Materiały źródłowe

• #1 Pathogenesis of liver cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4064077/

  Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. […] Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. […] Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. […] Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. […] Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. […] At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. […] Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.

• #2 Cirrhosis – Wikipedia

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

  Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced with scar tissue (fibrosis) and regenerative nodules as a result of chronic liver disease. Damage to the liver leads to repair of liver tissue and subsequent formation of scar tissue. Over time, scar tissue and nodules of regenerating hepatocytes can replace the parenchyma, causing increased resistance to blood flow in the liver’s capillaries the hepatic sinusoids and consequently portal hypertension, as well as impairment in other aspects of liver function. […] The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal tissue, which is normally organized into lobules. This scar tissue blocks the portal flow of blood through the organ, raising the blood pressure. This manifests as portal hypertension in which the pressure gradient between the portal circulation as compared to the systemic circulation is elevated. This portal hypertension leads to decreased sinusoidal flow from liver cells to nearby sinusoids in the liver, and increased lymph production with extravasation of lymph to the extracellular space, causing ascites. This also causes reduced cardiac return and central blood volume, which activates the renin-angiotensin system (RAAS) which causes kidneys to reabsorb sodium and water, causing water retention and further ascites. Activation of the RAAS also causes kidney vasoconstriction and may cause kidney injury.

• #3 Pathogenesis of liver cirrhosis

  https://www.wjgnet.com/1007-9327/full/v20/i23/7312.htm

  Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. […] Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis.

• #4 Cirrhosis – McMaster Pathophysiology Review

  https://www.pathophys.org/cirrhosis/

  Hepatic stellate cells (HSC) located in the space of Disse comprise 5-10% of hepatic cells. […] Parenchymal injury (acute or chronic) – apoptosis and/or necrosis of hepatocytes – phagocytosis of apoptotic cells and inflammation due to necrosis leads to activation of Kuppfer cells (sinusoidal macrophages), endothelial cells, platelets and leukocytes. […] Leukocytes lead to generation of lipid peroxides, reactive oxygen species and a number of cytokines (TGF beta, IL-1, TGF alpha, HGF, PDGF, and EGF). […] Stimulates regeneration of adjacent hepatocytes (HGF) ultimately contributing to nodule formation. […] Promote induction/expression of variety of cytokines/chemokines and receptors on neighbouring quiescent hepatic cells and activates them. […] Remodeling of matrix also leads to activation of nearby HSC.

• #5 Hepatic Cirrhosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482419/

  Cirrhosis is characterized by fibrosis and nodule formation of the liver secondary to chronic injury, leading to alteration of the normal lobular organization of the liver. […] After a chronic injury, most of the liver tissue becomes fibrotic, leading to loss of function and the development of cirrhosis. […] Multiple cells play a role in liver cirrhosis, including hepatocytes and sinusoidal lining cells such as hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs), and Kupffer cells (KCs). HSCs form a part of the wall of the liver sinusoids, and their function is to store vitamin A. When these cells are exposed to inflammatory cytokines, they get activated, transform into myofibroblasts, and start depositing collagen, which results in fibrosis. […] Hepatocytes are also involved in cirrhosis’s pathogenesis, as damaged hepatocytes release reactive oxygen species and inflammatory mediators that can promote activating HSCs and liver fibrosis.

• #6 Cirrhosis – Wikipedia

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

  Research has shown the pivotal role of the stellate cell, that normally stores vitamin A, in the development of cirrhosis. Damage to the liver tissue from inflammation leads to the activation of stellate cells, which increases fibrosis through the production of myofibroblasts, and obstructs hepatic blood flow. In addition, stellate cells secrete TGF beta 1, which leads to a fibrotic response and proliferation of connective tissue. TGF-1 have been implicated in the process of activating hepatic stellate cells (HSCs) with the magnitude of fibrosis being in proportion to increase in TGF levels. ACTA2 is associated with TGF pathway that enhances contractile properties of HSCs leading to fibrosis. Furthermore, HSCs secrete TIMP1 and TIMP2, naturally occurring inhibitors of matrix metalloproteinases (MMPs), which prevent MMPs from breaking down the fibrotic material in the extracellular matrix.

• #7 Cirrhosis – McMaster Pathophysiology Review

  https://www.pathophys.org/cirrhosis/

  The role of the activated hepatic stellate cell (AHSC) and myofibroblasts. […] Acquisition of the myofibroblast phenotype. […] HSC change phenotype from a quiescent vitamin A-rich phenotype to a myofibroblastic phenotype (AHSC). […] Though derived from two distinct cell populations, the phenotypic and functional properties of both types of myofibroblasts are grossly similar. […] AHSC show de novo fibrogenic properties. […] Proliferation and accumulation of AHSC in areas of parenchymal necrosis due to high mitogenic capacity. […] Enhanced ability to escape apoptosis (TNF alpha and TGF beta, matrix components). […] Chemotaxis to site of injury via chemokines and growth factors. […] Secretion of proinflammatory cytokines and chemokines. […] Synthesis of a large panel of matrix proteins and inhibitors of matrix degradation.

