Materiały źródłowe

• #1 Alcoholic hepatitis: A comprehensive review of pathogenesis and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4033465/

  Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality. Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. […] The pathogenesis of alcoholic hepatitis is multifactorial. Current evidence suggests that the damage is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. […] Such metabolic pathways generate reactive oxygen species that are potent inducers of lipid peroxidation, which in turn causes hepatocyte death by necrosis or apoptosis. High levels of endotoxemia also have been documented among patients who have AH, probably because of increased intestinal permeability. […] It is likely that both nonimmunologic (oxidative stress, cytokine injury) and immunologic factors play important roles in the pathogenesis of AH. […] A variety of treatment options in AH share a common treatment goal of blocking the myriad of innate immunologic responses.

• #2 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Alcoholic Liver Disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a complication of cirrhosis. The pathogenesis of ALD can be conceptually divided into 1) Ethanol mediated liver injury, 2) Inflammatory Immune response to injury, 3) Intestinal permeability and microbiome changes. […] Alcohol contributes to liver injury through a multitude of ways as depicted. Alcohol is metabolized to acetaldehyde; both alcohol and acetaldehyde have toxic effects on hepatocytes. Damaged hepatocytes in turn release DAMPs that recruit innate and adaptive immune cells that perpetuate further liver injury. […] Alcohol metabolism leads to oxidative stress and hepatocyte death. Damaged hepatocytes release endogenous DAMPs, which are usually hidden from the extracellular environment. DAMPs activate cellular pattern recognition receptors, which results in sterile inflammation.

• #3 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Steatosis is characterized by the accumulation of triglycerides, phospholipids, and cholesterol esters in hepatocytes. An early study attributed steatosis to the increased ratio of reduced nicotinamide adenine dinucleotide to oxidized nicotinamide adenine dinucleotide, which inhibits -oxidation of fatty acids in mitochondria. Recent studies have indicated that alcohol consumption regulates lipid metabolism transcription factors. […] Innate immune signaling is involved in the early stage of ALD with simple steatosis even before the onset of inflammation. […] Chronic alcohol leads to lipid peroxidation. Lipid peroxidation products, such as malondialdehyde and 4-hydroxynonenal, can form protein adducts and serve as antigens to activate adaptive immunity. […] The leading cause of death in AH is overwhelming bacterial infection, leading to multiorgan failure. Paradoxically, immune activity is heightened with inflammation.

• #4 Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04166-8

  Ethanol exposure can reduce mitochondrial volume and the F0 adenosine triphosphate (ATP) synthase levels and inhibit protein synthesis. Ethanol metabolism can also disrupt the phospholipid bilayer membrane structure of mitochondria, resulting in the release of a large number of oxygen free radicals, lipid peroxidation, unsaturated FA destruction, and the production of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). […] The oxidative metabolite of ethanol, acetaldehyde, is highly toxic and can readily undergo crosslinking with DNA or protein macromolecules in mitochondria. […] Ethanol oxidation leads to an increase in free radical production in the liver. Uncontrolled ROS are critical to hepatocyte swelling and apoptosis. […] Acetaldehyde can induce ROS production and lead to ALD.

• #5 Alcoholic Hepatitis (Alcohol-Associated Hepatitis): Background, Etiology and Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/170539-overview

  Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term, heavy intake of ethanol. The pathogenesis is not completely understood. […] Although the association of alcohol and liver disease has been known since antiquity, the precise mechanism of alcoholic liver disease remains in dispute. Genetic, environmental, nutritional, metabolic, and immunologic factors, as well as cytokines and viral disease, have been invoked. […] Ethanol and its metabolite, acetaldehyde, have been shown to damage liver cell membranes. Ethanol can alter the fluidity of cell membranes, thereby altering the activity of membrane-bound enzymes and transport proteins. Ethanol damage to the mitochondrial membranes may be responsible for the giant mitochondria (megamitochondria) observed in patients with alcoholic hepatitis. Acetaldehyde-modified proteins and lipids on the cell surface may behave as neoantigens and trigger immunologic injury.

• #6 Dissecting Alcoholic Liver Disease

  https://www.uspharmacist.com/article/dissecting-alcoholic-liver-disease

  Ethanol metabolism associated oxidative stress, glutathione depletion, abnormal methionine metabolism, malnutrition, and ethanol-mediated induction of gut endotoxins have important roles in the pathogenesis of ALD. […] Alcohol intake has also been shown to augment the supply of lipids to the liver from the small intestine, increasing mobilization of fatty acids from adipose tissue and uptake of fatty acids by the liver. This will subsequently prime and sensitize hepatocytes to injury. […] In hepatocytes, ethanol is primarily metabolized into acetaldehyde (a carcinogen with mutagenic properties) by alcohol dehydrogenase in the cytosol, cytochrome P450 in microsomes, and catalase in peroxisomes. […] Acetaldehyde is rapidly metabolized into acetate by aldehyde dehydrogenase in the mitochondria. While acetaldehyde is highly toxic to hepatocytes, acetate has no direct hepatotoxicity, but it is believed to regulate the inflammatory response in patients with AH via the up-regulation of proinflammatory cytokines in macrophages.

• #7 Alcoholic hepatitis – Wikipedia

  https://en.wikipedia.org/wiki/Alcoholic_hepatitis

  Alcohol is also directly damaging to liver cells. Alcohol is metabolized to acetaldehyde in the liver via the enzymes CYP2E1 and aldehyde dehydrogenase. […] Acetaldehyde forms reactive oxygen species in the liver as well as acting as a DNA adduct (binding to DNA) leading to direct hepatocyte damage. […] The chronic inflammation seen in alcoholic hepatitis leads to a distinctive fibrotic response, with fibrogenic cell type activation. […] This peri-cellular chickenwire fibrosis leads to portal hypertension or an elevated blood pressure in the portal veins that drain blood from the intestines to the liver. […] The chronic inflammation seen in alcoholic hepatitis also leads to impaired hepatocyte differentiation, impairments in hepatocyte regeneration and hepatocyte de-differentiation into cholangiocyte type cells. […] Due to the release of DAMPs and PAMPs, an acute systemic inflammatory state can develop after extensive alcohol intake that dominates the clinical landscape of acute severe alcoholic hepatitis.

• #8 Alcoholic Hepatitis (Alcohol-Associated Hepatitis): Background, Etiology and Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/170539-overview

  Acetaldehyde may be the principal mediator of alcoholic liver injury. The deleterious effects of acetaldehyde include impairment of the mitochondrial beta oxidation of fatty acids, formation of oxygen-derived free radicals, and depletion of mitochondrial glutathione. […] Active alcoholic hepatitis often persists for months after cessation of drinking. In fact, its severity may worsen during the first few weeks of abstinence. This observation suggests that an immunologic mechanism may be responsible for perpetuation of the injury. […] Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death (apoptosis) in liver cells. Several studies have demonstrated extremely high levels of TNF and several TNF-inducible cytokines, such as interleukin (IL)-1, IL-6, and IL-8, in the sera of patients with alcoholic hepatitis. Inflammatory cytokines (TNF, IL-1, IL-8) and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in modulating certain metabolic complications in alcoholic hepatitis, and they are probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis.

• #9 Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

  https://www.wjgnet.com/1007-9327/full/v20/i47/17756.htm

  Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). […] Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. […] Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. […] Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism.

• #10 Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04166-8

  Ethanol exposure can reduce mitochondrial volume and the F0 adenosine triphosphate (ATP) synthase levels and inhibit protein synthesis. Ethanol metabolism can also disrupt the phospholipid bilayer membrane structure of mitochondria, resulting in the release of a large number of oxygen free radicals, lipid peroxidation, unsaturated FA destruction, and the production of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). […] The oxidative metabolite of ethanol, acetaldehyde, is highly toxic and can readily undergo crosslinking with DNA or protein macromolecules in mitochondria. […] Ethanol oxidation leads to an increase in free radical production in the liver. Uncontrolled ROS are critical to hepatocyte swelling and apoptosis. […] Acetaldehyde can induce ROS production and lead to ALD.

• #11 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Steatosis is characterized by the accumulation of triglycerides, phospholipids, and cholesterol esters in hepatocytes. An early study attributed steatosis to the increased ratio of reduced nicotinamide adenine dinucleotide to oxidized nicotinamide adenine dinucleotide, which inhibits -oxidation of fatty acids in mitochondria. Recent studies have indicated that alcohol consumption regulates lipid metabolism transcription factors. […] Innate immune signaling is involved in the early stage of ALD with simple steatosis even before the onset of inflammation. […] Chronic alcohol leads to lipid peroxidation. Lipid peroxidation products, such as malondialdehyde and 4-hydroxynonenal, can form protein adducts and serve as antigens to activate adaptive immunity. […] The leading cause of death in AH is overwhelming bacterial infection, leading to multiorgan failure. Paradoxically, immune activity is heightened with inflammation.

