOLQLN oDOÕúPDODUGD NXOODQÕOPDN ]HUH 1$<.+¶Õ DNWLYLWH VNRUX 1$6 JHOLúWLULOPLúWLU%XVLVWHPGHKLVWRORMLNEXOJXNXOODQÕOPÕúWÕU
¶ \DUÕ kantitatif olarak steatozis (0-3), lobular inflamasyon (0-2), hepatoselüler EDORQODúPD -2) ve fibrozisi (0- GH÷HUOHQGLUPHNWHGLU'L÷HUGRNX]|]HOOLNLVHYDU veya yok olarak kaydedilmektedir. Bu skorlama sistemine göre NAS 1$6+ WDQÕVÕ LOH NRUHOH ROGX÷X EXOXQXUNHQ VNRUXQGD LVH WDQÕ RODUDN 1$6+ \RNWXU úHNOLQGHGH÷HUOHQGLULOPLúWLU
'R÷DOVH\LUYHSURJQR]
1$6+VÕNJ|UOPHVLQHYHSRWDQVL\HORODUDNFLGGLROPDVÕQDNDUúÕQGR÷DOVH\UL oRN L\L EHOLUOHQPHPLúWLU <DNÕQ ]DPDQGD 1$<.+¶Õ WDQÕOÕ KDVWDGD \DSÕODQ ELU oDOÕúPDGD KDVWDODU RUWDODPD \ÕO WDNLS HGLOPLúOHU %X VUHGH KDVWDQÕQ ¶ |OPú <DúDP EHNOHQWLVL QRUPDO SRSXODV\RQD J|UH EHNOHQHQGHQ GúNPú<NVHNPRUWDOLWH\DúER]XOPXúDoOÕNJOXNR]XYHVLUR]ODELUOLNWH\PLú 21 KDVWDGDVLUR]JHOLúLUNHQLNLKDVWDGDKHSDWRVHOOHUNDUVLQRPDVDSWDQPÕú
4.2.7. NASH patogenezi
1$6+SDWRJHQH]LKHQ]DoÕNGH÷LOGLU0HYFXWELOJLOHUHJ|UHLQVOLQGLUHQFL KLSHUWULJOLVHULGHPL YH KÕ]OÕ NLOR ND\EÕ ELU úHNLOGH 1$6+ SDWRJHQH]LQH NDWNÕda EXOXQPDNWDGÕU'L÷HU\DQGDQULVNWDúÕ\DQKHUNHVWH1$6+JHOLúPHPHVLPXKWHPHOHQ oHYUHVHOIDNW|UOHUYHJHQHWLN|]HOOLNOHULQHWNLVLROGX÷XQXGúQGUWPHNWHGLU
1$6+ SDWRJHQH]L ROGXNoD NDUÕúÕNWÕU $UWPÕú WP|U QHNUR]LV DOID 71)-. ekspresyonu, insülin dirHQFLYHNDUDFL÷HUHDUWPÕúVHUEHVW\D÷DVLGL 6<$ 71)-.YH NRUWL]RO VXQXPXQD QHGHQ RODQ DGLSR] GRNXGD OLSROL] DUDVÕQGDNL \DNÕQ LOLúNLOHU EDúODQJÕo RODUDN VWHDWR]LV JHOLúLPLQH QHGHQ ROXU $UWPÕú \D÷ ELULNLPL QLKDL RODUDN OLSRWRNVLVLWHQLQ ELU \DQGDúÕ RODUDk hepatik insülin direncine yol açar ve 1$<.+¶ÕQGD HYUHQVHO RODUDN EXOXQDQ LQVOLQ GLUHQFLQH NDWNÕGD EXOXQXU øQVOLQ GLUHQFL6<$¶LQLQRNVLGDV\RQXQGDDUWÕúDQHGHQROXU$UWPÕú\D÷RNVLGDV\RQX71)-. ile birlikte oksidatif stres ve mitokondriyel uncoupling pURWHLQVDOÕQÕPÕQDQHGHQROXU
+DVVDV NLúLOHUGH EX RNVLGDWLI VWUHV YH VRQXFXQGDNL OLSLG SHURNVLGDV\RQX 71)-. HNVSUHV\RQX YH PLWRNRQGUL\HO GLVIRQNVL\RQXQ E\NO÷ KHSDWRVLWOHUGH |OPH LQIODPDV\RQD YH HQ VRQ RODUDN GD ILEUR]LVH \RO DoDU 1$6+¶H GX\DUOÕOÕ÷Õ DUWÕUDQ IDNW|UOHU RNVLGDWLI VWUHV YH OLSLG SHURNVLGDV\RQXQX DUWÕUDQ oHYUHVHO YH JHQHWLN IDNW|UOHUWDUDIÕQGDQEHOLUOHQL\RUJLELJ|UQPHNWHGLU
%XJQ LoLQ 1$<.+ JHOLúLPLQGH WHPHO SDWRIL]\RORMLN IDNW|U RODUDN LQVOLQ direnci kabul edilmektedir (33). Esas olarak hepatik steatozun insülin direnci VHQGURPXQXQELUSDUoDVÕROGX÷XGDLOHULVUOPHNWHGLU
øQVOLQGLUHQFL
øQVOLQ GLUHQFLQLQ SDWRJHQH]L NDUÕúÕNWÕU YH LQVOLQ VHNUHV\RQX YH HWNLVLQL etkileyen birçok genetik polimorfizm ve obezite ve harekHWVL]OL÷H QHGHQ RODQ oHYUHVHOIDNW|UOHUNDWNÕGDEXOXQPDNWDGÕUøQVOLQLQDQWLOLSROLWLNHWNLVLQHNDUúÕGLUHQo PHYFXWWXU <D÷ DVLWOHUL YLVHUDO \D÷ GRNXVXQGDQ PRELOL]H ROXU VHUXP 6<$¶LQLQ G]H\OHUL DUWDU YH KHSDWRVLWOHUH VXQXPX DUWDU øQVOLQ GLUHQFLQH ED÷OÕ olarak KHSDWRVLWOHUGH\D÷ELULNLPLROXU1RUPDOGHNDUDFL÷HUGHNLOLSLGOHULQ¶LQLROXúWXUDQ WULJOLVHULGOHU\D÷ODQPDLOH¶\HoÕNDU (NRODUDNNURQLNKLSHULQVOLQHPLde
novoKHSDWLNOLSRJHQH]JHOLúLPLQH\DUGÕPFÕROXUYHED÷GRNXVXE\PHIDNW|UJibi
birçok profibrotik sitokini aktive edebilir (53).
