Journal of Clinical Medicine

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14 pages, 539 KiB

Open AccessArticle

Nonalcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma: Clinical Patterns, Outcomes, and Prognostic Factors for Overall Survival—A Retrospective Analysis of a Slovak Cohort

by Dominik Safcak, Sylvia Drazilova, Jakub Gazda, Igor Andrasina, Svetlana Adamcova-Selcanova, Radovan Barila, Michal Mego, Marek Rac, Lubomir Skladany, Miroslav Zigrai, Martin Janicko and Peter Jarcuska

J. Clin. Med. 2021, 10(14), 3186; https://doi.org/10.3390/jcm10143186 - 20 Jul 2021

Cited by 4 | Viewed by 2786

Abstract

Objective: To compare NAFLD-related HCC and other etiology-related HCC and to describe predictive factors for survival in patients with NAFLD-related HCC independent of the BCLC staging system. Methods: We performed a multicenter longitudinal retrospective observational study of patients diagnosed with HCC during the [...] Read more.

Objective: To compare NAFLD-related HCC and other etiology-related HCC and to describe predictive factors for survival in patients with NAFLD-related HCC independent of the BCLC staging system. Methods: We performed a multicenter longitudinal retrospective observational study of patients diagnosed with HCC during the period from 2010 through 2016. Results: 12.59% of patients had NAFLD-related HCC, and 21.91% had either NAFLD or cryptogenic etiology. NAFLD-related HCC patients were younger (p = 0.0007), with a higher proportion of women (p < 0.001) compared to other etiology-related HCC patients. The NAFLD group had a significantly lower proportion of patients with liver cirrhosis at the time of HCC diagnosis (p < 0.0001), and they were more frequently diagnosed with both diabetes and metabolic syndrome when compared to other etiology-related HCC (p < 0.0001). We did not find any difference in the overall survival or in the progression-free survival between NAFLD-related and other etiology-related HCC patients staged as BCLC B and BCLC C. NAFLD-related HCC patients with three or more liver lesions had a shorter overall survival when compared to patients with one or two liver lesions (p = 0.0097), while patients with baseline CRP values of ≥5 mg/L or with PLR ≥ 150 had worse overall survival (p = 0.012 and p = 0.0028, respectively). ALBI Grade 3 predicted worse overall survival compared to ALBI Grade 1 or 2 (p = 0.00021). In NAFLD-related HCC patients, PLR and ALBI remained significant predictors of overall survival even after adjusting for BCLC. Conclusion: NAFLD-related HCC patients have a similar prognosis when compared to other etiology-related HCC. In NAFLD-related HCC patients, ALBI and PLR are significant predictors of the overall survival independent of the BCLC staging system. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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16 pages, 1552 KiB

Open AccessArticle

Influence of Psychological Biomarkers on Therapeutic Adherence by Patients with Non-Alcoholic Fatty Liver Disease: A Moderated Mediation Model

by Jesús Funuyet-Salas, Agustín Martín-Rodríguez, María Ángeles Pérez-San-Gregorio and Manuel Romero-Gómez

J. Clin. Med. 2021, 10(10), 2208; https://doi.org/10.3390/jcm10102208 - 20 May 2021

Cited by 8 | Viewed by 2853

Abstract

Our aim was to analyze whether depressive symptoms mediated the association between physical quality of life (QoL) and adherence to physical activity in patients with non-alcoholic fatty liver disease (NAFLD), as well as the association between social support and adherence to diet. We [...] Read more.

Our aim was to analyze whether depressive symptoms mediated the association between physical quality of life (QoL) and adherence to physical activity in patients with non-alcoholic fatty liver disease (NAFLD), as well as the association between social support and adherence to diet. We also examined whether self-efficacy exerted a moderating role in these associations. QoL (SF-12), social support (MSPSS), depressive symptoms (HADS), self-efficacy (GSE), physical activity (IPAQ) and diet (MEDAS) were evaluated in 413 biopsy-proven NAFLD patients. Mediation and moderated mediation models were conducted using the SPSS PROCESS v3.5 macro. Results showed that depressive symptoms mediated the relationship between physical QoL and adherence to physical activity (indirect effect = 6.248, CI = 1.917–10.727), as well as the relationship between social support and adherence to diet (indirect effect = 0.148, CI = 0.035–0.275). Self-efficacy also moderated the indirect effects of QoL and social support on therapeutic adherence through depressive symptoms. Specifically, the higher self-efficacy was, the lower the negative impact on the NAFLD patient’s mental health. In conclusion, self-efficacy is defined as a protective factor for therapeutic adherence by NAFLD patients with a psychosocial risk profile. Self-efficacy should, therefore, be a main psychological target in future multidisciplinary NAFLD approaches. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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11 pages, 1146 KiB