• #8 Pathogenesis of liver cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4064077/

  KCs are involved in the activation of HSCs and formation of fibrosis. […] Hepatocyte apoptosis is a common event in liver injury and contributes to tissue inflammation, fibrogenesis, and development of cirrhosis. […] In the last fibrotic stage or cirrhosis, hypoxic hepatocytes become a predominant source of TGF-1, further exacerbating hepatic fibrogenesis. […] The pro-fibrogenesis effect of TGF-1 is complicated, involving multiple aspects: the primary effect of TGF-1 is to stimulate activation of HSCs, and the TGF-1 autocrine loop in activated HSCs is an important positive feedback to the progression of liver fibrosis. […] Given the critical role of TGF-1 in the pathogenesis of liver cirrhosis, specific blockade of TGF-1/Smad3 signaling has shown some therapeutic value for liver fibrosis. […] In summary, the etiology of cirrhosis is multifactorial and the mechanisms underlying pathogenesis of cirrhosis are far from being clarified.

• #9 Pathogenesis of liver cirrhosis

  https://www.wjgnet.com/1007-9327/full/v20/i23/7312.htm

  In the last fibrotic stage or cirrhosis, hypoxic hepatocytes become a predominant source of TGF-1, further exacerbating hepatic fibrogenesis. […] It is now thought that miRNAs can serve as biomarkers for HSC activation and liver fibrosis progression, and may represent therapeutic targets for hepatic fibrosis and cirrhosis.

• #10 Pathogenesis of liver cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4064077/

  Fibrosis as a precursor of cirrhosis is a pivotal pathological process in the evolution of all chronic liver diseases to cirrhosis. […] Thus, a better understanding of the pathogenesis of liver cirrhosis would facilitate the development of more effective treatment options. […] HSC activation is a pivotal event in initiation and progression of hepatic fibrosis and a major contributor to collagen deposition. […] Activation of HSCs is characterized by cell proliferation and migration, contraction after transforming into myofibroblasts, generation of a large amount of collagen and other extracellular matrix (ECM), ultimately leading to liver fibrosis. […] Defenestration and capillarization of the hepatic endothelium are believed to be important in the initiation of perisinusoidal fibrosis by altering retinol metabolism.

• #11 Pathogenesis of liver cirrhosis

  https://www.wjgnet.com/1007-9327/full/v20/i23/7312.htm

  HSC activation is a pivotal event in initiation and progression of hepatic fibrosis and a major contributor to collagen deposition. […] Defenestration and capillarization of the hepatic endothelium are believed to be important in the initiation of perisinusoidal fibrosis by altering retinol metabolism. […] Studies in animals and humans have revealed that LSECs can secrete the cytokine IL-33 to activate HSCs and promote fibrosis. […] Hepatocyte apoptosis is a common event in liver injury and contributes to tissue inflammation, fibrogenesis, and development of cirrhosis. […] Hepatocytes are the major sources of matrix metalloproteinases (MMP-2, MMP-3 and MMP-13) and tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2); all of which are involved in the pathogenesis of liver cirrhosis in CCl4-induced liver cirrhosis in rats.

• #12 Cirrhosis – McMaster Pathophysiology Review

  https://www.pathophys.org/cirrhosis/

  There is a quantitative change in expression and maintenance of different types of collagen. […] In cirrhosis the balance shifts to a predominance of type I and III collagen (fibril forming) within the space of Disse – these types cross-link into collagen bundles which build up a network resistant to fibrolysis. […] Leads to a remodeling to a fibrotic matrix. […] The fenestrated endothelia that line the hepatic sinusoids are lost (sinusoidal capillarization) due to fibrosis in the space of Disse which increases intrahepatic resistance and contributes to portal hypertension. […] The AHSC shift balance to fibrosis by synthesizing fibrotic matrix proteins and components that inhibit fibrosis degradation. […] The resultant vascular distortion leads to an alteration of the relationship between vascular structures which compromises exchange between hepatic sinusoids and adjacent parenchyma.

• #13 Cirrhosis pathophysiology – wikidoc

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

  The role of hepatic stellate cells in the pathogenesis of cirrhosis is described below: Kupffer cells are hepatic macrophages responsible for hepatic stellate cell activation during injury. […] Activated HSC induce the production of numerous cytokines and their receptors, such as platelet-derived growth factor (PDGF) and TGF-f31, which are responsible for fibrogenesis. […] The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, through a process called capillarization. […] Stellate cell activation leads to disturbance of the balance between matrix metalloproteinases and the naturally occurring inhibitors (TIMP 1 and TIMP2). […] Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. […] The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function.

