Cirrhosis pathophysiology: Difference between revisions

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{{Cirrhosis}}
{{Cirrhosis}}
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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>
* 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.
* 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]].
* [[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>
** [[Inflammation]]
** [[Ito cell|Hepatic stellate cell]] activation
** [[Angiogenesis]]
** [[Fibrosis|Fibrogenesis]]
'''Hepatic stellate cell activation'''


* The liver plays a vital role in the synthesis of proteins (e.g. [[serum albumin|albumin]], [[coagulation|clotting factors]] and [[complement system|complement]]), detoxification, and storage (e.g. [[vitamin A]]). In addition, it participates in the metabolism of [[lipid]]s and [[carbohydrate]]s.
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.
* 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 [[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-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]] 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 [[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]].  
* 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]], through a process called capillarization.
* [[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]]-2 and stromyelysin-1 are produced by [[Ito cell|stellate cells]].
* [[Matrix metalloproteinase|MMP]]-2 degrades [[collagen]] and stromelysin-1 degrades [[proteoglycan]] and [[glycoprotein]].
'''Microvascular changes'''


* Cirrhosis is often preceded by [[hepatitis]] and fatty liver ([[steatosis]]). If the cause is removed at this stage, the changes are still fully reversible.
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


* The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal [[parenchyma]], blocking the portal flow of blood through the organ and disturbing normal function. The development of [[fibrosis]] requires several months, or even years, of ongoing injury.
* [[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>
** 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]])
* The [[liver]] responds to injury with new [[blood vessel]] formation. Mediators involved in [[angiogenesis]] include:
**[[Platelet-derived growth factor|Platelet derived growth factor]] ([[Platelet-derived growth factor|PDGF]])
**[[Vascular endothelial growth factor]] ([[Vascular endothelial growth factor|VEGF]])
**[[Nitric oxide]]
**[[Carbon monoxide]]
'''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'''


* Recent research shows the pivotal role of the [[Ito cell|stellate cell]], a cell type that normally stores [[vitamin A]], in the development of cirrhosis. Damage to the hepatic [[parenchyma]] leads to the activation of the stellate cell, which becomes contractile (called [[myofibroblast]]) and obstructs blood flow in the circulation. In addition, it secretes [[TGF beta 1|TGF-β<sub>1</sub>]], which leads to a fibrotic response and proliferation of [[connective tissue]]. The [[extracellular matrix]] around [[hepatocytes]] is composed of [[collagen]]s (especially type I, III, IV), [[glycoprotein]] and [[proteoglycan]]s.  
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]].  
* 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).
* [[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.
* The formation of [[Fibrosis|fibrotic]] bands is accompanied by regenerative [[Nodule (medicine)|nodule]] formation in the [[Liver|hepatic]] [[parenchyma]].
* Advancement of cirrhosis may lead to [[Parenchyma|parenchymal]] dysfunction and development of [[portal hypertension]].  
* 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.  
'''Pathogenesis of cirrhosis according to cause'''


* Sinusoidal 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>
[[Pathogenesis]] of cirrhosis based upon the underlying cause is as follows:
* '''[[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]] and low grade damage to the [[liver]] that may eventually lead to cirrhosis after decades.
* '''[[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.
* '''[[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.


*In addition, the liver responds to injury with new blood vessel formation.  Platelet derived growth factor (PDGF), [[vascular endothelial growth factor]] (VEGF), [[nitric oxide]], and [[carbon monoxide]] are the mediators involved in angiogenesis. [[Angiogenesis]] in cirrhosis results in the production of immature and permeable VEGF induced neo-vessels that fail to correct 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>
* [[Portal hypertension]] may result from a combination of the following:
** Structural disturbances associated with advanced [[liver]] disease account for 70% 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]].


* Furthermore, it disturbs the balance between [[matrix metalloproteinase]]s and the naturally occurring inhibitors (TIMP 1 and 2), leading to[[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 enzyme]]s that specifically degrade [[collagen]] and non collagenous substrate.  There are five categories of MMP based upon their specificity for the substrate.  MMP-2 and stromyelysin-1 are produced from stellate cells.  MMP-2 degrades collagen and stromelysin-1 degrades [[proteoglycan]] and [[glycoprotein]].
===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]]


* The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout.
* [[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>
* The [[spleen]] becomes congested, which leads to [[hypersplenism]] and increased sequestration of [[platelet]]s.
** [[Lipoprotein]] secretion
* [[Portal hypertension]] is responsible for the most severe complications of cirrhosis.
** Decreased [[fatty acid]] [[Redox|oxidation]]
 
** Increased [[fatty acid]] uptake
* Pathogenesis of cirrhosis based upon its individual cause is as follows:
* [[Alcohol]] is converted by [[alcohol dehydrogenase]] to [[acetaldehyde]].  
** '''[[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].
* Due to the high reactivity of [[acetaldehyde]], it forms [[acetaldehyde]]-[[protein]] adducts which cause damage to [[Cells (biology)|cells]] by:
** '''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.
** Trafficking of [[Liver|hepatic]] [[Protein|proteins]]
** '''[[Non-alcoholic fatty liver disease|Non-alcoholic steatohepatitis]]''' (NASH):  In 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.
** Interrupting [[microtubule]] formation
** '''[[Primary sclerosing cholangitis]]:'''  PSC is a progressive cholestatic disorder presenting with [[pruritus]], [[steatorrhea]], fat soluble vitamin deficiencies, and [[metabolic bone disease]]. There is a strong association with [[inflammatory bowel disease]] (IBD), especially [[ulcerative colitis]].
** Interfering with [[enzyme]] activities
** '''[[Autoimmune hepatitis]]''':  This disease is caused by the immunologic damage to the liver causing [[inflammation]] and eventually scarring and cirrhosis.
* [[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]].
==Pathophysiology of Alcoholic liver disease==
*[[Stellate cell]] activation leads to [[connective tissue]] formation due to deposition [[extracellular matrix]] and [[collagen]].
*[[Ethanol]] [[metabolism]] in the [[liver]] is carried out mainly by two [[enzymes]]:<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>
* [[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]].  
**[[Alcohol dehydrogenase]]
* Shrinkage of the [[liver]] occurs over years due to repeated insults that lead to:
**[[Aldehyde dehydrogenase]]  
** Loss of [[Hepatocyte|hepatocytes]]
*Both of these [[enzymes]] use [[Nicotinamide adenine dinucleotide|NAD]]+ as a cofactor. [[Alcohol]] is converted to [[acetaldehyde]] and [[acetaldehyde]] is then further [[oxidized]] to [[acetate]]. [[Acetaldehyde]] is the [[toxic]] [[metabolite]] in this process.
** Increased production and deposition of [[collagen]] and regenerative [[Nodule (medicine)|nodule]] formation on a background of [[fibrosis]]
*The [[metabolism]] of [[alcohol]] in the [[liver]] ends up producing an excess of reduced [[nicotinamide adenine dinucleotide]] (NADH). This changes the reduction-oxidation potential in the [[liver]] and inhibits key [[metabolic]] processes in the [[liver]] such as, the [[tricarboxylic acid cycle]] and the [[oxidation]] of [[Fatty acid|fatty acids]] and thereby ends up promoting lipogenesis.<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>
===Pathophysiology of Portal Hypertension due to Cirrhosis===
*Since [[acetaldehyde]] has an [[electrophilic]] nature it can form [[covalent]] chemical bonds with [[Protein|proteins]], [[Lipid|lipids]] and [[DNA]]. These [[Covalent bond|covalent]] bonds that are formed are extremely [[pathogenic]], as they have the ability to alter [[cell]] environments, [[protein]] structures and they can enable [[DNA]] damage and [[mutation]].<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>
 