Open AccessArticle

Performance of Fatty Liver Index in Identifying Non-Alcoholic Fatty Liver Disease in Population Studies. A Meta-Analysis

by Marco Castellana, Rossella Donghia, Vito Guerra, Filippo Procino, Luisa Lampignano, Fabio Castellana, Roberta Zupo, Rodolfo Sardone, Giovanni De Pergola, Francesco Romanelli, Pierpaolo Trimboli and Gianluigi Giannelli

J. Clin. Med. 2021, 10(9), 1877; https://doi.org/10.3390/jcm10091877 - 26 Apr 2021

Cited by 51 | Viewed by 3152

Abstract

Background. Fatty liver index (FLI) is a non-invasive tool used to stratify the risk of non-alcoholic fatty liver disease (NAFLD) in population studies; whether it can be used to exclude or diagnose this disorder is unclear. We conducted a meta-analysis to assess the [...] Read more.

Background. Fatty liver index (FLI) is a non-invasive tool used to stratify the risk of non-alcoholic fatty liver disease (NAFLD) in population studies; whether it can be used to exclude or diagnose this disorder is unclear. We conducted a meta-analysis to assess the prevalence of NAFLD in each FLI class and the performance of FLI in detecting NAFLD. Methods. Four databases were searched until January 2021 (CRD42021231367). Original articles included were those reporting the performance of FLI and adopting ultrasound, computed tomography, or magnetic resonance as a reference standard. The numbers of subjects with NAFLD in FLI classes <30, 30–60, and ≥60, and the numbers of subjects classified as true/false positive/negative when adopting 30 and 60 as cut-offs were extracted. A random-effects model was used for pooling data. Results. Ten studies were included, evaluating 27,221 subjects without secondary causes of fatty liver disease. The prevalence of NAFLD in the three FLI classes was 14%, 42%, and 67%. Sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio for positive results, likelihood ratio for negative results, and diagnostic odds ratio were 81%, 65%, 53%, 84%, 2.3, 0.3, and 7.8 for the lower cut-off and 44%, 90%, 67%, 76%, 4.3, 0.6, and 7.3 for the higher cut-off, respectively. A similar performance was generally found in studies adopting ultrasound versus other imaging modalities. Conclusions. FLI showed an adequate performance in stratifying the risk of NAFLD. However, it showed only weak evidence of a discriminatory performance in excluding or diagnosing this disorder. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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14 pages, 2126 KiB

Open AccessArticle

Diagnostic Accuracy of Non-Imaging and Ultrasound-Based Assessment of Hepatic Steatosis Using Controlled Attenuation Parameter (CAP) as Reference

by Katarzyna Kozłowska-Petriczko, Ewa Wunsch, Jan Petriczko, Wing-Kin Syn and Piotr Milkiewicz

J. Clin. Med. 2021, 10(7), 1507; https://doi.org/10.3390/jcm10071507 - 4 Apr 2021

Cited by 11 | Viewed by 3000

Abstract

Background & Aims: In view of the limited reliability of biopsies in the assessment of liver fat, a non-invasive, trustworthy, and more accessible method estimating a degree of steatosis is urgently needed. While the controlled attenuation parameter (CAP) is used to quantify hepatic [...] Read more.