• #14 Cirrhosis – McMaster Pathophysiology Review

  https://www.pathophys.org/cirrhosis/

  Hepatic stellate cells (HSC) located in the space of Disse comprise 5-10% of hepatic cells. […] Parenchymal injury (acute or chronic) – apoptosis and/or necrosis of hepatocytes – phagocytosis of apoptotic cells and inflammation due to necrosis leads to activation of Kuppfer cells (sinusoidal macrophages), endothelial cells, platelets and leukocytes. […] Leukocytes lead to generation of lipid peroxides, reactive oxygen species and a number of cytokines (TGF beta, IL-1, TGF alpha, HGF, PDGF, and EGF). […] Stimulates regeneration of adjacent hepatocytes (HGF) ultimately contributing to nodule formation. […] Promote induction/expression of variety of cytokines/chemokines and receptors on neighbouring quiescent hepatic cells and activates them. […] Remodeling of matrix also leads to activation of nearby HSC.

• #15 Pathogenesis of liver cirrhosis

  https://www.wjgnet.com/1007-9327/full/v20/i23/7312.htm

  Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions. […] Although the causes of liver cirrhosis are multifactorial, there are some pathological characteristics that are common to all cases of liver cirrhosis, including degeneration and necrosis of hepatocytes, and replacement of liver parenchyma by fibrotic tissues and regenerative nodules, and loss of liver function. Fibrosis as a precursor of cirrhosis is a pivotal pathological process in the evolution of all chronic liver diseases to cirrhosis. […] Thus, a better understanding of the pathogenesis of liver cirrhosis would facilitate the development of more effective treatment options.

• #16 Liver Fibrosis Leading to Cirrhosis: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/2227-9059/12/10/2229

  Liver fibrosis is the pathological deposition of extracellular matrix rich in fibrillar collagen within the hepatocytes in response to chronic liver injury due to various causes. […] Multiple pathophysiological mechanisms and cell types are responsible for the progression of liver fibrosis and cirrhosis. Hepatic stellate cells and myofibroblast activation represent a key event in fibrosis. […] The progression towards cirrhosis involves many pathophysiologic mechanisms including liver inflammation, fibrogenesis, and angiogenesis. […] Hepatic endothelial dysfunction is the primary driver of increased hepatic portal pressure, the main mechanism for many of the complications seen in cirrhosis. […] The origin of fibrogenesis involves the interplay of various cell types. Hepatic stellate cells (HSCs) are considered the primary source of extracellular matrix (ECM) in liver fibrosis.

• #17 Cirrhosis – McMaster Pathophysiology Review

  https://www.pathophys.org/cirrhosis/

  Produce metalloproteinases (MMP) and MMP activators as well as tissue inhibitors of MMPs (TIMPS). […] Early on – express MMP but not TIMP – normal matrix is degraded and replaced with fibrillar collagen. […] Later on – do not express MMP but express TIMP – dramatic reduction in collagenolytic activity within liver. […] Eventually lead to progressive fibrosis and scar formation. […] Fibrosis is the net deposition of excess extracellular matrix (ECM) arising from an imbalance between hepatic fibrogenesis and fibrinolysis leading to replacement of injured tissue by a collagenous scar. […] Liver fibrosis results from the perpetuation of the normal wound healing response resulting in an abnormal continuation of fibrogenesis (connective tissue production and deposition). […] Fibrosis progresses at variable rates depending on the cause of liver disease, environmental factors, and host factors.

• #18 CIRRHOSIS part 1: Applied aspects, Basics, Etiology and Pathogenesis – Pathology Made Simple

  https://ilovepathology.com/cirrhosis-part-1-applied-aspects-basics-etiology-and-pathogenesis/

  II. Healing Following inflammation there is healing. Unlike in most other organs the liver tends to heal by two mechanisms- regeneration and repair Following inflammation initially the liver tends to regenerate. With time however it shifts healing towards the repair and starts laying down collagen (fibrosis). […] Fibrosis first begins in Space of Disse and is initiated by Ito cells. These cells under the influence of inflammatory mediators transform into hepatic stellate cells which lay down collagen. The collagen is laid down between the central vein and portal triads and eventually between the portal triads themselves. […] Result 1. The collagen in the space of Disse forms a physical barrier between the hepatocytes and the sinusoids and closes off exchange between the two. This prevents: nutrients from reaching the hepatocytes -causing hepatic synthetic and metabolic function derangement and hepatocyte death and dysfunction hepatocytes from releasing important materials into sinusoids- like albumin and coagulation factors- leading to their deficiency hepatocytes picking substances from blood that are normally metabolised by them ammonia, drugs, oestrogen and inhibiting their metabolism and leading to accumulation of such substances in the body producing the clinical features. 2. The process of damage, and fibrosis continues. The surviving hepatocytes attempt regeneration. The result is extensive bands of scar tissue (collagen) within the liver interspersed by the regenerative nodules created by the surviving hepatocytes.

