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Journal of Hepatology Aug 2023Liver disease accounts for two million deaths annually and is responsible for 4% of all deaths (1 out of every 25 deaths worldwide); approximately two-thirds of all... (Review)
Review
Liver disease accounts for two million deaths annually and is responsible for 4% of all deaths (1 out of every 25 deaths worldwide); approximately two-thirds of all liver-related deaths occur in men. Deaths are largely attributable to complications of cirrhosis and hepatocellular carcinoma, with acute hepatitis accounting for a smaller proportion of deaths. The most common causes of cirrhosis worldwide are related to viral hepatitis, alcohol, and non-alcoholic fatty liver disease. Hepatotropic viruses are the aetiological factor in most cases of acute hepatitis, but drug-induced liver injury increasingly accounts for a significant proportion of cases. This iteration of the global burden of liver disease is an update of the 2019 version and focuses mainly on areas where significant new information is available like alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis, and hepatocellular carcinoma. We also devote a separate section to the burden of liver disease in Africa, an area of the world typically neglected in such documents.
Topics: Male; Humans; Non-alcoholic Fatty Liver Disease; Carcinoma, Hepatocellular; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Neoplasms; Hepatitis, Viral, Human
PubMed: 36990226
DOI: 10.1016/j.jhep.2023.03.017 -
Clinical Gastroenterology and... Jul 2023Liver transplantation offers live-saving therapy for patients with complications of cirrhosis and stage T2 hepatocellular carcinoma. The demand for organs far outstrips... (Review)
Review
Liver transplantation offers live-saving therapy for patients with complications of cirrhosis and stage T2 hepatocellular carcinoma. The demand for organs far outstrips the supply, and innovations aimed at increasing the number of usable deceased donors as well as alternative donor sources are a major focus. The etiologies of cirrhosis are shifting over time, with more need for transplantation among patients with alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease and less for viral hepatitis, although hepatitis B remains an important indication for transplant in countries with high endemicity. The rise in transplantation for alcohol-associated liver disease and nonalcoholic/metabolic fatty liver disease has brought attention to how patients are selected for transplantation and the strategies needed to prevent recurrent disease. In this review, we present a status report on the most pressing topics in liver transplantation and future challenges.
Topics: Humans; Liver Transplantation; End Stage Liver Disease; Carcinoma, Hepatocellular; Liver Cirrhosis; Liver Diseases, Alcoholic; Fibrosis; Non-alcoholic Fatty Liver Disease; Liver Neoplasms
PubMed: 37084928
DOI: 10.1016/j.cgh.2023.04.005 -
Clinical Gastroenterology and... Jul 2023Chronic liver disease (CLD) and its associated complications (cirrhosis and liver cancer) cause significant mortality, morbidity, and economic burden. Published data... (Review)
Review
Chronic liver disease (CLD) and its associated complications (cirrhosis and liver cancer) cause significant mortality, morbidity, and economic burden. Published data from the World Health Organization and/or the Global Burden of Disease show that the burden of CLD is large and increasing, primarily owing to the increasing burden of nonalcoholic fatty liver disease and alcohol-related liver disease (ALD). Middle Eastern, Northern African, and Asian regions of the globe are most affected by hepatitis B and hepatitis C virus. Furthermore, Middle Eastern and North African regions also are affected by nonalcoholic fatty liver disease, and Eastern European, West African, and Central Asian regions are affected by ALD. In this context, the rate of increase for cirrhosis is highest in the Middle East, as well as in middle high and high sociodemographic index (SDI) regions. On the other hand, the highest SDI countries are experiencing increasing rates of hepatocellular carcinoma (HCC). Assessing HCC burden based on country and etiology shows that China, Korea, India, Japan, and Thailand have the highest hepatitis B virus-related HCC cases, while China, Japan, and the United States have the highest hepatitis C virus-related HCC cases. Additionally, the United States has the highest ALD-related HCC cases, while India, the United States, and Thailand have the highest nonalcoholic steatohepatitis-related HCC cases. Although the burden of CLD is increasing globally, regions of the world are impacted differently as a result of a number of sociodemographic factors.
Topics: Humans; United States; Carcinoma, Hepatocellular; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Liver Cirrhosis; Hepatitis C
PubMed: 37121527
DOI: 10.1016/j.cgh.2023.04.015 -
Molecular Biology Reports Sep 2023The liver is one of the pivotal organs in the human body and is fundamentally responsible for detoxification and metabolism. Various disorders such as non-alcoholic... (Review)
Review
The liver is one of the pivotal organs in the human body and is fundamentally responsible for detoxification and metabolism. Various disorders such as non-alcoholic fatty liver disease, fibrosis, cirrhosis, hepatocellular carcinoma, and hepatitis are associated with improper functions of the liver. Hence, biomarkers are needed to determine the severity. Further, many liver enzymes, including the cascade of aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and total bilirubin (TBIL), are conventional liver biomarkers. They are not, however, unique to the liver; hence, efforts are being made to identify the precise biomarkers for liver illness that can target liver diseases. HMGB1, cytokeratin 18 (K18), glutathione-S-transferase-α (GST-α), glutamate dehydrogenase (GLDH), malate dehydrogenase (MDH), and microRNAs (miRNA) are a few examples of developing biomarkers used to detect many liver diseases. Hence, the review has highlighted various novel biomarkers of the liver so that various pathophysiological pathways and treatments can be made easier.
