Materiały źródłowe

• #1 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.

• #2 Alcoholic Liver Disease: Pathogenesis and Current Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5513682/

  Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure.

• #3 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

  Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the leading cause of chronic liver disease. […] Therefore, the underlying mechanisms of ALD are complex, involving inflammation, mitochondrial damage, endoplasmic reticulum stress, nitrification, and oxidative stress. Moreover, recent evidence has demonstrated that the gut-liver axis plays a critical role in ALD pathogenesis. […] Although ethanol-induced liver injury has been of great concern in recent years, the underlying mechanisms of ethanol-induced liver injury are complex and involve multiple signaling pathways. Therefore, understanding these mechanisms is of great importance for the development of improved ALD treatments.

• #4 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 absorption and metabolism: 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.

• #5 Pathophysiology and Management of Alcoholic Liver Disease: Update 2016

  https://www.gutnliver.org/journal/view.html?pn=related&uid=1066&vmd=Full

  Alcoholic liver disease (ALD) is a leading cause of cirrhosis, liver cancer, and acute and chronic liver failure and as such causes significant morbidity and mortality. […] The pathophysiology of ALD is still incompletely understood but relates largely to the direct toxic effects of alcohol and its main intermediate, acetaldehyde. […] The cellular and molecular mechanisms of ALD pathogenesis are still incompletely understood but seem to be related to a complex interaction between behavioral, environmental and genetic factors. […] A pivotal component in the evolution of ALD is the direct toxicity of the first metabolite of alcohol degradation, acetaldehyde (AA). […] Both enzyme systems generate AA, a highly reactive toxic and mutagenic metabolite, by which they not only degrade ethanol (and other organic substances), but also contribute to alcohol-related toxicity.

• #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 (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.

• #8 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

  Alcohol-induced liver injury mainly involves structural damage to liver cells, lipid accumulation, and inflammation. Studies have demonstrated that transcription factors, kinases, and microRNAs (miRNAs) play critical regulatory roles in ALD. […] Several mechanisms are possibly associated with ethanol-induced liver diseases. For example, acute ethanol consumption can result in oxidative stress, nitrification stress, endoplasmic reticulum (ER) stress, inflammation, and apoptosis. Chronic ethanol consumption can result in dysregulated lipid metabolism, lipid accumulation, and AFL and alter the gut-liver axis by damaging the tightly connective structures of the intestinal epithelium. […] 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).

• #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 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. […] Activation of the hepatic stellate cell (HSC) is the key step in the pathogenesis of alcoholic liver fibrosis. […] 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. […] Acetaldehyde causes the dysfunction of mitochondrial fatty acid β-oxidation and hepatocyte secretion. […] In chronic alcohol consumption, CYP2E1 enzyme is absolutely responsible for the excessive production of ROS, considered the second messenger in the cell.

• #11 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

  Hepatic fat accumulation may predispose to subsequent oxidative damage. […] 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. […] Oxidative stress is increased by liver hypermetabolism, caused by alcohol consumption. […] Binding of alcohol oxidation products, such as acetaldehyde, to liver cell proteins, forming neoantigens and resulting in inflammation. […] A vicious circle of worsening inflammation occurs: Cell necrosis and apoptosis result in hepatocyte loss, and subsequent attempts at regeneration result in fibrosis. […] 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.

• #12 Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/1422-0067/22/10/5170

  Chronic alcohol use upregulates CYP2E1 production, which leads to increased acetaldehyde concentration, diminished ALDH activity, and reduced acetaldehyde oxidation, resulting in acetaldehyde accumulation, which directly damages the mitochondria and microtubules of hepatocytes in the liver. […] CYP2E1-mediated or ethanol-induced inflammatory oxidative stress causes ROS generation (e.g., superoxide, hydroxyl radicals), which can bind to proteins and result in structural or functional alterations. […] Chronic alcohol consumption is a known factor of intestinal endotoxin accumulation and intestinal wall permeability increasing, facilitating the translocation of endotoxins from the intestines to the liver in the form of LPS, which are toxic to hepatocytes. […] Numerous studies have revealed that alcohol consumption is correlated with iron overload and hepcidin synthesis downregulation in Kupffer cells and hepatocytes in the liver, while hepcidin was proposed as a key mediator in iron homeostasis.

• #13 Pathogenesis of Alcoholic Liver Disease – RCEMLearning India

  https://www.rcemlearning.org/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.

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

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

  In chronic alcohol abuse, alcohol increases the expression of CYP2E1 in liver, causing dysregulations in lipid peroxidation through ROS free radicals. […] Research has shown that chronic drinking can cause the imbalance of intestinal flora and intestinal toxin accumulation. […] 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. […] 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.

