Cirrhosis pathophysiology: Difference between revisions

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==Overview==
==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 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.
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==
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** [[Fibrosis|Fibrogenesis]]
** [[Fibrosis|Fibrogenesis]]
'''Hepatic stellate cell activation'''
'''Hepatic stellate cell activation'''
The role of [[Kupffer cell|hepatic stellate cells]] in the pathogenesis of cirrhosis is described below:
* [[Kupffer cell|Kupffer cells]] are [[Liver|hepatic]] [[Macrophage|macrophages]] responsible for [[Ito cell|hepatic stellate cell]] activation during injury.
* [[Kupffer cell|Kupffer cells]] are [[Liver|hepatic]] [[Macrophage|macrophages]] responsible for [[Ito cell|hepatic stellate cell]] activation during injury.
* The [[Ito cell|stellate cell]], (also known as the [[Ito cell|perisinusoidal cell]] or [[Ito cell]]) is a type of [[cell]] that normally stores [[vitamin A]] and plays a pivotal role in the development of cirrhosis.
* The [[Ito cell|stellate cell]], (also known as the [[Ito cell|perisinusoidal cell]] or [[Ito cell]]) is a type of [[cell]] that normally stores [[vitamin A]] and plays a pivotal role in the development of cirrhosis.
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* [[Matrix metalloproteinase|MMP]]-2 degrades [[collagen]] and stromelysin-1 degrades [[proteoglycan]] and [[glycoprotein]].
* [[Matrix metalloproteinase|MMP]]-2 degrades [[collagen]] and stromelysin-1 degrades [[proteoglycan]] and [[glycoprotein]].
'''Microvascular changes'''
'''Microvascular changes'''
* 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]]) 
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>
** [[Liver|Hepatic]] [[Endothelium|endothelial]] dysfunction  
* Formation of intra [[Liver|hepatic]] [[Shunt (medical)|shunts]] (due to [[angiogenesis]] and loss of [[Parenchyma|parenchymal cells]]) 
* [[Liver|Hepatic]] [[Endothelium|endothelial]] dysfunction  
 