.DUDFL÷HUGHNL \D÷ODQPD VRQUDVÕ GR÷DO VH\LUGHNL IDUNOÕOÕN VWHDWR] JHOLúLPLQGHQ VRQUDNL SDWRIL]\RORMLQLQ GDKD NRPSOHNV ROGX÷XQX YH ELUoRN IDNW|UQ URODOGÕ÷ÕQÕJ|VWHUPHNWHGLU
6HUEHVW\D÷DVLWOeri
6HUEHVW\D÷DVLWOHUL1$6+SDWRJHQH]LQGHDQDKWDUUROR\QDPDNWDGÕU1$6+¶LQ 6<$¶LQLQ VHUXP NRQVDQWUDV\RQODUÕQÕQ YH NDUDFL÷HUH 6<$¶LQLQ DOÕPÕQÕQ DUWWÕ÷Õ GXUXPODUODELUOLNWHROGX÷XEXOXQPXúWXU%XQODUDUDVÕQGDID]ODNLORKÕ]OÕNLORYHUPH
tip 2 diyabetes PHOOLWXVYHDONROYDUGÕU$\UÕFD6<$¶LQLQVHUXPNRQVDQWUDV\RQODUÕLOH 1$6+¶WHVDSWDQDQNDUDFL÷HUILEUR]XDUDVÕQGDELUNRUHODV\RQROGX÷XLOHULVUOPúWU (54). 6<$¶L \D÷OÕ NDUDFL÷HU JHOLúLPLQGH VDGHFH LON GDUEHGH GH÷LO D\QÕ ]DPDQGD 1$6+JHOLúLPLQGH\DQLLNLQFLGDUEHGHGHUROR\QD\DQ]DUDUOÕELUIDNW|UGU+HUQH NDGDU 526 UHWLPL YH RNVLGDWLI VWUHV 1$6+ JHOLúLPLQGH ]HPLQ KD]ÕUODVDODU GD LQIODPDV\RQ 1$<.+¶ÕQGDQ 1$6+¶H JHoLúWH PDM|U HN IDNW|UGU 6<$¶L EXUDGD anahtar rol oynayabilir. Çünkü, SYA’i inflamasyonNDVNDGÕQGD\HUDODQ,N%1)N%¶L direk olarak aktive eder (55, 56)
4.2.7.3. Oksidatif Stres
2NVLGDWLV VWUHV 526 YH EXQODUÕQ PHWDEROLWOHULQLQ UHWLPLQLQ EXQODUD NDUúÕ RODQ VDYXQPD YH GHWRNVLIL\H HWPH PHNDQL]PDODUÕQÕQ NDSDVLWHVLQL DúDUDN GHQJHQLQ ER]XOPDVÕile meydana gelir. Serbest radikaller genellikle serbest metallerle (Fe, Cu) ilgili enzimatik veya enzimatik olmayan oksido-UHGNVL\RQHVQDVÕQGDROXúDELOLU(Q önemli radikaller süperoksit anyonu, hidrojen peroksit ve aktif hidroksil radikalidir. <D÷PHWDEROL]PDVÕQGDNÕVD-, orta-YHX]XQ]LQFLUOL6<$¶LQLQDUWDQDNÕPÕVRQXFXQGD beta-RNVLGDV\RQ DUWPDNWDGÕU %X GD 1$6+ \ROXQGD HQ |QHPOL DGÕP RODQ VHUEHVW UDGLNDO UHWLPL LOH VRQXoODQPDNWDGÕU 6RQXoWD KLGURMHQ SHURNVLW YH KLGURNVLO radikallerine maruziyet lipidler, DNA ve proteinler gibi hücresel makromoleküllerde KDVDUDQHGHQRODELOLU*LGHUHNDUWDQELUúHNLOGHRUWD\DoÕNPDNWDGÕUNLIDUNOÕRNVLGDWLI VWUHV VHYL\HOHUL LOH KFUHOHU ]HULQGH IDUNOÕ HWNLOHU PH\GDQD JHOLU EHOLUJLQ ELU HWNL olmayabilir veya hücre b\PHVL E\PHQLQ GXUPDVÕ DSRSWR]LV YH QHNUR]XQ X\DUÕOPDVÕ JLEL HWNLOHU RODELOLU 0LWRNRQGUL EX 526¶ODU LoLQ HQ |QHPOL ND\QD÷Õ ROXúWXUPDNWDGÕU 5HNDWLIRNVLMHQWUOHULQLQDUWÕúÕD\QÕ]DPDQGDDQWLRNVLGDQDMDQ olan alfa tokoferol (vitamin E) ve glutat\RQXQ *6+ D]DOPDVÕLOHHú]DPDQOÕGÕU
Serbest radikal üretimi için önemli bir enzim sistemi endoplazmik UHWLNXOXPGDNLVLWRNURP3( &<3( VLVWHPLGLU%XVLVWHPDoOÕNDONROWLS diyabet, santral obezite ve insülin direnci gibi NASH patogenezindH |QHP WDúÕ\DQ IDNW|UOHUHED÷OÕRODUDNDUWDU&<3(HQ]LPLQLQX\DUÕOPDVÕ\DQUQOHULQVDOÕQÕPÕ LOH526ROXúXPXQDQHGHQROXU&<3(DONROLNNDUDFL÷HUKDVWDOÕ÷ÕQGD|QHPOLUROH VDKLS RODQ 526 ROXúXPX YH SDWRJHQH]GH PHUNH]L UROH VDKLSWLU øOJLQo ELU úHNLOde 1$6+ LQGNVL\RQXQGD GD SRWDQVL\HO ELU IDNW|U RODUDN VXoODQPDNWDGÕU 'HQH\VHO 1$6+¶WH &<3( HNVSUHV\RQXQXQ \D\JÕQOÕ÷Õ YH OREXODU GD÷ÕOÕPÕ VWHDWR]LV YH LQIODPDV\RQXQGD÷ÕOÕPÕLOH\DNÕQGDQLOLúNLOLEXOXQPXúWXU &<3(HNSUHV\RQX 1$6+KDVWDODUÕQÕQEL\RSVLOHULQGHGHDUWPÕúRODUDNEXOXQPXúWXU )DNDW&<3( HQGRMHQ OLSLGOHULQ SHURNVLGDV\RQXQGD WHN NDWDOL]|U GH÷LOGLU YH &<3( YH CYP4E14 de bu hastalarda up-UHJOH RODUDN EXOXQPDNWDGÕU YH RNVLGDWLI VWUHVLQ EDúODPDVÕQGDDOWHUQDWLIRODUDNURODODELOLUOer (3).
