Journal articles on the topic 'Liver fibrosis progression'
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Samokhodskaia, Larisa Mikhaylovna, Ekaterina Evgen'evna Starostina, Elena Borisovna Yarovaya, Tat'yana Nikolaevna Krasnova, Nikolay Alekseevich Mukhin, Vsevolod Arsen'evich Tkachuk, and Viktor Antonovich Sadovnichy. "Mathematic Model for Prediction of Liver Fibrosis Progression Rate in Patients with Chronic Hepatitis C Based on Combination of Genomic Markers." Annals of the Russian academy of medical sciences 70, no. 6 (December 3, 2015): 651–61. http://dx.doi.org/10.15690/vramn548.
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Aim of study. To evaluate clinical significance of different combinations of gene polymorphisms IL-1b, IL-6, IL-10, TNF, HFE, TGF-b, ATR1, NOS3894, CYBA, AGT, MTHFR, FII, FV, FVII, FXIII, ITGA2, ITGB3, FBG, PAI and their prognostic value for prediction of liver fibrosis progression rate in patients with chronic hepatitis C (CHC).Subjects and methods: 118 patients with CHC were divided into «fast» and «slow» (fibrosis rate progression ≥0,13 and 0,13 fibrosis units/yr; n =64 and n =54) fibrosis groups. Gene polymorphisms were determined. Statistical analysis was performed using Statistica 10.Results. A allele (p =0,012) and genotype AA (p =0,024) of AGT G-6T gene, as well as T allele (p =0,013) and MT+TT genotypes (p =0,005) of AGT 235 M/T gene were significantly more common in «fast fibrosers» than in «slow fibrosers». Patients with genotype TT of CYBA 242 C/T had a higher fibrosis progression rate than patients with CC+CT genotype (p =0,02). Our analysis showed a protective effect of TT genotype of ITGA2 807 C/T on fibrosis progression rate (p =0,03). There was a trend (p 0,15) to higher fibrosis progression rate in patients with mutant alleles and genotypes of TGFb +915 G/C, FXIII 103 G/T, PAI -675 5G/4G genes. Other gene polymorphisms were not associated with enhanced liver fibrosis. To build a mathematical model for prediction of liver fibrosis progression rate we performed coding with scores for genotypes and virus genotype. Total score correlated with the fibrosis progression rate (R =0,39, p =0,000).Conclusion: Determination of genetic profile of the patient and virus genotype allows to predict the course of CHC.
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Jarčuška, Peter, Martin Janičko, Eduard Veselíny, Pavol Jarčuška, and Ľubomír Skladaný. "Circulating markers of liver fibrosis progression." Clinica Chimica Acta 411, no. 15-16 (August 2010): 1009–17. http://dx.doi.org/10.1016/j.cca.2010.04.009.
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Hagström, Hannes, Olof Elfwén, Rolf Hultcrantz, and Per Stål. "Steatohepatitis Is Not Associated with an Increased Risk for Fibrosis Progression in Nonalcoholic Fatty Liver Disease." Gastroenterology Research and Practice 2018 (July 2, 2018): 1–7. http://dx.doi.org/10.1155/2018/1942648.
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Introduction. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease globally. The majority of NAFLD patients have fatty liver without inflammation (nonalcoholic fatty liver, NAFL), whereas a minority develop steatohepatitis (nonalcoholic steatohepatitis, NASH). Only NASH and not NAFL has been considered to increase the risk for fibrosis progression. The present study investigates risk factors for fibrosis progression in patients with NAFLD, and if fibrosis progression associates with subsequent mortality. Material and Methods. All patients with at least two liver biopsies more than a year apart at our hospital between 1971 and 2016 were identified. Data on plausible risk factors for fibrosis progression were collected. Biopsies were scored for the presence of NASH and fibrosis stage. Regression models were used to investigate the association between baseline NASH and fibrosis progression and fibrosis progression with future mortality. Results. 60 patients had undergone serial biopsies (median interval between biopsies 8.4 years, range 1–33 years), with 26 patients (43%) having fibrosis progression. We found no significant risk factors for progression of fibrosis except time between biopsies. Among patients with fibrosis progression, 54% had NAFL and 46% had NASH at baseline. There was a trend for an association between fibrosis progression per se and increased mortality (hazard ratio 2.83, 95% CI 1.0–8.1, p=0.05). Conclusions. In this study on NAFLD, baseline steatohepatitis was not associated with an increased risk for fibrosis progression. NAFLD patients without steatohepatitis may develop progressive fibrosis, and those with progressive fibrosis appear to have a higher mortality risk irrespective of baseline NASH status.
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Abenavoli, Ludovico, Christophe Corpechot, and Raoul Poupon. "Elastography in Hepatology." Canadian Journal of Gastroenterology 21, no. 12 (2007): 839–42. http://dx.doi.org/10.1155/2007/621489.
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A common characteristic of all chronic liver diseases is the occurrence and progression of fibrosis toward cirrhosis. Consequently, liver fibrosis assessment plays an important role in hepatology. Besides its importance for prognosis, determining the level of fibrosis reveals the natural history of the disease and the risk factors associated with its progression, to guide the antifibrotic action of different treatments. Currently, in clinical practice, there are three available methods for the evaluation of liver fibrosis: liver biopsy, which is still considered to be the ‘gold standard’; serological markers of fibrosis and their mathematical combination – suggested in recent years to be an alternative to liver biopsy – and, more recently, transient elastography (TE). TE is a new, simple and noninvasive method used to measure liver stiffness. This technique is based on the progressing speed of an elastic shear wave within the liver. Currently, there are only a few studies that have evaluated TE effectiveness in chronic liver diseases, mostly in patients infected with the hepatitis C virus. Further studies are needed in patients with chronic liver disease, to assess the effectiveness of the fibrosis treatment.
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Diamond, Tamir, and Nadia Ovchinsky. "Fontan-associated liver disease: Monitoring progression of liver fibrosis." Clinical Liver Disease 11, no. 1 (January 2018): 1–5. http://dx.doi.org/10.1002/cld.681.
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Koeckerling, David, Jeremy W. Tomlinson, and Jeremy F. Cobbold. "Fighting liver fat." Endocrine Connections 9, no. 7 (July 2020): R173—R186. http://dx.doi.org/10.1530/ec-20-0174.
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Non-alcoholic fatty liver disease is a chronic liver disease which is closely associated with components of the metabolic syndrome. Its high clinical burden results from the growing prevalence, inherent cardiometabolic risk and potential of progressing to cirrhosis. Patients with non-alcoholic fatty liver disease show variable rates of disease progression through a histological spectrum ranging from steatosis to steatohepatitis with or without fibrosis. The presence and severity of fibrosis are the most important prognostic factors in non-alcoholic fatty liver disease. This necessitates risk stratification of patients by fibrosis stage using combinations of non-invasive methods, such as composite scoring systems and/or transient elastography. A multidisciplinary approach to treatment is advised, centred on amelioration of cardiometabolic risk through lifestyle and pharmacological interventions. Despite the current lack of licensed, liver-targeted pharmacotherapy, several promising agents are undergoing late-phase clinical trials to complement standard management in patients with advanced disease. This review summarises the current concepts in diagnosis and disease progression of non-alcoholic liver disease, focusing on pragmatic approaches to risk assessment and management in both primary and secondary care settings.
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Nishimura, Norihisa, Davide De Battista, David R. McGivern, Ronald E. Engle, Ashley Tice, Rafaelle Fares-Gusmao, Juraj Kabat, et al. "Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis." Proceedings of the National Academy of Sciences 118, no. 17 (April 22, 2021): e2019633118. http://dx.doi.org/10.1073/pnas.2019633118.
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Older age at the time of infection with hepatitis viruses is associated with an increased risk of liver fibrosis progression. We hypothesized that the pace of fibrosis progression may reflect changes in gene expression within the aging liver. We compared gene expression in liver specimens from 54 adult donors without evidence of fibrosis, including 36 over 40 y old and 18 between 18 and 40 y old. Chitinase 3-like 1 (CHI3L1), which encodes chitinase-like protein YKL-40/CHI3L1, was identified as the gene with the greatest age-dependent increase in expression in liver tissue. We investigated the cellular source of CHI3L1 in the liver and its function using liver tissue specimens and in vitro models. CHI3L1 expression was significantly higher in livers of patients with cirrhosis of diverse etiologies compared with controls represented by patients who underwent liver resection for hemangioma. The highest intrahepatic CHI3L1 expression was observed in cirrhosis due to hepatitis D virus, followed by hepatitis C virus, hepatitis B virus, and alcohol-induced cirrhosis. In situ hybridization of CHI3L1 messenger RNA (mRNA) identified hepatocytes as the major producers of CHI3L1 in normal liver and in cirrhotic tissue, wherein hepatocytes adjacent to fibrous septa showed higher CHI3L1 expression than did those in more distal areas. In vitro studies showed that recombinant CHI3L1 promotes proliferation and activation of primary human hepatic stellate cells (HSCs), the major drivers of liver fibrosis. These findings collectively demonstrate that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression.
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Chen, Wei, Xiaoning Wu, Xuzhen Yan, Anjian Xu, Aiting Yang, and Hong You. "Multitranscriptome analyses reveal prioritized genes specifically associated with liver fibrosis progression independent of etiology." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 6 (June 1, 2019): G744—G754. http://dx.doi.org/10.1152/ajpgi.00339.2018.
