Ekspresija i distribucija kaveolina-1 i transformirajućeg čimbenika rasta beta u hepatocitima bolesnika s nealkoholnom masnom bolešću jetara [Expression and distribution of caveolin-1 and transforming growth factor beta in hepatocytes of patients with nonalcoholic fatty liver disease]

Gomerčić Palčić, Marija (2015) Ekspresija i distribucija kaveolina-1 i transformirajućeg čimbenika rasta beta u hepatocitima bolesnika s nealkoholnom masnom bolešću jetara [Expression and distribution of caveolin-1 and transforming growth factor beta in hepatocytes of patients with nonalcoholic fatty liver disease]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

NAFLD represents an emerging health problem because of its increasing prevalence, unresolved pathogenesis, inadequate diagnostic as well as therapeutic options. Cav-1 and TGF-β are two biomarkers that were investigated in this study in order to determine their expression and distribution in hepatocytes of NAFLD patients, as well as their relations to pathohistological changes, presence of MS, levels of liver enzymes and ultrasound characteristics. We included 66 biopsy proven NAFLD patients and 15 controls that underwent liver resection due to non-diffuse liver disease. Pathohistological analysis of collected liver specimens was performed as well as additional immunohystochemical analysis of cav-1 and TGF-β expression and distribution in hepatocytes. In NAFLD patients, cav-1 expression was positive in 59 (89.4%) cases while all controls had negative expression of cav-1 in cytoplasm of hepatocytes (X2, p<0.001). Patients with positive cav-1 expression were more likely younger (Mann-Withney U test, p=0.010) and male (X2, p=0.024). Almost 70% of NAFLD patients had altered cav-1 distribution in comparison to the control group (6.7%), what was statistically significant (X2, p<0.001). NASH and NAFL/borderline groups had similar expression (p=0.199) and distribution (p=0.709) of cav-1 in hepatocytes. Proportion of patients with cav-1 positive expression and altered distribution positively correlated with severity of the liver steatosis. Patients that had negative cav-1 expression had more common MS (p=0.041) and detected fasting hyperglycemia (p=0.038). Ones with altered cav-1 distribution had larger waist (p<0.001) and thighs (p=0,016) circumference and more common normal blood pressure (X2, p=0.048). TGF-β expression was higher (X2, p<0.001) and distribution altered (X2, p<0.001) in hepatocytes of NAFLD patients. Patients with NASH and NAFL/borderline group had similar expression (X2, p=0.482) and distribution (X2, p=0.402) of TGF-β in hepatocytes. This is the first study that showed high expression of cav-1 and TGF-β as well as their altered distribution in NAFLD patients compared to controls. Neither of these two biomarkers were shown as a possible predictor of NASH. Cav-1 is new and promising marker of liver steatosis and possible therapeutic target.

Abstract in Croatian

NAFLD zbog svoje visoke prevalencije i mogućih teških posljedica predstavlja značajan klinički problem, a naše spoznaje o patofiziologiji su još uvijek nedostatne i samim time dijagnostičke i terapijske mogućnosti. Ciljevi ovog istraživanja su bili ispitati ekspresiju i distribuciju cav-1 i TGF-ß u hepatocitima bolesnika s NAFLD-om te ih usporediti s patohistološkom slikom, korelirati sa stadijem bolesti, prisustvom MS-a i njegovih sastavnica, biokemijskim markerima bolesti jetre i sonografskim karakteristikama. U ovo prospektivno istraživanje uključeno je 66 bolesnika s NAFLD-om i 15 kontrolnih ispitanika. Bioptati jetre su dobiveni u skupini s NAFLD-om slijepom biopsijom jetre, a u kontrolnoj resekcijom zbog fokalne lezije jetre. Učinjena je patohistološka analiza svih bioptata jetre i dodatno analizirana imunohistokemijska reakcija u hepatocitima na cav-1 i TGF-β. U našem istraživanju niti jedan ispitanik iz kontrolne skupine nije imao povišenu ekspresiju cav-1 u hepatocitima dok je ista bila vidljiva u 59 (89,4%) bolesnika s NAFLD-om. Značajno češće su bolesnici s NAFLD-om i povišenom ekspresijom cav-1 u hepatocitima bili mlađi (Mann-Withney U test, p=0,010) muškarci (X2, p=0,024). Promijenjenu distribuciju cav-1 u hepatocitima imao je samo jedan ispitanik u kontrolnoj skupini (6,7%) za razliku od 46 (69,7%) bolesnika s NAFLD-om. Usporedbom ekspresije i distribucije cav-1 u hepatocitima bolesnika s NAFLD-om u odnosu na kontrolnu skupinu nađena je statistički značajna razlika (p<0,001). Unutar podskupina bolesnika s NAFLD-om (NASH i NAFL/granični nalaz) nije nađeno statistički značajne razlike u ekspresiji (p=0,199) i distribuciji (p=0,709) cav-1 u hepatocitima. Najveći broj bolesnika s povišenom ekspresijom (40,7%) i promijenjenom distribucijom (41,3%) cav-1 se prezentirao u trenutku dijagnoze 3. stupnjem steatoze, a njihov udio rastao je sa izraženošću steatoze. Bolesnici s NAFLD-om i sniženom ekspresijom cav-1 imali su značajno češće prisutan MS (p=0,041) i hiperglikemiju natašte (p=0,038) u odnosu na bolesnike s povišenom ekspresijom cav-1. Iako su bolesnici s NAFLD-om i nepromijenjenom distribucijom cav-1 u hepatocitima imali češće MS u odnosu na bolesnike s promijenjenom distribucijom, statistički značajna razlika nije nađena (p=0,578). Opseg struka (p<0,001) i bedara (p=0,016) koji determiniraju centralnu pretilost su bili značajno veći u bolesnika s promijenjenom distribucijom cav-1 dok su bolesnici s nepromijenjenom distribucijom cav-1 imali značajno češće arterijsku hipertenziju (p=0,048). Ekspresija TGF-β je bila češće povišena (p<0,001), a distribucija promijenjena (p<0,001) u 85 hepatocitima bolesnika s NAFLD-om u odnosu na kontrolnu skupinu. Bolesnici s NAFLD-om i povišenom ekspresijom (p=0,626) te promijenjenom distribucijom TGF-β (p=0,943) nisu imali značajno češće prisutan MS. Unutar podskupina bolesnika s NAFLD-om (NASH i NAFL/granični nalaz) nije nađeno statistički značajne razlike u ekspresiji (p=0,482) i distribuciji (p=0,402) TGF-β u hepatocitima. Zaključno se može reći da je ovo prva studija na ljudima koja je potvrdila da je ekspresija cav-1 i TGF-β povišena, a distribucija promijenjena u hepatocitima bolesnika s NAFLD-om u odnosu na kontrolnu skupinu. Niti jedan biomarker se nije pokazao kao mogući prediktor NASH-a niti fibroze. Cav-1 je mogući novi marker steatoze i potencijalni terapeutski cilj čijom bi se modifikacijom mogla prevenirati progresija NAFLD-a.

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