• #12 Alcohol-Related Liver Disease – Hepatic and Biliary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/alcohol-related-liver-disease/alcohol-related-liver-disease

  Alcohol (ethanol) is readily absorbed from the stomach, but most is absorbed from the small intestine. Alcohol cannot be stored. A small amount is degraded in transit through the gastric mucosa, but most is catabolized in the liver, primarily by alcohol dehydrogenase (ADH) but also by cytochrome P-450 2E1 (CYP2E1) and the microsomal enzyme oxidation system (MEOS). […] The increased redox potential inhibits fatty acid oxidation and gluconeogenesis, promoting fat accumulation in the liver. […] Chronic excessive alcohol consumption induces the MEOS (mainly in endoplasmic reticulum), increasing its activity. The main enzyme involved is CYP2E1. When induced, the MEOS pathway can account for 20% of alcohol metabolism. This pathway generates harmful reactive oxygen species, increasing oxidative stress and formation of oxygen-free radicals.

• #13 Alcoholic hepatitis: How far are we and where are we going? | Annals of Hepatology

  https://www.elsevier.es/es-revista-annals-hepatology-16-articulo-alcoholic-hepatitis-how-far-are-S1665268119311342

  The burden of alcoholic liver disease continues to be a major public health problem worldwide. […] Alcoholic hepatitis (AH) is a type of acute-on-chronic liver failure and the most severe form of alcoholic liver disease. […] This review summarizes the epidemiology, natural history, risk factors and pathogenesis of alcoholic liver disease with special focus on the latest advances in prognostic stratification and therapy of patients with alcoholic hepatitis. […] Alcoholic steatosis is a complex process manifested through several mechanisms. The main pathogenetic factors underlying this process are increased fatty acid (FA) and triglyceride synthesis, enhanced hepatic influx of free fatty acids from adipose tissue and of chylomicrons from the intestinal mucosa, increased hepatic lipogenesis, inhibited lipolysis, and damaged mitochondria and microtubules, all of which result in accumulation of very low-density lipoproteins.

• #14 Alcoholic hepatitis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Alcoholic_hepatitis_pathophysiology

  The pathophysiology of Alcoholic Hepatitis is caused by interplay between alcohol metabolism, inflammation and innate immunity. Alcohol metabolism leads to depletion of NAD and subsequent lipogenesis. Additionally, increased endotoxemia causes translocation of lipopolysaccharide from intestine to hepatocytes. In hepatocytes, lipopolysaccharide activates kupffer cells. Therefore, activated cells release inflammatory markers which lead to Alcoholic hepatitis. […] The pathogenesis of Alcoholic Hepatitis is multifactorial. Alcoholic Hepatitis is caused by interplay between alcohol metabolism, inflammation and innate immunity. […] The Alcohol metabolism leads to a reduced ratio of the nicotinamide adenine dinucleotide (NAD) to NADH. The NAD depletion inhibit fatty acid oxidation and causes fat accumulation in hepatocytes associated with lipogenesis.

• #15 Alcoholic Hepatitis (Alcohol-Associated Hepatitis): Background, Etiology and Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/170539-overview

  Hepatic injury in alcoholic hepatitis is most prominent in the perivenular area (zone 3) of the hepatic lobule. This zone is known to be sensitive to hypoxic damage. Ethanol induces a hypermetabolic state in the hepatocytes, partially because ethanol metabolism through MEOS does not result in energy capture via the formation of adenosine triphosphate (ATP). Rather, this pathway leads to the loss of energy in the form of heat. […] Free radicals, superoxides and hydroperoxides, are generated as byproducts of ethanol metabolism via the microsomal and peroxisomal pathways. In addition, acetaldehyde reacts with glutathione and depletes this key element of the hepatocytic defense against free radicals. Other antioxidant defenses, including selenium, zinc, and vitamin E, are often reduced in individuals with alcoholism.

• #16 Pathogenesis of alcoholic hepatitis: Role of inflammatory signaling and oxidative stress

  https://www.wjgnet.com/1948-5182/full/v3/i5/114.htm

  Oxidative stress occurs when there is an imbalance between antioxidants and reactive oxidizing species. […] Oxidative stress leads to damage of the mitochondria, endoplasmic reticulum (ER) stress and subsequent apoptosis, and increased lipid synthesis. […] ROS can also activate ERK1/2, p38 MAPK kinases, and NF-B which stimulates TNF-, complementing the LPS-induced pathways of TNF- production and creating a vicious cycle of inflammation and oxidative stress.

• #17 Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04166-8

  Ethanol exposure can reduce mitochondrial volume and the F0 adenosine triphosphate (ATP) synthase levels and inhibit protein synthesis. Ethanol metabolism can also disrupt the phospholipid bilayer membrane structure of mitochondria, resulting in the release of a large number of oxygen free radicals, lipid peroxidation, unsaturated FA destruction, and the production of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). […] The oxidative metabolite of ethanol, acetaldehyde, is highly toxic and can readily undergo crosslinking with DNA or protein macromolecules in mitochondria. […] Ethanol oxidation leads to an increase in free radical production in the liver. Uncontrolled ROS are critical to hepatocyte swelling and apoptosis. […] Acetaldehyde can induce ROS production and lead to ALD.

• #18 Pathogenesis, Early Diagnosis, and Therapeutic Management of Alcoholic Liver Disease

  https://www.mdpi.com/1422-0067/20/11/2712

  The acetaldehyde produced by the oxidation of ethanol has a high toxicity and high activity which can destroy the microtubule structure of hepatocyte, causing microtubule dysfunction and further affecting the transportation of nutrients. […] Heavy alcohol consumption is associated with the fibrosis progression in other types of liver diseases. The formation of acetaldehyde-protein adducts further leads the protease inactivation of hepatocytes, abnormalities in DNA repair, damages in hepatocyte mitochondrial structure, oxygen utilization disorders, stimulation of collagen synthesis, and the accumulation of extracellular matrix proteins to form liver fibrosis and cirrhosis. […] During the last decade, significant effort has been made to understand the underlying molecular mechanisms of ALD which contribute to its pathogenesis. According to previous studies, those mechanisms include direct hepatotoxicity, alcohol and its metabolites induced ROS production, the activation of innate immunity, and the production of pro-inflammatory cytokines.

• #19 Pathogenesis of alcoholic hepatitis: Role of inflammatory signaling and oxidative stress

  https://www.wjgnet.com/1948-5182/full/v3/i5/114.htm

  Oxidative stress occurs when there is an imbalance between antioxidants and reactive oxidizing species. […] Oxidative stress leads to damage of the mitochondria, endoplasmic reticulum (ER) stress and subsequent apoptosis, and increased lipid synthesis. […] ROS can also activate ERK1/2, p38 MAPK kinases, and NF-B which stimulates TNF-, complementing the LPS-induced pathways of TNF- production and creating a vicious cycle of inflammation and oxidative stress.

• #20 Pathogenesis, Early Diagnosis, and Therapeutic Management of Alcoholic Liver Disease

  https://www.mdpi.com/1422-0067/20/11/2712

  In chronic alcohol consumption, CYP2E1 enzyme is absolutely responsible for the excessive production of ROS, considered the second messenger in the cell. These produced ROS, such as hydrogen peroxide and superoxide ions, are associated with the pro-inflammatory profile of alcohol-mediated liver damages via recruiting immune cells and inducing pro-inflammatory cytokines circulation. […] Research has shown that chronic drinking can cause the imbalance of intestinal flora and intestinal toxin accumulation. Alcohol exposure causes the excessive proliferation of gram negative bacteria in the intestine. […] The research demonstrates that the iron deposition in liver is associated with ALD and more than 30% of patients with ALD suffer from iron metabolism disorders. Recent studies have shown that even mild alcohol consumption induces the iron stores in the liver.

• #21 Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

  https://www.mdpi.com/2218-273X/7/1/9

  Importantly, ethanol is the substance of abuse most used worldwide; as such, the prevalence of ALD is widespread. […] However, the complex pathogenesis of ALD influenced by host and environmental factors is currently only partially understood. […] Oxidant stress plays a dominant role in the pathogenesis of ALD, as multiple studies have shown that generation of ROS is key for the progression of fatty liver to steatohepatitis and cirrhosis. […] Over time, these cellular events increase and, again, the only well-established treatment is abstinence. […] Alcohol metabolism generates reduced nicotinamide adenine dinucleotide (NADH), which stimulates synthesis of excess fatty acids contributing to steatosis; and iron deposition in the liver, which increases reactive oxygen species (ROS) production, leading to a proinflammatory microenvironment, therefore enhancing the severity of ALD.

• #22 Alcoholic hepatitis: A comprehensive review of pathogenesis and treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4033465/

  Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality. Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. […] The pathogenesis of alcoholic hepatitis is multifactorial. Current evidence suggests that the damage is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. […] Such metabolic pathways generate reactive oxygen species that are potent inducers of lipid peroxidation, which in turn causes hepatocyte death by necrosis or apoptosis. High levels of endotoxemia also have been documented among patients who have AH, probably because of increased intestinal permeability. […] It is likely that both nonimmunologic (oxidative stress, cytokine injury) and immunologic factors play important roles in the pathogenesis of AH. […] A variety of treatment options in AH share a common treatment goal of blocking the myriad of innate immunologic responses.