&<3(VLVWHPL1$6+LQGNVL\RQXQGD|QHPOLELUUROHVDKLSWLU)DNDWEDúND kaynaklardan özellikle de mitokondrilerden gelen serbest radikallerin ve TNF-. VLWRNLQLQLQ URO PXKWHPHOHQ GDKD DQODPOÕGÕU (÷HU NDUDFL÷HUH PLWRNRQGULQLQ EHWD-oksidasyon kapaVLWHVLQLDúDFDNNDGDU6<$¶L JHOLUVHSHURNVL]RPODUYHVLWR]ROGL÷HU SRWDQVL\HO526UHWLFLOHULRODUDNURODOÕUODU
+HSDWLNDQWLRNVLGDQVDYXQPDODUÕQD]DOPDVÕGD526¶XQHWNLOHULQLDUWWÕUDELOLU +HPUDWKHPGHVÕoDQODUGD0&'GL\HWLLOH\DSÕODQoDOÕúPDODUda hepatik glutatyon VHYL\HOHULD]DOPÕúRODUDNKHSDWLNYHVLVWHPLNWL\REDUELWULNDVLW-reaktif maddeler (4-+1(YH0'$ LVHDUWPÕúRODUDNEXOXQPXúWXU
4.2.7.4. Lipid peroksidasyonu ve NASH
6HUEHVW UDGLNDOOHULQ ROXúXPX KFUHQLQ JHUHNVLQLPL RODQ RNVLMHQLQ ¶ÕQÕQ KDUFDQPDVÕQDoHúLWOLPHWDEROLNER]XNOXNODUDYHOLSLGSHURNVLGDV\RQXRODUDNELOLQHQ
GR\PDPÕú \D÷ DVLWOHULQLQ RNVLGDV\RQXQD \RO DoDU 2NVLGDWLI VWUHV NÕVPÕQGD EHOLUWLOGL÷L JLEL PLWRNRQGUL\DO PLNUR]RPDO SHURNVL]RPDO YH VLWRSOD]PLN OLSLG meWDEROL]PDVÕQGDQPDVLIVHUEHVWUDGLNDOoÕNÕúÕOLSLGSHURNVLGDV\RQXQDQHGHQROXU
'R\PDPÕú OLSLGOHULQ VHUEHVW UDGLNDOOHULQ HWNLVLQH PDUX]L\HWL ELU VHUEHVW UDGLNDO DUDFÕOÕ PHNDQL]PD RODQ OLSLG SHURNVLGDV\RQXQGD ]LQFLUOHPH ELU UHDNVL\RQ EDúODWÕUdRNOXGR\PDPÕú\D÷ODUÕQGL\HWHHNOHQPHVLEXOLSLGSHURNVLGD\RQXQXDUWWÕUÕU /LSLG SHURNVLGDV\RQX KFUHVHO PHPEUDQODUÕQ \DSÕVÕQGD EXOXQDQ oRNOX GR\PDPÕú \D÷ DVLWOHULQLQ RNVLGDWLI \ÕNÕPÕQD QHGHQ ROXU /LSLG SHURNVLGDV\RQXQXQ sitotoksik ürünleri, nükleotidler ve prRWHLQ VHQWH]L JLEL KFUHVHO IRQNVL\RQODUÕ bozabilir (60) ve hepatik stellat hücrelerdeki kollajen gen ekspresyonunu module HGHUHNNDUDFL÷HUILEURJHQH]LQGHUROR\QD\DELOLU
2NVLGH SURWHLQOHU YH\D OLSLGOHULQ YDUOÕ÷ÕQÕQ GHQH\VHO oDOÕúPDODUGD gösteriOPHVLLOHRNVLGDWLIVWUHVLQ1$<.+¶ÕYH1$6+¶OLKDVWDODUGDEXOXQGX÷XQDGDLU NDQÕWROPXúWXU526DUDFÕOÕOLSLGSHURNVLGDV\RQXQXQ1$6+SDWRJHQH]LQGHPHUNH]L UROHVDKLSROPDVÕLoLQELUoRNQHGHQPHYFXWWXUgQFHOLNOH3HVVD\UHYHDUNDGDúODUÕQÕQ (61) derlemesinde EHOLUWLOGL÷L JLEL 526 YH OLSLG SHURNVLGDV\RQX SRWDQVL\HO RODUDN 1$6+¶WHNL WP WLSLN KLVWRORMLN |]HOOLNOHUL DoÕNODPDNWDGÕU 3OD]PD YH LQWUDVHOOHU PHPEUDQODUÕQ SHURNVLGDV\RQX GLUHN RODUDN KFUH QHNUR]XDSRSWR]LVH YH megamitokondriye neden olabilir.
Lipid SHURNVLGDV\RQXQXQ|QHPOL \ÕNÕPUQOHUL0'$YH-HNE NASH’te \NVHN NRQVDQWUDV\RQGD L]OHQPLúWLU -HNE ve MDA hepatik proteinleri NRYDOHQRODUDNED÷OD\DUDNSRWDQVL\HORODUDN]DUDUOÕLPPQFHYDEÕEDúODWDQELOHúHQOHU ROXúWXUDELOLUOHU $\UÕFD KHSDWRVHOOer stellat hücrelerinde ekstraselüler matriks SURWHLQOHULQ VHQWH]LQL 0DOORU\ FLVLPFLNOHULQLQ ROXúPDVÕQÕ X\DUDELOLUOHU YH +1( nötrofil kemotaksisini uyarabilir.
1$<.+¶Õ EXOXQDQ KDVWDODUGD \DSÕODQ ELU oDOÕúPDGD OLSLG peroksidasyonunun majör aldehidik metaboliti 4-HNE ELOHúHQOHUL LPQRKLVWRNLP\DVDOER\DPDLOHNDUDFL÷HUGH\D\JÕQRODUDNEXOXQPXúWXU
4-+1(YH0'$ PLWRNRQGUL'1$¶VÕQDSURWHLQOHULQH]DUDUYHUHUHNVROXQXP ]LQFLUOHULQGH DNVDPD\D QHGHQ ROXU %|\OHFH \HQLGHQ DoÕ÷D oÕNDQ VHUEHVW UDGLNDOler NXSIHUKFUHOHULQGHKHSDWRVLWOHUGHYH\D÷GRNXVXQGD71)-.HNVSUHV\RQXQXDNWLYH ederler. TNF-.PLWRNLQGULOHUGH \DSÕVDOYHIRQNVL\RQHORODUDNKDVDUYHULU Bu, serbest radikalerin, lipid peroksidasyon ürünlerinin ve sitokinlerin elektron trasport ziQFLULQLQ YH E|\OHFH WP KFUHOHULQ PHWDEROL]PDVÕQÕQ DNWLYLWHOHULQGH D]DOPD\D QHGHQROPDODUÕDQODPÕQDJHOLU
Hepatositlerdeki oksidatif stres nükleer faktör K beta (NFkB)’yi aktive ederek VWHDWRWLN NDUDFL÷HULQ EHOLUJLQ úHNLOGH GX\DUOÕ ROGX÷X VLWRNLQOHULQGH GDKLO ROGX÷X proinflamatuvar genlerin ekspresyonuna neden olur (65).