*The [[cytochrome]] [[Cytochrome P450|P450]] enzymes (CYP) are a part of the [[Microsomal Ethanol Oxidizing System|microsomal ethanol oxidizing system]]. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.<ref name="pmid3678578">{{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>
 
*There is an ethanol inducible form of CYP enzymes that is working in a small amount under normal physiological conditions. This enzyme [[CYP2E1]] is converting [[ethanol]] to [[acetaldehyde]] and then to [[acetate]]. When there is chronic [[alcohol]] abuse, there is induction of the microsomal system and there is an increase in the expression of [[CYP2E1]]. This increase in [[CYP2E1]] expression under chronic [[ethanol]] consumption can be hazardous, as this [[oxidation]] reaction can produces many different ROS; O<sub>2</sub><sup>-</sup>, H<sub>2</sub>O<sub>2</sub>, OH<sup>-</sup> and hydroxyethyl radical (HER).<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>
 
*[[Ethanol]] [[metabolism]] additionally promotes [[lipogenesis]] through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound [[Transcription (genetics)|transcription]] factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.<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>
 
*Two key factors that play an important role in the [[inflammatory]] process that leads to the alcohol mediated liver injury are:<ref name="pmid6433728">{{cite journal |vauthors=Tsukamoto H, Reidelberger RD, French SW, Largman C |title=Long-term cannulation model for blood sampling and intragastric infusion in the rat |journal=Am. J. Physiol. |volume=247 |issue=3 Pt 2 |pages=R595–9 |year=1984 |pmid=6433728 |doi= |url=}}</ref><ref name="pmid11431739">{{cite journal |vauthors=Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG |title=Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice |journal=Hepatology |volume=34 |issue=1 |pages=101–8 |year=2001 |pmid=11431739 |doi=10.1053/jhep.2001.25350 |url=}}</ref>
**[[Endotoxin]]
**Gut permeability
*[[Endotoxin]] is associated to the [[lipopolysaccharide]] (LPS) component of the outer wall of [[gram-negative bacteria]] and is thought to be the key trigger in this [[Inflammation|inflammatory]] process.<ref name="pmid15723320">{{cite journal |vauthors=Wiest R, Garcia-Tsao G |title=Bacterial translocation (BT) in cirrhosis |journal=Hepatology |volume=41 |issue=3 |pages=422–33 |year=2005 |pmid=15723320 |doi=10.1002/hep.20632 |url=}}</ref><ref name="pmid8171045">{{cite journal |vauthors=Nanji AA, Khettry U, Sadrzadeh SM |title=Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease) |journal=Proc. Soc. Exp. Biol. Med. |volume=205 |issue=3 |pages=243–7 |year=1994 |pmid=8171045 |doi= |url=}}</ref>
*Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation.<ref name="pmid7806045">{{cite journal |vauthors=Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG |title=Antibiotics prevent liver injury in rats following long-term exposure to ethanol |journal=Gastroenterology |volume=108 |issue=1 |pages=218–24 |year=1995 |pmid=7806045 |doi= |url=}}</ref><ref name="pmid6141332">{{cite journal |vauthors=Bjarnason I, Peters TJ, Wise RJ |title=The leaky gut of alcoholism: possible route of entry for toxic compounds |journal=Lancet |volume=1 |issue=8370 |pages=179–82 |year=1984 |pmid=6141332 |doi= |url=}}</ref>
*The fact that long term exposure to [[alcohol]] increases gut permeability has been observed in humans as LPS-endotoxin levels have been found to be elevated in patients with [[alcoholic]] [[liver]] injury.<ref name="pmid11236841">{{cite journal |vauthors=Urbaschek R, McCuskey RS, Rudi V, Becker KP, Stickel F, Urbaschek B, Seitz HK |title=Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease |journal=Alcohol. Clin. Exp. Res. |volume=25 |issue=2 |pages=261–8 |year=2001 |pmid=11236841 |doi= |url=}}</ref>
 
*After the entry of LPS-[[endotoxin]] in to the [[portal]] [[circulation]] it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to [[alcohol]] ingestion.<ref name="pmid11884468">{{cite journal |vauthors=Uesugi T, Froh M, Arteel GE, Bradford BU, Wheeler MD, Gäbele E, Isayama F, Thurman RG |title=Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice |journal=J. Immunol. |volume=168 |issue=6 |pages=2963–9 |year=2002 |pmid=11884468 |doi= |url=}}</ref>
*The LPS-LPS binding protein complex binds to the [[CD14]] receptor on the cell surface membrane of the [[Kupffer cells]] in the [[liver]]. 
*Activation of these [[Kupffer cell|Kupffer cells]] requires 3 main cellular proteins:<ref name="pmid8045507">{{cite journal |vauthors=Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG |title=Inactivation of Kupffer cells prevents early alcohol-induced liver injury |journal=Hepatology |volume=20 |issue=2 |pages=453–60 |year=1994 |pmid=8045507 |doi= |url=}}</ref>
**[[CD14]] (monocyte differentiation antigen)<ref name="pmid11254735">{{cite journal |vauthors=Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG |title=Reduced early alcohol-induced liver injury in CD14-deficient mice |journal=J. Immunol. |volume=166 |issue=7 |pages=4737–42 |year=2001 |pmid=11254735 |doi= |url=}}</ref>
**Toll-like receptor 4 (TLR4)<ref name="pmid18792393">{{cite journal |vauthors=Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G |title=The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88 |journal=Hepatology |volume=48 |issue=4 |pages=1224–31 |year=2008 |pmid=18792393 |doi=10.1002/hep.22470 |url=}}</ref>
**MD2, a protein, binds [[TLR 4|TLR4]] with LPS-LPS binding protein
*The [[TLR 4|TLR4]] then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.<ref name="pmid11477402">{{cite journal |vauthors=Akira S, Takeda K, Kaisho T |title=Toll-like receptors: critical proteins linking innate and acquired immunity |journal=Nat. Immunol. |volume=2 |issue=8 |pages=675–80 |year=2001 |pmid=11477402 |doi=10.1038/90609 |url=}}</ref> 
*The nuclear factor-kB ([[NF-kB]]) and the [[TLR 4|TLR4]] adapter also play an important role in the activation of the [[Kupffer cell|kupffer cells]].<ref name="pmid18713975">{{cite journal |vauthors=Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK |title=TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol |journal=J. Immunol. |volume=181 |issue=5 |pages=3049–56 |year=2008 |pmid=18713975 |pmc=3690475 |doi= |url=}}</ref> 
*EGR1 plays the pivotal role in [[lipopolysaccharide]]-stimulated [[Tumor necrosis factor-alpha|TNF-α]] production. 
*In mice the absence of EGR1 prevents [[alcohol]] induced [[liver]] injury.<ref name="pmid15940638">{{cite journal |vauthors=McMullen MR, Pritchard MT, Wang Q, Millward CA, Croniger CM, Nagy LE |title=Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice |journal=Gastroenterology |volume=128 |issue=7 |pages=2066–76 |year=2005 |pmid=15940638 |pmc=1959407 |doi= |url=}}</ref>
 
*[[Ethanol]] administration stimulates the release of [[mitochondrial]] [[cytochrome]] c and the expression of the [[Fas ligand]], this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway.<ref name="pmid11438480">{{cite journal |vauthors=Zhou Z, Sun X, Kang YJ |title=Ethanol-induced apoptosis in mouse liver: Fas- and cytochrome c-mediated caspase-3 activation pathway |journal=Am. J. Pathol. |volume=159 |issue=1 |pages=329–38 |year=2001 |pmid=11438480 |pmc=1850406 |doi=10.1016/S0002-9440(10)61699-9 |url=}}</ref> 
*The cumulative effect of [[Tumor necrosis factor-alpha|TNF-α]] and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the [[liver]].<ref name="pmid15131799">{{cite journal |vauthors=Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G |title=Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption |journal=Gastroenterology |volume=126 |issue=5 |pages=1387–99 |year=2004 |pmid=15131799 |doi= |url=}}</ref>
 
