-
Cells Apr 2020Liver 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... (Review)
Review
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.
Topics: Animals; Apoptosis; Gastrointestinal Microbiome; Humans; Liver Cirrhosis; Models, Biological; Oxidative Stress; Signal Transduction
PubMed: 32260126
DOI: 10.3390/cells9040875 -
American Family Physician Dec 2019Cirrhosis is the 12th leading cause of death in the United States. Newer research has established that liver fibrosis is a dynamic process and that early cirrhosis may...
Cirrhosis is the 12th leading cause of death in the United States. Newer research has established that liver fibrosis is a dynamic process and that early cirrhosis may be reversible. Only one in three people with cirrhosis knows they have it. Most patients with cirrhosis remain asymptomatic until the onset of decompensation. When clinical signs, symptoms, or abnormal liver function tests are discovered, further evaluation should be pursued promptly. The most common causes of cirrhosis are viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis. Initial workup includes viral hepatitis serologies, ferritin, transferrin saturation, and abdominal ultrasonography as well as complete blood count, liver function tests, and prothrombin time/international normalized ratio, if not already ordered. Additional testing is based on demographics and risk factors. Common serum and ultrasound-based screening tests to assess fibrosis include the aspartate transaminase to platelet ratio index score, Fibrosis 4 score, FibroTest/FibroSure, nonalcoholic fatty liver fibrosis score, standard ultrasonography, and transient elastography. Generally, noninvasive tests are most useful in identifying patients with no to minimal fibrosis or advanced fibrosis. Chronic liver disease management includes directed counseling, laboratory testing, and ultrasound monitoring. Treatment goals are preventing cirrhosis, decompensation, and death. Varices are monitored with endoscopy and often require prophylaxis with nonselective beta blockers. Ascites treatment includes diuresis, salt restriction, and antibiotic prophylaxis for spontaneous bacterial peritonitis, when indicated. Hepatic encephalopathy is managed with lifestyle and nutritional modifications and, as needed, with lactulose and rifaximin. Hepatocellular carcinoma screening includes ultrasound screening every six months for patients with cirrhosis.
Topics: Chronic Disease; Humans; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease
PubMed: 31845776
DOI: No ID Found -
Abdominal Radiology (New York) Sep 2022Elastography has emerged as a preferred non-invasive imaging technique for the clinical assessment of liver fibrosis. Elastography methods provide liver stiffness... (Review)
Review
Elastography has emerged as a preferred non-invasive imaging technique for the clinical assessment of liver fibrosis. Elastography methods provide liver stiffness measurement (LSM) as a surrogate quantitative biomarker for fibrosis burden in chronic liver disease (CLD). Elastography can be performed either with ultrasound or MRI. Currently available ultrasound-based methods include strain elastography, two-dimensional shear wave elastography (2D-SWE), point shear wave elastography (pSWE), and vibration-controlled transient elastography (VCTE). MR Elastography (MRE) is widely available as two-dimensional gradient echo MRE (2D-GRE-MRE) technique. US-based methods provide estimated Young's modulus (eYM) and MRE provides magnitude of the complex shear modulus. MRE and ultrasound methods have proven to be accurate methods for detection of advanced liver fibrosis and cirrhosis. Other clinical applications of elastography include liver decompensation prediction, and differentiation of non-alcoholic steatohepatitis (NASH) from simple steatosis (SS). In this review, we briefly describe the different elastography methods, discuss current clinical applications, and provide an overview of advances in the field of liver elastography.
Topics: Elasticity Imaging Techniques; Humans; Liver; Liver Cirrhosis; Magnetic Resonance Imaging; Non-alcoholic Fatty Liver Disease
PubMed: 34687329
DOI: 10.1007/s00261-021-03269-4 -
Frontiers in Immunology 2022The systemic immune-inflammation index (SII) is a novel marker of inflammation, and hepatic steatosis and fibrosis are associated with inflammation. This study aimed to...
BACKGROUND
The systemic immune-inflammation index (SII) is a novel marker of inflammation, and hepatic steatosis and fibrosis are associated with inflammation. This study aimed to investigate the possible relationship between SII and hepatic steatosis and fibrosis.
METHODS
The datasets from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 were used in a cross-sectional investigation. Multivariate linear regression models were used to examine the linear connection between SII and controlled attenuation parameter (CAP) and liver stiffness measurement (LSM). Fitted smoothing curves and threshold effect analysis were used to describe the nonlinear relationship.
RESULTS
This population-based study included a total of 6,792 adults aged 18-80 years. In a multivariate linear regression analysis, a significant positive association between SII and CAP was shown [0.006 (0.001, 0.010)]. This positive association in a subgroup analysis was maintained in men [0.011 (0.004, 0.018)] but not in women. Furthermore, the association between SII and CAP was nonlinear; using a two-segment linear regression model, we found an inverted U-shaped relationship between SII and CAP with an inflection point of 687.059 (1,000 cells/µl). The results of the multiple regression analysis showed that the relationship between SII and LSM was not significant (P = 0.263).
CONCLUSIONS
Our findings imply that increased SII levels are linked to hepatic steatosis, but SII is not linked to liver fibrosis. To confirm our findings, more large-scale prospective investigations are needed.
Topics: Adult; Biopsy; Cross-Sectional Studies; Elasticity Imaging Techniques; Female; Humans; Inflammation; Liver Cirrhosis; Male; Non-alcoholic Fatty Liver Disease; Nutrition Surveys; Prospective Studies
PubMed: 36189280
DOI: 10.3389/fimmu.2022.925690 -
Cells Oct 2021Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix.... (Review)
Review
Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.