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Elimination or suppression of causative factors can raise the possibility of liver fibrosis regression. However, different injurious stimuli will give fibrosis from somewhat different etiologies, which, in turn, may hamper the discovery of liver fibrosis-specific therapeutic drugs. Therefore, the analogical cellular and molecular events shared by various etiology-evoked liver fibrosis should be clarified. Our present study systematically integrated five publicly available transcriptomic data sets regarding liver fibrosis with different etiologies from the Gene Expression Omnibus database and performed a series of bioinformatics analyses and experimental verifications. A total of 111 significantly upregulated and 16 downregulated genes were identified specific to liver fibrosis independent of any etiology. These genes were predominately enriched in some Kyoto Encyclopedia of Genes and Genomes pathways, including the “PI3K-AKT signaling pathway,” “Focal adhesion,” and “ECM-receptor interaction.” Subsequently, five prioritized liver fibrosis-specific genes, including COL4A2, THBS2, ITGAV, LAMB1, and PDGFRA, were screened. These genes were positively associated with each other and liver fibrosis progression. In addition, they could robustly separate all stages of samples in both training and validation data sets with diverse etiologies when they were regarded as observed variables applied to principal component analysis plots. Expressions of all five genes were confirmed in activated primary mouse hepatic stellate cells (HSCs) and transforming growth factor β1-treated LX-2 cells. Moreover, THBS2 protein was enhanced in liver fibrosis rodent models, which could promote HSC activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs. Overall, our current study may provide potential targets for liver fibrosis therapy and aid to a deeper understanding of the molecular underpinnings of liver fibrosis. NEW & NOTEWORTHY Prioritized liver fibrosis-specific genes THBS2, COL4A2, ITGAV, LAMB1, and PDGFRA were identified and significantly associated with liver fibrosis progression and could be combined to discriminate liver fibrosis stages regardless of any etiology. Among the identified prioritized liver fibrosis-specific targets, THBS2 protein was confirmed to be enhanced in liver fibrosis rodent models, which could promote hepatic stellate cell (HSC) activation and proliferation and facilitate NOTCH1/JAG1 expression in HSCs.
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He, Yuting, Chiang Huen Kang, Shuoyu Xu, Xiaoye Tuo, Scott Trasti, Dean C. S. Tai, Anju Mythreyi Raja, et al. "Toward surface quantification of liver fibrosis progression." Journal of Biomedical Optics 15, no. 5 (2010): 056007. http://dx.doi.org/10.1117/1.3490414.
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Rosenberg, William M. C. "Rating fibrosis progression in chronic liver diseases." Journal of Hepatology 38, no. 3 (March 2003): 357–60. http://dx.doi.org/10.1016/s0168-8278(03)00010-2.
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Rowe, R. G., Y. Lin, R. Shimizu-Hirota, S. Hanada, E. G. Neilson, J. K. Greenson, and S. J. Weiss. "Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression." Molecular and Cellular Biology 31, no. 12 (April 11, 2011): 2392–403. http://dx.doi.org/10.1128/mcb.01218-10.
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Shoukry, Naglaa H., Thomas Fabre, Manuel Flores Molina, Genevieve Soucy, Bernard Willems, Jean-Pierre Villeneuve, and Marc Bilodeau. "Th17 Cytokines Drive Liver Fibrosis Progression by Regulating TGF-β Signaling through Activation of MAPKs." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 197.12. http://dx.doi.org/10.4049/jimmunol.198.supp.197.12.
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Abstract Activation of hepatic stellate cells (HSCs) is a key event in the initiation of liver fibrosis. We and others have demonstrated that IL-17A produced by Th17 cells promotes activation of HSCs. Th17 cells also produce IL-22, an enigmatic cytokine with pro-inflammatory and hepatoprotective properties. In addition, regulatory T cells (Treg) negatively modulate activation of HSCs. We hypothesized that liver fibrosis progression results from an alteration in the Th17/Treg ratio leading to an imbalance in pro-fibrotic Th17 cytokines in the liver. We examined ex vivo the frequency of Th17 and Treg populations and the cytokine profile of intrahepatic lymphocytes in liver biopsy samples (n=32). We observed increased Th17/Treg ratio in advanced as compared to moderate or no-fibrosis. Furthermore, we observed a bias towards Th17 cytokines in fibrotic livers with viral-hepatitis both in situ and ex vivo. All biopsies exhibited a 5-fold increase in IL-22 in fibrotic livers irrespective of aetiology. In vitro stimulation of HSCs with IL-22 sensitized them to suboptimal doses of TGF-β and activated p38 pathways. Chemical inhibition of p38 suppressed the pro-fibrogenic effect of IL-22. In vivo, lack of IL-22 signaling protected mice against liver fibrosis. IL-22RA1 Knockout mice exhibited reduced collagen deposition and expression of pro-fibrotic genes (ACTA2, LOXL2, TIMP-I, TGFb1, COL1A1) in comparison to wild-type littermates. Our results suggest a dysregulated Th17 response with increased IL-22 signaling in advanced fibrosis from all different aetiologies. Finally, we have identified IL-22 as a common factor in advanced liver fibrosis acting through sensitization of HSCs to TGF-β in a p38-dependent manner.
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Delgado, M. Eugenia, Beatriz I. Cárdenas, Núria Farran, and Mercedes Fernandez. "Metabolic Reprogramming of Liver Fibrosis." Cells 10, no. 12 (December 20, 2021): 3604. http://dx.doi.org/10.3390/cells10123604.
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Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against fibrosis exists yet. Worryingly, due to the growing obesity pandemic, fibrosis incidence is on the rise. Here, we aim to summarize the main components and mechanisms involved in the progression of liver fibrosis, with special focus on the metabolic regulation of key effectors of fibrogenesis, hepatic stellate cells (HSCs), and their role in the disease progression. Hepatic cells that undergo metabolic reprogramming require a tightly controlled, fine-tuned cellular response, allowing them to meet their energetic demands without affecting cellular integrity. Here, we aim to discuss the role of ribonucleic acid (RNA)-binding proteins (RBPs), whose dynamic nature being context- and stimuli-dependent make them very suitable for the fibrotic situation. Thus, we will not only summarize the up-to-date literature on the metabolic regulation of HSCs in liver fibrosis, but also on the RBP-dependent post-transcriptional regulation of this metabolic switch that results in such important consequences for the progression of fibrosis and CLD.
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Méndez-Sánchez, Nahum, Eira Cerda-Reyes, Fátima Higuera-de-la-Tijera, Ana K. Salas-García, Samantha Cabrera-Palma, Guillermo Cabrera-Álvarez, Carlos Cortez-Hernández, et al. "Dyslipidemia as a risk factor for liver fibrosis progression in a multicentric population with non-alcoholic steatohepatitis." F1000Research 9 (January 28, 2020): 56. http://dx.doi.org/10.12688/f1000research.21918.1.
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Background: Nonalcoholic fatty liver disease (NAFLD) is a serious worldwide health problem, with an estimated global prevalence of 24%; it has a notable relationship with other metabolic disorders, like obesity and type 2 diabetes mellitus (T2DM). Nonalcoholic steatohepatitis (NASH) is one of the most important clinical entities of NAFLD, which is associated with an increased risk of progression to liver cirrhosis and hepatocellular carcinoma (HCC). Mexico is one of the countries with the highest prevalence of metabolic diseases; therefore, we sought to investigate the impact that these clinical entities have in the progression to advanced fibrosis in Mexican patients with NASH. Methods: We performed a multicenter retrospective cross-sectional study, from January 2012 to December 2017. A total of 215 patients with biopsy-proven NASH and fibrosis were enrolled. NASH was diagnosed according NAS score and liver fibrosis was staged by the Kleiner scoring system. For comparing the risk of liver fibrosis progression, we divided our sample into two groups. Those patients with stage F0-F2 liver fibrosis were included in the group with non-significant liver fibrosis (n=178) and those individuals with F3-F4 fibrosis were included in the significant fibrosis group (n=37). We carried out a multivariate analysis to find risk factors associated with liver fibrosis progression. Results: From the 215 patients included, 37 had significant liver fibrosis (F3-4). After logistic regression analysis T2DM (p=0.044), systemic arterial hypertension (p=0.014), cholesterol (p=0.041) and triglycerides (p=0.015) were the main predictor of advanced liver fibrosis. Conclusions: In a Mexican population, dyslipidemia was the most important risk factor associated with advanced liver fibrosis and cirrhosis.
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Markovic, Jovana, Amar Deep Sharma, and Asha Balakrishnan. "MicroRNA-221: A Fine Tuner and Potential Biomarker of Chronic Liver Injury." Cells 9, no. 8 (July 23, 2020): 1767. http://dx.doi.org/10.3390/cells9081767.
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The last decade has witnessed significant advancements in our understanding of how small noncoding RNAs, such as microRNAs (miRNAs), regulate disease progression. One such miRNA, miR-221, has been shown to play a key role in the progression of liver fibrosis, a common feature of most liver diseases. Many reports have demonstrated the upregulation of miR-221 in liver fibrosis caused by multiple etiologies such as viral infections and nonalcoholic steatohepatitis. Inhibition of miR-221 via different strategies has shown promising results in terms of the suppression of fibrogenic gene signatures in vitro, as well as in vivo, in independent mouse models of liver fibrosis. In addition, miR-221 has also been suggested as a noninvasive serum biomarker for liver fibrosis and cirrhosis. In this review, we discuss the biology of miR-221, its significance and use as a biomarker during progression of liver fibrosis, and finally, potential and robust approaches that can be utilized to suppress liver fibrosis via inhibition of miR-221.
