Genetic Determinants of Cirrhosis and Hepatocellular Carcinoma Due to Fatty Liver Disease: What's the Score?
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ABSTRACT:
SUBMITTER: Pfeiffer RM
PROVIDER: S-EPMC8900528 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
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Genetic Determinants of Cirrhosis and Hepatocellular Carcinoma Due to Fatty Liver Disease: What's the Score?
Pfeiffer Ruth M RM Rotman Yaron Y O'Brien Thomas R TR
Hepatology (Baltimore, Md.) 20200901 3
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Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD is a hepatic manifestation of insulin resistance, the core pathophysiology of diabetes. Multiple clinical studies show that diabetes increases the risk of liver disease progression and cirrhosis development in patients with NAFLD. Diabetes has causal associations with many different cancers, including hepatocellular carcinoma (HCC). More recent studies demonstrate that diabetes increases the risk of HCC in patients with underlying NAFLD cirrhosis, confirming the direct hepatocarcinogenic effect of diabetes among cirrhosis patients. Diabetes promotes hepatocarcinogenesis via the activation of inflammatory cascades producing reactive oxygen species and proinflammatory cytokines, leading to genomic instability, cellular proliferation, and inhibition of apoptosis. Given the global increase in the burden of NAFLD and HCC, high-risk patients such as older diabetic individuals should be carefully monitored for HCC development. Future larger studies should explore whether the effect of diabetes on HCC risk in NAFLD cirrhosis is modifiable by the type of antidiabetic medication and the effectiveness of diabetes control.
| S-EPMC9840929 | biostudies-literature
Project description:Obesity has been labeled as the global pandemic of the 21st century, resulting from a sedentary lifestyle and caloric excess. Nonalcoholic fatty liver disease (NAFLD), characterized by excessive hepatic steatosis, is strongly associated with obesity and metabolic syndrome and is estimated to be present in one-quarter of the world population, making it the most common cause of the chronic liver disease (CLD). NAFLD spectrum varies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The burden of NAFLD has been predicted to increase in the coming decades resulting in increased rates of decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths. In the current review, we describe the pathophysiology of NAFLD and NASH, risk factors associated with disease progression, related complications, and mortality. Later, we have discussed the changing epidemiology of HCC, with NAFLD emerging as the most common cause of CLD and HCC. We have also addressed the risk factors of HCC development in the NAFLD population (including demographic, metabolic, genetic, dietary, and lifestyle factors), presentation of NAFLD-associated HCC, its prognosis, and the issue of HCC development in non-cirrhotic NAFLD. Lastly, the problems related to HCC screening in the NAFLD population, the remaining challenges, and future directions, especially the need to identify the high-risk individuals, will be discussed. We will conclude the review by summarizing the clinical evidence for treating fibrosis and preventing HCC in those at risk with NAFLD-associated HCC.
| S-EPMC9167599 | biostudies-literature
Project description:Metabolic-associated fatty liver disease (MAFLD) is a major cause of liver-related complications, including hepatocellular carcinoma (HCC). While MAFLD-related HCC is known to occur in the absence of cirrhosis, our understanding of MAFLD-related HCC in this setting is limited. Here, we characterize MAFLD-related HCC and the impact of cirrhosis and screening on survival. This was a multicenter, retrospective, cohort study of MAFLD-related HCC. MAFLD was defined based on the presence of race-adjusted overweight, diabetes, or both hypertension and dyslipidemia in the absence of excess alcohol use or other underlying cause of liver disease. The primary outcome of interest was overall survival, and the primary dependent variables were cirrhosis status and prior HCC screening. We used Kaplan-Meier methods to estimate overall survival and Cox proportional hazards models and random forest machine learning to determine factors associated with prognosis. This study included 1,382 patients from 11 centers in the United States and East/Southeast Asia. Cirrhosis was present in 62% of patients, but under half of these patients had undergone imaging within 12 months of HCC diagnosis. Patients with cirrhosis were more likely to have early stage disease but less often received curative therapy. After adjustment, cirrhosis was not associated with prognosis, but the presence of cancer-related symptoms at diagnosis was associated with poorer prognosis. Conclusion: Cirrhosis was not associated with overall survival in this cohort of MAFLD-related HCC, while diagnosis in the presence of symptoms was associated with poorer prognosis. The HCC surveillance rate in patients with MAFLD-related HCC was disappointingly low in a multicenter cohort.
| S-EPMC7789832 | biostudies-literature
Project description:Most hepatocellular carcinoma (HCC) patients occur on a background of liver cirrhosis, the molecular mechanisms of liver cirrhosis and its progression to HCC remain to be fully elucidated. Single cell differentiation trajectory analysis has been used in cell classification and tumor molecular typing, which correlated with disease progression and patient prognosis. Here we use cell differentiation trajectory analysis to investigate the relevance of liver cirrhosis and HCC. Single-cell RNA sequencing (scRNA-seq) data of liver cirrhosis and bulk RNA-seq and clinical data of HCC were downloaded from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) for analysis. HCC samples were divided into three subtypes, based on differentiation-related genes (DRGs) of liver cirrhosis, each with a different expression profile and overall survival (OS). A two- DRGs (CD34 and RAMP3) based prognostic risk scoring (RS) signature was established which could differentiate OS between high-risk and low-risk groups. And expression levels of CD34 and RAMP3 were predominantly high in endothelial cells. By integrating the RS and clinicopathological features, a nomogram was constructed and can accurately predicted the 1-year, 3-years, and 5-years OS. In conclusion, cell differentiation trajectory of liver cirrhosis can predict the prognosis of HCC, and provides new perspectives on the mechanisms of progression of liver cirrhosis to HCC.