==Pathophysiology of Portal Hypertension==
==== Increased resistance ====
==== Increased resistance ====
* Portal hypertension is related to elevation of [[Portal venous system|portal vasculature]] resistance.  
* Portal hypertension is related to elevation of resistance in the [[Portal venous system|portal vasculature]].  
* Increased resistance in [[Portal venous system|portal system]] can be due to both intra-[[hepatic]] and also portosystemic [[collaterals]] resistances.
* 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'''
** '''Intra-hepatic resistance'''
*** The main factor in intra-[[hepatic]] resistance is [[hepatic]] vascular [[compliance]], which is greatly decreased in various liver diseases, such as liver [[fibrosis]] or [[cirrhosis]].
*** 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>
*** [[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 are 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>
*** 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>
*** [[Schistosomiasis]] causes both pre-[[sinusoidal]] and [[sinusoidal]] pathologies. The [[granulomas]] compress the pre-[[sinusoidal]] [[veins]]. In late stages [[sinusoidal]] resistance is also increased.<ref name="BekerValencia-Parparcén1968">{{cite journal|last1=Beker|first1=Simón G.|last2=Valencia-Parparcén|first2=Joel|title=Portal hypertension syndrome|journal=The American Journal of Digestive Diseases|volume=13|issue=12|year=1968|pages=1047–1054|issn=0002-9211|doi=10.1007/BF02233549}}</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>
*** [[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]] (e.g., [[nitric oxide]], [[Prostacyclin|prostacyclins]]) and [[vasoconstrictor]]  (e.g., [[endothelin]] and [[Prostanoid|prostanoids]]) [[chemicals]].<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>
*** [[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]].
*** 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]] response in [[myofibrils]] is higher than 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>
*** 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'''
** '''Portosystemic collateral resistance'''
*** [[Collateral]] formation is the consequence of portal hypertension which is also the main contributor to [[esophageal varices]].
*** [[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 the [[portal]] blood flow.
*** The main purpose of the [[collaterals]] is to decompress and bypass [[portal]] [[blood]] flow.  
*** However, the resistance in [[collaterals]] is less than the normal liver.  
*** However, [[Portocaval anastomoses|portosystemic collaterals]] may not lead to a complete decompression.  
*** Thus, [[Portocaval anastomoses|portosystemic collaterals]] can 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>
*** [[Portocaval anastomoses|Portosystemic collateraling]] occurs between the [[short gastric]], [[coronary]] veins, 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]] and 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 ====
==== 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>
* 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'''
* '''Systemic vasodilation'''
** Three main mechanisms which contribute to the peripheral vasodilation are as following:
** 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 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>
*** 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>
*** 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'''
* '''Plasma volume'''
** There are several events which contribute to the [[hyperdynamic circulation]] such as:
** There are several events which contribute to the [[hyperdynamic circulation]] such as:
*** Initial [[vasodilatation]], induced by systemic and local [[endothelial]] factors
*** 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>
*** 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===
==Genetics==
 
* Certain TERT (Telomerase reverese transcriptase)gene variants resulting in reduced telomerase activity has 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, 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 Utp4/cirhin and other SSU processome proteins may cause North American Indian childhood cirrhosis<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>
*[[Genes]] are involved in the [[pathogenesis]] of portal hypertension include the following:
{|
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Gene
! style="background:#4479BA; color: #FFFFFF;" align="center" + |OMIM number
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Chromosome
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Function
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Gene expression in portal hypertension
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Notes
|-
| style="background:#DCDCDC;" align="center" + |'''[[DGUOK|Deoxyguanosine kinase (DGUOK)]]'''
| style="background:#F5F5F5;" align="center" + |601465
| style="background:#F5F5F5;" align="center" + |2p13.1
| style="background:#F5F5F5;" + |[[DNA replication]]
| style="background:#F5F5F5;" + |[[Point mutation]]
| style="background:#F5F5F5;" + |[[Mutation]] leads to:<ref name="pmid11687800">{{cite journal |vauthors=Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N |title=The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA |journal=Nat. Genet. |volume=29 |issue=3 |pages=337–41 |year=2001 |pmid=11687800 |doi=10.1038/ng746 |url=}}</ref>
* [[Liver failure]]
* [[Neurologic]] abnormalities
* [[Hypoglycemia]]
* Increased [[Lactic acid|lactate]] in [[body fluids]]
[[Homozygous]] [[missense mutation]] leads to:<ref name="pmid26874653">{{cite journal |vauthors=Vilarinho S, Sari S, Yilmaz G, Stiegler AL, Boggon TJ, Jain D, Akyol G, Dalgic B, Günel M, Lifton RP |title=Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension |journal=Hepatology |volume=63 |issue=6 |pages=1977–86 |year=2016 |pmid=26874653 |pmc=4874872 |doi=10.1002/hep.28499 |url=}}</ref>
* [[Non-cirrhotic portal hypertension]]
|-
| style="background:#DCDCDC;" align="center" + |'''[[Adenosine deaminase|Adenosine deaminase (ADA)]]'''
| style="background:#F5F5F5;" align="center" + |608958
| style="background:#F5F5F5;" align="center" + |20q13.12
| style="background:#F5F5F5;" + |Irreversible [[deamination]] of [[adenosine]] and [[deoxyadenosine]] in the [[Purine metabolism|purine catabolic pathway]]
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015">{{cite journal|last1=Kotani|first1=Kohei|last2=Kawabe|first2=Joji|last3=Morikawa|first3=Hiroyasu|last4=Akahoshi|first4=Tomohiko|last5=Hashizume|first5=Makoto|last6=Shiomi|first6=Susumu|title=Comprehensive Screening of Gene Function and Networks by DNA Microarray Analysis in Japanese Patients with Idiopathic Portal Hypertension|journal=Mediators of Inflammation|volume=2015|year=2015|pages=1–10|issn=0962-9351|doi=10.1155/2015/349215}}</ref>
| style="background:#F5F5F5; + |Some roles in modulating tissue response to [[Interleukin 13|IL-13]]
 
