Serum keratin‐18 fragments as cell death biomarker in association with disease progression and prognosis in hepatitis B virus‐related cirrhosis

Abstract

Extensive hepatocyte death leads to hepatic inflammation and contributes to systemic inflammation in decompensated cirrhosis. We aimed to investigate the prognostic value of serum cell death markers in patients with hepatitis B virus (HBV)‐related acute decompensation (AD) of cirrhosis with and without acute‐on‐chronic liver failure (ACLF). We studied two cohorts—cohort 1: 201 outpatients with stable chronic hepatitis B (49 cirrhosis); cohort 2: 232 inpatients with HBV‐related cirrhosis admitted for AD. Cell death was determined with serum keratin‐18 (K18) for total death and serum caspase‐cleaved‐K18 (cK18) for apoptosis. Survival analyses were performed using competing risk method. We found that serum K18 and cK18 were significantly (P < 0.001) higher in patients from cohort 2 than those from cohort 1. Among cohort 2, ACLF patients had significantly (P < 0.001) increased K18 and cK18 comparing to those without ACLF. Increased K18 and cK18 were mainly attributed to HBV flare and were associated with liver and coagulation failure. HBV‐AD patients without ACLF who admitted with upper tertile of K18 or cK18 were at higher risk of developing ACLF during follow‐up. Baseline serum K18 or cK18 was significantly associated with transplant‐free 90‐day survival independent of leucocytes, HBV DNA, bacterial infection, encephalopathy and severity scores. The combination of cell death biomarkers significantly improved the prognostic value of the currently established prognostic scores. The reduction of cell death level after standard treatment was associated with increased short‐term survival. In conclusion, measurements of serum K18 or cK18 in HBV decompensated cirrhosis are a promising tool for predicting ACLF and risk stratification of short‐term outcome.

The impact of HBV flare on the outcome of HBV‐related decompensated cirrhosis patients with bacterial infection

“…We have recently provided evidence that the high level of cell death in HBV decompensated cirrhosis patients is mostly due the flare‐up of hepatitis B and leads to poor short‐term outcome . Recognizing that the presence of HBV flare could have potential negative impacts on patients with decompensated HBV cirrhosis, it is imperative that every effort should be made to assess patients with HBV, and provide access to anti‐HBV treatment as appropriate.…”

Acute-on-Chronic Liver Failure: Pathophysiological Mechanisms and Management

“…Cell death mechanisms including apoptotic pathways influence the recovery of HBV-related ACLF ( 28 ). Recently, it has been identified that caspase-cleaved keratin-18 (ck18) can predict the progression of acute decompensation to ACLF ( 29 ). Biomarkers including caspase-cleaved neoepitope of cytokeratin-18 and intact cytokeratin-18 variant recognized as M30 and M65, respectively have been investigated in ACLF.…”

Circulating Receptor-Interacting Protein Kinase 3 Are Increased in HBV Patients With Acute-on-Chronic Liver Failure and Are Associated With Clinical Outcome

“…It has been reported that cell death in large numbers is a core event in the progression of liver diseases (Malhi et al, 2010;Cao et al, 2016). Development of CHB is mainly due to persistent hepatic inflammation and hepatocyte death, including apoptosis and necrosis, which ultimately leads to liver failure (Luedde et al, 2014;Cao et al, 2015Cao et al, , 2019a. More recently a caspase-independent mode of programmed cell death, termed necroptosis, has been shown to be similar to apoptosis because of the tight regulation by distinct molecules, but it is also characterized by morphological features of necrosis (Declercq et al, 2009;He et al, 2009;Christofferson and Yuan, 2010).…”