High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B

Int J Cancer. 2009 Jun 15;124(12):2766-70. doi: 10.1002/ijc.24281.


Increased interleukin-6 (IL-6) production is implicated in the pathogenesis of hepatocellular carcinoma (HCC) in animal models. Although previous studies showed that HCC patients had higher serum IL-6 level at the time of diagnosis, it is unclear if the cytokine contributes to the development of HCC or is just a reaction to cancer. To address this question, we performed a nested case-control study. Consecutive chronic hepatitis B patients were recruited from 1997 to 2000 and followed till 2008. Profiling of 27 cytokines, chemokines and growth factors was performed at baseline, date of peak alanine aminotransferase (ALT) level and the last visit. Thirty-seven patients developed HCC at a median follow-up of 62 months (interquartile range: 41-110). Serum IL-6 was higher in patients with HCC than controls both during peak ALT and at the last visit (both p = 0.02). Patients with IL-6 above 7 pg/ml during peak ALT had increased risk of HCC or death (adjusted hazard ratio 3.0; 95% confidence interval 1.2, 7.8; p = 0.02). The sensitivity, specificity, positive and negative predictive values of this cutoff to predict future HCC development were 70%, 73%, 72% and 71%, respectively. Combination of IL-6 and AFP improved the sensitivity in diagnosing HCC or predicting future HCC development. In conclusion, high serum IL-6 level predates the development of HCC in chronic hepatitis B patients, and has moderate accuracy in predicting future cancer. This may assist clinicians in selecting high-risk patients for HCC surveillance program.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / blood*
  • Carcinoma, Hepatocellular / blood*
  • Carcinoma, Hepatocellular / virology
  • Case-Control Studies
  • False Positive Reactions
  • Female
  • Hepatitis B virus / isolation & purification*
  • Hepatitis B, Chronic / blood*
  • Hepatitis B, Chronic / virology
  • Humans
  • Interleukin-6 / blood*
  • Liver Neoplasms / blood*
  • Liver Neoplasms / virology
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Predictive Value of Tests
  • Prognosis
  • Risk Factors
  • Sensitivity and Specificity


  • Biomarkers, Tumor
  • Interleukin-6