Koncentracija endotelina-1 i serumska aktivnost angiotenzin konvertirajućeg enzima u serumu uz Doplersku procjenu jetrenih protoka krvi u kroničnih jetrenih bolesnika

Kardum, Duško (2005) Koncentracija endotelina-1 i serumska aktivnost angiotenzin konvertirajućeg enzima u serumu uz Doplersku procjenu jetrenih protoka krvi u kroničnih jetrenih bolesnika. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Former research showed elevated values of ACE serum activity and ET-1 serum concentration in liver cirrhosis. Experiments also proved elevated ACE serum activity in chronic hepatitis, except for ET-1. There is no data in literature due to interaction between ACE and ET-1, neither their relationship with Doppler determined parameters hemodynamic status in blood circulation of patients with chronic liver diseases which was the subject of this investigation. The research included all together 70 patients divided due to pathohistological examination of biopsy obtained liver tissue divided in three groups. In Group I were included patients with liver steatosis, which showed pore fibrosis; group II, contained patients with alcohol and chronic virus hepatitis and primary biliary cirrhosis (PBC), diseases which showed moderate fibrosis and group III, were patients with alcohol liver disease on which samples of liver tissue prevailated cirrhosis. ACE serum activity was determined by Olympus AU 2700, kit «InfnityTM ACE Liquid Stable Reagent» for determine angiotensin converting enzyme company Thermo Electron Corporation was used. This procedure of determing ACE serum activity was based on reaction described by Holmquist and associates. Results were expressed in units per liter (U/L). ET-1 serum concentration was determined by ELISA test using reagens ASYBUF for ET-1. Results were expressed in pg/ml of serum. Experiment results showed increase of ACE and ET-1 serum activity in all patients with various stages of chronic liver lesions what correlates with previous papers. Increase of ACE and ET-1 serum activity in patients is proportional to stage liver disease. The lowest ACE activity were found in patients with liver steatosis and poor fibrosis (group I) - median, range: 57, 16-94 IU/L, while in patients with most severe liver fibrosis – cirrhosis (group III) ACE activity was the highest - median, range: 89, 65-139 IU/L. ET-1 serum concentration also shows distribution which follows stage of illness, similar as ACE serum activity. The lowest ET-1 concentration were noticed in u serum of patients with low and moderate fibrosis (group I) - median 6,25 pg/mL, range 2,38-11,80 pg/mL, while the highest concentration was determined in patients with liver cirrhosis (group III) - median, range: 18,95, 12,05-59,38 pg/mL. ACE serum activity shows emphasized increase in transition of liver fibrosis from poor to moderate while ET-1 serum concentration shows marked increase in emerging liver cirrhosis from moderate fibrosis. Border value of ACE serum activity which separates patients with poor liver fibrosis from patients with moderate liver fibrosis is 59,0 U/I. Border value of ET-1 serum activity which separates patients with poor and moderate liver fibrosis from patients with liver cirrhosis is 12,4 pg/ml. Correlation of ACE serum activity and ET-1 serum concentration was examined by Spearman test in correlation range. Analysis showed positive correlation of these two variables: with increase ACE serum activity there was also found increase of ET-1 serum concentration (p=0,004). RI flow through liver artery is the lowest among the patients with lighter form of poor liver fibrosis (group I): - median, range: 0,65, 0,32-0,89 among patients with liver cirrhosis, (group III) -median, range: 0,81, 0,71-0,91. TAMV flow in portal vein shows values reversed association to scale of liver disease: in group I the highest values of TAMV were found - median, range: 18,60, 14,50-21,30 cm/s. In patients with heavier form of liver illness and cirrhosis (group III), TAMV values were the lowest - median, range: 12,50, 7,50-17,20 cm/s. ET-1serum concentrations showed positive correlation with RI ( p<0,001) and reversed association to TAMV (p<0,001). Correlation analysis did not show correlation between ACE serum activity and RI in liver artery (p=0.0757) while correlation between ACE serum activity and TAMV was reversed association, but little (p=0,0269). These results allow us to conclude justification of using these Doppler parameters with determination of ACE serum activity and ET-1 serum concentration and in evaluation of noninvasive intensity of liver fibrosis and cirrhosis.

