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Sökning: L773:2471 254X

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1.
  • Aberg, Fredrik, et al. (författare)
  • A Dynamic Aspartate-to-Alanine Aminotransferase Ratio Provides Valid Predictions of Incident Severe Liver Disease
  • 2021
  • Ingår i: HEPATOLOGY COMMUNICATIONS. - : John Wiley & Sons. - 2471-254X.
  • Tidskriftsartikel (refereegranskat)abstract
    • The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations.
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2.
  • Bartlett, Sofia R., et al. (författare)
  • Sequencing of Hepatitis C Virus for Detection of Resistance to Direct-Acting Antiviral Therapy : A Systematic Review
  • 2017
  • Ingår i: HEPATOLOGY COMMUNICATIONS. - : JOHN WILEY & SONS LTD. - 2471-254X. ; 1:5, s. 379-390
  • Forskningsöversikt (refereegranskat)abstract
    • The significance of the clinical impact of direct-acting antiviral (DAA) resistance-associated substitutions (RASs) in hepatitis C virus (HCV) on treatment failure is unclear. No standardized methods or guidelines for detection of DAA RASs in HCV exist. To facilitate further evaluations of the impact of DAA RASs in HCV, we conducted a systematic review of RAS sequencing protocols, compiled a comprehensive public library of sequencing primers, and provided expert guidance on the most appropriate methods to screen and identify RASs. The development of standardized RAS sequencing protocols is complicated due to a high genetic variability and the need for genotype- and subtype-specific protocols for multiple regions. We have identified several limitations of the available methods and have highlighted areas requiring further research and development. The development, validation, and sharing of standardized methods for all genotypes and subtypes should be a priority.
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3.
  • Caputo, Mara, et al. (författare)
  • STE20-Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes
  • 2021
  • Ingår i: Hepatology Communications. - 2471-254X. ; 5:7, s. 1183-1200
  • Tidskriftsartikel (refereegranskat)abstract
    • Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide, primarily because of the massive global increase in obesity. Despite intense research efforts in this field, the factors that govern the initiation and subsequent progression of NAFLD are poorly understood, which hampers the development of diagnostic tools and effective therapies in this area of high unmet medical need. Here we describe a regulator in molecular pathogenesis of NAFLD: STE20-type protein kinase MST4. We found that MST4 expression in human liver biopsies was positively correlated with the key features of NAFLD (i.e., hepatic steatosis, lobular inflammation, and hepatocellular ballooning). Furthermore, the silencing of MST4 attenuated lipid accumulation in human hepatocytes by stimulating beta-oxidation and triacylglycerol secretion, while inhibiting fatty acid influx and lipid synthesis. Conversely, overexpression of MST4 in human hepatocytes exacerbated fat deposition by suppressing mitochondrial fatty acid oxidation and triacylglycerol efflux, while enhancing lipogenesis. In parallel to these reciprocal alterations in lipid storage, we detected substantially decreased or aggravated oxidative/endoplasmic reticulum stress in human hepatocytes with reduced or increased MST4 levels, respectively. Interestingly, MST4 protein was predominantly associated with intracellular lipid droplets in both human and rodent hepatocytes. Conclusion: Together, our results suggest that hepatic lipid droplet-decorating protein MST4 is a critical regulatory node governing susceptibility to NAFLD and warrant future investigations to address the therapeutic potential of MST4 antagonism as a strategy to prevent or mitigate the development and aggravation of this disease.
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4.
  • Dongiovanni, Paola, et al. (författare)
  • Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease.
  • 2018
  • Ingår i: Hepatology communications. - 2471-254X. ; 2:6, s. 666-675
  • Tidskriftsartikel (refereegranskat)abstract
    • Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross-sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.42-0.95; P = 0.03) and clinically significant fibrosis (OR, 0.35; 95% CI, 0.14-0.87; P = 0.02) and with reduced circulating cholesterol (P = 0.02). This translated into protection against hepatocellular carcinoma development (OR, 0.22; 95% CI, 0.07-0.70; P = 0.01). At the population level, the rs4841132 variation was not associated with nonalcoholic or nonviral diseases of the liver but was associated with lower cholesterol (P = 1.7 × 10-8). In individuals with obesity, the A allele protecting against steatosis was associated with increased PPP1R3B messenger RNA expression and activation of lipid oxidation and with down-regulation of pathways related to lipid metabolism, inflammation, and cell cycle. Conclusion: The rs4841132 A allele is associated with protection against hepatic steatosis and fibrosis in individuals at high risk of NAFLD but not in the general population and against dyslipidemia. The mechanism may be related to modulation of PPP1R3B expression and hepatic lipid metabolism. (Hepatology Communications 2018;2:666-675).