• #23 Alcoholic hepatitis – Wikipedia

  https://en.wikipedia.org/wiki/Alcoholic_hepatitis

  Alcoholic hepatitis is characterized by a number of symptoms, which may include feeling unwell, enlargement of the liver, development of fluid in the abdomen (ascites), and modest elevation of liver enzyme levels (as determined by liver function tests). […] The pathological mechanisms in alcoholic hepatitis are incompletely understood but a combination of direct hepatocyte damage by alcohol and its metabolites in addition to increased intestinal permeability are thought to play a role. […] Heavy alcohol consumption increases intestinal permeability by causing direct damage to enterocytes (intestinal absorptive cells) and causing disruptions of tight junctions that form a barrier between the enterocytes. […] This leads to increased intestinal permeability which then leads to pathogenic gut bacteria (such as enterococcus faecalis) or immunogenic fungi entering the portal circulation, and travelling to the liver where they cause hepatocyte damage.

• #24 Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04166-8

  Ethanol also initiates NF-B-mediated transactivation of iNOS expression in hepatic Kupffer cells. […] The liver and digestive tract are closely associated and their interactions form the gut-liver axis. The translocation of bacterial or microbial products from the intestine to the liver is a key inflammatory factor that induces the transition from alcoholic steatosis to ASH. […] Ethanol exposure results in the loss of epithelial cells at the tip of intestinal villi. […] After long-term ethanol intake, the intestinal epithelial cell structure in rats is markedly changed, exhibiting mitochondrial and endoplasmic reticulum dilation. […] Ethanol can change the composition of the intestinal microbiota. Therefore, regulating the microbiota through probiotics and faecal bacteria transplantation may be potent treatments for ALD.

• #25 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Alcoholic liver disease is associated with bacterial overgrowth and a lower proportion of Bacteroidaceae and probiotic bacteria such as Lactobacillus. […] Zinc deficiency is common in ALD. Animal models have demonstrated that zinc deficiency attenuates alcohol-induced liver injury through various mechanisms, but most importantly, zinc deficiency impairs the intestinal barrier. […] Usually, liver damage induces mature hepatocytes to proliferate and replace damaged tissue. Given massive or chronic liver damage that is beyond the proliferative capacity of hepatocytes, progenitor cells proliferate to produce a ductular reaction. […] The general mechanism for the development of HCC includes i) limitation of the regenerative reserve and induction of chromosomal instability by telomeres, ii) cancer induction by the loss of replicative competition due to impaired hepatocyte proliferation, iii) an altered microenvironment promoting tumor cell proliferation, and 4) the loss of cell cycle check point, including resistance to apoptosis and activation of oncogenic pathways.

• #26 Pathogenesis of alcoholic hepatitis: Role of inflammatory signaling and oxidative stress

  https://www.wjgnet.com/1948-5182/full/v3/i5/114.htm

  Initiating events include expression of gut-derived lipopolysaccharides (LPS), interaction of LPS with TLR4 receptors, activation of inflammatory signaling pathways, cytokine release, and Kupffer cells. […] Chronic alcohol exposure increases gut permeability and facilitates translocation of endotoxins from the intestinal lumen to the portal circulation. […] TLR4 signals activate early growth response 1 (EGR1, a transcription factor), nuclear factor-kappaB (NF-B), and TLR4 adaptor (toll-interleukin-1-receptor-domain-containg adapter-inducing interferon-beta or TRIF). […] Chronic alcohol intake primes the liver through continued NF-B activation and increased TNF- production in response to LPS. […] All these pathways result in recruitment of inflammatory cells (polymorphs and mononuclear cells) and cause necroinflammation.

• #27 Pathogenesis of alcoholic hepatitis: Role of inflammatory signaling and oxidative stress

  https://www.wjgnet.com/1948-5182/full/v3/i5/114.htm

  Inflammatory signaling and oxidative stress are two major components in the pathogenesis of alcoholic hepatitis. […] Alcohol consumption results in translocation of gut bacteria into the portal system along with lipopolysaccharides that interact with toll-like receptors and results in the production of inflammatory and immunogenic mediators such as tumor necrosis factor-alpha (TNF-) and interferons. […] Chronic consumption of alcohol causes priming of this process in which there is enhanced production of cytokines, interferon, interleukins, and TNF-. […] Oxidative stress, genetic predisposition, and the unfolded protein response are other contributory mechanisms. […] Against the background of steatosis and existing liver damage, heavy and continued drinking in some patients causes AH. Two main mechanisms are involved: inflammation and oxidative stress.

• #28 Pathogenesis of alcoholic hepatitis: Role of inflammatory signaling and oxidative stress

  https://www.wjgnet.com/1948-5182/full/v3/i5/114.htm

  Initiating events include expression of gut-derived lipopolysaccharides (LPS), interaction of LPS with TLR4 receptors, activation of inflammatory signaling pathways, cytokine release, and Kupffer cells. […] Chronic alcohol exposure increases gut permeability and facilitates translocation of endotoxins from the intestinal lumen to the portal circulation. […] TLR4 signals activate early growth response 1 (EGR1, a transcription factor), nuclear factor-kappaB (NF-B), and TLR4 adaptor (toll-interleukin-1-receptor-domain-containg adapter-inducing interferon-beta or TRIF). […] Chronic alcohol intake primes the liver through continued NF-B activation and increased TNF- production in response to LPS. […] All these pathways result in recruitment of inflammatory cells (polymorphs and mononuclear cells) and cause necroinflammation.

• #29

  https://www.xiahepublishing.com/2310-8819/JCTH-2016-00006

  Alcohol is one of the most common etiologies of liver disease, and alcoholic liver disease overall is the second most common indication for liver transplantation in the United States. […] Management of the mild disease consists mainly of abstinence and supportive care. Severe AH is associated with significant mortality. Currently, there is no ideal medical treatment for this condition. […] Currently, early stage trials are underway, mainly targeting novel pathways based on disease pathogenesis, including modulation of innate immune system, inhibition of gut-liver axis and cell death pathways, and activation of transcription factor farnesyl X receptor (FXR). […] Alcohol disrupts the intestinal epithelial barrier, resulting in increased gut permeability to microbiota. The bacterial endotoxin lipopolysaccharide (LPS) increases in portal circulation and activates toll-like receptor 4 (TLR4), leading to activation of the innate immune system and release of various cytokines. Blockage of these pathways could have therapeutic implications for the treatment of AH.

• #30 Alcohol-Related Liver Disease – Hepatic and Biliary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/alcohol-related-liver-disease/alcohol-related-liver-disease

  Alcohol changes gut permeability, increasing absorption of endotoxins released by bacteria in the gut. In response to the endotoxins (which the impaired liver can no longer detoxify), liver macrophages (Kupffer cells) release free radicals, increasing oxidative damage. […] A vicious circle of worsening inflammation occurs: Cell necrosis and apoptosis result in hepatocyte loss, and subsequent attempts at regeneration result in fibrosis. Stellate (Ito) cells, which line blood channels (sinusoids) in the liver, proliferate and transform into myofibroblasts, producing an excess of type I collagen and extracellular matrix. As a result, the sinusoids narrow, limiting blood flow. Fibrosis narrows the terminal hepatic venules, compromising hepatic perfusion and thus contributing to portal hypertension. Extensive fibrosis is associated with an attempt at regeneration, resulting in liver nodules. This process culminates in cirrhosis.

• #31 Alcoholic Hepatitis (Alcohol-Associated Hepatitis): Background, Etiology and Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/170539-overview

  Acetaldehyde may be the principal mediator of alcoholic liver injury. The deleterious effects of acetaldehyde include impairment of the mitochondrial beta oxidation of fatty acids, formation of oxygen-derived free radicals, and depletion of mitochondrial glutathione. […] Active alcoholic hepatitis often persists for months after cessation of drinking. In fact, its severity may worsen during the first few weeks of abstinence. This observation suggests that an immunologic mechanism may be responsible for perpetuation of the injury. […] Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death (apoptosis) in liver cells. Several studies have demonstrated extremely high levels of TNF and several TNF-inducible cytokines, such as interleukin (IL)-1, IL-6, and IL-8, in the sera of patients with alcoholic hepatitis. Inflammatory cytokines (TNF, IL-1, IL-8) and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in modulating certain metabolic complications in alcoholic hepatitis, and they are probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis.

• #32 Alcoholic hepatitis | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4020-8767-7_20

  Severe alcoholic hepatitis is still associated with high mortality and the presence of liver failure manifested by jaundice, coagulopathy and encephalopathy is a poor prognostic indicator. […] Tumor necrosis factor and alcoholic liver disease. […] Increased plasma tumor necrosis factor in severe alcoholic hepatitis. […] Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. […] Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. […] Increased plasma interleukin-8 concentrations in alcoholic hepatitis. […] Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration. […] Presence of plasma endotoxin is correlated with tumour necrosis factor receptor levels and disease activity in alcoholic cirrhosis.

