Clinico-histological and molecular features of hepatocellular carcinoma from nonalcoholic fatty liver disease

Abstract

Patients with nonalcoholic fatty liver disease (NAFLD) continue to increase with the epidemics of obesity, and NAFLD is estimated to become the most prevalent etiology of hepatocellular carcinoma (HCC). Recently, NAFLD-HCC has been recognized to have clinico-histologically and molecularly distinct features from those from other etiologies, including a lower incidence rate of HCC and less therapeutic efficacy to immune checkpoint inhibitors (ICIs). Consistent with the clinical observations that up to 50% of NAFLD-HCC occurs in the absence of cirrhosis, the imbalance of pro- and antitumorigenic hepatic stellate cells termed as myHSC and cyHSC can contribute to the creation of an HCC-prone hepatic environment, independent of the absolute fibrosis abundance. Immune deregulations by accumulated metabolites in NAFLD-affected livers, such as a fatty-acid-induced loss of cytotoxic CD4 T cells serving for immune surveillance and "auto-aggressive" CXCR6+ CD8 T cells, may promote hepatocarcinogenesis and diminish therapeutic response to ICIs. Steatohepatitic HCC (SH-HCC), characterized by the presence of fat accumulation in tumor cells, ballooned tumor cells, Mallory-Denk body, interstitial fibrosis, and intratumor immune cell infiltration, may represent a metabolic reprogramming for adapting to a lipid-rich tumor microenvironment by downregulating CPT2 and leveraging its intermediates as an "oncometabolite." Genome-wide analyses suggested that SH-HCC may be more responsive to ICIs given its mutual exclusiveness with β-catenin mutation/activation that promotes immune evasion. Thus, further understanding of NAFLD-specific hepatocarcinogenesis and HCC would enable us to improve the current daily practice and eventually the prognoses of patients with NAFLD.

Keywords: nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; noncirrhosis; steatohepatitic hepatocellular carcinoma; subtype.

FIGURE 1

Immune deregulations driving hepatocarcinogenesis from nonalcoholic fatty liver disease (NAFLD). (A) CXCR6+ CD8 T cells attack hepatocytes by being exposed to acetate and extracellular ATP in an MHC‐class‐I‐independent manner. (B) Altered gut microbiota‐induced IgA+ plasma cells in NAFLD create an immune‐permissive hepatic environment by leading CD8 T cells to the exhaustion state. (C) Excessive linoleic acid induces selective loss of cytotoxic CD4 T cells. (D) The interaction between IDO1+ dendritic cells and CD8 T cells may shape an HCC‐prone environment in NALFD. Figure created with BioRender.com. CXCR6, C‐X‐C motif chemokine receptor 6; IDO1, indoleamine 2, 3‐dioxygenase; IL, interleukin; PD‐1, programmed cell death‐1; PD‐L1, programmed cell death ligand 1; ROS, reactive oxygen species; TNF, tumor necrosis factor.

FIGURE 2

Metabolic reprogramming of steatohepatitic hepatocellular carcinoma (SH‐HCC) to adapt to a lipid‐rich environment. CPT2 downregulation adapts SH‐HCC to a lipid‐rich harsh environment and leverages the intermediate oleoylcarnitine to promote HCC self‐renewal. Figure created with BioRender.com. ACSL, long‐chain acyl‐CoA synthetase; CACT, carnitine‐acylcarnitine translocase; CPT, carnitine palmitoyltransferase; TCA, tricarboxylic acid.

FIGURE 3

Molecular features of steatotic/steatohepatitic hepatocellular carcinoma (HCC). Figure created with BioRender.com. CRP, C‐reactive protein; GS, glutamine synthetase; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; SAA, serum amyloid A.