Predictive and preventive significance of AMPK activation on hepatocarcinogenesis in patients with liver cirrhosis.
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ABSTRACT:
SUBMITTER: Yang X
PROVIDER: S-EPMC5833839 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
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Project description:In almost all cases, hepatocellular carcinoma (HCC) develops as the endpoint of a sequence that starts with chronic liver injury, progresses to liver cirrhosis, and finally, over years and decades, results in liver cancer. Recently, the role of non-coding RNA such as microRNA (miRNA) has been demonstrated in the context of chronic liver diseases and HCC. Moreover, data from a phase II trial suggested a potential role of microRNAs as therapeutics in hepatitis-C-virus infection, representing a significant risk factor for development of liver cirrhosis and HCC. Despite progress in the clinical management of chronic liver diseases, pharmacological treatment options for patients with liver cirrhosis and/or advanced HCC are still limited. With their potential to regulate whole networks of genes, miRNA might be used as novel therapeutics in these patients but could also serve as biomarkers for improved patient stratification. In this review, we discuss available data on the role of miRNA in the transition from liver cirrhosis to HCC. We highlight opportunities for clinical translation and discuss open issues applicable to future developments.
| S-EPMC7867354 | biostudies-literature
Project description:Abstract Background and Aim Polypharmacy and sarcopenia are increasing public health problems worldwide. However, data on the prevalence, association, and prognostic significance of polypharmacy and sarcopenia in patients with liver cirrhosis are limited. Methods Polypharmacy and sarcopenia were assessed in 239 patients with liver cirrhosis. Polypharmacy was defined as the daily use of six or more medications, and sarcopenia was diagnosed based on muscle strength and mass evaluated on computed tomography. The association between polypharmacy and sarcopenia and their effects on mortality were analyzed using logistic regression and Cox proportional hazards models. Results Among the 239 patients, 52% were men, the median age was 68 years, and the number of medications used per patient was 6. Further, 53% and 29% patients had polypharmacy and sarcopenia, respectively. The number of medications used and the prevalence of sarcopenia increased with age. Patients with polypharmacy and sarcopenia had similar characteristics, such as older age, increased medication use, advanced liver disease, and decreased muscle strength and mass. After adjusting for confounders, polypharmacy was significantly associated with sarcopenia (odds ratio, 2.11; 95% confidence interval [CI], 1.07–4.17). During the median follow‐up of 2.2 years, 62 (26%) patients died. Polypharmacy (hazard ratio [HR], 1.83; 95% CI, 1.01–3.37) and sarcopenia (HR, 2.00; 95% CI, 1.12–3.50) independently predicted mortality. The prognostic significance of polypharmacy was more prominent in older adults than in younger adults (HR, 2.31; 95% CI, 1.01–5.67). Conclusion Polypharmacy and sarcopenia are interrelated and associated with poor prognosis in patients with cirrhosis. Further large, prospective, population‐based studies are required to validate these findings. Polypharmacy and sarcopenia are increasing public health problems worldwide, but the prevalence, association, and prognostic significance of polypharmacy and sarcopenia in patients with liver cirrhosis remain unclear. Our data indicate that polypharmacy and sarcopenia are common, interconnected, and associated with mortality in patients with cirrhosis.
| S-EPMC10037035 | biostudies-literature
Project description:Autophagy is a pathophysiological phenomenon in liver cirrhosis that can further progress into hepatocarcinoma. Liver cancer stem cells (CSCs) are believed to initiate hepatocarcinogenesis. To investigate the precise mechanism related to the origin of CSCs in liver cirrhosis and hepatocarcinogenesis, we labeled Axin2+ hepatic cells with EGFP in Axin2Cre;Rosa26EGFP transgenic rats, and then stratified clinical and rat liver cirrhosis samples by autophagy flux. Clinical follow-up and lineage tracing in transgenic rat liver cirrhosis revealed that while Axin2/EGFP+ hepatic cells were present in normal livers and cirrhotic livers without aberrant autophagy, hepatic Axin2/EGFP+CD90+ cells were generated exclusively in cirrhotic livers with aberrant autophagy and promoted hepatocarcinogenesis. Aberrant autophagy in liver cirrhosis resulted in hepatocyte growth factor (HGF) expression, leading to activation of Met/JNK and Met/STAT3 signaling in sorted hepatic Axin2/EGFP+ cells and their transition into Axin2/EGFP+CD90+ cells that possess CSC properties. In a transgenic rat liver cirrhosis model, induction or inhibition of autophagy in cirrhotic livers by systemic administration of rapamycin or chloroquine or transfection with Atg3- and Atg7-shRNAs significantly induced or suppressed HGF expression, which in turn increased or reduced generation of EGFP+CD90+ hepatic cells by activating or inactivating Met/JNK and Met/STAT3 signaling, thereby promoting or preventing hepatocarcinogenesis. Systemic treatment with HGF-shRNA, SP600125 or stattic also reduced generation of EGFP(Axin2)+ hepatic cell-originated CD90+ CSCs in aberrant autophagic cirrhotic livers by inactivating HGF/Met/JNK or HGF/Met/STAT3 signaling, further preventing hepatocarcinogenesis. These data suggest that activation of Met/JNK and Met/STAT3 signaling in Axin2+ hepatic cells via autophagy-dependent HGF expression and the resultant generation of Axin2+CD90+ CSCs is a major mechanism of hepatocarcinogenesis in cirrhotic livers.