Background & Aims: In view of the limited reliability of biopsies in the assessment of liver fat, a non-invasive, trustworthy, and more accessible method estimating a degree of steatosis is urgently needed. While the controlled attenuation parameter (CAP) is used to quantify hepatic fat, its availability in routine practice is limited. Therefore, the aim of this study was to compare the diagnostic accuracy of biomarker- and ultrasound-based techniques for the diagnosis and grading of hepatic steatosis. Methods: This was a prospective study of 167 adults with and without non-alcoholic fatty liver disease. As measured against CAP, we assessed Hamaguchi’s score and the hepatorenal index (HRI), and the following biochemical measures: the fatty liver index, hepatic steatosis index, and lipid accumulation product scores during a single out-patient visit. Area under the receiver operating curve (AUROC) analyses were used to evaluate the diagnostic accuracy of each test and to calculate optimal thresholds for the ultrasound techniques. Results: All non-invasive methods displayed high accuracy in detecting steatosis (mean AUC value ≥ 0.90), with Hamaguchi’s score and the HRI being the most precise. These two tests also had the highest sensitivity and specificity (82.2% and 100%; 86.9% and 94.8%, respectively). We propose new thresholds for Hamaguchi’s score and HRI for hepatic steatosis grading, indicated by optimal sensitivity and specificity. Conclusions: Ultrasound-based techniques are the most accurate for assessing liver steatosis compared to other non-invasive tests. Given the accessibility of ultrasonography, this finding is of practical importance for the assessment of liver steatosis in clinical settings. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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18 pages, 3756 KiB

Open AccessArticle

Inhibition of MLKL Attenuates Necroptotic Cell Death in a Murine Cell Model of Hepatic Ischaemia Injury

by Raji Baidya, Jérémie Gautheron, Darrell H. G. Crawford, Haolu Wang and Kim R. Bridle

J. Clin. Med. 2021, 10(2), 212; https://doi.org/10.3390/jcm10020212 - 8 Jan 2021

Cited by 9 | Viewed by 4473

Abstract

Background: Steatosis in donor livers poses a major risk of organ dysfunction due to their susceptibility to ischaemia-reperfusion (I/R) injury during transplant. Necroptosis, a novel form of programmed cell death, is orchestrated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) [...] Read more.

Background: Steatosis in donor livers poses a major risk of organ dysfunction due to their susceptibility to ischaemia-reperfusion (I/R) injury during transplant. Necroptosis, a novel form of programmed cell death, is orchestrated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), has been implicated in I/R injury. Here we investigated the mechanisms of cell death pathways in an in vitro model of hepato-steatotic ischaemia. Methods: Free fatty acid (FFA) treated alpha mouse liver 12 (AML-12) cells were incubated in oxygen-glucose-deprivation (OGD) conditions as seen during ischaemia. Results: We found that OGD triggered upregulation of insoluble fraction of RIPK3 and MLKL in FFA + OGD cells compared to FFA control cells. We report that intervention with small interfering (si) MLKL and siRIPK3 significantly attenuated cell death in FFA + OGD cells. Absence of activated CASPASE8 and cleaved-CASPASE3, no change in the expression of CASPASE1 and prostaglandin-endoperoxide synthase 2 (Ptgs2) in FFA + OGD treated cells compared to FFA control cells indicated that apoptosis, pyroptosis and ferroptosis, respectively, are unlikely to be active in this model. Conclusion: Our findings indicate that RIPK3-MLKL dependent necroptosis contributed to cell death in our in vitro model. Both MLKL and RIPK3 are promising therapeutic targets to inhibit necroptosis during ischaemic injury in fatty liver. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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9 pages, 443 KiB

Open AccessArticle

Relative Skeletal Muscle Mass Is an Important Factor in Non-Alcoholic Fatty Liver Disease in Non-Obese Children and Adolescents

by Yoowon Kwon and Su Jin Jeong

J. Clin. Med. 2020, 9(10), 3355; https://doi.org/10.3390/jcm9103355 - 19 Oct 2020

Cited by 29 | Viewed by 2996

Abstract

Recently, sarcopenia was identified as a risk factor for non-alcoholic fatty liver disease (NAFLD) in adults. We here investigated the association between skeletal muscle mass (SMM) and NAFLD in non-obese children and adolescents. A retrospective medical chart review was performed for individuals aged [...] Read more.