• #15 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 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. […] Nitrification stress refers to the biochemical action of reactive nitrogen species, where nitric oxide (NO) is attached to a tyrosine residue, resulting in the generation of intracellular proteins carrying 3-nitrotyrosine (3-NT) residues. […] Sustained ER stress may lead to cell and tissue damage. […] Ethanol can trigger the ER stress response, which is followed by the stimulation of apoptosis-related gene expression, cell proliferation, and apoptosis imbalance. […] The ethanol-induced second-hit theory of ALD. […] Numerous studies have revealed that ethanol significantly induces fat accumulation and steatosis in the liver.

• #16 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. Endoplasmic reticulum stress activates interferon regulatory factor 3 (IRF3) via the adaptor molecule STRING. […] 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.

• #17 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. Peroxidation of membrane lipids accompanies alcoholic liver injury and may be involved in cell death and inflammation.

• #18 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.

• #19 Alcohol and hepatocellular carcinoma | BMJ Open Gastroenterology

  https://bmjopengastro.bmj.com/content/6/1/e000260

  Acetaldehyde has been shown to be a carcinogen in animal studies. With regard to direct DNA mutagenic mechanisms, it has been reported that acetaldehyde increases the point mutation frequency in the hypoxanthine phosphoribosyltransferase (HPRT) gene in lymphocytes, and induces sister chromatid exchanges. […] The metabolism of ethanol through the CYP2E1-dependent pathway produces ROS. Subsequently, the increase of ROS results in the generation of lipid peroxidation products, such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE). […] Aberrant DNA methylation and protein methylation may play important roles in the development of various cancers, including HCC. In most cases, DNA methylation is associated with a decreased gene expression because of interference with the interaction of transcription factor and CpG islands of promoter lesions (usually unmethylated).

• #20 Protein that drives the development of alcohol-associated liver disease identified by IU researchers

  https://medicine.iu.edu/news/2023/04/alcohol-associated-liver-disease-protein-identified

  Alcohol-associated liver disease (ALD), a complex disorder that occurs in some patients who have engaged in excessive alcohol use, is one of the leading causes of chronic liver disease among veterans and liver transplant patients in the United States. […] Liangpunsakul’s team have identified the novel role of a protein called Pyruvate dehydrogenase kinase 4, or PDK4, in the development of ALD, which may pave the way for new treatments. […] In the paper, Liangpunsakul and his team report that PDK4 plays a mediatory role with the formation of the membrane of the mitochondria-associated endoplasmic reticulum, which drives calcium accumulation in the mitochondria. […] PDK4 is therefore a key mediator of alcohol-induced liver injury, said Liangpunsakul. […] The accumulation of calcium in the mitochondria has been linked to mitochondrial dysfunction. However, the factors involved in promoting mitochondrial calcium accumulation and dysfunction during the pathogenesis of ALD have not been well understood until now, he said. […] This novel study extends the role of PDK4 on alcohol-associated liver disease, notably on its effect on mitochondria and endoplasmic reticulum, he said, emphasizing the importance of PDK4 as a potential therapeutic target for ALD.

• #21 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.

• #22 Alcoholic hepatitis – Wikipedia

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

  Damaged hepatocytes release Danger associated molecular patterns (DAMPs) which are molecules that lead to further activation of the immune system’s inflammatory response and further hepatocyte damage. […] The chronic inflammation seen in alcoholic hepatitis leads to a distinctive fibrotic response, with fibrogenic cell type activation. […] This occurs via an increased extracellular matrix deposition around hepatocytes and sinusoidal cells which causes a peri-cellular fibrosis known as „chickenwire fibrosis”. […] 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. […] This causes many of the sequelae of chronic liver disease including esophageal varices (with associated variceal bleeding), ascites and splenomegaly.

• #23 Alcoholic Liver Disease: Pathogenesis and Current Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5513682/

  Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences, accounting for 3.3 million deaths in 2012. […] After a brief overview of alcohol metabolism in the liver, this article will summarize the mechanisms through which excessive alcohol consumption contributes to the development of various types of alcohol-induced liver damage. […] Alcoholic hepatitis is a more severe, inflammatory type of liver injury characterized by swollen, dying hepatocytes (i.e., ballooning degeneration), neutrophilic infiltration, and the development of tangled aggregates of insoluble proteins called Mallory-Denk bodies within hepatocytes. Central to hepatitis development is the activation of KCs, the resident liver macrophages. […] The ability of macrophages to regulate inflammation depends on their polarization—that is, their ability to develop into one of two different functional states, namely M1 (i.e., proinflammatory) or M2 (i.e., anti-inflammatory) macrophages.

