Epidemiological investigations of liver cancer
:  Biomarkers, reproductive factors and modifiable risk factors

  • Kim Tu Tran

Student thesis: Doctoral ThesisDoctor of Philosophy


Liver cancer is one of the leading causes of deaths in many countries around the world therefore identifying new risk factors for liver cancer is a priority. The aim of this thesis was to investigate new risk factors for liver cancer and add new insights to previously identified liver cancer risk factors.

Excessive iron levels due to hemochromatosis have been shown to increase liver cancer risk. However, the association between elevated iron levels and liver cancer risk in people not predisposed to hemochromatosis has not been well studied. We conducted a systematic review and meta-analysis to synthesize evidence from previous cohort and nested-case control studies. We found some evidence of an increased risk of primary liver cancer with high iron levels as measured by serum ferritin or serum iron.

Proton pump inhibitors and histamine-2 receptor antagonists are commonly used. Proton pump inhibitors have been shown to promote liver cancer in rats; however, only one study has examined the association in humans. We conducted the first study on the use of proton pump inhibitors and histamine-2 receptor antagonist in relation to liver cancer risk. We conducted a nested case-control study using Primary Care Clinical Informatics Unit (PCCIU) and a cohort study using UK Biobank. We found an increased risk of liver cancer, especially of intrahepatic bile duct carcinoma in proton pump inhibitors users but not in histamine-2 receptor antagonists users. This novel association requires further research to determine whether it is causal or reflects confounding. Using these study designs in PCCIU and UK Biobank, we also explored the relationship between statin use and liver cancer risk. We found a consistent decreased risk of liver cancer in statin users, specifically for hepatocellular carcinoma, even after adjusting for high cholesterol and chronic liver disease.

Previous studies have shown an inverse association between coffee consumption and liver cancer, but have not investigated coffee by type. We examined the role of different types of coffee on liver cancer risk using the UK Biobank. Findings showed that any type of coffee (caffeinated, decaffeinated, or instant coffee) was similarly associated with a reduced risk of liver cancer, specifically for hepatocellular carcinoma. Future studies should further investigate which components of coffee may have anti-carcinogenetic properties. Another cohort study based on China Kadoorie Biobank investigated the relationship between household air pollution, from cooking and heating, and the risk of liver cancer mortality. We found use of coal and smoke in the household were associated with an increased risk of liver cancer mortality.

Consistent reports of a lower risk of liver cancer in women compared to men suggest female sex hormones may be protective. We conducted a cohort study in the China Kadoorie Biobank exploring a range of reproductive factors in relation to liver cancer mortality. Among reproductive factors, only menopausal status was found to increase the risk of liver cancer mortality. We also investigated circulating sex hormones and liver cancer risk in men and women from UK Biobank cohort. Our findings showed that men who had higher levels of testosterone and SHBG had higher risk of liver cancer, specifically of HCC, but this association was not found in women.

In summary, the current thesis has contributed to the literature by identifying new risk factors for liver cancer and clarifying previously identified associations. Future studies are required to replicate the novel associations observed in this thesis.
Date of AwardDec 2020
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsVietnam International Education Development
SupervisorChristopher Cardwell (Supervisor), Helen Coleman (Supervisor) & Blánaid Hicks (Supervisor)


  • liver cancer
  • hepatocellular carcinoma
  • intrahepatic bile duct carcinoma
  • cohort study
  • nested-case control study
  • UK Biobank
  • PCCIU database
  • China Kadoorie Biobank
  • iron
  • proton-pump inhibitors
  • statins
  • coffee
  • household air pollution
  • reproductive factors
  • sex hormones
  • epidemiology
  • risk factors

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