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Gastroenterologie Clinique Et Biologique Sep 2008Transient elastography (FibroScan) is a non-invasive method proposed for the assessment of hepatic fibrosis in patients with chronic liver disease by measuring liver...
Transient elastography (FibroScan) is a non-invasive method proposed for the assessment of hepatic fibrosis in patients with chronic liver disease by measuring liver stiffness. It can be easily performed at the bedside or in the outpatients clinic with immediate results and good reproducibility. Limitations include failure (no value) in around 5% of cases, mainly in patients with substantial thoracic fat. In France, FibroScan or FibroTest are recommended for the initial evaluation of liver fibrosis in previously untreated patients with chronic hepatitis C and no concomitant health disorders. FibroScan is validated for the diagnosis of significant fibrosis and cirrhosis in chronic hepatitis C, recurrence of hepatitis C after liver transplantation, co-infections in HIV-HCV patients and chronic cholestatic diseases, but needs further evaluation in other chronic liver diseases. FibroScan is an excellent tool for early detection of cirrhosis and evaluation of portal hypertension, for which it may have prognostic value as well. Studies are needed using FibroScan for the follow-up of patients with and without treatment, and for the screening of patients at risk of liver disease. However, although FibroScan is a good method for the evaluation of fibrosis in patients with chronic liver disease, it has to be borne in mind that FibroScan evaluates liver stiffness. Therefore, FibroScan values have to be interpreted according to clinical, biological and morphological data.
Topics: Elasticity Imaging Techniques; Humans; Liver Cirrhosis
PubMed: 18973847
DOI: 10.1016/S0399-8320(08)73994-0 -
World Journal of Gastroenterology Dec 2014Liver cirrhosis is a common and growing public health problem globally. The diagnosis of cirrhosis portends an increased risk of morbidity and mortality. Liver biopsy is... (Review)
Review
Liver cirrhosis is a common and growing public health problem globally. The diagnosis of cirrhosis portends an increased risk of morbidity and mortality. Liver biopsy is considered the gold standard for diagnosis of cirrhosis and staging of fibrosis. However, despite its universal use, liver biopsy is an invasive and inaccurate gold standard with numerous drawbacks. In order to overcome the limitations of liver biopsy, a number of non-invasive techniques have been investigated for the assessment of cirrhosis. This review will focus on currently available non-invasive markers of cirrhosis. The evidence behind the use of these markers will be highlighted, along with an assessment of diagnostic accuracy and performance characteristics of each test. Non-invasive markers of cirrhosis can be radiologic or serum-based. Radiologic techniques based on ultrasound, magnetic resonance imaging and elastography have been used to assess liver fibrosis. Serum-based biomarkers of cirrhosis have also been developed. These are broadly classified into indirect and direct markers. Indirect biomarkers reflect liver function, which may decline with the onset of cirrhosis. Direct biomarkers, reflect extracellular matrix turnover, and include molecules involved in hepatic fibrogenesis. On the whole, radiologic and serum markers of fibrosis correlate well with biopsy scores, especially when excluding cirrhosis or excluding fibrosis. This feature is certainly clinically useful, and avoids liver biopsy in many cases.
Topics: Animals; Biomarkers; Biopsy; Diagnostic Imaging; Elasticity Imaging Techniques; Humans; Liver; Liver Cirrhosis; Liver Function Tests; Predictive Value of Tests; Prognosis
PubMed: 25492996
DOI: 10.3748/wjg.v20.i45.16820 -
International Journal of Molecular... Dec 2020Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, diseases such as steatohepatitis, autoimmune hepatitis,... (Review)
Review
Liver cirrhosis is one of the most prevalent chronic liver diseases worldwide. In addition to viral hepatitis, diseases such as steatohepatitis, autoimmune hepatitis, sclerosing cholangitis and Wilson's disease can also lead to cirrhosis. Moreover, alcohol can cause cirrhosis on its own and exacerbate chronic liver disease of other causes. The treatment of cirrhosis can be divided into addressing the cause of cirrhosis and reversing liver fibrosis. To this date, there is still no clear consensus on the treatment of cirrhosis. Recently, there has been a lot of interest in potential treatments that modulate the gut microbiota and gut-liver axis for the treatment of cirrhosis. According to recent studies, modulation of the gut microbiome by probiotics ameliorates the progression of liver disease. The precise mechanism for relieving cirrhosis via gut microbial modulation has not been identified. This paper summarizes the role and effects of the gut microbiome in cirrhosis based on experimental and clinical studies on absorbable antibiotics, probiotics, prebiotics, and synbiotics. Moreover, it provides evidence of a relationship between the gut microbiome and liver fibrosis.