• #33 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Alcoholic Liver Disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a complication of cirrhosis. The pathogenesis of ALD can be conceptually divided into 1) Ethanol mediated liver injury, 2) Inflammatory Immune response to injury, 3) Intestinal permeability and microbiome changes. […] Alcohol contributes to liver injury through a multitude of ways as depicted. Alcohol is metabolized to acetaldehyde; both alcohol and acetaldehyde have toxic effects on hepatocytes. Damaged hepatocytes in turn release DAMPs that recruit innate and adaptive immune cells that perpetuate further liver injury. […] Alcohol metabolism leads to oxidative stress and hepatocyte death. Damaged hepatocytes release endogenous DAMPs, which are usually hidden from the extracellular environment. DAMPs activate cellular pattern recognition receptors, which results in sterile inflammation.

• #34 Alcoholic Hepatitis (Alcohol-Associated Hepatitis): Background, Etiology and Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/170539-overview

  Acetaldehyde may be the principal mediator of alcoholic liver injury. The deleterious effects of acetaldehyde include impairment of the mitochondrial beta oxidation of fatty acids, formation of oxygen-derived free radicals, and depletion of mitochondrial glutathione. […] Active alcoholic hepatitis often persists for months after cessation of drinking. In fact, its severity may worsen during the first few weeks of abstinence. This observation suggests that an immunologic mechanism may be responsible for perpetuation of the injury. […] Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death (apoptosis) in liver cells. Several studies have demonstrated extremely high levels of TNF and several TNF-inducible cytokines, such as interleukin (IL)-1, IL-6, and IL-8, in the sera of patients with alcoholic hepatitis. Inflammatory cytokines (TNF, IL-1, IL-8) and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in modulating certain metabolic complications in alcoholic hepatitis, and they are probably instrumental in the liver injury of alcoholic hepatitis and cirrhosis.

• #35

  https://www.jci.org/articles/view/157780

  Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. […] Accumulating evidence suggests that multiple types of immune cells are involved in the pathogenesis of AH, including neutrophils, resident and infiltrating macrophages, and other cell types in the innate and adaptive immune system. […] Neutrophils cause tissue injury by producing inflammatory mediators, proteases, and ROS. […] Mechanistically, we found that hepatic NCF1 expression is markedly upregulated and correlates with neutrophil infiltration in SAH patients. […] Our data provide a mechanistic insight into the role of neutrophils in ALD, suggesting that neutrophilic NCF1-dependent ROS generation promotes steatosis and hepatic inflammation by inhibiting AMPK and miR-223, respectively.

• #36 Researchers Gain New Insight Into the Development of Severe Alcohol-Associated Hepatitis – News from the National Institute on Alcohol Abuse and Alcoholism

  https://niaaa.scienceblog.com/439/researchers-gain-new-insight-into-the-development-of-severe-alcohol-associated-hepatitis/

  Alcohol misuse can lead to alcohol-associated hepatitis (AH), a form of liver disease with a high short-term mortality rate in severe cases. […] A better understanding of how AH develops could help improve AH treatment and prevent progression to severe disease. […] Researchers found a mechanism by which neutrophils—a type of white blood cell—contribute to liver injury in AH. […] A growing body of evidence indicates that various types of cells in the body’s immune system are involved in AH, including neutrophils. […] The authors showed that neutrophil-derived reactive oxygen species (ROS) promoted liver injury and inflammation in the experimental model. […] This suggests that neutrophil-generated ROS is one of the mechanisms that contribute to liver injury and dysfunction in severe AH in addition to many other cell types involved in severe AH pathogenesis.

• #37 Alcoholic hepatitis | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4020-8767-7_20

  Severe alcoholic hepatitis is still associated with high mortality and the presence of liver failure manifested by jaundice, coagulopathy and encephalopathy is a poor prognostic indicator. […] Tumor necrosis factor and alcoholic liver disease. […] Increased plasma tumor necrosis factor in severe alcoholic hepatitis. […] Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. […] Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients. […] Increased plasma interleukin-8 concentrations in alcoholic hepatitis. […] Circulating and tissue levels of the neutrophil chemotaxin interleukin-8 are elevated in severe acute alcoholic hepatitis, and tissue levels correlate with neutrophil infiltration. […] Presence of plasma endotoxin is correlated with tumour necrosis factor receptor levels and disease activity in alcoholic cirrhosis.

• #38 Molecular pathogenesis of T lymphocyte-induced liver injury in alcoholic hepatitis

  https://www.imrpress.com/journal/fbl/7/4/10.2741/batey

  The development of alcohol-induced liver injury is, in part, a consequence of the immunological/inflammatory response that alcohol stimulates. […] Cytokines, especially TNF α, produced from macrophages/Kupffer cells, play a role in the induction of liver cell necrosis and apoptosis. […] Furthermore, chronic ethanol consumption may damage the liver by inhibiting the hepatotrophic and hepatoprotective actions of TNF α and other cytokines. […] Our recent work has demonstrated the role of liver-associated T lymphocytes in the pathogenesis of alcohol related liver injury initiated by a variety of stimuli such as endotoxin (lipopolysaccharide, LPS) or concanavalin A (Con A). […] Our studies have, for the first time, suggested that alcohol consumption alone does not lead to the development of marked liver necrosis (at least in the rat), but rather that a second insult is required for this to occur. […] It suggested that liver-associated T lymphocytes are involved in the inflammatory process associated with alcohol related liver injury through increased cytokine secretion (TNF α).

• #39 Alcoholic hepatitis | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4020-8767-7_20

  Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis. […] Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis. […] Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. […] Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. […] Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis.

• #40 Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

  https://www.wjgnet.com/1007-9327/full/v20/i47/17756.htm

  Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor–dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). […] Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. […] Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. […] Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility.

• #41 Alcoholic Hepatitis (Alcohol-Associated Hepatitis): Background, Etiology and Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/170539-overview

  Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term, heavy intake of ethanol. The pathogenesis is not completely understood. […] Although the association of alcohol and liver disease has been known since antiquity, the precise mechanism of alcoholic liver disease remains in dispute. Genetic, environmental, nutritional, metabolic, and immunologic factors, as well as cytokines and viral disease, have been invoked. […] Ethanol and its metabolite, acetaldehyde, have been shown to damage liver cell membranes. Ethanol can alter the fluidity of cell membranes, thereby altering the activity of membrane-bound enzymes and transport proteins. Ethanol damage to the mitochondrial membranes may be responsible for the giant mitochondria (megamitochondria) observed in patients with alcoholic hepatitis. Acetaldehyde-modified proteins and lipids on the cell surface may behave as neoantigens and trigger immunologic injury.

• #42 Pathogenesis of Alcoholic Liver Disease – RCEMLearning

  https://www.rcemlearning.co.uk/modules/alcoholic-liver-disease/lessons/pathogenesis-of-alcoholic-liver-disease/

  Hepatitis C infection and alcohol have an additive effect together. This is thought to occur as alcohol may alter the immune systems efforts at clearing the virus, or increased iron deposition in liver secondary to high levels of alcohol which may alter the pathophysiology of the virus. […] Acetaldehyde forms covalent bonds with proteins which are antigenic. Long-term exposure to alcohol causes the body to amass circulating antibodies to these proteins resulting in harmful humeral and cellular responses. […] In alcoholic liver injury the expression of pro-inflammatory cytokines is up-regulated resulting in fibrosis. Collagen is deposited in the space of disse which progresses to fibrosis and cell linkage formation resulting in cirrhosis. Lesions occur in the hepatic veins causing thickened veins and perisinusoidal fibrosis which can lead to cirrhosis.

• #43 Molecular pathogenesis of T lymphocyte-induced liver injury in alcoholic hepatitis

  https://www.imrpress.com/journal/fbl/7/4/10.2741/batey

  The development of alcohol-induced liver injury is, in part, a consequence of the immunological/inflammatory response that alcohol stimulates. […] Cytokines, especially TNF α, produced from macrophages/Kupffer cells, play a role in the induction of liver cell necrosis and apoptosis. […] Furthermore, chronic ethanol consumption may damage the liver by inhibiting the hepatotrophic and hepatoprotective actions of TNF α and other cytokines. […] Our recent work has demonstrated the role of liver-associated T lymphocytes in the pathogenesis of alcohol related liver injury initiated by a variety of stimuli such as endotoxin (lipopolysaccharide, LPS) or concanavalin A (Con A). […] Our studies have, for the first time, suggested that alcohol consumption alone does not lead to the development of marked liver necrosis (at least in the rat), but rather that a second insult is required for this to occur. […] It suggested that liver-associated T lymphocytes are involved in the inflammatory process associated with alcohol related liver injury through increased cytokine secretion (TNF α).

