Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Current Progresses and Challenges

Abstract

The rising global prevalence of metabolic diseases has increased the prevalence of non-alcoholic fatty liver disease (NAFLD), leading to an increase in cases of NAFLD-related hepatocellular carcinoma (HCC). To provide an updated literature review detailing epidemiology, risk factors, pathogenic pathways, and treatment strategies linked to NAFLD-related HCC, we conducted a literature search on PubMed from its inception to December 31, 2021. About 25% of the global population suffers from NAFLD. The annual incidence of HCC among NAFLD patients is approximately 1.8 per 1,000 person-years. Older age, male sex, metabolic comorbidities, unhealthy lifestyle habits (such as smoking and alcohol consumption), physical inactivity, genetic susceptibility, liver fibrosis, and degree of cirrhosis in NAFLD patients are important risk factors for NAFLD-related HCC. Therefore, low-calorie diet, moderate-intensity exercise, treatment of metabolic comorbidities, and cessation of smoking and alcohol are the main measures to prevent NAFLD-related HCC. In addition, all patients with advanced NAFLD-related fibrosis or cirrhosis should be screened for HCC. Immune suppression disorders and changes in the liver microenvironment may be the main pathogenesis of NAFLD-related HCC. Hepatic resection, liver transplantation, ablation, transarterial chemoembolization, radiotherapy, targeted drugs, and immune checkpoint inhibitors are used to treat NAFLD-related HCC. Lenvatinib treatment may lead to better overall survival, while immune checkpoint inhibitors may lead to worse overall survival. Given the specific risk factors for NAFLD-related HCC, primary prevention is key. Moreover, the same treatment may differ substantially in efficacy against NAFLD-related HCC than against HCC of other etiologies.

Prognosis after hepatic resection of patients with hepatocellular carcinoma related to non-alcoholic fatty liver disease: meta-analysis

“…All five of those studies reported similar OS between patients with NAFLD- or NASH-related HCC and patients with HCC related to viral hepatitis or alcohol ( Table S2 ). However, other studies found that lenvatinib treatment may lead to better OS, while immune checkpoint inhibitors may lead to worse OS when treating NAFLD-related HCC compared with HCC of other aetiologies 67 , 68 . In addition to hepatectomy, liver transplantation and radiofrequency ablation can be applied as radical therapies against HCC.…”

Research status and hotspots on the mechanisms of liver X receptor in cancer progression: A bibliometric analysis

“…[52,53] In the visualization analysis, hepatocellular carcinoma has received much attention as an important class of cancer cell lines that have been studied in recent years, and the liver itself, as a major lipid-and cholesterol-metabolizing organ, has been closely associated with cancer in the known pathways of the LXR mechanism. Notably, with the overall improvement of global health conditions, the proportion of hepatocellular carcinoma caused by etiologies such as hepatitis and aflatoxin has declined, replaced by hepatocellular carcinoma caused by high-fat factors such as nonalcoholic fatty liver disease, [54] Nonalcoholic fatty liver disease is also reflected as an important cluster in the term clustering. Many studies have revealed the crosstalk mechanism between multiple signaling pathways and LXR in hepatocellular carcinoma progression, such as the crosstalk of LXR by TGFβ under the Snail factor contributes to the activation of mesenchymal transition process by hepatocyte apoptosis, which enhances the aggressiveness of hepatocellular carcinoma [55] ; LXR activates and weakens the phosphorylation process of protein kinase and induces the accumulation of ABCG1 to promote efflux cholesterol and reduce the function of lipid rafts, thereby leading to the inactivation of Akt pathway and interfering with the progression of hepatocellular carcinoma through PI3K/Akt pathway.…”

Impact of Sex and Gender on Clinical Management of Patients with Advanced Chronic Liver Disease and Type 2 Diabetes

“…In patients with NAFLD the prevalence of HCC is 2.6%, four times higher in males than females [ 54 , 82 ]. Although several factors are decisive in the onset of HCC, such as advanced age, pro-inflammatory cytokines, the action of adipokines, smoking habits, the presence of obesity and T2D, a key role is certainly played by sexual hormones [ 83 , 84 ]. Oestrogens play a protective role against liver disease, but, as demonstrated by the epidemiological trend of liver cirrhosis and HCC, this protection is drastically reduced in women aged >65 years [ 85 ].…”