Addressing Profiles of Systemic Inflammation Across the Different Clinical Phenotypes of Acutely Decompensated Cirrhosis

Abstract

Background: Patients with acutely decompensated cirrhosis (AD) may or may not develop acute-on-chronic liver failure (ACLF). ACLF is characterized by high-grade systemic inflammation, organ failures (OF) and high short-term mortality. Although patients with AD cirrhosis exhibit distinct clinical phenotypes at baseline, they have low short-term mortality, unless ACLF develops during follow-up. Because little is known about the association of profile of systemic inflammation with clinical phenotypes of patients with AD cirrhosis, we aimed to investigate a battery of markers of systemic inflammation in these patients. Methods: Upon hospital admission baseline plasma levels of 15 markers (cytokines, chemokines, and oxidized albumin) were measured in 40 healthy controls, 39 compensated cirrhosis, 342 AD cirrhosis, and 161 ACLF. According to EASL-CLIF criteria, AD cirrhosis was divided into three distinct clinical phenotypes (AD-1: Creatinine<1.5, no HE, no OF; AD-2: creatinine 1.5-2, and or HE grade I/II, no OF; AD-3: Creatinine<1.5, no HE, non-renal OF). Results: Most markers were slightly abnormal in compensated cirrhosis, but markedly increased in AD. Patients with ACLF exhibited the largest number of abnormal markers, indicating "full-blown" systemic inflammation (all markers). AD-patients exhibited distinct systemic inflammation profiles across three different clinical phenotypes. In each phenotype, activation of systemic inflammation was only partial (30% of the markers). Mortality related to each clinical AD-phenotype was significantly lower than mortality associated with ACLF (p < 0.0001 by gray test). Among AD-patients baseline systemic inflammation (especially IL-8, IL-6, IL-1ra, HNA2 independently associated) was more intense in those who had poor 28-day outcomes (ACLF, death) than those who did not experience these outcomes. Conclusions: Although AD-patients exhibit distinct profiles of systemic inflammation depending on their clinical phenotypes, all these patients have only partial activation of systemic inflammation. However, those with the most extended baseline systemic inflammation had the highest the risk of ACLF development and death.

Keywords: ACLF; acute decompensation; cirrhosis; organ dysfunction; organ failure; signature.

Figure 1

Heat-map highlighting medians of the levels of the different biomarkers of systemic inflammation in patients with acutely decompensated (AD) cirrhosis (with and without ACLF). The patients with “ACLF-free” AD cirrhosis were stratified into three phenotypes. The first phenotype (AD-1) included patients without any single OF, who have serum creatinine of <1.5 mg/dL and do not have hepatic encephalopathy. The second phenotype (AD-2) included patients with isolated renal dysfunction and/or cerebral dysfunction, i.e., without any associated single non-renal, non-cerebral OF. The third phenotype (AD-3) included patients with a single non-renal OF, without any kidney dysfunction. The magnitude of the levels is color-coded and the clustering for each marker with the rest of the markers is shown to the left of the heat-map.

Figure 2

Cumulative incidence function assessing survival in patients' groups analyzed in Figure 1. Mortality was significantly higher in patients with ACLF than in those without, irrespective of their phenotype, AD-1, AD-2, or AD-3 (Gray's test p < 0.0001). Mortality did not significantly differ between the three phenotypes AD-1, AD-2, and AD-3. For definitions of these phenotypes, see Figure 1 legend.

Figure 3

Heat-map showing the median levels of systemic inflammation markers at enrollment of patients with acutely decompensated cirrhosis who were free of ACLF. For the comparison, patients were divided into two groups according to their outcome (i.e., development of ACLF or not, during 28 days of follow-up). The magnitude of the levels is color-coded and the clustering for each marker with the rest of the markers is shown to the left of the heat-map.

Figure 4

Heat-map showing the median levels of systemic inflammation markers at enrollment of patients with acutely decompensated cirrhosis who were free of ACLF. For the comparison, patients were divided into two groups according to their outcome (i.e., occurrence of death or not during 90 days of follow-up). The magnitude of the levels is color-coded and the clustering for each marker with the rest of the markers is shown to the left of the heat-map.