Nonalcoholic Fatty Liver Disease Hepatocellular Carcinoma Research Articles

Perilipin 5 deletion protects against nonalcoholic fatty liver disease and hepatocellular carcinoma by modulating lipid metabolism and inflammatory responses

The molecular mechanisms underlying the transition from nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC) are incompletely understood. During the development of NAFLD, Perilipin 5 (PLIN5) can regulate lipid metabolism by suppressing lipolysis and preventing lipotoxicity. Other reports suggest that the lack of PLIN5 decreases hepatic injury, indicating a protective role in NAFLD pathology. To better understand the role of PLIN5 in liver disease, we established mouse models of NAFLD and NAFLD-induced HCC, in which wild-type and Plin5 null mice were exposed to a single dose of acetone or 7,12-dimethylbenz[a]anthracene (DMBA) in acetone, followed by a 30-week high-fat diet supplemented with glucose/fructose. In the NAFLD model, RNA-seq revealed significant changes in genes related to lipid metabolism and immune response. At the intermediate level, pathways such as AMP-activated protein kinase (AMPK), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and protein kinase B (AKT) were blunted in Plin5-deficient mice (Plin5−/−) compared to wild-type mice (WT). In the NAFLD-HCC model, only WT mice developed liver tumors, while Plin5−/− mice were resistant to tumorigenesis. Furthermore, only 32 differentially expressed genes associated with NALFD progession were identified in Plin5 null mice. The markers of mitochondrial function and immune response, such as the peroxisome proliferator‐activated receptor-γ, coactivator 1‐α (PGC-1α) and phosphorylated STAT3, were decreased. Lipidomic analysis revealed differential levels of some sphingomyelins between WT and Plin5−/− mice. Interestingly, these changes were not detected in the HCC model, indicating a possible shift in the metabolism of sphingomelins during carcinogenesis.

Incidence and predictors of hepatocellular carcinoma in NAFLD without diagnosed cirrhosis: a nationwide real-world U.S. study.

A substantial proportion of patients with nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) do not have cirrhosis. Data regarding the incidence and predictors of HCC development in NAFLD without cirrhosis are limited. We conducted a large, national study of NAFLD patients without documented cirrhosis to examine the incidence and predictors for HCC development. This retrospective study included 751,603 NAFLD patients (54% female) without documented cirrhosis derived from the deidentified Optum Clinformatics® Data Mart Database. Patients with cirrhosis, platelets < 120,000/µL or FIB-4 values > 2.67 were excluded. The mean age was 53.7 ± 15.0years, 45.9% were male, 39.5% had diabetes, 57.6% were White, 18.4% Hispanic, 8.2% Black and 4.9% were Asian. The mean platelet count was 264,000 ± 72,000/µL, and 96.3% of patients had a FIB-4 < 1.30. Over 1,686,607 person-years of follow-up, there were 76 incident cases of HCC, resulting in an HCC incidence rate of 0.05 per 1000 person-years. There was a higher HCC incidence rate among patients with platelets ≤ 150,000/µL, versus those with platelets > 150,000/µL (0.23 per 1000 person-years, vs. 0.04 per 1000 person-years, p = 0.02) but not in subgroup analyses for age, sex, race/ethnicity or diabetes. Using multivariable Cox proportional hazards model adjusted multiple confounders, platelet count ≤ 150,000/µL remained an independent predictor of HCC development (adjusted HR 5.80, 95% CI 1.67-20.1, p = 0.006). HCC incidence in NAFLD without documented cirrhosis was below the threshold for cost-effective HCC surveillance in overall and multiple subgroup analyses. Platelet count < 150,000/µL may be a useful predictor of HCC development in this population.

Risk factors of hepatocellular carcinoma in non-alcoholic fatty liver disease: a systematic review and meta-analysis.

