Cirrhosis pathophysiology: Difference between revisions

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{{Cirrhosis}}
{{Cirrhosis}}
{{CMG}} {{AE}}
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==Overview==
==Overview==
Cirrhosis occurs due to long term [[liver]] injury which causes an imbalance between [[matrix]] production and degradation. Early disruption of the normal hepatic matrix results in its replacement by [[scar tissue]], which in turn has deleterious effects on cell function.
Cirrhosis occurs due to long term [[liver]] injury which causes an imbalance between [[matrix]] production and degradation. The pathological hallmark of cirrhosis is the development of [[scar tissue]] which leads to replacement of normal [[liver]] [[parenchyma]], leading to blockade of [[Portal vein|portal blood flow]] and disturbance of normal [[liver]] function. When [[fibrosis]] of the [[liver]] reaches an advanced stage where distortion of the [[Liver|hepatic]] [[Circulatory system|vasculature]] also occurs, it is termed as cirrhosis of the [[liver]]. The [[pathogenesis]] of cirrhosis involves [[inflammation]], [[Ito cell|hepatic stellate cell]] activation, [[angiogenesis]], and [[Fibrosis|fibrogenesis]]. [[Kupffer cell|Kupffer cells]] are [[Liver|hepatic]] [[Macrophage|macrophages]] responsible for [[Ito cell|hepatic stellate cell]] activation during injury. [[Ito cell|Hepatic stellate cells (HSC)]] which are located in the [[Space of Disse|subendothelial space of Disse]], become activated in areas of [[liver]] injury and secrete [[TGF-beta|transforming growth factor-beta 1]] ([[TGF beta 1|TGF-β<sub>1</sub>]]), which leads to a [[Fibrosis|fibrotic]] response and proliferation of [[connective tissue]]. Cirrhosis may also lead to [[Liver|hepatic]] [[Microvascular bed|microvascular]] changes including the formation of intra-[[Liver|hepatic]] [[Shunt (medical)|shunts]] (due to [[angiogenesis]] and loss of [[Parenchyma|parenchymal cells]]) and [[Endothelium|endothelial]] dysfunction. [[Fibrosis]] eventually leads to formation of [[Septum (disambiguation)|septae]] that grossly distort the [[liver]] architecture which includes both the [[liver]] [[parenchyma]] and the [[Circulatory system|vasculature]], accompanied by regenerative [[Nodule (medicine)|nodule]] formation. HAYOP


==Pathophysiology==
==Pathophysiology==
The pathogenesis of cirrhosis is as follows: <ref name="pmid7932316">{{cite journal |vauthors=Arthur MJ, Iredale JP |title=Hepatic lipocytes, TIMP-1 and liver fibrosis |journal=J R Coll Physicians Lond |volume=28 |issue=3 |pages=200–8 |year=1994 |pmid=7932316 |doi= |url=}}</ref><ref name="pmid8502273">{{cite journal |vauthors=Friedman SL |title=Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies |journal=N. Engl. J. Med. |volume=328 |issue=25 |pages=1828–35 |year=1993 |pmid=8502273 |doi=10.1056/NEJM199306243282508 |url=}}</ref><ref name="pmid8682489">{{cite journal |vauthors=Iredale JP |title=Matrix turnover in fibrogenesis |journal=Hepatogastroenterology |volume=43 |issue=7 |pages=56–71 |year=1996 |pmid=8682489 |doi= |url=}}</ref><ref name="pmid7959178">{{cite journal |vauthors=Gressner AM |title=Perisinusoidal lipocytes and fibrogenesis |journal=Gut |volume=35 |issue=10 |pages=1331–3 |year=1994 |pmid=7959178 |pmc=1374996 |doi= |url=}}</ref><ref name="pmid17332881">{{cite journal |vauthors=Iredale JP |title=Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ |journal=J. Clin. Invest. |volume=117 |issue=3 |pages=539–48 |year=2007 |pmid=17332881 |pmc=1804370 |doi=10.1172/JCI30542 |url=}}</ref><ref name="pmid11984538">{{cite journal |vauthors=Arthur MJ |title=Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C |journal=Gastroenterology |volume=122 |issue=5 |pages=1525–8 |year=2002 |pmid=11984538 |doi= |url=}}</ref>
The [[pathogenesis]] of cirrhosis is as follows:<ref name="pmid7932316">{{cite journal |vauthors=Arthur MJ, Iredale JP |title=Hepatic lipocytes, TIMP-1 and liver fibrosis |journal=J R Coll Physicians Lond |volume=28 |issue=3 |pages=200–8 |year=1994 |pmid=7932316 |doi= |url=}}</ref><ref name="pmid8502273">{{cite journal |vauthors=Friedman SL |title=Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies |journal=N. Engl. J. Med. |volume=328 |issue=25 |pages=1828–35 |year=1993 |pmid=8502273 |doi=10.1056/NEJM199306243282508 |url=}}</ref><ref name="pmid8682489">{{cite journal |vauthors=Iredale JP |title=Matrix turnover in fibrogenesis |journal=Hepatogastroenterology |volume=43 |issue=7 |pages=56–71 |year=1996 |pmid=8682489 |doi= |url=}}</ref><ref name="pmid7959178">{{cite journal |vauthors=Gressner AM |title=Perisinusoidal lipocytes and fibrogenesis |journal=Gut |volume=35 |issue=10 |pages=1331–3 |year=1994 |pmid=7959178 |pmc=1374996 |doi= |url=}}</ref><ref name="pmid17332881">{{cite journal |vauthors=Iredale JP |title=Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ |journal=J. Clin. Invest. |volume=117 |issue=3 |pages=539–48 |year=2007 |pmid=17332881 |pmc=1804370 |doi=10.1172/JCI30542 |url=}}</ref><ref name="pmid11984538">{{cite journal |vauthors=Arthur MJ |title=Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C |journal=Gastroenterology |volume=122 |issue=5 |pages=1525–8 |year=2002 |pmid=11984538 |doi= |url=}}</ref>
* When an injured [[Tissue (biology)|tissue]] is replaced by a [[Collagen|collagenous]] [[scar]], it is termed as [[fibrosis]]. The development of [[fibrosis]] requires several months, or even years, of ongoing [[injury]].
* When an injured [[Tissue (biology)|tissue]] is replaced by a [[Collagen|collagenous]] [[scar]], it is termed as [[fibrosis]]. The development of [[fibrosis]] requires several months, or even years of ongoing [[injury]].
* The pathological hallmark of cirrhosis is the development of [[scar tissue]] that leads to replacement of normal [[liver]] [[parenchyma]], leading to blockade of [[Portal vein|portal blood flow]] and disturbance of normal [[liver]] function.
* The [[pathological]] hallmark of cirrhosis is the development of [[scar tissue]] that leads to replacement of normal [[liver]] [[parenchyma]], leading to blockade of [[Portal vein|portal blood flow]] and disturbance of normal [[liver]] function.
* When [[fibrosis]] of the [[liver]] reaches an advanced stage where distortion of the [[Liver|hepatic]] [[Circulatory system|vasculature]] also occurs, it is termed as cirrhosis of the [[liver]]. If the damage progresses, panlobular cirrhosis may result.  
* When [[fibrosis]] of the [[liver]] reaches a point where distortion of the [[Liver|hepatic]] [[Circulatory system|vasculature]] also occurs, it is termed as cirrhosis of the [[liver]]. If the damage progresses, panlobular cirrhosis may result.  
* The cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the [[Hepatic lobule|liver lobule]].
* The [[cellular]] mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the [[Hepatic lobule|liver lobule]].
* [[Hepatitis|Viral hepatitis]] involves the periportal region, whereas involvement in [[alcoholic liver disease]] is largely pericentral.  
* [[Hepatitis|Viral hepatitis]] involves the periportal region, whereas involvement in [[alcoholic liver disease]] is largely pericentral.  
* Cirrhosis involves the following steps:<ref name="pmid7737629">{{cite journal |vauthors=Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G |title=Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension |journal=Hepatology |volume=21 |issue=5 |pages=1238–47 |year=1995 |pmid=7737629 |doi= |url=}}</ref>
* Cirrhosis involves the following steps:<ref name="pmid7737629">{{cite journal |vauthors=Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G |title=Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension |journal=Hepatology |volume=21 |issue=5 |pages=1238–47 |year=1995 |pmid=7737629 |doi= |url=}}</ref>
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** [[Angiogenesis]]  
** [[Angiogenesis]]  
** [[Fibrosis|Fibrogenesis]]
** [[Fibrosis|Fibrogenesis]]
'''Hepatic stellate cell activation'''
The role of [[Kupffer cell|hepatic stellate cells]] in the pathogenesis of cirrhosis is described below:
* [[Kupffer cell|Kupffer cells]] are [[Liver|hepatic]] [[Macrophage|macrophages]] responsible for [[Ito cell|hepatic stellate cell]] activation during injury.
* [[Kupffer cell|Kupffer cells]] are [[Liver|hepatic]] [[Macrophage|macrophages]] responsible for [[Ito cell|hepatic stellate cell]] activation during injury.
* The [[Ito cell|stellate cell]], (also known as the [[Ito cell|perisinusoidal cell]] or [[Ito cell]]) is a cell type that normally stores [[vitamin A]] and plays a pivotal role in the development of cirrhosis.
* The [[Ito cell|stellate cell]], (also known as the [[Ito cell|perisinusoidal cell]] or [[Ito cell]]) is a type of [[cell]] that normally stores [[vitamin A]] and plays a pivotal role in the development of cirrhosis.
* [[Ito cell|Hepatic stellate cells (HSC)]] are usually located in the subendothelial space of Disse and become activated to a [[myofibroblast]]-like phenotype in areas of [[liver]] injury. This contractile cell (known as a [[myofibroblast]]) obstructs [[blood flow]] in the [[Circulatory system|circulation]].  
* [[Ito cell|Hepatic stellate cells (HSC)]] are usually located in the [[Space of Disse|subendothelial space of Disse]] and become activated to a [[myofibroblast]]-like [[cell]] in areas of [[liver]] injury. This contractile [[Cell (biology)|cell]] (known as a [[myofibroblast]]) obstructs [[blood flow]] in the [[Circulatory system|circulation]].  
* The [[stellate cell]] secretes [[TGF beta 1|TGF-β<sub>1</sub>]], which leads to a [[Fibrosis|fibrotic]] response and proliferation of [[connective tissue]].
* The [[stellate cell]] secretes [[TGF-β|transforming growth factor-beta 1]] ([[TGF beta 1|TGF-β<sub>1</sub>]]), which leads to a [[Fibrosis|fibrotic]] response and [[proliferation]] of [[connective tissue]].
* [[Connective tissue]] proliferation leads to the formation of [[extracellular matrix]] around [[hepatocytes]] and is composed of [[collagen]]s (especially type I, III, IV), [[glycoprotein]] and [[proteoglycan]]s.  
* [[Connective tissue]] [[proliferation]] leads to the formation of [[extracellular matrix]] around [[hepatocytes]] that is composed of [[collagen]]s (especially type I, III, IV), [[glycoprotein]] and [[proteoglycan]]s.  
* [[Collagen]] and non collagenous [[matrix]] [[Protein|proteins]] responsible for [[fibrosis]] are produced by the activated [[Ito cell|Hepatic Stellate Cells]] ([[Ito cell|HSC]]).  
* [[Collagen]] and non-[[collagenous]] [[matrix]] [[Protein|proteins]] responsible for [[fibrosis]] are produced by the activated [[Stellate cell|hepatic stellate cells]] ([[Ito cell|HSC]]).  
* [[Hepatocyte]] damage causes the release of [[lipid]] [[Peroxidase|peroxidases]] from injured [[Cell membrane|cell membranes]] leading to [[necrosis]] of [[Parenchyma|parenchymal cells]].  
* [[Hepatocyte]] damage causes the release of [[lipid]] [[Peroxidase|peroxidases]] from injured [[Cell membrane|cell membranes]] leading to [[necrosis]] of [[Parenchyma|parenchymal cells]].  
* Activated [[Ito cell|HSC]] produce numerous [[Cytokine|cytokines]] and their receptors, such as [[Platelet-derived growth factor|PDGF]] and [[Transforming growth factor|TGF-f31]] which are responsible for [[Fibrosis|fibrogenesis]].  
* Activated [[Ito cell|HSC]] induce the production of numerous [[Cytokine|cytokines]] and their receptors, such as [[platelet-derived growth factor]] ([[Platelet-derived growth factor|PDGF]]) and [[Transforming growth factor|TGF-f31]], which are responsible for [[Fibrosis|fibrogenesis]].  
* The matrix formed due to [[Ito cell|HSC]] activation is deposited in the space of Disse and leads to loss of fenestrations of [[Endothelium|endothelial cells]], which is a process called capillarization.
* The matrix formed due to [[Ito cell|HSC]] activation is deposited in the [[space of Disse]] and leads to loss of fenestrations of [[Endothelium|endothelial cells]], through a process called capillarization.
* [[Stellate cell]] activation leads to disturbance of the balance between [[matrix metalloproteinase]]s and the naturally occurring inhibitors (TIMP 1 and 2). This is followed by [[matrix (biology)|matrix]] breakdown and replacement by [[connective tissue]]-secreted [[matrix]].<ref>Iredale JP. Cirrhosis: new research provides a basis for rational and targeted treatments. [[British Medical Journal|BMJ]] 2003;327:143-7.[http://bmj.bmjjournals.com/cgi/content/full/327/7407/143 Fulltext.] PMID 12869458.</ref>
* [[Stellate cell]] activation leads to disturbance of the balance between [[matrix metalloproteinase]]s and the naturally occurring inhibitors ([[TIMP1|TIMP 1]] and [[TIMP2]]). This is followed by [[matrix (biology)|matrix]] breakdown and replacement by [[connective tissue]]-secreted [[matrix]].<ref>Iredale JP. Cirrhosis: new research provides a basis for rational and targeted treatments. [[British Medical Journal|BMJ]] 2003;327:143-7.[http://bmj.bmjjournals.com/cgi/content/full/327/7407/143 Fulltext.] PMID 12869458.</ref>
* [[Matrix metalloproteinase]] (MMP) are [[calcium]] dependent [[enzymes]] that specifically degrade [[collagen]] and non [[Collagen|collagenous]] substrate.
* [[Matrix metalloproteinase]] (MMP) are [[calcium]] dependent [[enzymes]] that specifically degrade [[collagen]] and non [[Collagen|collagenous]] substrate.
* MMP-2 and stromyelysin-1 are produced by [[Ito cell|stellate cells]].  
* [[Matrix metalloproteinase|MMP]]-2 and stromyelysin-1 are produced by [[Ito cell|stellate cells]].  
* MMP-2 degrades [[collagen]] and stromelysin-1 degrades [[proteoglycan]] and [[glycoprotein]].
* [[Matrix metalloproteinase|MMP]]-2 degrades [[collagen]] and stromelysin-1 degrades [[proteoglycan]] and [[glycoprotein]].
* Cirrhosis leads to [[Liver|hepatic]] microvascular changes characterised by:<ref name="pmid19157625">{{cite journal |vauthors=Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J |title=Angiogenesis in liver disease |journal=J. Hepatol. |volume=50 |issue=3 |pages=604–20 |year=2009 |pmid=19157625 |doi=10.1016/j.jhep.2008.12.011 |url=}}</ref>
'''Microvascular changes'''
** Formation of intra [[Liver|hepatic]] [[Shunt (medical)|shunts]] (due to [[angiogenesis]] and loss of [[Parenchyma|parenchymal cells]]) 
 