| S-EPMC8960263 | biostudies-literature
Project description:AimSingle-nucleotide polymorphisms (SNPs) in PNPLA3 and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) genes are associated with fatty liver disease (FLD) progression and carcinogenesis. In the present study, we evaluated the characteristics of Japanese FLD patients according to HSD17B13 polymorphisms.MethodsWe enrolled 402 patients who were clinically and pathologically diagnosed with FLD (alcoholic: 63 cases, nonalcoholic: 339 cases) at our hospital in 1990-2018 (228 males; median age: 54.9 [14.6-83.6] years). FLD patients with HSD17B13 A/A (212 cases) and others (A/AA or AA/AA; 190 cases) were compared.ResultsCompared to patients with HSD17B13 A/A and others, those with the A/A genotype showed increased incidence of hepatocellular carcinoma (HCC) (A/A vs. others; 18.4% vs. 9.5%, p = 0.01), cardiovascular diseases (14.2% vs. 4.2%, p < 0.01), and hypertension (56.6% vs. 47.4%, p = 0.06). In patients without A/A, the HCC incidence was significantly reduced in those with alcohol-related FLD, fibrosis-4 index <2.67, and the PNPLA3 CC genotype; however, there was no significant difference in nonalcoholic-FLD. Patients without HSD17B13 A/A showed severe steatosis (77% vs. 88.6%, p < 0.01). New HCC developed in 11 cases and the 5-year incidence rate of HCC was 3.3% in patients with both PNPLA3 GG/GC and HSD17B13 A/A, which was significantly higher than the rate for those with other SNP profiles (0.6%, p = 0.03).ConclusionsInhibiting HSD17B13 activity may prevent HCC development, particularly in alcohol-related FLD and low-risk patients. Therefore, combinations of SNPs and other risk factors can be used for screening FLD-HCC.
| S-EPMC10524060 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the fourth cause of cancer related mortality, and its incidence is rapidly increasing. Viral hepatitis, alcohol abuse, and exposure to hepatotoxins are major risk factors, but nonalcoholic fatty liver disease (NAFLD) associated with obesity, insulin resistance, and type 2 diabetes, is an increasingly recognized trigger, especially in developed countries. Older age, severity of insulin resistance and diabetes, and iron overload have been reported to predispose to HCC in this context. Remarkably, HCCs have been reported in non-cirrhotic livers in a higher proportion of cases in NAFLD patients than in other etiologies. Inherited factors have also been implicated to explain the different individual susceptibility to develop HCC, and their role seems magnified in fatty liver, where only a minority of affected subjects progresses to cancer. In particular, the common I148M variant of the PNPLA3 gene influencing hepatic lipid metabolism influences HCC risk independently of its effect on the progression of liver fibrosis. Recently, rare loss-of-function mutations in Apolipoprotein B resulting in very low density lipoproteins hepatic retention and in Telomerase reverse transcriptase influencing cellular senescence have also been linked to HCC in NAFLD. Indeed, hepatic stellate cells senescence has been suggested to bridge tissue aging with alterations of the intestinal microbiota in the pathogenesis of obesity-related HCC. A deeper understanding of the mechanisms mediating hepatic carcinogenesis during insulin resistance, and the identification of its genetic determinants will hopefully provide new diagnostic and therapeutic tools.
| S-EPMC4177475 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) is one of the deadliest cancers and is mainly developed from chronic liver diseases such as hepatitis-B infection-associated liver cirrhosis (LC). The progression from LC to HCC makes the detection of diagnostic biomarkers to be challenging. Hence, there have been constant efforts to improve on identifying the critical and predictive changes accompanying the disease progression.MethodsIn this study, we looked to using the mass spectrometry mediated spatial metabolomics technique to simultaneous examine hundreds of metabolites in an untargeted fashion. Additionally, metabolic profiles were compared between six subregions within the HCC tissue to collect spatial information.ResultsThrough those metabolites, altered metabolic pathways in LC and HCC were identified. Specifically, the amino acid metabolisms and the glycerophospholipid metabolisms experienced the most changes. Many of the altered metabolites and metabolic pathways were able to be connected through the urea cycle.ConclusionsThe identification of the key metabolites and pathways can expand our knowledge on HCC metabolic reprogramming and help us exam potential biomarkers for earlier detection of the malignant disease progression.
| S-EPMC9686114 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2014-02-28 | GSE27641 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-02-28 | E-GEOD-27641 | biostudies-arrayexpress
Project description:The presence of cirrhosis in nonalcoholic-fatty-liver-disease (NAFLD) is the most important predictor of liver-related mortality. Limited data exist concerning the diagnostic accuracy of gut-microbiome-derived signatures for detecting NAFLD-cirrhosis. Here we report 16S gut-microbiome compositions of 203 uniquely well-characterized participants from a prospective twin and family cohort, including 98 probands encompassing the entire spectrum of NAFLD and 105 of their first-degree relatives, assessed by advanced magnetic-resonance-imaging. We show strong familial correlation of gut-microbiome profiles, driven by shared housing. We report a panel of 30 features, including 27 bacterial features with discriminatory ability to detect NAFLD-cirrhosis using a Random Forest classifier model. In a derivation cohort of probands, the model has a robust diagnostic accuracy (AUROC of 0.92) for detecting NAFLD-cirrhosis, confirmed in a validation cohort of relatives of proband with NAFLD-cirrhosis (AUROC of 0.87). This study provides evidence for a fecal-microbiome-derived signature to detect NAFLD-cirrhosis.
| S-EPMC6440960 | biostudies-literature