• #24

  https://www.jci.org/articles/view/176345

  Hepatocyte death and impaired liver regeneration play an important role in promoting ALD progression and have been investigated as therapeutic targets. […] Various mechanisms and factors have been implicated in induction of hepatocyte death in ALD, such as alcohol metabolism-associated endoplasmic reticulum stress, oxidative stress, proinflammatory cytokines, danger-associated molecular patterns, and dysregulation of autophagy. […] Inflammation acts as a key factor driving ALD progression to steatohepatitis, cirrhosis, and HCC; many different cell types and inflammatory mediators participate in the inflammation underlying ALD. […] The major factors that trigger ALD inflammation include hepatocyte death, increased gut permeability, and disrupted intestinal bacterial homeostasis. […] Given its important role in the pathogenesis of ALD, inflammation has been actively investigated as a therapeutic target for sAH therapy.

• #25 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. In addition, acetaldehyde may bind covalently with several hepatic macromolecules, such as amines and thiols, in cell membranes, enzymes, and microtubules to form acetaldehyde adducts. […] 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. […] 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.

• #26 Alcoholic Liver Disease | Cleveland Clinic

  https://my.clevelandclinic.org/departments/digestive/medical-professionals/hepatology/alcoholic-liver-disease

  Chronic alcohol exposure also activates hepatic macrophages, which then produce tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induces mitochondria to increase the production of reactive oxygen species. This oxidative stress promotes hepatocyte necrosis and apoptosis, which is exaggerated in the alcoholic who is deficient in antioxidants such as glutathione and vitamin E. […] Free radicals initiate lipid peroxidation, which causes inflammation and fibrosis. Inflammation is also incited by acetaldehyde that, when bound covalently to cellular proteins, forms adducts that are antigenic.

• #27 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. In addition, acetaldehyde may bind covalently with several hepatic macromolecules, such as amines and thiols, in cell membranes, enzymes, and microtubules to form acetaldehyde adducts. […] 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. […] 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.

• #28 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 increases the mRNA and protein levels of CD36/FAT and FATP5. […] Acetaldehyde plays a role in the development of a fatty liver. […] Ethanol exposure induces the production of many inflammatory cytokines and chemokines. […] 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. […] The gut barrier mainly regulates the water balance and nutrient absorption rate and selectively protects intestinal microorganisms. […] After long-term ethanol intake, the intestinal epithelial cell structure in rats is markedly changed, exhibiting mitochondrial and endoplasmic reticulum dilation.

• #29 Unraveling the Role of Gut Microbiota in Alcoholic Liver Disease – International Probiotics Association

  https://internationalprobiotics.org/home/unraveling-the-role-of-gut-microbiota-in-alcoholic-liver-disease/

  Amassing evidence confirms that the gut microbiome is involved in the complex development of alcoholic liver disease (ALD). […] The pathogenesis of ALD is intricate, involving environmental factors, genetic predisposition, and immune response. Increasingly, evidence points to interactions of the gut microbiome as a key factor. […] Alcohol disturbs the gut-liver axis across a range of areas, affecting the gut microbiome, mucus barrier, epithelial barrier, and antimicrobial peptide production. This disruption leads to heightened microbial exposure and a proinflammatory environment within the liver. […] Alcohol-induced gut dysbiosis leads to increased intestinal permeability, which allows transit of microbial products into the bloodstream (endotoxemia). The liver is the first organ to encounter endotoxins originating from the gut.

• #30 Pathogenesis of Alcoholic Liver Disease

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

  The leading cause of death in AH is overwhelming bacterial infection, leading to multiorgan failure. Paradoxically, immune activity is heightened with inflammation. […] 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.

• #31 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. […] Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. […] Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. […] In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver.

• #32 Pathophysiology and Management of Alcoholic Liver Disease: Update 2016

  https://www.gutnliver.org/journal/view.html?pn=related&uid=1066&vmd=Full

  Importantly, AA is also a powerful carcinogen in experimental animals and in humans, and considered an important reason for the association of certain cancers with alcohol consumption. […] The initial liver lesion in alcoholics is steatosis which occurs in literally all heavy drinkers as a result of disrupted lipid turnover. […] Similar to non-ASH, inflammation can occur as an important feature in alcoholic steatosis resulting in ASH, and evolve as a major driving force for fibrogenesis leading to fibrosis, cirrhosis and most likely, hepatocarcinogenesis. […] A key pathogenic pathway in this stage is the gut-liver axis. […] The key lesion in chronic liver disease is fibrosis that, in essence, resembles the process of excessive wound healing as a result of increased fibrogenesis and decreased fibrolysis.