This study aimed to systematically review and quantitatively synthesize the existing evidence to better identify the high-risk population of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD). We searched databases including MEDLINE, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov up to February 2023. The meta-analysis was performed using RevMan5.3 software, and we calculated the estimated combined effect using inverse variance weighting of OR. I2 statistics were used to quantify the inter-study heterogeneity. Funnel plots and Egger test were used to assess publication bias, and sensitivity analysis was carried out through the transformation effect model or the removal of literature one by one. Finally, 29 articles were included in the study, which involved a total of 726,656 patients with NAFLD. A total of 15 major risk factors were evaluated. Statistically significant risk factors were: advanced liver fibrosis (OR=6.40), diabetes (OR=2.38), obesity (OR=1.46), hypertension (OR=1.75), older age (OR=3.57), male (OR=2.45), alcohol intake (OR=2.98), smoking (OR=1.44), PNPLA3 genotype variation (OR=1.76), elevated liver enzymes (OR=2.92), low platelet counts (OR=4.61), and low albumin levels (OR=2.11). Our results showed that advanced liver fibrosis, diabetes, obesity, hypertension, older age, male, alcohol intake, smoking, PNPLA3 genotype variation, elevated liver enzymes, low platelet counts, and low albumin levels were all significant risk factors for HCC in NAFLD. However, dyslipidemia was not found to be a risk factor. Further exploration is needed to confirm whether Hispanic ethnicity and high ferritin levels are also risk factors.

Distinct Morphological and Molecular Profiles of NAFLD and NAFLD-associated HCC Revealed by Immunohistochemistry and MicroRNA Analysis.

Non-alcoholic fatty liver disease (NAFLD) is a common hepatic condition that can progress to hepatocellular carcinoma (HCC) in non-cirrhotic livers. To better understand the development of NAFLD-associated HCC, we performed an integrated morphological and molecular analysis to identify new insights that can improve the follow-up of NAFLD patients. Our study included a cohort of 14 NAFLD-associated HCC and 41 NAFLD patients. We analyzed clinical parameters, a four-microRNA (miRNA) panel (miR-21-5p, miR-34a-5p, miR-130a-3p, and miR-155-3p) panel and their relationship with p53 and β-catenin expression. In the study cohort, the NAFLD-associated HCC patients were predominantly male, older, had significantly altered hepatic function, and a higher incidence of hypertension, type 2 diabetes, and dyslipidemia. Morphologically, the NAFLD-HCC group had substantially higher steatosis, ballooning, and fibrosis grades than the NAFLD group. The β-catenin expression was higher in both adjacent non-tumoral liver tissue (ANT) from NAFLD-associated HCC patients and in HCC tissue com-pared with NAFLD samples. The 4 miRNAs panel showed a dysregulated expression profile between NAFLD, ANT and HCC samples. This study provides important insights regarding the molecular mechanisms underlying HCC progression in NAFLD patients, allowing for the development of better screening strategies for the early detection of NAFLD-associated HCC.

Nonalcoholic Fatty Liver Disease and the Intestinal Microbiome: An Inseparable Link.

Nonalcoholic fatty liver disease (NAFLD) particularly affects patients with type 2 diabetes and obesity. The incidence of NAFLD has increased significantly over the last decades and is now pandemically across the globe. It is a complex systemic disease comprising hepatic lipid accumulation, inflammation, lipotoxicity, gut dysbiosis, and insulin resistance as main features and with the potential to progress to cirrhosis and hepatocellular carcinoma (HCC). In numerous animal and human studies the gut microbiota plays a key role in the pathogenesis of NAFLD, NAFLD-cirrhosis and NAFLD-associated HCC. Lipotoxicity is the driver of inflammation, insulin resistance, and liver injury. Likewise, western diet, obesity, and metabolic disorders may alter the gut microbiota, which activates innate and adaptive immune responses and fuels hereby hepatic and systemic inflammation. Indigestible carbohydrates are fermented by the gut microbiota to produce important metabolites, such as short-chain fatty acids and succinate. Numerous animal and human studies suggested a pivotal role of these metabolites in the progression of NAFLD and its comorbidities. Though, modification of the gut microbiota and/or the metabolites could even be beneficial in patients with NAFLD, NAFLD-cirrhosis, and NAFLD-associated HCC. In this review we collect the evidence that exogenous and endogenous hits drive liver injury in NAFLD and propel liver fibrosis and the progressing to advanced disease stages. NAFLD can be seen as the product of a complex interplay between gut microbiota, the immune response and metabolism. Thus, the challenge will be to understand its pathogenesis and to develop new therapeutic strategies.

Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets.

Obesity is a global epidemic and overwhelming evidence indicates that it is a risk factor for numerous cancers, including hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Obesity-associated hepatic tumorigenesis develops from nonalcoholic fatty liver disease (NAFLD), progressing to nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately to HCC. The rising incidence of obesity is resulting in an increased prevalence of NAFLD and NASH, and subsequently HCC. Obesity represents an increasingly important underlying etiology of HCC, in particular as the other leading causes of HCC such as hepatitis infection, are declining due to effective treatments and vaccines. In this review, we provide a comprehensive overview of the molecular mechanisms and cellular signaling pathways involved in the pathogenesis of obesity-associated HCC. We summarize the preclinical experimental animal models available to study the features of NAFLD/NASH/HCC, and the non-invasive methods to diagnose NAFLD, NASH and early-stage HCC. Finally, since HCC is an aggressive tumor with a 5-year survival of less than 20%, we will also discuss novel therapeutic targets for obesity-associated HCC and ongoing clinical trials.

Identification of Hub Genes and Immune Infiltration in Non-alcoholic Fatty Liver Disease -Related Hepatocellular Carcinoma by Bioinformatics Analysis.

Non-alcoholic fatty liver disease has been a significant risk factor for hepatocellular carcinoma. In the study, we aimed to identify the key genes associated with the transition from non-alcoholic fatty liver disease to hepatocellular carcinoma through bioinformatics analysis. The GSE164760 dataset was used for identifying differentially expressed genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were performed to explore the potential function of the differentially expressed genes. Subsequently, the protein-protein interaction network was constructed to select hub genes, and the immune cell infiltration was analyzed. Finally, the receiver operating characteristic analysis was performed to assess the diagnostic ability of the crucial genes. A total of 156 differentially expressed genes were identified. Gene Ontology enrichment analysis indicated that differentially expressed genes were strongly associated with cellular hormone metabolic process, response to xenobiotic stimulus, collagen-containing extracellular matrix, detoxification, and regulation of growth. In the protein-protein interaction network, ESR1, CAT, CXCL8, CD4, SPP1, CYP2E1, CYP3A4, UGT2B7, GSTA1 and THBS1 were selected as the hub genes. Immune infiltration analysis demonstrated that M0 macrophages, plasma cells, CD8+T cell and M2 macrophages were significantly changed in tumor tissues. Finally, we verified the hub gene expression and selected CD4, UGT2B7, and CYP3A4 as the potential diagnostic biomarkers. CD4, UGT2B7, and CYP3A4 were selected as the potential diagnostic biomarkers of non-alcoholic fatty liver disease-hepatocellular carcinoma.

Identification of potential feature genes in non-alcoholic fatty liver disease using bioinformatics analysis and machine learning strategies

The prevalence of non-alcoholic fatty liver disease (NAFLD) and NAFLD-associated hepatocellular carcinoma (HCC) has continuously increased in recent years. Machine learning is an effective method for screening the feature genes of a disease for prediction, prevention and personalized treatment. Here, we used the “limma” package and weighted gene co-expression network analysis (WGCNA) to screen 219 NAFLD-related genes and found that they were mainly enriched in inflammation-related pathways. Four feature genes (AXUD1, FOSB, GADD45B, and SOCS2) were screened by LASSO regression and support vector machine-recursive feature elimination (SVM-RFE) machine learning algorithms. Therefore, a clinical diagnostic model with an area under the curve (AUC) value of 0.994 was constructed, which was superior to other indicators of NAFLD. Significant correlations existed between feature genes expression and steatohepatitis histology or clinical variables. These findings were also validated in external datasets and a mouse model. Finally, we found that feature genes expression was significantly decreased in NAFLD-associated HCC and that SOCS2 may be a prognostic biomarker. Our findings may provide new insights into the diagnosis, prevention and treatment targets of NAFLD and NAFLD-associated HCC.

