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.

Keywords: Epidemiology; Hepatocellular carcinoma; Non-alcoholic fatty liver disease; Risk factors; Risk stratification; Surveillance.

Figure 1

The molecular pathways that regulate non-alcoholic fatty liver disease-related hepatocellular carcinoma along with their interactions are represented. Activation of downstream signaling pathways is indicated by full or dot lines whereas inhibition of them is indicated by blunted lines with a circular-shaped “X”. Bidirectional arrows highlight the interplay between distinct molecular pathways. Molecules acting as mediators of signaling paths are indicated over a full, dot or blunted line in a box along with their names. MicroRNAs that promote hepatocellular carcinoma development are collectively represented in the upper left of the figure while tumor suppressor microRNAs are represented in the lower left of the schema. Cas: Caspase; DCA: Deoxycholic acid; ER: Endoplasmic reticulum; FFAs: Free fatty acids; HCC: Hepatocellular carcinoma; HDAC8: Histone deacetylase 8; HSCs: Hepatic stellate cells; IGF: Insulin growth factor; IL-6: Interleukin-6; IRec: Insulin receptor; IRes: Insulin resistance; JNK: Jun-(N)-terminal kinase; KC: Kuppfer cell; lncRNAs: Long non-coding RNAs; LPS: Lipopolysaccharides; MAPK: Mitogen-activated protein kinase; PAMPs: Pathogen-associated molecular patterns; SASP: Senescence associated secretory phenotype; STAT3: Signal transducer and activator of transcription 3; TGF-B: Transforming growth factor-B; TLR: Toll-liκe receptor.

Figure 2

Proposed algorithm for hepatocellular carcinoma surveillance in non-alcoholic fatty liver disease patients based on the latest guidelines. HCC: Hepatocellular carcinoma; NAFLD: Non-alcoholic fatty liver disease; US: Ultrasonography; AFP: Alpha-fetoprotein; CT: Computer tomography; MRI: Magnetic resonance imaging; BMI: Body mass index.

Figure 3

Proposed algorithm for hepatocellular carcinoma surveillance in non-alcoholic fatty liver disease patients based on future perspectives. HCC: Hepatocellular carcinoma; NAFLD: Non-alcoholic fatty liver disease; PNPLA3: Patatin-like phospholipase domain-containing protein 3; MiRNAs: Micro-RNAs; lnc-RNAs: Long non-coding-RNAs; ALP: Alkaline phosphatase; AFP: Alpha-fetoprotein; US: Ultrasonography; CT: Computer tomography; MRI: Magnetic resonance imaging; BMI: Body mass index.