• #19 Hepatic Cirrhosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482419/

  The major cause of morbidity and mortality in cirrhotic patients is the development of portal hypertension and hyperdynamic circulation. Portal hypertension develops secondary to fibrosis and vasoregulatory changes intrahepatically and systematically, leading to collateral circulation formation and hyperdynamic circulation. […] In patients with cirrhosis, there is an increase in ET-1 production and the sensitivity of its receptors with a decrease in NO production. This leads to increased intrahepatic vasoconstriction and resistance, initiating portal hypertension. […] Thus, in cirrhosis with portal hypertension, there is a depletion of vasodilators (predominantly NO) intrahepatic-ally but a renin-excess of NO extrahepatically in the splanchnic and systemic circulation, leading to sinusoidal vasoconstriction and splanchnic (systemic) vasodilation.

• #20 CIRRHOSIS part 1: Applied aspects, Basics, Etiology and Pathogenesis – Pathology Made Simple

  https://ilovepathology.com/cirrhosis-part-1-applied-aspects-basics-etiology-and-pathogenesis/

  Due to presence of extensive fibrosis, the surviving hepatocytes are unable to recreate the original architecture. […] The entire liver loses its lobular architecture and becomes composed of small nodules either small( micronodular) or big ( macronodular 3mm in diameter) […] 3. The regenerative nodules do not have the correct arrangement of the portal triad and the central vein. This results in hampering of proper blood flow and bile flow through the liver. 4. The resistance to blood flow in the distorted vessels put a backward pressure on the portal vein. The portal vein dilates (Portal Hypertension). […] 5. The pressure experienced by the portal vein is transmitted to its tributaries leading to congestion of spleen (Congestive splenomegaly) and intestines (dysfunction)

• #21 Cirrhosis – McMaster Pathophysiology Review

  https://www.pathophys.org/cirrhosis/

  There is obliteration of portal and/or hepatic veins due partly to intraluminal thrombosis, intimal thickening and inflammation which leads to hypoxia, then ischemia and finally parenchymal extinction (loss of liver cell plates and accompanying sinusoids). […] Subsequent angiogenesis contributes to the arterialization at the level of portal tracts with increased formation of de novo intra-hepatic arterio-venous shunts which effectively bypass the parenchyma. […] Blood flows preferentially through these vascular channels due to the relative low resistance of these shunts and leaves the remainder of the hepatic parenchyma almost bereft of meaningful blood flow which leads to hepatocyte dysfunction.

• #22 Pathogenesis of liver cirrhosis

  https://wjgnet.com/1007-9327/abstract/v20/i23/7312.htm

  Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. […] Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.

• #23 Fibrosis and hepatic regeneration mechanism – Zuñiga-Aguilar – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/5977/html

  The activation of HSC constitutes the cornerstone of the pathogenesis in hepatic fibrosis when they differentiate between contractile, proliferative and fibrogenic cells, producing extracellular matrix in excess, in the cirrhotic patient. The key mediators in the activation of stellate liver cells include a series of cytokines, reactive oxygen intermediates and other paracrine and autocrine signals. […] Significant progress has been made in understanding the molecular aspects of liver cirrhosis. The detailed understanding of this mechanism would be the basis for investigating the therapeutic possibilities in the reversion of fibrogenesis. The cellular and molecular regulation of hepatic fibrosis provides an explanation of the possible reversibility of the process. […] The process of hepatic fibrosis is not yet fully understood, during the last years the continuous studies about its cellular and molecular biology have allowed to understand many details related to its physiopathogenesis.

• #24 Pathogenesis of Alcoholic Liver Disease – RCEMLearning

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

  Acetaldehyde concentration is increased in the liver with sustained alcohol intake resulting in hepatocytes becoming susceptible to hypoxia and hypoxic injury. […] Oxygen free radicals cause injury to hepatocytes by lipid peroxidation. […] 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. […] 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). […] Hepatitis C infection and alcohol have an additive effect together.

• #25 Pathogenesis of Alcoholic Liver Disease – RCEMLearning

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

  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. […] Hepatitis C and ALD also increases the chance of developing hepatocellular carcinoma significantly. […] Development of ALD is mutifactorial and includes sex, hepatitis infections and genetics. […] 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.

• #26 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

  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).

• #27 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 metabolite of ethanol, acetaldehyde, is highly toxic and can readily undergo crosslinking with DNA or protein macromolecules in mitochondria. […] Excessive ROS can alter the function of glutathione (GSH) transporter channels, leading to progressive GSH deficiency in mitochondria and inactivation of oxidative phosphorylase, resulting in an irregular mitochondrial shape, decreases in mitochondrial protein synthesis, and altered ATP production in mitochondria. […] Ethanol can trigger the ER stress response, which is followed by the stimulation of apoptosis-related gene expression, cell proliferation, and apoptosis imbalance. […] The intake of a large amount of ethanol induces the expression of ASS, which enzymatically activates the nitrification stress response and apoptosis in liver cells.