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Tsai, Tsung-Ying, Pai-Feng Hsu, Cheng-Hsueh Wu, Shao-Sung Huang, Wan-Leong Chan, Shing-Jong Lin, Jaw-Wen Chen, Tse-Min Lu, and Hsin-Bang Leu. "Association between Coronary Artery Plaque Progression and Liver Fibrosis Biomarkers in Population with Low Calcium Scores." Nutrients 14, no. 15 (July 30, 2022): 3163. http://dx.doi.org/10.3390/nu14153163.
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Background: The severity of nonalcoholic fatty liver disease (NAFLD) has been found to be associated with atherosclerosis burden. However, whether liver fibrosis scores can be used to predict atherosclerosis progression, especially for patients with low calcium scores, remains undetermined. Methods: A total of 165 subjects who underwent repeated coronary computed tomography angiography (CCTA) and had low calcium scores (<100) were enrolled. The segment stenosis score (SSS) from the CCTA was measured, and the association between SSS progression and biochemical parameters was analyzed in addition to liver fibrosis scores, including nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 index (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI), and Forns score. Results: When compared with those without plaque at baseline (SSS = 0), subjects with plaque had higher blood pressure, higher coronary artery calcium (CAC) scores, and higher liver fibrosis scores, including Forns score, Fib-4, and NFS. During the medium follow-up interval of 24.7 months, 60 (39.4%) patients displayed SSS progression, while the remaining 105 (63.6%) patients showed no CAD progression. In a multivariate analysis, being male having a high diastolic blood pressure (DBP), and having a high NFS liver fibrosis score were independently associated with the odds ratio for SSS progression. Conclusions: Higher baseline blood pressure and liver fibrosis markers are associated with the presence of coronary artery disease (CAD) plaques in subjects in early CAD stages. For disease progression, the male gender, DBP, and NFS appear to be independently associated with coronary atherosclerosis plaque progression in subjects with low calcium scores.
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Foglia, Beatrice, Erica Novo, Francesca Protopapa, Marina Maggiora, Claudia Bocca, Stefania Cannito, and Maurizio Parola. "Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis." Cells 10, no. 7 (July 13, 2021): 1764. http://dx.doi.org/10.3390/cells10071764.
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Liver fibrosis is a potentially reversible pathophysiological event, leading to excess deposition of extracellular matrix (ECM) components and taking place as the net result of liver fibrogenesis, a dynamic and highly integrated process occurring during chronic liver injury of any etiology. Liver fibrogenesis and fibrosis, together with chronic inflammatory response, are primarily involved in the progression of chronic liver diseases (CLD). As is well known, a major role in fibrogenesis and fibrosis is played by activated myofibroblasts (MFs), as well as by macrophages and other hepatic cell populations involved in CLD progression. In the present review, we will focus the attention on the emerging pathogenic role of hypoxia, hypoxia-inducible factors (HIFs) and related mediators in the fibrogenic progression of CLD.
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Han, Man-Hoon, Jee Hyun Lee, Gyeonghwa Kim, Eunhye Lee, Yu Rim Lee, Se Young Jang, Hye Won Lee, et al. "Expression of the Long Noncoding RNA GAS5 Correlates with Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease." Genes 11, no. 5 (May 13, 2020): 545. http://dx.doi.org/10.3390/genes11050545.
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Background: Advanced liver fibrosis is the most important prognostic factor in nonalcoholic fatty liver disease (NAFLD). The long noncoding RNA (lncRNA), growth arrest-specific transcript 5 (GAS5), is associated with the inhibition of liver fibrogenesis, and its levels are decreased in cirrhotic liver. Methods: We analyzed 51 patients with NAFLD, the diagnosis of which was confirmed by liver biopsy. Expression of GAS5 in both the liver and plasma of the patients was analyzed using a quantitative real-time polymerase chain reaction according to the fibrosis stage. Results: Plasma GAS5 expression was significantly higher in patients with advanced fibrosis than in those without. As the fibrosis progressed, GAS5 expression in plasma increased, with the exception of that in cirrhotic livers. Plasma levels of GAS5 were lower in patients with cirrhosis than in those with advanced fibrosis. Conclusion: Elevated circulating levels of the lncRNA GAS5 are associated with the progression of liver fibrosis prior to the development of cirrhosis.
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Roehlen, Natascha, Emilie Crouchet, and Thomas F. Baumert. "Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives." Cells 9, no. 4 (April 3, 2020): 875. http://dx.doi.org/10.3390/cells9040875.
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Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.
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Ananiev, Julian, Mariana Penkova, Georgi Tchernev, and Maya Gulubova. "Macrophages, TGF-β1 expression and iron deposition in development of NASH." Open Medicine 7, no. 5 (October 1, 2012): 599–603. http://dx.doi.org/10.2478/s11536-012-0033-9.
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AbstractA wide range of molecular markers and different types of cells in liver are possible factors for progression of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) development of liver fibrosis. We investigated biopsies from 57 patients with NASH. The material was obtained from livers and was proceed immunohistochemistry antibodies against CD68 and TGF-beta 1. In addition, biopsies were evaluated for iron content. Macrophages/-positive/could be found in all 57 cases. The number of macrophages in the sinusoids correlated with the degree of portal fibrosis:64.% of the patients with mild or intensive fibrosis had high infiltration with CD68-positive cells, while 100% of the patients without fibrosis hadlow infiltration (χ2=8.56; p=0.003). In specimens we, 69.% of patients with different degree of fibrosis expressed TGF-β1 in their portal tracts, and 100% of patients without fibrosis did demonstrate expression of the protein (χ2=23.7; p<0.001). Hepatic iron was found in 100% (9) of patients with intensive fibrosis vs. 10.3% of the patients mild fibrosis (χ2=23.4; p<0.001). Our results suggest that the macrophages and macrophage-derived TGF-beta1 are the major factors responsible for development of fibrosis and progression of chronic liver disease.
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González Rodríguez, Águeda, Stephania C. Isaza, Patricia Marañón, Esthe Rey, and Carmelo García-Monzón. "Regulation of BMP8A expression during hepatic fibrogenesis process." IBJ Plus 1, s5 (June 3, 2022): 8. http://dx.doi.org/10.24217/2531-0151.22v1s5.00008.
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Introduction: Hepatocellular injury is the main triggering event of wound healing response that leads to liver fibrosis. Hepatic stellate cell (HSC) activation is crucial in the progression of fibrogenic process since they represent the major source of extracellular matrix components and contribute to the inflammatory response by secreting proinflammatory cytokines. Bone morphogenetic proteins (BMPs) are soluble growth factors which exert pleiotropic effects in various tissues regulating different physiological processes of cellular homeostasis. Regarding BMP8A, its implication in liver damage has been poorly investigated. Therefore, the aim of this study was to determine BMP8A expression in different fibrosis-mediated liver damage scenarios. Materials and methods: Histological study of livers was performed and hepatic BMP8A expression levels were determined by RT-qPCR in different experimental models of hepatic fibrosis: carbon tetrachloride injected mice, as a classic hepatic fibrosis model, mice subjected to bile duct ligation, as a model of cholestatic damage-derived hepatic fibrosis, and high fat diet fed mice, reproducing the progression of non-alcoholic fatty liver disease (NAFLD) which curses with variable states of concomitant fibrosis in advanced stages. Likewise, the same analysis was conducted in livers from 11 patients with biopsy proven NAFLD-derived fibrosis and 25 NAFLD patients without fibrosis. To reproduce the experimental conditions of the murine models, BMP8A levels were determined in hepatocytes stimulated with conditioned media derived from TGFbeta-stimulated hepatic stellate cells (LX2). Results: Firstly, murine models were validated through a histological examination of the liver and a molecular analysis of fibrotic specific markers. Next, hepatic BMP8A mRNA expression was significant increased in all studied models of hepatic fibrosis comparing with the respective controls. In fact, there is a positive correlation between hepatic BMP8A levels and fibrosis stage as well as with markers of fibrosis. Accordingly, the clinical study revealed an elevated BMP8A expression in fibrotic livers, in comparison with those without any fibrotic sign. Furthermore, in vitro experiments also showed an increased BMP8A expression in Huh7 cells treated with conditioned media derived from TGFbeta-activated LX2 cells. Conclusions: This study reveals for the first time an increased BMP8A hepatic expression in the context of hepatic fibrosis. Its detection in serum might be useful as a non-invasive tool for the diagnosis/prognosis of patients affected by this liver disease. Moreover, these results suggest that BMP8A is involved in hepatic fibrosis progression, being possibly relevant in its therapeutic manage.
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Carvalho-Gontijo, Raquel, Cuijuan Han, Lei Zhang, Vivian Zhang, Mojgan Hosseini, Kristin Mekeel, Bernd Schnabl, et al. "Metabolic Injury of Hepatocytes Promotes Progression of NAFLD and AALD." Seminars in Liver Disease 42, no. 03 (August 2022): 233–49. http://dx.doi.org/10.1055/s-0042-1755316.
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Nonalcoholic liver disease is a component of metabolic syndrome associated with obesity, insulin resistance, and hyperlipidemia. Excessive alcohol consumption may accelerate the progression of steatosis, steatohepatitis, and fibrosis. While simple steatosis is considered a benign condition, nonalcoholic steatohepatitis with inflammation and fibrosis may progress to cirrhosis, liver failure, and hepatocellular cancer. Studies in rodent experimental models and primary cell cultures have demonstrated several common cellular and molecular mechanisms in the pathogenesis and regression of liver fibrosis. Chronic injury and death of hepatocytes cause the recruitment of myeloid cells, secretion of inflammatory and fibrogenic cytokines, and activation of myofibroblasts, resulting in liver fibrosis. In this review, we discuss the role of metabolically injured hepatocytes in the pathogenesis of nonalcoholic steatohepatitis and alcohol-associated liver disease. Specifically, the role of chemokine production and de novo lipogenesis in the development of steatotic hepatocytes and the pathways of steatosis regulation are discussed.