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6.
  • Gilg, Stefan, et al. (författare)
  • The Molecular Adsorbent Recirculating System in Posthepatectomy Liver Failure : Results From a Prospective Phase I Study
  • 2018
  • Ingår i: HEPATOLOGY COMMUNICATIONS. - : JOHN WILEY & SONS LTD. - 2471-254X. ; 2:4, s. 445-454
  • Tidskriftsartikel (refereegranskat)abstract
    • Posthepatectomy liver failure (PHLF) represents the single most important cause of postoperative mortality after major liver resection, yet no effective treatment option is available. Extracorporeal liver support devices might be helpful, but systematic studies are lacking. Accordingly, we aimed to assess the safety and feasibility of the Molecular Adsorbent Recirculating System (MARS) in patients with PHLF. Between December 2012 and May 2015, a total of 206 patients underwent major or extended hepatectomy, and 10 consecutive patients with PHLF (according to the Balzan 50: 50 criteria) were enrolled into the study. MARS treatment was initiated on postoperative day 5-7, and five to seven consecutive treatment sessions were completed for each patient. In total, 59 MARS cycles were implemented, and MARS was initiated and completed without major complications in any patient. However, 1 patient developed an immense asymptomatic hyperbilirubinemia (without encephalopathy), 1 had repeated clotting problems in the MARS filter, and 2 patients experienced access problems with the central venous line. Otherwise, no adverse events were observed. In 9 patients, the bilirubin level and international normalized ratio decreased significantly (P < 0.05) during MARS treatment. The 60- and 90-day mortality was 0% and 10%, respectively. Among the 9 survivors, 4 still had liver dysfunction at 90 days postoperatively. Five patients were alive 1 year postoperatively without any signs of liver dysfunction or disease recurrence. Conclusion: The use of MARS in PHLF is feasible and safe and improves liver function in patients with PHLF. In the present study, 60- and 90-day mortality rates were unexpectedly low compared to a historical control group. The impact of MARS treatment on mortality in PHLF should be further evaluated in a randomized controlled clinical trial.
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7.
  • Hagstrom, H., et al. (författare)
  • Outcomes of Pregnancy in Mothers With Cirrhosis: A National Population-Based Cohort Study of 1.3 Million Pregnancies
  • 2018
  • Ingår i: Hepatology Communications. - : John Wiley & Sons. - 2471-254X. ; 2:11, s. 1299-1305
  • Tidskriftsartikel (refereegranskat)abstract
    • There are limited data on pregnancy outcomes in women with cirrhosis. To address this gap, we examined the records of singleton births from Sweden's National Patient Register (NPR), Cause of Death Register (CDR), and Medical Birth Register (MBR) between 1997 and 2011 to assess exposure and pregnancy-related and liver-related outcomes of pregnant women with cirrhosis. Exposure status was defined as having an International Classification of Diseases (ICU) code for cirrhosis obtained prior to or during pregnancy. Poisson regression with cluster-robust standard errors was used to estimate relative risks (RRs) adjusted for maternal age, smoking, and body mass index (BMI). We identified 103 pregnancies in women with cirrhosis and compared these to 1,361,566 pregnancies in women without cirrhosis. Pregnancies in women with cirrhosis were at increased risk of caesarean delivery (36% versus 16%, respectively; adjusted RR [aRR], 2.00; 95% confidence interval [CI] 1.47-2.73), low birth weight (15% versus 3%; aRR, 3.87; 95% CI, 2.11-7.06), and preterm delivery (19% versus 5%; aRR, 3.51; 95% CI, 2.16-5.72). Rates of maternal mortality during pregnancy (no cases), gestational diabetes, preeclampsia, small for gestational age, congenital malformations, and stillbirth were not increased when compared to the pregnant women without cirrhosis. There were 12 hospitalizations during pregnancy due to liver-related events, including one case with bleeding esophageal varices. Conclusion: Women with cirrhosis are at increased risk for adverse pregnancy outcomes. However, severe maternal and fetal adverse events were rare in our study, and most pregnancies in women with cirrhosis ended without complications.