** [[Liver|Hepatic]] [[Endothelium|endothelial]] dysfunction  
Cirrhosis leads to [[Liver|hepatic]] microvascular changes characterised by:<ref name="pmid19157625">{{cite journal |vauthors=Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J |title=Angiogenesis in liver disease |journal=J. Hepatol. |volume=50 |issue=3 |pages=604–20 |year=2009 |pmid=19157625 |doi=10.1016/j.jhep.2008.12.011 |url=}}</ref>
* Formation of intra [[Liver|hepatic]] [[Shunt (medical)|shunts]] (due to [[angiogenesis]] and loss of [[Parenchyma|parenchymal cells]]) 
* [[Liver|Hepatic]] [[Endothelium|endothelial]] dysfunction  
 
* [[Sinusoid (blood vessel)|Sinusoidal]] [[Endothelium|endothelial cells]] are also important contributors of early [[fibrosis]]. [[Endothelial cell]]s from a normal [[liver]] produces [[collagen]], [[laminin]] and [[fibronectin]].<ref>{{cite journal |author=Maher JJ, McGuire RF |title=Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo |journal=J. Clin. Invest. |volume=86 |issue=5 |pages=1641–8 |year=1990 |month=November |pmid=2243137 |pmc=296914 |doi=10.1172/JCI114886 |url=}}</ref><ref>{{cite journal |author=Herbst H, Frey A, Heinrichs O, ''et al.'' |title=Heterogeneity of liver cells expressing procollagen types I and IV in vivo |journal=Histochem. Cell Biol. |volume=107 |issue=5 |pages=399–409 |year=1997 |month=May |pmid=9208331 |doi= |url=}}</ref>
* [[Sinusoid (blood vessel)|Sinusoidal]] [[Endothelium|endothelial cells]] are also important contributors of early [[fibrosis]]. [[Endothelial cell]]s from a normal [[liver]] produces [[collagen]], [[laminin]] and [[fibronectin]].<ref>{{cite journal |author=Maher JJ, McGuire RF |title=Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo |journal=J. Clin. Invest. |volume=86 |issue=5 |pages=1641–8 |year=1990 |month=November |pmid=2243137 |pmc=296914 |doi=10.1172/JCI114886 |url=}}</ref><ref>{{cite journal |author=Herbst H, Frey A, Heinrichs O, ''et al.'' |title=Heterogeneity of liver cells expressing procollagen types I and IV in vivo |journal=Histochem. Cell Biol. |volume=107 |issue=5 |pages=399–409 |year=1997 |month=May |pmid=9208331 |doi= |url=}}</ref>
* The [[Endothelium|endothelial]] dysfunction is characterised by<ref name="pmid22504334">{{cite journal |vauthors=García-Pagán JC, Gracia-Sancho J, Bosch J |title=Functional aspects on the pathophysiology of portal hypertension in cirrhosis |journal=J. Hepatol. |volume=57 |issue=2 |pages=458–61 |year=2012 |pmid=22504334 |doi=10.1016/j.jhep.2012.03.007 |url=}}</ref>
* The [[Endothelium|endothelial]] dysfunction is characterised by:<ref name="pmid22504334">{{cite journal |vauthors=García-Pagán JC, Gracia-Sancho J, Bosch J |title=Functional aspects on the pathophysiology of portal hypertension in cirrhosis |journal=J. Hepatol. |volume=57 |issue=2 |pages=458–61 |year=2012 |pmid=22504334 |doi=10.1016/j.jhep.2012.03.007 |url=}}</ref>
** Insufficient release of [[Vasodilator|vasodilators]], such as [[nitric oxide]] due to [[oxidative stress]]  
** Insufficient release of [[Vasodilator|vasodilators]], such as [[nitric oxide]] due to [[oxidative stress]]  
** Increased production of [[Vasoconstrictor|vasoconstrictors]] (mainly [[adrenergic]] stimulation and activation of [[Endothelin|endothelins]] and [[Renin-angiotensin system|RAAS]])
** Increased production of [[Vasoconstrictor|vasoconstrictors]] (mainly [[adrenergic]] stimulation and activation of [[Endothelin|endothelins]] and [[Renin-angiotensin system|RAAS]])
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**[[Nitric oxide]]  
**[[Nitric oxide]]  
**[[Carbon monoxide]]  
**[[Carbon monoxide]]  
*[[Angiogenesis]] in cirrhosis results in the production of immature and permeable [[Vascular endothelial growth factor|VEGF]] induced neo-[[Blood vessel|vessels]] that further exacerbate [[liver]] injury. <ref>{{cite journal |author=Lee JS, Semela D, Iredale J, Shah VH |title=Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? |journal=Hepatology |volume=45 |issue=3 |pages=817–25 |year=2007 |month=March |pmid=17326208 |doi=10.1002/hep.21564 |url=}}</ref><ref>{{cite journal |author=Rosmorduc O, Housset C |title=Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease |journal=Semin. Liver Dis. |volume=30 |issue=3 |pages=258–70 |year=2010 |month=August |pmid=20665378 |doi=10.1055/s-0030-1255355 |url=}}</ref>
'''Angiogenesis'''
*[[Angiogenesis]] in cirrhosis results in the production of immature and permeable [[vascular endothelial growth factor]] ([[Vascular endothelial growth factor|VEGF]]) induced neo-[[Blood vessel|vessels]] that further exacerbate [[liver]] injury.<ref>{{cite journal |author=Lee JS, Semela D, Iredale J, Shah VH |title=Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? |journal=Hepatology |volume=45 |issue=3 |pages=817–25 |year=2007 |month=March |pmid=17326208 |doi=10.1002/hep.21564 |url=}}</ref><ref>{{cite journal |author=Rosmorduc O, Housset C |title=Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease |journal=Semin. Liver Dis. |volume=30 |issue=3 |pages=258–70 |year=2010 |month=August |pmid=20665378 |doi=10.1055/s-0030-1255355 |url=}}</ref>
'''Fibrosis'''
 
The role of [[fibrosis]] in the pathogenesis of cirrhosis is described below:
* [[Fibrosis]] eventually leads to formation of [[Septum (disambiguation)|septae]] that grossly distort the [[liver]] architecture which includes both the [[liver]] [[parenchyma]] and the [[Circulatory system|vasculature]].  
* [[Fibrosis]] eventually leads to formation of [[Septum (disambiguation)|septae]] that grossly distort the [[liver]] architecture which includes both the [[liver]] [[parenchyma]] and the [[Circulatory system|vasculature]].  
* A cirrhotic [[liver]] compromises [[Liver|hepatic]] sinusoidal exchange by shunting [[Artery|arterial]] and [[Portal vein|portal blood]] directly into the [[Central vein|central veins]] ([[Liver|hepatic]] outflow).
* A cirrhotic [[liver]] compromises [[Hepatic sinusoids|hepatic sinusoidal]] exchange by shunting [[Artery|arterial]] and [[Portal vein|portal blood]] directly into the [[Central vein|central veins]] ([[Liver|hepatic]] outflow).
* Vascularized [[Fiber|fibrous]] [[Septum (disambiguation)|septa]] connect [[Central vein|central veins]] with [[Portal triad|portal tracts]] leading to islands of [[Hepatocyte|hepatocytes]] surrounded by [[Fiber|fibrous]] bands without [[Central vein|central veins]].<ref name="pmid18328931">{{cite journal |vauthors=Schuppan D, Afdhal NH |title=Liver cirrhosis |journal=Lancet |volume=371 |issue=9615 |pages=838–51 |year=2008 |pmid=18328931 |pmc=2271178 |doi=10.1016/S0140-6736(08)60383-9 |url=}}</ref><ref name="pmid15094237">{{cite journal |vauthors=Desmet VJ, Roskams T |title=Cirrhosis reversal: a duel between dogma and myth |journal=J. Hepatol. |volume=40 |issue=5 |pages=860–7 |year=2004 |pmid=15094237 |doi=10.1016/j.jhep.2004.03.007 |url=}}</ref><ref name="pmid11079009">{{cite journal |vauthors=Wanless IR, Nakashima E, Sherman M |title=Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis |journal=Arch. Pathol. Lab. Med. |volume=124 |issue=11 |pages=1599–607 |year=2000 |pmid=11079009 |doi=10.1043/0003-9985(2000)124<1599:ROHC>2.0.CO;2 |url=}}</ref>
* [[Vascularity|Vascularized]] [[Fiber|fibrous]] [[Septum (disambiguation)|septa]] connect [[Central vein|central veins]] with [[Portal triad|portal tracts]] leading to islands of [[Hepatocyte|hepatocytes]] surrounded by [[Fiber|fibrous]] bands without [[Central vein|central veins]].<ref name="pmid18328931">{{cite journal |vauthors=Schuppan D, Afdhal NH |title=Liver cirrhosis |journal=Lancet |volume=371 |issue=9615 |pages=838–51 |year=2008 |pmid=18328931 |pmc=2271178 |doi=10.1016/S0140-6736(08)60383-9 |url=}}</ref><ref name="pmid15094237">{{cite journal |vauthors=Desmet VJ, Roskams T |title=Cirrhosis reversal: a duel between dogma and myth |journal=J. Hepatol. |volume=40 |issue=5 |pages=860–7 |year=2004 |pmid=15094237 |doi=10.1016/j.jhep.2004.03.007 |url=}}</ref><ref name="pmid11079009">{{cite journal |vauthors=Wanless IR, Nakashima E, Sherman M |title=Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis |journal=Arch. Pathol. Lab. Med. |volume=124 |issue=11 |pages=1599–607 |year=2000 |pmid=11079009 |doi=10.1043/0003-9985(2000)124<1599:ROHC>2.0.CO;2 |url=}}</ref>
* These mechanisms simultaneously occurring in the [[liver]] lead to [[Fibrous tissue|fibrous tissue band]] (septa) and regenerative [[hepatocyte]] [[Nodule (medicine)|nodule]] formation, which eventually replace the entire [[liver]] architecture, leading to decreased [[blood flow]] throughout.
* These mechanisms simultaneously occurring in the [[liver]] lead to [[Fibrous tissue|fibrous tissue band]] (septa) and regenerative [[hepatocyte]] [[Nodule (medicine)|nodule]] formation, which eventually replace the entire [[liver]] architecture, leading to decreased [[blood flow]] throughout.
* The formation of [[Fibrosis|fibrotic]] bands is accompanied by regenerative [[Nodule (medicine)|nodule]] formation in the [[Liver|hepatic]] [[parenchyma]].
* The formation of [[Fibrosis|fibrotic]] bands is accompanied by regenerative [[Nodule (medicine)|nodule]] formation in the [[Liver|hepatic]] [[parenchyma]].
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* The pathological hallmark of cirrhosis is the development of [[scar tissue]] that replaces normal [[parenchyma]], leading to blockade of [[Portal vein|portal blood flow]] and disturbance of normal [[liver]] function.  
* The pathological hallmark of cirrhosis is the development of [[scar tissue]] that replaces normal [[parenchyma]], leading to blockade of [[Portal vein|portal blood flow]] and disturbance of normal [[liver]] function.  
* Due to [[portal hypertension]], the [[spleen]] becomes congested, which leads to [[hypersplenism]] and increased [[platelet]] sequestration.  
* Due to [[portal hypertension]], the [[spleen]] becomes congested, which leads to [[hypersplenism]] and increased [[platelet]] sequestration.  
* Pathogenesis of cirrhosis based upon the underlying cause is as follows:
'''Pathogenesis of cirrhosis according to cause'''
** '''[[Alcoholic liver disease]]''':  [[Alcohol]] seems to injure the [[liver]] by blocking the normal metabolism of [[protein]], [[fat]]s, and [[carbohydrate]]s. Patients may also have concurrent [[alcoholic hepatitis]] with [[fever]], [[hepatomegaly]], [[jaundice]], and anorexia. [[Liver]] damage due to [[alcoholic hepatitis]] may progress to cirrhosis.
 