• #33 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

  The oxidative stress initiated by ethanol led to the oxidation of cytoskeletal microtubules and TJ decomposition. […] The physical interaction between ethanol and intestinal microbes may be a key reason for the ethanol-driven alteration in the intestinal flora contents. […] The liver and digestive tract are closely associated and their interactions form the gut-liver axis.

• #34 Alcoholic hepatitis – Wikipedia

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

  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. […] In the case of enterococcus faecalis, the bacterium can release an exotoxin which is directly damaging to liver cells.

• #35 Alcoholic Liver Disease: Pathogenesis and Current Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5513682/

  Excessive alcohol consumption is a global healthcare problem. The liver sustains the greatest degree of tissue injury by heavy drinking because it is the primary site of ethanol metabolism. Chronic and excessive alcohol consumption produces a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, and fibrosis/cirrhosis. Steatosis is the earliest response to heavy drinking and is characterized by the deposition of fat in hepatocytes. Steatosis can progress to steatohepatitis, which is a more severe, inflammatory type of liver injury. This stage of liver disease can lead to the development of fibrosis, during which there is excessive deposition of extracellular matrix proteins. The fibrotic response begins with active pericellular fibrosis, which may progress to cirrhosis, characterized by excessive liver scarring, vascular alterations, and eventual liver failure.

• #36 Alcoholic liver disease – Wikipedia

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

  Fatty change, or steatosis, is the accumulation of fatty acids in liver cells. This can be seen as fatty globules under the microscope. Alcoholism causes development of large fatty globules (macro-vesicular steatosis) throughout the liver and can begin to occur after a few days of heavy drinking. Alcohol is metabolized by alcohol dehydrogenase (ADH) into acetaldehyde, then further metabolized by aldehyde dehydrogenase (ALDH) into acetic acid, which is finally oxidized into carbon dioxide (CO2) and water (H2O). This process generates NADH, and increases the NADH/NAD+ ratio. A higher NADH concentration induces fatty acid synthesis while a decreased NAD level results in decreased fatty acid oxidation. Subsequently, the higher levels of fatty acids signal the liver cells to compound it to glycerol to form triglycerides. These triglycerides accumulate, resulting in fatty liver.

• #37 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 absorption and metabolism: 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.

• #38

  https://www.jci.org/articles/view/176345

  Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. […] The pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. […] In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. […] Alcohol is mainly absorbed in the small intestine and metabolized by the liver and other organs, leading to disruption of liver metabolic homeostasis and forming the basis for ALD. […] Multiple mechanisms contribute to steatosis, including disruption of mitochondrial fatty acid oxidation, migration of lipids to the liver from extrahepatic organs, and alteration of lipid metabolism-associated transcription factors.

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

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

  Alcoholic liver disease (ALD) refers to the damages to the liver and its functions due to alcohol overconsumption. It consists of fatty liver/steatosis, alcoholic hepatitis, steatohepatitis, chronic hepatitis with liver fibrosis or cirrhosis, and hepatocellular carcinoma. However, the mechanisms behind the pathogenesis of alcoholic liver disease are extremely complicated due to the involvement of immune cells, adipose tissues, and genetic diversity. […] Long-term excessive drinking can cause oxidative stress in the liver through the accumulation of reactive oxygen species (ROS) produced from alcohol metabolism. It causes liver inflammation through the toxicity of lipopolysaccharides (LPS) and acetaldehyde. […] Fat accumulation in the liver, an early stage of ALD, is the only stage of ALD which can be completely reversible through abstinence without any drug intervention.

• #40 Alcoholic liver disease: Symptoms, treatment, and causes

  https://www.medicalnewstoday.com/articles/215638

  Alcoholic liver disease is liver damage from overconsuming alcohol. It can cause a buildup of fats, inflammation, and scarring. […] Alcoholic liver disease has four main stages: alcoholic fatty liver disease, alcoholic hepatitis, fibrosis, and cirrhosis. […] If a person continues to drink alcohol it will lead to ongoing liver inflammation. This can occur after many years of heavy drinking. It can also occur acutely during periods of binge drinking. […] Alcoholic hepatitis usually progresses to cirrhosis if a person continues to drink alcohol. Hepatitis heals in a person who stops drinking alcohol, but any cirrhosis does not reverse. […] Fibrosis is a buildup of certain types of protein in the liver, including collagen. It features in most types of chronic liver disease. […] Cirrhosis occurs when the liver has been inflamed for a long time, leading to scarring and loss of function. This can be a life threatening condition. Cirrhosis damage is irreversible, but a person can prevent further damage by continuing to avoid alcohol.