øQVDQODUGDNL 1$6+¶WH RNVLGDWLI VWUHVLQ YDUOÕ÷ÕQD \|QHOLN LQGLUHN NDQÕWODU 1$6+¶LQ WHGDYLVL LoLQ DQWLRNVLGDQÕQ NXOODQÕOGÕ÷Õ SLORW oDOÕúPDODUGDQ HOGH HGLOHQ ROXPOXVRQXoODUROPXúWXU <DNÕQ]DPDQGDELUGL\HWDQNHWLLOH\DSÕODQ oDOÕúPDGD 1$6+¶OL REH] KDVWDODUÕQ 1$6+¶OL QRUPDO NLOROX KDVWDODUD J|UH DQWLRNVLGDQODUGDQ IDNLU GL\HWOH EHVOHQGLNOHUL ELOGLULOPLúWLU 1$6+ KDVWDODUÕQÕQ NDUDFL÷HU EL\RSVLVLQLQ PLNURDUUD\ LOH LQFHOHPHsinde birçok antioksidan enzimi NRGOD\DQP51$¶ODUÕQHNVSUHV\RQXQXQQRUPDONDUDFL÷HUHJ|UHYH\DGL÷HUNDUDFL÷HU KDVWDOÕ÷Õ RODQODUD J|UH GDKD GúN RODUDN UDSRU HGLOPLúWLU 7P <.¶OHUGH LQIODPDV\RQYHILEUR]LVJHOLúHPHGL÷LLoLQLNLQFLOILEURMHQLNGDUEHolan oksidatif stres diyet, genetik ve çevresel faktörlerden etkilenebilir.
/LSLG SHURNVLGDV\RQXQXQ GHUHFHVL VHUEHVW \D÷ DVLWOHULQLQ PHYFXGL\HWL LOH NRUHOHGLU YHVWHDWRWLNNDUDFL÷HUGHFLGGL]DUDUYHUHFH÷LQLJ|VWHUPHNWHGLU
MDA ve HNE, NASH’li hastalarÕQ ¶QÕQGD VWHDWR]OX KDVWDODUD J|UH RNVLGDWLIVWUHVLQDUWWÕ÷ÕQÕJ|VWHULUELUúHNLOGHDUWPÕúRODUDNEXOXQPXúWXU
1$6+3DWRJHQH]LQGHQVRUXPOXGL÷HUIDNW|UOHU
4.4.7.5.1. Sitokinler: TNF-. WUDQVIRUPLQJ JURZWK IDNWör (TGF) beta, interlökin (IL YHJLELoRNVD\ÕGDVLWRNLQOHULQHNSUHV\RQXRNVLGDWLIVWUHVLQELU KFUHVHO UHDNVL\RQXGXU 6HUEHVW UDGLNDOOHU YH VLWRNLQOHU NDUDFL÷HULQ 71)-.µ\D GX\DUOÕOÕ÷ÕQÕ DUWWÕUÕUODU 71)-. HNVSUHV\RQX HQWHUDO HQGRWRNVLQOHU JLEL GL÷HU IDNW|UOHUOHGHX\DUÕOÕU71F-.OHSWLQHNVLNOL÷LQGHGHXS-UHJOHROXUYHDUWPÕú71)-. NRQVDQWUDV\RQODUÕLQVOLQGLUHQFLQLDJUHYHHGHU6LWRNLQOHUILEURJHQH]LVLX\DUÕUODUYH LGDPHHWPHVLQLVD÷ODUODU
4.4.7.5.2. Genetik: 7P ULVN JUXSODUÕQGD 1$6+ JHOLúPHPHVL EX DQWLWHGHQ genetik IDNW|UOHULQGH NÕVPHQ GH ROVD VRUXPOX ROGX÷XQX GúQGUWPHNWHGLU )DNDW 1$6+ LoLQ JHQHWLN HWNL DoÕN GH÷LOGLU *HQHWLN IDNW|UOHU QLKDL RODUDN 1$6+ JHOLúLPLQH QHGHQ RODQ ED]Õ PHNDQL]PDODUÕ WHWLNOH\HELOLU ELUoRN VLWRNLQLQ HNSUHV\RQXQX YH LNLQFL GDUEHQLQ \D\JÕQOÕ÷ÕQÕ HWNLOH\HELOLUOHU $GD\ ED]Õ JHQHWLN IDNW|UOHUKHQ]DUDúWÕUPDVDIKDVÕQGDGÕU
4.4.7.6. øNLGDUEHKLSRWH]L:
*QP]GH 1$6+ SDWRJHQH]LQL DoÕNODPDN LoLQ HQ oRN NDEXO J|UHQ J|Uú \ÕOÕQGDNOLQLNYHGHQH\VHOoDOÕúPDODUDGD\DQÕODUDN|QHULOHQiki darbe hipotezi" GLU %LULQFL GDUEH NDUDFL÷HULQ \D÷OÕ GHMHQHUDV\RQX YH\D VWHDWR]LV KHSDWLV LoLQ VXEVWUDW RODQ KHSDWRVLWOHUGH \D÷ ELULNLPLGLU %X \D÷OÕ ELULNLP NDUDFL÷HULQ LNLQFL GDUEHOHUH RODQ GX\DUOÕOÕ÷ÕQÕ GD DUWWÕUPDNWDGÕU øNLQFL GDUEH ROXúDQD NDGDU NDUDFL÷HU \D÷ODQPDVÕ VWHDWR]LVGHQ EDúND ELU úH\ GH÷LOGLU øNLQFL GDUEH EDUVDNODUD FHUUDKL PGDKDOH \DSÕOPDVÕ EHOLUOL LODoODUÕQ DOÕQPDVÕ YH\D WLS GLD\DEHWHV PHOOLWXVXQ JHOLúPHVLRODELOLU%XVHQDU\RGD6<$¶QLQDQLDUWÕúÕ|QHPOLUROR\QD\DELOLU
Bu nedenle1$6+WLSLNRODUDNWLSGL\DEHWOLOHUVDQWUDOREH]LWHOLOHUKÕ]OÕNLORND\EÕ YH DONRO NXOODQÕPÕ JLEL 6<$¶OHULQ PRELOL]DV\RQXQD YH NDUDFL÷HUH DOÕPÕQD \RO DoDQODUGDPH\GDQDJHOPHNWHGLUøNLQFLGDUEHLOHKHSDWRVLWOHUGHKDVDULQIODPDV\RQYH nihai olarak fibrozis meydana gelir.
Steatozis: Birinci darbe: *LGHUHNDUWDQRUDQGDNDQÕWODUVWHDWR]LVLQPDVXPELU
GXUXPGDQ ]L\DGH 1$<.+¶ÕQÕQ 1$6+¶H YH ILEUR]LVH LOHUOHPHVLQGH UROQQ ROGX÷XQX J|VWHUPHNWHGLU 6WHDWR]LVLQ úLGGHWL KHP HúOLN HGHQ VWHDWRKHSDWLWLQ ve/veya fibrozisin riskini hem de siroza ilerleme riskini önceden haber verebilir (32, %XQXQ \DQÕQGD\D÷ODQPDQÕQúLGGHWLKHSDWLNVWHOODWKFUHOHULQDNWLYDV\RQXQXQ derecesi ile koreledir (73).