The main effects of [[IL-13]] are:<ref name="pmid12897202">{{cite journal |vauthors=Blackburn MR, Lee CG, Young HW, Zhu Z, Chunn JL, Kang MJ, Banerjee SK, Elias JA |title=Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway |journal=J. Clin. Invest. |volume=112 |issue=3 |pages=332–44 |year=2003 |pmid=12897202 |pmc=166289 |doi=10.1172/JCI16815 |url=}}</ref>
* [[Inflammation]]
* [[Chemokine]] elaboration
* [[Fibrosis]]
|-
| style="background:#DCDCDC;" align="center" + |'''[[Phospholipase A2|Phospholipase A2 (PL2G10)]]'''
| style="background:#F5F5F5;" align="center" + |603603
| style="background:#F5F5F5;" align="center" + |16p13.12
| style="background:#F5F5F5;" + |Catalyzing the release of [[Fatty acid|fatty acids]] from [[phospholipids]]
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5;" + |Identifier of PL2G10 expression:
* [[Arachidonic acid|Arachidonic acid (AA)]]
* [[Prostaglandins|Prostaglandins (PG)]]
* [[Leukotrienes|Leukotrienes (LT)]]
|-
| style="background:#DCDCDC;" align="center" + |'''[[CYP4F3|Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3)]]'''
| style="background:#F5F5F5;" align="center" + |601270
| style="background:#F5F5F5;" align="center" + |19p13.12
| style="background:#F5F5F5;" + |Catalyzing the omega-[[hydroxylation]] of [[Leukotriene B4|leukotriene B4 (LTB4)]]
| style="background:#F5F5F5;" + |Increased<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5;" + | -
|-
| style="background:#DCDCDC;" align="center" + |'''[[Glutathione peroxidase|Glutathione peroxidase 3 (GPX3)]]'''
| style="background:#F5F5F5;" align="center" + |138321
| style="background:#F5F5F5;" align="center" + |5q33.1
| style="background:#F5F5F5;" + |Reduction of [[glutathione]] which reduce:<ref name="pmid3015592">{{cite journal |vauthors=Chambers I, Frampton J, Goldfarb P, Affara N, McBain W, Harrison PR |title=The structure of the mouse glutathione peroxidase gene: the selenocysteine in the active site is encoded by the 'termination' codon, TGA |journal=EMBO J. |volume=5 |issue=6 |pages=1221–7 |year=1986 |pmid=3015592 |pmc=1166931 |doi= |url=}}</ref>
* [[Hydrogen peroxide]]
* [[Organic peroxide|Organic hydroperoxide]]
* [[Lipid peroxidation|Lipid peroxides]]
| style="background:#F5F5F5;" + |Increased<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5;" + |Protects various organs against [[oxidative stress]]:<ref name="pmid1339300">{{cite journal |vauthors=Chu FF, Esworthy RS, Doroshow JH, Doan K, Liu XF |title=Expression of plasma glutathione peroxidase in human liver in addition to kidney, heart, lung, and breast in humans and rodents |journal=Blood |volume=79 |issue=12 |pages=3233–8 |year=1992 |pmid=1339300 |doi= |url=}}</ref>
* [[Liver]]
* [[Kidney]]
* [[Breast]]
|-
| style="background:#DCDCDC;" align="center" + |'''[[Leukotriene B4|Leukotriene B4 (LTB4)]]'''
| style="background:#F5F5F5;" align="center" + |601531
| style="background:#F5F5F5;" align="center" + |14q12
| style="background:#F5F5F5;" + |Include:<ref name="pmid9177352">{{cite journal |vauthors=Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T |title=A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis |journal=Nature |volume=387 |issue=6633 |pages=620–4 |year=1997 |pmid=9177352 |doi=10.1038/42506 |url=}}</ref>
* Increasing intra-cellular [[calcium]]
* Elevation of [[Inositol-3-phosphate synthase|inositol 3-phosphate (IP3)]]
* Inhibition of [[Adenylate cyclase|adenylyl cyclase]]
| style="background:#F5F5F5;" + |Mutated
| style="background:#F5F5F5;" + |Increase [[blood flow]] to target [[tissue]] (esp. [[heart]]) about 4 times more.<ref name="pmid16293697">{{cite journal |vauthors=Bäck M, Bu DX, Bränström R, Sheikine Y, Yan ZQ, Hansson GK |title=Leukotriene B4 signaling through NF-kappaB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue=48 |pages=17501–6 |year=2005 |pmid=16293697 |pmc=1297663 |doi=10.1073/pnas.0505845102 |url=}}</ref>
|-
| style="background:#DCDCDC;" align="center" + |'''[[Prostaglandin E2 receptor|Prostaglandin E receptor 2 (PTGER2)]]'''
| style="background:#F5F5F5;" align="center" + |176804
| style="background:#F5F5F5;" align="center" + |14q22.1
| style="background:#F5F5F5;" + |Various biological activities in diverse tissues
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5;" + | -
|-
| style="background:#DCDCDC;" align="center" + |'''[[Endothelin|Endothelin (EDN1)]]'''
| style="background:#F5F5F5;" align="center" + |131240
| style="background:#F5F5F5;" align="center" + |6p24.1
| style="background:#F5F5F5;" + |[[Vasoconstriction]]<ref name="pmid15148269">{{cite journal |vauthors=Campia U, Cardillo C, Panza JA |title=Ethnic differences in the vasoconstrictor activity of endogenous endothelin-1 in hypertensive patients |journal=Circulation |volume=109 |issue=25 |pages=3191–5 |year=2004 |pmid=15148269 |doi=10.1161/01.CIR.0000130590.24107.D3 |url=}}</ref>
| style="background:#F5F5F5;" + |Increased
| style="background:#F5F5F5;" + |The most powerful [[vasoconstrictor]] known<ref name="pmid2670930">{{cite journal |vauthors=Inoue A, Yanagisawa M, Takuwa Y, Mitsui Y, Kobayashi M, Masaki T |title=The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression |journal=J. Biol. Chem. |volume=264 |issue=25 |pages=14954–9 |year=1989 |pmid=2670930 |doi= |url=}}</ref>
|-
| style="background:#DCDCDC;" align="center" + |'''[[Endothelin receptor type A|Endothelin receptor type A (EDNRA)]]'''
| style="background:#F5F5F5;" align="center" + |131243
| style="background:#F5F5F5;" align="center" + |4q31.22-q31.23
| style="background:#F5F5F5;" + |[[Vasoconstriction]] through binding to [[endothelin]]
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5;" + |Directly related to [[hypertension]] in patients<ref name="pmid15148269" />
|-
| style="background:#DCDCDC;" align="center" + |'''[[Natriuretic peptides|Natriuretic peptide receptor 3 (NPR3)]]'''
| style="background:#F5F5F5;" align="center" + |108962
| style="background:#F5F5F5;" align="center" + |5p13.3
| style="background:#F5F5F5;" + |Maintenance of:
* [[Blood pressure]]
* [[Extracellular fluid|Extracellular fluid volume]]
| style="background:#F5F5F5;" + |Increased<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5;" + |Released from [[heart muscle]] in response to increase in wall tension. [[Atrial natriuretic peptide|ANP]] can modulate [[blood pressure]] by binding to NPR3<ref name="pmid7477288">{{cite journal |vauthors=Lopez MJ, Wong SK, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers DL, Beuve A |title=Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide |journal=Nature |volume=378 |issue=6552 |pages=65–8 |year=1995 |pmid=7477288 |doi=10.1038/378065a0 |url=}}</ref>
|-
| style="background:#DCDCDC;" align="center" + |'''[[Cluster of differentiation|Cluster of differentiation 44 (CD44)]]'''
| style="background:#F5F5F5;" align="center" + |107269
| style="background:#F5F5F5;" align="center" + |11p13
| style="background:#F5F5F5;" + |
* [[Lymphocyte]] activation
* [[Lymph node]] homing<ref name="pmid1694723">{{cite journal |vauthors=Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B |title=CD44 is the principal cell surface receptor for hyaluronate |journal=Cell |volume=61 |issue=7 |pages=1303–13 |year=1990 |pmid=1694723 |doi= |url=}}</ref>
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5;" + |
* Related to [[Fibroblast growth factor|fibroblast growth factor (FGF)]]<ref name="pmid12697740">{{cite journal |vauthors=Nedvetzki S, Golan I, Assayag N, Gonen E, Caspi D, Gladnikoff M, Yayon A, Naor D |title=A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of FGF with its receptor |journal=J. Clin. Invest. |volume=111 |issue=8 |pages=1211–20 |year=2003 |pmid=12697740 |doi=10.1172/JCI17100 |url=}}</ref>
* Increased expression during [[collateral]] [[arteriogenesis]]<ref name="pmid15023889">{{cite journal |vauthors=van Royen N, Voskuil M, Hoefer I, Jost M, de Graaf S, Hedwig F, Andert JP, Wormhoudt TA, Hua J, Hartmann S, Bode C, Buschmann I, Schaper W, van der Neut R, Piek JJ, Pals ST |title=CD44 regulates arteriogenesis in mice and is differentially expressed in patients with poor and good collateralization |journal=Circulation |volume=109 |issue=13 |pages=1647–52 |year=2004 |pmid=15023889 |doi=10.1161/01.CIR.0000124066.35200.18 |url=}}</ref>
|-
| style="background:#DCDCDC;" align="center" + |'''[[Transforming growth factor-β|Transforming growth factor (TGF)-β]]'''
| style="background:#F5F5F5;" align="center" + |190180
| style="background:#F5F5F5;" align="center" + |19q13.2
| style="background:#F5F5F5;" + |
* [[Transformation|Tissue transformation]]
* [[Apoptosis]] regulation<ref name="pmid11586292">{{cite journal |vauthors=Derynck R, Akhurst RJ, Balmain A |title=TGF-beta signaling in tumor suppression and cancer progression |journal=Nat. Genet. |volume=29 |issue=2 |pages=117–29 |year=2001 |pmid=11586292 |doi=10.1038/ng1001-117 |url=}}</ref>
| style="background:#F5F5F5; + |Reduced<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5; + |Hyper-expressed in African-American hypertensive patients<ref name="pmid10725360">{{cite journal |vauthors=Suthanthiran M, Li B, Song JO, Ding R, Sharma VK, Schwartz JE, August P |title=Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue=7 |pages=3479–84 |year=2000 |pmid=10725360 |pmc=16265 |doi=10.1073/pnas.050420897 |url=}}</ref>
|-
| style="background:#DCDCDC;" align="center" + |'''Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4)'''
| style="background:#F5F5F5;" align="center" + |607577
| style="background:#F5F5F5;" align="center" + |8p21.3
| style="background:#F5F5F5;" + |Increasing [[phosphatase]] activity in [[intracellular]] membrane-bound [[nucleosides]]
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />
| style="background:#F5F5F5;" + | -
|-
| style="background:#DCDCDC;" align="center" + |'''[[ABCC1|ATP-binding cassette, subfamily C, member 1 (ABCC1)]]'''
| style="background:#F5F5F5;" align="center" + |158343
| style="background:#F5F5F5;" align="center" + |16p13.11
| style="background:#F5F5F5;" + |[[Multidrug resistance|Multi-drug resistance]] in [[small cell lung cancer]]<ref name="pmid1360704">{{cite journal |vauthors=Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG |title=Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line |journal=Science |volume=258 |issue=5088 |pages=1650–4 |year=1992 |pmid=1360704 |doi= |url=}}</ref>
| style="background:#F5F5F5;" + |Reduced
| style="background:#F5F5F5;" + | -
|}
 
