Increases in prostaglandin E₂ (PGE₂) are found to promote inflammation in cirrhosis and increase the risk for mortality within 3 months while increases in interleukin 4 (IL4) is associated with increased survival, according to study results published in Clinical Gastroenterology and Hepatology.
In this study, researchers investigated the link between the inflammatory response in albumin-treated patients with cirrhosis and mortality within 3 months. Patients were recruited as part of the ATTIRE study, a randomized, controlled trial investigating feasibility of daily 20% human albumin solution (HAS) infusions to bind and catalyze PGE₂ to reduce infection in patients with acute decompensated cirrhosis. The ATTIRE study demonstrated that HAS infusion could restore serum albumin levels and immune function via antagonism of PGE₂, but did not examine clinical outcomes of treatment.
This follow-up study investigated inflammatory response by group, dividing patients who were survivors (n=45) vs nonsurvivors (n=27) at 3 months posttreatment. Plasma was collected from all patients on days 1 (baseline), 5, 10, and 15 (end of trial), and randomly selected plasma samples from both groups were analyzed to determine whether temporal inflammatory response throughout trial period differentiated survivors from nonsurvivors. Researchers also incubated monocyte-derived macrophages from healthy volunteers with plasma samples from the patients and measured activation after administration of lipopolysaccharide by measuring levels of secreted tumor necrosis factor and soluble mediators of inflammation.
Results revealed that plasma samples in patients who survived 30 days showed differences in inflammatory profiles as compared with nonsurvivors. Levels of IL4 increased in plasma collected on day 5 in survivors and was associated with survival at 3 months. Incubation studies showed that tumor necrosis factor alpha (TNF-α) production increased 2.6-fold between days 1 and 5 in cells incubated with nonsurvivor plasma (P <.001) compared with a 1.26-fold increase in those treated with survivor plasma (P >.05).
Inflammatory response phenotype differentiated survivors (gradual response) from nonsurvivors (rapid response) within the critical period of 1 to 6 days following treatment initiation. Baseline white cell count and C-reactive protein levels were similar in survivors and nonsurvivors, but white cell count levels were significantly higher in nonsurvivors (P =.029) by day 6. C-reactive protein levels were also higher in nonsurvivors, but the absolute difference was nonsignificant.
This study had several limitations. It was a single-arm study, therefore researchers were unable to compare findings with patients not treated with albumin, and the immune assay was developed to observe effects of plasma from patients with acute decompensation or acute-on-chronic-liver failure on macrophage function, rather than on primary cells.
Additionally, study patients mainly had alcohol-driven cirrhosis, which limits generalizability to patients with viral hepatitis or nonalcoholic steatohepatitis. Researchers also did not have sufficient samples to power a comparison of acute decompensation with acute-on-chronic-liver failure.
The study researchers concluded that the “inflammatory response trajectory may represent the critical determinant of clinical outcome,” with increases in PGE₂ driving inflammation within the first few days after hospitalization for acute decompensated cirrhosis, and that increased levels of IL4 within the first 5 days are associated with increased survival rates.
Becares N, Härmälä S, China L, et al. Immune regulatory mediators in plasma from patients with acute decompensation are associated with 3-month mortality [published online August 22, 2019]. Clin Gastroenterol Hepatol. doi: 10.1016/j.cgh.2019.08.036.