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8.
  • Hagström, Hannes, et al. (författare)
  • Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease : A long-term follow-up study.
  • 2018
  • Ingår i: Hepatology communications. - : John Wiley & Sons. - 2471-254X. ; 2:1, s. 48-57
  • Tidskriftsartikel (refereegranskat)abstract
    • Most patients with nonalcoholic fatty liver disease (NAFLD) are overweight or obese. However, a significant proportion of patients have a normal body mass index (BMI), denoted as lean NAFLD. The long-term prognosis of lean NAFLD is unclear. We conducted a cohort study of 646 patients with biopsy-proven NAFLD. Patients were defined as lean (BMI < 25.0), overweight (BMI 25.0-29.9), or obese (BMI ≥ 30.0) at the time of biopsy. Each case was matched for age, sex, and municipality to 10 controls. Overall mortality and development of severe liver disease were evaluated using population-based registers. Cox regression models adjusted for age, sex, type 2 diabetes, and fibrosis stage were used to examine the long-term risk of mortality and liver-related events in lean and nonlean NAFLD. Lean NAFLD was seen in 19% of patients, while 52% were overweight and 29% were obese. Patients with lean NAFLD were older, had lower transaminases, lower stages of fibrosis, and lower prevalence of nonalcoholic steatohepatitis at baseline compared to patients with a higher BMI. During a mean follow-up of 19.9 years (range 0.4-40 years) representing 12,631 person years and compared to patients who were overweight, patients with lean NAFLD had no increased risk for overall mortality (hazard ratio 1.06; P =  0.73) while an increased risk for development of severe liver disease was found (hazard ratio 2.69; P =  0.007). Conclusion: Although patients with lean NAFLD have lower stages of fibrosis, they are at higher risk for development of severe liver disease compared to patients with NAFLD and a higher BMI, independent of available confounders. (Hepatology Communications 2018;2:48-57).
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9.
  • Jungwirth, E., et al. (författare)
  • Meta-analysis and Consolidation of Farnesoid X Receptor Chromatin Immunoprecipitation Sequencing Data Across Different Species and Conditions
  • 2021
  • Ingår i: Hepatology Communications. - 2471-254X. ; 5:10, s. 1721-1736
  • Tidskriftsartikel (refereegranskat)abstract
    • Farnesoid X receptor (FXR) is a nuclear receptor that controls gene regulation of different metabolic pathways and represents an upcoming drug target for various liver diseases. Several data sets on genome-wide FXR binding in different species and conditions exist. We have previously reported that these data sets are heterogeneous and do not cover the full spectrum of potential FXR binding sites. Here, we report the first meta-analysis of all publicly available FXR chromatin immunoprecipitation sequencing (ChIP-seq) data sets from mouse, rat, and human across different conditions using a newly generated analysis pipeline. All publicly available single data sets were biocurated in a standardized manner and compared on every relevant level from raw reads to affected functional pathways. Individual murine data sets were then virtually merged into a single unique "FXR binding atlas" spanning all potential binding sites across various conditions. Comparison of the single biocurated data sets showed that the overlap of FXR binding sites between different species is modest and ranges from 48% (mouse-human) to 55% (mouse-rat). Moreover, in vivo data among different species are more similar than human in vivo data compared to human in vitro data. The consolidated murine global FXR binding atlas virtually increases sequencing depth and allows recovering more and novel potential binding sites and signaling pathways that were missed in the individual data sets. The FXR binding atlas is publicly searchable (). Conclusion: Published single FXR ChIP-seq data sets and large-scale integrated omics data sets do not cover the full spectrum of FXR binding. Combining different individual data sets and creating an "FXR super-binding atlas" enhances understanding of FXR signaling capacities across different conditions. This is important when considering the potential wide spectrum for drugs targeting FXR in liver diseases.
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  • Resultat 1-10 av 14
  • [1]2Nästa

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