** '''Chronic hepatitis C''':  Infection with the [[hepatitis C]] virus causes inflammation of and low grade damage to the [[liver]] that over several decades can lead to cirrhosis.
[[Pathogenesis]] of cirrhosis based upon the underlying cause is as follows:
** '''[[Non-alcoholic fatty liver disease|Non-alcoholic steatohepatitis]]''' (NASH):  In [[Non-alcoholic fatty liver disease|NASH]], fat builds up in the [[liver]] and eventually causes [[scar tissue]]. This type of [[hepatitis]] appears to be associated with [[diabetes]], [[protein malnutrition]], [[obesity]], [[coronary artery disease]], and treatment with [[corticosteroid]] medications.
* '''[[Alcoholic liver disease]]''':  [[Alcohol]] seems to injure the [[liver]] by blocking the normal metabolism of [[protein]], [[fat]]s, and [[carbohydrate]]s. Patients may also have concurrent [[alcoholic hepatitis]] with [[fever]], [[hepatomegaly]], [[jaundice]], and [[anorexia]]. [[Liver]] damage due to [[alcoholic hepatitis]] may progress to cirrhosis.
** '''[[Primary sclerosing cholangitis]]:'''  [[Primary sclerosing cholangitis|PSC]] is a progressive [[Cholestasis|cholestatic]] disorder presenting with [[pruritus]], [[steatorrhea]], [[Fat soluble vitamins|fat soluble vitamin]] deficiencies, and metabolic bone disease.  
* '''Chronic hepatitis C''':  Infection with the [[hepatitis C]] virus causes [[inflammation]] and low grade damage to the [[liver]] that may eventually lead to cirrhosis after decades.
*** There is a strong association with [[inflammatory bowel disease]] (IBD), especially [[ulcerative colitis]].
* '''[[Non-alcoholic fatty liver disease|Non-alcoholic steatohepatitis]]''' (NASH):  In [[Non-alcoholic fatty liver disease|NASH]], fat builds up in the [[liver]] and eventually causes [[scar tissue]]. This type of [[hepatitis]] appears to be associated with [[diabetes]], [[protein malnutrition]], [[obesity]], [[coronary artery disease]], and treatment with [[corticosteroid]] medications.
** '''[[Autoimmune hepatitis]]''':  Immunologic damage to the [[liver]] leads to [[inflammation]], [[Scar|scarring]] and cirrhosis.
* '''[[Primary sclerosing cholangitis]] (PSC):'''  [[Primary sclerosing cholangitis|PSC]] is a progressive [[Cholestasis|cholestatic]] disorder presenting with [[pruritus]], [[steatorrhea]], [[Fat soluble vitamins|fat soluble vitamin]] deficiencies, and [[metabolic]] bone disease.  
** There is a strong association with [[inflammatory bowel disease]] (IBD), especially [[ulcerative colitis]].
* '''[[Autoimmune hepatitis]]''':  [[Immunological|Immunologic]] damage to the [[liver]] leads to [[inflammation]], [[Scar|scarring]] and cirrhosis.


* [[Portal hypertension]] may result from a combination of the following:
* [[Portal hypertension]] may result from a combination of the following:
Line 70: Line 82:
**  Functional abnormalities such as [[Endothelium|endothelial]] dysfunction and increased [[Liver|hepatic]] [[vascular]] tone account for 30% of total [[Liver|hepatic]] [[vascular resistance]].
**  Functional abnormalities such as [[Endothelium|endothelial]] dysfunction and increased [[Liver|hepatic]] [[vascular]] tone account for 30% of total [[Liver|hepatic]] [[vascular resistance]].


Pathogenesis of Cirrhosis due to Alcohol:
===Pathophysiology of Cirrhosis due to Alcohol===
Mechanisms of [[alcohol]]-induced [[liver]] damage include:<ref name="pmid25548474">{{cite journal |vauthors=Ceni E, Mello T, Galli A |title=Pathogenesis of alcoholic liver disease: role of oxidative metabolism |journal=World J. Gastroenterol. |volume=20 |issue=47 |pages=17756–72 |year=2014 |pmid=25548474 |pmc=4273126 |doi=10.3748/wjg.v20.i47.17756 |url=}}</ref><ref name="pmid15194557">{{cite journal |vauthors=You M, Crabb DW |title=Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=287 |issue=1 |pages=G1–6 |year=2004 |pmid=15194557 |doi=10.1152/ajpgi.00056.2004 |url=}}</ref><ref name="pmid16088993">{{cite journal |vauthors=Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR |title=Recent advances in alcohol-induced adduct formation |journal=Alcohol. Clin. Exp. Res. |volume=29 |issue=7 |pages=1310–6 |year=2005 |pmid=16088993 |doi= |url=}}</ref><ref name="pmid17590995">{{cite journal |vauthors=Niemelä O |title=Acetaldehyde adducts in circulation |journal=Novartis Found. Symp. |volume=285 |issue= |pages=183–92; discussion 193–7 |year=2007 |pmid=17590995 |doi= |url=}}</ref>
* Impairment of:
** [[Protein synthesis]]
** [[Secretion]]
** [[Glycosylation]]


