Specific patterns in NAFLD patients with HCC

25 May 2021

As Nonalcoholic Fatty Liver Disease (NAFLD) has become progressively the most frequent causes of cirrhosis worldwide [Ref 1], complications related to such etiology are becoming more and more frequent. It is therefore likely to hypothesize that NAFLD will soon become the leading cause of Hepatocellular Carcinoma (HCC) in the world, far surpassing viral etiologies, so far responsible for the largest number of cancer cases and therefore the most studied in this context.

In fact, the current knowledge on the pathogenesis patterns of HCC in patients with cirrhosis is mainly based on studies done on patients with viral cirrhosis (i.e. HCV and HBV). In these patients, HCC drivers genes such as Telomerase Reverse Transcriptase (TERT), Catenin beta 1 (CTNNB1), TP53 with associated mutational signatures and alterations of Wnt/β-catenin, PI3K/Ras, cell-cycle pathways leading to the development of HCC have been identified over time [Ref 2]. Recently, some studies have been performed on both mouse and in vitro models to try to highlight characteristic patterns that explain the link between HCC and NAFLD.

As far as murine models is concerned, a recent study by Dudek et al analyzed the role of CD8+ T-cells in NASH mice [Ref 3].

In this study, CD8+ T-cells were accumulated in liver tissue and showed phenotypes that combined tissue residency proteins like C-X-C Motif Chemokine Receptor 6 (CXCR6), effectors (granzyme) and programmed death cell proteins (like PD1). This particular pattern seemed to be induced by IL-15 through FOXO1 downregulation and CXCR6 upregulation. Modified CD8+ T-cells were more prone to trigger auto-aggression. This auto-aggression, however, is driven by mechanisms that differ from those of the normal CD8+ T-cells antigen-specific killing.

Recently, Pinyol R et al tried to identify in vitro the possible molecular characterization of HCC in patients with Nonalcoholic Staetohepatitis (NASH) [Ref 4]. They collected 125 samples from patients with NASH and 80 samples of patients with NASH and HCC and performed expression array and exome sequencing, comparing data with those from patients with HCC and other etiologies of liver disease. TERT-promoter, CTNNB1, TP53 and Activin A Receptor Type 2A (ACVR2A, a cytokine receptor involved in cell differentiation and proliferation) were the most-frequently mutated genes, with ACVR2A mutation being the more frequent in patients with NASH than in patients with HCC and other etiologies. The analysis performed observed a specific role of ACVR2A as tumour suppressor in HCC, which is something that would need validation in vivo and could have a role for specific target therapy. Moreover, a new mutation was found to be frequent in patients with NASH and HCC (16% of patients with NASH and HCC vs 2% of patients with HCC and other etiologies of liver cirrhosis).

When signaling pathways were explored, HCC patients with NASH presented significantly   higher rates of Wnt/TGF-β proliferation and a lower prevalence of the CTNNB1 subclass compared to patients with HCC of other etiologies.

When transcriptomes were analyzed, a significant upregulation of inflammatory signatures like IFN, IL17-A, IL6 and chemokine signaling were found. These findings confirm even once more the fundamental role of inflammation in the pathogenesis of NAFLD and its complications. Moreover, when compared with HCC in patients with other etiologies of liver disease, patients with HCC and NASH showed a significant enrichment of signatures related to bile acid and fatty acid metabolism and oxidative stress.

In summary, this study shows how NASH microenvironment and stimulation in a pro-inflammatory sense constitute a fundamental aspect in the etiopathogenesis of NASH and its complications, and plays a role also in the development of HCC. In fact, HCC in patients with NAFLD shows patterns of development and signaling that are characteristic and differ from those of patients with different etiologies. This data is very important because it allows us to hypothesize possible personalized diagnosis and treatment strategies for this category of patients. Obviously, many future studies are needed to confirm this prospect, which has an absolute huge potential, given the well-known growing prevalence of NAFLD in the world.


  1. Younossi  ZM,  Koenig  AB,  Abdelatif  D,  Fazel  Y,  Henry  L,  Wymer  M.  Global epidemiology   of   nonalcoholic   fatty   liver   disease—Meta-analytic   assessment   of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
  2. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 2015;149:1226–39.
  3. Dudek M, Pfister D, Donakonda S et al Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature. 2021 Apr;592(7854):444-449.
  4. Pinyol R, Torrecilla S, Wang H, et al. Molecular characterization of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol. 2021 May 13:S0168-8278(21)00326-3.