6<$¶L KHSDWRVLWOHUGH PLWRNRQGUL YH\D GL÷HU KFUH RUJDQHOOHULQde okside ROXUODUYH\DWULJOLVHULGIRVIROLSLGYHNROHVWHUROHVWHUOHULQLQVHQWH]LQGHNXOODQÕOÕUODU (÷HU 6<$¶L VXQXPX DúÕUÕ ROXUVD \D÷ PHWDEROL]PDVÕ ID]ODFD DNWLYH ROXU YH \ÕNÕP D]DOÕUYHWULJOLVHULGGHSRODQPDVÕPH\GDQDJHOLU
$úÕUÕDNWLYHROPXú\D÷PHWDEROL]PDVÕVHUEHVWUDGLNDOOHUGHDUWÕúLOHELUOLNWHGLU %X GXUXPGD RNVLGDWLI VWUHV PH\GDQD JHOPHNWHGLU <D÷OÕ GHMHQHUDV\RQD X÷UDPD\DQ NDUDFL÷HULNLQFLGDUEH\HNDUúÕ|QHPVL] RODUDNUHDNVL\RQJ|VWHULU'X\DUOÕNDUDFL÷HUGH LVHDUWPÕú\D÷LoHUL÷LOLSLGOHULQEHWDRNVLGDV\RQLOH\R÷XQODúWÕUÕOPDODUÕLOHNRUHOHGLU YHVRQXoWDVHUEHVWUDGLNDOOHUDUWDU$73D]DOÕU0DNURIDMODUÕQIRQNVL\RQXQGDD]DOPD ile bireysel hasarlar tetiklenir.
4.4.7.7. 1$6+ SDWRJHQH]LQGH VRQ J|UúOHU *|UOG÷ JLEL 1$<.+¶Õ YH NASH’in patogenezi ROGXNoD NDUÕúÕNWÕU YH ELOJLOHU DUWWÕNoD GDKD GD NDUPDúÕN KDOH gelmektedir.
<DNÕQ ]DPDQGD WHN ELU GDUEHQLQ \DQL QVOLQ GLUHQFLQLQ 1$<.+¶ÕQÕQ WP VSHNWUXPXQXDoÕNODPD\D\HWHUOLRODELOHFH÷LLOHULVUOPúWU Son zamanlarda
hangi faktörlerin rol oynadÕ÷Õ QHW RODUDN LIDGH HGLOPHPLúVH GH oQFG|UGQF GDUEH LOH GH VLUR] YH KHSDWRVHOOHU NDQVHULQ JHOLúWL÷L LOHUL VUOPHNWHGLU Wanless ve Shiota (76) LVHGDKDNDSVDPOÕG|UWEDVDPDNOÕELUPRGHO|QHUPLúOHUGLU %LULQFLEDVDPDNWDLQVOLQLOHNROD\ODúWÕUÕODQVWHDWR]LVLNLQFLEDVDPDNWDLQWUDVHOOHU lipid toksisitesi veya lipid peroksidasyonu ile indüklenen nekroz, üçüncü basamak hepatositlerden intersiyuma \Õ÷ÕQ KDOLQGH OLSLGOHULQ VDOÕQPDVÕ YH EXQODUÕQ KHSDWLN venlere direk ve inflamatuvar hasar yapmasÕ YH VRQ RODUDN G|UGQF EDVDPDNWD VHNRQGHUNROODSVODYHQ|]REVWUXNVL\RQJHOLúPHVLYHQLKDLRODUDNILEU|]VHSWDODúPDYH VLUR]ROXúXPX
NASH patogenezi ùHNLO¶GHNÕVDFD|]HWOHQPLúWLU
<D÷ peroksidasyonu GúN TNF-alfa ve endotoksinlere GX\DUVÕ]OÕN <D÷ peroksidasyonu DUWÕúÕ
Makrofaj fonsiyonuD]DOÕU
EndotoksinlereGX\DUOÕOÕNDUWDU Örn:Beslenme, Fazla kilo ATP UCP2 Normal Steatosis Oksidatif stres ?TNF-. ? ATP ihtiyacÕ øNLQFLG DUEH Hepatik fibrozis Steatohepatit Normal Birinc i darbe ùHNLO 1$6+SDWRJHQH]L øNLGDUEHKLpotezi.
'(1(<6(/121$/.2/ø.67($72+(3$7ø702'(//(5ø +HSDWRVLWOHUGH \D÷ ELULNLPLQGHQ YH VRQXoWD VWHDWRKHSDWLW JHOLúLPLQGHQ VRUXPOX SDWRJHQHWLN PHNDQL]PDODUÕQ GDKD L\L DQODúÕOPDVÕ ULVN LOHUOHPHVLQL D]DOWÕFÕ NRUX\XFX \ROODUÕQ YH WHGDYL VHoHQHNOHULQLQ EHOLUOHQPHVLQH \DUGÕPFÕ RODFDNWÕU +HSDWLN VWHDWR]LV YH VWHDWRKHSDWLWLQ KD\YDQ PRGHOOHUL 1$<.+¶ÕQÕQ GDKD L\L DQODúÕOPDVÕQD \DUGÕPFÕ ROPDNWDGÕU %X PRGHOOHU LOH GHYDP HWWLULOHQ oDOÕúPDODU LOH SDWRJHQH] D\GÕQODPD\D GHYDP HGHFHN YH 1$<.+¶ÕQÕQ WDQÕ YH WHGDYLVL daha iyi noktalara gelecektir. Birçok deneysel model mevcuttur. Steatozis ve steatohepatitin SDWRJHQH]LQGHQ VRUXPOX PHNDQL]PDODUÕ DoÕNODPDN LoLQ HQ oRN NXOODQÕODQ o DQD PRGHO |]HOOLNOH ELOJL YHULFL ROPXúODUGÕU JHQHWLN RODUDN REH] RERE VÕoDQODU lipoatroILN VÕoDQODU YH NROLQGHQ HNVLN PHWL\RQLQGHQ NÕVÕWOÕ GL\HWOH 0&' QRUPDO UDWODUÕQ EHVOHQPHVL %X o DQD PRGHO GH 1$<.+¶Õ LoLQ oRNOX GDUEH KLSRWH]LQL GHVWHNOHPHNWHGLU %X PRGHOOHULQ WPQGH VWHDWR]LV VSRQWDQ RODUDN JHOLúLUNHQ steatohepatit ve siroza iOHUOHPHGH÷LúNHQGLU