==Pathophysiology of cirrhosis due to alcohol==
* Mechanisms of [[alcohol]]-induced [[liver]] damage include:<ref name="pmid25548474">{{cite journal |vauthors=Ceni E, Mello T, Galli A |title=Pathogenesis of alcoholic liver disease: role of oxidative metabolism |journal=World J. Gastroenterol. |volume=20 |issue=47 |pages=17756–72 |year=2014 |pmid=25548474 |pmc=4273126 |doi=10.3748/wjg.v20.i47.17756 |url=}}</ref><ref name="pmid15194557">{{cite journal |vauthors=You M, Crabb DW |title=Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=287 |issue=1 |pages=G1–6 |year=2004 |pmid=15194557 |doi=10.1152/ajpgi.00056.2004 |url=}}</ref><ref name="pmid16088993">{{cite journal |vauthors=Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR |title=Recent advances in alcohol-induced adduct formation |journal=Alcohol. Clin. Exp. Res. |volume=29 |issue=7 |pages=1310–6 |year=2005 |pmid=16088993 |doi= |url=}}</ref><ref name="pmid17590995">{{cite journal |vauthors=Niemelä O |title=Acetaldehyde adducts in circulation |journal=Novartis Found. Symp. |volume=285 |issue= |pages=183–92; discussion 193–7 |year=2007 |pmid=17590995 |doi= |url=}}</ref><ref name="pmid11841919">{{cite journal |vauthors=Tuma DJ |title=Role of malondialdehyde-acetaldehyde adducts in liver injury |journal=Free Radic. Biol. Med. |volume=32 |issue=4 |pages=303–8 |year=2002 |pmid=11841919 |doi= |url=}}</ref><ref name="pmid15540799">{{cite journal |vauthors=Tuma DJ, Casey CA |title=Dangerous byproducts of alcohol breakdown--focus on adducts |journal=Alcohol Res Health |volume=27 |issue=4 |pages=285–90 |year=2003 |pmid=15540799 |doi= |url=}}</ref><ref name="pmid16054980">{{cite journal |vauthors=Brooks PJ, Theruvathu JA |title=DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis |journal=Alcohol |volume=35 |issue=3 |pages=187–93 |year=2005 |pmid=16054980 |doi=10.1016/j.alcohol.2005.03.009 |url=}}</ref><ref name="pmid17718399">{{cite journal |vauthors=Seitz HK, Becker P |title=Alcohol metabolism and cancer risk |journal=Alcohol Res Health |volume=30 |issue=1 |pages=38–41, 44–7 |year=2007 |pmid=17718399 |pmc=3860434 |doi= |url=}}</ref><ref name="pmid9857222">{{cite journal |vauthors=Biewald J, Nilius R, Langner J |title=Occurrence of acetaldehyde protein adducts formed in various organs of chronically ethanol fed rats: an immunohistochemical study |journal=Int. J. Mol. Med. |volume=2 |issue=4 |pages=389–96 |year=1998 |pmid=9857222 |doi= |url=}}</ref><ref name="pmid17543846">{{cite journal |vauthors=Seitz HK, Meier P |title=The role of acetaldehyde in upper digestive tract cancer in alcoholics |journal=Transl Res |volume=149 |issue=6 |pages=293–7 |year=2007 |pmid=17543846 |doi=10.1016/j.trsl.2006.12.002 |url=}}</ref><ref name="pmid36785782">{{cite journal |vauthors=Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV |title=Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans |journal=Biochem. Soc. Trans. |volume=15 |issue=4 |pages=576–8 |year=1987 |pmid=3678578 |doi= |url=}}</ref><ref name="pmid5009602">{{cite journal |vauthors=Lieber CS |title=Metabolism of ethanol and alcoholism: racial and acquired factors |journal=Ann. Intern. Med. |volume=76 |issue=2 |pages=326–7 |year=1972 |pmid=5009602 |doi= |url=}}</ref><ref name="pmid4402282">{{cite journal |vauthors=Lieber CS, DeCarli LM |title=The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo |journal=J. Pharmacol. Exp. Ther. |volume=181 |issue=2 |pages=279–87 |year=1972 |pmid=4402282 |doi= |url=}}</ref><ref name="pmid9114822">{{cite journal |vauthors=Lieber CS |title=Cytochrome P-4502E1: its physiological and pathological role |journal=Physiol. Rev. |volume=77 |issue=2 |pages=517–44 |year=1997 |pmid=9114822 |doi= |url=}}</ref><ref name="pmid2333153">{{cite journal |vauthors=Hansson T, Tindberg N, Ingelman-Sundberg M, Köhler C |title=Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system |journal=Neuroscience |volume=34 |issue=2 |pages=451–63 |year=1990 |pmid=2333153 |doi= |url=}}</ref><ref name="pmid17760783">{{cite journal |vauthors=Donohue TM, Cederbaum AI, French SW, Barve S, Gao B, Osna NA |title=Role of the proteasome in ethanol-induced liver pathology |journal=Alcohol. Clin. Exp. Res. |volume=31 |issue=9 |pages=1446–59 |year=2007 |pmid=17760783 |doi=10.1111/j.1530-0277.2007.00454.x |url=}}</ref><ref name="pmid17854134">{{cite journal |vauthors=Osna NA, Donohue TM |title=Implication of altered proteasome function in alcoholic liver injury |journal=World J. Gastroenterol. |volume=13 |issue=37 |pages=4931–7 |year=2007 |pmid=17854134 |pmc=4434615 |doi= |url=}}</ref><ref name="pmid18078827">{{cite journal |vauthors=Lu Y, Cederbaum AI |title=CYP2E1 and oxidative liver injury by alcohol |journal=Free Radic. Biol. Med. |volume=44 |issue=5 |pages=723–38 |year=2008 |pmid=18078827 |pmc=2268632 |doi=10.1016/j.freeradbiomed.2007.11.004 |url=}}</ref><ref name="pmid1545775">{{cite journal |vauthors=Yun YP, Casazza JP, Sohn DH, Veech RL, Song BJ |title=Pretranslational activation of cytochrome P450IIE during ketosis induced by a high fat diet |journal=Mol. Pharmacol. |volume=41 |issue=3 |pages=474–9 |year=1992 |pmid=1545775 |doi= |url=}}</ref><ref name="pmid2005876">{{cite journal |vauthors=Raucy JL, Lasker JM, Kraner JC, Salazar DE, Lieber CS, Corcoran GB |title=Induction of cytochrome P450IIE1 in the obese overfed rat |journal=Mol. Pharmacol. |volume=39 |issue=3 |pages=275–80 |year=1991 |pmid=2005876 |doi= |url=}}</ref><ref name="pmid11826398">{{cite journal |vauthors=Woodcroft KJ, Hafner MS, Novak RF |title=Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression |journal=Hepatology |volume=35 |issue=2 |pages=263–73 |year=2002 |pmid=11826398 |doi=10.1053/jhep.2002.30691 |url=}}</ref><ref name="pmid7700245">{{cite journal |vauthors=De Waziers I, Garlatti M, Bouguet J, Beaune PH, Barouki R |title=Insulin down-regulates cytochrome P450 2B and 2E expression at the post-transcriptional level in the rat hepatoma cell line |journal=Mol. Pharmacol. |volume=47 |issue=3 |pages=474–9 |year=1995 |pmid=7700245 |doi= |url=}}</ref><ref name="pmid9765518">{{cite journal |vauthors=Peng HM, Coon MJ |title=Regulation of rabbit cytochrome P450 2E1 expression in HepG2 cells by insulin and thyroid hormone |journal=Mol. Pharmacol. |volume=54 |issue=4 |pages=740–7 |year=1998 |pmid=9765518 |doi= |url=}}</ref><ref name="pmid1822117">{{cite journal |vauthors=Terelius Y, Norsten-Höög C, Cronholm T, Ingelman-Sundberg M |title=Acetaldehyde as a substrate for ethanol-inducible cytochrome P450 (CYP2E1) |journal=Biochem. Biophys. Res. Commun. |volume=179 |issue=1 |pages=689–94 |year=1991 |pmid=1822117 |doi= |url=}}</ref><ref name="pmid9726291">{{cite journal |vauthors=Wu YS, Salmela KS, Lieber CS |title=Microsomal acetaldehyde oxidation is negligible in the presence of ethanol |journal=Alcohol. Clin. Exp. Res. |volume=22 |issue=5 |pages=1165–9 |year=1998 |pmid=9726291 |doi= |url=}}</ref><ref name="pmid9309320">{{cite journal |vauthors=Brooks PJ |title=DNA damage, DNA repair, and alcohol toxicity--a review |journal=Alcohol. Clin. Exp. Res. |volume=21 |issue=6 |pages=1073–82 |year=1997 |pmid=9309320 |doi= |url=}}</ref>
** Impairment of:
*** [[Protein synthesis]]
*** [[Secretion]]
*** [[Glycosylation]]
* [[Ethanol]] intake leads to elevated accumulation of intracellular [[Triglyceride|triglycerides]] by:<ref name="pmid12791698">{{cite journal |vauthors=Fischer M, You M, Matsumoto M, Crabb DW |title=Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice |journal=J. Biol. Chem. |volume=278 |issue=30 |pages=27997–8004 |year=2003 |pmid=12791698 |doi=10.1074/jbc.M302140200 |url=}}</ref><ref name="pmid15578517">{{cite journal |vauthors=You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW |title=The role of AMP-activated protein kinase in the action of ethanol in the liver |journal=Gastroenterology |volume=127 |issue=6 |pages=1798–808 |year=2004 |pmid=15578517 |doi= |url=}}</ref><ref name="pmid16879892">{{cite journal |vauthors=Ji C, Chan C, Kaplowitz N |title=Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model |journal=J. Hepatol. |volume=45 |issue=5 |pages=717–24 |year=2006 |pmid=16879892 |doi=10.1016/j.jhep.2006.05.009 |url=}}</ref>