| S-EPMC5717078 | biostudies-literature
Project description:Malnutrition is common in patients with chronic liver disease. We aimed to evaluate malnutrition assessment tools in predicting severity and survival of patients with liver cirrhosis.We examined patients with liver cirrhosis. Nutritional evaluation was performed on admission, using subjective global assessment (SGA), handgrip strength (HGS), and anthropometry. Patients were followed up for 6 months.We included 100 patients, 72 men, with mean age of 59.2 years. According to disease severity, patients were 23% Child-Pugh A, 46% Child-Pugh B, and 31% Child-Pugh C. SGA and HGS significantly correlated with Child-Pugh, MELD, and MELD-Na scores on admission. At 6 months follow-up, 80.4% (78 of 97) of patients survived, while 3 patients were lost from observation. Survival was predicted by SGA (1 death in 32 patients SGA A, 8 deaths in 46 patients SGA B, and 9 deaths in 19 patients SGA C, p = 0.001) and HGS (25.1 ± 8.5 in deceased versus 30.6 ± 10.9 in survivors, p = 0.046). The mean BMI and MAMC values did not significantly differ between patients who survived or were deceased at 6 months.HGS and SGA may predict severity and short-term survival in cirrhotic patients.
| S-EPMC5540494 | biostudies-other
Project description:Background & aimThe association of circulating sphingosine-1-phosphate (S1P), a bioactive lipid involved in various cellular processes, and related metabolites such as sphinganine-1-phosphate (SA1P) and sphingosine (SPH) with mortality in patients with end-stage liver disease is investigated in the presented study. S1P as a bioactive lipid mediator, is involved in several cellular processes, however, in end-stage liver disease its role is not understood.MethodsThe study cohort consisted of 95 patients with end-stage liver disease and available information on one-year outcome. The median MELD (Model for end-stage liver disease) score was 12.41 (Range 6.43-39.63). The quantification of sphingolipids in citrated plasma specimen was performed after methanolic protein precipitation followed by hydrophilic interaction liquid chromatography and tandem mass spectrometric detection.ResultsS1P and SA1P displayed significant correlations with the MELD score. Patients with circulating S1P levels below the lowest tertile (110.68 ng/ml) showed the poorest one-year survival rate of only 57.1%, whereas one-year survival rate in patients with S1P plasma levels above 165.67 ng/ml was 93.8%. In a multivariate cox regression analysis including platelet counts, concentrations of hemoglobin and MELD score, S1P remained a significant predictor for three-month and one-year mortality.ConclusionsLow plasma S1P concentrations are highly significantly associated with prognosis in end-stage liver disease. This association is independent of the stage of liver disease. Further studies should be performed to investigate S1P, its role in the pathophysiology of liver diseases and its potential for therapeutic interventions.
| S-EPMC5363961 | biostudies-literature
Project description:BackgroundThe relationship between hepatitis B surface antigen (HBsAg)-positive carrier status and liver cancer has been extensively studied. However, the epigenetic changes that occur during progression from HBsAg-positive carrier status or cirrhosis to liver cancer are unknown. The epigenetic modification of DNA hydroxymethylation is critical in tumor development. Further, 5-hydroxymethylcytosine (5hmC) is an important base for DNA demethylation and epigenetic regulation. It is also involved in the assembly of chromosomes and the regulation of gene expression. However, the mechanism of action of 5hmC in HBsAg-positive carriers or patients with cirrhosis who develop liver cancer has not been fully elucidated.AimTo investigate the possible epigenetic mechanism of HBsAg-positive carriers and hepatocellular carcinoma (HCC) progression from cirrhosis.MethodsForty HBsAg-positive carriers, forty patients with liver cirrhosis, and forty patients with liver cancer admitted to the First People's Hospital of Yongkang between March 2020 and November 2021 were selected as participants. Free DNA was extracted using a cf-DNA kit. cfDNA was extracted by 5hmC DNA sequencing for principal component analysis, the expression profiles of the three groups of samples were detected, and the differentially expressed genes (DEGs) modified by hydroxymethylation were screened. Bioinformatic analysis was used to enrich DEGs, such as in biological pathways.ResultsA total of 16455 hydroxymethylated genes were identified. Sequencing results showed that 32 genes had significant 5hmC modification differences between HBsAg carriers and liver cancer patients, of which 30 were upregulated and 2 downregulated in patients with HCC compared with HBsAg-positive carriers. Significant 5hmC modification differences between liver cirrhosis and liver cancer patients were identified in 20 genes, of which 17 were upregulated and 3 were downregulated in patients with HCC compared with those with cirrhosis. These genes may have potential loci that are undiscovered or unelucidated, which contribute to the development and progression of liver cancer. Analysis of gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes showed that the major signaling pathways involved in the differential genes were biliary secretion and insulin secretion. The analysis of protein interactions showed that the important genes in the protein-protein interaction network were phosphoenolpyruvate carboxykinase and solute carrier family 2.ConclusionThe occurrence and development of liver cancer involves multiple genes and pathways, which may be potential targets for preventing hepatitis B carriers from developing liver cancer.