Topics: Bacterial Translocation; Dietary Supplements; Dysbiosis; Gastrointestinal Microbiome; Humans; Liver Cirrhosis
PubMed: 33379148
DOI: 10.3390/ijms22010199 -
Molecular Aspects of Medicine Feb 2024Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory... (Review)
Review
Liver fibrosis, as an excess deposition of extracellular matrix (ECM) components, results from chronic liver injury as well as persistent activation of inflammatory response and of fibrogenesis. Liver fibrosis is a major determinant for chronic liver disease (CLD) progression and in the last two decades our understanding on the major molecular and cellular mechanisms underlying the fibrogenic progression of CLD has dramatically improved, boosting pre-clinical studies and clinical trials designed to find novel therapeutic approaches. From these studies several critical concepts have emerged, starting to reveal the complexity of the pro-fibrotic microenvironment which involves very complex, dynamic and interrelated interactions between different hepatic and extrahepatic cell populations. This review will offer first a recapitulation of established and novel pathophysiological basic principles and concepts by intentionally focus the attention on NAFLD/NASH, a metabolic-related form of CLD with a high impact on the general population and emerging as a leading cause of CLD worldwide. NAFLD/NASH-related pro-inflammatory and profibrogenic mechanisms will be analysed as well as novel information on cells, mediators and signalling pathways which have taken advantage from novel methodological approaches and techniques (single cell genomics, imaging mass cytometry, novel in vitro two- and three-dimensional models, etc.). We will next offer an overview on recent advancement in diagnostic and prognostic tools, including serum biomarkers and polygenic scores, to support the analysis of liver biopsies. Finally, this review will provide an analysis of current and emerging therapies for the treatment of NAFLD/NASH patients.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Liver; Biomarkers; Myofibroblasts
PubMed: 38056058
DOI: 10.1016/j.mam.2023.101231 -
JCI Insight Dec 2021In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the...
In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion toward a quiescent-like state, a process called deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the deactivation and/or activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cell quiescence. In this work, we show that lack of GATA4 in adult mice caused hepatic stellate cell activation and, consequently, liver fibrosis. During regression of liver fibrosis, Gata4 was reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promoted liver fibrosis regression in CCl4-treated mice. GATA4 induced changes in the expression of fibrogenic and antifibrogenic genes, promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly repressed EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.
Topics: Animals; GATA4 Transcription Factor; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Mice; Transfection
PubMed: 34699385
DOI: 10.1172/jci.insight.150059 -
Cardiovascular Research Mar 2022Hepatic capillaries are lined with specialized liver sinusoidal endothelial cells (LSECs) which support macromolecule passage to hepatocytes and prevent fibrosis by...
AIMS
Hepatic capillaries are lined with specialized liver sinusoidal endothelial cells (LSECs) which support macromolecule passage to hepatocytes and prevent fibrosis by keeping hepatic stellate cells (HSCs) quiescent. LSEC specialization is co-determined by transcription factors. The zinc-finger E-box-binding homeobox (Zeb)2 transcription factor is enriched in LSECs. Here, we aimed to elucidate the endothelium-specific role of Zeb2 during maintenance of the liver and in liver fibrosis.