• #44 Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis

  https://elifesciences.org/reviewed-preprints/86678v1

  The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. […] The presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in the liver may participate in the pathogenesis of SAH. […] Using explanted livers from SAH patients, we discovered massive antibody deposition in ballooned hepatocytes which is associated with complement activation. Antibodies from the SAH liver but not patient serum exhibited hepatocyte killing efficacy in vitro. Unique antibodies found in the SAH liver not only recognize bacterial (E. coli) antigens but also cross-react with a large number of human antigens. […] Our data support the hypothesis that anti-bacterial antibodies and/or plasma cells originating from gut translocate to the liver due to gut leakiness caused by excessive alcohol drinking and that these hepatic plasma cells produce antibodies which not only recognize intestinal bacterial antigens but also cross react with antigens of human hepatocytes. […] Antibody deposition, with complement activation as well as immune cell activation, may result in acute liver failure due to antibody-mediated inflammation.

• #45 Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis

  https://elifesciences.org/reviewed-preprints/86678

  The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. […] The presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in the liver may participate in the pathogenesis of SAH. […] Using explanted livers from SAH patients, we discovered massive antibody deposition in ballooned hepatocytes which is associated with complement activation. […] Our data support the hypothesis that anti-bacterial antibodies and/or plasma cells originating from gut translocate to the liver due to gut leakiness caused by excessive alcohol drinking and that these hepatic plasma cells produce antibodies which not only recognize intestinal bacterial antigens but also cross react with antigens of human hepatocytes. […] Antibody deposition, with complement activation as well as immune cell activation, may result in acute liver failure due to antibody-mediated inflammation. […] This pathophysiology implies severe damage from short-lived leaky gut due to a transient interval of high alcohol intake with ongoing residual continued damage due to the antibody production that continues only within the liver to be replaced.

• #46 Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis

  https://elifesciences.org/reviewed-preprints/86678v1

  The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. […] The presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in the liver may participate in the pathogenesis of SAH. […] Using explanted livers from SAH patients, we discovered massive antibody deposition in ballooned hepatocytes which is associated with complement activation. Antibodies from the SAH liver but not patient serum exhibited hepatocyte killing efficacy in vitro. Unique antibodies found in the SAH liver not only recognize bacterial (E. coli) antigens but also cross-react with a large number of human antigens. […] Our data support the hypothesis that anti-bacterial antibodies and/or plasma cells originating from gut translocate to the liver due to gut leakiness caused by excessive alcohol drinking and that these hepatic plasma cells produce antibodies which not only recognize intestinal bacterial antigens but also cross react with antigens of human hepatocytes. […] Antibody deposition, with complement activation as well as immune cell activation, may result in acute liver failure due to antibody-mediated inflammation.

• #47 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Alcoholic liver disease is associated with bacterial overgrowth and a lower proportion of Bacteroidaceae and probiotic bacteria such as Lactobacillus. […] Zinc deficiency is common in ALD. Animal models have demonstrated that zinc deficiency attenuates alcohol-induced liver injury through various mechanisms, but most importantly, zinc deficiency impairs the intestinal barrier. […] Usually, liver damage induces mature hepatocytes to proliferate and replace damaged tissue. Given massive or chronic liver damage that is beyond the proliferative capacity of hepatocytes, progenitor cells proliferate to produce a ductular reaction. […] The general mechanism for the development of HCC includes i) limitation of the regenerative reserve and induction of chromosomal instability by telomeres, ii) cancer induction by the loss of replicative competition due to impaired hepatocyte proliferation, iii) an altered microenvironment promoting tumor cell proliferation, and 4) the loss of cell cycle check point, including resistance to apoptosis and activation of oncogenic pathways.

• #48 Alcoholic hepatitis – Wikipedia

  https://en.wikipedia.org/wiki/Alcoholic_hepatitis

  Alcohol is also directly damaging to liver cells. Alcohol is metabolized to acetaldehyde in the liver via the enzymes CYP2E1 and aldehyde dehydrogenase. […] Acetaldehyde forms reactive oxygen species in the liver as well as acting as a DNA adduct (binding to DNA) leading to direct hepatocyte damage. […] The chronic inflammation seen in alcoholic hepatitis leads to a distinctive fibrotic response, with fibrogenic cell type activation. […] This peri-cellular chickenwire fibrosis leads to portal hypertension or an elevated blood pressure in the portal veins that drain blood from the intestines to the liver. […] The chronic inflammation seen in alcoholic hepatitis also leads to impaired hepatocyte differentiation, impairments in hepatocyte regeneration and hepatocyte de-differentiation into cholangiocyte type cells. […] Due to the release of DAMPs and PAMPs, an acute systemic inflammatory state can develop after extensive alcohol intake that dominates the clinical landscape of acute severe alcoholic hepatitis.

• #49 Mechanism responsible for the loss of identity of hepatocytes in alcoholic hepatitis described

  https://www.clinicbarcelona.org/en/news/mechanism-responsible-for-the-loss-of-identity-of-hepatocytes-in-alcoholic-hepatitis-described

  Pau Sancho-Bru and his team lead the study that links CXCR4 with the process of dedifferentiation of hepatocytes and tissue damage. […] The loss of identity of liver cells is associated with the deterioration of liver function in alcohol-related hepatitis. In this context, the liver cells undergo a process called dedifferentiation; that is, they regress to a more immature state and become hepatobiliary cells. […] According to the bioinformatic analysis of the sequencing data, the CXCR4 receptor may play a key role in the dedifferentiation of liver cells. It appears that there is a link between the increased levels of expression of CXCR4 and the loss of identity of the liver cells and the exacerbation of the alcoholic hepatitis, says Beatriz Aguilar-Bravo. […] In these three-dimensional cell cultures that reproduce the characteristics of real tissue, we observed that, indeed, the expression of CXCR4 increased, whereas the typical markers for liver cells decreased, showing the loss of identity.

• #50 Mechanism responsible for the loss of identity of hepatocytes in alcoholic hepatitis described

  https://www.clinicbarcelona.org/en/news/mechanism-responsible-for-the-loss-of-identity-of-hepatocytes-in-alcoholic-hepatitis-described

  Pau Sancho-Bru and his team lead the study that links CXCR4 with the process of dedifferentiation of hepatocytes and tissue damage. […] The loss of identity of liver cells is associated with the deterioration of liver function in alcohol-related hepatitis. In this context, the liver cells undergo a process called dedifferentiation; that is, they regress to a more immature state and become hepatobiliary cells. […] According to the bioinformatic analysis of the sequencing data, the CXCR4 receptor may play a key role in the dedifferentiation of liver cells. It appears that there is a link between the increased levels of expression of CXCR4 and the loss of identity of the liver cells and the exacerbation of the alcoholic hepatitis, says Beatriz Aguilar-Bravo. […] In these three-dimensional cell cultures that reproduce the characteristics of real tissue, we observed that, indeed, the expression of CXCR4 increased, whereas the typical markers for liver cells decreased, showing the loss of identity.

• #51 Mechanism responsible for the loss of identity of hepatocytes in alcoholic hepatitis described – Biotech Spain

  https://biotech-spain.com/en/articles/mechanism-responsible-for-the-loss-of-identity-of-hepatocytes-in-alcoholic-hepatitis-described/

  The loss of identity of liver cells is associated with the deterioration of liver function in alcohol-related hepatitis. […] The study evaluates the levels of expression of the genes of hepatobiliary cells. […] According to the bioinformatic analysis of the sequencing data, the CXCR4 receptor may play a key role in the dedifferentiation of liver cells. […] In order to confirm this hypothesis, we simulated the process of dedifferentiation in vitro using organoids derived from samples from patients with the disease. […] Furthermore, in the mouse model of liver disease, overexpression of CXCR4 induces dedifferentiation of liver cells and causes liver damage. […] Altogether, it indicates that the CXCR4 pathway may be a therapeutic target for preventing dedifferentiation of liver cells.

• #52 Mechanism responsible for the loss of identity of hepatocytes in alcoholic hepatitis described

  https://www.clinicbarcelona.org/en/news/mechanism-responsible-for-the-loss-of-identity-of-hepatocytes-in-alcoholic-hepatitis-described

  Furthermore, in the mouse model of liver disease, overexpression of CXCR4 induces dedifferentiation of liver cells and causes liver damage. On the other hand, inhibition attenuates the loss of liver cells and stops the progression of liver damage. Altogether, it indicates that the CXCR4 pathway may be a therapeutic target for preventing dedifferentiation of liver cells.

• #53 Deadly alcoholic hepatitis finds hope in epigenetics | Drug Discovery News

  https://www.drugdiscoverynews.com/deadly-alcoholic-hepatitis-finds-hope-in-epigenetics-15807

  In 2021, they found that indeed, 25HC3S modifies the epigenome by inhibiting all three of the human DNA methyltransferases: DNMT1, DNMT3a, and DNMT3b, which add methyl groups to DNA to repress gene expression. […] It changes DNA hypermethylation and then in turn, changes inflammatory states, changes apoptosis and autophagy, and stabilizes the mitochondrial membrane. […] Recent analysis of liver samples from people with alcoholic hepatitis revealed evidence of hypermethylation and increased expression of DNA methyltransferases, further supporting treatment of these patients with larsucosterol. […] The half-life of the drug is two hours, but it goes to the nucleus. Then, its effect lasts for a long time because you’re literally up and down regulating more than 1000 genes.