4.5.1. *HQHWLNRODUDNREH]GL\DEHWLNREREVÕoDQODU:1$<.+¶ÕLoLQGR÷DO RODUDN ROXúDQ ELU PRGHOL WHPVLO HWPHNWHGLU %XQODUGD RE JHQLQGHNL PXWDV\RQ GROD\ÕVÕ\OD EH\D] \D÷ GRNXVXQGD VHQWH]OHQHQ GR\JXQOXN KRUPRQX OHSWLQ HNVLNWLU Leptin HNVLNOL÷LQGH DúÕUÕ \HPH QHGHQL\OH RERE VÕoDQODUGD REH]LWH JHOLúLU %X VÕoDQODUGD D\UÕFD LQVOLQ GLUHQFL KLSHULQVOLQHPL KLSHUJOLVHPL YH KLSHUOLSLGHPL YDUGÕU(Q|QHPOLVLEXQODUGDVSRQWDQRODUDN\D÷OÕNDUDFL÷HUJHOLúLU+LSHUOHSWLQHPLN olup da, leptinin HWNLOHULQH NDUúÕ GLUHQo EXOXQDQ GEGE VÕoDQODU YH IDID UDWODUGD IHQRWLS RODUDN RERE VÕoDQODUD EHQ]HUOHU . BX PRGHOOHUGH OHSWLQ HNVLNOL÷L YH\D HWNLVLQH NDUúÕ GLUHQo VRQXFXQGD REH]LWH LQVOLQ GLUHQFL GLVOLSLGHPL YH 1$<.+¶Õ meydana gelmektedir. Fakat EXPRGHOGHHNVLNOLNRODUDNDúLNkUYH\DEL\RNLP\DVDO RODUDNKHSDWLNLQIODPDV\RQEXOJXODUÕ \DQLVWHDWRKHSDWLW PH\GDQDJHOPH]
%X PRGHOOHU KHSDWLN VWHDWR]XQ GL÷HU KHSDWRWRNVLN PDGGHOHUH GX\DUOÕOÕ÷Õ DUWWÕUÕS DUWWÕUPDGÕ÷ÕQÕ YH D\UÕFD EX PDGGHOHU LOH NDUúÕODúÕOÕQFD VWHDWRKHSDWLW JHOLúLS JHOLúPH\HFH÷LKLSRWH]OHULQLDUDúWÕUPDGDNXOODQÕOPDNWDGÕU
4.5.2. 'L\DEHWOH EHUDEHU RODQ OLSRDWURILN VÕoDQODU 'H÷LúLN úHNLOOHUGH ROXúPDNWDGÕU $GLSR] GRNX OHSWLQLQ WHPHO ND\QD÷Õ ROGX÷X LoLQ DGLSR] GRNXQXQ KDUDS HGLOGL÷L YH\D JHQHWLN RODUDN HNVLN ROGX÷X WP OLSRDWURILN VÕoDQODU OHSWLQGHQ IDNLUGLU %X QHGHQOH RERE VÕoDQODUGD ROGX÷X JLEL EX PRGHOGH GH LQVOLQ GLUHQFL DUWPÕú 71)-. HNVSUHV\RQX YH \D÷OÕ NDUDFL÷HU JHOLúPHNWHGLU Lipoatrofik VÕoDQODUOD\DSÕODQoDOÕúPDODUGDREH]LWHQLQNHQGLOL÷LQGHQ YH\DWHNEDúÕQD 1$<.+¶Õ YH\DLQVOLQGLUHQFLQH\RODoPDGÕ÷ÕJ|VWHULOPLúWLU
%XLNLPRGHOLQKDQGLNDSÕVDGHFHKHSDWLNVWHDWR]LVJHOLúPHVLGLUYH1$6+LOH LOJLOL oDOÕúPDODU \DSÕOPDVÕ LoLQ HN KHSDWRWRNVLN PDGGHOHU LOH 1$6+ LQGNOHQmesi gerekmektedir.
4.5.3. .ROLQGHQ IDNLU PHWL\RQLQGHQ NÕVÕWOÕ GL\HWOH EHVOHQHQ QRUPDO UDWVÕoDQODU: 1RUPDO UDW YH VÕoDQODUÕQ 0&' LOH EHVOHQPHVL KHSDWLN DQWLRNVLGDQODUÕ úLGGHWOL RUDQGD D]DOWÕU YH *6+ YH 6-adenozilmetiyonin (S-$0H G]H\OHUL D]DOÕU (80). KROLQYHPHWL\RQLQGHQIDNLUGL\HWRNVLGDWLIVDYXQPDPHNDQL]PDODUÕQÕD]DOWDUDN RNLGDWLI VWUHVL DUWÕUÕU %X PRGHO KHSDWLN VWHDWR]LV YH VWHDWRKHSDWLWWH RNVLGDWLI VWUHVLQ SDWRJHQHWLN |QHPLQL J|VWHUPHQLQ \DQÕQGD RNVLGDWLI VWUHVLQ REH]LWHGHQ ED÷ÕPVÕ]OÕ÷ÕQÕGa göstermektedir.
Kolin ve metiyoninden fakir diyetin eksik yönü ise insülin ve leptin direnci, REH]LWH JLEL LQVDQ 1$6+¶LQLQ WHPHO SDWRJHQHWLN IDNW|UOHULQLQ JHOLúPHPHVL YH LQVDQODUGD PH\GDQD JHOHQ 1$6+¶LQ ELU |]HOOL÷L ROPD\DQ QWULV\RQHO \|QGHQ eksiliklerHQHGHQROPDVÕGÕU
%X o DQD PRGHOLQ \DQÕQGD GDKD D] NXOODQÕODQ EDúND PRGHOOHUGH YDUGÕU 5DWODUGD &<3( LQGNVL\RQX LOH GH \D÷OÕ NDUDFL÷HU ROXúWXUXODELOPHNWHGLU )DNDW EX PRGHOLQ KDQGLNDSÕ UDWODUÕQ oRN X]XQ VUH \DNODúÕN ELU \ÕO WHGDYL edilmelerinin gerekmesidir (83). 'L÷HUELUPRGHOGHLVHJHQHWLNRODUDNVLWRNURP3 HQ]LPVLVWHPLQGHGHIHNWRODQURGHQWOHUNXOODQÕOPDNWDGÕU
<D÷OÕNDUDFL÷HUYH1$6+LoLQELUoRNPRGHONXOODQÕOPDVÕQDUD÷PHQEXQODUGD SDWRJHQHWLN IDNW|UOHUGHQ ELU NÕVPÕ HNVLNWLU (Nsik yönler nedeniyle uygun modelin ROPD\ÕúÕ1$6+¶LQSDWRJHQHWLNIDNW|UOHULQLYHEXQODUD\|QHOLNWHGDYLOHULDUDúWÕUPD\D \|QHOLNoDOÕúPDODUÕQ\DSÕOPDVÕQÕHQJHOOHPHNWHGLU