Abstract B009: A liver-tropic BCL-xL PROTAC effectively clears senescent hepatocytes and prevents NASH-driven HCC in mice

Abstract Accumulation of senescent cells (SnCs) plays a causative role in many age-related diseases and has been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Senolytics that can selectively kill SnCs have the potential to be developed as therapeutics for these diseases. Here we reported the discovery of 753b, a BCL-xL proteolysis targeting chimera (PROTAC), as a potent and liver-tropic senolytic. We found that 753b can selectively clear senescent hepatocytes in aged mice and the STAM mice even though it can potently kill various SnCs in vitro. This is in part because 753b is enriched in the liver after its administration by ip injection. Moreover, 753b treatment can effectively reduce the development of non-alcoholic steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma (HCC) in the STAM mice. These findings suggest that 753b has the potential to be developed as a novel therapeutic for NAFLD and NASH-driven HCC. Citation Format: Yang Yang, Natacha Jn-Simon, Wanyi Hu, Peiyi Zhang, Guangrong Zheng, Liya Pi, Yonghan He, Daohong Zhou. A liver-tropic BCL-xL PROTAC effectively clears senescent hepatocytes and prevents NASH-driven HCC in mice [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B009.

Is Hepatocellular Carcinoma in Fatty Liver Different to Non-Fatty Liver?

Background: Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in Australia and is recognised to play a role in the development of hepatocellular carcinoma (HCC). There are no clear guidelines regarding screening for HCC in NAFLD. The aim of this retrospective study was to compare the characteristics and survival rates of NAFLD-HCC to patients with non-NAFLD-HCC to help guide future research in this area. Methods: A total of 152 HCC patients with either NAFLD (n = 36) or non-NAFLD (n = 116) were retrospectively analysed from the HCC database and medical records. Chi-square and independent t-test were used to compare baseline characteristics and Kaplan–Meier curves and Cox models were used for survival analysis. Results: Patients with NAFLD-HCC were more likely to be diagnosed due to symptoms rather than through screening, and at an older age, compared with non-NAFLD HCC. The median survival rates were lower in NAFLD-HCC (17.2 months) than in those with non-NAFLD-HCC (23.5 months). Conclusion: There is a rise in the number of HCC cases in patients with NAFLD, and this has significant implications for hepatologists as they are presented with more advanced diseases and have poorer outcomes. Future studies on HCC will need to identify this group earlier in order to have an impact on the HCC survival rate.

Radiological Features of Microvascular Invasion of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease

Background: The aim of the present study was to evaluate the presence and the prognostic value of the radiological signs of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). Methods: Between January 2015 and December 2017, all patients (91 patients) with de novo HCC or HCC recurrence occurring at least 2 years after the last treatment in NAFLD (36 patients) or with hepatitis C virus (HCV) liver disease (55 patients) were included. Each HCC was treated with liver resection and transplantation to obtain the anatomopathological confirmation of MVI. All patients had at least one available computed tomography (CT) scan or magnetic resonance imaging (MRI) performed no more than one month prior to the treatment. The clinical data of each patient, tumor burden (diameter, margins, two-trait predictor of venous invasion (TTPVI), and peritumoral enhancement), the recurrence rate (RR) after a 1-year follow-up, and the time to recurrence (TTR) were collected. Results: The NAFLD–HCC nodules were larger as compared to HCV–HCC (51 mm vs. 36 mm, p = 0.004) and showed a higher prevalence of TTPVI (38.9 vs. 20.0%, p = 0.058). At multivariate analysis, nodule diameter &gt;50 mm was found to be the only independent prognostic factor of TTPVI (hazard ratio: 21.3, 95% confidence interval: 4.2–107.7, p &lt; 0.001), and the presence of TTPVI was confirmed to be the only independent prognostic factors of recurrence (hazard ratio: 2.349, 95% confidence interval: 1.369–4.032, p = 0.002). No correlations were found between TTR and irregular tumor margins or peritumoral enhancement. Conclusion: The NAFLD–HCC patients had larger tumors at diagnosis and showed a more frequent presence of radiological signs of MVI as compared to the HCV–HCC patients. The MVI was related to a more rapid recurrence after curative treatments, demonstrating the prognostic value of this radiological diagnosis.

