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==Pathophysiology of Portal Hypertension==
==== Increased resistance ====
* Portal hypertension is related to elevation of [[Portal venous system|portal vasculature]] resistance.
* Increased resistance in [[Portal venous system|portal system]] may be due to both intra-[[hepatic]] and also portosystemic collateral 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]].
*** 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>
*** [[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>
*** [[Hepatic]] vascular [[endothelium]] synthesizes and secretes both [[Vasodilator|vasodilators]] (e.g., [[nitric oxide]], [[Prostacyclin|prostacyclins]]) and [[Vasoconstrictor|vasoconstrictors]]  (e.g., [[endothelin]] and [[Prostanoid|prostanoids]]).<ref name="pmid1874796">{{cite journal |vauthors=Rubanyi GM |title=Endothelium-derived relaxing and contracting factors |journal=J. Cell. Biochem. |volume=46 |issue=1 |pages=27–36 |year=1991 |pmid=1874796 |doi=10.1002/jcb.240460106 |url=}}</ref><ref name="EpsteinVane1990">{{cite journal|last1=Epstein|first1=Franklin H.|last2=Vane|first2=John R.|last3=Änggård|first3=Erik E.|last4=Botting|first4=Regina M.|title=Regulatory Functions of the Vascular Endothelium|journal=New England Journal of Medicine|volume=323|issue=1|year=1990|pages=27–36|issn=0028-4793|doi=10.1056/NEJM199007053230106}}</ref>
*** Increased resistance due to the elevation of [[vascular]] tone may be caused by excess of [[vasoconstrictors]] or lack of [[vasodilators]].
*** It is postulated that in [[Cirrhosis|cirrhotic liver]] the [[nitric oxide]] level is lower and the response to [[endothelin]] 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>
** '''Portosystemic collateral resistance'''
*** [[Collateral]] blood circulation develops as a consequence of portal hypertension which is the main contributor to [[esophageal varices]].
*** The main purpose of the [[collaterals]] is to decompress and bypass [[portal]] blood flow.
*** However, [[Portocaval anastomoses|portosystemic collaterals]] may not lead to a complete decompression.
*** [[Portocaval anastomoses|Portosystemic 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]], the venous system of abdominal organs juxtaposed with the retroperitoneum and abdominal wall; the left renal vein, the splanchnic, the adrenal, and the spermatic veins.<ref name="pmid1415713">{{cite journal |vauthors=Mosca P, Lee FY, Kaumann AJ, Groszmann RJ |title=Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium |journal=Am. J. Physiol. |volume=263 |issue=4 Pt 1 |pages=G544–50 |year=1992 |pmid=1415713 |doi= |url=}}</ref>
==== Hyperdynamic circulation in portal hypertension ====
* Peripheral [[vasodilatation]] is the basis for decreased systemic [[vascular resistance]] and [[mean arterial pressure]], plasma volume expansion, elevated [[splanchnic]] [[blood flow]], and elevated [[cardiac index]].<ref name="pmid1735537">{{cite journal |vauthors=Colombato LA, Albillos A, Groszmann RJ |title=Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats |journal=Hepatology |volume=15 |issue=2 |pages=323–8 |year=1992 |pmid=1735537 |doi= |url=}}</ref>
* '''Systemic vasodilation'''
** Three main mechanisms which contribute to the peripheral vasodilation are as following:
*** Increased [[vasodilators]] production in systemic circulation<ref name="pmid2372062">{{cite journal |vauthors=Genecin P, Polio J, Colombato LA, Ferraioli G, Reuben A, Groszmann RJ |title=Bile acids do not mediate the hyperdynamic circulation in portal hypertensive rats |journal=Am. J. Physiol. |volume=259 |issue=1 Pt 1 |pages=G21–5 |year=1990 |pmid=2372062 |doi= |url=}}</ref>
*** Increased [[vasodilators]] production in local [[endothelium]]<ref name="CasadevallPanés1993">{{cite journal|last1=Casadevall|first1=María|last2=Panés|first2=Julián|last3=Piqué|first3=Josep M.|last4=Marroni|first4=Norma|last5=Bosch|first5=Jaume|last6=Whittle|first6=Brendan J. R.|title=Involvement of nitric oxide and prostaglandins in gastric mucosal hyperemia of portal-hypertensive anesthetized rats|journal=Hepatology|volume=18|issue=3|year=1993|pages=628–634|issn=02709139|doi=10.1002/hep.1840180323}}</ref>
*** Decreased vascular response to local [[vasoconstrictors]]<ref name="pmid1616049">{{cite journal |vauthors=Sieber CC, Groszmann RJ |title=In vitro hyporeactivity to methoxamine in portal hypertensive rats: reversal by nitric oxide blockade |journal=Am. J. Physiol. |volume=262 |issue=6 Pt 1 |pages=G996–1001 |year=1992 |pmid=1616049 |doi= |url=}}</ref>
* '''Plasma volume'''
** There are several events which contribute to the [[hyperdynamic circulation]] such as:
*** Initial [[vasodilatation]], induced by systemic and local [[endothelial]] factors
*** Subsequent [[Blood plasma|plasma]] volume expansion<ref name="pmid8425700">{{cite journal |vauthors=Albillos A, Colombato LA, Lee FY, Groszmann RJ |title=Octreotide ameliorates vasodilatation and Na+ retention in portal hypertensive rats |journal=Gastroenterology |volume=104 |issue=2 |pages=575–9 |year=1993 |pmid=8425700 |doi= |url=}}</ref>
===Genetics===
* Certain TERT (Telomerase 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, 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]] 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" + |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|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==
==Associated Conditions==

Revision as of 16:47, 21 December 2017

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

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.

