Article Text

Download PDFPDF
Original research
Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies
  1. Alessandro Mantovani1,
  2. Graziana Petracca1,
  3. Giorgia Beatrice1,
  4. Alessandro Csermely1,
  5. Herbert Tilg2,
  6. Christopher D Byrne3,
  7. Giovanni Targher1
  1. 1 Endocrinology and Metabolism, Department of Medicine, University of Verona, Verona, Italy
  2. 2 Gastroenterology, Hepatology, Endocrinology and Metabolism, Department of Internal Medicine I, Medizinische Universität Innsbruck, Innsbruck, Austria
  3. 3 Nutrition and Metabolism, Faculty of Medicine, Southampton General Hospital, Southampton, UK
  1. Correspondence to Professor Giovanni Targher, Endocrinology and Metabolism, Department of Medicine, University of Verona, Verona 37129, Italy; giovanni.targher{at}


Objective We performed a meta-analysis of observational studies to quantify the magnitude of the association between non-alcoholic fatty liver disease (NAFLD) and risk of extrahepatic cancers.

Design We systematically searched PubMed, Scopus and Web of Science databases from the inception date to 30 December 2020 using predefined keywords to identify observational cohort studies conducted in individuals, in which NAFLD was diagnosed by imaging techniques or International Classification of Diseases codes. No studies with biopsy-proven NAFLD were available for the analysis. Meta-analysis was performed using random-effects modelling.

Results We included 10 cohort studies with 182 202 middle-aged individuals (24.8% with NAFLD) and 8485 incident cases of extrahepatic cancers at different sites over a median follow-up of 5.8 years. NAFLD was significantly associated with a nearly 1.5-fold to twofold increased risk of developing GI cancers (oesophagus, stomach, pancreas or colorectal cancers). Furthermore, NAFLD was associated with an approximately 1.2-fold to 1.5-fold increased risk of developing lung, breast, gynaecological or urinary system cancers. All risks were independent of age, sex, smoking, obesity, diabetes or other potential confounders. The overall heterogeneity for most of the primary pooled analyses was relatively low. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias.

Conclusion This large meta-analysis suggests that NAFLD is associated with a moderately increased long-term risk of developing extrahepatic cancers over a median of nearly 6 years (especially GI cancers, breast cancer and gynaecological cancers). Further research is required to decipher the complex link between NAFLD and cancer development.

  • fatty liver
  • meta-analysis
  • nonalcoholic steatohepatitis
  • cancer

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

View Full Text


  • Contributors Study concept and design: AM, GT. Acquisition of data: AM, GP, GB, AC, GT. Statistical analysis of data: AM. Analysis and interpretation of data: AM, GT. Drafting of the manuscript: AM, GT. Critical revision of the manuscript for important intellectual content: HT, CDB. All authors have read and approved the final version of the manuscript.

  • Funding GT is supported in part by grants from the University School of Medicine of Verona, Italy. CDB is supported in part by the Southampton National Institute for Health Research (NIHR) Biomedical Research Centre. HT is supported by the excellence initiative Centre for Promoting Vascular Health in the Ageing Community (VASCage), an R&D K-Centre (Competence Centers for Excellent Technologies (COMET) programme) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.