METHODS AND RESULTS
To study the role of Zeb2 in liver endothelium we generated EC-specific Zeb2 knock-out (ECKO) mice. Sequencing of liver EC RNA revealed that deficiency of Zeb2 results in prominent expression changes in angiogenesis-related genes. Accordingly, the vascular area was expanded and the presence of pillars inside ECKO liver vessels indicated that this was likely due to increased intussusceptive angiogenesis. LSEC marker expression was not profoundly affected and fenestrations were preserved upon Zeb2 deficiency. However, an increase in continuous EC markers suggested that Zeb2-deficient LSECs are more prone to dedifferentiation, a process called 'capillarization'. Changes in the endothelial expression of ligands that may be involved in HSC quiescence together with significant changes in the expression profile of HSCs showed that Zeb2 regulates LSEC-HSC communication and HSC activation. Accordingly, upon exposure to the hepatotoxin carbon tetrachloride (CCl4), livers of ECKO mice showed increased capillarization, HSC activation, and fibrosis compared to livers from wild-type littermates. The vascular maintenance and anti-fibrotic role of endothelial Zeb2 was confirmed in mice with EC-specific overexpression of Zeb2, as the latter resulted in reduced vascularity and attenuated CCl4-induced liver fibrosis.
CONCLUSION
Endothelial Zeb2 preserves liver angioarchitecture and protects against liver fibrosis. Zeb2 and Zeb2-dependent genes in liver ECs may be exploited to design novel therapeutic strategies to attenuate hepatic fibrosis.
Topics: Animals; Biomarkers; Endothelial Cells; Endothelium; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Mice
PubMed: 33909875
DOI: 10.1093/cvr/cvab148 -
Biomedicine & Pharmacotherapy =... Jan 2019Liver fibrosis is a progression of chronic liver disease, which lacks effective therapies in the world. Attractively, more and more evidences show that natural products...
Liver fibrosis is a progression of chronic liver disease, which lacks effective therapies in the world. Attractively, more and more evidences show that natural products are safe and effective in the prevention and treatment of hepatic fibrosis. Artesunate, a water-soluble hemisuccinate derivative of artemisinin, exerts various pharmacological activities such as anti-inflammatory, anti-tumor and immunomodulating abilities. However, the effects of artesunate on hepatic fibrosis are little-known. Here our study was performed to investigate the effect of artesunate on carbon tetrachloride (CCl)-induced mouse liver fibrosis and elucidate whether artesunate could alleviate liver fibrosis by regulating ferritinophagy- mediated ferroptosis in hepatic stellate cells (HSCs). Firstly, our results demonstrated that artesunate treatment could induce activated HSC ferroptosis in fibrotic livers. Moreover, primary HSCs isolated from different animal groups were cultured to detect biomarkers of ferroptosis including iron, lipid peroxidation, glutathione (GSH) and prostaglandin endoperoxide synthase 2 (ptgs2) levels. The results revealed that artesunate remarkably promoted ferroptosis of activated HSCs. Furthermore, consistent with the experimental results in vivo, the data in vitro still indicated that artesunate treatment markedly induced ferroptosis in activated HSCs, which mainly embodied as declined cell vitality, increased cell death rate, accumulated iron, elevated lipid peroxides and reduced antioxidant capacity. Conversely, inhibition of ferroptosis by deferoxamine (DFO) completely abolished artesunate-induced anti-fibrosis effect. Surprisingly, artesunate also evidently triggered ferritinophagy accompanied by up-regulation of LC3 (microtubule-associated protein light chain 3), Atg3, Atg5, Atg6/beclin1, Atg12 (autophagy related genes) and down-regulation of p62, FTH1 (ferritin heavy chain), NCOA4 (nuclear receptor co-activator 4) in activated HSCs. Nevertheless, depletion of ferritinophagy by specific inhibitor lysosomal lumen alkalizer-chloroquine (CQ) inhibited artesunate-induced ferroptosis and anti-fibrosis function. These results suggested that ferritinophagy-mediated HSC ferroptosis was responsible for artesunate-induced anti-fibrosis efficacy, which provided new clues for further pharmacological study of artesunate.
Topics: Animals; Antineoplastic Agents; Apoptosis; Artesunate; Iron; Liver Cirrhosis; Male; Mice; Mice, Inbred ICR; Random Allocation; Signal Transduction
PubMed: 30551460
DOI: 10.1016/j.biopha.2018.11.030 -
Cell Aug 2008Cellular senescence acts as a potent mechanism of tumor suppression; however, its functional contribution to noncancer pathologies has not been examined. Here we show...