| S-EPMC10080600 | biostudies-literature
Project description:Several polymorphisms in the vitamin D receptor (VDR) are associated with the occurrence of chronic liver disease. Here, we investigated the association between BsmI, ApaI, TaqI and FokI VDR polymorphisms and the severity of liver cirrhosis in relation to serum cytokine and lipopolysaccharide binding protein (LBP) levels and their role on survival in cirrhotic patients. We found that patients harboring the BB genotype had higher MELD score, and they were mainly at CP stage C; patients harboring the AA genotype had increased LBP, IL-1? and IL-8 levels, and they were mostly at CP stage C; TT genotype carriers had higher MELD score and they were mainly at CP stage C and FF genotype carriers had lower IL-1? levels when compared to Bb/bb, Aa/aa, Tt/tt and Ff/ff genotypes respectively. In the multivariate analysis ApaI, BsmI and TaqI polymorphisms were independently associated with liver cirrhosis severity. In the survival analysis, the independent prognostic factors were CP score, MELD and the FF genotype. Our results indicate that the ApaI, TaqI and BsmI polymorphisms are associated with the severity of liver cirrhosis, through the immunoregulatory process. Survival is related to the FF genotype of FokI polymorphism, imparting a possible protective role in liver cirrhosis.
| S-EPMC6138740 | biostudies-literature
Project description:Strong gut microbiome biomarkers for Liver cirrhosis
| PRJEB6336 | ENA
Project description:Tolvaptan has been approved in Japan for the treatment of hepatic edema. An important consideration in providing a clinical benefit to patients with liver cirrhosis is the improvement of ascites-related clinical symptoms. In the present post hoc analysis, we aimed to identify factors that were predictive of the potency of tolvaptan, and to examine the relationship between changes in initial urine volume and improvement in ascites-related clinical symptoms.This post hoc analysis was based on three previous phase 2 and 3 clinical trials of tolvaptan in patients with liver cirrhosis. Predictive factors associated with a change in initial urine volume were identified. A change of ?500 mL from baseline confirmed the pharmacological action of tolvaptan treatment. The relationship between the change in initial urine volume and improvement in ascites-related clinical symptoms was also examined.A total of 152 patients were enrolled in this study. Body weight and BUN were identified as predictive parameters. Among patients with a change in initial urine volume of ?500 mL, 75 % demonstrated improvement in ascites-related clinical symptoms, while no improvement was seen in those with a change of <500 mL. None of the patients with initial urine volume of <500 mL showed resolution of symptoms.Change in urine volume was affected by both baseline body weight and BUN in tolvaptan-treated subjects. Higher urine output was associated with improvements in ascites-related clinical symptoms.
| S-EPMC5281662 | biostudies-literature
Project description:Liver cirrhosis is an increasing public health threat worldwide. Malnutrition is a serious complication of cirrhosis and is associated with worse outcomes. With this review, we aim to describe the prevalence of malnutrition, pathophysiological mechanisms, diagnostic tools and therapeutic targets to treat malnutrition. Malnutrition is frequently underdiagnosed and occurs-depending on the screening methods used and patient populations studied-in 5-92% of patients. Decreased energy and protein intake, inflammation, malabsorption, altered nutrient metabolism, hypermetabolism, hormonal disturbances and gut microbiome dysbiosis can contribute to malnutrition. The stepwise diagnostic approach includes a rapid prescreen, the use of a specific screening tool, such as the Royal Free Hospital Nutritional Prioritizing Tool and a nutritional assessment by dieticians. General dietary measures-especially the timing of meals-oral nutritional supplements, micronutrient supplementation and the role of amino acids are discussed. In summary malnutrition in cirrhosis is common and needs more attention by health care professionals involved in the care of patients with cirrhosis. Screening and assessment for malnutrition should be carried out regularly in cirrhotic patients, ideally by a multidisciplinary team. Further research is needed to better clarify pathogenic mechanisms such as the role of the gut-liver-axis and to develop targeted therapeutic strategies.
| S-EPMC7915767 | biostudies-literature