Recently, sarcopenia was identified as a risk factor for non-alcoholic fatty liver disease (NAFLD) in adults. We here investigated the association between skeletal muscle mass (SMM) and NAFLD in non-obese children and adolescents. A retrospective medical chart review was performed for individuals aged 9–15 years diagnosed with NAFLD. Healthy volunteers aged 9–15 years were recruited as controls. Participants were subject to laboratory tests, abdominal sonography, and multi-frequency bioelectrical impedance analysis. SMM data were calculated as the skeletal muscle-to-body fat ratio (MFR), and the diagnosis of fatty liver was established by abdominal sonography. The control and NAFLD groups included 73 and 53 individuals, respectively. No significant difference was observed in gender and body mass index (BMI) distribution between the groups. Mean MFR was significantly lower in individuals with NAFLD than in those without (0.83 vs. 1.04, p = 0.005). After adjusting for age, sex, BMI, and serum glucose, the risk of having NAFLD was significantly associated with a decreased MFR (p = 0.016). NAFLD is significantly associated with relatively low SMM in non-obese children and adolescents. Increasing SMM, such as weight training, can be suggested as one of the treatment strategies in pediatric NAFLD without obesity. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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15 pages, 458 KiB

Open AccessArticle

Irisin in Liver Cirrhosis

by Michał Kukla, Lubomir Skladany, Tomasz Menżyk, Aleksandra Derra, Dominika Stygar, Magdalena Skonieczna, Dorota Hudy, Katarzyna Nabrdalik, Janusz Gumprecht, Wojciech Marlicz, Anastasios Koulaouzidis and Tomas Koller

J. Clin. Med. 2020, 9(10), 3158; https://doi.org/10.3390/jcm9103158 - 29 Sep 2020

Cited by 16 | Viewed by 2962

Abstract

Background: Sarcopenia is a prevalent muscle abnormality characterized by progressive and generalized loss of skeletal muscle mass and strength, common among patients with decompensated advanced chronic liver disease (dACLD). Irisin is a recently identified myokine, which is mainly expressed and secreted by skeletal [...] Read more.

Background: Sarcopenia is a prevalent muscle abnormality characterized by progressive and generalized loss of skeletal muscle mass and strength, common among patients with decompensated advanced chronic liver disease (dACLD). Irisin is a recently identified myokine, which is mainly expressed and secreted by skeletal muscle. Pointing to the essential role of irisin in metabolic regulation and energy expenditure we hypothesize that it plays an important role in cirrhosis development and progression. Aim: To assess irisin serum levels in patients with dACLD, with different cirrhosis stage and etiology. To analyze relationship between sarcopenia and irisin serum levels. Methods: Serum irisin concentrations were measured with commercially available ELISA kits in 88 cirrhotic patients. Recorded parameters of muscle mass were hand-grip strength (HGS), mid-arm muscle circumference (MAC), and transversal psoas muscle index (TPMI). Results: There was no difference in serum irisin levels between cirrhotic patients with different Child-Pugh (CTP) and model of end-stage liver disease (MELD) score, and those with and without ascites. The Liver Frailty Index (LFI) was significantly higher in patients with more advanced liver disease according to CTP and MELD. There was no association between serum irisin level with MAC (r = 0.04, p = 0.74) nor with TPMI (r = 0.20, p = 0.06). We observed significant negative correlation between serum irisin level and age (r = −0.35, p < 0.001). Conclusions: Serum irisin levels did not correlate with sarcopenia. There was no difference in serum irisin levels between cirrhotic patients with and without diabetes. There was no difference in serum irisin levels among patients with more severe dACLD, although we observed significant LFI increase among patients with more advanced liver disease. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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11 pages, 2071 KiB

Open AccessArticle

Comparative Assessment and External Validation of Hepatic Steatosis Formulae in a Community-Based Setting

by Tae Yang Jung, Myung Sub Kim, Hyun Pyo Hong, Kyung A Kang and Dae Won Jun

J. Clin. Med. 2020, 9(9), 2851; https://doi.org/10.3390/jcm9092851 - 3 Sep 2020

Cited by 33 | Viewed by 3529

Abstract

Several hepatic steatosis formulae have been validated in various cohorts using ultrasonography. However, none of these studies has been validated in a community-based setting using the gold standard method. Thus, the aim of this study was to externally validate hepatic steatosis formulae in [...] Read more.

