Introduction Acute on Chronic Liver Failure (ACLF) is characterised by progressive multi-organ failure and an unacceptably high mortality. This distinguishes it clinically and prognostically from Acute Decompensation (AD) of cirrhosis. We have previously demonstrated elevated markers of apoptosis in a rat model of ACLF and a small cohort of human ACLF patients. The aim of this study is to measure plasma levels of caspase-cleaved keratin 18 (cK18), a product of apoptosis, in a well-characterised cohort of subjects with progressive degrees of liver injury, with the aim of confirming our observation of elevated apoptosis in decompensated liver disease and establishing the utility of cK18 as a biomarker of severity of liver injury. Additionally, the correlation of cK18 levels with prognostic clinical scores will be assessed.
Methods 78 patients with acutely decompensated liver disease were enrolled and divided into AD (n = 25), ACLF1 (n = 25) and ACLF2 (n = 28) using the CLIF-C ACLF and AD scores. Additionally, 27 stable compensated cirrhotic patients (SC) and 12 healthy volunteers were recruited. Plasma cK18 levels were measured by enzyme linked immunosorbent assay (ELISA) using the M30 antibody for detection. Results were analysed using Prism 6 Software (GraphPad). As the data were not normally distributed, a non-parametric test (Mann-Whitney-Wilcoxon test) was used. Spearman rank test was used for correlation studies.
Results cK18 levels rose progressively with the severity of liver injury (median values and interquartile range): healthy 100.5 U/L (IR 76.97–144.7), stable cirrhosis 155.5 U/L (IR 102.5–269.8), AD 341.9 U/L (IR 102.5–489.9), ACLF1 603.6 U/L (IR 342.4–1046) and ACLF2 1028 U/L (IR 513.6–2641), respectively). Statistically significant differences were observed between healthy controls vs SC (p = 0.0232), SC vs AD (p = 0.0054), AD vs ACLF1 and 2 (p = 0.0054 and 0.0006 respectively), ACLF1 and 2 (0.068) (Figure 1). Additionally, cK18 values correlated with model for end-stage liver disease (MELD) score, (r = 0.48, p < 0.0001), MELD Sodium (r = 0.44, p = 0.0001), sepsis-related organ failure (SOFA) (r = 0.39, p = 0.0021) and Childs-Pugh (r = 0.2562, p = 0.0323) scores.
Conclusion Our data clearly demonstrates a statistically significant, progressive increase in circulating cK18 and apoptosis with increasing clinical severity of decompensated liver disease. These values also correlated with major prognostic scores used in current practice. cK18 is therefore a promising biomarker of severity of liver injury and further studies are needed to assess its role both as a prognostic tool and in monitoring therapeutic response.
Disclosure of Interest None Declared