<DNÕQ]DPDQGD/LHEHUYHDUNDGDúODUÕ WDUDIÕQGDQHUNHN6SUDJXH-dawley cinsi ratlardD\D÷GDQ]HQJLQGL\HWOH <=' \DSÕODQoDOÕúPDGDHOGHHGLOHQVRQXoODUEX HNVLNOL÷LQ JLGHULOPHVL \|QQGHQ XPXW YHULFL ROPXúWXU %X PRGHOGH WP HVDQVL\HO EHVLQOHU\HWHUOLPLNWDUGDPHYFXWWXU6WDQGDUWUDWGL\HWLQLQLoHUL÷LQGHHQHUMLQLQ¶L proteinden, %47’si NDUERQKLGUDWODUGDQ ¶L \D÷ODUGDQ HOGH HGLOLUNHQ <=' GL\HWLQGH SURWHLQ RUDQÕ VDELW LNHQ NDUERQKLGDUDWWDQ VD÷ODQDQ HQHUML PLNWDUÕ ¶H GúHUNHQ\D÷GDQHOGHHGLOHQHQHUMLPLNWDUÕLVHRUDQÕQDoÕNPDNWDGÕU%XGL\HWLQ LoHUL÷LTablo 2’de J|VWHULOPLúWLU%XGL\HWOHoKDIWDJLELNÕVDELUVUHGH1$6+¶LQ WLSLN KHSDWLN OH]\RQODUÕ RODQ VWHDWR]LV LQIODPDV\RQ YH HUNHQ ILEUR]LV PH\GDQD JHOPLúWLU3DWRJHQH]GHVXoODQDQLQVOLQGLUHQFLKLSHULQVOLQHPLKHSDWLN71)-.YH &<3(HNSUHV\RQXQGDDUWÕúYHRNVLGDWLIVWUHVEHOLUWHoOHULQGHDUWÕúGDVDSWDQPÕúWÕU (OGH HGLOHQ EXOJXODU DoÕNoD J|VWHUPLúWLU NL LQVDQ 1$6+¶LQGH PHYFXW RODQ DQDKWDU |]HOOLNOHUEXPRGHOOHRUWD\DNRQXOPXúWXU
7DEOR <D÷GDQ]HQJLQGL\HWLQLoHUL÷L* øoHULN <D÷GDQ ]HQJLQ GL\HW (gr/litre) Kazein 41.4 L-sistein 0.5 DL-metiyonin 0.3 0ÕVÕU\D÷Õ 48.5 =H\WLQ\D÷Õ 28.4 $\oLoHN\D÷Õ 2.7 Dekstrin-maltoz 25.6 Kolin bitartrat 0.53 Fiber 10.0 Xantan gum 3.0 * : (85) QR¶OXND\QDNWDQDOÕQPÕúWÕU'L\HWHD\UÕFDJUDPYLWDPLQ-PL[HNOHQPLúWLU 4.6.7('$9ø
(Q D] YLUDO KHSDWLWOHU NDGDU VÕN RODUDN UDVWODQÕODQ 1$6+¶LQ VLUR]D LOHUOHPH ULVNLGHEXKDVWDOÕNODULOHEHQ]HUGLU)DNDW1$6+LoLQHWNLOLELUWHGDYLKHQ]\RNWXU 1$6+¶LQSURJQR]XDoÕNGH÷LOGLU%XQHGHQOHWHUDS|WLN\DNODúÕPODUÕQKHGHIL KDVWDOÕ÷ÕQLOHUOHPHVLQLQGXUGXUXOPDVÕYHH÷HUPPNQVHVLUR]JHOLúLPLQLQ|QOHQPHVL ROPDOÕGÕU 1$6+ SDWRJHQH]L GH KHQ] WDP RODUDN D\GÕQODWÕODPDGÕ÷Õ LoLQ WHGDYL DPSLULNWLUYH1$6+¶HHúOLNHGHQGXUXPODUD\|QHOLNWLU
0HYFXW1$6+WHGDYL\DNODúÕPODUÕNRQVHUYDWLIWLUYHtablo 3’teJ|VWHULOPLúWLU gQHPOL ELU VD÷OÕN VRUXQX RODQ 1$6+ KDNNÕQGD WRSOXP YH KDVWDODU ELOJLOHQGLULOPHOLEHVOHQPHWDU]ÕYH\DúDPVWLOLQGHG]HQOHPH\HGDLUH÷LWLPYHULOPHVL LON\DSÕOPDVÕJHUHNHQEDVDPDNWÕU$ONROYHGL÷HUKHSDWRWRNVLQOHUGHQNDoÕQPDOÕGÕUODU øODoODUOD \DSÕODQ 1$6+ WHGDYLVLQH EDúODQPDGDQ |QFH EHGHQVHO DNWLYLWH YH GL\HW GHQHQPHOLGLU%XQXQ\DQÕQGDLODoYHGL\HWHJ]HUVL]WHGDYLOHULNRPELQHGHHGLOHELOLU
7DEOR 1$6+KDVWDODUÕYH\DGHQH\VHOoDOÕúPDODUGD\DUDUOÕHWNLOHULJ|VWHULOHQ terap|WLN\DNODúÕPODU
Strateji Tedavi
Tedrici olarak kilo verme .DORULNÕVÕWODPDVÕ Egzersiz
.LORYHUGLULFLFHUUDKLLúOHPOHU øQVOLQGX\DUOÕOÕ÷ÕQÕDUWWÕUPD Metformin
33$5 OLJDQGODUÕ 5R]LJOLWD]RQ Pioglitazon)
/LSLGD]DOWÕFÕLODoODU Fibratlar (Klofibrat) %DOÕN\D÷Õ
Antioksidanlar Vitamin E
N-asetil-sistein Betain
Sitokin modulasyonu Vitamin E
Apoptoz Ursodeoksikolik asit
.DUDFL÷HUGHPLUL Flebotomi
4.6.1. Vücut kilosunda azalma: +Õ]OÕIDNDWD\QÕ]DPDQGD\DYDúRODUDN ile 30 kilo veUPH úLGGHWOL RODUDN DúÕUÕ NLOROX NLúLOHUGH NDUDFL÷HU \D÷ LoHUL÷LQL D]DOWDELOLU KDWWD QRUPDOH G|QGUHELOLU RUDQÕQGD DúÕUÕ NLOR\D VDKLS DúÕUÕ NLOROX NLúLOHUGH YFXW D÷ÕUOÕ÷ÕQGD \DNODúÕN RUDQÕQGD D]DOPD ODERUDWXYDU SDUDPHWUHOHULQGH\DUDUOÕG]HOPHOHUHQHGHQROXU'L÷HU\DQGDQoRNKÕ]OÕYHDúÕUÕNLOR YHUPH6<$GHúDUMÕQD\RODoDUDNSRUWDOILEUR]LVYHLQIODPDV\RQDQHGHQRODELOLU
(QHWNLQWHGDYLX]XQ]DPDQSHUL\RGXQGDVUGUOHQGúNNDORULOLGL\HWWLU'L\HWWH LVH GúN NDORULQLQ \DQÕQGD |]HOOLNOH GH oRNOX GR\PDPÕú \D÷ DVLWOHUL HWNLOLGLU 'L\DEHWOLYHNDUGL\RYDVNOHUKDVWDOÕ÷ÕYHOLSLGER]XNOX÷XEXOXQDQKDVWDODUGDLVH|]HO EDNÕP JHUHNLU YH PHWDEROLN ER]XNOXNODUÕQ RSWLPDO NRQWURO |QHPOLGLU øúWDK NHVLFLOHULQ\DUDUÕEHOLUOHQPHPLúWLUD\UÕFDEXLODoODUÕQSXOPRQHUVLVWHP]HULQH]DUDUOÕ etkileri bulunabilir.