==Associated Conditions==
 
{{family tree/start}}
{{family tree| | | | | | | | | | | A01 | | | | | | | | | |A01='''Portal Hypertension'''<br>associated conditions}}
{{family tree| | | | | | | | | | | |!| | | | | | | | | | |}}
{{family tree| | | |,|-|-|-|v|-|-|-|+|-|-|-|v|-|-|-|.| | | |}}
{{family tree| | | B01 | | B02 | | B03 | | B04 | | B05 | | |B01='''''Immunological disorders'''''|B02='''''Infections'''''|B03='''''Medication and toxins'''''|B04='''''Genetic disorders'''''|B05='''''Prothrombotic conditions'''''}}
{{family tree| | | |!| | | |!| | | |!| | | |!| | | |!| | | |}}
{{family tree|boxstyle=text-align: left; | | | B01 | | B02 | | B03 | | B04 | | B05 | | |B01=• [[Common variable immunodeficiency|Common variable immunodeficiency syndrome]]<ref name="pmid23420139">{{cite journal |vauthors=Fuss IJ, Friend J, Yang Z, He JP, Hooda L, Boyer J, Xi L, Raffeld M, Kleiner DE, Heller T, Strober W |title=Nodular regenerative hyperplasia in common variable immunodeficiency |journal=J. Clin. Immunol. |volume=33 |issue=4 |pages=748–58 |year=2013 |pmid=23420139 |pmc=3731765 |doi=10.1007/s10875-013-9873-6 |url=}}</ref><br>• [[Connective tissue disease|Connective tissue diseases]]<ref name="pmid21393872">{{cite journal |vauthors=Vaiphei K, Bhatia A, Sinha SK |title=Liver pathology in collagen vascular disorders highlighting the vascular changes within portal tracts |journal=Indian J Pathol Microbiol |volume=54 |issue=1 |pages=25–31 |year=2011 |pmid=21393872 |doi=10.4103/0377-4929.77319 |url=}}</ref><br>• [[Crohn’s disease]]<ref name="pmid18415755">{{cite journal |vauthors=De Boer NK, Tuynman H, Bloemena E, Westerga J, Van Der Peet DL, Mulder CJ, Cuesta MA, Meuwissen SG, Van Nieuwkerk CM, Van Bodegraven AA |title=Histopathology of liver biopsies from a thiopurine-naïve inflammatory bowel disease cohort: prevalence of nodular regenerative hyperplasia |journal=Scand. J. Gastroenterol. |volume=43 |issue=5 |pages=604–8 |year=2008 |pmid=18415755 |doi=10.1080/00365520701800266 |url=}}</ref><br>• [[Organ transplant|Solid organ transplant]]<br>•• [[Renal transplantation]]<ref name="pmid1438671">{{cite journal |vauthors=Allison MC, Mowat A, McCruden EA, McGregor E, Burt AD, Briggs JD, Junor BJ, Follett EA, MacSween RN, Mills PR |title=The spectrum of chronic liver disease in renal transplant recipients |journal=Q. J. Med. |volume=83 |issue=301 |pages=355–67 |year=1992 |pmid=1438671 |doi= |url=}}</ref><br>••  [[Liver transplantation]]<ref name="pmid8020909">{{cite journal |vauthors=Gane E, Portmann B, Saxena R, Wong P, Ramage J, Williams R |title=Nodular regenerative hyperplasia of the liver graft after liver transplantation |journal=Hepatology |volume=20 |issue=1 Pt 1 |pages=88–94 |year=1994 |pmid=8020909 |doi= |url=}}</ref><br>• [[Hashimoto's thyroiditis]]<ref name="pmid2944377">{{cite journal |vauthors=Imai Y, Minami Y, Miyoshi S, Kawata S, Saito R, Noda S, Tamura S, Nishikawa M, Tajima K, Tarui S |title=Idiopathic portal hypertension associated with Hashimoto's disease: report of three cases |journal=Am. J. Gastroenterol. |volume=81 |issue=9 |pages=791–5 |year=1986 |pmid=2944377 |doi= |url=}}</ref><br>• [[Autoimmune disease]]<ref name="pmid11831999">{{cite journal |vauthors=Li X, Gao W, Chen J, Tang W |title=[Non-cirrhotic portal hypertension associated with autoimmune disease] |language=Chinese |journal=Zhonghua Wai Ke Za Zhi |volume=38 |issue=2 |pages=101–3 |year=2000 |pmid=11831999 |doi= |url=}}</ref>
|B02=• [[Bacterial]] intestinal [[Infection|infections]]<br>• Recurrent [[Escherichia coli|E.coli]] infection<ref name="pmid3276575">{{cite journal |vauthors=Kono K, Ohnishi K, Omata M, Saito M, Nakayama T, Hatano H, Nakajima Y, Sugita S, Okuda K |title=Experimental portal fibrosis produced by intraportal injection of killed nonpathogenic Escherichia coli in rabbits |journal=Gastroenterology |volume=94 |issue=3 |pages=787–96 |year=1988 |pmid=3276575 |doi= |url=}}</ref><br>• [[Human Immunodeficiency Virus (HIV)|Human immunodeficiency virus (HIV) infection]]<ref name="pmid24155091">{{cite journal |vauthors=Siramolpiwat S, Seijo S, Miquel R, Berzigotti A, Garcia-Criado A, Darnell A, Turon F, Hernandez-Gea V, Bosch J, Garcia-Pagán JC |title=Idiopathic portal hypertension: natural history and long-term outcome |journal=Hepatology |volume=59 |issue=6 |pages=2276–85 |year=2014 |pmid=24155091 |doi=10.1002/hep.26904 |url=}}</ref><br>• [[AIDS antiretroviral drugs|Antiretroviral therapy]]<ref name="pmid18389904">{{cite journal |vauthors=Maida I, Garcia-Gasco P, Sotgiu G, Rios MJ, Vispo ME, Martin-Carbonero L, Barreiro P, Mura MS, Babudieri S, Albertos S, Garcia-Samaniego J, Soriano V |title=Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome |journal=Antivir. Ther. (Lond.) |volume=13 |issue=1 |pages=103–7 |year=2008 |pmid=18389904 |doi= |url=}}</ref>|B03=• [[Thiopurine|Thiopurine derivatives]]<br>•• [[Didanosine]]<br>•• [[Azathioprine]]<ref name="pmid17504943">{{cite journal |vauthors=Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, Cadiot G, Bouhnik Y, De Vos M, Boureille A, Duclos B, Seksik P, Mary JY, Colombel JF |title=Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine |journal=Gut |volume=56 |issue=10 |pages=1404–9 |year=2007 |pmid=17504943 |pmc=2000290 |doi=10.1136/gut.2006.114363 |url=}}</ref><br>•• [[Thioguanine|Cis-thioguanine]]<ref name="pmid21272804">{{cite journal |vauthors=Calabrese E, Hanauer SB |title=Assessment of non-cirrhotic portal hypertension associated with thiopurine therapy in inflammatory bowel disease |journal=J Crohns Colitis |volume=5 |issue=1 |pages=48–53 |year=2011 |pmid=21272804 |doi=10.1016/j.crohns.2010.08.007 |url=}}</ref> <br>• [[Arsenicals]]<ref name="pmid2398270">{{cite journal |vauthors=Nevens F, Fevery J, Van Steenbergen W, Sciot R, Desmet V, De Groote J |title=Arsenic and non-cirrhotic portal hypertension. A report of eight cases |journal=J. Hepatol. |volume=11 |issue=1 |pages=80–5 |year=1990 |pmid=2398270 |doi= |url=}}</ref><br>• [[Vitamin A]]<ref name="pmid2019375">{{cite journal |vauthors=Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C |title=Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases |journal=Gastroenterology |volume=100 |issue=6 |pages=1701–9 |year=1991 |pmid=2019375 |doi= |url=}}</ref>|B04=• Adams-Olivier syndrome<ref name="pmid15832360">{{cite journal |vauthors=Girard M, Amiel J, Fabre M, Pariente D, Lyonnet S, Jacquemin E |title=Adams-Oliver syndrome and hepatoportal sclerosis: occasional association or common mechanism? |journal=Am. J. Med. Genet. A |volume=135 |issue=2 |pages=186–9 |year=2005 |pmid=15832360 |doi=10.1002/ajmg.a.30724 |url=}}</ref><br>• [[Turner syndrome]]<ref name="pmid23121401">{{cite journal |vauthors=Roulot D |title=Liver involvement in Turner syndrome |journal=Liver Int. |volume=33 |issue=1 |pages=24–30 |year=2013 |pmid=23121401 |doi=10.1111/liv.12007 |url=}}</ref><br>• Phosphomannose isomerase deficiency<ref name="pmid19101627">{{cite journal |vauthors=de Lonlay P, Seta N |title=The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib |journal=Biochim. Biophys. Acta |volume=1792 |issue=9 |pages=841–3 |year=2009 |pmid=19101627 |doi=10.1016/j.bbadis.2008.11.012 |url=}}</ref><br>• Familial cases<ref name="pmid3499813">{{cite journal |vauthors=Sarin SK, Mehra NK, Agarwal A, Malhotra V, Anand BS, Taneja V |title=Familial aggregation in noncirrhotic portal fibrosis: a report of four families |journal=Am. J. Gastroenterol. |volume=82 |issue=11 |pages=1130–3 |year=1987 |pmid=3499813 |doi= |url=}}</ref>
|B05=• [[Inherited thrombophilia|Inherited thrombophilias]] <ref name="pmid18685811">{{cite journal |vauthors=Bayan K, Tüzün Y, Yilmaz S, Canoruc N, Dursun M |title=Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension |journal=J. Thromb. Thrombolysis |volume=28 |issue=1 |pages=57–62 |year=2009 |pmid=18685811 |doi=10.1007/s11239-008-0244-8 |url=}}</ref><br>• [[Myeloproliferative neoplasm]]<ref name="pmid18685811" /><br>• [[Antiphospholipid syndrome]]<ref name="pmid18685811" /><br>• [[Sickle cell disease]]<ref name="pmid17558079">{{cite journal |vauthors=Kumar S, Joshi R, Jain AP |title=Portal hypertension associated with sickle cell disease |journal=Indian J Gastroenterol |volume=26 |issue=2 |pages=94 |year=2007 |pmid=17558079 |doi= |url=}}</ref>}}
{{family tree/end}}