• #28 Liver Fibrosis Leading to Cirrhosis: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/2227-9059/12/10/2229

  Myofibroblasts are a major contributor to ECM deposition. […] Liver sinusoidal endothelial cells (LSECs) are specialized cells lining the liver’s sinusoidal capillaries. […] Pathological angiogenesis driven by VEGF increases the stiffness of the liver microenvironment, further activating HSCs through mechanotransduction pathways. […] A key component in the pathogenesis of liver fibrosis is inflammation. […] Interactions between the various immune cells play a significant role in the pathogenesis of liver fibrosis. […] Metabolic factors such as non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome have also been linked to fibrosis. […] Extracellular matrix (ECM) remodeling is the hallmark of liver fibrosis. […] Recent studies have also demonstrated the role of epigenetic modifications, such as DNA methylation, histone modification, and non-coding RNAs in the regulation of gene expression in fibrosis.

• #29 Cirrhosis – Pathogenesis & Clinical Manifestations – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/cirrhosis-pathogenesis-clinical-manifestations

  Cirrhosis is the result of long-term liver damage, where normal liver tissue is replaced by scar tissue (fibrosis). This scarring is mainly caused by activation of liver stellate cells in the perisinusoidal space. Upon injury, these cells transform into myofibroblasts, which produce excess collagen, leading to a greater fibrous extracellular matrix in place of normal liver tissue. In response to injury, new hepatocytes are created by liver stem cells that form regenerative nodules surrounded by bands of fibrosis. As fibrosis becomes widespread, the sinusoids are compressed, leading to increased intrasinusoidal pressure and complications such as portal hypertension. […] Portal hypertension is a common complication of cirrhosis, resulting from increased intrasinusoidal pressure due to widespread fibrosis and compression of sinusoids. This elevated pressure in the portal venous system can lead to various complications such as esophageal and gastric varices, hemorrhoids, and engorged paraumbilical veins known as caput medusae. Portal hypertension also causes splenomegaly and splenic dysfunction, which can result in thrombocytopenia due to sequestration of platelets in the spleen.

• #30 Pathogenesis of ascites in patients with cirrhosis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-ascites-in-patients-with-cirrhosis

  Pathogenesis of ascites in patients with cirrhosis […] The development of ascites is the final consequence of a series of anatomic, pathophysiologic, and biochemical abnormalities occurring in patients with cirrhosis. […] However, the most recent theory, the arterial vasodilation hypothesis, appears to match best with the actual hemodynamic data and has become the most widely accepted theory. […] The formation of ascites is governed by the same principles as edema formation at other sites: net capillary permeability and the hydraulic and oncotic pressure gradients. […] Gut lymphatics may play a more important role than previously recognized. […] The development of portal hypertension (PHT) is the first step toward fluid retention in the setting of cirrhosis. […] A portal pressure >12 mmHg appears to be required for fluid retention; on the other hand, ascites will usually disappear if portal pressure is reduced below 12 mmHg. […] Sinusoidal hypertension appears to be required for fluid retention to occur; presinusoidal portal hypertension, as in portal vein thrombosis, does not result in ascites formation in the absence of another predisposing factor.

• #31 Pathophysiology, diagnosis and treatment of ascites in cirrhosis | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-pathophysiology-diagnosis-treatment-ascites-in-S1665268119321787

  The mechanism by which ascites develops in cirrhosis is multifactorial Severe sinusoidal portal hypertension and hepatic insufficiency are the initial factors. They lead to a circulatory dysfunction characterized by arterial vasodilation, arterial hypotension, high cardiac output and hypervolemia and to renal sodium and water retention. […] There are evidences that arterial vasodilation in cirrhosis occurs in the splanchnic circulation and is related to an increased synthesis of local vasodilators. Vascular resistance is normal or increased in the remaining major vascular territories (kidney, muscle and skin and brain). […] The rapid and high inflow of arterial blood into the splanchnic microcirculation is the main factor increasing hydrostatic pressure in the splanchnic capillaries leading to an excessive production of splanchnic lymph over lymphatic return. Lymph leakage from the liver and other splanchnic organs is the mechanism of fluid accumulation in the abdominal cavity. Continuous renal sodium and water retention perpetuates ascites formation.

• #32 Cirrhosis – Pathogenesis & Clinical Manifestations – Free Sketchy Medical Lesson

  https://www.sketchy.com/medical-lessons/cirrhosis-pathogenesis-clinical-manifestations

  In cirrhosis, fibrosis disrupts the liver’s ability to detoxify the blood. The thickened extracellular matrix and narrowed openings in the liver’s blood vessels, or sinusoids, limit the exchange of substances between the blood and liver cells. One consequence is that the liver becomes less efficient at converting ammonia into less toxic forms through the urea cycle, leading to elevated levels of ammonia in the blood. High ammonia levels can penetrate the blood-brain barrier and result in hepatic encephalopathy, which may manifest as cognitive changes, seizures, or even death.

