Circulating Cytokines Reflect the Etiology-Specific Immune Environment in Cirrhosis and HCC

Abstract

Background and Aims: Chronic liver disease—from any etiology—can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The progression of liver cirrhosis to the end stages of disease is influenced by a variety of factors, including inflammatory cytokines. We pursued a study of cytokine-mediated inflammatory responses in hepatitis B (HBV), hepatitis C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) patients with liver cirrhosis. Methods: Immune profiles were determined through the serum multiplex profiling of >100 cytokines in a 188 cirrhotic patients, 35 healthy controls and 196 early-stage HCC patients. Results: Patients with liver cirrhosis exhibited a vast upregulation of proinflammatory cytokines (p < 0.0001), including those with pro-oncogenic features, when compared to healthy individuals. In contrast to prevailing assumptions, each etiological cause of cirrhosis exhibited a unique cytokine profile in blood. Regardless of antiviral therapy, HBV cirrhosis patients had the largest number of upregulated proinflammatory mediators, compared to HCV, ALD and NAFLD (p < 0.0001). To further evaluate the etiology-dependent modulation of cytokine response in relation to liver cancer, we studied cytokine profiles in early-stage HCC patients strictly stratified by underlying liver disease. We observed unique sets of differentially expressed cytokines in each cohort of early-stage HCC patients of different cirrhosis etiologies. Conclusions: Our findings, therefore, underscore the importance of stratification by the etiological cause of liver cirrhosis in immune-based studies.

Serum CXCL5 Detects Early Hepatocellular Carcinoma and Indicates Tumor Progression

“…Previous reports pointed at specific circulating cytokine profiles that may be indicative for the presence of HCC at a very early stage of its development, suggesting a potential role for cytokines as diagnostic biomarkers [ 11 , 12 , 13 , 14 ]. Accordingly, we evaluated whether the formerly identified HCC-discriminant chemokines were robust in early HCC stages, defined as BCLC 0 (very early stage) and BCLC A (early stage), when compared to sera of HCC-free cirrhotic controls.…”

“…As previous reports emphasized the impact of underlying etiology on the circulating cytokine profiles [ 12 , 14 ], we compared the chemokine composition in patients with or without HCC according to etiology (ALD, NAFLD, viral, cholestatic/autoimmune, others). Indeed, there was a common HCC-associated chemokine profile across underlying etiologies.…”

“…They are known drivers of liver cirrhosis and HCC development as well as progression. In addition to ubiquitous pro-fibrogenic and pro-oncogenic mechanisms, etiology-specific chemokine profiles also appear to play a role [ 14 ]. In this context, chemokines represent an important tool to gain new insights into the mechanisms of hepatocarcinogenesis.…”

“…Nevertheless, no common panel could be identified. A recent study illuminates the impact of etiology on circulating immune mediators [ 14 ]. Unlike previous reports, we were able to identify CXCL5, CXCL9, and CXCL10 as universal HCC markers independent from underlying etiology.…”

“…However, it remained unclear if those HCC-discriminant biomarkers also add value in other viral etiologies that are viral, as well as if they correlate with HCC progression. Most recently, a pilot study found etiology-specific cytokine panels for the detection of early HCC [ 14 ]. Interestingly, no common HCC-discriminant chemokines shared between all etiologies could be identified, although former data indicate common hepatocarcinogenetic chemokine pathways [ 15 ].…”