Liver Cirrhosis. Part 1 Pathogenesis. Fibrogenesis. Regeneration ( literature review 2019)



cirrhosis by definition is end-stage liver damage citrus acquire persistent injury to develop and characterized by diffuse transformation of central Ava into regenerative parenchymal nodules that is surrounded by fibrous bands and with variable degrees of wasps collage hunting so let's explain this definition word by word so what does it mean and stage liver damage for example in the model of normal coholic fatty liver disease so it starts here is normal liver and then with development of insulin resistance fatty liver develops with excessive accumulation of fat mass little or no information and in some critical point of fat accumulation oxidative injury develops which cause inflammation in the liver and this condition named non coholic starter hepatitis or ascites of course means inflammation an inflammation is always accompanied by fibrosis which is very important where is information there is always a fibrotic processes to prevent an impaired tissue injury so this persistent injury is a risk persistent fibrotic processes that always a yes eventually to cirrhosis which is an stage liver damage but liver damage when the same structural changes in the liver tissue because we know that eventually cirrhosis can be complicated when malignus transformation to better selves our carcinoma but it's now plastic changes and not structural while liver cirrhosis require persistent injury to develop because fiber Genesis is a dynamic process was persistent injury there will be fab rhotic progression that eventually lead to cirrhosis what if we eliminate the pathogenic stimulated cause persistent injury the bra'tac regression may occur so for cirrhosis development persistent injury is essential if user information means that process blood who went try liver and generative parenchymal nodules it's royal parasites that a suggestion to die tissue and is regenerating by mitotic replication fibrous bands is a scar tissue that is produced to limited the material damage and in circles through irenna parasites thereby forming a generative no you Moscoe accountant by the way convention action hepatic in this section we'll discuss the central hub addictions so a normal condition blood from portal vein and hepatic artery is going to capillary system to supply tissue by oxygen and nutrients must enforce all hypertension because of hypertension and liver capillaries which is called sinusoids for example due to my trojan horses blood bypasses hypertensive capillary system and moves directly from offering vessels which is the portal vein and hepatic artery through efferent vessel which is hepatic veins this formation of intrahepatic when is shown in this picture of liver tissue we can see liver fibrous bands that encircles souviron hepatocytes that results information of regenerative parenchymal module so what does fiber Genesis means in terms of liver disease first of all confirmation it's a natural moon hidden response to a tissue injury and of course on almost all tissues after exposure to almost an in destructive stimulus that cause disruption tissue unity for example myocardial function gunshot wounds burns and many other conditions repairable formation of scottish so scottish working like biological glue to keep tissue unity in liver disease the goal of fibrous genesis is first of all to live in damaged by insolence women hypothesis from areas with high level of inflammation thereby saving them and second to keep tissue unity for example ever start destroying walls of the building one way one eventually the building collapses the same thing with liver parenchyma so to prevent tissue collapse fibrous tissue produced by process it's a dynamic process that means with Stronach injuries are always serious of a brutal progression as well as for project regression everything depends on disease activity is there a secured phase of the disease for brushing progression-free whales and if decision a remission phase for grocery aggression prevails the principal cells that are responsible for scottish information I have a text islet cells to understand what and where happens in cirrhosis when subscribe leave a sinusoid functional unit so first of all live a sinusoid functional units located in capillary bed that is located inside the liver between the afferent vessels which is portal vein and hepatic artery an afferent vessel which is the hepatic vein the simple scheme of sinusoid partial unit is to hepatocytes returns the epical membrane series bile canaliculi on their basement membranes there is hepatic microvilli also to the basement membrane hepatic stellate cells attached which ASIS besides the most important cells and fiber Genesis basically they are located in the nexus allometric space that is called space of disa the endothelial cells separate axilla metrics from leave a sinusoid Wasco space so what is the difference between the regular capillary vessel and liver sinusoid versa the difference is the endothelial cells liver sinusoids vessels are fenestrated this means they have pores through which nutrients from sinusoids can pass to excess aromatics than to have parasites more easily than in regular capillary vessel this structure of liver sinusoid is explained by Harley metabolic of state in liver and all that liver has numerous very important highly energy consuming functions and to provide energy for them there must be adequate energy supplied to hepatocyte this pores provides the foster diffusion rate of nutrients thereby providing hepatocyte whose adequate energy supply Koufos