• #33 Hepatic Encephalopathy: Definition, Pathogenesis, Clinical Features of Hepatic Encephalopathy

  https://emedicine.medscape.com/article/186101-overview

  A number of theories have been proposed to explain the development of hepatic encephalopathy in patients with cirrhosis. Some investigators contend that hepatic encephalopathy is a disorder of astrocyte function. Astrocytes account for about one third of the cortical volume. They play a key role in the regulation of the blood-brain barrier. They are involved in maintaining electrolyte homeostasis and in providing nutrients and neurotransmitter precursors to the neurons. They also play a role in the detoxification of a number of chemicals, including ammonia. […] It is theorized that neurotoxic substances, including ammonia and manganese, may gain entry into the brain in the setting of liver failure. These neurotoxic substances may then contribute to morphologic changes in the astrocytes. In cirrhosis, astrocytes may undergo Alzheimer type II astrocytosis. Here, astrocytes become swollen. They may develop a large pale nucleus, a prominent nucleolus, and margination of chromatin. In ALF, astrocytes may also become swollen. The other changes of Alzheimer type II astrocytosis are not seen in ALF. But, in contrast to cirrhosis, astrocyte swelling in ALF may be so marked as to produce brain edema. This may lead to increased intracranial pressure and, potentially, brain herniation.

• #34 Molecular Mechanism Contributing to Malnutrition and Sarcopenia in Patients with Liver Cirrhosis

  https://www.mdpi.com/1422-0067/21/15/5357

  Liver cirrhosis is frequently accompanied by disease-related malnutrition (DRM) and sarcopenia, defined as loss of skeletal muscle mass and function. […] The concise pathophysiological mechanisms and interactions of DRM and sarcopenia in liver cirrhosis are not completely understood. […] The mechanisms of DRM and sarcopenia in liver cirrhosis are multifactorial, complex and not completely understood. […] Leading to muscle depletion, sarcopenia in liver cirrhosis is affected by DRM, alterations in protein turnover, energy disposal, hormonal and metabolic changes, increased myostatin expression, reactive oxygen species and inflammatory cytokines. […] Although the pathogenesis of sarcopenia in liver cirrhosis is poorly understood, a number of proposed mechanisms have been previously described representing an imbalance between muscle breakdown and formation.

• #35 Molecular Mechanism Contributing to Malnutrition and Sarcopenia in Patients with Liver Cirrhosis

  https://www.mdpi.com/1422-0067/21/15/5357

  In liver cirrhosis, decreased energy intake further aggravates impaired muscle biosynthesis and increased muscle proteolysis caused by low glycogen stores resulting in an increased need for gluconeogenesis. […] The best characterized factor contributing to sarcopenia in liver cirrhosis is hyperammonemia. […] Hyperammonemia mediates the activation of p65-nuclear factor kappa B (NF-kB) which is associated with the transcriptional upregulation and increased expression of myostatin. […] Myostatin is a transforming growth factor beta (TGF-β) superfamily member and a critical autocrine/paracrine inhibitor of skeletal muscle growth and mass. […] In liver cirrhosis, hyperammonemia is associated with increased muscle autophagy, too, probably explaining why hepatic encephalopathy is more frequent in sarcopenic than non-sarcopenic cirrhotic patients.

• #36

  https://www.jci.org/articles/view/111873

  Insulin resistance in liver cirrhosis may depend on either reduced sensitivity (receptor defect) and/or reduced response to insulin (postreceptor defect). […] These results suggest that insulin resistance in human cirrhosis is more dependent on depressed peripheral glucose use than on increased endogenous glucose production, and that a combined receptor and postreceptor defect in insulin action on target cells seems to be present.

• #37 A Study on the Mechanism of Anemia and Leukopenia in Liver Cirrhosis

  https://www.jstage.jst.go.jp/article/internalmedicine1962/27/2/27_2_155/_article

  To elucidate the mechanism of anemia and leukopenia in the patients with liver cirrhosis, we investigated hematopoietic progenitor cell contents in their bone marrow, and the effects of their sera and blood mononuclear cells on hematopoietic progenitors from normal subjects. […] the number of marrow CFU-C was significantly reduced in liver cirrhosis patients. […] Patients’ sera suppressed in vitro colony formation of normal CFU-E, BFU-E, and CFU-C, and the degree of suppression was well correlated with severity of anemia or granulocytopenia. […] These results indicate that the appearance of humoral inhibitor(s) of hematopoietic progenitors plays a role in the development of anemia and granulocytopenia in liver cirrhosis.

• #38 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.

• #39 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. […] Ethanol exposure results in the loss of epithelial cells at the tip of intestinal villi. […] 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. […] The physical interaction between ethanol and intestinal microbes may be a key reason for the ethanol-driven alteration in the intestinal flora contents. […] Ethanol treatment significantly alters bile acid homeostasis and the composition of the BA pool in FXR-KO mice. […] Chronic ethanol exposure inactivates FXR by increasing the acetylation of FXR and interrupting the interaction between FXR and RXR. […] Ethanol modulates bile acid synthesis in the liver through the FXRFGF15 axis.