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Anisonyan, A. V., Yu G. Sandler, T. Yu Khaimenova, V. A. Keyan, K. G. Saliev, E. S. Sbikina, and E. V. Vinnitskaya. "Non-alcoholic fatty liver disease and type 2 diabetes mellitus: issues of the liver fibrosis diagnostics." Terapevticheskii arkhiv 92, no. 8 (September 3, 2020): 73–78. http://dx.doi.org/10.26442/00403660.2020.08.000770.
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Aim. To evaluate the frequency of liver fibrosis progression to stage 34 among patients with non-alcoholic fatty liver disease (NAFLD), type 2 diabetes and obesity, to identify predictors of severe liver fibrosis, to propose an algorithm for diagnosing fibrosis in this category of patients.
Materials and methods. 160 patients with NAFLD, type 2 diabetes mellitus (DM) and obesity and 50 patients with NAFLD without diabetes were comprehensively examined. Patients underwent laboratory examination (clinical blood test, biochemical analysis, immunoglobulins G, M, autoantibody assay, coagulogram), liver ultrasound. All patients underwent determination of the liver fibrosis stage by two methods: the serological test FibroMax and indirect ultrasound elastometry of the liver; 40 patients underwent a liver biopsy. Statistical data processing was performed using the programming language and statistical calculations R: we used correlation analysis, multiple logistic regression method, one-way analysis of variance, multi-factor analysis, the Kruskal-Wallis method, and comparison of the number of patients using the Fisher test.
Results. DM is a risk factor for the liver fibrosis progression in patients with NAFLD. Significant markers of severe fibrosis in this category of patients are increased levels of GGTP, haptoglobin and alpha-2-macroglobulin, lower platelet and prothrombin levels. Obesity and isolated steatosis without steatohepatitis are not markers of severe liver fibrosis at present, but obesity can be considered a risk factor for the progression of fibrosis in the future.
Conclusion. All patients with NAFLD in combination with diabetes need screening to detect advanced liver fibrosis: it is advisable to determine the levels of GGTP, haptoglobin and alpha-2-macroglobulin.
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Schattenberg, Jörn M., Michael Nagel, Yong Ook Kim, Tobias Kohl, Marcus A. Wörns, Tim Zimmermann, Arno Schad, et al. "Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 4 (August 15, 2012): G498—G506. http://dx.doi.org/10.1152/ajpgi.00525.2011.
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Chronic liver disease promotes hepatocellular injury involving apoptosis and triggers compensatory regeneration that leads to the activation of quiescent stellate cells in the liver. The deposition of extracellular matrix from activated myofibroblasts promotes hepatic fibrosis and the progression to cirrhosis with deleterious effects on liver physiology. The role of apoptosis signaling pathways in the development of fibrosis remains undefined. The aim of the current study was to determine the involvement of the caspase-8 homologue cellular FLICE-inhibitory protein (cFLIP) during the initiation and progression of fibrosis. Liver injury and fibrosis from carbon tetrachloride (CCl4) and thioacetamide (TAA) were examined in mice exhibiting a hepatocyte-specific deletion of cFLIP ( flip −/−). Acute liver injury from CCl4 and TAA were enhanced in flip −/− mice. This was accompanied by increased activation of caspase-3 and -9, pronounced phosphorylation of JNK, and decreased phosphorylation of Erk. Deletion of the cJun NH2-terminal kinase 2 (JNK2) in flip −/− mice protected from injury. Hepatic fibrosis was increased at baseline in 12-wk-old flip −/− mice, and progression of fibrosis from TAA was accelerated compared with the wild type. In conclusion, deletion of cFLIP in hepatocytes leads to increased fibrosis and accelerated fibrosis progression. This is accompanied by increased injury involving the activation of caspases and JNK2. Thus predisposition to liver injury involving increased hepatocellular apoptosis is a critical mediator of accelerated fibrogenesis, and prevention of liver injury will be a most important measure for patients with chronic liver disease.
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Liu, Yan, Xuehua Kong, Yan You, Linwei Xiang, Yan Zhang, Rui Wu, Lan Zhou, and Liang Duan. "S100A8-Mediated NLRP3 Inflammasome-Dependent Pyroptosis in Macrophages Facilitates Liver Fibrosis Progression." Cells 11, no. 22 (November 12, 2022): 3579. http://dx.doi.org/10.3390/cells11223579.
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NLRP3 inflammasome-dependent pyroptosis has been implicated in liver fibrosis progression. However, the definite intrahepatic cell types that undergo pyroptosis and the underlying mechanism as well as the clinical importance remain unclear. Here, augmented levels of pyroptosis-related indicators GSDMD, IL-1β, and IL-18 were verified in both liver fibrosis patients and CCl4-induced fibrotic mouse model. Confocal imaging of NLRP3 with albumin, F4/80 or α-SMA revealed that enhanced NLRP3 was mainly localized to kupffer cells (KCs), indicating that KCs are major cell types that undergo pyroptosis. Targeting pyroptosis by inhibitor MCC950 attenuated the severity and ameliorated liver function in fibrosis models. In addition, elevated S100A8 in liver fibrosis patients was correlated with pyroptosis-related indicators. S100A8 stimulated pyroptotic death of macrophages, which resulted in activation of human hepatic stellate cell line LX-2 cells and increased collagen deposition. Mechanistically, S100A8 activated TLR4/NF-κB signaling and upregulated its target genes NLRP3, pro-IL-1β, and pro-IL-18 expression, and induced reactive oxygen (ROS) abundance to activate NLRP3 inflammasome, finally leading to pyroptotic cell death in macrophages. More importantly, circulating GSDMD had the optimal predicting value for liver fibrosis progression. In conclusion, S100A8-mediated NLRP3 inflammasome-dependent pyroptosis by TLR4/NF-κB activation and ROS production in macrophages facilitates liver fibrosis progression. The identified GSDMD has the potential to be a biomarker for liver fibrosis evaluation.
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Henderson, Neil C., and John P. Iredale. "Liver fibrosis: cellular mechanisms of progression and resolution." Clinical Science 112, no. 5 (February 1, 2007): 265–80. http://dx.doi.org/10.1042/cs20060242.
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Liver fibrosis represents a major worldwide health care burden. The last 15 years have seen a rapid growth in our understanding of the pathogenesis of this clinically relevant model of inflammation and repair. This work is likely to inform the design of effective antifibrotic therapies in the near future. In this review, we examine how the innate and adaptive immune response interacts with other key cell types in the liver, such as the myofibroblast, regulating the process of hepatic fibrosis and, where relevant, resolution of fibrosis with remodelling. Emphasis is placed on the increasing knowledge that has been generated by the use of transgenic animals and animals in which specific cell lines have been deleted. Additionally, we review the increasing evidence that, although significant numbers of wound-healing myofibroblasts are derived from the hepatic stellate cell, significant contributions may occur from other cell lineages, including those from distant sites such as bone marrow stem cells.
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Karsdal, Morten A., Sara T. Hjuler, Yi Luo, Daniel G. K. Rasmussen, Mette J. Nielsen, Signe Holm Nielsen, Diana J. Leeming, et al. "Assessment of liver fibrosis progression and regression by a serological collagen turnover profile." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 1 (January 1, 2019): G25—G31. http://dx.doi.org/10.1152/ajpgi.00158.2018.
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There is a need for noninvasive biomarkers that can identify patients with progressive liver fibrosis and monitor response to antifibrotic therapy. An equally important need is identification of patients with spontaneous fibrosis regression, since they may not need treatment nor be included in clinical studies with fibrosis as end point. Circulating biomarkers, originating from defined fragments of the scar tissue itself, may serve as valuable tools for this aspect of precision medicine. We investigated a panel of serological collagen formation and degradation markers to identify patients likely to regress or progress in absence of a therapeutic intervention. Plasma samples from patients with moderate-stage hepatitis C receiving placebo treatment in a phase II trial of the peroxisome proliferator-activated receptor agonist farglitazar were included. The patients had matched liver biopsies at baseline and 52 wk of follow-up. Serological biomarkers of collagen formation (PRO-C3, PRO-C4, PRO-C5) and collagen degradation (C3M, C4M, and C6M) were analyzed. Logistic regression analysis including PRO-C3 and C6M identified subjects with progressive liver fibrosis with an AUROC of 0.91 ( P < 0.0001) and positive and negative predictive values (PPV/NPV) of 75.0%/88.6%. Low levels of PRO-C5 predicted a spontaneous regression phenotype, with an odds ratio of 33.8 times higher compared with patients with high levels ( P < 0.0025) with an AUROC of 0.78 ( P < 0.0001) and PPV/NPV of 60.0%/95.7%. Two collagen fragments (PRO-C3 and C6M) identified liver fibrosis progressors, and one collagen fragment (PRO-C5) identified liver fibrosis regressors. These biomarkers may improve patient stratification and monitor treatment efficacy in studies with fibrosis as clinical end point. NEW & NOTEWORTHY In this study we report two biomarkers of collagen fragments (PRO-C3 and C6M) that are able to identify liver fibrosis progressors while one biomarker (PRO-C5) identified liver fibrosis regressors. In particular, we present three noninvasive biomarkers that can be used to identify patients with progressive liver fibrosis, monitor response to antifibrotic therapy, and also identify the spontaneous liver fibrosis regression phenotype.