• #54

  https://journals.lww.com/hep/abstract/9900/alcohol_induced_disruption_of_hepatic_m6a.1265.aspx

  In this study, we found that the levels of RNA N6-methyladenosine (m6A) modification and its key writer, METTL3, are markedly reduced in mice livers during ASH. […] Mechanistically, ethanol promotes METTL3 degradation via E3-ubiquitin-ligase STUB1-mediated ubiquitination and disrupts the protective interaction between HSP70 and METTL3, impairing hepatic m6A modification. […] Collectively, our results demonstrate that alcohol consumption disrupts the homeostasis of hepatic immune microenvironment in ASH through impairment of METTL3-dependent m6A RNA modification. Targeting METTL3 to preserve its enzymatic activity and stability could represent a novel therapeutic avenue for ASH intervention.

• #55 Deadly alcoholic hepatitis finds hope in epigenetics | Drug Discovery News

  https://www.drugdiscoverynews.com/deadly-alcoholic-hepatitis-finds-hope-in-epigenetics-15807

  In 2021, they found that indeed, 25HC3S modifies the epigenome by inhibiting all three of the human DNA methyltransferases: DNMT1, DNMT3a, and DNMT3b, which add methyl groups to DNA to repress gene expression. […] It changes DNA hypermethylation and then in turn, changes inflammatory states, changes apoptosis and autophagy, and stabilizes the mitochondrial membrane. […] Recent analysis of liver samples from people with alcoholic hepatitis revealed evidence of hypermethylation and increased expression of DNA methyltransferases, further supporting treatment of these patients with larsucosterol. […] The half-life of the drug is two hours, but it goes to the nucleus. Then, its effect lasts for a long time because you’re literally up and down regulating more than 1000 genes.

• #56

  https://journals.lww.com/hep/abstract/9900/alcohol_induced_disruption_of_hepatic_m6a.1265.aspx

  In this study, we found that the levels of RNA N6-methyladenosine (m6A) modification and its key writer, METTL3, are markedly reduced in mice livers during ASH. […] Mechanistically, ethanol promotes METTL3 degradation via E3-ubiquitin-ligase STUB1-mediated ubiquitination and disrupts the protective interaction between HSP70 and METTL3, impairing hepatic m6A modification. […] Collectively, our results demonstrate that alcohol consumption disrupts the homeostasis of hepatic immune microenvironment in ASH through impairment of METTL3-dependent m6A RNA modification. Targeting METTL3 to preserve its enzymatic activity and stability could represent a novel therapeutic avenue for ASH intervention.

• #57 Alcoholic hepatitis – Wikipedia

  https://en.wikipedia.org/wiki/Alcoholic_hepatitis

  Alcohol is also directly damaging to liver cells. Alcohol is metabolized to acetaldehyde in the liver via the enzymes CYP2E1 and aldehyde dehydrogenase. […] Acetaldehyde forms reactive oxygen species in the liver as well as acting as a DNA adduct (binding to DNA) leading to direct hepatocyte damage. […] The chronic inflammation seen in alcoholic hepatitis leads to a distinctive fibrotic response, with fibrogenic cell type activation. […] This peri-cellular chickenwire fibrosis leads to portal hypertension or an elevated blood pressure in the portal veins that drain blood from the intestines to the liver. […] The chronic inflammation seen in alcoholic hepatitis also leads to impaired hepatocyte differentiation, impairments in hepatocyte regeneration and hepatocyte de-differentiation into cholangiocyte type cells. […] Due to the release of DAMPs and PAMPs, an acute systemic inflammatory state can develop after extensive alcohol intake that dominates the clinical landscape of acute severe alcoholic hepatitis.

• #58 Alcohol-Related Liver Disease – Hepatic and Biliary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/alcohol-related-liver-disease/alcohol-related-liver-disease

  Alcohol changes gut permeability, increasing absorption of endotoxins released by bacteria in the gut. In response to the endotoxins (which the impaired liver can no longer detoxify), liver macrophages (Kupffer cells) release free radicals, increasing oxidative damage. […] A vicious circle of worsening inflammation occurs: Cell necrosis and apoptosis result in hepatocyte loss, and subsequent attempts at regeneration result in fibrosis. Stellate (Ito) cells, which line blood channels (sinusoids) in the liver, proliferate and transform into myofibroblasts, producing an excess of type I collagen and extracellular matrix. As a result, the sinusoids narrow, limiting blood flow. Fibrosis narrows the terminal hepatic venules, compromising hepatic perfusion and thus contributing to portal hypertension. Extensive fibrosis is associated with an attempt at regeneration, resulting in liver nodules. This process culminates in cirrhosis.

• #59 Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

  https://www.wjgnet.com/1007-9327/full/v20/i47/17756.htm

  Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor–dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). […] Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. […] Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. […] Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility.

• #60 Alcoholic liver disease: Types & Pathogenesis – Pathology Made Simple

  https://ilovepathology.com/alcoholic-liver-disease-types-pathogenesis/

  Induction of microsomes with CYP2E1 generates ROS leading to hepatocyte injury excess alcohol also Impairs methionine metabolism resulting in low glutathione, which causes increased susceptibility to oxidative stress leading to hepatocyte injury Lastly, increased Bacterial endotoxin uptake in the gut Induces inflammatory response in liver leading to hepatocyte injury. […] Inflammation of hepatocytes, Kupfer cells, endothelial cells, releases cytokines and chemokines ( TGF-) thus, Activating stellate cells. These cells are transformed into FIBROGENIC CELLS which leads to deposition of type I III collagen in lobule resulting in fibrosis.

• #61 Alcohol-Related Liver Disease – Hepatic and Biliary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/alcohol-related-liver-disease/alcohol-related-liver-disease

  Alcohol changes gut permeability, increasing absorption of endotoxins released by bacteria in the gut. In response to the endotoxins (which the impaired liver can no longer detoxify), liver macrophages (Kupffer cells) release free radicals, increasing oxidative damage. […] A vicious circle of worsening inflammation occurs: Cell necrosis and apoptosis result in hepatocyte loss, and subsequent attempts at regeneration result in fibrosis. Stellate (Ito) cells, which line blood channels (sinusoids) in the liver, proliferate and transform into myofibroblasts, producing an excess of type I collagen and extracellular matrix. As a result, the sinusoids narrow, limiting blood flow. Fibrosis narrows the terminal hepatic venules, compromising hepatic perfusion and thus contributing to portal hypertension. Extensive fibrosis is associated with an attempt at regeneration, resulting in liver nodules. This process culminates in cirrhosis.

• #62 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Alcoholic liver disease is associated with bacterial overgrowth and a lower proportion of Bacteroidaceae and probiotic bacteria such as Lactobacillus. […] Zinc deficiency is common in ALD. Animal models have demonstrated that zinc deficiency attenuates alcohol-induced liver injury through various mechanisms, but most importantly, zinc deficiency impairs the intestinal barrier. […] Usually, liver damage induces mature hepatocytes to proliferate and replace damaged tissue. Given massive or chronic liver damage that is beyond the proliferative capacity of hepatocytes, progenitor cells proliferate to produce a ductular reaction. […] The general mechanism for the development of HCC includes i) limitation of the regenerative reserve and induction of chromosomal instability by telomeres, ii) cancer induction by the loss of replicative competition due to impaired hepatocyte proliferation, iii) an altered microenvironment promoting tumor cell proliferation, and 4) the loss of cell cycle check point, including resistance to apoptosis and activation of oncogenic pathways.

• #63 Pathogenesis of Alcoholic Liver Disease – RCEMLearning

  https://www.rcemlearning.co.uk/modules/alcoholic-liver-disease/lessons/pathogenesis-of-alcoholic-liver-disease/

  Alcohol causes damage to the liver by various mechanisms which can be exacerbated by other factors. […] Acetaldehyde concentration is increased in the liver with sustained alcohol intake resulting in hepatocytes becoming susceptible to hypoxia and hypoxic injury. […] Genetic factors have been implicated by studies which have found a relationship between ALD and polymorphisms of alcohol metabolising enzyme systems (ALDH2, Cytochrome p450) and cytokines (TNF, IL1, IL10). […] The metabolism of ethanol (alcohol) occurs in the mitochondria where it is oxidised to alcohol dehydrogenase. This is then oxidised to acetate by acetaldehyde dehydrogenase. These reactions alter the redox state of the cell and can have detrimental effects on lipid and carbohydrate delivery, metabolism and export from the liver causing triglyceride accumulation (fatty liver).