===Gross Pathology===
* 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>
Macroscopically, 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.
* 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>
* In the micronodular form ([[René Laennec|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.


==Gross Pathology==
==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"
{| class="wikitable"
| colspan="3" |
*On [[gross pathology]], [[Cirrhosis|cirrhotic liver]], [[splenomegaly]], and [[esophageal varices]] are characteristic findings in portal hypertension.
|-
|-
|
|
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=== Esophageal Varices ===
=== Esophageal Varices ===
On gross pathology, prominent, congested, and tortoise [[veins]] in the lower parts of [[esophagus]] are characteristic findings of [[esophageal varices]].
On gross pathology, prominent, congested, and tortoise [[veins]] in the lower parts of [[esophagus]] are characteristic findings of [[esophageal varices]].
|colspan="2"|
| 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>]]
[[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]
[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>
<gallery>
Line 352: Line 226:
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)  
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>
</gallery>
===Microscopic Pathology===
Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa. In these nodules, regenerating [[hepatocyte]]s are disorderly disposed.  Portal tracts, [[central vein]]s and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate ([[lymphocyte]]s, [[macrophage]]s). If it is a [[secondary biliary cirrhosis]], biliary ducts are damaged, proliferated or distended - bile stasis.  These 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, as the so called "bile lakes".<ref>[http://www.pathologyatlas.ro/Cirrhosis.html Pathology atlas], "cirrhosis".</ref>
==Microscopic 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 [[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"
{| class="wikitable"
| colspan="2"|
*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]].
|-
|-
|
|
=== Cirrhosis ===
=== 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>
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]]
* Bridging [[fibrosis]]
* [[Nodule]] formation
* [[Nodule]] formation
Line 373: Line 256:
=== Esophageal varices ===
=== Esophageal varices ===
The main microscopic [[histopathological]] findings in [[esophageal varices]] are:
The main microscopic [[histopathological]] findings in [[esophageal varices]] are:
* Large dilated submucosal [[veins]] ('''key feature''')
* Large dilated [[submucosal]] [[veins]] ('''key feature''')
* [[Blood]] (fresh)
* [[Blood]] (fresh)
* [[Hemosiderin]]-laden [[macrophages]].
* [[Hemosiderin]]-laden [[macrophages]].
Line 381: Line 264:
|
|
=== Hepatic amyloidosis ===
=== Hepatic amyloidosis ===
The main microscopic [[histopathological]] findings in [[Hepatic amyloidosis with intrahepatic cholestasis|hepatic amyloidosis]] is amorphous extracellular pink stuff on H&E staining.
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>]]
[[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>]]
Line 387: Line 270:
|
|
=== Congestive hepatopathy ===
=== Congestive hepatopathy ===
The main microscopic [[histopathological]] findings in congestive [[hepatopathy]] (due to [[heart failure]] or [[Budd-Chiari syndrome]]) are:
The main [[microscopic]] [[histopathological]] findings in congestive [[hepatopathy]] (due to [[heart failure]] or [[Budd-Chiari syndrome]]) are:
* [[Atrophy]] of zone III
* [[Atrophy]] of the centrilobular zone (zone III)
* Distension of portal [[venule]] ([[central vein]])
* Distension of portal [[venule]] ([[central vein]])
* Perisinusoidal [[fibrosis]] which may progress to centrilobular [[fibrosis]] and then diffuse [[fibrosis]]
* Perisinusoidal [[fibrosis]] which may progress to centrilobular [[fibrosis]] and then diffuse [[fibrosis]]
* [[Sinusoidal]] dilation in ''all'' zone III areas ('''key feature)'''
* [[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>]]
[[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>]]
|}
|}