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Rosa-Caldwell, Megan E., Jacob L. Brown, David E. Lee, Michael P. Wiggs, Richard A. Perry Jr., Wesley S. Haynie, Aaron R. Caldwell, Tyrone A. Washington, Wen-Juo Lo, and Nicholas P. Greene. "Hepatic alterations during the development and progression of cancer cachexia." Applied Physiology, Nutrition, and Metabolism 45, no. 5 (May 2020): 500–512. http://dx.doi.org/10.1139/apnm-2019-0407.
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Cancer-associated bodyweight loss (cachexia) is a hallmark of many cancers and is associated with decreased quality of life and increased mortality. Hepatic function can dramatically influence whole-body energy expenditure and may therefore significantly influence whole-body health during cancer progression. The purpose of this study was to examine alterations in markers of hepatic metabolism and physiology during cachexia progression. Male C57BL/6J mice were injected with 1 × 106 Lewis Lung Carcinoma cells dissolved in 100 μL PBS and cancer was allowed to develop for 1, 2, 3, or 4 weeks. Control animals were injected with an equal volume of phosphate-buffered saline. Livers were analyzed for measures of metabolism, collagen deposition, protein turnover, and mitochondrial quality. Animals at 4 weeks had ∼30% larger livers compared with all other groups. Cancer progression was associated with altered regulators of fat metabolism. Additionally, longer duration of cancer development was associated with ∼3-fold increased regulators of collagen deposition as well as phenotypic collagen content, suggesting increased liver fibrosis. Mitochondrial quality control regulators appeared to be altered before any phenotypic alterations to collagen deposition. While induction of Akt was noted, downstream markers of protein synthesis were not altered. In conclusions, cancer cachexia progression is associated with hepatic pathologies, specifically liver fibrosis. Alterations to mitochondrial quality control mechanisms appear to precede this fibrotic phenotype, potentially suggesting mitochondrial mechanisms for the development of hepatic pathologies during the development and progression of cancer cachexia. Novelty Cachexia progression results in liver collagen deposition and fibrosis. Alterations in mitochondrial quality control may precede liver pathologies during cachexia.
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Zhang, Yuan, Wenjun Lu, Xiaorong Chen, Yajuan Cao, and Zongguo Yang. "A Bioinformatic Analysis of Correlations between Polymeric Immunoglobulin Receptor (PIGR) and Liver Fibrosis Progression." BioMed Research International 2021 (April 10, 2021): 1–12. http://dx.doi.org/10.1155/2021/5541780.
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Objective. This study is aimed at investigating the enriched functions of polymeric immunoglobulin receptor (PIGR) and its correlations with liver fibrosis stage. Methods. PIGR mRNA expression in normal liver, liver fibrosis, hepatic stellate cells (HSCs), and hepatitis virus infection samples was calculated in Gene Expression Omnibus (GEO) and Oncomine databases. Enrichment analysis of PIGR-related genes was conducted in Metascape and Gene Set Enrichment Analysis (GSEA). Logistic model and ROC curve were performed to evaluate the correlations between pIgR and liver fibrosis. Results. PIGR mRNA was upregulated in advanced liver fibrosis, cirrhosis compared to normal liver (all p < 0.05 ). PIGR mRNA was also overexpressed in activated HSCs compared to senescent HSCs, liver stem/progenitor cells, and reverted HSCs (all p < 0.05 ). Enrichment analysis revealed that PIGR-related genes involved in the defense response to virus and interferon (IFN) signaling. In GEO series, PIGR mRNA was also upregulated by hepatitis virus B, C, D, and E infection (all p < 0.05 ). After adjusting age and gender, multivariate logistic regression models revealed that high PIGR in the liver was a risk factor for liver fibrosis ( OR = 82.2 , p < 0.001 ). The area under curve (AUC), positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of PIGR for liver fibrosis stage >2 were 0.84, 0.86, 0.7, 0.61, and 0.90. Conclusion. PIGR was correlated with liver fibrosis and might involve in hepatitis virus infection and HSC transdifferentiation.
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Livzan, M. A., V. A. Akhmedov, T. S. Krolevets, O. V. Gaus, and N. A. Cherkaschenko. "The informative value of non-invasive liver fibrosis markers in patients with nonalcoholic fatty liver disease." Terapevticheskii arkhiv 88, no. 12 (December 15, 2016): 62–68. http://dx.doi.org/10.17116/terarkh2016881262-68.
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Aim. To estimate the diagnostic and informative value of clinical and laboratory parameters in the development and progression of liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) to enhance efficiency of their treatment. Subjects and methods. An open-label case-control study included 77 patients with NAFLD. Clinical and laboratory examinations were done. To search for additional noninvasive fibrosis markers, the investigators studied the serum concentrations of insulin, leptin, adiponectin, matrix metalloproteinase-9 (MMP-9) and its inhibitors, such as tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) and TIMP-2. All the patients underwent elastometry to assess the degree of liver fibrosis with the Metavir scale with the use of a Fibroscan machine. Results. The serum levels of low-density lipoproteins, glucose, MMP-9, and leptin proved to be most informative in assessing the progression of the initial stages (1-2) of fibrosis, as were the increased liver size detected by physical examination, systolic blood pressure, carbohydrate metabolic disorders, alanine/aspartate aminotransferase levels, waist-to-hip ratio, TIMP-1, and TIMP-2 in evaluating the progression of Stage II fibrosis 2 to Stage 3. Conclusion. The clinical and laboratory parameters can serve as reliable noninvasive markers that reflect the progression of fibrotic changes in liver tissue.
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Gieling, Roben G., Karen Wallace, and Yuan-Ping Han. "Interleukin-1 participates in the progression from liver injury to fibrosis." American Journal of Physiology-Gastrointestinal and Liver Physiology 296, no. 6 (June 2009): G1324—G1331. http://dx.doi.org/10.1152/ajpgi.90564.2008.
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Interleukin-1 (IL-1) is rapidly expressed in response to tissue damage; however, its role in coordinating the progression from injury to fibrogenesis is not fully understood. Liver fibrosis is a consequence of the activation of hepatic stellate cells (HSCs), which reside within the extracellular matrix (ECM) of subsinusoids. We have hypothesized that, among the hepatic inflammatory cytokines, IL-1 may directly activate HSCs through autocrine signaling and stimulate the matrix metalloproteinases (MMPs) produced by HSCs within the space of Disse, resulting in liver fibrogenesis. In this study, we first established a temporal relationship between IL-1, MMPs, HSC activation, and early fibrosis. The roles of IL-1 and MMP-9 in HSC activation and fibrogenesis were determined by mice deficient of these genes. After liver injury, IL-1, MMP-9, and MMP-13 levels were found to be elevated before the onset of HSC activation and fibrogenesis. IL-1 receptor-deficient mice exhibited ameliorated liver damage and reduced fibrogenesis. Similarly, advanced fibrosis, as determined by type-I and -III collagen mRNA expression and fibrotic septa, was partially attenuated by the deficiency of IL-1. In the early phase of liver injury, the MMP-9, MMP-13, and TIMP-1 expression correlated well with IL-1 levels. In injured livers, MMP-9 was predominantly colocalized to desmin-positive cells, suggesting that HSCs are MMP-producing cells in vivo. MMP-9-deficient mice were partially protected from liver injury and HSC activation. Thus IL-1 is an important participant, along with other cytokines, and controls the progression from liver injury to fibrogenesis through activation of HSCs in vivo.
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Mohammad Omar, Jan, Yang Hai, and Shizhu Jin. "Hypoxia-induced factor and its role in liver fibrosis." PeerJ 10 (December 6, 2022): e14299. http://dx.doi.org/10.7717/peerj.14299.
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Liver fibrosis develops as a result of severe liver damage and is considered a major clinical concern throughout the world. Many factors are crucial for liver fibrosis progression. While advancements have been made to understand this disease, no effective pharmacological drug and treatment strategies have been established that can effectively prevent liver fibrosis or even could halt the fibrotic process. Most of those advances in curing liver fibrosis have been aimed towards mitigating the causes of fibrosis, including the development of potent antivirals to inhibit the hepatitis virus. It is not practicable for many individuals; however, a liver transplant becomes the only suitable alternative. A liver transplant is an expensive procedure. Thus, there is a significant need to identify potential targets of liver fibrosis and the development of such agents that can effectively treat or reverse liver fibrosis by targeting them. Researchers have identified hypoxia-inducible factors (HIFs) in the last 16 years as important transcription factors driving several facets of liver fibrosis, making them possible therapeutic targets. The latest knowledge on HIFs and their possible role in liver fibrosis, along with the cell-specific activities of such transcription factors that how they play role in liver fibrosis progression, is discussed in this review.
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Focà, Emanuele, Massimiliano Fabbiani, Mattia Prosperi, Eugenia Quiros Roldan, Francesco Castelli, Franco Maggiolo, Elisa Di Filippo, et al. "Liver fibrosis progression and clinical outcomes are intertwined." Medicine 95, no. 29 (July 2016): e4091. http://dx.doi.org/10.1097/md.0000000000004091.
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Poupon, Raoul. "Non-Invasive Assessment of Liver Fibrosis Progression and Prognosis in Primary Biliary Cholangitis." Digestive Diseases 33, Suppl. 2 (2015): 115–17. http://dx.doi.org/10.1159/000440758.