• #41 Alcoholic Liver Disease: Pathogenesis and Current Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5513682/

  The main pathological feature of cirrhosis is the formation of regenerative nodules of hepatic parenchyma surrounded by fibrous septa. Cirrhosis development progresses from a compensated phase, in which part of the liver remains undamaged and functionally compensates for the damaged regions, to a decompensated phase, in which scar tissue fully envelops the organ. […] HSCs are the key players in the development of fibrosis. These cells normally reside in the space of Disse as quiescent, lipid (retinyl-ester)-storing cells. Following hepatic injury, HSCs undergo a complex activation process and become the principal source for the increased and irregular deposition of extracellular-matrix components that characterize fibrosis. Activated HSCs also contribute to the inflammatory response, coordinating the recruitment and stimulation of leukocytes by releasing chemokines and proinflammatory cytokines as well as expressing adhesion molecules.

• #42 Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/1422-0067/22/10/5170

  Chronic alcohol use upregulates CYP2E1 production, which leads to increased acetaldehyde concentration, diminished ALDH activity, and reduced acetaldehyde oxidation, resulting in acetaldehyde accumulation, which directly damages the mitochondria and microtubules of hepatocytes in the liver. […] CYP2E1-mediated or ethanol-induced inflammatory oxidative stress causes ROS generation (e.g., superoxide, hydroxyl radicals), which can bind to proteins and result in structural or functional alterations. […] Chronic alcohol consumption is a known factor of intestinal endotoxin accumulation and intestinal wall permeability increasing, facilitating the translocation of endotoxins from the intestines to the liver in the form of LPS, which are toxic to hepatocytes. […] Numerous studies have revealed that alcohol consumption is correlated with iron overload and hepcidin synthesis downregulation in Kupffer cells and hepatocytes in the liver, while hepcidin was proposed as a key mediator in iron homeostasis.

• #43 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. […] Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. […] Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. […] In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver.

• #44 Pathogenesis of Alcoholic Liver Disease – RCEMLearning India

  https://www.rcemlearning.org/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.

• #45 Alcoholic Liver Disease: Pathogenesis and Current Management

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5513682/

  The main pathological feature of cirrhosis is the formation of regenerative nodules of hepatic parenchyma surrounded by fibrous septa. Cirrhosis development progresses from a compensated phase, in which part of the liver remains undamaged and functionally compensates for the damaged regions, to a decompensated phase, in which scar tissue fully envelops the organ. […] HSCs are the key players in the development of fibrosis. These cells normally reside in the space of Disse as quiescent, lipid (retinyl-ester)-storing cells. Following hepatic injury, HSCs undergo a complex activation process and become the principal source for the increased and irregular deposition of extracellular-matrix components that characterize fibrosis. Activated HSCs also contribute to the inflammatory response, coordinating the recruitment and stimulation of leukocytes by releasing chemokines and proinflammatory cytokines as well as expressing adhesion molecules.

• #46 Alcoholic liver disease – Wikipedia

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

  Alcoholic hepatitis is characterized by the inflammation of hepatocytes. Inflammatory cytokines (TNF-alpha, IL-6 and IL-8) are thought to be essential in the initiation and perpetuation of liver injury and cytotoxic hepatomegaly by inducing apoptosis and severe hepatotoxicity. One possible mechanism for the increased activity of TNF- is the increased intestinal permeability due to liver disease. This facilitates the absorption of the gut-produced endotoxin into the portal circulation. The Kupffer cells of the liver then phagocytose endotoxin, stimulating the release of TNF-. TNF- then triggers apoptotic pathways through the activation of caspases, resulting in cell death. […] Cirrhosis is a late stage of serious liver disease marked by inflammation (swelling), fibrosis (cellular hardening) and damaged membranes preventing detoxification of chemicals in the body, ending in scarring and necrosis (cell death). Acetaldehyde may be responsible for alcohol-induced fibrosis by stimulating collagen deposition by hepatic stellate cells. The production of oxidants derived from NADPH oxidase and/or cytochrome P-450 2E1 and the formation of acetaldehyde-protein adducts damage the cell membrane.