===Chronic active hepatitis - Cirrhosis===
=== Videos ===
 
{{#ev:youtube|CzKGvWZrUpU}}
{{#ev:youtube|CzKGvWZrUpU}}
===Micronodular cirrhosis===


{{#ev:youtube|CV8OYeIUXko}}
{{#ev:youtube|CV8OYeIUXko}}
===Primary biliary cirrhosis===


{{#ev:youtube|Jj8ozr_IttM}}
{{#ev:youtube|Jj8ozr_IttM}}


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


[[Category:Medicine]]
[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Up-To-Date]]
[[Category:Hepatology]]
[[Category:Hepatology]]
[[Category:Disease]]
{{WS}}
{{WH}}

Latest revision as of 16:51, 11 October 2022

https://https://www.youtube.com/watch?v=5szNmKtyBW4%7C350}}

Cirrhosis Microchapters

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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

  • Cirrhosis: Gross, external view of micronodular cirrhosis

    Cirrhosis: Gross, external view of micronodular cirrhosis

  • Cirrhosis: Gross, cut section of previous one (an excellent example)

    Cirrhosis: Gross, cut section of previous one (an excellent example)

  • Cirrhosis: Gross, close-up image

    Cirrhosis: Gross, close-up image

  • Macronodular cirrhosis and hepatoma

    Macronodular cirrhosis and hepatoma

  • Cirrhosis: Gross, close-up, natural color (an excellent example)

    Cirrhosis: Gross, close-up, natural color (an excellent example)

  • Cirrhosis: Gross, close-up (an excellent example)

    Cirrhosis: Gross, close-up (an excellent example)

  • Cirrhosis: Gross, close-up view

    Cirrhosis: Gross, close-up view

  • Micronodular cirrhosis: Gross, external view (an excellent example)

    Micronodular cirrhosis: Gross, external view (an excellent example)

  • Micronodular cirrhosis: Gross, close-up image

    Micronodular cirrhosis: Gross, close-up image

  • Micronodular cirrhosis: Gross (an excellent example)

    Micronodular cirrhosis: Gross (an excellent example)

  • Macronodular cirrhosis: Gross, natural color (perfect color for cirrhosis), close-up, an excellent example

    Macronodular cirrhosis: Gross, natural color (perfect color for cirrhosis), close-up, an excellent example

  • Cirrhosis with portocaval shunt: Gross, severe cirrhosis with extensive liver necrosis due to thrombosis of portocaval shunt (well shown)

    Cirrhosis with portocaval shunt: Gross, severe cirrhosis with extensive liver necrosis due to thrombosis of portocaval shunt (well shown)

  • Endstage cirrhosis: Gross, natural color, close-up (an excellent example)

    Endstage cirrhosis: Gross, natural color, close-up (an excellent example)

  • 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

    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

  • 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)

    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)

  • Macronodular cirrhosis: Gross, natural color, external view of liver and very enlarged spleen (liver has variable size nodules up to about 2 cm)

    Macronodular cirrhosis: Gross, natural color, external view of liver and very enlarged spleen (liver has variable size nodules up to about 2 cm)

  • 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.

    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.

  • 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

    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

  • Macronodular cirrhosis: Gross, natural color slab of liver

    Macronodular cirrhosis: Gross, natural color slab of liver

  • 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)

    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)

  • 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.

    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.

  • Endstage cirrhosis with lobular necrosis: Gross, natural color, very close-up view (an excellent example of alcoholic cirrhosis)

    Endstage cirrhosis with lobular necrosis: Gross, natural color, very close-up view (an excellent example of alcoholic cirrhosis)

  • Micronodular cirrhosis: Gross, natural color view of whole liver through capsule with obvious cirrhosis (note to quite large liver)

    Micronodular cirrhosis: Gross, natural color view of whole liver through capsule with obvious cirrhosis (note to quite large liver)

  • Micronodular cirrhosis: Gross, natural color, view of whole liver showing external surface typical cirrhotic liver (history of alcoholism)

    Micronodular cirrhosis: Gross, natural color, view of whole liver showing external surface typical cirrhotic liver (history of alcoholism)

  • Lung: Idiopathic Interstitial Fibrosis: Gross, natural color, an excellent photo of lung cirrhosis (close-up view)

    Lung: Idiopathic Interstitial Fibrosis: Gross, natural color, an excellent photo of lung cirrhosis (close-up view)

  • Endstage cirrhosis: Gross, natural color, slice of liver. Portal vein is opened to show size and patency.

    Endstage cirrhosis: Gross, natural color, slice of liver. Portal vein is opened to show size and patency.

  • Endstage cirrhosis: Gross, natural color, severe cirrhosis with bile stasis

    Endstage cirrhosis: Gross, natural color, severe cirrhosis with bile stasis

  • Portal Vein Thrombosis with cirrhosis: Gross, close-up, micronodular cirrhosis with portal vein thrombosis

    Portal Vein Thrombosis with cirrhosis: Gross, close-up, micronodular cirrhosis with portal vein thrombosis

  • Lung: Hematite: Gross, natural color, external view of "pulmonary cirrhosis" with typical hematite color

    Lung: Hematite: Gross, natural color, external view of "pulmonary cirrhosis" with typical hematite color

  • 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)

    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)