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PBC (formerly known as primary biliary cirrhosis and now named primary biliary cholangitis) is a disease with a wide range of severity and variable rate of progression. The diagnosis of advanced liver fibrosis/cirrhosis portends an increased risk of liver-related morbidity and mortality. Because of its invasiveness, liver biopsy tends to be replaced by non-invasive tools for assessing liver fibrosis, making prognosis and optimising risk stratification for selection of patients, requiring new medical approaches. Many direct or indirect biomarkers have been found to correlate with the severity of liver fibrosis in PBC. They are easy to use but lack sensitivity and reproducibility in individuals with early stage disease. Three main radiologic approaches are currently proposed to assess liver fibrosis: vibration controlled transient elastography (VCTE), acoustic radiation force impulse and magnetic resonance elastography. Data using VCTE are available only for the longitudinal evaluation of liver fibrosis and prognosis in PBC. VCTE outperformed all other non-invasive current surrogate markers of liver fibrosis in PBC. Because of its high acceptability and its ability to predict hepatic decompensation, VCTE could be a useful tool to help allocate cirrhotic patients into different categories of risk. None of the radiologic and serum markers have a perfect accuracy in studies so far published. Concordance between VCTE and serum biomarkers is a prerequisite for a correct prognosis assessment in individuals in clinical practice.
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Zhang, Di, Jiaming Zheng, Guobin Qiu, Tongjuan Niu, Yuneng Gong, and Sheng Cui. "CCl4 inhibits the expressions of hepatic taurine biosynthetic enzymes and taurine synthesis in the progression of mouse liver fibrosis." Human & Experimental Toxicology 41 (January 2022): 096032712211350. http://dx.doi.org/10.1177/09603271221135033.
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Carbon tetrachloride (CCl4) is a widely used hepatotoxin for the studies of liver fibrosis and cirrhosis, and taurine has function to abate liver fibrosis induced by CCl4. But the interacting mechanisms between taurine and CCl4 in liver are still largely unknown. These made us to hypothesize that CCl4 may induce liver fibrosis by affecting the expressions of taurine biosynthetic enzymes and taurine synthesis. We thus assayed the expressions of hepatic cysteine dioxygenase (CDO), cysteine sulfonate acid decarboxylase (CSAD) and taurine transporter (TauT) in the progression of mouse liver fibrosis induced by CCl4. The results demonstrated that CCl4 treatment markedly decreased hepatic CSAD, CDO expressions, and taurine levels in hepatic tissue, although TauT expression did not exhibit significant decline. It was contrasting that hepatic α-SMA, serum AST, ALT, ALP kept increasing, which were accompanied by the pathological characters of liver, whereas taurine supplement attenuated the progression of liver fibrosis induced by CCl4. These results demonstrate that CCl4 may induce liver fibrosis by inhibiting hepatic CSAD and CDO expressions and taurine synthesis, which are crucial for our understanding the mechanisms of liver fibrosis induced by CCl4, and also potential for establishing therapeutic strategies of liver fibrosis and related diseases.
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Pace, Fábio Heleno de Lima, Lincoln Eduardo Vieira de Castro Ferreira, Antonio Eduardo Benedito Silva, and Maria Lucia Gomes Ferraz. "Liver fibrosis progression in HIV/hepatitis C virus coinfected patients with normal aminotransferases levels." Revista da Sociedade Brasileira de Medicina Tropical 45, no. 4 (August 2012): 444–47. http://dx.doi.org/10.1590/s0037-86822012000400005.
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INTRODUCTION: Approximately 30% of hepatitis C virus (HCV) monoinfected patients present persistently normal alanine aminotransferase (ALT) levels. Most of these patients have a slow progression of liver fibrosis. Studies have demonstrated the rate of liver fibrosis progression in hepatitis C virus-human immunodeficiency virus (HCV-HIV) coinfected patients is faster than in patients infected only by HCV. Few studies have evaluated the histological features of chronic hepatitis C in HIV-infected patients with normal ALT levels. METHODS: HCV-HIV coinfected patients (HCV-RNA and anti-HIV positive) with known time of HCV infection (intravenous drugs users) were selected. Patients with hepatitis B surface antigen (HBsAg) positive or hepatitis C treatment before liver biopsy were excluded. Patients were considered to have a normal ALT levels if they had at least 3 normal determinations in the previous 6 months prior to liver biopsy. All patients were submitted to liver biopsy and METAVIR scale was used. RESULTS: Of 50 studied patients 40 (80%) were males. All patients were treated with antiretroviral therapy. The ALT levels were normal in 13 (26%) patients. HCV-HIV co-infected patients with normal ALT levels had presented means of the liver fibrosis stages (0.77±0.44 versus 1.86±1.38; p<0.001) periportal inflammatory activity (0.62±0.77 versus 2.24±1.35; p<0.001) and liver fibrosis progression rate (0.058±0.043 fibrosis unit/year versus 0.118±0.102 fibrosis unit/year) significantly lower as compared to those with elevated ALT. CONCLUSIONS: HCV-HIV coinfected patients with persistently normal ALTs showed slower progression of liver fibrosis. In these patients the development of liver cirrhosis is improbable.
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Pinzani, Massimo. "Pathophysiology of Liver Fibrosis." Digestive Diseases 33, no. 4 (2015): 492–97. http://dx.doi.org/10.1159/000374096.
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Progressive accumulation of fibrillar extracellular matrix (ECM) in the liver is the consequence of reiterated liver tissue damage due to infective (mostly hepatitis B and C viruses), toxic/drug-induced, metabolic and autoimmune causes, and the relative chronic activation of the wound-healing reaction. The process may result in clinically evident liver cirrhosis and hepatic failure. Although cirrhosis is the common result of progressive fibrogenesis, there are distinct patterns of fibrotic development related to the underlying disorders causing the fibrosis. These different patterns of fibrogenic evolution are related to different factors and particularly: (1) the topographic localization of tissue damage, (2) the relative concentration of profibrogenic factors and (3) the prevalent profibrogenic mechanism(s). The mechanisms responsible for the fibrogenic evolution of chronic liver diseases can be summarized in three main groups: chronic activation of the wound-healing reaction, oxidative stress-related molecular mechanisms, and the derangement of the so-called ‘epithelial-mesenchymal' interaction leading to the generation of reactive cholangiocytes and peribiliary fibrosis. Most of the knowledge on the cell and molecular biology of hepatic fibrosis derives from in vitro studies employing culture of activated hepatic stellate cells isolated from rat, mouse or human liver. It is now evident that other ECM-producing cells, i.e. fibroblasts and myofibroblasts of the portal tract and circulating ‘fibrocytes', are likely to contribute to liver fibrosis. More recently, the attention is progressively shifting to the profibrotic microenvironment of the liver with increasing interest for the role of immune cells and specific subsets of macrophages regulating the progression or the regression of fibrosis, the role of intestinal microbiota and the influence of tissue stiffness. Other major areas of development include the role of tissue hypoxia and the establishment of an anaerobic proinflammatory environment and the influence of epigenetic modification in conditioning the progression of fibrosis.
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Koo, Dae-Jeong, Mi Yeon Lee, Inha Jung, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, and Won-Young Lee. "Baseline homeostasis model assessment of insulin resistance associated with fibrosis progression in patients with nonalcoholic fatty liver disease without diabetes: A cohort study." PLOS ONE 16, no. 8 (August 25, 2021): e0255535. http://dx.doi.org/10.1371/journal.pone.0255535.
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Background and aims Fibrosis progression is the most important prognostic factor, and insulin resistance is one of the main mechanisms associated with fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD). We evaluate the association between baseline insulin resistance and future fibrosis progression in patients with NAFLD without diabetes. Approach and results This retrospective longitudinal study with 8-year follow-up period included 32,606 (men, 83%) participants aged >20 years (average age, 38.0 years) without diabetes at baseline who completed at least two comprehensive health checkups from January 1, 2010 to December 31, 2018. NAFLD was diagnosed based on ultrasonography. The homeostasis model assessment of insulin resistance (HOMA-IR) was used to evaluate baseline insulin resistance. Fibrosis progression was assessed using the aspartate aminotransferase to platelet ratio index (APRI). The advanced liver fibrosis with an APRI value above the intermediate fibrosis probability (≥0.5) developed in a total of 2,897 participants during 136,108 person-years. 114 participants progressed to a high fibrosis probability stage (APRI >1.5) during 141,064 person-years. Using the lowest baseline HOMA-IR quartile group (Q1) as a reference, the multivariate-adjusted hazard ratio (HR) for development of advanced liver fibrosis (APRI ≥0.5) in the highest baseline HOMA-IR quartile group (Q4) was 1.95 (95% confidence interval [CI] 1.74–2.19; Model 4). And the HR for development of advanced liver fibrosis with high fibrosis probability was 1.95 (95% CI 1.10–3.46; Model 4). The positive association was maintained throughout the entire follow-up period. The baseline HOMA-IR model was superior to the baseline body mass index (BMI) model in predicting the progression of fibrosis probability. Conclusions In this longitudinal study, we found that the degree of baseline insulin resistance, assessed by HOMA-IR values, was positively associated with future fibrosis progression in patients with NAFLD without diabetes.
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Luangmonkong, Theerut, Pittaya Puphancharoensuk, Varisara Tongsongsang, Peter Olinga, and Warisara Parichatikanond. "Hepatoprotective Efficacy of Cycloastragenol Alleviated the Progression of Liver Fibrosis in Carbon-Tetrachloride-Treated Mice." Biomedicines 11, no. 1 (January 16, 2023): 231. http://dx.doi.org/10.3390/biomedicines11010231.