cells adhere to endothelium an allocated an intravascular sinusoid space so there are three major functional cells endothelial cells cook for cells and hepatic stellate cells so as we mentioned the most characteristic feature of liver sinusoid endothelium cells in normal condition which is very important in normal conditions as i Afeni stated to provide adequate nutrient supply to her parasites they're also the major regulators of a barracks telesales activity the thinner thuds produces a major fibrinogen excite again which is known as the transforming growth factor beta one Koufos as a liver macrophages their antigen presenting cells means they take up antigen and present them to lymphocyte fulfills an immune response also Kufa cells produced cytokines and chemokines the triggers information and liver tissue hepatic stellate cells are the key cells and scar tissue production in normal condition it's a major Waterman a storing cells the contain approximately 40 to 70% of the total original content in human body but in relation to cirrhosis the most important function is a production of connective tissue matrix in space of descent connective tissue matrix is composed of three components glycoproteins proteoglycans and the collagen you know there are many types of collagen a human body but the characteristical feature of normal connective tissue matrix is collagen type 4 this is a type of collagen that we usually mention when we are talking about composition of basement membranes through the human body because the normal condition collagen type 4 is a essential component the specific fish of excess our matrix is a structure the sources of deposition and growth factors for example Hobart acid growth factor which is the most potent mitogenic factor for hepatocyte they release these factors on the matrix metalloproteinase activity so what is matrix metalloproteinases and what are they a function matrix metalloproteinases is a collective name for cards and abandon zinc containing and the peptidases first of all this name was given to them to emphasize their functional dependence on metal ions as calcium and zinc as cofactors fizzy activity because without him in one of them is a function will be close to zero so about which under peptidases we are talking about in relation to matrix metalloproteinases the most well-known are collagenase is a degrade quality and gelatinous is a degrade irreversibly hydrolyzed collagen called gelatin this is a general simplified picture of cirrhosis development first of all there is some pathogenic factors at costly Ranger II the liver injury lead to progressive death of a parasites that cause formation of zones of parenchyma lost and this disruption of tissue unit a trick is activation of hydrogenases by activation of hepatic stellate cells that produce scar tissue the scar tissues progressively accumulating in space of descent and from dense fibrous scepters the trying to separate her parasites by insulin same from all of this information around and this results information of regenerative nodules wisconsin's damage this process repeated Norway Norway gained this progressive substitution of functional hypothesized by non-functional scar tissue that lead to progressive loss of liver function and cirrhosis development but if this chronic damage to the race interrupted or eliminated this lead to reversion of fibrosis listed by hepatic stellate cells an activation or apoptosis that markedly decreased Scottish reproduction eventually the Scottish she became more compact and after that matrix metalloproteinase is a breaking apart Scottish use at and so cost regenerative nodules this cause coalescence of a live tissue we know the 0 of 3 types of hepatocyte des it's necrosis apoptosis and necroptosis it resumed to some extent dis present in every pathological condition but in different proportion for example in ischemic injury or drug-induced liver injury necrosis is predominant you know that necrosis is uncontrolled death of a parasites as an example in toxic injury cell reaches a critical point of sour stress and energy depletion this eventually results in defects in a smaller circulation the defects in a smallest regulation because what retention inside the cells and this lead to cell as Welland and eventually the cell rupture which cause inflammation iran's is died cell apoptosis in contrast to necrosis its program non inflammatory cell death which results in hobart acid shrinkage and eventually in sour fragmentation into the apoptotic bodies crepitus it's relatively neutral this process have both features of necrosis and apoptosis from apoptosis process means it's a program process of cell death and Negro from necrosis means that unlike apoptosis this process eventually results in a rupture of plasma membrane with subsequent release of cellular content and this release of sawa Contin triggers substantial inflammation around this tight cell regardless of pathological factor is a direct damage to liver cells lead to release of reactive oxygen species in other inflammatory mediators viscose activation of immune cells and this activation of immune cells promote inflammation and this information subsequently lead to activation of fibrous Genesis as a protective mechanism hepatic stellate cells activation is a key step in fiber Genesis the major stimuli fuzzy activation are first of all chronic inflammation that cause permanent oxidant stress in this pathological condition of chronic oxidant stress stimulate activation of scar tissue production whereas this scar tissue trying to limit inflamed area and provide safety for life