Abstract in Croatian

Dosadašnja istraživanja su pokazala povišene vrijednosti serumske aktivnosti ACE i serumske koncentracije ET-1 u cirozi jetre. Za razliku od ET-1, istraživanja su dokazala povećnu serumsku aktivnost ACE-a i u kroničnom hepatitisu. U literaturi nema podataka o međusobnoj povezanosti ACE i ET-1, niti njihove povezanosti s doplerski određenim parametrima hemodinamskog stanja u krvnom optoku bolesnika s kroničnim bolestima jetre što je predmet ovog istražiavanja. U istraživanje je uključeno ukupno 70 bolesnika koji su temeljem patohistološkog pregleda biopsijom dobivenog uzorka jetrenog tkiva podjeljeni u tri skupine. U skupinu i su bili uključeni bolesnici s masnom promjenom jetre, koja pokazuje oskudnu fibrozu; skupina II, obuhvaćala je bolesnike oboljele od alkoholnog i kroničnih virusnih hepatitisa te primarne bilijarne ciroze (PBC), bolesti koje pokazuju umjerenu fibrozu; a skupinu III, činili su ispitanici s alkoholnom bolesti jetre na čijim je uzorcima jetrenog tkiva prevladavala ciroza. Serumska aktivnost ACE je određena na uređaju Olympus AU 2700 upotrebom kita «InfnityTM ACE Liquid Stable Reagent» za određivanje angiotenzin konvertirajućeg enzima tvrtke Thermo Electron Corporation. Ovaj se postupak određivanja serumske aktivnosti ACE temelji na reakciji koju su opisali Holmquist i suradnici. Rezultati su izraženi u jedinicama po litri (U/L). Serumska koncentracija ET-1 određena je ELISA testom uz uporabu reagensa ASYBUF za određivanje ET-1.Rezultati su izraženi u pg/ml seruma. Rezultati istraživanja su pokazala porast serumske aktivnosti ACE i ET-1 u svih ispitanika s kroničnim oštečenjima jetre različitog stadija što je u skladu s do sada objavljenim radovima . Porast serumske aktivnosti ACE i ET-1 u ispitanika je proporcionalan težini jetrene bolesti. Najniže su aktivnosti ACE zabilježene u serumu bolesnika sa steatozom jetre i oskudnom fibrozom (skupina I) - medijan, raspon: 57, 16-94 IU/L, dok je u serumu bolesnika s najtežim oblikom fibroze – cirozom (skupina III) aktivnost ACE bila najveća - medijan, raspon: 89, 65-139 IU/L. Serumska koncentracija ET-1 također pokazuje raspodjelu koja prati težinu bolesti, slično kao i serumska aktivnost ACE. Najniže koncentracije ET-1 zabilježene su u serumu bolesnika s oskudnom i umjerenom fibrozom (skupina I) - medijan 6,25 pg/mL, raspon 2,38-11,80 pg/mL, dok su najviše koncentracije određene u bolesnika sa cirozom jetre (skupina III) - medijan, raspon: 18,95, 12,05-59,38 pg/mL. Serumska aktivnost ACE pokazuje naglašen porast pri prijelazu jetrene fibroze iz oskudne u umjerenu dok serumska koncentracija ET-1 pokazuje naznačen porast pri nastajanju jetrene ciroze iz umjerene fibroze.Granična vrijednost serumske aktivnosti ACE koja odvaja bolesnike s oskudnom jetrenom fibrozom od bolesnika s umjerenom fibrozom jetre i cirozom iznosi 59,0 U/I. Granična vrijednost serumske koncentracije ET-1 koja odvaja bolesnike s oskudnom i umjerenom fibrozom od bolesnika s jetrenom cirozom jetre 12,4 pg/ml. Povezanost serumske aktivnosti ACE i serumske koncentracije ET-1 ispitana je Spearmanovim testom korelacije rangova. Analiza je pokazala pozitivnu povezanost ove dvije varijable: uz povećanje serumske aktivnosti ACE pronađeno je i povećanje serumske koncentracije ET-1 (p=0,004). RI protoka jetrenom arterijom je najniži kod bolesnika s lakšim oblicima bolesti s oskudnm jetrenom fibrozom (skupina I): - medijan, raspon: 0,65, 0,32-0,89 a najviši kod bolesnika s jetrenom cirozom, (skupina III) -medijan, raspon: 0,81, 0,71-0,91. TAMV protoka u portalnoj veni pokazuje vrijednosti obrnuto proporcionalne težini jetrene bolesti : u skupini i određene su najviše vrijednosti TAMV-a - medijan, raspon: 18,60, 14,50-21,30 cm/s. U bolesnika s težim oblikom jetrene bolesti i cirozom (skupina III), određene vrijednosti TAMV-a bile su najniže - medijan, raspon: 12,50, 7,50-17,20 cm/s. Serumske koncentracije ET-1 pokazuje značajnu pozitivnu korelaciju s RI ( p<0,001) a obrnuto proporcionalnu povezanost s TAMV (p<0,001). Analiza korelacije nije pokazala povezanost serumske aktivnosti ACE s RI u jetrenoj arteriji (p=0.0757) dok je povezanost serumske aktivnosti ACE s TAMV-om bila obrnuto proporcionalna, ali mala (p=0,0269). Ovi rezultati dopuštaju zaključak o opravdanosti korištenja ovih doplerskih parametara uz određivanje serumske aktivnosti ACE te serumske koncentracije ET-1 u neinvazivnoj prosudbi intenziteta razvoja jetrene fibroze i ciroze.

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