Several hepatic steatosis formulae have been validated in various cohorts using ultrasonography. However, none of these studies has been validated in a community-based setting using the gold standard method. Thus, the aim of this study was to externally validate hepatic steatosis formulae in community-based settings using magnetic resonance imaging (MRI). A total of 1301 community-based health checkup subjects who underwent liver fat quantification with MRI were enrolled in this study. Diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUROC). Non-alcoholic fatty liver disease (NAFLD) liver fat score showed the highest diagnostic performance with an AUROC of 0.72, followed by Framingham steatosis index (0.70), hepatic steatosis index (HSI, 0.69), ZJU index (0.69), and fatty liver index (FLI, 0.68). There were considerable gray zones in three fatty liver prediction models using two cutoffs (FLI, 28.9%; HSI, 48.9%; and ZJU index, 53.6%). The diagnostic performance of NAFLD liver fat score for detecting steatosis was comparable to that of ultrasonography. The diagnostic agreement was 72.7% between NAFLD liver fat score and 70.9% between ultrasound and MRI. In conclusion, the NAFLD liver fat score showed the best diagnostic performance for detecting hepatic steatosis. Its diagnostic performance was comparable to that of ultrasonography in a community-based setting. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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Review

Jump to: Research

14 pages, 3178 KiB

Open AccessReview

Serum Visfatin Levels in Nonalcoholic Fatty Liver Disease and Liver Fibrosis: Systematic Review and Meta-Analysis

by Abdulrahman Ismaiel, Daniel-Corneliu Leucuta, Stefan-Lucian Popa and Dan L. Dumitrascu

J. Clin. Med. 2021, 10(14), 3029; https://doi.org/10.3390/jcm10143029 - 7 Jul 2021

Cited by 18 | Viewed by 2763

Abstract

(1) Background: Recently, adipokines, including visfatin, have been studied in nonalcoholic fatty liver disease (NAFLD). Several studies evaluated visfatin levels in NAFLD, the presence and severity of hepatic steatosis, liver fibrosis, lobar inflammation, nonalcoholic steatohepatitis (NASH), and gender differences. However, inconclusive results have [...] Read more.

(1) Background: Recently, adipokines, including visfatin, have been studied in nonalcoholic fatty liver disease (NAFLD). Several studies evaluated visfatin levels in NAFLD, the presence and severity of hepatic steatosis, liver fibrosis, lobar inflammation, nonalcoholic steatohepatitis (NASH), and gender differences. However, inconclusive results have been reported. Accordingly, we performed a systematic review and meta-analysis, aiming to address these gaps in evidence. (2) Methods: We performed a systematic electronic search on PubMed, EMBASE, and Cochrane Library using predefined keywords. Diagnosis of NAFLD by liver biopsy or imagistic investigations was accepted. Full articles satisfying our inclusion and exclusion criteria were included. NHLBI quality assessment tools were used to evaluate included studies. The principal summary outcome was the mean difference in visfatin levels. (3) Results: There were 21 studies involving 1923 individuals included in our qualitative assessment, while 14 studies were included in the quantitative assessment. No statistical significance was found assessing visfatin levels in NAFLD [3.361 (95% CI −0.175–6.897)], simple steatosis [7.523 (95% CI −16.221–31.267)], hepatic steatosis severity [−0.279 (95% CI −1.843–1.285)], liver fibrosis [4.133 (95% CI −3.176–11.443)], lobar inflammation [0.358 (95% CI −1.470–2.185)], NASH [−2.038 (95% CI −6.839–2.763)], and gender [(95% CI −0.554–0.556)]. (4) Conclusions: In conclusion, visfatin levels are not associated with NAFLD, presence or severity of hepatic steatosis, liver fibrosis, lobar inflammation, NASH, and gender. However, due to the limited methodological quality of the included studies, results should be interpreted with caution. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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17 pages, 1243 KiB

Open AccessReview

FibroTest for Evaluating Fibrosis in Non-Alcoholic Fatty Liver Disease Patients: A Systematic Review and Meta-Analysis

by Yasaman Vali, Jenny Lee, Jérôme Boursier, René Spijker, Joanne Verheij, M. Julia Brosnan, Quentin M. Anstee, Patrick M. Bossuyt, Mohammad Hadi Zafarmand and on behalf of the LITMUS Systematic Review Team

J. Clin. Med. 2021, 10(11), 2415; https://doi.org/10.3390/jcm10112415 - 29 May 2021

Cited by 39 | Viewed by 4501

Abstract

(1) Background: FibroTest™ is a multi-marker panel, suggested by guidelines as one of the surrogate markers with acceptable performance for detecting fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). A number of studies evaluating this test have been published after publication of [...] Read more.

