The role of exercise in limiting progression from liver inflammation and fibrosis to cirrhosis and carcinoma: a systematic review of human and animal studies

Liver cancer is the sixth most common cancer worldwide (excluding non-melanoma skin cancer), with approximately 840,000 cases diagnosed in 2018 (Bray et al). It is the fourth most common cause of cancer mortality, resulting in over 780,000 deaths (Bray et al). The primary risk factor for liver cancer is chronic hepatitis B, the prevalence of which is highest in the WHO Western Pacific and African regions.( https://www.who.int/news-room/fact-sheets/detail/hepatitis-b) Wide-spread vaccination against hepatitis B during childhood has been achieved in many countries around the world, and liver cancer rates are expected to decline as this cohort reach middle age (Bray et al).

In high income countries liver cancer is two to three times more common in males, and there has been an upward trend in incidence in recent decades, largely driven by the obesity epidemic (Bray et al; AIHW Cancer in Australia). The World Cancer Research Fund/American Institute for Cancer Research Continuous Update Project on liver cancer concludes that, in addition to obesity, there is strong evidence that consuming three or more alcoholic drinks a day or foods contaminated by aflatoxins increases risk, and that drinking coffee decreases risk (WCRF CUP, 2018). The report also concludes that there is consistent evidence that physical activity decreases liver cancer risk; however the heterogeneity of exposure assessment across studies resulted in a conclusion of ‘limited evidence’.

The Physical Activity Collaboration of the National Cancer Institute (NCI) Cohort Consortium published a pooled analysis of data from 1.44 million adults from the U.S. and Europe. This study addressed some of the methodological limitations of previous reviews and meta-analyses by harmonising exposure data. This analysis found that a higher (90th percentile) vs lower (10th percentile) duration of leisure-time physical activity was associated with a decreased the risk of liver cancer (HR=0.73, 95% CI: 0.55-0.98) (Moore et al, 2016). A dose-response analysis from this Consortium was conducted on approximately half the sample, for whom detailed physical activity information (MET hrs/wk) was available. Engagement in 7.5 - 15 MET hs/week of leisure time physical activity (equivalent to the recommended 150 to 300 minutes of moderate-intensity activity; 2018 US Physical Activity Guidelines; Australian guidelines) versus none was associated with a 18% to 27% lower risk within this range. The dose-response was curvilinear, showing a clear trend up until 15 MET hrs/wk, but no evidence of increased risk reduction beyond that point (Matthews et al, 2020).

Whilst the epidemiological evidence consistently suggests a protective effect of physical activity against liver cancer, this evidence is not yet considered conclusive. Mechanistic evidence (e.g. from human and animal studies, or human biomarker studies) can provide evidence of biological plausibility, and thus help to elucidate whether these epidemiological associations are causal, or due to confounding or other biases. In the case of liver cancer, understanding how physical activity effects intermediate biological processes may also provide insight into the best ways to alter exposures for disease prevention.

The aim of this study is to undertake a systematic review to combine mechanistic evidence from human and animal studies on the effect of physical activity on progressive stages of chronic liver disease. The results will provide a robust critique of whether it is biologically plausible that physical activity can prevent the development of liver cancer.