Contribution of organokines in the development of NAFLD/NASH associated hepatocellular carcinoma

Globally the incidence of hepatocellular carcinoma (HCC) is on an upsurge. Evidence is accumulating that liver disorders like nonalcoholic fatty liver disease (NAFLD) and its more progressive form nonalcoholic steatohepatitis (NASH) are associated with increased risk of developing HCC. NAFLD has a prevalence of about 25% and 50%-90% in obese population. With the growing burden of obesity epidemic worldwide, HCC presents a major healthcare burden. While cirrhosis is one of the major risk factors of HCC, available literature suggests that NAFLD/NASH associated HCC also develops in minimum or noncirrhotic livers. Therefore, there is an urgent need to understand the pathogenesis and risk factors associated with NAFLD and NASH related HCC that would help in early diagnosis and favorable prognosis of HCC secondary to NAFLD. Adipokines, hepatokines and myokines are factors secreted by adipocytes, hepatocytes and myocytes, respectively, playing essential roles in cellular homeostasis, energy balance and metabolism with autocrine, paracrine and endocrine effects. In this review, we endeavor to focus on the role of these organokines in the pathogenesis of NAFLD/NASH and its progression to HCC to augment the understanding of the factors stimulating hepatocytes to acquire a malignant phenotype. This shall aid in the development of novel therapeutic strategies and tools for early diagnosis of NAFLD/NASH and HCC.

Imaging features of hepatocellular carcinoma in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: a systematic review and meta-analysis.

To investigate the imaging features of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) through a systematic review and meta-analysis. MEDLINE, EMBASE, and the Cochrane Library database were searched for studies providing data on imaging features of HCC in NAFLD and NASH between January 1, 2011 and July 19, 2021. Random effects models were used to calculate the pooled percentages of the three major features of arterial-phase hyperenhancement (APHE), washout, and enhancing capsule. Sensitivity analysis and subgroup analysis were performed according to underlying liver disease (NASH vs. NAFLD) and imaging modality (CT vs. MRI). Five studies (170 patients with 193 HCCs) were included in the analysis. The pooled percentages of APHE, washout, and enhancing capsule were 94.0% (95% confidence interval [CI] 89.1-96.7%), 72.7% (95% CI 63.3-80.4%), and 57.5% (95% CI 45.1-69.1%), respectively. The percentages of these three major features did not significantly differ between NAFLD and NASH (p ≥ 0.21). MRI showed similar pooled percentages of APHE (94.3% vs. 93.4%, p = 0.82) and washout (70.4% vs. 77.2%, p = 0.38) to CT, but a higher pooled percentage of enhancing capsule (67.1% vs. 44.7%, p = 0.02). HCC in patients with NAFLD and NASH had a similar frequency of APHE to HCC with other etiology. However, it showed a relatively low frequency of washout and enhancing capsule.

NUSAP1 Could be a Potential Target for Preventing NAFLD Progression to Liver Cancer.