* [[Ethanol]] intake leads to elevated accumulation of intracellular [[Triglyceride|triglycerides]] by:<ref name="pmid12791698">{{cite journal |vauthors=Fischer M, You M, Matsumoto M, Crabb DW |title=Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice |journal=J. Biol. Chem. |volume=278 |issue=30 |pages=27997–8004 |year=2003 |pmid=12791698 |doi=10.1074/jbc.M302140200 |url=}}</ref><ref name="pmid15578517">{{cite journal |vauthors=You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW |title=The role of AMP-activated protein kinase in the action of ethanol in the liver |journal=Gastroenterology |volume=127 |issue=6 |pages=1798–808 |year=2004 |pmid=15578517 |doi= |url=}}</ref><ref name="pmid16879892">{{cite journal |vauthors=Ji C, Chan C, Kaplowitz N |title=Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model |journal=J. Hepatol. |volume=45 |issue=5 |pages=717–24 |year=2006 |pmid=16879892 |doi=10.1016/j.jhep.2006.05.009 |url=}}</ref>
** [[Lipoprotein]] secretion
** [[Lipoprotein]] secretion
** Decreased [[fatty acid]] [[Redox|oxidation]]
** Decreased [[fatty acid]] [[Redox|oxidation]]
** Increased [[fatty acid]] uptake
** Increased [[fatty acid]] uptake
* [[Alcohol]] is converted by [[Alcohol dehydrogenase]] to [[acetaldehyde]].  
* [[Alcohol]] is converted by [[alcohol dehydrogenase]] to [[acetaldehyde]].  
* Due to the high reactivity of [[acetaldehyde]], it forms [[acetaldehyde]]-[[protein]] adducts which cause damage to cells by:
* Due to the high reactivity of [[acetaldehyde]], it forms [[acetaldehyde]]-[[protein]] adducts which cause damage to [[Cells (biology)|cells]] by:
** Trafficking of [[Liver|hepatic]] [[Protein|proteins]]
** Trafficking of [[Liver|hepatic]] [[Protein|proteins]]
** Interrupting [[microtubule]] formation
** Interrupting [[microtubule]] formation
** Interfering with enzyme activities
** Interfering with [[enzyme]] activities
* [[Reactive oxygen species]] begin to form as a result of [[hepatocyte]] damage that activate [[Kupffer cell|Kupffer cells]].<ref name="pmid11984538">{{cite journal |vauthors=Arthur MJ |title=Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C |journal=Gastroenterology |volume=122 |issue=5 |pages=1525–8 |year=2002 |pmid=11984538 |doi= |url=}}</ref>
* [[Reactive oxygen species]] begin to form as a result of [[hepatocyte]] damage that activate [[Kupffer cell|Kupffer cells]].<ref name="pmid11984538">{{cite journal |vauthors=Arthur MJ |title=Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C |journal=Gastroenterology |volume=122 |issue=5 |pages=1525–8 |year=2002 |pmid=11984538 |doi= |url=}}</ref>
*[[Kupffer cell]] activation leads to the production of profibrogenic [[Cytokine|cytokines]] which in turn, stimulates [[Stellate cell|stellate]] cells.
*[[Kupffer cell]] activation leads to the production of profibrogenic [[Cytokine|cytokines]] which in turn, stimulates [[Stellate cell|stellate cells]].
*[[Stellate cell]] activation leads to [[connective tissue]] formation due to deposition [[extracellular matrix]] and [[collagen]].
*[[Stellate cell]] activation leads to [[connective tissue]] formation due to deposition [[extracellular matrix]] and [[collagen]].
* [[Portal triad|Portal triads]] develop connections with central veins due to [[connective tissue]] formation in pericentral and periportal zones, leading to the formation of regenerative [[Nodule (medicine)|nodules]].  
* [[Portal triad|Portal triads]] develop connections with central [[veins]] due to [[connective tissue]] formation in pericentral and periportal zones, leading to the formation of regenerative [[Nodule (medicine)|nodules]].  
* Shrinkage of the [[liver]] occurs over years due to repeated insults that lead to:
* Shrinkage of the [[liver]] occurs over years due to repeated insults that lead to:
** Loss of [[Hepatocyte|hepatocytes]]
** Loss of [[Hepatocyte|hepatocytes]]
** Increased production and deposition of [[collagen]] and regenerative [[Nodule (medicine)|nodule]] formation in a background of [[fibrosis]]
** Increased production and deposition of [[collagen]] and regenerative [[Nodule (medicine)|nodule]] formation on a background of [[fibrosis]]
===Pathophysiology of Portal Hypertension due to Cirrhosis===
==== Increased resistance ====
* Portal hypertension is related to elevation of resistance in the [[Portal venous system|portal vasculature]].
* Increased resistance in [[Portal venous system|portal system]] may be due to both intra-[[hepatic]] and also [[Portocaval anastomoses|portosystemic collateral]] resistance.
** '''Intra-hepatic resistance'''
*** The main factor responsible for intra-[[hepatic]] resistance is [[hepatic]] vascular [[compliance]], which is greatly decreased in liver [[fibrosis]] or [[cirrhosis]].
*** [[Portal hypertension]] occurs when [[compliance]] is decreased and [[blood flow]] is increased in [[liver]].<ref name="pmid5543903">{{cite journal |vauthors=Greenway CV, Stark RD |title=Hepatic vascular bed |journal=Physiol. Rev. |volume=51 |issue=1 |pages=23–65 |year=1971 |pmid=5543903 |doi= |url=}}</ref>
*** Pre-[[hepatic]] and post-[[hepatic]] [[portal hypertension]] arise due to some secondary obstruction before or after [[liver]] [[vasculature]], respectively.<ref>{{cite book | last = Schiff | first = Eugene | title = Schiff's diseases of the liver | publisher = John Wiley & Sons | location = Chichester, West Sussex, UK | year = 2012 | isbn = 9780470654682 }}</ref>
*** [[Alcoholic hepatitis]] causes both [[sinusoidal]] and post-[[sinusoidal]] pathologies.<ref name="pmid13976646">{{cite journal |vauthors=SCHAFFNER F, POPER H |title=Capillarization of hepatic sinusoids in man |journal=Gastroenterology |volume=44 |issue= |pages=239–42 |year=1963 |pmid=13976646 |doi= |url=}}</ref><ref name="pmid5775031">{{cite journal |vauthors=Reynolds TB, Hidemura R, Michel H, Peters R |title=Portal hypertension without cirrhosis in alcoholic liver disease |journal=Ann. Intern. Med. |volume=70 |issue=3 |pages=497–506 |year=1969 |pmid=5775031 |doi= |url=}}</ref>
*** [[Hepatic]] vascular [[endothelium]] synthesizes and secretes both [[Vasodilator|vasodilators]] (e.g., [[nitric oxide]], [[Prostacyclin|prostacyclins]]) and [[Vasoconstrictor|vasoconstrictors]]  (e.g., [[endothelin]] and [[Prostanoid|prostanoids]]).<ref name="pmid1874796">{{cite journal |vauthors=Rubanyi GM |title=Endothelium-derived relaxing and contracting factors |journal=J. Cell. Biochem. |volume=46 |issue=1 |pages=27–36 |year=1991 |pmid=1874796 |doi=10.1002/jcb.240460106 |url=}}</ref><ref name="EpsteinVane1990">{{cite journal|last1=Epstein|first1=Franklin H.|last2=Vane|first2=John R.|last3=Änggård|first3=Erik E.|last4=Botting|first4=Regina M.|title=Regulatory Functions of the Vascular Endothelium|journal=New England Journal of Medicine|volume=323|issue=1|year=1990|pages=27–36|issn=0028-4793|doi=10.1056/NEJM199007053230106}}</ref>
*** Increased resistance due to the elevation of [[vascular]] tone may be caused by excess of [[vasoconstrictors]] or lack of [[vasodilators]].
*** It is postulated that in [[Cirrhosis|cirrhotic liver]] the [[nitric oxide]] level is lower and the response to [[endothelin]] in [[myofibrils]] is stronger than in normal [[liver]].<ref name="pmid8707268">{{cite journal |vauthors=Rockey DC, Weisiger RA |title=Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance |journal=Hepatology |volume=24 |issue=1 |pages=233–40 |year=1996 |pmid=8707268 |doi=10.1002/hep.510240137 |url=}}</ref>
** '''Portosystemic collateral resistance'''
*** [[Collateral]] blood circulation develops as a consequence of [[portal hypertension]] which is the main contributor to [[Gastrointestinal varices|esophageal and gastric varices]]
*** The main purpose of the [[collaterals]] is to decompress and bypass [[portal]] [[blood]] flow.
*** However, [[Portocaval anastomoses|portosystemic collaterals]] may not lead to a complete decompression.
*** [[Portocaval anastomoses|Portosystemic circulation]] occurs between the [[short gastric]], [[left gastric vein]], and the [[esophageal]], [[azygos]] and the [[intercostal veins]]; the superior, the middle, and the inferior [[Hemorrhoidal plexus|hemorrhoidal veins]]; the [[Paraumbilical veins|paraumbilical venous plexus]], the [[venous]] system of [[abdominal]] [[organs]] juxtaposed with the [[retroperitoneum]] and [[abdominal wall]]; the left [[renal vein]], the [[splanchnic]], the [[adrenal]], and the [[spermatic veins]].<ref name="pmid1415713">{{cite journal |vauthors=Mosca P, Lee FY, Kaumann AJ, Groszmann RJ |title=Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium |journal=Am. J. Physiol. |volume=263 |issue=4 Pt 1 |pages=G544–50 |year=1992 |pmid=1415713 |doi= |url=}}</ref>
 