(1) Background: FibroTest™ is a multi-marker panel, suggested by guidelines as one of the surrogate markers with acceptable performance for detecting fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). A number of studies evaluating this test have been published after publication of the guidelines. This study aims to produce summary estimates of FibroTest™ diagnostic accuracy. (2) Methods: Five databases were searched for studies that evaluated FibroTest™ against liver biopsy as the reference standard in NAFLD patients. Two authors independently screened the references, extracted data, and assessed the quality of included studies. Meta-analyses of the accuracy in detecting different levels of fibrosis were performed using the bivariate random-effects model and the linear mixed-effects multiple thresholds model. (3) Results: From ten included studies, seven were eligible for inclusion in our meta-analysis. Five studies were included in the meta-analysis of FibroTest™ in detecting advanced fibrosis and five in significant fibrosis, resulting in an AUC of 0.77 for both target conditions. The meta-analysis of three studies resulted in an AUC of 0.69 in detecting any fibrosis, while analysis of three other studies showed higher accuracy in cirrhosis (AUC: 0.92). (4) Conclusions: Our meta-analysis showed acceptable performance (AUC > 0.80) of FibroTest™ only in detecting cirrhosis. We observed more limited performance of the test in detecting significant and advanced fibrosis in NAFLD patients. Further primary studies with high methodological quality are required to validate the reliability of the test for detecting different fibrosis levels and to compare the performance of the test in different settings. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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9 pages, 502 KiB

Open AccessReview

Role of Angiogenesis in the Pathogenesis of NAFLD

by Lin Lei, Haquima EI Mourabit, Chantal Housset, Axelle Cadoret and Sara Lemoinne

J. Clin. Med. 2021, 10(7), 1338; https://doi.org/10.3390/jcm10071338 - 24 Mar 2021

Cited by 22 | Viewed by 3318

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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11 pages, 1158 KiB

Open AccessReview

Ex-Vivo Pharmacological Defatting of the Liver: A Review

by Claire Goumard, Célia Turco, Mehdi Sakka, Lynda Aoudjehane, Philippe Lesnik, Eric Savier, Filomena Conti and Olivier Scatton

J. Clin. Med. 2021, 10(6), 1253; https://doi.org/10.3390/jcm10061253 - 18 Mar 2021

Cited by 10 | Viewed by 2450

Abstract

The ongoing organ shortage has forced transplant teams to develop alternate sources of liver grafts. In this setting, ex-situ machine perfusion has rapidly developed as a promising tool to assess viability and improve the function of organs from extended criteria donors, including fatty [...] Read more.

The ongoing organ shortage has forced transplant teams to develop alternate sources of liver grafts. In this setting, ex-situ machine perfusion has rapidly developed as a promising tool to assess viability and improve the function of organs from extended criteria donors, including fatty liver grafts. In particular, normothermic machine perfusion represents a powerful tool to test a liver in full 37 °C metabolism and add pharmacological corrections whenever needed. In this context, many pharmacological agents and therapeutics have been tested to induce liver defatting on normothermic machine perfusion with promising results even on human organs. This systematic review makes a comprehensive synthesis on existing pharmacological therapies for liver defatting, with special focus on normothermic liver machine perfusion as an experimental ex-vivo translational model. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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16 pages, 953 KiB

Open AccessReview

Natural History of NAFLD

by Raluca Pais and Thomas Maurel

J. Clin. Med. 2021, 10(6), 1161; https://doi.org/10.3390/jcm10061161 - 10 Mar 2021

Cited by 27 | Viewed by 5551

Abstract

The epidemiology and the current burden of chronic liver disease are changing globally, with non-alcoholic fatty liver disease (NAFLD) becoming the most frequent cause of liver disease in close relationship with the global epidemics of obesity, type 2 diabetes and metabolic syndrome. The [...] Read more.