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The continuous death of hepatocytes induced by various etiologies leads to an aberrant tissue healing process and promotes the progression of liver fibrosis and ultimately chronic liver diseases. To date, effective treatments to delay this harmful process remain an unmet clinical need. Cycloastragenol is an active phytochemical substance isolated from Astragalus membranaceus, a plant used in traditional Chinese medicine to protect the liver. Therefore, our study aimed to elucidate the efficacy of cycloastragenol on carbon-tetrachloride (CCl4)-induced liver fibrosis in mice. We found that cycloastragenol at 200 mg/kg dosage exhibited anti-fibrotic efficacy as demonstrated by a decrease in collagen deposition, downregulation of mRNA expression of collagen type 1, and a reduction in the content of total collagens. In addition, cycloastragenol further augmented the levels of anti-fibrotic matrix metalloproteinases (Mmps), that is, Mmp8, proMmp9, and Mmp12, which play a pivotal role in fibrosis resolution. According to histological analysis and serum markers of hepatotoxicity, cycloastragenol protected the livers from damage and mitigated the increment of serum alanine aminotransferase and bilirubin implicating hepatoprotective efficacy against CCl4. Moreover, cycloastragenol upregulated the mRNA expression of interleukin 6, a pleiotropic cytokine plays a vital role in the promotion of hepatocyte regeneration. In conclusion, cycloastragenol alleviated the progression of liver fibrosis in CCl4-treated mice and its anti-fibrotic efficacy was mainly due to the hepatoprotective efficacy.
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Minamikawa, Takeo, Eiji Hase, Mayuko Ichimura-Shimizu, Yuki Morimoto, Akihiro Suzuki, Takeshi Yasui, Satoko Nakamura, Akemi Tsutsui, Koichi Takaguchi, and Koichi Tsuneyama. "Assessment of Ultra-Early-Stage Liver Fibrosis in Human Non-Alcoholic Fatty Liver Disease by Second-Harmonic Generation Microscopy." International Journal of Molecular Sciences 23, no. 6 (March 20, 2022): 3357. http://dx.doi.org/10.3390/ijms23063357.
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Non-alcoholic fatty liver disease (NAFLD) is associated with the chronic progression of fibrosis. In general, the progression of liver fibrosis is determined by a histopathological assessment with a collagen-stained section; however, the ultra-early stage of liver fibrosis is challenging to identify because of the low sensitivity in the collagen-selective staining method. In the present study, we demonstrate the feasibility of second-harmonic generation (SHG) microscopy in the histopathological diagnosis of the liver of NAFLD patients for the quantitative assessment of the ultra-early stage of fibrosis. We investigated four representative NAFLD patients with early stages of fibrosis. SHG microscopy visualised well-matured fibrotic structures and early fibrosis diffusely involving liver tissues, whereas early fibrosis is challenging to be identified by conventional histopathological methods. Furthermore, the SHG emission directionality analysis revealed the maturation of each collagen fibre of each patient. As a result, SHG microscopy is feasible for assessing liver fibrosis on NAFLD patients, including the ultra-early stage of liver fibrosis that is difficult to diagnose by the conventional histopathological method. The assessment method of the ultra-early fibrosis by using SHG microscopy may serve as a crucial means for pathological, clinical, and prognostic diagnosis of NAFLD patients.
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Gitau, Samuel Nguku, Sudhir Vinayak, Micah Silaba, Rodney Adam, and Reena Shah. "High Prevalence of Liver Fibrosis in Patients with Human Immunodeficiency Virus Monoinfection and Human Immunodeficiency Virus Hepatitis-B Co-infection as Assessed by Shear Wave Elastography: Study at a Teaching Hospital in Kenya." Journal of Clinical Imaging Science 6 (June 7, 2016): 22. http://dx.doi.org/10.4103/2156-7514.183582.
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Objectives: The aim of this study was to determine the prevalence of liver fibrosis in patients with human immunodeficiency virus (HIV) monoinfection versus those with HIV hepatitis-B virus (HBV) co-infection as assessed with shear wave elastography (SWE) in a tertiary sub-Saharan Africa hospital. Materials and Methods: A total of 105 consecutive patients, 70 with HIV monoinfection and 35 with HIV-HBV co-infection, had liver elastography obtained using SWE to assess for the presence of liver fibrosis the cutoff of which was 5.6 kPa. Assessment of aspartate aminotransferase-to-platelet ratio index (APRI) score (a noninvasive serum biomarker of liver fibrosis) in these patients was also done. Results: The prevalence of liver fibrosis was significantly higher (P < 0.0001) in patients with HIV-HBV co-infection, 25.7%, compared to those with HIV monoinfection, 7.1%. APRI score was greater in patients with HIV-HBV co-infection than those with HIV monoinfection. HIV co-infection with HBV accelerates progression to liver fibrosis. Association of a low cluster of differentiation 4 (CD-4) count with advanced fibrosis supports earlier starting of antiretroviral therapy to prevent rapid progression of liver disease in HIV-positive patients. Conclusion: In view of the high prevalence of liver fibrosis in patients with HIV-HBV co-infection, regular monitoring of the disease progression is recommended.
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Malov, S. I., L. S. Orlova, L. A. Stepanenko, O. B. Ogarkov, I. V. Malov, and N. D. Yushchuk. "Evaluation of predictors of liver fibrosis progression in patients with hepatitis C after successful virus elimination." Infekcionnye bolezni 20, no. 1 (2022): 64–73. http://dx.doi.org/10.20953/1729-9225-2022-1-64-73.
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Objective. To determine environmental and genetic factors associated with fibrosis progression after virus elimination as a result of direct-acting antiviral therapy by follow-up dispensary observation of patients with chronic hepatitis C with moderate and severe liver fibrosis (F2–F3 according to the METAVIR scoring system). Patients and methods. This study included 301 patients (166 men and 135 women) aged 20-64 years with chronic hepatitis C virus (HCV). A sustained virologic response was achieved in all patients after therapy with direct-acting antiviral agents. Patients were followed up for an average of 38 weeks (16–64). Patients were divided into two groups in order to perform comparative evaluation: group I included 257 patients with regression of liver fibrosis and group II – 44 patients with progression of liver fibrosis. Questionnaire and clinical and laboratory data were assessed. In addition, genetic studies of 24 singlenucleotide polymorphisms of genes involved in intracellular immune signaling pathway activation, interferon synthesis, metabolic regulation and cell proliferation were performed in both groups. Results. It was revealed that validated predictors of liver fibrosis progression in patients with chronic HCV after successful virus elimination as a result of therapy with direct-acting antiviral agents are the presence of concomitant type 2 diabetes mellitus, low ALT activity and serum osteopontin levels over 80 ng/mL at the beginning of therapy. Genetic predisposition to liver fibrosis progression is mediated by carriage of the AA genotype of HNF4α rs4812829 (OR = 3.55; 95% CI 1.21–10.41; p = 0.015). Additionally, the G-allele of NAT2 rs1495741, which marks fast xenobiotic acetylation, was found to have protective properties in the dominant genetic model. Carriers of GG- and GA-genotypes had an almost 2-fold lower risk of liver fibrosis progression after antiviral therapy than AA-genotype carriers (OR = 0.49; 95% CI 0.25–0.94; p = 0.029). Conclusion. The risk after successful hepatitis C virus elimination is significantly higher in patients with concomitant type 2 diabetes mellitus. ALT activity and serum osteopontin levels at the beginning of therapy can be estimated as predictors of liver fibrosis progression among laboratory parameters. Moreover, some genetic markers in the form of single-nucleotide polymorphisms of the HNF4α and NAT2 genes were established, which can be used to predict the development of liver fibrosis in patients with hepatitis C after therapy with direct-acting antiviral agents. Key words: hepatitis C, liver fibrosis, predictors, risk factors, diabetes mellitus, osteopontin, single-nucleotide polymorphisms, HNF4α gene, NAT2 gene
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Kim, Moon Young. "The Progression of Liver Fibrosis in Non-alcoholic Fatty Liver Disease." Korean Journal of Gastroenterology 69, no. 6 (2017): 341. http://dx.doi.org/10.4166/kjg.2017.69.6.341.
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TOVO, Cristiane Valle, Smile Calisto da Costa BECKER, Paulo Roberto Lerias de ALMEIDA, Bruno GALPERIM, and Silvia CHAVES. "PROGRESSION OF LIVER FIBROSIS IN MONOINFECTED PATIENTS BY HEPATITIS C VIRUS AND COINFECTED BY HCV AND HUMAN IMMUNODEFICIENCY VIRUS." Arquivos de Gastroenterologia 50, no. 1 (March 2013): 19–22. http://dx.doi.org/10.1590/s0004-28032013000100005.
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ContextThe progression of liver fibrosis in patients coinfected by hepatitis C virus and human immunodeficiency virus (HCV/HIV) has been increasingly studied in the past decade. Studies made before the highly active antiretroviral therapy suggest that HIV can change the natural history of the HCV infection, leading to a faster progression of the liver fibrosis.ObjectiveTo evaluate and compare the fibrosis progression in two groups of patients (HCV/HIV coinfected and HCV monoinfected)MethodsSeventy patients HCV monoinfected and 26 patients HCV/HIV coinfected who had not undertaken HCV treatment and were submitted to serial percutaneous liver biopsies were retrospectively evaluated. There was no difference in the fibrosis progression between the two groups.ConclusionThe fibrosis grade evolution was not worse in the coinfected patients. The immunosuppression absence and the shortest time period between the biopsies in the coinfected group are possible explanations.
