Inflammatory status in human hepatic cirrhosis

Abstract

This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.

Keywords: Alcohol; Cirrhosis; Cytokines; Hepatitis C virus; Inflammation; Liver; Macrophages.

Figure 1

Progression and complications in human liver cirrhosis. The evolution of the liver cirrhotic disease, according to the clinical criteria, mortality rate, pathology characteristic, HVPG, signs and the presence of ascites, is shown. Stage 1 in a compensated cirrhosis differs from stage 2 in the appearance of esophageal varices as well as the increase of portal pressure. Stage 3 is characterized by the presence of ascites and/or esophageal varices. If variceal hemorrhage occurs, cirrhosis gets to stage 4. Cirrhosis could be a reversible process in the earlier stages, as indicated with the orange arrows. HVPG: Hepatic venous pressure gradient; SBP: Spontaneous bacterial peritonitis.

Figure 2

Inflammatory status in alcohol- and hepatitis C virus-induced human liver cirrhosis. The direct injury mediated by the hepatitis C virus infection on the liver (1) and by the toxicity of alcohol simultaneously on the liver (1) and GALT (2), produces an inflammatory response that is spread in the systemic blood circulation. This induces increases in translocation of bacterial products in the earlier stages, and of alive bacteria in advanced stages, which trigger a local inflammatory response within the GALT that further augments intestinal permeability, perpetuating BT. Local abdominal inflammation promotes and maintains systemic inflammation, that would close the loop, aggravating the situation with the progression of the disease, leading to the exhaustion of the immune system defenses. The differences in the inflammatory status between both etiologies are indicated in the figure. HCV: Hepatitis C virus; GALT: Gut associated lymphoid tissue; BT: Bacterial translocation; TNF: Tumor necrosis factor; IL: Interleukin; ALC: Alcohol; Th: T helper; pERK: Phosphorylated extracellular signal-regulated kinase.