Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention

Abstract

One quarter of the global population is estimated to have nonalcoholic fatty liver disease (NAFLD). The incidence of nonalcoholic steatohepatitis (NASH) is projected to increase by up to 56% in the next 10 years. NAFLD is already the fastest growing cause of hepatocellular carcinoma (HCC) in the USA, France and the UK. Globally, the prevalence of NAFLD-related HCC is likely to increase concomitantly with the growing obesity epidemic. The estimated annual incidence of HCC ranges from 0.5% to 2.6% among patients with NASH cirrhosis. The incidence of HCC among patients with non-cirrhotic NAFLD is lower, approximately 0.1 to 1.3 per 1,000 patient-years. Although the incidence of NAFLD-related HCC is lower than that of HCC of other aetiologies such as hepatitis C, more people have NAFLD than other liver diseases. Urgent measures that increase global awareness and tackle the metabolic risk factors are necessary to reduce the impending burden of NAFLD-related HCC. Emerging evidence indicates that reduced immune surveillance, increased gut inflammation and gut dysbiosis are potential key steps in tumorigenesis. In this Review, we discuss the global epidemiology, projections and risk factors for NAFLD-related HCC, and propose preventive strategies to tackle this growing problem.

Fig. 1 |. The estimated proportion of HCC attributed to NAFLD.

The proportion of hepatocellular carcinoma (HCC) attributable to nonalcoholic fatty liver disease (NAFLD) is high in the UK, India, Germany and the Middle East^{,–,,–,–,–,,,}.

Fig. 2 |. Pathogenesis and prevention of NAFLD-related HCC.

Insulin resistance and metabolic dysfunction promote the release of free fatty acids. β-Oxidation of free fatty acids induces the generation of reactive oxygen species (ROS) and the release of pro-inflammatory cytokines. Obesity further induces elevation of IL-6 and tumour necrosis factor (TNF), which promotes the development of chronic inflammation and activates STAT3, an oncogenic transcription factor that promotes tumour formation. The free fatty acid linoleic acid disrupts mitochondrial function and mediates selective ROS-mediated death of CD4⁺ T lymphocytes, reducing immune surveillance. IgA⁺ cells accumulate in nonalcoholic steatohepatitis (NASH), suppressing CD8⁺ T cells and accelerating hepatocarcinogenesis. Loss of protective gut bacteria and dysregulated farnesoid X receptor (FXR) signalling in nonalcoholic fatty liver disease (NAFLD) increases intestinal permeability and hepatic inflammation, hastening hepatocarcinogenesis. HCC, hepatocellular carcinoma.

Fig. 3 |. Proposed algorithm for HCC screening in NAFLD.

Hepatocellular carcinoma (HCC) screening might be considered in patients with nonalcoholic fatty liver disease (NAFLD) without cirrhosis when the results of at least two non-invasive tests are concordant and indicate the presence of advanced fibrosis. The adequacy of liver ultrasonography should be documented, and alternative imaging modalities should be considered when the ultrasound image quality is inadequate. AFP, α-fetoprotein.