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Garbuzenko, Dmitry V. "Diagnostic and risk stratification aspects of liver fibrosis progression in chronic hepatitis B and C viral infection." Medical Journal of the Russian Federation 27, no. 4 (July 15, 2021): 373–84. http://dx.doi.org/10.17816/0869-2106-2021-27-4-373-384.
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The treatment strategy and prognosis for chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection largely depend on the presence and stage of liver fibrosis. This study aimed to reveal the diagnostic and risk stratification aspects of liver fibrosis progression in patients with chronic HBV and HCV infection. The PubMed database, the Google Scholar search engine, the Cochrane systematic reviews, and the scientific electronic library eLibrary.Ru, as well as the reference lists, were used to search for scientific articles. Relevant aims of the publication review were selected over the period from 2005 to 2021 using the keywords chronic HBV infection, chronic HCV infection, liver fibrosis, diagnostics, and prognosis. Inclusion criteria were limited to liver fibrosis diagnostics in chronic HBV and HCV infection. Considering biopsy as a gold standard for studying morphological abnormalities in the liver, its indications for serum biomarkers of liver fibrosis and imaging methods assessments are currently significantly limited. Additionally, noninvasive methods are required to monitor the progression of liver fibrosis. The combined use of two unrelated noninvasive methods, for example, transient elastography and one of the serum biomarkers, can improve the accuracy of clinically diagnosing significant liver fibrosis. Considering that the development of liver fibrosis is an unfavorable event in the natural course of chronic HBV and HCV infection, the distribution of patients by risk groups will increase the efficiency of antiviral therapy and improve the disease prognosis.
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Livingston, Stephen E., Heike Deubner, Dana L. Bruden, Brian J. McMahon, Chriss E. Homan, Lisa J. Townshend-Bulson, Michael G. Bruce, Thomas W. Hennessy, James L. Williams, and David R. Gretch. "Factors Associated with the Progression of Fibrosis on Liver Biopsy in Alaska Native and American Indian Persons with Chronic Hepatitis C." Canadian Journal of Gastroenterology 24, no. 7 (2010): 445–51. http://dx.doi.org/10.1155/2010/692036.
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BACKGROUND: Various factors influence the development and rate of fibrosis progression in chronic hepatitis C virus (HCV) infection.OBJECTIVES: To examine factors associated with fibrosis in a long-term outcomes study of Alaska Native/American Indian persons who underwent liver biopsy, and to examine the rate of fibrosis progression in persons with subsequent biopsies.METHODS: A cross-sectional analysis of the demographic, inflammatory and viral characteristics of persons undergoing liver biopsy compared individuals with early (Ishak fibrosis score of lower than 3) with those with advanced (Ishak score of 3 or greater) fibrosis. Persons who underwent two or more biopsies were analyzed for factors associated with fibrosis progression.RESULTS: Of 253 HCV RNA-positive persons who underwent at least one liver biopsy, 76 (30%) had advanced fibrosis. On multivariate analysis, a Knodell histological activity index score of 10 to 14 and an alpha-fetoprotein level of 8 ng/mL or higher were found to be independent predictors of advanced liver fibrosis (P<0.0001 for each). When surrogate markers of liver inflammation (alanine aminotransferase, aspartate aminotransferase/alanine aminotransferase ratio and alpha-fetoprotein) were removed from the model, type 2 diabetes mellitus (P=0.001), steatosis (P=0.03) and duration of HCV infection by 10-year intervals (P=0.02) were associated with advanced fibrosis. Among 52 persons who underwent two or more biopsies a mean of 6.2 years apart, the mean Ishak fibrosis score increased between biopsies (P=0.002), with progression associated with older age at initial biopsy and HCV risk factors.CONCLUSIONS: The presence of type 2 diabetes mellitus, steatosis and duration of HCV infection were independent predictors of advanced fibrosis in the present cohort, with significant fibrosis progression demonstrated in persons who underwent serial biopsies.
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Hagiwara, Satoru, Naoshi Nishida, Kazuomi Ueshima, Yasunori Minami, Yoriaki Komeda, Tomoko Aoki, Masahiro Takita, et al. "Accumulation of Genetic and Epigenetic Alterations in the Background Liver and Emergence of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease." Cells 10, no. 11 (November 21, 2021): 3257. http://dx.doi.org/10.3390/cells10113257.
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The incidence of hepatocellular carcinoma (HCC) related to non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. We analyzed 16 surgically resected HCC cases in which the background liver was pathologically diagnosed as NAFLD. Specimens with Brunt classification grade 3 or higher were assigned as the fibrotic progression group (n = 8), and those with grade 1 or lower were classified as the non-fibrosis progression group (n = 8). Comprehensive mutational and methylome analysis was performed in cancerous and noncancerous tissues. The target gene mutation analysis with deep sequencing revealed that CTNNB1 and TP53 mutation was observed in 37.5% and TERT promoter mutation was detected in 50% of cancerous samples. Furthermore, somatic mutations in non-cancerous samples were less frequent, but were observed regardless of the progression of fibrosis. Similarly, on cluster analysis of methylome data, status for methylation events involving non-cancerous liver was similar regardless of the progression of fibrosis. It was found that, even in cases of non-progressive fibrosis, accumulation of gene mutations and abnormal methylation within non-cancerous areas were observed. Patients with NAFLD require a rigorous liver cancer surveillance due to the high risk of HCC emergence based on the accumulation of genetic and epigenetic abnormalities, even when fibrosis is not advanced.
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Chen, Wei, Xuzhen Yan, Aiting Yang, Anjian Xu, Tao Huang, and Hong You. "miRNA-150-5p promotes hepatic stellate cell proliferation and sensitizes hepatocyte apoptosis during liver fibrosis." Epigenomics 12, no. 1 (January 2020): 53–67. http://dx.doi.org/10.2217/epi-2019-0104.
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Aim: To explore the role of miRNA-150-5p (miR-150-5p) in liver fibrosis. Materials & methods: miRNA expression profiles, CCl4-induced liver fibrosis progression and regression rodent models, quantitative real-time PCR, miR-150-5p mimics and inhibitors, cell proliferation and apoptosis detection, RNA sequencing and bioinformatics analysis were employed. Results: Liver tissue miR-150-5p expression was positively associated with liver fibrosis progression and regression; however, miR-150-5p exhibited a cell-specific expression pattern, namely, it was enhanced in hepatocytes but reduced in hepatic stellate cells (HSCs) during liver fibrosis; miR-150-5p overexpression promoted HSC apoptosis and sensitized hepatocyte apoptosis; miR-150-5p mimic had a larger influence on the transcriptomic stability of HSCs than that of hepatocytes; miR-150-5p mediated activation of interferon signaling pathways might be responsible for HSC apoptosis. Conclusion: miR-150-5p exhibited an opposite regulation and function pattern between HSCs and hepatocytes during liver fibrosis.
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Riaz, Farooq, and Dongmin Li. "Non-coding RNA Associated Competitive Endogenous RNA Regulatory Network: Novel Therapeutic Approach in Liver Fibrosis." Current Gene Therapy 19, no. 5 (December 27, 2019): 305–17. http://dx.doi.org/10.2174/1566523219666191107113046.
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Liver fibrosis or scarring is the most common pathological feature caused by chronic liver injury, and is widely considered one of the primary causes of morbidity and mortality. It is primarily characterised by hepatic stellate cells (HSC) activation and excessive extracellular matrix (ECM) protein deposition. Overwhelming evidence suggests that the dysregulation of several noncoding RNAs (ncRNAs), mainly long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) contributes to the activation of HSC and progression of liver fibrosis. These ncRNAs not only bind to their target genes for the development and regression of liver fibrosis but also act as competing endogenous RNAs (ceRNAs) by sponging with miRNAs to form signaling cascades. Among these signaling cascades, lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA are critical modulators for the initiation, progression, and regression of liver fibrosis. Thus, targeting these interacting ncRNA cascades can serve as a novel and potential therapeutic target for inhibition of HSC activation and prevention and regression of liver fibrosis.
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Kim, Min, Changhu Lee, Dae Yun Seo, Hyojung Lee, Jay D. Horton, Jiyoung Park, and Philipp E. Scherer. "The impact of endotrophin on the progression of chronic liver disease." Experimental & Molecular Medicine 52, no. 10 (October 2020): 1766–76. http://dx.doi.org/10.1038/s12276-020-00520-8.
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Abstract Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The fibrotic liver is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Type VI collagen alpha3 (Col6a3) is a biomarker of hepatic fibrosis, and its cleaved form, endotrophin (ETP), plays a critical role in adipose tissue dysfunction, insulin resistance, and breast cancer development. Here, we studied the effects of the Col6a3-derived peptide ETP on the progression of chronic liver diseases, such as NASH and liver cancer. We used a doxycycline (Dox)-inducible liver-specific ETP-overexpressing mouse model on a NAFLD-prone (liver-specific SREBP1a transgenic) background. For this, we evaluated the consequences of local ETP expression in the liver and its effect on hepatic inflammation, fibrosis, and insulin resistance. Accumulation of ETP in the liver induced hepatic inflammation and the development of fibrosis with associated insulin resistance. Surprisingly, ETP overexpression also led to the emergence of liver cancer within 10 months in the SREBP1a transgenic background. Our data revealed that ETP can act as a “second hit” during the progression of NAFLD and can play an important role in the development of NASH and hepatocellular carcinoma (HCC). These observations firmly link elevated levels of ETP to chronic liver disease.