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

Boris J.B. Beudeker, Zwier M.A. Groothuismink, Annemiek A. van der Eijk, Jose D. Debes, Andre Boonstra

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Article number4900
Issue number19
StatePublished - Oct 2022

Bibliographical note

Funding Information:
This research was funded by the European-Latin American ESCALON consortium, funded by the EU Horizon 2020 program, project number 825510 and was sponsored by the Foundation for Liver and Gastrointestinal Research (SLO). Financial support was provided by TKI Health Holland (project number EMCLSH-19-019) and Fujirebio Europe. Partially funded by Robert Wood Johnson Foundation, AFMDP and University of Minnesota AIRP to JDD. The APC was funded by the Foundation for Liver and Gastrointestinal Research (SLO). All authors: No reported conflicts of interest.

Publisher Copyright:
© 2022 by the authors.


  • cirrhosis
  • cytokines
  • liver cancer
  • liver disease etiology


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