• #40 Pathophysiology of liver cirrhosis and risk correlation between immune status and the pathogenesis of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2024.141

  Chronic liver disease (CLD) and cirrhosis are leading contributors to global morbidity and mortality, with hepatocellular carcinoma (HCC) frequently arising in patients with advanced liver damage. This review explores the interplay between immune dysfunction and the progression of cirrhosis to HCC, emphasizing the pivotal role of immune status in HCC pathogenesis. Chronic inflammation, cirrhosis-associated immune dysfunction syndrome (CAIDS), and immunosenescence create a permissive environment for tumorigenesis by impairing immune surveillance and promoting hepatocyte stress. Key mechanisms include T cell exhaustion, dysregulated cytokine signaling, and gut-liver axis dysfunction, which collectively drive malignant transformation. […] Emerging evidence suggests that immune dysfunction plays a pivotal role in the progression of liver cirrhosis and the development of HCC. Cirrhosis-associated immune dysfunction syndrome (CAIDS) is characterized by systemic inflammation and impaired immune surveillance, creating an environment conducive to malignant transformation. Chronic inflammation, mediated by dysregulated cytokines and immune cell exhaustion, drives hepatocyte stress and genetic alterations that promote tumorigenesis.

• #41 Pathophysiology of liver cirrhosis and risk correlation between immune status and the pathogenesis of hepatocellular carcinoma

  https://www.oaepublish.com/articles/2394-5079.2024.141

  The progression of CLD, whether due to viral hepatitis, alcohol consumption, MASLD, or other risk factors, typically follows one of two distinct pathways: one leading to HCC and the other to cirrhosis. Cirrhosis, though primarily a structural disorder marked by fibrotic nodules, is heavily influenced by the persistent inflammatory signals and immune deviations that characterize advanced liver disease. Apoptotic hepatocytes release DAMPs, which sustain inflammation and stimulate HSCs. Over time, cumulative genetic and epigenetic insults lead to dysplastic nodules and eventual malignant transformation. […] In cirrhosis, immune paralysis or CAIDS impairs immune surveillance, fostering a microenvironment conducive to tumorigenesis. Structural changes in cirrhosis, including vascular distortion and sinusoidal capillarization, combined with chronic inflammation, drive hepatocellular stress, epigenetic modifications, and DNA damage, further accelerating HCC development.

• #42 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230928/Study-uncovers-previously-unknown-compensatory-mechanism-in-liver-disease.aspx

  A team of researchers has uncovered a previously unknown compensatory mechanism found in liver disease. […] Researchers from the Cumming School of Medicine at the University of Calgary and Charit Universitätsmedizin Berlin have observed for the first time how the liver preserves its bacterial filtration function even in the presence of disease. […] In severe disease, especially chronic liver disease, damage to the liver causes a buildup of scar tissue known as fibrosis, which impairs the organ’s function. […] One of their primary aims was to improve treatment options in the future for patients with liver fibrosis. […] Heavy alcohol consumption and fatty liver disease are the main causes of liver fibrosis and its final stage, cirrhosis. […] Using an innovative microscopy technique that makes it possible to observe cellular functions in detail in a living organism and other microscopy techniques, the researchers closely studied the functioning of Kupffer cells in the animal model and in tissue samples taken from patients with liver cirrhosis.

• #43 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230928/Study-uncovers-previously-unknown-compensatory-mechanism-in-liver-disease.aspx

  These are a kind of giant cells larger, multinucleated clusters of cells formed out of immune cells originating in the bone marrow that have traveled to the scene in response. […] The newly formed KC-like syncytia take over the filtration function of the actual Kupffer cells from then on. […] The researchers describe the molecular mechanisms involved in these processes in their work. […] „These findings change the way we think about the role of the immune system in liver fibrosis,” says Kubes, the head of the study. […] Instead of suppressing immune function in advanced disease, it could even be a good idea to promote it. […] The study was performed at three large liver transplantation centers. […] As a result, these discoveries raise fundamental questions for the treatment of patients with fibrotic liver disease.

• #44 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230928/Study-uncovers-previously-unknown-compensatory-mechanism-in-liver-disease.aspx

  „We suspect that the liver preserves its function up to a certain level of damage by recruiting the KC-like syncytia. […] Ultimately, formation of scar tissue in the liver is also an evolutionarily advantageous mechanism by which a damaged organ ensures survival. […] The current study contributes to an improved understanding of how the body’s most important microbial filter functions as liver disease emerges which could be a basis for developing innovative treatments. […] Supporting this process could help protect patients, since improved microbial filtration function lowers the risk of death from liver cirrhosis and can delay the time of transplantation, which is currently the only treatment option available.