hepatocytes the disruption of XSL a matrix caused disruption of tissue unity and when all worries disruption of tissue unit is eris activation of scar tissue productions that is working like biological glue to give tissue unity also fiber Genesis can be activated by Peregrine's stimulation for example antigen stimulation of Kufa cells can activate hepatic stellate cells also direct toxin stimulation can activate fibrous Genesis and we see this after acetaminophen intoxication at the same time with activation of hepatic stellate cells very substantial changes in endothelial cells when then the falafels receives his densha pro-inflammatory signals and the falafels start to produce transforming growth factor one beta which is known as a major fiber genic factor the most important function of the cytokines it is released from endothelial cells and fiber Genesis is his ability to stimulate conversion of hepatic stellate cells into Maya fibroblasts also there is one very important process in the field ourselves that as a ghostwriter of the tissue injury was first science of information and this process name capitalization of endothelial cells so what does the strong capitalization means remember we said that to maintain Holley metabolic instead the capillaries in the liver that is called sinusoids her in the fetal cells with spores that is called finestra's that facilitate nutrients delivery from lot ensign research to hepatocytes but in liver injury the hepatocytes are going to full protective regime for example we are going to put protective regime inside the house we barricade those windows litter everything in same story for hepatocyte they close their pores so we can say they lose their fenestration and because after losing fenestration they start to look like regular capillary vessel this process called capitalization in addition to capitalization hopera says lose a micro villi and that makes sense renova to normal conditions this micro villi serves to increase hepatocyte surface area and the big as the surface area is amorous a badasses capacity to absorb nutrients because we know that hepatis eyes need a lot of them to maintain their very high metabolic rate but risk capitalizations the nutrients delivery from sinusoids to hepatocyte substantially decreased so there is no need in so high absorbent capacity so there is no need to maintain so large surface area thereby hepatocytes lose their micro villi with activation hepatic stellate cells conversion into Maya for robust so activated hepatic stellate cells named Maya fabulous first of all because during inflammation there is energy depletion and liberty issue due to capitalization hepatic stellate cells find the extra energy research remember we say that hepatic stellate cells as a major vitamin a store in cells so to provide energies a hydrolyzed retina droplets for free fatty acids to maintain energy homeostasis in Maya fibroblast there is substantial increase compared to hepatic stellate cells in normal condition an expression of smooth muscle specific alpha actinin myosin this molecules provides substantial contractivity this marvelous contractility is regulated primarily by two mediators in the fillion one stimulate contractivity and his antagonist nitric oxide to decrease contractility by the way this conductivity of my foie gras blades substantially contributed to rise in port operation due to fibrosis and development of portal hypertension also activated hepatic stellate cells product pro-inflammatory cytokines and chemokines that regulate inflammation and finally the most important feature in cirrhosis activated hepatic stellate cells start to excessively secret Austrade access aromatics what does it mean excessive because there is substantial three to eight fold increase in X 7 matrix production and this substantial increase in production is provided by the effect of transforming growth factor beta 1 in all trade-ins there is substantial changes in composition of excess 7 matrix an if composition of glycoproteins and proteoglycans remain relatively constant the collagen is totally different why is this important collagen type 4 is known fybel forming types of collagen it means that each collagen type 4 molecule is linked to each other by head-to-head connection that results in very thin soft or so-called sheath like structure in contrast to this collagen type 1 and 3 as a fiber forming types of collagen they from fibrosis by Fabrice we mean that assembly of collagen molecules that are connected in parallel fashion this pair whole fashion connection cause very dense thick excess aromatic structure and lead to tissue stiffening as a result in loss of organ function moreover we say the zuri substantial 3 tight fold increase in excess our matrix production missouri's also decrease in fabrina lysis rate this is balanced and fibrinolysis caused by decreased level of matrix metalloproteinases and increased level of z inhibitors called tissue inhibitors of matrix metalloproteinases but matrix metalloproteinases we already talked about but what the inhibitors do we mentioned that matrix metalloproteinases are calcium dependents in containing endopeptidase is basically they inhibitors binds to catalytic zinc in a matrix metalloproteinases active site and wises binding they markedly decrease the activity why is clinically important nowadays there is no non-invasive certain markets of both synthesis and degradation of excess aromatics public Genesis or we can call it excessive excess aromatic synthesis can basis by process three test which is determines the level or and terminal type three college