==== Hyperdynamic circulation in portal hypertension ====
* Peripheral [[vasodilatation]] is the basis for decreased systemic [[vascular resistance]] and [[mean arterial pressure]], [[plasma]] volume expansion, elevated [[splanchnic]] [[blood flow]], and elevated [[cardiac index]].<ref name="pmid1735537">{{cite journal |vauthors=Colombato LA, Albillos A, Groszmann RJ |title=Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats |journal=Hepatology |volume=15 |issue=2 |pages=323–8 |year=1992 |pmid=1735537 |doi= |url=}}</ref>
* '''Systemic vasodilation'''
** Three main mechanisms which contribute to the peripheral [[vasodilation]] are as follows:
*** Increased [[vasodilators]] production in systemic circulation<ref name="pmid2372062">{{cite journal |vauthors=Genecin P, Polio J, Colombato LA, Ferraioli G, Reuben A, Groszmann RJ |title=Bile acids do not mediate the hyperdynamic circulation in portal hypertensive rats |journal=Am. J. Physiol. |volume=259 |issue=1 Pt 1 |pages=G21–5 |year=1990 |pmid=2372062 |doi= |url=}}</ref>
*** Increased [[vasodilators]] production in local [[endothelium]]<ref name="CasadevallPanés1993">{{cite journal|last1=Casadevall|first1=María|last2=Panés|first2=Julián|last3=Piqué|first3=Josep M.|last4=Marroni|first4=Norma|last5=Bosch|first5=Jaume|last6=Whittle|first6=Brendan J. R.|title=Involvement of nitric oxide and prostaglandins in gastric mucosal hyperemia of portal-hypertensive anesthetized rats|journal=Hepatology|volume=18|issue=3|year=1993|pages=628–634|issn=02709139|doi=10.1002/hep.1840180323}}</ref>
*** Decreased [[vascular]] response to local [[vasoconstrictors]]<ref name="pmid1616049">{{cite journal |vauthors=Sieber CC, Groszmann RJ |title=In vitro hyporeactivity to methoxamine in portal hypertensive rats: reversal by nitric oxide blockade |journal=Am. J. Physiol. |volume=262 |issue=6 Pt 1 |pages=G996–1001 |year=1992 |pmid=1616049 |doi= |url=}}</ref>
* '''Plasma volume'''
** There are several events which contribute to the [[hyperdynamic circulation]] such as:
*** Initial [[vasodilatation]], induced by [[systemic]] and local [[endothelial]] factors
*** Subsequent [[Blood plasma|plasma]] volume expansion<ref name="pmid8425700">{{cite journal |vauthors=Albillos A, Colombato LA, Lee FY, Groszmann RJ |title=Octreotide ameliorates vasodilatation and Na+ retention in portal hypertensive rats |journal=Gastroenterology |volume=104 |issue=2 |pages=575–9 |year=1993 |pmid=8425700 |doi= |url=}}</ref>
==Genetics==
 
* Certain [[TERT]] ([[Telomerase reverse transcriptase|Telomerase reverese transcriptase]]) [[gene]] variants resulting in reduced [[telomerase]] activity have been found to be a [[risk factor]] for sporadic cirrhosis<ref>{{cite journal |author=Calado RT, Brudno J, Mehta P, ''et al.'' |title=Constitutional telomerase mutations are genetic risk factors for cirrhosis |journal=Hepatology |volume=53 |issue=5 |pages=1600–7 |year=2011 |month=May |pmid=21520173 |pmc=3082730 |doi=10.1002/hep.24173 |url=}}</ref>
* An uncharacterized [[Nucleolar protein, member A1|nucleolar protein]], NOL11, has a role in the [[pathogenesis]] of North American Indian childhood cirrhosis<ref>{{cite journal |author=Freed EF, Prieto JL, McCann KL, McStay B, Baserga SJ |title=NOL11, Implicated in the Pathogenesis of North American Indian Childhood Cirrhosis, Is Required for Pre-rRNA Transcription and Processing |journal=PLoS Genet. |volume=8 |issue=8 |pages=e1002892 |year=2012 |month=August |pmid=22916032 |pmc=3420923 |doi=10.1371/journal.pgen.1002892 |url=}}</ref>
* Loss of interaction between the [[C-terminus]] of a protein called Utp4/cirhin and other SSU processome [[proteins]] may cause cirrhosis in children<ref>{{cite journal |author=Freed EF, Baserga SJ |title=The C-terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis |journal=Nucleic Acids Res. |volume=38 |issue=14 |pages=4798–806 |year=2010 |month=August |pmid=20385600 |pmc=2919705 |doi=10.1093/nar/gkq185 |url=}}</ref>
 