The epidemiology and the current burden of chronic liver disease are changing globally, with non-alcoholic fatty liver disease (NAFLD) becoming the most frequent cause of liver disease in close relationship with the global epidemics of obesity, type 2 diabetes and metabolic syndrome. The clinical phenotypes of NAFLD are very heterogeneous in relationship with multiple pathways involved in the disease progression. In the absence of a specific treatment for non-alcoholic steatohepatitis (NASH), it is important to understand the natural history of the disease, to identify and to optimize the control of factors that are involved in disease progression. In this paper we propose a critical analysis of factors that are involved in the progression of the liver damage and the occurrence of extra-hepatic complications (cardiovascular diseases, extra hepatic cancer) in patients with NAFLD. We also briefly discuss the impact of the heterogeneity of the clinical phenotype of NAFLD on the clinical practice globally and at the individual level. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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11 pages, 751 KiB

Open AccessReview

From Nonalcoholic Fatty Liver Disease (NAFLD) to Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—New Terminology in Pediatric Patients as a Step in Good Scientific Direction?

by Marta Flisiak-Jackiewicz, Anna Bobrus-Chociej, Natalia Wasilewska and Dariusz Marek Lebensztejn

J. Clin. Med. 2021, 10(5), 924; https://doi.org/10.3390/jcm10050924 - 1 Mar 2021

Cited by 35 | Viewed by 5440

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, which predispose to more serious hepatic conditions. It ranges from simple liver steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, and even end-stage liver disease. Since [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, which predispose to more serious hepatic conditions. It ranges from simple liver steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis, and even end-stage liver disease. Since obesity became one of the most important health concerns wordwide, a considerable increase in the prevalance of NAFLD and other metabolic implications has been observed, both in adults and children. Due to the coexistence of visceral obesity, insulin resistance, dyslipidemia, NAFLD is considered to be the hepatic manifestation of metabolic syndrome (MetS). These relationships between NAFLD and MetS led to the set up in adults of a new term combining both of these conditions, called metabolic dysfunction-associated fatty liver disease (MAFLD). Based on these findings, we propose a set of criteria, which may be useful to diagnose MAFLD in children and adolescents. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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19 pages, 1577 KiB

Open AccessReview

Roles of Ceramides in Non-Alcoholic Fatty Liver Disease

by Eric Hajduch, Floriane Lachkar, Pascal Ferré and Fabienne Foufelle

J. Clin. Med. 2021, 10(4), 792; https://doi.org/10.3390/jcm10040792 - 16 Feb 2021

Cited by 59 | Viewed by 5687

Abstract

Non-alcoholic fatty liver disease is one of the most common chronic liver diseases, ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Its prevalence is rapidly increasing and presently affects around 25% of the general population of Western countries, due to the obesity [...] Read more.

Non-alcoholic fatty liver disease is one of the most common chronic liver diseases, ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Its prevalence is rapidly increasing and presently affects around 25% of the general population of Western countries, due to the obesity epidemic. Liver fat accumulation induces the synthesis of specific lipid species and particularly ceramides, a sphingolipid. In turn, ceramides have deleterious effects on hepatic metabolism, a phenomenon called lipotoxicity. We review here the evidence showing the role of ceramides in non-alcoholic fatty liver disease and the mechanisms underlying their effects. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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23 pages, 637 KiB

Open AccessReview

NAFLD and Cardiovascular Diseases: Epidemiological, Mechanistic and Therapeutic Considerations

by David Niederseer, Bernhard Wernly, Elmar Aigner, Felix Stickel and Christian Datz

J. Clin. Med. 2021, 10(3), 467; https://doi.org/10.3390/jcm10030467 - 26 Jan 2021

Cited by 48 | Viewed by 6054

Abstract

Overwhelming evidence suggests an association of cardiovascular disease (CVD) with non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanisms remain largely speculative. It is, however, likely that common mechanisms contribute to the development of CVD and NAFLD, with lifestyle factors such as smoking, [...] Read more.