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

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References

  1. ↑ Arthur MJ, Iredale JP (1994). "Hepatic lipocytes, TIMP-1 and liver fibrosis". J R Coll Physicians Lond. 28 (3): 200–8. PMID 7932316.
  2. ↑ Friedman SL (1993). "Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies". N. Engl. J. Med. 328 (25): 1828–35. doi:10.1056/NEJM199306243282508. PMID 8502273.
  3. ↑ Iredale JP (1996). "Matrix turnover in fibrogenesis". Hepatogastroenterology. 43 (7): 56–71. PMID 8682489.
  4. ↑ Gressner AM (1994). "Perisinusoidal lipocytes and fibrogenesis". Gut. 35 (10): 1331–3. PMC 1374996. PMID 7959178.
  5. ↑ Iredale JP (2007). "Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ". J. Clin. Invest. 117 (3): 539–48. doi:10.1172/JCI30542. PMC 1804370. PMID 17332881.
  6. ↑ 6.0 6.1 Arthur MJ (2002). "Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C". Gastroenterology. 122 (5): 1525–8. PMID 11984538.
  7. ↑ Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G (1995). "Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension". Hepatology. 21 (5): 1238–47. PMID 7737629.
  8. ↑ Iredale JP. Cirrhosis: new research provides a basis for rational and targeted treatments. BMJ 2003;327:143-7.Fulltext. PMID 12869458.
  9. ↑ Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J (2009). "Angiogenesis in liver disease". J. Hepatol. 50 (3): 604–20. doi:10.1016/j.jhep.2008.12.011. PMID 19157625.
  10. ↑ Maher JJ, McGuire RF (1990). "Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo". J. Clin. Invest. 86 (5): 1641–8. doi:10.1172/JCI114886. PMC 296914. PMID 2243137. Unknown parameter |month= ignored (help)
  11. ↑ Herbst H, Frey A, Heinrichs O; et al. (1997). "Heterogeneity of liver cells expressing procollagen types I and IV in vivo". Histochem. Cell Biol. 107 (5): 399–409. PMID 9208331. Unknown parameter |month= ignored (help)
  12. ↑ García-Pagán JC, Gracia-Sancho J, Bosch J (2012). "Functional aspects on the pathophysiology of portal hypertension in cirrhosis". J. Hepatol. 57 (2): 458–61. doi:10.1016/j.jhep.2012.03.007. PMID 22504334.
  13. ↑ Lee JS, Semela D, Iredale J, Shah VH (2007). "Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte?". Hepatology. 45 (3): 817–25. doi:10.1002/hep.21564. PMID 17326208. Unknown parameter |month= ignored (help)
  14. ↑ Rosmorduc O, Housset C (2010). "Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease". Semin. Liver Dis. 30 (3): 258–70. doi:10.1055/s-0030-1255355. PMID 20665378. Unknown parameter |month= ignored (help)
  15. ↑ Schuppan D, Afdhal NH (2008). "Liver cirrhosis". Lancet. 371 (9615): 838–51. doi:10.1016/S0140-6736(08)60383-9. PMC 2271178. PMID 18328931.
  16. ↑ Desmet VJ, Roskams T (2004). "Cirrhosis reversal: a duel between dogma and myth". J. Hepatol. 40 (5): 860–7. doi:10.1016/j.jhep.2004.03.007. PMID 15094237.
  17. ↑ Wanless IR, Nakashima E, Sherman M (2000). "Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis". Arch. Pathol. Lab. Med. 124 (11): 1599–607. doi:10.1043/0003-9985(2000)124<1599:ROHC>2.0.CO;2. PMID 11079009.
  18. ↑ Ceni E, Mello T, Galli A (2014). "Pathogenesis of alcoholic liver disease: role of oxidative metabolism". World J. Gastroenterol. 20 (47): 17756–72. doi:10.3748/wjg.v20.i47.17756. PMC 4273126. PMID 25548474.
  19. ↑ You M, Crabb DW (2004). "Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver". Am. J. Physiol. Gastrointest. Liver Physiol. 287 (1): G1–6. doi:10.1152/ajpgi.00056.2004. PMID 15194557.
  20. ↑ Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR (2005). "Recent advances in alcohol-induced adduct formation". Alcohol. Clin. Exp. Res. 29 (7): 1310–6. PMID 16088993.
  21. ↑ Niemelä O (2007). "Acetaldehyde adducts in circulation". Novartis Found. Symp. 285: 183–92, discussion 193–7. PMID 17590995.
  22. ↑ Fischer M, You M, Matsumoto M, Crabb DW (2003). "Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice". J. Biol. Chem. 278 (30): 27997–8004. doi:10.1074/jbc.M302140200. PMID 12791698.
  23. ↑ You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW (2004). "The role of AMP-activated protein kinase in the action of ethanol in the liver". Gastroenterology. 127 (6): 1798–808. PMID 15578517.
  24. ↑ Ji C, Chan C, Kaplowitz N (2006). "Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model". J. Hepatol. 45 (5): 717–24. doi:10.1016/j.jhep.2006.05.009. PMID 16879892.
  25. ↑ Greenway CV, Stark RD (1971). "Hepatic vascular bed". Physiol. Rev. 51 (1): 23–65. PMID 5543903.
  26. ↑ Schiff, Eugene (2012). Schiff's diseases of the liver. Chichester, West Sussex, UK: John Wiley & Sons. ISBN 9780470654682.
  27. ↑ SCHAFFNER F, POPER H (1963). "Capillarization of hepatic sinusoids in man". Gastroenterology. 44: 239–42. PMID 13976646.
  28. ↑ Reynolds TB, Hidemura R, Michel H, Peters R (1969). "Portal hypertension without cirrhosis in alcoholic liver disease". Ann. Intern. Med. 70 (3): 497–506. PMID 5775031.
  29. ↑ Rubanyi GM (1991). "Endothelium-derived relaxing and contracting factors". J. Cell. Biochem. 46 (1): 27–36. doi:10.1002/jcb.240460106. PMID 1874796.
  30. ↑ Epstein, Franklin H.; Vane, John R.; Änggård, Erik E.; Botting, Regina M. (1990). "Regulatory Functions of the Vascular Endothelium". New England Journal of Medicine. 323 (1): 27–36. doi:10.1056/NEJM199007053230106. ISSN 0028-4793.
  31. ↑ Rockey DC, Weisiger RA (1996). "Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance". Hepatology. 24 (1): 233–40. doi:10.1002/hep.510240137. PMID 8707268.
  32. ↑ Mosca P, Lee FY, Kaumann AJ, Groszmann RJ (1992). "Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium". Am. J. Physiol. 263 (4 Pt 1): G544–50. PMID 1415713.
  33. ↑ Colombato LA, Albillos A, Groszmann RJ (1992). "Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats". Hepatology. 15 (2): 323–8. PMID 1735537.
  34. ↑ Genecin P, Polio J, Colombato LA, Ferraioli G, Reuben A, Groszmann RJ (1990). "Bile acids do not mediate the hyperdynamic circulation in portal hypertensive rats". Am. J. Physiol. 259 (1 Pt 1): G21–5. PMID 2372062.
  35. ↑ Casadevall, María; Panés, Julián; Piqué, Josep M.; Marroni, Norma; Bosch, Jaume; Whittle, Brendan J. R. (1993). "Involvement of nitric oxide and prostaglandins in gastric mucosal hyperemia of portal-hypertensive anesthetized rats". Hepatology. 18 (3): 628–634. doi:10.1002/hep.1840180323. ISSN 0270-9139.
  36. ↑ Sieber CC, Groszmann RJ (1992). "In vitro hyporeactivity to methoxamine in portal hypertensive rats: reversal by nitric oxide blockade". Am. J. Physiol. 262 (6 Pt 1): G996–1001. PMID 1616049.
  37. ↑ Albillos A, Colombato LA, Lee FY, Groszmann RJ (1993). "Octreotide ameliorates vasodilatation and Na+ retention in portal hypertensive rats". Gastroenterology. 104 (2): 575–9. PMID 8425700.
  38. ↑ Calado RT, Brudno J, Mehta P; et al. (2011). "Constitutional telomerase mutations are genetic risk factors for cirrhosis". Hepatology. 53 (5): 1600–7. doi:10.1002/hep.24173. PMC 3082730. PMID 21520173. Unknown parameter |month= ignored (help)
  39. ↑ Freed EF, Prieto JL, McCann KL, McStay B, Baserga SJ (2012). "NOL11, Implicated in the Pathogenesis of North American Indian Childhood Cirrhosis, Is Required for Pre-rRNA Transcription and Processing". PLoS Genet. 8 (8): e1002892. doi:10.1371/journal.pgen.1002892. PMC 3420923. PMID 22916032. Unknown parameter |month= ignored (help)
  40. ↑ Freed EF, Baserga SJ (2010). "The C-terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis". Nucleic Acids Res. 38 (14): 4798–806. doi:10.1093/nar/gkq185. PMC 2919705. PMID 20385600. Unknown parameter |month= ignored (help)
  41. ↑ <CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)>
  42. ↑ "www.meddean.luc.edu".
  43. ↑ Amadalvarez - Own work, <"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
  44. ↑ <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">
  45. ↑ Pathology atlas, "cirrhosis".
  46. ↑ Mitchell, Richard (2012). Pocket companion to Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier Saunders. ISBN 978-1416054542.
  47. ↑ "File:Cirrhosis high mag.jpg - Libre Pathology".
  48. ↑ "Esophageal varices - Libre Pathology".
  49. ↑ "File:Hepatic amyloidosis - high mag.jpg - Libre Pathology".
  50. ↑ "File:2 CEN NEC 1 680x512px.tif - Libre Pathology".
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