Changes in cellular proliferation and plasma products are associated with liver failure

Abstract

AIMTo study the differences in immune response and cytokine profile between acute liver failure and self-limited acute hepatitis.METHODSForty-six patients with self-limited acute hepatitis (AH), sixteen patients with acute liver failure (ALF), and twenty-two healthy subjects were involved in this study. The inflammatory and anti-inflammatory products in plasma samples were quantified using commercial enzyme-linked immunoassays and quantitative real-time PCR. The cellular immune responses were measured by proliferation assay using flow cytometry. The groups were divided into viral- and non-viral-induced self-limited AH and ALF. Thus, we worked with five groups: Hepatitis A virus (HAV)-induced self-limited acute hepatitis (HAV-AH), HAV-induced ALF (HAV-ALF), non-viral-induced self-limited acute hepatitis (non-viral AH), non-viral-induced acute liver failure (non-viral ALF), and healthy subjects (HC). Comparisons among HAV and non-viral-induced AH and ALF were performed.RESULTSThe levels of mitochondrial DNA (mtDNA) and the cytokines investigated [interleukin (IL)-6, IL-8, IL-10, interferon gamma, and tumor necrosis factor] were significantly increased in ALF patients, independently of etiology (P < 0.05). High plasma mtDNA and IL-10 were the best markers associated with ALF [mtDNA: OR = 320.5 (95%CI: 14.42-7123.33), P < 0.0001; and IL-10: OR = 18.8 (95%CI: 1.38-257.94), P = 0.028] and death [mtDNA: OR = 12.1 (95%CI: 2.57-57.07), P = 0.002; and IL-10: OR = 8.01 (95%CI: 1.26-50.97), P = 0.027]. In the cellular proliferation assay, NKbright, NKT and regulatory T cells (TReg) predominated in virus-specific stimulation in HAV-induced ALF patients with an anergic behavior in the cellular response to mitotic stimulation. Therefore, in non-viral-induced ALF, anergic behavior of activated T cells was not observed after mitotic stimulation, as expected and as described by the literature.CONCLUSIONmtDNA and IL-10 may be predictors of ALF and death. TReg cells are involved in immunological disturbance in HAV-induced ALF.

In vivo evidence for extracellular DNA trap formation

“…However, these structures containing mtDNA are able to provoke a rapid type I interferon (IFN-I) production in peripheral blood mononuclear cells, suggesting that lymphocytes and monocytes use mtDNA as a rapid signaling molecule to communicate danger 21 . Interestingly, mtDNA being enriched in unmethylated cytosine-phosphate-guanine (CpG) dinucleotide motifs similar to bacterial and viral DNA could provoke IL-10 secretion 21,22 , and transforming growth factor beta (TGF-β) release 23 . IL-10 is known to be an anti-inflammatory cytokine 24 , and TGF-β mediates the suppression of macrophage-directed inflammation, reducing TNF-α release 25 .…”

Complement System as a Target for Therapies to Control Liver Regeneration/Damage in Acute Liver Failure Induced by Viral Hepatitis

“…Inclusion criteria included the presence of coagulopathy (INR ≥ 1.5) and encephalopathy score above II, according to O'Grady et al [ 21 ] and as described previously [ 7 , 22 , 23 ]. Clinical details of the study population are shown in Table 1 .…”

“…ALF can be induced by viral infections and toxicity promoted by drug abuse or alcoholism. In Brazil, viral infections are responsible for the majority of ALF cases, including viral hepatitis viruses such as hepatitis A virus (HAV) and hepatitis B virus (HBV), as well as coinfections related to hepatitis C virus (HCV), HIV, Epstein-Barr virus, and CMV [ 5 – 7 ].…”

Decreased activity of plasma ADAMTS13 are related to enhanced cytokinemia and endotoxemia in patients with acute liver failure

“…High serum proinflammatory cytokines levels have been reported (21,22) and are related to the development of multiorgan dysfunction (23). Pro-inflammatory cytokines are also involved in the systemic inflammatory response syndrome pathophysiology (24).…”

“…ALF is characterized by massive necroinflammation of liver tissue and is associated with high mortality (21,22). High serum proinflammatory cytokines levels have been reported (21,22) and are related to the development of multiorgan dysfunction (23).…”