Systemic inflammation in alcoholic hepatitis: Mechanisms and consequences

Sandra Helinski

Ramon Bataller, MD, PhD
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, NC, USA.
Patients with heavy alcohol can develop a form of acute-on-chronic liver injury known as alcoholic hepatitis (AH). AH is one of the most deadliest diseases in clinical hepatology and bears a very high short-term mortality (20-40% at 3 months). The mechanisms leading to early death in patients with AH are largely unknown. Most attention has ben focused on intrahepatic inflammation. However, patients often show clinical criteria of systemic inflammatory response syndrome (SIRS), which could predispose to extrahepatic complications. We recently studied a large cohort of patients with biopsy-proven AH. More than one third of the patients developed multiorgan failure (MOF), being the kidney the most frequently affected organ. As expected, 90-day mortality was significantly higher in patients that developed MOF (62.1% vs. 3.8%). In the multivariate analysis, we found that the presence of SIRS at admission independently predicted the development of MOF and death. SIRS in the setting of AH may be related to a bacterial infection (sepsis) given that around 25% of patients with AH present with a bacterial infection at admission. However, many patients with AH show features of SIRS (e.g. leukocytosis, fever) without any identifiable bacterial infection. SIRS in these patients may be secondary to sterile inflammation of the liver, namely, an inflammatory response in the absence of a documented bacteria infection. In the liver of patients with AH, we found a marked overexpression of pro-inflammatory cytokines such as interleukin 8 and CCL20. The serum levels of both cytokines correlate with short-term mortality, suggesting that inflammatory mediators produced by the injured liver could play a role in the development of SIRS in patients with AH. Importantly, short-term mortality was similar in patients with infection-associated SIRS and SIRS without infection (39 % and 34 %, respectively) and was much higher than in patients without SIRS (14 %). Overall, the results from our study clearly showed that, regardless of the origin, the presence of SIRS at admission predisposes to the development of MOF and death. Maneuvers aimed at attenuating SIRS could be beneficial in this patient population.