3URJUHVLI NLOR YHUPH YH PHWDEROLN NRQWUROQ \DQÕQGD WHGULFL HJ]HUVL] GH NDUDFL÷HUER]XNOX÷XQGDNLG]HOHPH\HNDWNÕGDEXOXQDELOLU
4.6.2. NASH için ilaç tedavisi
0DDOHVHI REH] NLúLOHUGH GL\HW YH HJ]HUVL] SURJUDPODUÕQD X\XP ROGXNoD GúNWU (SL]RGLN NLOR YHUPH VRQUDVÕQGD WHNUDU ID]OD \HPH YH NLOR DOPDODU J|UOPHNWHGLU%XQHGHQOHED]HQX\XPVX]GL\HWOHU|]HOOLNOHGHKÕ]OÕNLORYHUPHYH VRQUDVÕQGD WHNUDU NLOR DOPD úHNOLQGH yoyo etkisi \DSWÕNODUÕ ]DPDQ LúOHU N|W\H GH gidebilir.
Bu nedenle patofizyolojik zemindeki mevcut faktörlere yönelik tedaviler DUDúWÕUÕOPDNWDGÕU)DNDW1$6+¶H\|QHOLNYHULOHQWHGDYLOHULQE\NoR÷XQOX÷XNoN YH NRQWUROO ROPD\DQ oDOÕúPDODUGÕU %XQGDQ GROD\Õ EXJQ HQ \DUDUOÕ LODFÕQ KDQJLVL ROGX÷XQDGDLUNDUDUYHUPHNROGXNoD]RUGXU)D]ODNLOROXROPD\DQODUGDID]ODNLOROX ROXS GD NLOR YHUHPH\HQ YH\D YHUGL÷L NLORGD NDODPD\DQODUGD LODo WHGDYLVL X\JXODQPDOÕGÕU
øQVOLQ GLUHQFLQLQ 1$6+ SDWRJHQH]LQGHNL WHPHO UROQGHQ GROD\Õ LQsülin GLUHQFLQL D]DOWDQ YH KHSDWLN LQVOLQ GX\DUOÕOÕ÷ÕQÕ DUWWÕUDQ LODoODUD LOJL ID]ODGÕU 0HWIRUPLQLQ 1$6+¶WH QHNURLQIODPPDWXYDU DNWLYLWH\L D]DOWWÕ÷Õ ELOGLULOPLúWLU Etkilerini insülin direncini peroksizom proliferatör-aktive reseptör gama (PPAR gama) nükleer reseptörlerini aktive ederek düzelterek gösteren roziglitazon ve
SLDJOLWD]RQGD1$6+¶WH\DUDUOÕHWNLOHUJ|VWHUPHNWHGLUOHU )DNDWEXLODoODUÕQ X]XQG|QHPHWNLOHULELOLQPHPHNWHGLU$\UÕFDWLD]ROLGLQOHULQSRWDQVL\HOKHSDWRWRNVLN yan etkileri ROPDVÕ EX LODoODUÕQ X]XQ G|QHPGH 1$6+¶WH JYHQOH NXOODQÕPODUÕ LoLQ D\UÕELUKDQGLNDSWÕU
4.6.2.1. NASH tedavisinde antioksidanlar
2EH] YH DúÕUÕ NLOROX 1$6+ KDVWDODUÕ LoLQ NLOR YHUPH ROGXNoD ]RUGXU YH JHQHOOLNOH EDúDUÕVÕ]OÕNOD VRQXoODQPDNWDGÕU $\UÕFD KÕ]OÕ NLOR YHUPH GH KHSDWLN ER]XNOX÷X KÕ]ODQGÕUDELOLU YH GDKD N|WOHúWLUHELOLU øQVOLQ GX\DUOÕOÕ÷ÕQÕ DUWWÕUDQ WHGDYLOHUXUVRGHRNVLNROLNDVLWJLELGHQHQHQGL÷HUWHGDYL \|QWHPOHULLOHHOGHHGLOHQ VRQXoODUGDIDUNOÕOÕNODUDU]HWPHNWHGLUYHKHQ]NDEXOJ|UPúetkili bir tedavi yoktur.
1$6+ SDWRJHQH]LQLQ GDKD L\L DQODúÕOPDVÕ \HQL WHUDS|WLN DoÕOÕPODUÕQ EXOXQPDVÕLoLQJHUHNOLGLU2NVLGDWLIVWUHV1$6+SDWRJHQH]LQGHPHUNH]LUROHVDKLSWLU ve en önemli faktörlerden birisidir.
1$6+¶OL KDVWDODUÕQ NDUDFL÷HUL RNVLGDtif stresin tetiklenmesi ve sürmesi için JHUHNOL LoHUL÷L VDKLSWLU +HSDWRVHOOHU VWHDWR]LVLQ NHQGLVL GH OLSLG SHURNVLGDV\RQXQ LOHUOHPHVLQL WHWLNOH\HELOLU 3HVVD\UH YH JUXEX NDUDFL÷HUGH RNVLGH HGLOHELOLU \D÷ÕQ YDUOÕ÷ÕQÕQWHNEDúÕQDOLSLGSHURNVLGDV\RQXQXWHWLNOH\HELOHFH÷LQLJ|VWHUPLúOHUGLU Hücreleri serbest oksijen radikallerinde korumak için süperoksit dismutaz, NDWDOD] YH JOXWDW\RQ SHURNVLGD] JLEL ELUoRN VDYXQPD PHNDQL]PDVÕ PHYFXWWXU %XQODUÕQ \DQÕQGD NDURWHQ OLNRSHQ DVNRUELW DVLW YH WRNRIHURO Jibi birçok besinin antioksidan etikleri mevcuttur.
7P \D÷OÕ NDUDFL÷HUOHU ILEURWLN KDOH JHOPL\RU )LEURMHQLN LNLQFL GDUEH oksidatif stresin nedeni diyet, çevresel faktörler ve genetik polimorfizm olabilir. )DNDWNRUX\XFXPHNDQL]PDODUÕQHNVLNOL÷LQHGHED÷OÕRODELOLU$QWLRNVLGDQODUGDU|ODWLI