Topics: Humans; Liver; Liver Cirrhosis; Carcinoma, Hepatocellular; Non-alcoholic Fatty Liver Disease; Alanine Transaminase; Liver Neoplasms; Biomarkers; Aspartate Aminotransferases
PubMed: 37482588
DOI: 10.1007/s11033-023-08666-0 -
Journal of Hepatology Aug 2023Acute-on-chronic liver failure (ACLF), which was described relatively recently (2013), is a severe form of acutely decompensated cirrhosis characterised by the existence...
Acute-on-chronic liver failure (ACLF), which was described relatively recently (2013), is a severe form of acutely decompensated cirrhosis characterised by the existence of organ system failure(s) and a high risk of short-term mortality. ACLF is caused by an excessive systemic inflammatory response triggered by precipitants that are clinically apparent (e.g., proven microbial infection with sepsis, severe alcohol-related hepatitis) or not. Since the description of ACLF, some important studies have suggested that patients with ACLF may benefit from liver transplantation and because of this, should be urgently stabilised for transplantation by receiving appropriate treatment of identified precipitants, and full general management, including support of organ systems in the intensive care unit (ICU). The objective of the present Clinical Practice Guidelines is to provide recommendations to help clinicians recognise ACLF, make triage decisions (ICU vs. no ICU), identify and manage acute precipitants, identify organ systems that require support or replacement, define potential criteria for futility of intensive care, and identify potential indications for liver transplantation. Based on an in-depth review of the relevant literature, we provide recommendations to navigate clinical dilemmas followed by supporting text. The recommendations are graded according to the Oxford Centre for Evidence-Based Medicine system and categorised as 'weak' or 'strong'. We aim to provide the best available evidence to aid the clinical decision-making process in the management of patients with ACLF.
Topics: Humans; Acute-On-Chronic Liver Failure; Prognosis; Liver Transplantation; Medical Futility; Intensive Care Units; Hepatitis, Alcoholic; Liver Cirrhosis
PubMed: 37364789
DOI: 10.1016/j.jhep.2023.04.021 -
Cell Aug 2023Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through...
Hepatocytes, the major metabolic hub of the body, execute functions that are human-specific, altered in human disease, and currently thought to be regulated through endocrine and cell-autonomous mechanisms. Here, we show that key metabolic functions of human hepatocytes are controlled by non-parenchymal cells (NPCs) in their microenvironment. We developed mice bearing human hepatic tissue composed of human hepatocytes and NPCs, including human immune, endothelial, and stellate cells. Humanized livers reproduce human liver architecture, perform vital human-specific metabolic/homeostatic processes, and model human pathologies, including fibrosis and non-alcoholic fatty liver disease (NAFLD). Leveraging species mismatch and lipidomics, we demonstrate that human NPCs control metabolic functions of human hepatocytes in a paracrine manner. Mechanistically, we uncover a species-specific interaction whereby WNT2 secreted by sinusoidal endothelial cells controls cholesterol uptake and bile acid conjugation in hepatocytes through receptor FZD5. These results reveal the essential microenvironmental regulation of hepatic metabolism and its human-specific aspects.
Topics: Animals; Humans; Mice; Endothelial Cells; Hepatocytes; Kupffer Cells; Liver; Non-alcoholic Fatty Liver Disease; Fibrosis
PubMed: 37562401
DOI: 10.1016/j.cell.2023.07.017 -
Nature Reviews. Gastroenterology &... Oct 2023Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis.... (Review)
Review
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Immunity, Innate; Lymphocytes; Liver; Liver Cirrhosis; Inflammation; Fibrosis
PubMed: 37400694
DOI: 10.1038/s41575-023-00807-x -
Hepatology (Baltimore, Md.) Oct 2023Chronic liver disease is a growing epidemic, leading to fibrosis and cirrhosis. TGF-β is the pivotal profibrogenic cytokine that activates HSC, yet other molecules can...
BACKGROUND AND AIMS
Chronic liver disease is a growing epidemic, leading to fibrosis and cirrhosis. TGF-β is the pivotal profibrogenic cytokine that activates HSC, yet other molecules can modulate TGF-β signaling during liver fibrosis. Expression of the axon guidance molecules semaphorins (SEMAs), which signal through plexins and neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. This study aims at determining their function in the regulation of HSCs.
APPROACH AND RESULTS
We analyzed publicly available patient databases and liver biopsies. We used transgenic mice, in which genes are deleted only in activated HSCs to perform ex vivo analysis and animal models. SEMA3C is the most enriched member of the semaphorin family in liver samples from patients with cirrhosis. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis, or HBV-induced hepatitis discriminates those with a more profibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs on activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-β-mediated myofibroblast activation, as shown by increased SMAD2 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained on activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice.
CONCLUSION
SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.
Topics: Animals; Humans; Mice; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Phosphorylation; Semaphorins; Transforming Growth Factor beta
PubMed: 37055018
DOI: 10.1097/HEP.0000000000000407