• #47 Alcoholic hepatitis – Wikipedia

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

  Damaged hepatocytes release Danger associated molecular patterns (DAMPs) which are molecules that lead to further activation of the immune system’s inflammatory response and further hepatocyte damage. […] The chronic inflammation seen in alcoholic hepatitis leads to a distinctive fibrotic response, with fibrogenic cell type activation. […] This occurs via an increased extracellular matrix deposition around hepatocytes and sinusoidal cells which causes a peri-cellular fibrosis known as „chickenwire fibrosis”. […] 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. […] This causes many of the sequelae of chronic liver disease including esophageal varices (with associated variceal bleeding), ascites and splenomegaly.

• #48 How alcohol affects the liver

  https://www2.hse.ie/living-well/alcohol/health/effects-on-your-body/the-liver/

  More serious and life-threatening inflammation of the liver can cause: a loss of appetite, sickness, tummy pain, jaundice (yellow skin), liver failure, cirrhosis. […] Around 1 in 3 people who develop acute alcoholic hepatitis will die from it. […] Around 1 in 5 heavy drinkers have cirrhosis. […] Fat and inflammation in the liver lead to scarring. When the scarring is severe, this is called cirrhosis. […] Scar tissue replaces healthy cells. This means that the liver cannot work properly and can fail. Liver failure is a life-threatening condition. […] Cirrhosis may not cause symptoms. […] Most people who develop cirrhosis and liver failure do not notice symptoms until its too late. […] Cirrhosis can also be caused by non-alcoholic fatty liver disease. […] You can reduce the risk of liver damage by cutting down or giving up alcohol. All liver diseases improve from giving up alcohol.

• #49

  https://www.nhs.uk/conditions/alcohol-related-liver-disease-arld/

  Alcohol-related liver disease (ARLD) refers to liver damage caused by excess alcohol intake. […] The liver can develop new cells, but prolonged alcohol misuse (drinking too much) over many years can reduce its ability to regenerate. This can result in serious and permanent damage to your liver. […] Alcoholic hepatitis, which is unrelated to infectious hepatitis, is a potentially serious condition that can be caused by alcohol misuse over a longer period. […] The liver damage associated with mild alcoholic hepatitis is usually reversible if you stop drinking permanently. […] Cirrhosis is a stage of ARLD where the liver has become significantly scarred. Even at this stage, there may not be any obvious symptoms. […] It’s generally not reversible, but stopping drinking alcohol immediately can prevent further damage and significantly increase your life expectancy.

• #50 How alcohol affects the liver

  https://www2.hse.ie/living-well/alcohol/health/effects-on-your-body/the-liver/

  If you have significant liver scarring or cirrhosis, do not drink alcohol. […] Fatty liver can be reversed and further damage avoided by not drinking alcohol. […] There is no cure for cirrhosis. But cutting out alcohol completely gives a much better chance of survival. You can live for decades with cirrhosis, if you give up alcohol in time.

• #51 Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/1422-0067/22/10/5170

  Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. […] Although there is a clear correlation between the amount and duration of alcohol intake and ALD progression, it is postulated that other co-factors (e.g., genetic, epigenetic, and environment factors) also play a role in ALD development, as only 10–20% of individuals with chronic alcohol use will progress to advanced ALD. […] The underlying molecular mechanisms responsible for ALD development include direct ethanol hepatotoxicity and lipid peroxidation, oxidative stress and ROS production, immune response activation and cytokine accumulation, and hepatic metabolism disorder.

• #52 Pathogenesis of alcohol-associated liver disease – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-alcohol-associated-liver-disease

  Pathogenesis of liver disease associated with alcohol ingestion is incompletely understood. What is known is that some patients with alcohol use disorder develop liver disease, primarily because the liver metabolizes the majority of ingested ethanol. Furthermore, the metabolism of ethanol is required for hepatic injury to occur, although variations in ethanol metabolism do not completely explain the variable susceptibility to alcohol-associated liver disease. […] This topic will focus on the following issues related to risk of alcohol-associated liver disease: […] Mechanisms that may be responsible for the development of liver disease.

• #53 Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/1422-0067/22/10/5170

  The genetic impact on alcohol use disorder (AUD) and ALD development was elucidated in previous studies, as individual variation exists after chronic alcohol consumption. […] Several genome-wide association studies (GWAS) have identified several genetic risk loci for ALD development, including Patatin-like phospholipase domain-containing-3 (PNPLA3) gene, which is the major risk factor for the progression of ALD. […] Epigenetics refers to a process that changes the gene activity without DNA sequence alteration, such as DNA methylation, histone modification, or RNA silencing by microRNAs (miRNAs). […] The ongoing metabolism of ethanol produces excessive ROS and depletes glutathione, diverting the reaction from the production of methionine and S-adenosylmethionine (SAM), which is the predominant methyl donor in DNA methylation.