Background: Non-alcoholic fatty liver disease (NAFLD) has gradually emerged as the most prevalent cause of chronic liver diseases. However, specific changes during the progression of NAFLD from non-fibrosis to advanced fibrosis and then hepatocellular carcinoma (HCC) are unresolved. Here, we firstly identify the key gene linking NAFLD fibrosis and HCC through analysis and experimental verification. Methods: Two GEO datasets (GSE89632, GSE49541) were performed for identifying differentially expressed genes (DEGs) associated with NAFLD progression from non-fibrosis to early fibrosis and eventually to advanced fibrosis. Subsequently, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment analysis, protein-protein interaction (PPI) network were integrated to explore the potential function of the DEGs and hub genes. The expression of NUSAP1 was confirmed in vivo and in vitro NAFLD models at mRNA and protein level. Then, cell proliferation and migration under high fat conditions were verified by cell counting kit-8 (CCK-8) and wound-healing assays. The lipid content was measured with Oil Red O staining. Finally, the analysis of clinical survival curves was performed to reveal the prognostic value of the crucial genes among HCC patients via the online web-tool GEPIA2 and KM plotter. Results: 5510 DEGs associated with non-fibrosis NAFLD, 3913 DEGs about NAFLD fibrosis, and 739 DEGs related to NAFLD progression from mild fibrosis to advanced fibrosis were identified. Then, a total of 112 common DEGs were found. The result of enrichment analyses suggested that common DEGs were strongly associated with the glucocorticoid receptor pathway, regulation of transmembrane transporter activity, peroxisome, and proteoglycan biosynthetic process. Six genes, including KIAA0101, NUSAP1, UHRF1, RAD51AP1, KIF22, and ZWINT, were identified as crucial candidate genes via the PPI network. The expression of NUSAP1 was validated highly expressed in vitro and vivo NAFLD models at mRNA and protein level. NUSAP1 silence could inhibit the ability of cell proliferation, migration and lipid accumulation in vitro. Finally, we also found that NUSAP1 was significantly up-regulated at transcriptional and protein levels, and associated with poor survival and advanced tumor stage among HCC patients. Conclusion: NUSAP1 may be a potential therapeutic target for preventing NAFLD progression to liver cancer.

DETECT: Development of Technologies for Early HCC Detection

DETECT: Development of Technologies for Early HCC Detection

Statin Use and Reduced Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Fatty Liver Disease

Recent evidence suggests potential clinical benefits of statin in cancer chemoprevention and treatment. Nonalcoholic fatty liver disease (NAFLD) is expected to become the leading cause of hepatocellular carcinoma (HCC). We aimed to investigate the association between statin initiation and the risk of HCC among patients with NAFLD. In this study using the Optum de-identified Clinformatics database, Cox proportional hazards regression model was performed to determine the risk of HCC in statin initiators versus nonusers. We incorporated inverse probability of treatment weighting (IPTW) to minimize potential confounding. Among 272,431 adults with NAFLD diagnosis, IPTW model shows that statin initiators had 53% less risk of developing HCC compared with nonusers (hazard ratio [HR], 0.47; 95% confidence interval, 0.36-0.60). In the subcohort with fibrosis-4 index data available, statin initiation was associated with 56% hazard reduction of developing HCC in NAFLD after adjusting for fibrosis-4 index score (HR, 0.44; 0.30-0.65). The association between statin initiation and lower risk of HCC development was observed for both lipophilic statin (HR, 0.49; 0.37-0.65) and hydrophilic statin (HR, 0.40; 0.21-0.76). Moreover, we observed greater hazards reduction as the dose and duration of statin use increased. NAFLD patients with more than 600 cumulative defined daily doses of statin had 70% reduction in hazards of developing HCC (HR, 0.30; 0.20-0.43). Our study provides strong evidence for the association between statin initiation and reduced risk of HCC development in NAFLD patients. These findings imply that statin can be used as a protective medication for NAFLD patients to reduce the risk of HCC.

Hepatocellular carcinoma on the background of nonalcoholic fatty liver disease: epidemiological update

The epidemiological features of hepatocellular carcinoma have changed significantly in the last decades. While for a long-time viral hepatitis and alcohol consumption have been the leading risk factors, the current spread of obesity and type 2 diabetes has contributed to the emergence of non-alcoholic fatty liver disease (NAFLD) worldwide, which has become the leading chronic liver disease as well as one of the main etiologies of hepatocellular carcinoma (HCC), especially in western countries. In this review, we resume the latest data about the epidemiology of metabolic liver disease and HCC arising from NAFLD and discuss the main clinical and molecular features leading to the progression of liver disease and the development of HCC in NAFLD. The emerging concept of metabolic associated fatty liver disease and its association with the development of HCC are also introduced.