• #45 Why do we use non-selective beta-blockers in cirrhosis? – Part 1 | AASLD

  https://www.aasld.org/liver-fellow-network/core-series/why-series/why-do-we-use-non-selective-beta-blockers-cirrhosis

  Beta blockers were first developed by Sir James Black after the sudden death of his father from a heart attack when he was in medical school. His goal was to stop the effects of adrenaline on the heart and improve chest pain. The first beta blocker was propranolol, which is nonselective. […] Nonselective means that it has a similar affinity for both B1 and B2 receptors and some affinity for B3 as well. With the development of new cardioselective beta blockers such as metoprolol, propranolol went out of favor. However, the nonselective nature of these beta blockers is what makes them perfect for management of portal HTN. B1 receptors are located in the cardiac muscle, and blocking it will result in a decrease in cardiac output. B2 is located in the splanchnic vessels and blocking it will leave a1 receptors unopposed, resulting in splanchnic vasoconstriction. The latter is actually much more important for decreasing portal pressure compared to the B1 effect.

• #46 Why do we use non-selective beta-blockers in cirrhosis? – Part 1 | AASLD

  https://www.aasld.org/liver-fellow-network/core-series/why-series/why-do-we-use-non-selective-beta-blockers-cirrhosis

  The first study showing the effect of NSBBs on portal HTN in patients with cirrhosis dates back to 1980, in a study by Lebrec et al. which showed propranolol is able to decrease the portal pressure in patients with variceal hemorrhage. […] Following this study, multiple trials showed benefits of NSBBs in primary and secondary prevention. […] A newer NSBB is carvedilol, which has the additional benefit of inhibiting a1 receptors by which it can result in intrahepatic vasodilation, thus decreasing intrahepatic vascular resistance and bringing down the portal pressure even further. […] Although based on the guidelines, patients can be started on NSBBs or banded, there is significant evidence that NSBBs do much more than just preventing variceal bleeding. In patients with varices, prevention of decompensation should be the ultimate goal, and the most common decompensation is actually development of ascites (not variceal bleed). NSBBs work by decreasing portal pressure and thus preventing decompensation (both development of ascites and/or VB), whereas ligation is only a local treatment and does not alter the progression of the disease.

• #47

  https://journals.lww.com/hepcomm/fulltext/2023/11010/lactulose_in_cirrhosis__current_understanding_of.6.aspx

  Lactulose reverses minimal HE, prevents overt HE, improves quality of life, increases the rate of recovery from overt HE, and improves survival rates. […] Lactulose’s clinical effect appears to be derived from its impact on intestinal microbes, likely a result of its pH-lowering effect, positive pressure on beneficial taxa, and improvement of gut barrier function. […] While the literature is not uniform on its actions, it appears that lactulose’s benefits in HE are mediated through changes in intestinal microbes, likely a result of its pH-lowering effect, positive pressure on beneficial taxa, and an improvement in gut barrier function. […] In 1969, Haemmerli and Bircher wrote the exciting aspect of lactulose therapy, however, is its mechanism of action. Once completely elucidated, it may shed new light on the pathogenesis of hepatic coma. Nearly half a century later, we have a better understanding of lactulose’s mechanism of action, but the picture is still not complete.

• #48 Liver Fibrosis Leading to Cirrhosis: Basic Mechanisms and Clinical Perspectives

  https://www.mdpi.com/2227-9059/12/10/2229

  The primary mechanisms of morbidity due to the complications of cirrhosis are increased hepatic resistance and the development of hyperdynamic circulatory alterations. […] The increase in hepatic resistance is driven mainly by anatomical disruptions caused by fibrosis in advanced liver disease and by functional alterations such as endothelial dysfunction. […] Several clinical and experimental studies have shown that liver fibrosis is reversible upon removal of the etiological source. […] However, evidence now shows that HSCs can revert to an inactivated phenotype. […] The exact moment when liver fibrosis becomes irreversible is still unknown.

• #49 “The pathogenesis of hepatic fibrosis: basic facts and clinical challenges”—assessment of liver fibrosis: a narrative review – Brol – Digestive Medicine Research

  https://dmr.amegroups.org/article/view/8412/html

  Liver biopsy is the gold standard of liver fibrosis assessment. […] With upcoming treatment options for chronic liver diseases, the histopathological assessment of liver fibrosis regression is an important issue. […] Liver fibrosis assessment helps to stratify patients care and may save health care resources.

• #50 Pathogenesis of liver cirrhosis

  https://wjgnet.com/1007-9327/abstract/v20/i23/7312.htm

  Cirrhosis is the end-stage condition of many types of chronic liver diseases but the underlying mechanisms are far from being clarified. Multiple cellular and molecular factors might be involved in the initiation and progression of cirrhosis. Activation of hepatic stellate cells is a pivotal event in the development of cirrhosis. Animal models are crucial for understanding the pathogenesis and the development of more efficient therapeutic strategies for cirrhosis, with which cirrhosis may become a treatable or even a reversible disease.

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