• #54

• #55 Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/1422-0067/22/10/5170

  The genetic impact on alcohol use disorder (AUD) and ALD development was elucidated in previous studies, as individual variation exists after chronic alcohol consumption. […] Several genome-wide association studies (GWAS) have identified several genetic risk loci for ALD development, including Patatin-like phospholipase domain-containing-3 (PNPLA3) gene, which is the major risk factor for the progression of ALD. […] Epigenetics refers to a process that changes the gene activity without DNA sequence alteration, such as DNA methylation, histone modification, or RNA silencing by microRNAs (miRNAs). […] The ongoing metabolism of ethanol produces excessive ROS and depletes glutathione, diverting the reaction from the production of methionine and S-adenosylmethionine (SAM), which is the predominant methyl donor in DNA methylation.

• #56

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

  Alcohol-associated steatohepatitis (ASH), a severe form of alcohol-associated liver disease (ALD), is characterized by pronounced steatosis and immune cells infiltration. […] This study aimed to investigate the alteration of RNA modification in ASH and its specific roles in regulating immune homeostasis. […] 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 Alcohol and hepatocellular carcinoma | BMJ Open Gastroenterology

  https://bmjopengastro.bmj.com/content/6/1/e000260

  Acetaldehyde has been shown to be a carcinogen in animal studies. With regard to direct DNA mutagenic mechanisms, it has been reported that acetaldehyde increases the point mutation frequency in the hypoxanthine phosphoribosyltransferase (HPRT) gene in lymphocytes, and induces sister chromatid exchanges. […] The metabolism of ethanol through the CYP2E1-dependent pathway produces ROS. Subsequently, the increase of ROS results in the generation of lipid peroxidation products, such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE). […] Aberrant DNA methylation and protein methylation may play important roles in the development of various cancers, including HCC. In most cases, DNA methylation is associated with a decreased gene expression because of interference with the interaction of transcription factor and CpG islands of promoter lesions (usually unmethylated).

• #58 Pathogenesis of Alcoholic Liver Disease

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

  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. […] Alcohol affects multiple steps in methionine metabolism. S-adenosylmethionine (SAM) is the substrate for the methylation reaction. After donating the methyl group, SAM is converted to S-adenosylhomocysteine (SAH). […] Selective intestinal decontamination has been shown to improve liver hemodynamics in decompensated alcoholic cirrhosis. Rifaximin has been shown to improve thrombocytopenia (a marker of portal hypertension) and MELD in alcoholic cirrhosis through the reduction of endotoxemia. […] The IL1 receptor antagonist anakinra will be tested in the NIH consortium.

• #59

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

  Alcohol-associated steatohepatitis (ASH), a severe form of alcohol-associated liver disease (ALD), is characterized by pronounced steatosis and immune cells infiltration. […] This study aimed to investigate the alteration of RNA modification in ASH and its specific roles in regulating immune homeostasis. […] 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.

• #60 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.

• #61 Alcoholic liver disease: Symptoms, treatment, and causes

  https://www.medicalnewstoday.com/articles/215638

  Alcohol use speeds up the liver’s destruction, reducing the liver’s ability to compensate for the current damage. […] People who drink beer and liquor may be more likely to experience liver disease when compared with those who consume other alcoholic beverages, such as wine. […] Females are more susceptible to the negative effects of alcohol, even at the same levels of alcohol intake as males, so are more likely to quickly develop fibrosis, inflammation, and liver injury as a result of alcohol. […] Having hepatitis C increases the risk, and a person who consumes alcohol regularly and has had any type of hepatitis faces a higher chance of developing liver disease. […] The first step in treating any level of alcoholic liver disease focuses on removing alcohol from the diet. […] This can help to reverse some early stages of liver disease.

• #62 Pathogenesis of Alcoholic Liver Disease – RCEMLearning India

  https://www.rcemlearning.org/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.

• #63

• #64 Metabolic Alcoholic Liver Disease: 5 Things to Know

  https://www.medscape.com/viewarticle/metabolic-alcoholic-liver-disease-5-things-know-2025a1000a7e

  One subtype metabolic alcoholic liver disease (MetALD) is generally considered more concerning because of the increase in alcohol consumption. […] The term MetALD acknowledges the dual etiologic role of metabolic dysfunction and alcohol use in promoting liver damage. […] MetALD arises from the interaction between metabolic dysfunction and alcohol use. […] Alcohol metabolism increases the production of acetaldehyde, damaging liver cells while also inducing hepatic inflammation and fibrosis. […] This synergistic effect increases the risk for more severe liver outcomes, such as cirrhosis or hepatocellular carcinoma. […] Early recognition and differentiation of MetALD from pure ALD or MASLD are crucial to guiding treatment and preventing rapid disease progression or liver failure.

