RESUMO
Acute-on-chronic liver failure (ACLF) is a condition characterized by acute decompensation of cirrhosis, associated with organ failure(s), and high short-term mortality. The microRNAs or miRNAs are small non-coding RNA molecules, stable in circulating samples such as biological fluids, and the difference in expression levels may indicate the presence, absence and/or stage of the disease. We analyzed here the miRNA profiling to identify potential diagnostic or prognostic biomarkers for ACLF. The major miRNAs discovered were validated in a cohort of patients with acute decompensation of cirrhosis grouped in no ACLF or ACLF according to EASL-CLIF definition. Relationship between serum miRNAs and variables associated with liver-damage and survival outcomes were verified to identify possible prognostic markers. Our results showed twenty altered miRNAs between no ACLF and ACLF patients, and twenty-seven in patients who died in 30 days compared with who survived. In validation phase, miR-223-3p and miR-25-3p were significantly altered in ACLF patients and in those who died in 30 days. miR-223-3p and miR-25-3p expression were associated with the lowest survival in 30 days. The decrease in miR-223-3p and miR-25-3p expression was associated with the presence of ACLF and poor prognosis. Of these, miR-25-3p was independently related to ACLF and 30-day mortality.
Assuntos
Insuficiência Hepática Crônica Agudizada/mortalidade , Biomarcadores/sangue , Cirrose Hepática/mortalidade , MicroRNAs/genética , Insuficiência Hepática Crônica Agudizada/sangue , Insuficiência Hepática Crônica Agudizada/genética , Insuficiência Hepática Crônica Agudizada/patologia , Estudos de Casos e Controles , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Prognóstico , Curva ROC , Índice de Gravidade de Doença , Taxa de SobrevidaRESUMO
Acute-on-chronic liver failure (ACLF) is a life-threatening condition characterized by a rapid deterioration of previously well-compensated chronic liver diseases. One of the main obstacles in ACLF is the lack of knowledge of the pathogenesis and specific broad-spectrum treatments. An excessive systemic inflammatory response has been proposed to explain the pathogenesis of ACLF; this hypothesis involves stellate cells, which are implicated in many liver homeostatic functions that include vitamin A storage, regulation of sinusoidal blood flow, local inflammation, maintenance of the hepatocyte phenotype and extracellular matrix remodeling. However, when there is damage to the liver, these cells are the main target of the inflammatory stimulus, as a result, the secretion of the extracellular matrix is altered. Activated hepatic stellate cells raise the survival of neutrophils by the stimulation of granulocytes colonies and macrophages, which exacerbates liver inflammation and promotes damage to hepatocytes. Elevation of pathogen-associated molecular patterns is related to liver damage by different pathophysiological mechanisms of decompensation, showing ballooning degeneration and cell death with a predominance of cholestatic infection. Moreover, patients with ACLF present a marked elevation of C-reactive protein together with an elevation of the leukocyte count. Chronic liver disease is a complex pathological state with a heterogeneous pathophysiology in which genetic factors of the host and external triggers interact and culminate in hepatic insufficiency. The better understanding of such interactions should lead to a better comprehension of the disease and to the discovery of new treatment targets that will make acute decompensations preventable and even decrease mortality.
Assuntos
Insuficiência Hepática Crônica Agudizada/patologia , Cirrose Hepática/patologia , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/genética , Proteína C-Reativa/análise , Citocinas/metabolismo , Hepatite B/complicações , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Fatores Imunológicos/metabolismo , Leucócitos/citologia , Leucócitos/imunologia , Leucócitos/metabolismo , Cirrose Hepática/complicações , Polimorfismo de Nucleotídeo ÚnicoRESUMO
INTRODUCTION AND OBJECTIVES: Hypoxia-inducible factor-1α is critically involved in the pathogenesis of liver diseases. Its inhibitor genistein attenuated D-galactosamine (D-GalN)-induced liver damage. However, the role of genistein in acute-on-chronic liver failure (ACLF) is unclear. The influence of genistein on reactive oxygen species (ROS) and hepatocyte functions were evaluated in a rat model of ACLF. MATERIAL AND METHODS: Genistein [20mg/ (kg. day)]/coenzyme Q10 [10mg/ (kg. day)]/lipoic acid [20mg/ (kg. day)] was administered via the intra-gastric route daily for 6 weeks as co-treatment to the rats in the experimental groups. Then, 100µg/kg LPS combined with 0.5g/kg D-GalN was injected intraperitoneally to attack the rats. RESULTS: Genistein significantly attenuated LPS/D-GalN-induced ACLF, characterized by ameliorated gross appearance and microscopic histopathology of liver, reduced AST level in serum, whereas increased levels of ATP, ADP/O, and respiratory control ratio (RCR) in mitochondria. Genistein suppressed necrosis and ROS production. CONCLUSION: These results suggested that genistein could protect against ACLF through inhibiting cellular ROS production and necrosis, improving RCR, and decreasing permeability transition pores in mitochondrial, which was similar as mitochondrial protective agent coenzyme Q10.
Assuntos
Insuficiência Hepática Crônica Agudizada/tratamento farmacológico , Genisteína/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Insuficiência Hepática Crônica Agudizada/metabolismo , Insuficiência Hepática Crônica Agudizada/patologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION AND AIM: Patients with acute on chronic liver failure (ACLF) have abnormal conventional coagulation tests- platelet count and international normalized ratio (INR). Thromboelastography (TEG) is a rapid, point-of-care assay, more comprehensive than platelet count and INR as it assesses for platelet adequacy (number and function), coagulation factors and clot retraction. The aim of the study was to evaluate the TEG parameters in patients with ACLF, chronic liver disease having acute decompensation (AD) and healthy subjects (HC). MATERIAL AND METHODS: TEG parameters were assessed in patients with ACLF and AD within 24 h of admission. Consecutive patients were included in the study over 12 months. Healthy subjects were recruited as controls. RESULTS: 179 patients were included- 68 ACLF, 53 AD and 58 HC. The mean values of INR in ACLF, AD and HC groups were 2.9 ± 1.4, 1.6 ± 0.4 and 1.1 ± 0.2; P < 0.001. Among TEG parameters - maximum amplitude (MA) was low in ACLF and AD patients as compared with HC (53.8 ± 15, 58.3 ± 13.9 mm and 67.2 ± 12.1 mm, respectively; P < 0.001). Lysis at 30 min (LY30) was high in ACLF patients, as compared to AD and HC (8.6 ± 14.1%, 5.0 ± 9.5% and 4.9 ± 9.8%, respectively; P = 0.060). There were no differences in r time, k time, and alpha angle between groups; normal in >90% patients. There was no difference in TEG parameters between different ACLF grades, whereas CCTs were more deranged with increasing grades of ACLF. CONCLUSION: Despite abnormal conventional coagulation tests, TEG parameters in ACLF patients are essentially normal, except reduced maximum amplitude. Future studies are needed to explore the utility of TEG in clinical management of ACLF patients.