* [[Sinusoid (blood vessel)|Sinusoidal]] [[Endothelium|endothelial cells]] are also important contributors of early [[fibrosis]]. [[Endothelial cell]]s from a normal [[liver]] produces [[collagen]], [[laminin]] and [[fibronectin]].<ref>{{cite journal |author=Maher JJ, McGuire RF |title=Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo |journal=J. Clin. Invest. |volume=86 |issue=5 |pages=1641–8 |year=1990 |month=November |pmid=2243137 |pmc=296914 |doi=10.1172/JCI114886 |url=}}</ref><ref>{{cite journal |author=Herbst H, Frey A, Heinrichs O, ''et al.'' |title=Heterogeneity of liver cells expressing procollagen types I and IV in vivo |journal=Histochem. Cell Biol. |volume=107 |issue=5 |pages=399–409 |year=1997 |month=May |pmid=9208331 |doi= |url=}}</ref>
* [[Sinusoid (blood vessel)|Sinusoidal]] [[Endothelium|endothelial cells]] are also important contributors of early [[fibrosis]]. [[Endothelial cell]]s from a normal [[liver]] produces [[collagen]], [[laminin]] and [[fibronectin]].<ref>{{cite journal |author=Maher JJ, McGuire RF |title=Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo |journal=J. Clin. Invest. |volume=86 |issue=5 |pages=1641–8 |year=1990 |month=November |pmid=2243137 |pmc=296914 |doi=10.1172/JCI114886 |url=}}</ref><ref>{{cite journal |author=Herbst H, Frey A, Heinrichs O, ''et al.'' |title=Heterogeneity of liver cells expressing procollagen types I and IV in vivo |journal=Histochem. Cell Biol. |volume=107 |issue=5 |pages=399–409 |year=1997 |month=May |pmid=9208331 |doi= |url=}}</ref>
* The [[Endothelium|endothelial]] dysfunction is characterised by:<ref name="pmid22504334">{{cite journal |vauthors=García-Pagán JC, Gracia-Sancho J, Bosch J |title=Functional aspects on the pathophysiology of portal hypertension in cirrhosis |journal=J. Hepatol. |volume=57 |issue=2 |pages=458–61 |year=2012 |pmid=22504334 |doi=10.1016/j.jhep.2012.03.007 |url=}}</ref>
* The [[Endothelium|endothelial]] dysfunction is characterised by:<ref name="pmid22504334">{{cite journal |vauthors=García-Pagán JC, Gracia-Sancho J, Bosch J |title=Functional aspects on the pathophysiology of portal hypertension in cirrhosis |journal=J. Hepatol. |volume=57 |issue=2 |pages=458–61 |year=2012 |pmid=22504334 |doi=10.1016/j.jhep.2012.03.007 |url=}}</ref>
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*[[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>
*[[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'''
'''Fibrosis'''
The role of [[fibrosis]] in the pathogenesis of cirrhosis is described below:
* [[Fibrosis]] eventually leads to formation of [[Septum (disambiguation)|septae]] that grossly distort the [[liver]] architecture which includes both the [[liver]] [[parenchyma]] and the [[Circulatory system|vasculature]].  
* [[Fibrosis]] eventually leads to formation of [[Septum (disambiguation)|septae]] that grossly distort the [[liver]] architecture which includes both the [[liver]] [[parenchyma]] and the [[Circulatory system|vasculature]].  
* A cirrhotic [[liver]] compromises [[Hepatic sinusoids|hepatic sinusoidal]] exchange by shunting [[Artery|arterial]] and [[Portal vein|portal blood]] directly into the [[Central vein|central veins]] ([[Liver|hepatic]] outflow).
* A cirrhotic [[liver]] compromises [[Hepatic sinusoids|hepatic sinusoidal]] exchange by shunting [[Artery|arterial]] and [[Portal vein|portal blood]] directly into the [[Central vein|central veins]] ([[Liver|hepatic]] outflow).
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* Due to [[portal hypertension]], the [[spleen]] becomes congested, which leads to [[hypersplenism]] and increased [[platelet]] sequestration.  
* Due to [[portal hypertension]], the [[spleen]] becomes congested, which leads to [[hypersplenism]] and increased [[platelet]] sequestration.  
'''Pathogenesis of cirrhosis according to cause'''
'''Pathogenesis of cirrhosis according to cause'''
* [[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.
[[Pathogenesis]] of cirrhosis based upon the underlying cause is as follows:
** '''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.
* '''[[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.
** '''[[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.
* '''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.
** '''[[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.  
* '''[[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.
*** There is a strong association with [[inflammatory bowel disease]] (IBD), especially [[ulcerative colitis]].
* '''[[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.  
** '''[[Autoimmune hepatitis]]''':  [[Immunological|Immunologic]] damage to the [[liver]] leads to [[inflammation]], [[Scar|scarring]] and cirrhosis.
** There is a strong association with [[inflammatory bowel disease]] (IBD), especially [[ulcerative colitis]].
* '''[[Autoimmune hepatitis]]''':  [[Immunological|Immunologic]] damage to the [[liver]] leads to [[inflammation]], [[Scar|scarring]] and cirrhosis.