• #64 Pathogenesis, Early Diagnosis, and Therapeutic Management of Alcoholic Liver Disease

  https://www.mdpi.com/1422-0067/20/11/2712

  The apoptosis and autophagy of hepatocytes are pathological conditions that accompany ALD. Alcoholic liver toxicity and alcohol metabolism induce oxidative stress and inflammatory reactions which then cause hepatocyte apoptosis and accelerate the progression of liver diseases. […] According to previous reports, more than 95% of chronic alcoholics suffer from alcoholic fatty liver disease. However, only approximately 30% of patients develop severe stages and the potential protective mechanisms behind this are still unclear.

• #65 Alcoholic Hepatitis (Alcohol-Associated Hepatitis): Background, Etiology and Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/170539-overview

  Alcohol consumption may exacerbate liver injury caused by other pathogenic factors, including hepatitis viruses. Approximately 20% of patients presenting with alcoholic hepatitis have concomitant hepatitis C virus infection. Extensive epidemiologic studies suggest that the risk of cirrhosis in patients with chronic hepatitis C infection is greatly exacerbated by heavy alcohol ingestion.

• #66 Pathogenesis of Alcoholic Liver Disease – RCEMLearning

  https://www.rcemlearning.co.uk/modules/alcoholic-liver-disease/lessons/pathogenesis-of-alcoholic-liver-disease/

  Hepatitis C infection and alcohol have an additive effect together. This is thought to occur as alcohol may alter the immune systems efforts at clearing the virus, or increased iron deposition in liver secondary to high levels of alcohol which may alter the pathophysiology of the virus. […] Acetaldehyde forms covalent bonds with proteins which are antigenic. Long-term exposure to alcohol causes the body to amass circulating antibodies to these proteins resulting in harmful humeral and cellular responses. […] In alcoholic liver injury the expression of pro-inflammatory cytokines is up-regulated resulting in fibrosis. Collagen is deposited in the space of disse which progresses to fibrosis and cell linkage formation resulting in cirrhosis. Lesions occur in the hepatic veins causing thickened veins and perisinusoidal fibrosis which can lead to cirrhosis.

• #67 Key Events Participating in the Pathogenesis of Alcoholic Liver Disease

  https://www.mdpi.com/2218-273X/7/1/9

  Key Events Participating in the Pathogenesis of Alcoholic Liver Disease […] Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. […] The pathogenesis of ALD, influenced by host and environmental factors, is currently only partially understood. […] To date, lipopolysaccharide (LPS) translocation from the gut to the portal blood, aging, gender, increased infiltration and activation of neutrophils and bone marrow-derived macrophages along with alcohol plus iron metabolism, with its associated increase in reactive oxygen species (ROS), are all key events contributing to the pathogenesis of ALD. […] Progressive inflammatory liver injury due to ethanol intake leads to AH, characterized by poor liver function, ductular reaction, high levels of LPS and impaired hepatocyte proliferation. […] All these events, along with sterile and non-sterile inflammation, are mechanisms involved in the pathogenesis of the disease.

• #68 Pathogenesis, Early Diagnosis, and Therapeutic Management of Alcoholic Liver Disease

  https://www.mdpi.com/1422-0067/20/11/2712

  In chronic alcohol consumption, CYP2E1 enzyme is absolutely responsible for the excessive production of ROS, considered the second messenger in the cell. These produced ROS, such as hydrogen peroxide and superoxide ions, are associated with the pro-inflammatory profile of alcohol-mediated liver damages via recruiting immune cells and inducing pro-inflammatory cytokines circulation. […] Research has shown that chronic drinking can cause the imbalance of intestinal flora and intestinal toxin accumulation. Alcohol exposure causes the excessive proliferation of gram negative bacteria in the intestine. […] The research demonstrates that the iron deposition in liver is associated with ALD and more than 30% of patients with ALD suffer from iron metabolism disorders. Recent studies have shown that even mild alcohol consumption induces the iron stores in the liver.

• #69 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1007391

  Alcoholic hepatitis (AH) is defined as an acute hepatic manifestation resulting from heavy alcohol intake. Histologically, alcoholic steatohepatitis (ASH) is characterized by hepatocellular steatosis, inflammation, and fibrosis. […] Tactically, we should explore novel therapeutic targets to suppress inflammation based on cytokine profiles, promote hepatic regeneration, limit innate immune responses, and restore altered gut mucosal integrity in severe ASH. […] Summary of Potential Molecular Targets and Novel Targeted Therapies for Alcoholic Hepatitis. Key element of the pathogenesis Treatment Effect Clinical trial FXR dysregulation OCA55 FXR agonist Moderately severe AH (placebo vs. OCA) Altered gut integrity Zinc56 Restoration of gut integrity Severe AH LGG57 Probiotic effect Mild to moderate AH (placebo vs. LGG) Rifaximin58 Intestinal decontamination Severe AH (steroid vs. steroid+ rifaximin) Innate immune activation Imm 12-E59 Anti-LPS antibody Severe AH (steroid vs. steroid+ low/high dose Imm 12-E) Anakinra60-62 IL-1RA Severe AH (steroid vs. anakinra+ pentoxifylline+ zinc) Rilonacept60,61 IL-1 inhibitor Severe AH with response to steroid at day 7 (steroid vs. steroid+ rilonacept) Mycophenolate mofetil IMPDH inhibitor Severe AH without response to steroid at day 7 (standard of care vs. steroid+ mycophenolate) Sterile necrosis and apoptosis Emricasan Pancaspase inhibitor Severe AH with steroid contraindications (placebo vs. emricasan) Impaired regeneration G-CSF63,64 HPC mobilization Severe AH without response to steroid at day 7 (placebo vs. G-CSF) IL-2265-67 Hepatoprotective effect Only preclinical studies.

• #70

  https://www.xiahepublishing.com/2310-8819/JCTH-2016-00006

  Activation of the innate immune system is one of the main steps in the development of AH. Activation of kupffer cells causes release of IL-1, a potent pro-inflammatory cytokine. […] Apoptosis is a prominent feature in the pathophysiology of AH. Excessive hepatocyte apoptosis stimulates inflammation and results in the production of proinflammatory cytokines and reactive oxygen species by the innate immune system. […] FXR is a nuclear receptor for bile acids, and its activation has been shown to be essential in the treatment of primary biliary cirrhosis (PBC).

• #71 KoreaMed Synapse

  https://synapse.koreamed.org/articles/1007391

  Alcoholic hepatitis (AH) is defined as an acute hepatic manifestation resulting from heavy alcohol intake. Histologically, alcoholic steatohepatitis (ASH) is characterized by hepatocellular steatosis, inflammation, and fibrosis. […] Tactically, we should explore novel therapeutic targets to suppress inflammation based on cytokine profiles, promote hepatic regeneration, limit innate immune responses, and restore altered gut mucosal integrity in severe ASH. […] Summary of Potential Molecular Targets and Novel Targeted Therapies for Alcoholic Hepatitis. Key element of the pathogenesis Treatment Effect Clinical trial FXR dysregulation OCA55 FXR agonist Moderately severe AH (placebo vs. OCA) Altered gut integrity Zinc56 Restoration of gut integrity Severe AH LGG57 Probiotic effect Mild to moderate AH (placebo vs. LGG) Rifaximin58 Intestinal decontamination Severe AH (steroid vs. steroid+ rifaximin) Innate immune activation Imm 12-E59 Anti-LPS antibody Severe AH (steroid vs. steroid+ low/high dose Imm 12-E) Anakinra60-62 IL-1RA Severe AH (steroid vs. anakinra+ pentoxifylline+ zinc) Rilonacept60,61 IL-1 inhibitor Severe AH with response to steroid at day 7 (steroid vs. steroid+ rilonacept) Mycophenolate mofetil IMPDH inhibitor Severe AH without response to steroid at day 7 (standard of care vs. steroid+ mycophenolate) Sterile necrosis and apoptosis Emricasan Pancaspase inhibitor Severe AH with steroid contraindications (placebo vs. emricasan) Impaired regeneration G-CSF63,64 HPC mobilization Severe AH without response to steroid at day 7 (placebo vs. G-CSF) IL-2265-67 Hepatoprotective effect Only preclinical studies.

• #72 Deadly alcoholic hepatitis finds hope in epigenetics | Drug Discovery News

  https://www.drugdiscoverynews.com/deadly-alcoholic-hepatitis-finds-hope-in-epigenetics-15807

  Excessive alcohol consumption can lead to severe liver inflammation a serious disease called alcoholic hepatitis. […] Alcoholic hepatitis typically occurs in people who drink heavily over the course of many years, but not always. Some moderate drinkers develop the disease, while some heavy drinkers don’t. […] Because patients typically only show symptoms at advanced stages of the disease, 30 percent of those who get diagnosed with alcoholic hepatitis die within 90 days, and 25 percent die within one month. There is no treatment. […] Now, Brown and his colleagues may have found a way to help these patients by using a novel cholesterol-derived molecule called larsucosterol. […] As they began working together, Ren and the DURECT researchers noticed that this molecule and other related oxysterols always seemed to end up in the cell nucleus. Because these oxysterols influenced multiple aspects of cellular function, the research team hypothesized that these molecules act as epigenetic regulators.