Impact of NAFLD on clinical outcomes in hepatocellular carcinoma treated with sorafenib: an international cohort study.

Background:The impact of nonalcoholic fatty liver disease (NAFLD) on overall survival (OS), treatment response and toxicity in patients with hepatocellular carcinoma (HCC) treated with sorafenib is unknown. We examined the impact of NAFLD on survival and toxicity in an international cohort of patients receiving sorafenib.Methods:Clinical and demographic data were collected from patients consecutively treated at specialist centres in Europe and North America. The impact of NAFLD on OS, sorafenib-specific survival and toxicity compared with other aetiologies of liver disease using multivariable Cox-proportional hazards and logistic regression modelling was assessed.Results:A total of 5201 patients received sorafenib; 183 (3.6%) had NAFLD-associated HCC. NAFLD-associated HCC patients were more likely to be older women (median age 65.8 versus 63.0 years, p < 0.01 and 10.4% versus 2.3%, < 0.01), with a median body mass index (BMI) of 29.4. After controlling for known prognostic factors, no difference in OS in patients with or without NAFLD was observed [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.84–1.18, p = 0.98]. NAFLD-associated patients had more advanced stage HCC when they commenced sorafenib [Barcelona Clinic Liver Class (BCLC) C/D 70.9% versus 58.9%, p < 0.01] and were more likely to be commenced on a lower starting dose of sorafenib (51.4 versus 36.4%, p < 0.01). There was no difference in sorafenib-specific survival between NAFLD and other aetiologies (HR: 0.96, 95% CI: 0.79–1.17, p = 0.96). Adverse events were similar between NAFLD and non-NAFLD HCC groups, including rates of greater than grade 2 hypertension (6.3% versus 5.8%, p = 1.00).Conclusion:Survival in HCC does not appear to be influenced by the presence of NAFLD. NAFLD-associated HCC derive similar clinical benefit from sorafenib compared with other aetiologies.

Hepatocellular carcinoma in nonalcoholic fatty liver disease with or without cirrhosis: a population-based study

BackgroundThere are limited data regarding the factors associated with hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) patients without cirrhosis. We sought to determine the prevalence and factors associated with HCC in NAFLD patients with or without cirrhosis.MethodsAdults with NAFLD (June 2015 to May 2020) were identified using the electronic health record database (Explorys Inc, Cleveland, OH) from 26 major integrated US healthcare systems. The prevalence of HCC was calculated. Multivariable analyses adjusting for covariates were performed to evaluate the associated risk factors and the presence of HCC.ResultsA total of 392,800 NAFLD patients were identified. Among 1110 patients with HCC, 170 (15.3%) had no cirrhosis. The prevalence of HCC in non-cirrhotic and cirrhotic NAFLD patients was 4.6/10,000 persons (95% CI 3.9–5.3), and 374.4/10,000 persons (95% CI 350.9–398.8), respectively. Age > 65 years (adjusted OR; 3.37, 95% CI 2.47–4.59), ever had elevated alanine aminotransferase (2.69; 2.14–3.37), male gender (2.57; 1.88–3.49), smoker (1.75; 1.23–2.49), and diabetes (1.56; 1.15–2.11) were associated with HCC in non-cirrhotic NAFLD (all P < 0.05). The prevalence of HCC in the non-cirrhotic with all five risk factors was 45.5/10,000 persons (95% CI 17.4–73.6). The factors associated with HCC in cirrhotic NAFLD included clinical decompensation, age > 65 years, male gender, Hispanic race, elevated alanine aminotransferase, diabetes and smoker (all P < 0.05).ConclusionsThese data identified the major risk factors for the development of HCC in NAFLD patients. In the non-cirrhotics, older male patients with smoking history, diabetes and an elevated alanine aminotransferase had highest risk and may need increased judicious monitoring.

Liver Field during Immunotherapy of Hepatocellular Carcinoma: Some Like It Hot

Liver Field during Immunotherapy of Hepatocellular Carcinoma: Some Like It Hot