Overwhelming evidence suggests an association of cardiovascular disease (CVD) with non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanisms remain largely speculative. It is, however, likely that common mechanisms contribute to the development of CVD and NAFLD, with lifestyle factors such as smoking, sedentary lifestyle with poor nutrition habits and physical inactivity being major candidates. These behavioral factors, on a predisposing genetic background, trigger changes in gut microbiota, inflammation, dyslipidemia and oxidative stress, leading to metabolic syndrome, diabetes and obesity as well as atherosclerosis. Treatment options to counteract both the progression and development of CVD and NAFLD include lifestyle interventions, optimal medical therapy of comorbid conditions and, as final possibility, bariatric surgery. As no causal pharmacotherapy of NAFLD is available, further research is urgently needed to address the unmet need of a growing population with NAFLD and CVD. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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18 pages, 1455 KiB

Open AccessReview

In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal

by Pierre-Antoine Soret, Julie Magusto, Chantal Housset and Jérémie Gautheron

J. Clin. Med. 2021, 10(1), 36; https://doi.org/10.3390/jcm10010036 - 24 Dec 2020

Cited by 78 | Viewed by 10603

Abstract

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), represents the hepatic manifestation of obesity and metabolic syndrome. Due to the spread of the obesity epidemic, NAFLD is becoming the most common chronic liver disease and one of [...] Read more.

Non-alcoholic fatty liver disease (NAFLD), including non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), represents the hepatic manifestation of obesity and metabolic syndrome. Due to the spread of the obesity epidemic, NAFLD is becoming the most common chronic liver disease and one of the principal indications for liver transplantation. However, no pharmacological treatment is currently approved to prevent the outbreak of NASH, which leads to fibrosis and cirrhosis. Preclinical research is required to improve our knowledge of NAFLD physiopathology and to identify new therapeutic targets. In the present review, we summarize advances in NAFLD preclinical models from cellular models, including new bioengineered platforms, to in vivo models, with a particular focus on genetic and dietary mouse models. We aim to discuss the advantages and limits of these different models. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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15 pages, 2374 KiB

Open AccessReview

Fatty Liver Disease and Non-Alcoholic Fatty Liver Disease Worsen the Outcome in Acute Pancreatitis: A Systematic Review and Meta-Analysis

by Szilárd Váncsa, Dávid Németh, Péter Hegyi, Zsolt Szakács, Péter Jeno Hegyi, Dániel Pécsi, Alexandra Mikó, Bálint Erőss, Adrienn Erős and Gabriella Pár

J. Clin. Med. 2020, 9(9), 2698; https://doi.org/10.3390/jcm9092698 - 20 Aug 2020

Cited by 20 | Viewed by 3907

Abstract

The prevalence of fatty liver disease (FLD) and that of non-alcoholic fatty liver disease (NAFLD) share some risk factors known to exacerbate the course of acute pancreatitis (AP). This meta-analysis aimed to investigate whether FLD or NAFLD carry a higher risk of untoward [...] Read more.

The prevalence of fatty liver disease (FLD) and that of non-alcoholic fatty liver disease (NAFLD) share some risk factors known to exacerbate the course of acute pancreatitis (AP). This meta-analysis aimed to investigate whether FLD or NAFLD carry a higher risk of untoward outcomes in AP. In accordance with PRISMA guidelines, we performed a systematic search in seven medical databases for cohort studies that compared the outcomes of AP for the presence of FLD or NAFLD, and we calculated pooled odds ratio (OR) or weighted mean difference (WMD) with 95% confidence interval (CI). We included 13 articles in our meta-analysis. AP patients with FLD were more likely to die (5.09% vs 1.89%, OR = 3.56, CI = 1.75–7.22), develop severe AP (16.33% vs 7.87%, OR = 2.67, CI = 2.01–3.56), necrotizing pancreatitis (34.83% vs 15.75%, OR = 3.08, CI = 2.44–3.90) and had longer in-hospital stay (10.8 vs 9.2 days, WMD = 1.46, OR = 0.54–2.39). Patients with NAFLD were more likely to have severe AP and longer hospital stay. Both FLD and NAFLD proved to be independent risk factors of a more severe disease course (OR = 3.68, CI = 2.16–6.29 and OR = 3.39, CI = 1.52–7.56 for moderate/ severe vs. mild AP, respectively). FLD and NAFLD worsen the outcomes of AP, which suggests that incorporating FLD or NAFLD into prognostic scoring systems of AP outcomes might improve the prediction of severity and contribute to a more individualized patient care. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease (NAFLD): Updates and Future Directions)

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