• Main
  • Useful links
  • Information for Contributors
  • About
  • Editorial board

  • Article
    Virstyuk N.G., Slyvka N.A.


    About the author: Virstyuk N.G., Slyvka N.A.
    Type of article Scentific article
    Annotation Hepatorenal syndrome (HRS) is a serious complication of alcohol liver cirrhosis (ALC). Studying of the mechanisms of molecular response to hypoxia in HRS is a promising direction of research in hepatology. The aim of present study was to evaluate the role of hypoxia-inducible factor HIF-1α in the pathogenesis of HRS at the acute-on-chronic (ACLF) liver failure (CLF) in patients with ALC. The total number of enrolled patients with ALC+HRS was 150, they were divided into 2 groups: group I (n=67) - CLF, group ІІ (n=83) - ACLF. The average age of patients at the time of inclusion in the study was (42.3±12.6) years; average duration of ALC - (3,5±1,4) years; average duration of alcohol abuse (8.4±3.5) years; gender distribution: 79.6% (n=119) males, 20.4% (n=31) - females (p <0.05). The antemortem ALC was diagnosed based on laboratory investigations and medical imaging methods, postmortem, on autopsy – based on macro- and micromorphological features taking into account clinical data. To evaluate the severity of ALC we used Child-Pugh scale and CLIF-C-ACLF scale (Chronic Lіver Failure-Consortium-Acute-on-Chronic Liver Failure), which counts the number of decompensated organs/systems (liver, kidneys, brain, coagulation, blood circulation , lungs). The diagnosis of HRS was based on the criteria of the International Ascites Club (2005) and Doppler examination. The level of HIF-1α was determined by the enzyme-linked immunosorbent assay (ELISA) with monoclonal antibodies. In addition to the clinical and laboratory criteria for HRS in patients of group 2, we observed the changes in renal dopplerography except Vmax of the left and right RA, which was a significant difference compared to group 1. Group 2 showed a significant decrease in Vmean, Vmin in the right and left renal arteries (RA), and also increase of RI and PI in the right and left RA. Only the values of Vmax in the right and left RA did not have statistically significant changes. Analysis of obtained results have revealed that level of HIF-1α in the most severe category of patients in group 2, with stage IV by CLIF-C-ACLF scale, was almost three times higher than that of a similar category in group 1, with Child-Pugh C class, and was 30±7,9 ng/ml. Dramatic increase of HIF-1α level in the group 2 patients with the IV stage by CLIF-C-ACLF scale confirms the severe tissue hypoxia, which is caused by a significant deterioration of the splanchnic blood flow and spasm of renal vessels at the HRS. The analysis of correlations has revealed the relationship between HIF-1α level and hepatic-renal failure indicators in the examined ALC patients. There was no correlation between HIF-1α and bilirubin level, between HIF-1α and INR (p>0.05). The strong direct correlation was detected between HIF-1α level and Child-Pugh ALC class, between HIF-1α level and CLIF-C-ACLF ALC stage; moderate direct correlation - between HIF-1α and dopamine, creatinine, oxygen saturation, resistive and pulsating indices of both RA; weak direct correlation - between HIF-1α level and the degree of hepatic encephalopathy (presumably because of the greater role of toxins than actually hypoxia in it’s pathogenesis) and moderate inverse correlation between HIF-1α and doppler values of the average velocity of the blood in the left and right RA. Thereby, HIF-1α levels closely correlate with the indicators of hepatic and renal failure in the patients with ALC+HRS, which allows to use it as an indicator for comprehensive diagnosis of this disease.
    Tags hepatorenal syndrome (HRS), alcoholic liver cirrhosis (ALC), hypoxia-inducible factor, hepatic renal failure
    • Burnstock G, Boeynaems JM. Purinergic signalling and immune cells. Purinergic Signal. 2014; 10: 529–564.
    • Campbell EL, Bruyninckx WJ, Kelly CJ, et al. Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity. 2014; 40: 66–77.
    • Colli A, Fraquelli V, Pometta R, et al. Renovascular impedance and esophageal varices in patients with child-pugh class a cirrhosis. Radiol. 2011; 219(3): 712–715.
    • Eltzschig HK, Bratton DL, Colgan SP. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov. 2014; 13: 852–869.
    • Francoz C, Glotz D, Moreau R, et al. The evaluation of renal function and disease in patients with cirrhosis. J of Hepatol. 2011; 52(4): 605–613.
    • Guo X, Li D, Chen Y, et al. SNP rs2057482 in HIF1A gene predicts clinical outcome of aggressive hepatocellular carcinoma patients after surgery. Sci Rep. 2015; 5: 11846.
    • Idzko M, Ferrari D, Eltzschig HK. Nucleotide signalling during inflammation. Nature. 2014; 509: 310–317.
    • Jalan R, Saliba F, Pavesi M, et al. CANONIC study investigators of the EASL-CLIF Consortium. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J. Hepatol. 2014; 61(5): 1038–1047.
    • Karakike E, Moreno C, Gustot T. Infections in severe alcoholic hepatitis. Ann Gastroenterol. 2017; 30(2): 152-160.
    • Liu LP, Hu BG, Ye C, et al. HBx mutants differentially affect the activation of hypoxia-inducible factor-1alpha in hepatocellular carcinoma. Br J Cancer. 2014; 110: 1066–1073.
    • Liu Y, Liu Y, Yan X, et al. HIFs enhance the migratory and neoplastic capacities of hepatocellular carcinoma cells by promoting EMT. Tumour Biol. 2014; 35: 8103–8114.
    • Mehta G, Mookerjee R, Sharma V, Jalan R. Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure. Liver Int. 2014; 35(3): 724–734.
    • Roychowdhury S, Chiang DJ, McMullen MR, Nagy LE. Moderate, chronic ethanol feeding exacerbates carbon-tetrachloride-induced hepatic fibrosis via hepatocyte-specific hypoxia inducible factor 1alpha. Pharmacol Res Perspect. 2014; 2: e00061..
    • Suzuki T, Shinjo S, Arai T, Kanai M, Goda N. Hypoxia and fatty liver. World J Gastroenterol. 2014; 20: 15087–15097.
    • Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature. 2013; 496: 238–242.
    Publication of the article «World of Medicine and Biology» №3(65), 2018 year, 023-028 pages, index UDK 616.36-06:616.61]-008.64:616.149-008.341.1
    DOI 10.26724/2079-8334-2018-3-65-23-28