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

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

  Alcoholic liver disease (ALD) is characterized by a complex spectrum of histological lesions, ranging from steatosis to cirrhosis. […] ALD is characterized by oxidative stress, disturbance of hepatocyte metabolism, liver inflammation, modifications in the regeneration process and translocation of bacterial products from the gut microbiota into the portal blood stream. […] Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. […] For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. […] 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. […] This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.

• #66 Alcoholic liver disease: pathogenesis and new targets for therapy | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/nrgastro.2011.134

  Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. […] The basic mechanisms of alcoholic liver disease have been evaluated in both animal models and translational studies, but further research is needed to confirm the results. […] Studies in human liver samples have identified novel therapeutic targets for alcoholic liver disease, including CXC chemokines, osteopontin, tumor necrosis factor receptor superfamily member 12A receptor and nostrin. […] The pathogenetic roles of these targets, however, remain to be confirmed in animal models. […] This Review summarizes the epidemiology, natural history, risk factors and current knowledge of the pathogenetic mechanisms of ALD. […] The spectrum of alcoholic liver disease encompasses simple steatosis, steatohepatitis, progressive fibrosis, cirrhosis and hepatocellular carcinoma.

• #67 Alcohol-associated liver disease: Epidemiology and management | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-alcohol-associated-liver-disease-epidemiology-management-S166526812300265X

  Alcohol is the leading cause of preventable liver morbidity and mortality worldwide, as it is also the most frequent cause of advanced liver disease. Alcohol-associated liver disease (ALD) covers different phenotypes ranging from steatosis to the development of inflammation (steatohepatitis), fibrosis and ultimately, in a proportion of patients, the development of liver cirrhosis and its associated complications. ALD has a complex pathogenesis that includes the interplay of both genetic and environmental factors, yet the precise mechanisms are largely unknown. […] Currently, there are no approved targeted therapies able to interfere in the pathogenesis of ALD and halt the progression of the disease, therefore alcohol abstinence is the most effective measure to improve prognosis in this patient population.

• #68 Alcohol-associated liver disease: Epidemiology and management | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-alcohol-associated-liver-disease-epidemiology-management-S166526812300265X

  In this review, we provide an update on the epidemiology, risk factors, natural history, diagnosis, pathogenesis, and current treatments for ALD, taking into account the importance of assessing and managing alcohol consumption as the etiological factor and the main driver of prognosis in patients with ALD.

• #69 Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/1422-0067/22/10/5170

  The hypomethylation of DNA further facilitates hepatocyte proliferation and tumorigenesis. […] Alcohol-induced gut-liver axis dysfunction was initiated with an intestinal microbiome composition change and permeability increase, which stimulates bacterial translocation, LPS release, and endotoxemia. […] The strategy to reverse these processes may be achieved by intestinal decontamination. […] The administration of probiotic or antibiotic therapy is another potential approach for AH management. […] MicroRNA modulation has emerged as a novel and practical therapeutic approach for AH treatment. […] Mesenchymal stem cells (MSCs) can provide support to hematopoietic stem cells and initiate the hematopoiesis process, and they also play an important role in organ homeostasis in past studies. […] The implementation of MSCs can be an attractive strategy in ALD treatment if their survival rate and activity could be further enhanced in the future field of regenerative medicine.

• #70

  https://www.jci.org/articles/view/176345

  Alcohol misuse can cause a profound impairment of intestinal functions, including a disease called alcohol-associated bowel disease. […] Alcohol-mediated reduction of intestinal immune cells results in intestinal immune dysfunction and subsequently contributes to gut barrier disruption. […] The origin of the expanded cholangiocytes is controversial, and multiple origins have been proposed, including cholangiocyte proliferation, hepatic progenitor cell differentiation into cholangiocytes, and dedifferentiation of hepatocytes toward a cholangiocyte-like phenotype. […] Hepatocytes are rich in mitochondria, which play important roles in glucose, lipid, and protein metabolism as well as ROS homeostasis. […] Heavy alcohol consumption causes impairment of mitochondrial biogenesis, mitochondrial DNA damage, and subsequent oxidative stress and cell death. […] Over the last 20 years, many molecular mechanisms have been identified that may contribute to the pathogenesis of ALD, but translation of these mechanisms to therapeutic targets needs further attention.

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