• #73 Deadly alcoholic hepatitis finds hope in epigenetics | Drug Discovery News

  https://www.drugdiscoverynews.com/deadly-alcoholic-hepatitis-finds-hope-in-epigenetics-15807

  Excessive alcohol consumption can lead to severe liver inflammation a serious disease called alcoholic hepatitis. […] Alcoholic hepatitis typically occurs in people who drink heavily over the course of many years, but not always. Some moderate drinkers develop the disease, while some heavy drinkers don’t. […] Because patients typically only show symptoms at advanced stages of the disease, 30 percent of those who get diagnosed with alcoholic hepatitis die within 90 days, and 25 percent die within one month. There is no treatment. […] Now, Brown and his colleagues may have found a way to help these patients by using a novel cholesterol-derived molecule called larsucosterol. […] As they began working together, Ren and the DURECT researchers noticed that this molecule and other related oxysterols always seemed to end up in the cell nucleus. Because these oxysterols influenced multiple aspects of cellular function, the research team hypothesized that these molecules act as epigenetic regulators.

• #74 Deadly alcoholic hepatitis finds hope in epigenetics | Drug Discovery News

  https://www.drugdiscoverynews.com/deadly-alcoholic-hepatitis-finds-hope-in-epigenetics-15807

  In 2021, they found that indeed, 25HC3S modifies the epigenome by inhibiting all three of the human DNA methyltransferases: DNMT1, DNMT3a, and DNMT3b, which add methyl groups to DNA to repress gene expression. […] It changes DNA hypermethylation and then in turn, changes inflammatory states, changes apoptosis and autophagy, and stabilizes the mitochondrial membrane. […] Recent analysis of liver samples from people with alcoholic hepatitis revealed evidence of hypermethylation and increased expression of DNA methyltransferases, further supporting treatment of these patients with larsucosterol. […] The half-life of the drug is two hours, but it goes to the nucleus. Then, its effect lasts for a long time because you’re literally up and down regulating more than 1000 genes.

• #75

  https://www.jci.org/articles/view/157780

  Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. […] Accumulating evidence suggests that multiple types of immune cells are involved in the pathogenesis of AH, including neutrophils, resident and infiltrating macrophages, and other cell types in the innate and adaptive immune system. […] Neutrophils cause tissue injury by producing inflammatory mediators, proteases, and ROS. […] Mechanistically, we found that hepatic NCF1 expression is markedly upregulated and correlates with neutrophil infiltration in SAH patients. […] Our data provide a mechanistic insight into the role of neutrophils in ALD, suggesting that neutrophilic NCF1-dependent ROS generation promotes steatosis and hepatic inflammation by inhibiting AMPK and miR-223, respectively.

• #76

  https://www.jci.org/articles/view/157780

  Our results suggest that the reduction of ROS production secondary to the absence of neutrophilic NCF1 leads to hepatic activation of SIRT1 and AMPK, shifts the intracellular lipid metabolism toward fatty acid oxidation, and ameliorates alcohol-induced hepatic steatosis. […] Our data revealed that the number of intrahepatic neutrophils correlated with MELD scores and serum ALT levels in SAH patients and that neutrophil-derived ROS promoted liver injury and inflammation in the experimental model. […] The varying degree of hepatic neutrophil infiltration in SAH patients may have differential effects in driving downstream liver injury and liver failure through the inflammatory process and ROS production.

• #77 Researchers Gain New Insight Into the Development of Severe Alcohol-Associated Hepatitis – News from the National Institute on Alcohol Abuse and Alcoholism

  https://niaaa.scienceblog.com/439/researchers-gain-new-insight-into-the-development-of-severe-alcohol-associated-hepatitis/

  More specifically, the researchers found increased expression of neutrophil cytosolic factor 1 (NCF1), a gene involved in controlling ROS. […] They found that NCF1 contributes to higher levels of ROS and thus liver inflammation/injury by inhibiting adenosine monophosphate-activated protein kinase (AMPK, a key regulator of lipid metabolism) and by inhibiting microRNA-223 (a key anti-inflammatory microRNA). […] These findings provide important insight into the mechanisms that may drive liver injury, and ultimately liver failure, in individuals with severe AH. […] Additional clinical and translational research is needed to more fully characterize the pathological mechanisms that contribute to severe AH and to identify novel therapeutic targets for this devastating disease.

• #78 Alcoholic Hepatitis: Pathogenesis, Diagnosis and Treatment

  https://eurekaselect.com/public/article/77274

  Alcohol represents the oldest substance of abuse known and Alcoholic Liver Disease (ALD) is the most common cause of chronic liver disease worldwide. […] Because of the complex pathogenetic mechanisms, the therapy of ALD and especially of severe Alcoholic Hepatitis (AH), represents a thorny problem in the clinical practice. […] In severe forms of acute AH, some specific drug treatments, including glucorticoids or pentoxifylline, have been defined and are, at the moment, recommended by international guidelines.

• #79

  https://www.xiahepublishing.com/2310-8819/JCTH-2016-00006

  Alcohol is one of the most common etiologies of liver disease, and alcoholic liver disease overall is the second most common indication for liver transplantation in the United States. […] Management of the mild disease consists mainly of abstinence and supportive care. Severe AH is associated with significant mortality. Currently, there is no ideal medical treatment for this condition. […] Currently, early stage trials are underway, mainly targeting novel pathways based on disease pathogenesis, including modulation of innate immune system, inhibition of gut-liver axis and cell death pathways, and activation of transcription factor farnesyl X receptor (FXR). […] Alcohol disrupts the intestinal epithelial barrier, resulting in increased gut permeability to microbiota. The bacterial endotoxin lipopolysaccharide (LPS) increases in portal circulation and activates toll-like receptor 4 (TLR4), leading to activation of the innate immune system and release of various cytokines. Blockage of these pathways could have therapeutic implications for the treatment of AH.

• #80 Alcoholic liver disease: mechanisms of injury and targeted treatment | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/nrgastro.2015.35

  Alcoholic hepatitis is a specific entity, which is associated with a fast progression to cirrhosis and with liver failure and a poor outcome in its most severe form […] Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. […] Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. […] This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.

• #81 Alcoholic hepatitis: a comprehensive review of pathogenesis and treatment. – Drugs and Alcohol

  https://www.drugsandalcohol.ie/29614/

  Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality. Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. […] Because of the limitations in the therapeutic options, it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.

• #82 Deadly alcoholic hepatitis finds hope in epigenetics | Drug Discovery News

  https://www.drugdiscoverynews.com/deadly-alcoholic-hepatitis-finds-hope-in-epigenetics-15807

  Excessive alcohol consumption can lead to severe liver inflammation a serious disease called alcoholic hepatitis. […] Alcoholic hepatitis typically occurs in people who drink heavily over the course of many years, but not always. Some moderate drinkers develop the disease, while some heavy drinkers don’t. […] Because patients typically only show symptoms at advanced stages of the disease, 30 percent of those who get diagnosed with alcoholic hepatitis die within 90 days, and 25 percent die within one month. There is no treatment. […] Now, Brown and his colleagues may have found a way to help these patients by using a novel cholesterol-derived molecule called larsucosterol. […] As they began working together, Ren and the DURECT researchers noticed that this molecule and other related oxysterols always seemed to end up in the cell nucleus. Because these oxysterols influenced multiple aspects of cellular function, the research team hypothesized that these molecules act as epigenetic regulators.

• #83 Alcoholic hepatitis: a comprehensive review of pathogenesis and treatment. – Drugs and Alcohol

  https://www.drugsandalcohol.ie/29614/

  Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality. Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism, inflammation and innate immunity. […] Because of the limitations in the therapeutic options, it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.

• #84 Researchers make new discoveries about severe alcoholic hepatitis

  https://medicine.iu.edu/news/2022/07/severe-alcoholic-hepatitis-research

  Researchers from Indiana University School of Medicine and the National Institutes of Health are learning more about what happens to the body when someone develops severe alcoholic hepatitis and how it could be treated in the future. […] In severe cases, the short-term mortality is extremely high. One in three people will die when they develop it. But so far, not much is known about the mechanism of how all of this happens. […] Scientists focused on describing the patterns of neutrophils, which are a type of white blood cell, and their involvement in severe alcoholic hepatitis pathogenesis. […] When someone develops severe alcoholic hepatitis, their neutrophil levels increase, but it is unclear how those neutrophils can trigger inflammation or what is happening in the liver. […] We are able to characterize the two distinct phenotypes based on these cells, suggesting there is a separate mechanism driving liver injury and/or failure in these patients, Liangpunsakul said.

• #85 Researchers make new discoveries about severe alcoholic hepatitis

  https://medicine.iu.edu/news/2022/07/severe-alcoholic-hepatitis-research

  If they receive steroids, we may not get a response because neutrophils poorly respond to steroid treatment, said Bin Gao, MD, PhD, another co-corresponding author and the Chief of Laboratory of Liver Diseases at the National Institute on Alcohol Abuse and Alcoholism. More study is needed to identify how high versus low neutrophils can impact responses to treatment.

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