==Gross Pathology==
On [[gross examination]], the [[liver]] may initially be enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm, and the color is often yellow (if associates [[steatosis]]). Depending on the size of the [[Nodule (medicine)|nodules]] there are three macroscopic types: micronodular, macronodular and mixed cirrhosis.
* In the micronodular form ([[René Laennec|Laennec]]'s cirrhosis or portal cirrhosis) regenerating [[Nodule (medicine)|nodules]] are under 3 mm.
* In macronodular cirrhosis (post-necrotic cirrhosis), the [[Nodule (medicine)|nodules]] are larger than 3 mm.
* The mixed cirrhosis consists of a variety of [[Nodule (medicine)|nodules]] with different sizes.
On [[gross pathology]], [[Cirrhosis|cirrhotic liver]], [[splenomegaly]], and [[esophageal varices]] are characteristic findings in portal hypertension.
{| class="wikitable"
|-
|
=== Cirrhosis ===
On [[gross pathology]] there are two types of [[cirrhosis]]:
* Micronodular [[cirrhosis]] which is uniform and diffuse, mostly due to [[alcohol]].
* Macronodular [[cirrhosis]] which is irregular, mostly due to [[viral hepatitis]].
|
[[image:Cirrosi micronodular.1427.jpg|thumb|200px|Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons<ref><CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)></ref>]]
|
[[image:Fig78x.jpg|thumb|200px|Macronodular cirrhosis<ref name="urlwww.meddean.luc.edu">{{cite web |url=http://www.meddean.luc.edu/lumen/MedEd/orfpath/images/fig78x.jpg |title=www.meddean.luc.edu |format= |work= |accessdate=}}</ref>]]
|-
|
=== Splenomegaly ===
On [[gross pathology]], diffuse enlargement and [[congestion]] of the [[spleen]] are characteristic findings of [[splenomegaly]].
| colspan="2" |
[[image:Esplenomegalia i hiperplasia linfoide folicular reactiva. IMG 2865.jpg|thumb|200px|center|Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons<ref>Amadalvarez - <span class="int-own-work" lang="en">Own work</span>, <"https://creativecommons.org/licenses/by-sa/4.0" title="Creative Commons Attribution-Share Alike 4.0">CC BY-SA 4.0, <"https://commons.wikimedia.org/w/index.php?curid=49669333">Link</ref>]]
|-
|
=== Esophageal Varices ===
On gross pathology, prominent, congested, and tortoise [[veins]] in the lower parts of [[esophagus]] are characteristic findings of [[esophageal varices]].
| colspan="2" |
[[image:F21. Venous enlargement in hepatic cirrhosis. Alfred Kast Wellcome L0074357.jpg|thumb|200px|center|Esophageal varices<ref><http://wellcomeimages.org/indexplus/obf_images/29/b4/13f38971164f946a97f9d32ddd93.jpg>Gallery: <"http://wellcomeimages.org/indexplus/image/L0074357.html"><"http://creativecommons.org/licenses/by/4.0> CC BY 4.0, <"https://commons.wikimedia.org/w/index.php?curid=36297209"></ref>]]
|}
 
=== Images of gross pathology of cirrhosis ===
[http://www.peir.net Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
<gallery>
Image:Cirrhosis 001.jpg|Cirrhosis: Gross, external view of micronodular cirrhosis 
Image:Cirrhosis 002.jpg|Cirrhosis: Gross, cut section of previous one (an excellent example)
Image:Cirrhosis 003.jpg|Cirrhosis: Gross, close-up image
Image:Cirrhosis 004.jpg|Macronodular cirrhosis and hepatoma
</gallery>
 
<gallery>
Image:Cirrhosis 005.jpg|Cirrhosis: Gross, close-up, natural color (an excellent example)
Image:Cirrhosis 006.jpg|Cirrhosis: Gross, close-up (an excellent example)
Image:Cirrhosis 007.jpg|Cirrhosis: Gross, close-up view
Image:Cirrhosis 008.jpg|Micronodular cirrhosis: Gross, external view (an excellent example)
</gallery>
 
<gallery>
Image:Cirrhosis 009.jpg|Micronodular cirrhosis: Gross, close-up image
Image:Cirrhosis 010.jpg|Micronodular cirrhosis: Gross (an excellent example)
Image:Cirrhosis 011.jpg|Macronodular cirrhosis: Gross, natural color (perfect color for cirrhosis), close-up, an excellent example
Image:Cirrhosis 012.jpg|Cirrhosis with portocaval shunt: Gross, severe cirrhosis with extensive liver necrosis due to thrombosis of portocaval shunt (well shown)
</gallery>
 
<gallery>
Image:Cirrhosis 013.jpg|Endstage cirrhosis: Gross, natural color, close-up (an excellent example)
Image:Cirrhosis 014.jpg|Endstage cirrhosis: Gross, natural color, close-up view is an excellent example for nodules of yellow-orange liver tissue and broad irregular bands of fibrosis
Image:Cirrhosis 015.jpg|Endstage cirrhosis: Gross, natural color, close-up cut surface, very well shown nodules of yellow and necrotic opaque liver tissue with broad and irregular bands of fibrosis (an excellent example)
Image:Cirrhosis 016.jpg|Macronodular cirrhosis: Gross, natural color, external view of liver and very enlarged spleen (liver has variable size nodules up to about 2 cm)
</gallery>
 
<gallery>
Image:Cirrhosis 017.jpg|Macronodular cirrhosis: Gross, natural color, cut surface, large irregular bands of fibrosis with variable size liver cell nodules up to about 8 mm and all necrotic appears to be an end stage liver disease.
Image:Cirrhosis 018.jpg|Macronodular cirrhosis: Gross, natural color view of frontal sections of liver and spleen showing a contracted macronodular liver and an enlarged spleen as large as the liver
Image:Cirrhosis 019.jpg|Macronodular cirrhosis: Gross, natural color slab of liver 
Image:Cirrhosis 020.jpg|Fatty change and early cirrhosis: Gross, natural color, rather close-up image showing typical fatty color, and in lighting at lower right of micrography micronodularity is evident (quite good example)
</gallery>
 
<gallery>
Image:Cirrhosis 021.jpg|Cirrhosis with portal vein thrombosis: Gross, natural color, sectioned liver with portal vein exposed and filled with red thrombus. A good example of end stage cirrhosis.
Image:Cirrhosis 022.jpg|Endstage cirrhosis with lobular necrosis: Gross, natural color, very close-up view (an excellent example of alcoholic cirrhosis) 
Image:Cirrhosis 023.jpg|Micronodular cirrhosis: Gross, natural color view of whole liver through capsule with obvious cirrhosis (note to quite large liver) 
Image:Cirrhosis 024.jpg|Micronodular cirrhosis: Gross, natural color, view of whole liver showing external surface typical cirrhotic liver (history of alcoholism)
</gallery>
 
<gallery>
Image:Cirrhosis 025.jpg|Lung: Idiopathic Interstitial Fibrosis: Gross, natural color, an excellent photo of lung cirrhosis (close-up view)
Image:Cirrhosis 026.jpg|Endstage cirrhosis: Gross, natural color, slice of liver. Portal vein is opened to show size and patency.
Image:Cirrhosis 027.jpg|Endstage cirrhosis: Gross, natural color, severe cirrhosis with bile stasis
Image:Cirrhosis 028.jpg|Portal Vein Thrombosis with cirrhosis: Gross, close-up, micronodular cirrhosis with portal vein thrombosis
</gallery>
 
<gallery>
Image:Cirrhosis 029.jpg|Lung: Hematite: Gross, natural color, external view of "pulmonary cirrhosis" with typical hematite color 
Image:Cirrhosis 030.jpg|Gross, natural color of liver and stomach view from external surfaces, micronodular cirrhosis and hemorrhagic gastritis (as the surgeon would see these in natural color)
</gallery>
==Microscopic Pathology==
*Microscopic pathology reveals the four stages of cirrhosis as it progresses:
**Chronic nonsuppurative destructive [[cholangitis]]: inflammation and necrosis of portal tracts with lymphocyte infiltration leads to the destruction of the [[bile ducts]]
**Development of biliary stasis and [[fibrosis]]
**Periportal [[fibrosis]] progresses to bridging [[fibrosis]]
**Increased proliferation of smaller [[bile ductules]] leads to regenerative [[nodule]] formation
*Microscopically, cirrhosis is characterized by regeneration [[nodules]] surrounded by fibrous septa.
*In these nodules, regenerating [[hepatocyte]]s are present.
*Portal tracts, [[central vein]]s and the radial pattern of hepatocytes are absent.
*Fibrous septa are present and inflammatory infiltrate composed of [[lymphocyte]]s and [[macrophage]]s) are also visible.
*If the underlying cause is [[secondary biliary cirrhosis]], biliary ducts are damaged, proliferated or distended leading to bile stasis.
*Dilated ducts contain inspissated bile which appears as bile casts or bile thrombi (brown-green, amorphous).
*Bile retention may be found also in the parenchyma and are referred to as "bile lakes".<ref>[http://www.pathologyatlas.ro/Cirrhosis.html Pathology atlas], "cirrhosis".</ref>
 