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


==Pathophysiology Of Cirrhosis Due To Alcohol==
===Pathophysiology of Cirrhosis due to Alcohol===
* Mechanisms of [[alcohol]]-induced [[liver]] damage include:<ref name="pmid25548474">{{cite journal |vauthors=Ceni E, Mello T, Galli A |title=Pathogenesis of alcoholic liver disease: role of oxidative metabolism |journal=World J. Gastroenterol. |volume=20 |issue=47 |pages=17756–72 |year=2014 |pmid=25548474 |pmc=4273126 |doi=10.3748/wjg.v20.i47.17756 |url=}}</ref><ref name="pmid15194557">{{cite journal |vauthors=You M, Crabb DW |title=Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=287 |issue=1 |pages=G1–6 |year=2004 |pmid=15194557 |doi=10.1152/ajpgi.00056.2004 |url=}}</ref><ref name="pmid16088993">{{cite journal |vauthors=Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR |title=Recent advances in alcohol-induced adduct formation |journal=Alcohol. Clin. Exp. Res. |volume=29 |issue=7 |pages=1310–6 |year=2005 |pmid=16088993 |doi= |url=}}</ref><ref name="pmid17590995">{{cite journal |vauthors=Niemelä O |title=Acetaldehyde adducts in circulation |journal=Novartis Found. Symp. |volume=285 |issue= |pages=183–92; discussion 193–7 |year=2007 |pmid=17590995 |doi= |url=}}</ref><ref name="pmid11841919">{{cite journal |vauthors=Tuma DJ |title=Role of malondialdehyde-acetaldehyde adducts in liver injury |journal=Free Radic. Biol. Med. |volume=32 |issue=4 |pages=303–8 |year=2002 |pmid=11841919 |doi= |url=}}</ref><ref name="pmid15540799">{{cite journal |vauthors=Tuma DJ, Casey CA |title=Dangerous byproducts of alcohol breakdown--focus on adducts |journal=Alcohol Res Health |volume=27 |issue=4 |pages=285–90 |year=2003 |pmid=15540799 |doi= |url=}}</ref><ref name="pmid16054980">{{cite journal |vauthors=Brooks PJ, Theruvathu JA |title=DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis |journal=Alcohol |volume=35 |issue=3 |pages=187–93 |year=2005 |pmid=16054980 |doi=10.1016/j.alcohol.2005.03.009 |url=}}</ref><ref name="pmid17718399">{{cite journal |vauthors=Seitz HK, Becker P |title=Alcohol metabolism and cancer risk |journal=Alcohol Res Health |volume=30 |issue=1 |pages=38–41, 44–7 |year=2007 |pmid=17718399 |pmc=3860434 |doi= |url=}}</ref><ref name="pmid9857222">{{cite journal |vauthors=Biewald J, Nilius R, Langner J |title=Occurrence of acetaldehyde protein adducts formed in various organs of chronically ethanol fed rats: an immunohistochemical study |journal=Int. J. Mol. Med. |volume=2 |issue=4 |pages=389–96 |year=1998 |pmid=9857222 |doi= |url=}}</ref><ref name="pmid17543846">{{cite journal |vauthors=Seitz HK, Meier P |title=The role of acetaldehyde in upper digestive tract cancer in alcoholics |journal=Transl Res |volume=149 |issue=6 |pages=293–7 |year=2007 |pmid=17543846 |doi=10.1016/j.trsl.2006.12.002 |url=}}</ref><ref name="pmid36785782">{{cite journal |vauthors=Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV |title=Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans |journal=Biochem. Soc. Trans. |volume=15 |issue=4 |pages=576–8 |year=1987 |pmid=3678578 |doi= |url=}}</ref><ref name="pmid5009602">{{cite journal |vauthors=Lieber CS |title=Metabolism of ethanol and alcoholism: racial and acquired factors |journal=Ann. Intern. 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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:
* Impairment of:
*** [[Protein synthesis]]  
** [[Protein synthesis]]  
*** [[Secretion]]  
** [[Secretion]]  
*** [[Glycosylation]]
** [[Glycosylation]]
 
