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With great interest, we read the meta-analysis of observational cohort studies by Mantovani et al 1 providing significant evidence for an increased long-term risk of developing certain extrahepatic malignancies (especially gastrointestinal (GI), breast and gynaecological cancers) in patients with non-alcoholic fatty liver disease (NAFLD). Given the dramatically increasing global relevance of NAFLD, which currently has a prevalence of 25%,2–4 these findings are of immense clinical importance and may lead to prevention and screening algorithms.
In a retrospective cohort study, we identified 86 777 NAFLD patients (International Classification of Diseases (Version 10) (ICD-10): K75.8, K76.0) and a matched cohort of equal size without NAFLD from the Disease Analyzer database (IQVIA) compiling diagnoses and demographic data from general practitioners in Germany (online supplemental figure 1).5 Propensity score matching included the following variables: sex, age, index year, yearly consultation frequency, diabetes (ICD-10: E10–E14), obesity (ICD-10: E00–E07), thyroid gland disorders (ICD-10: E00–E07), chronic bronchitis and chronic obstructive pulmonary disease (COPD) (ICD-10: J42–J44) diagnoses. Mean age was 57.7 years. 46.4% of patients were female (online supplemental table 1). Incidence of extrahepatic malignancies was analysed as a function of NAFLD over a 10-year observation period using Poisson regression models. To counteract the problem of multiple comparisons, a corrected p<0.01 was considered statistically significant. Within 10 years of the index date, 14.9% and 12.9% of patients with or without NALFD were diagnosed with extrahepatic cancer, respectively (p<0.001, figure 1), which was confirmed in regression analysis (incidence rate ratio (IRR) 1.16, 95% CI 1.12 to 1.21, p<0.001). In terms of different cancer sites, a positive association was observed for skin cancer (IRR 1.40, 95% CI 1.29 to 1.51, p<0.001), digestive organ cancer excluding liver cancer (IRR 1.23, 95% CI 1.13 to 1.34, p<0.001), prostate cancer (IRR 1.21, 95% CI 1.09 to 1.34, p<0.001) as well as female breast cancer (IRR 1.18, 95% CI 1.06 to 1.32, p=0.003, figure 2). Moreover, we observed a strong trend towards an increased incidence of female genital organ cancer among NAFLD patients (IRR 1.28, 95% CI 1.06 to 1.56, p=0.012).
Supplemental material
Kaplan-Meier curves showing the time to cancer diagnosis in patients with and without NAFLD. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.
Association between NAFLD and the incidence of different cancer diagnoses (Poisson regression models).ICD-10, International Classification of Diseases (Version 10).
Our results add nicely to the study of Mantovani and colleagues1 and confirm a significant association between NAFLD and the incidence of extrahepatic malignancies such as GI, breast and gynaecological cancer in a large real-world cohort of NAFLD patients in Germany. In addition, we observed a positive association between NAFLD and skin as well as prostate cancer. Neither our analysis nor the study by Mantovani et al are able to provide insights on the putative mechanisms by which NAFLD may contribute to the development of cancers. In their study, Mantovani et al 1 pointed out that ‘[…] further research is needed to test the effects of NAFLD/obesity/diabetes’. In addition, time-varying covariates, such as changes in glucose tolerance status during the follow-up period (ie, negative impact of new-onset type 2 diabetes on the risk of cancer development), were not considered. Due to propensity score matching for comorbidities including obesity and diabetes mellitus type 2, we can show that NAFLD itself rather than shared metabolic risk factors represents a critical factor in cancer development. Obviously, the association between NAFLD and cancer development raises the question on the interdependence and crosstalk between the liver and other organs and it is likely that patients with NAFLD display subtle changes in the balance between procancer and anticancer chemokines, putatively leading to cancer.4 6 7
In summary, our analysis revealed a moderately increased incidence of skin, digestive organ, prostate and female breast cancer among NAFLD patients, corroborating the hypothesis of an increased risk of extrahepatic cancers in individuals with NAFLD. If these results were confirmed in further studies, we believe that the rapidly growing population of NAFLD patients worldwide should be encouraged to participate in regular cancer prevention and screening programmes.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants but was not approved by the 'Disease Analyser' database, used for analysis, contains anonymised electronic patient records. Patient data were analysed in aggregated form without individual data being available. An individual consent form was not obtained following national and European legislation. An individual consent form was not obtained following national and European legislation.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
TL and SHL are joint senior authors.
CR and KK are joint first authors.
Contributors SHL, KK and CR designed the study, KK performed statistical analyses and generated figures and tables, SHL and CR wrote the manuscript, TL and AM provided intellectual input, all authors agreed to the final version of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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.