== Microscopic pathology ==
The main microscopic [[histopathological]] findings in portal hypertension are related to [[Cirrhosis (patient information)|cirrhosis]], [[esophageal varices]], [[Hepatic amyloidosis with intrahepatic cholestasis|hepatic amyloidosis]], and congestive [[hepatopathy]] due to [[heart failure]] or [[Budd-Chiari syndrome]].
{| class="wikitable"
|-
|
=== Cirrhosis ===
Robbins definition of [[microscopic]] [[histopathological]] findings in cirrhosis includes (all three is needed for diagnosis):<ref>{{cite book | last = Mitchell | first = Richard | title = Pocket companion to Robbins and Cotran pathologic basis of disease | publisher = Elsevier Saunders | location = Philadelphia, PA | year = 2012 | isbn = 978-1416054542 }}</ref>
* Bridging [[fibrosis]]
* [[Nodule]] formation
* Disruption of the [[hepatic]] architecture
|
[[image:Cirrhosis.jpg|thumb|200px|Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org<ref name="urlFile:Cirrhosis high mag.jpg - Libre Pathology">{{cite web |url=https://librepathology.org/wiki/File:Cirrhosis_high_mag.jpg#filelinks |title=File:Cirrhosis high mag.jpg - Libre Pathology |format= |work= |accessdate=}}</ref>]]
|-
|
=== Esophageal varices ===
The main microscopic [[histopathological]] findings in [[esophageal varices]] are:
* Large dilated [[submucosal]] [[veins]] ('''key feature''')
* [[Blood]] (fresh)
* [[Hemosiderin]]-laden [[macrophages]].
|
[[image:Eso-varices.jpg|thumb|200px|Esophageal varices with submucosal vein (black arrow), via Librepathology.org<ref name="urlEsophageal varices - Libre Pathology">{{cite web |url=https://librepathology.org/wiki/Esophageal_varices#cite_note-3 |title=Esophageal varices - Libre Pathology |format= |work= |accessdate=}}</ref>]]
|-
|
=== Hepatic amyloidosis ===
The main [[microscopic]] [[histopathological]] findings in [[Hepatic amyloidosis with intrahepatic cholestasis|hepatic amyloidosis]] is amorphous extracellular pink stuff on [[H&E stain|H&E]] staining.
|
[[image:Amyloidosis - high mag.jpg|thumb|200px|Hepatic amyloidosis with amorphous amyloids (black arrow) and normal hepatocytes (blue arrow), via Librepathology.org<ref name="urlFile:Hepatic amyloidosis - high mag.jpg - Libre Pathology">{{cite web |url=https://librepathology.org/wiki/File:Hepatic_amyloidosis_-_high_mag.jpg |title=File:Hepatic amyloidosis - high mag.jpg - Libre Pathology |format= |work= |accessdate=}}</ref>]]
|-
|
=== Congestive hepatopathy ===
The main [[microscopic]] [[histopathological]] findings in congestive [[hepatopathy]] (due to [[heart failure]] or [[Budd-Chiari syndrome]]) are:
* [[Atrophy]] of the centrilobular zone (zone III)
* Distension of portal [[venule]] ([[central vein]])
* Perisinusoidal [[fibrosis]] which may progress to centrilobular [[fibrosis]] and then diffuse [[fibrosis]]
* [[Sinusoidal]] dilation in all zone III areas ('''key feature)'''
|
[[image:Congestive hepatopathy.jpg|thumb|200px|Congestive hepatopathy with central vein (yellow arrowhead), inflammatory cells, Councilman body (green arrowhead), and hepatocyte with mitotic figure (red arrowhead), via Librepathology.org<ref name="urlFile:2 CEN NEC 1 680x512px.tif - Libre Pathology">{{cite web |url=https://librepathology.org/wiki/File:2_CEN_NEC_1_680x512px.tif |title=File:2 CEN NEC 1 680x512px.tif - Libre Pathology |format= |work= |accessdate=}}</ref>]]
|}
 
=== Videos ===
{{#ev:youtube|CzKGvWZrUpU}}
 
{{#ev:youtube|CV8OYeIUXko}}
 
{{#ev:youtube|Jj8ozr_IttM}}


==References==
{{Reflist|2}}


Pathology
[[Category:Medicine]]
* There are four stages of Cirrhosis as it progresses:
[[Category:Gastroenterology]]
** Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading to the destruction of the bile ducts.
[[Category:Up-To-Date]]
** Development of biliary stasis and fibrosis
[[Category:Hepatology]]
*Periportal fibrosis progresses to bridging fibrosis
*Increased proliferation of smaller bile ductules leading to regenerative nodule formation.
<references />

Latest revision as of 16:51, 11 October 2022

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Sudarshana Datta, MD [2]

Overview

Cirrhosis occurs due to long term liver injury which causes an imbalance between matrix production and degradation. The pathological hallmark of cirrhosis is the development of scar tissue which leads to replacement of normal liver parenchyma, leading to blockade of portal blood flow and disturbance of normal liver function. When fibrosis of the liver reaches an advanced stage where distortion of the hepatic vasculature also occurs, it is termed as cirrhosis of the liver. The pathogenesis of cirrhosis involves inflammation, hepatic stellate cell activation, angiogenesis, and fibrogenesis. Kupffer cells are hepatic macrophages responsible for hepatic stellate cell activation during injury. Hepatic stellate cells (HSC) which are located in the subendothelial space of Disse, become activated in areas of liver injury and secrete transforming growth factor-beta 1 (TGF-β1), which leads to a fibrotic response and proliferation of connective tissue. Cirrhosis may also lead to hepatic microvascular changes including the formation of intra-hepatic shunts (due to angiogenesis and loss of parenchymal cells) and endothelial dysfunction. Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature, accompanied by regenerative nodule formation. HAYOP

Pathophysiology

The pathogenesis of cirrhosis is as follows:[1][2][3][4][5][6]

Hepatic stellate cell activation

The role of hepatic stellate cells in the pathogenesis of cirrhosis is described below:

Microvascular changes

Cirrhosis leads to hepatic microvascular changes characterised by:[9]

Angiogenesis

Fibrosis

The role of fibrosis in the pathogenesis of cirrhosis is described below:

Pathogenesis of cirrhosis according to cause

Pathogenesis of cirrhosis based upon the underlying cause is as follows:

Pathophysiology of Cirrhosis due to Alcohol

Mechanisms of alcohol-induced liver damage include:[18][19][20][21]

Pathophysiology of Portal Hypertension due to Cirrhosis

Increased resistance

Hyperdynamic circulation in portal hypertension

Genetics

Gross Pathology

On gross examination, the liver may initially be enlarged, but with progression of the disease, it becomes smaller. Its surface is irregular, the consistency is firm, and the color is often yellow (if associates steatosis). Depending on the size of the nodules there are three macroscopic types: micronodular, macronodular and mixed cirrhosis.

  • In the micronodular form (Laennec's cirrhosis or portal cirrhosis) regenerating nodules are under 3 mm.
  • In macronodular cirrhosis (post-necrotic cirrhosis), the nodules are larger than 3 mm.
  • The mixed cirrhosis consists of a variety of nodules with different sizes.

On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension.

Cirrhosis

On gross pathology there are two types of cirrhosis:

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[41]
Macronodular cirrhosis[42]

Splenomegaly

On gross pathology, diffuse enlargement and congestion of the spleen are characteristic findings of splenomegaly.

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[43]

Esophageal Varices

On gross pathology, prominent, congested, and tortoise veins in the lower parts of esophagus are characteristic findings of esophageal varices.

Esophageal varices[44]

Images of gross pathology of cirrhosis

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Pathology

  • Microscopic pathology reveals the four stages of cirrhosis as it progresses:
    • Chronic nonsuppurative destructive cholangitis: inflammation and necrosis of portal tracts with lymphocyte infiltration leads to the destruction of the bile ducts
    • Development of biliary stasis and fibrosis
    • Periportal fibrosis progresses to bridging fibrosis
    • Increased proliferation of smaller bile ductules leads to regenerative nodule formation
  • Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa.
  • In these nodules, regenerating hepatocytes are present.
  • Portal tracts, central veins and the radial pattern of hepatocytes are absent.
  • Fibrous septa are present and inflammatory infiltrate composed of lymphocytes and macrophages) are also visible.
  • If the underlying cause is secondary biliary cirrhosis, biliary ducts are damaged, proliferated or distended leading to bile stasis.
  • Dilated ducts contain inspissated bile which appears as bile casts or bile thrombi (brown-green, amorphous).
  • Bile retention may be found also in the parenchyma and are referred to as "bile lakes".[45]

Microscopic pathology

The main microscopic histopathological findings in portal hypertension are related to cirrhosis, esophageal varices, hepatic amyloidosis, and congestive hepatopathy due to heart failure or Budd-Chiari syndrome.

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[46]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[47]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[48]

Hepatic amyloidosis

The main microscopic histopathological findings in hepatic amyloidosis is amorphous extracellular pink stuff on H&E staining.

Hepatic amyloidosis with amorphous amyloids (black arrow) and normal hepatocytes (blue arrow), via Librepathology.org[49]

Congestive hepatopathy

The main microscopic histopathological findings in congestive hepatopathy (due to heart failure or Budd-Chiari syndrome) are:

Congestive hepatopathy with central vein (yellow arrowhead), inflammatory cells, Councilman body (green arrowhead), and hepatocyte with mitotic figure (red arrowhead), via Librepathology.org[50]

Videos

{{#ev:youtube|CzKGvWZrUpU}}

{{#ev:youtube|CV8OYeIUXko}}

{{#ev:youtube|Jj8ozr_IttM}}

References

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