and pro peptide the principle is this my fiberglass produced pro-collagen three precursor that have annainsea terminals processes in the blood leaves his terminals and produce collagen type three molecule plus and terminal peptide and c terminal peptide collagen type three molecule eventually from fibrous and N and c-terminal peptides go to the blood where their level can be evaluated so the more activist fiber genesis the more molecule of collagen types reproduced the more n terminal baptized is going to the blood and by evaluation of n terminal peptide we can determine fibrosis progression in contrast or axisymmetric synthesis we can also assess the level of excess our matrix degradation and threat of excess our matrix accreditation is measured by CCM molecule or his sister e stands for type three collagen and m is emphasized this collagen was degraded by MMP activities of the full name is matrix metalloproteinase is degraded type three collagen the idea of this test is this the chronic injury cost for Bruce's development and for brother's development is characterized by excessive deposition of collagen molecules and excellent matrix especially types three collagen molecules but with interruption of chronic injuries ever before logic regression and in fabric regression fabrina lysis prevails over fabrina genesis so infant brain Eliza's hepatic macrophages increase their production of matrix metalloproteinases and in addition to that the level of tissue inhibitors of matrix meta-analysis is markedly decreased this two factors secretion of matrix material analysis by macrophages and the level of z tissue inhibitors determines the overall for analysis activity so with increase in matrix metalloproteinases activity and which decrease in the level of the inhibitors there is an increase in fiber analysis activity and the highest for analysis today the highest rate of excess aromatics degradation remember that collagen is one of three components of excess our matrix so the rate of the collagen degradation will be increased and we know that in pathological condition during fibrin and Genesis there is successive the position of pathogenic collagen markers particular type 3 collagen so this type 3 collagen more cows are degraded into fragments and one of those fragments that can be detected in serum name system molecule and because this molecule is the final product of x7 metrics documentation the level of this CCM molecule is used to assess the verb logic regression processes it's necessary to say is that Libre has a man's regenerative capacity liver tissue can regenerate Heavin result storm cells this generation occurs when mitotic replication of a bat asserts itself but in the sentence of a chronic injury excessive inflammation can overwhelm her better sis regenerative capacity and if damaged head is more than regeneration rate Scott tissue substitute functional hepatocyte in that lead to cirrhosis and loss of organ function so how's this immense regeneration capacity can be overwhelmed first of all energy chronic injury caused chronic inflammation and chronic inflammation caused capitalization of sinusoids and excess aromatics changes that characterized by excessive the position of corinth type 1 and 3 molecules in this pathological collagen molecules was very dense in stiff axis so a metric structure and because nutrients must be transported from sinusoid vessel to hepatocytes through excellent metrics this stiffened dense excess aromatic structure lead to decrease in metabolic exchange between blood and hepatocyte Enrico's regeneration is highly energy consuming process this energy depletion markedly decreased hypothesis proliferation the second factor is vestrana control a hypothesis that divided who where know again and resist division about a certificate of capacity decrease and eventually they reach they replicative senescence when they can divide it no more and in this moment stem cells activation occurs and this process of activation of storm cells name dr. Lurie action interestings exists stem cells are like Universal soldiers in liver disease when there is a badass eyes damage they give rise to hepatocytes and if there is biller disease with kalanchoe sites damage they can also give rise to colon Geoscience so to explain this this is a parasite this is wild canaliculus this is bile duct with Kalonji site and this is cannibal Heron westrom cells located by the way named dr. reaction was given because this stone self activation is accompanied by processes of proliferation and hyperplasia in bile duct so because canal of herring is located between hepatocytes and Kalonji assigns storm cells can give rise to both of them if chronic injury is interrupted for example is clearance of war infection at secession of alcohol consumption the reversion of fibrosis may happen so first of all to stop Bible Genesis there is hepatic stellate cells apoptosis or inactivation and if there is no additional Scottish reproduction the Scottish who became dense and thinner this process named condensation of scar tissue so because of hepatic Stars has apoptosis and inactivation there is no production of new scar tissue and to eliminate all scar tissue that is already here the macrophages start to produce matrix metalloproteinases and by the activities the scar tissues it encircles the life tissue in regenerative not used is breaking apart in our life tissue assemble to Collison's which dozen thereby forming aureus of pure life tissue such as this is how as a reversion of a process occurs this is end of chapter 1

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