* [[Ethanol]] intake leads to elevated accumulation of intracellular [[Triglyceride|triglycerides]] by:<ref name="pmid12791698">{{cite journal |vauthors=Fischer M, You M, Matsumoto M, Crabb DW |title=Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice |journal=J. Biol. Chem. |volume=278 |issue=30 |pages=27997–8004 |year=2003 |pmid=12791698 |doi=10.1074/jbc.M302140200 |url=}}</ref><ref name="pmid15578517">{{cite journal |vauthors=You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW |title=The role of AMP-activated protein kinase in the action of ethanol in the liver |journal=Gastroenterology |volume=127 |issue=6 |pages=1798–808 |year=2004 |pmid=15578517 |doi= |url=}}</ref><ref name="pmid16879892">{{cite journal |vauthors=Ji C, Chan C, Kaplowitz N |title=Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model |journal=J. Hepatol. |volume=45 |issue=5 |pages=717–24 |year=2006 |pmid=16879892 |doi=10.1016/j.jhep.2006.05.009 |url=}}</ref>
* [[Ethanol]] intake leads to elevated accumulation of intracellular [[Triglyceride|triglycerides]] by:<ref name="pmid12791698">{{cite journal |vauthors=Fischer M, You M, Matsumoto M, Crabb DW |title=Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice |journal=J. Biol. Chem. |volume=278 |issue=30 |pages=27997–8004 |year=2003 |pmid=12791698 |doi=10.1074/jbc.M302140200 |url=}}</ref><ref name="pmid15578517">{{cite journal |vauthors=You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW |title=The role of AMP-activated protein kinase in the action of ethanol in the liver |journal=Gastroenterology |volume=127 |issue=6 |pages=1798–808 |year=2004 |pmid=15578517 |doi= |url=}}</ref><ref name="pmid16879892">{{cite journal |vauthors=Ji C, Chan C, Kaplowitz N |title=Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model |journal=J. Hepatol. |volume=45 |issue=5 |pages=717–24 |year=2006 |pmid=16879892 |doi=10.1016/j.jhep.2006.05.009 |url=}}</ref>
** [[Lipoprotein]] secretion
** [[Lipoprotein]] secretion
Line 97: Line 105:
** Loss of [[Hepatocyte|hepatocytes]]
** Loss of [[Hepatocyte|hepatocytes]]
** Increased production and deposition of [[collagen]] and regenerative [[Nodule (medicine)|nodule]] formation on a background of [[fibrosis]]
** Increased production and deposition of [[collagen]] and regenerative [[Nodule (medicine)|nodule]] formation on a background of [[fibrosis]]
==Pathophysiology Of Portal Hypertension==
===Pathophysiology of Portal Hypertension due to Cirrhosis===
==== Increased resistance ====
==== Increased resistance ====
* Portal hypertension is related to elevation of resistance in the [[Portal venous system|portal vasculature]].  
* Portal hypertension is related to elevation of resistance in the [[Portal venous system|portal vasculature]].  
* Increased resistance in [[Portal venous system|portal system]] may be due to both intra-[[hepatic]] and also [[Portocaval anastomoses|portosystemic collateral]] resistance.
* 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 responsible for 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]] 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>
*** 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 may also be 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|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>
*** [[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>
Line 132: Line 139:
* 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>
* An uncharacterized [[Nucleolar protein, member A1|nucleolar protein]], NOL11, has a role in the [[pathogenesis]] of North American Indian childhood cirrhosis<ref>{{cite journal |author=Freed EF, Prieto JL, McCann KL, McStay B, Baserga SJ |title=NOL11, Implicated in the Pathogenesis of North American Indian Childhood Cirrhosis, Is Required for Pre-rRNA Transcription and Processing |journal=PLoS Genet. |volume=8 |issue=8 |pages=e1002892 |year=2012 |month=August |pmid=22916032 |pmc=3420923 |doi=10.1371/journal.pgen.1002892 |url=}}</ref>
* Loss of interaction between the [[C-terminus]] of a protein called Utp4/cirhin and other SSU processome [[proteins]] may cause cirrhosis in children<ref>{{cite journal |author=Freed EF, Baserga SJ |title=The C-terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis |journal=Nucleic Acids Res. |volume=38 |issue=14 |pages=4798–806 |year=2010 |month=August |pmid=20385600 |pmc=2919705 |doi=10.1093/nar/gkq185 |url=}}</ref>
* 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>
*[[Genes]] involved in the [[pathogenesis]] of cirrhosis and [[portal hypertension]] include the following:
{|
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Gene
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Chromosome (Locus)
! 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" + |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>
* [[Portal hypertension]]
|-
| style="background:#DCDCDC;" align="center" + |'''[[Adenosine deaminase|Adenosine deaminase (ADA)]]'''
| 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 (biology)|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" + |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" + |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" + |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" + |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" + |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" + |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" + |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" + |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" + |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" + |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 [[Hypertension|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" + |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" + |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;" + | -
|}
==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.
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.
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* In macronodular cirrhosis (post-necrotic cirrhosis), the [[Nodule (medicine)|nodules]] are larger than 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.
* 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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=== 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>
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*Dilated ducts contain inspissated bile which appears as bile casts or bile thrombi (brown-green, amorphous).  
*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>
*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]].
|-
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[[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>]]
|}
|}
=== Videos ===
{{#ev:youtube|CzKGvWZrUpU}}
{{#ev:youtube|CzKGvWZrUpU}}


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[[Category:Medicine]]
[[Category:Medicine]]
[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Primary care]]
[[Category:Up-To-Date]]
[[Category:Up-To-Date]]
[[Category:Hepatology]]
[[Category:Hepatology]]

Latest revision as of 16:51, 11 October 2022

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

Cirrhosis Microchapters

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Cirrhosis pathophysiology On the Web

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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

{{#ev:youtube|CzKGvWZrUpU}}

{{#ev:youtube|CV8OYeIUXko}}

{{#ev:youtube|Jj8ozr_IttM}}

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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