Hepatocellular and extrahepatic cancers in non-alcoholic fatty liver disease: A systematic review and meta-analysis

Eur J Cancer. 2022 Sep;173:250-262. doi: 10.1016/j.ejca.2022.06.051. Epub 2022 Aug 6.


Background: Hepatocellular (HCC) and extrahepatic cancers have been associated with non-alcoholic fatty liver disease (NAFLD); however, the extent and nature of these relationships remain unclear. We aimed to estimate the absolute incidence rates of these cancers in adults with NAFLD with respect to key demographic and clinical factors.

Methods: We searched PubMed, Embase, Cochrane Library and Web of Science databases for studies reporting the incidence rates of any cancer in adults with NAFLD from inception to 31 August 2020. The main meta-analysis outcomes were pooled incidences of cancers in NAFLD using random-effects modelling. Subgroup analyses examined the effects of NAFLD disease stage.

Findings: In total, 64 studies were eligible for analysis of HCC and extrahepatic cancer incidence including 625,984 and 41,027 patients, respectively. The pooled HCC incidence rate was 1.25 per 1000 person-years (95% CI 1.01 to 1.49; I2 = 94.8%). In patients with NAFLD with advanced liver fibrosis or cirrhosis, the HCC incidence rate was 14.46 per 1000 person-years (95% CI 10.89 to 18.04; I2 = 91.3%). The pooled extrahepatic cancer incidence rate was 10.58 per 1000 person-years (95% CI 8.14 to 13.02; I2 = 97.1%). The most frequently occurring extrahepatic cancers were uterine, breast, prostate, colorectal, and lung. Extrahepatic cancer incidence rates were not higher in patients with NAFLD with advanced liver fibrosis or cirrhosis.

Interpretation: The rate of HCC development in patients with NAFLD who have progressed to advanced liver fibrosis or cirrhosis supports current HCC surveillance recommendations targeted for this group. Extrahepatic cancers are over eight-fold more frequent than HCC in NAFLD and not associated with liver fibrosis stage. As the global prevalence of NAFLD is approximately 25% and increasing, these findings support a focus on its prevention and the early detection of cancer in adults with NAFLD.

Keywords: Cancer incidence; Cirrhosis; Liver fibrosis; NAFLD; NASH.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Carcinoma, Hepatocellular* / diagnosis
  • Fibrosis
  • Humans
  • Incidence
  • Liver Cirrhosis
  • Liver Neoplasms* / diagnosis
  • Male
  • Non-alcoholic Fatty Liver Disease* / complications
  • Non-alcoholic Fatty Liver Disease* / diagnosis
  • Non-alcoholic Fatty Liver Disease* / epidemiology
  • Risk Factors