Topics: Animals; Extracellular Matrix; Humans; Inflammation; Liver Cirrhosis; Myofibroblasts; Remission Induction; Vascular Remodeling
PubMed: 34685739
DOI: 10.3390/cells10102759 -
Experimental Biology and Medicine... Jan 2020Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic... (Review)
Review
UNLABELLED
Hepatic fibrogenesis is a pathophysiological outcome of chronic liver injury hallmarked by excessive accumulation of extracellular matrix proteins. Fibrosis is a dynamic process that involves cross-talk between parenchymal cells (hepatocytes), hepatic stellate cells, sinusoidal endothelial cells and both resident and infiltrating immune cells. In this review, we focus on key cell-types that contribute to liver fibrosis, cytokines, and chemokines influencing this process and what it takes for fibrosis to regress. We discuss how mitochondria and metabolic changes in hepatic stellate cells modulate the fibrogenic process. We also briefly review how the presence of fibrosis affects development of hepatocellular carcinoma.
IMPACT STATEMENT
Advanced liver fibrosis results in cirrhosis, portal hypertension, and liver failure and often requires liver transplantation. Advanced liver fibrosis and cirrhosis are also major risk factors for hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) play a pivotal role in the pathogenesis of liver fibrosis. In this review, we summarize the basic mechanisms that influence liver fibrosis development and how oxidative stress, mitochondrial dysfunction, and metabolic remodeling modulate HSC activation and indicate areas of potential therapeutic intervention.
Topics: Animals; Chemokines; Humans; Liver Cirrhosis; Liver Neoplasms; Mitochondria; Myofibroblasts; Oxidative Stress
PubMed: 31924111
DOI: 10.1177/1535370219898141 -
Journal of Advanced Research May 2023High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood.
INTRODUCTION
High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood.
OBJECTIVES
This study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation.
METHODS
The ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout(KO) mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8's mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression.
RESULTS
ANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved anti-diabetic drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo.
CONCLUSIONS
Our data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis.
Topics: Mice; Animals; Non-alcoholic Fatty Liver Disease; Diet, High-Fat; Liver Cirrhosis; Inflammation; Signal Transduction; Angiopoietin-Like Protein 8
PubMed: 36031141
DOI: 10.1016/j.jare.2022.08.006 -
Mechanisms of Ageing and Development Oct 2021Myofibroblasts play an important role in fibrogenesis. Hepatic stellate cells are the main precursors of myofibroblasts. Cellular senescence is the terminal cell fate in... (Review)
Review
Myofibroblasts play an important role in fibrogenesis. Hepatic stellate cells are the main precursors of myofibroblasts. Cellular senescence is the terminal cell fate in which proliferating cells undergo irreversible cell cycle arrest. Senescent hepatic stellate cells were identified in liver fibrosis. Senescent hepatic stellate cells display decreased collagen production and proliferation. Therefore, induction of senescence could be a protective mechanism against progression of liver fibrosis and the concept of therapy-induced senescence has been proposed to treat liver fibrosis. In this review, characteristics of senescent hepatic stellate cells and the essential signaling pathways involved in senescence are reviewed. Furthermore, the potential impact of senescent hepatic stellate cells on other liver cell types are discussed. Senescent cells are cleared by the immune system. The persistence of senescent cells can remodel the microenvironment and interact with inflammatory cells to induce aging-related dysfunction. Therefore, senolytics, a class of compounds that selectively induce death of senescent cells, were introduced as treatment to remove senescent cells and consequently decrease the disadvantageous effects of persisting senescent cells. The effects of senescent hepatic stellate cells in liver fibrosis need further investigation.
Topics: Animals; Cellular Senescence; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Senotherapeutics
PubMed: 34536446
DOI: 10.1016/j.mad.2021.111572 -
Cells Nov 2019Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic... (Review)
Review
Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.
Topics: Animals; Autophagy; Biomarkers; Cellular Microenvironment; Cellular Senescence; Circadian Rhythm; Disease Susceptibility; Energy Metabolism; Epigenesis, Genetic; Gene Expression Regulation; Hepatic Stellate Cells; Humans; Liver Cirrhosis; Myofibroblasts; Oxidative Stress; Signal Transduction; Transforming Growth Factor beta
PubMed: 31718044
DOI: 10.3390/cells8111419 -
World Journal of Gastroenterology Oct 2020Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key factor influencing its prognosis is the progression of liver fibrosis. This review aimed to propose a practical and stepwise approach to the evaluation and management of liver fibrosis in patients with NAFLD, analyzing the currently available literature. In the assessment of NAFLD patients, it is important to identify clinical, genetic, and environmental determinants of fibrosis development and its progression. To properly detect fibrosis, it is important to take into account the available methods and their supporting scientific evidence to guide the approach and the sequential selection of the best available biochemical scores, followed by a complementary imaging study (transient elastography, magnetic resonance elastography or acoustic radiation force impulse) and finally a liver biopsy, when needed. To help with the selection of the most appropriate method a Fagan's nomogram analysis is provided in this review, describing the diagnostic yield of each method and their post-test probability of detecting liver fibrosis. Finally, treatment should always include diet and exercise, as well as controlling the components of the metabolic syndrome, +/- vitamin E, considering the presence of sleep apnea, and when available, allocate those patients with advanced fibrosis or high risk of progression into clinical trials. The final end of this approach should be to establish an opportune diagnosis and treatment of liver fibrosis in patients with NAFLD, aiming to decrease/stop its progression and improve their prognosis.
Topics: Biopsy; Elasticity Imaging Techniques; Humans; Liver; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Prognosis
PubMed: 33132645
DOI: 10.3748/wjg.v26.i39.5919