Cellular senescence acts as a potent mechanism of tumor suppression; however, its functional contribution to noncancer pathologies has not been examined. Here we show that senescent cells accumulate in murine livers treated to produce fibrosis, a precursor pathology to cirrhosis. The senescent cells are derived primarily from activated hepatic stellate cells, which initially proliferate in response to liver damage and produce the extracellular matrix deposited in the fibrotic scar. In mice lacking key senescence regulators, stellate cells continue to proliferate, leading to excessive liver fibrosis. Furthermore, senescent activated stellate cells exhibit gene expression profile consistent with cell-cycle exit, reduced secretion of extracellular matrix components, enhanced secretion of extracellular matrix-degrading enzymes, and enhanced immune surveillance. Accordingly natural killer cells preferentially kill senescent activated stellate cells in vitro and in vivo, thereby facilitating the resolution of fibrosis. Therefore, the senescence program limits the fibrogenic response to acute tissue damage.
Topics: Animals; Carbon Tetrachloride; Cells, Cultured; Cellular Senescence; Female; Fibroblasts; Humans; Killer Cells, Natural; Liver; Liver Cirrhosis; Liver Cirrhosis, Experimental; Mice
PubMed: 18724938
DOI: 10.1016/j.cell.2008.06.049 -
Journal of Hepatology May 2021In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction,...
BACKGROUND & AIMS
In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor in 2 preclinical models of ACLD, as well as in liver cells from patients with ACLD.
METHODS
Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle.
RESULTS
TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor.
CONCLUSIONS
Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD.
LAY SUMMARY
Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects.
Topics: Animals; Anti-Inflammatory Agents; Antifibrotic Agents; Antihypertensive Agents; Benzothiazoles; Cells, Cultured; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hypertension, Portal; Liver; Liver Cirrhosis; Peroxisome Proliferator-Activated Receptors; Portal Pressure; Rats; Sulfonamides; Vascular Resistance
PubMed: 33278455
DOI: 10.1016/j.jhep.2020.11.045 -
Annals of Medicine Dec 2022Selenium was one of the essential trace elements that played a pivotal role in human health. Although previous studies have investigated the relationship between...
BACKGROUND & OBJECTIVE
Selenium was one of the essential trace elements that played a pivotal role in human health. Although previous studies have investigated the relationship between selenium and non-alcoholic fatty liver disease (NAFLD) and fibrosis, these findings were still inconclusive. Our study was aimed to explore the association between blood selenium level and NAFLD and advanced liver fibrosis diagnosed by vibration controlled transient elastography (VCTE) in US adults.
METHODS
All data were extracted from National Health and Nutrition Examination Survey database (2017-2018). Participants were divided into four groups according to quartile of blood selenium level. Liver stiffness and controlled attenuation parameter (CAP) were measured by VCTE. Multiple logistic regression models and subgroup analyses were conducted to determine the association between blood selenium level and NAFLD and advanced liver fibrosis diagnosed by a variety of methods.
RESULTS
A total of 3336 participants were enrolled in main analysis. In multiple logistic regression models, the higher blood selenium level (>205.32, ≤453.62 μg/L) had a significant positive association with NAFLD (β = 1.31). Moreover, high blood selenium level had significantly inversely association to advanced liver fibrosis (β = 0.61). In subgroup analysis, the main inversely correlation between blood selenium and advanced liver fibrosis was found in males with high blood selenium level. Despite dietary selenium intake being adjusted or in different subgroups, the associations between blood selenium level and NAFLD/advanced liver fibrosis remained significant.
CONCLUSIONS
This study showed that blood selenium level were positively association with NAFLD among US population. Participants with lower blood selenium level showed a higher percentage of advanced liver fibrosis. Blood selenium is more likely to cause NAFLD and liver fibrosis due to imbalances in selenium homeostasis rather than dietary selenium intake.Key messagesHigh blood selenium level was association with NAFLD diagnosed by vibration controlled transient elastography.Participants with lower blood selenium level had high percentage of advanced liver fibrosis.NAFLD and liver fibrosis are caused by an imbalance of selenium homeostasis, not by dietary selenium intake.
Topics: Adult; Elasticity Imaging Techniques; Fibrosis; Humans; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Nutrition Surveys; Selenium
PubMed: 35975984
DOI: 10.1080/07853890.2022.2110277