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Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common liver disorder worldwide mainly attributed to the epidemic spread of obesity and type 2 diabetes mellitus. Although it is considered a benign disease, NAFLD can progress to non-alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). Most data regarding the epidemiology of NAFLD-related HCC are derived from cohort and population studies and show that its incidence is increasing as well as it is likely to emerge as the leading indication for liver transplantation, especially in the Western World. Although cirrhosis constitutes the main risk factor for HCC development, in patients with NAFLD, HCC can arise in the absence of cirrhosis, indicating specific carcinogenic molecular pathways. Since NAFLD as an underlying liver disease for HCC is often underdiagnosed due to lack of sufficient surveillance in this population, NAFLD-HCC patients are at advanced HCC stage at the time of diagnosis making the management of those patients clinically challenging and affecting their prognostic outcomes. In this current review, we summarize the latest literature on the epidemiology, other than liver cirrhosis-pathogenesis, risk factors and prognosis of NAFLD-HCC patients. Finally, we emphasize the prevention of the development of NAFLD-associated HCC and we provide some insight into the open questions and issues regarding the appropriate surveillance policies for those patients.

SUBMITTER: Chrysavgis L

PROVIDER: S-EPMC8771615 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, its carcinogenic mechanism is still unclear, looking for both diseases' transcriptome levels, the same changes as we are looking for NAFLD may provide a potential mechanism of action of HCC. Thus, our study aimed to discover the coexisting pathogenic genes of NAFLD and HCC.MethodsWe performed a variance analysis with public data for both diseases. At the same time, weighted gene correlation network analysis (WGCNA) was used to find highly correlated gene modules in both diseases. The darkturquoise gene module was found to be highly correlated with both diseases. Based on the diagnosis related module genes and the differential genes of the two diseases, we constructed diagnostic and prognostic models by logistic regression, univariate Cox regression, and LASSO regression. Public datasets verified the results. Meanwhile, we built a competing endogenous RNA (ceRNA) network based on the model genes and explored the related pathways and immune correlation involved in the two diseases by using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses. Immunohistochemistry was used to verify the different expression of ABCC5 and TUBG1 among the normal liver, NAFLD, and HCC tissues. Sodium palmitate/sodium oleate was used to establish high-fat cell models, and Real Time Quantitative Polymerase Chain Reaction (RT-qPCR) was used to verify the messenger RNA (mRNA) expression of ABCC5 in lipidization cells.ResultsA total of 26 upregulated genes and 87 downregulated genes were found using limma package identification analysis. According to WGCNA, the darkturquoise gene module was highly correlated with the prognosis of both diseases. The coexisting genes acquired by the two groups were only three central genes, that is, ABCC5, DHODH and TUBG1. The results indicated that the diagnostic and prognostic models constructed by ABCC5 and TUBG1 genes had high accuracy in both diseases. The results of immunohistochemistry showed that ABCC5 and TUBG1 were significantly overexpressed in NAFLD and HCC tissues compared with normal liver tissues. The Oil Red O staining and triglyceride identified the successful construction of HepG2 and LO2 high-fat models using PA/OA. The results of RT-qPCR showed that the lipidization of LO2 and HepG2 increased the mRNA expression of ABCC5.ConclusionsThe gene model constructed by ABCC5 and TUBG1 has high sensibility and veracity in the diagnosis of NAFLD as well as the diagnosis and prognosis of HCC. ABCC5 and TUBG1 may play an important role in the development of NAFLD to HCC. In addition, lipidization could upregulate the mRNA expression of ABCC5 in HCC.

Project description:Background & aimsHepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification.MethodsWe examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5).ResultsIn the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10-5) and without cirrhosis (p <0.05).ConclusionsOur results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings.Lay summaryBy analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.

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Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link

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