NAFLD-Related Hepatocarcinoma: The Malignant Side of Metabolic Syndrome

Abstract

Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the second leading cause of cancer-related mortality. HCC typically arises within a cirrhotic liver, but in about 20% of cases occurs in absence of cirrhosis. Among non-cirrhotic risk factors, non-alcoholic fatty liver disease (NAFLD) currently represents the most important emerging cause of HCC in developed countries. It has been estimated that annual incidence of HCC among patients with non-cirrhotic NAFLD is approximately 0.1-1.3 per 1000 patients/year and ranges from 0.5% to 2.6% among patients with non-alcoholic steatohepatitis (NASH) cirrhosis. However, only a few clinical trials enrolling HCC patients actually distinguished NAFLD/NASH-related cases from other non-cirrhotic causes and therefore evidence is still lacking in this subset of patients. This review aims to describe the biology underpinning NAFLD development, to investigate the main molecular pathways involved in its progression to NASH and HCC and to describe how different pathogenetic mechanisms underlying the onset of HCC can have an impact in clinical practice. We hereby also provide an overview of current HCC treatment options, with a particular focus on the available data on NAFLD-related cases in practice-changing clinical trials.

Keywords: HCC; NAFLD; NASH; hepatocellular carcinoma; insulin resistance; metabolic syndrome.

Figure 1

Pathogenesis of non-alcoholic fatty liver disease. The complex interplay between environmental, genetic, and metabolic factors results in an imbalance between intrahepatic lipid retention and disposal. Increased FFAs uptake derives from both high fat diet and adipose tissue lipolysis. Peripheral insulin resistance promotes adipose tissue proliferation and adipocyte disfunction, induces lipolysis and release of adipokines, namely leptin and adiponectin with pro-inflammatory effects. Insulin resistance also determines an increase in hepatic de novo lipogenesis, worsening lipid liver accumulation. Toxic lipid species cause mitochondrial dysfunction, oxidative stress with ROS production and ER stress leading to the activation of UPR response. All these processes are involved in the activation of an inflammatory response through JNK e and NF-κβ pathways. Gut microbiota dysbiosis is also implicated in hepatotoxic oxidative damage. Abbreviations: FFAs, free fatty acids; β-ox, beta oxidation; mtDNA, mitochondrial DNA; ROS, reactive oxygen species; ER, endoplasmic reticulum; UPR, unfolded protein response; MTP, microsomal triglyceride transfer protein; JNK, c-Jun N-terminal kinase; NF-Kβ, nuclear factor kappa-light-chain-enhancer of activated B cells; VLDL, very low-density lipoprotein; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.