Pathophysiology

Pathology

  • There are four stages of Cirrhosis as it progresses:
    • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading 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 leading to regenerative nodule formation.



Associated Conditions

 
 
 
 
 
 
 
 
 
 
Portal Hypertension
associated conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological disorders
 
Infections
 
Medication and toxins
 
Genetic disorders
 
Prothrombotic conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Common variable immunodeficiency syndrome[1]
• Connective tissue diseases[2]
• Crohn’s disease[3]
• Solid organ transplant
•• Renal transplantation[4]
•• Liver transplantation[5]
• Hashimoto's thyroiditis[6]
• Autoimmune disease[7]
 
• Bacterial intestinal infections
• Recurrent E.coli infection[8]
• Human immunodeficiency virus (HIV) infection[9]
• Antiretroviral therapy[10]
 
• Thiopurine derivatives
•• Didanosine
•• Azathioprine[11]
•• Cis-thioguanine[12]
• Arsenicals[13]
• Vitamin A[14]
 
• Adams-Olivier syndrome[15]
• Turner syndrome[16]
• Phosphomannose isomerase deficiency[17]
• Familial cases[18]
 
• Inherited thrombophilias [19]
• Myeloproliferative neoplasm[19]
• Antiphospholipid syndrome[19]
• Sickle cell disease[20]
 
 

Gross Pathology

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.

  • 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.

Gross Pathology

Cirrhosis

On gross pathology there are two types of cirrhosis:

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[21]
Macronodular cirrhosis[22]

Splenomegaly

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

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[23]

Esophageal Varices

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

Esophageal varices[24]

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

Microscopically, cirrhosis is characterized by regeneration nodules surrounded by fibrous septa. In these nodules, regenerating hepatocytes are disorderly disposed. Portal tracts, central veins and the radial pattern of hepatocytes are absent. Fibrous septa are important and may present inflammatory infiltrate (lymphocytes, macrophages). 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".[25]

Microscopic Pathology

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[26]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[27]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[28]

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[29]

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[30]

Chronic active hepatitis - Cirrhosis

{{#ev:youtube|CzKGvWZrUpU}}

Micronodular cirrhosis

{{#ev:youtube|CV8OYeIUXko}}

Primary biliary cirrhosis

{{#ev:youtube|Jj8ozr_IttM}}

References

  1. ↑ Fuss IJ, Friend J, Yang Z, He JP, Hooda L, Boyer J, Xi L, Raffeld M, Kleiner DE, Heller T, Strober W (2013). "Nodular regenerative hyperplasia in common variable immunodeficiency". J. Clin. Immunol. 33 (4): 748–58. doi:10.1007/s10875-013-9873-6. PMC 3731765. PMID 23420139.
  2. ↑ Vaiphei K, Bhatia A, Sinha SK (2011). "Liver pathology in collagen vascular disorders highlighting the vascular changes within portal tracts". Indian J Pathol Microbiol. 54 (1): 25–31. doi:10.4103/0377-4929.77319. PMID 21393872.
  3. ↑ 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 (2008). "Histopathology of liver biopsies from a thiopurine-naïve inflammatory bowel disease cohort: prevalence of nodular regenerative hyperplasia". Scand. J. Gastroenterol. 43 (5): 604–8. doi:10.1080/00365520701800266. PMID 18415755.
  4. ↑ Allison MC, Mowat A, McCruden EA, McGregor E, Burt AD, Briggs JD, Junor BJ, Follett EA, MacSween RN, Mills PR (1992). "The spectrum of chronic liver disease in renal transplant recipients". Q. J. Med. 83 (301): 355–67. PMID 1438671.
  5. ↑ Gane E, Portmann B, Saxena R, Wong P, Ramage J, Williams R (1994). "Nodular regenerative hyperplasia of the liver graft after liver transplantation". Hepatology. 20 (1 Pt 1): 88–94. PMID 8020909.
  6. ↑ Imai Y, Minami Y, Miyoshi S, Kawata S, Saito R, Noda S, Tamura S, Nishikawa M, Tajima K, Tarui S (1986). "Idiopathic portal hypertension associated with Hashimoto's disease: report of three cases". Am. J. Gastroenterol. 81 (9): 791–5. PMID 2944377.
  7. ↑ Li X, Gao W, Chen J, Tang W (2000). "[Non-cirrhotic portal hypertension associated with autoimmune disease]". Zhonghua Wai Ke Za Zhi (in Chinese). 38 (2): 101–3. PMID 11831999.
  8. ↑ Kono K, Ohnishi K, Omata M, Saito M, Nakayama T, Hatano H, Nakajima Y, Sugita S, Okuda K (1988). "Experimental portal fibrosis produced by intraportal injection of killed nonpathogenic Escherichia coli in rabbits". Gastroenterology. 94 (3): 787–96. PMID 3276575.
  9. ↑ Siramolpiwat S, Seijo S, Miquel R, Berzigotti A, Garcia-Criado A, Darnell A, Turon F, Hernandez-Gea V, Bosch J, Garcia-Pagán JC (2014). "Idiopathic portal hypertension: natural history and long-term outcome". Hepatology. 59 (6): 2276–85. doi:10.1002/hep.26904. PMID 24155091.
  10. ↑ 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 (2008). "Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome". Antivir. Ther. (Lond.). 13 (1): 103–7. PMID 18389904.
  11. ↑ 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 (2007). "Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine". Gut. 56 (10): 1404–9. doi:10.1136/gut.2006.114363. PMC 2000290. PMID 17504943.
  12. ↑ Calabrese E, Hanauer SB (2011). "Assessment of non-cirrhotic portal hypertension associated with thiopurine therapy in inflammatory bowel disease". J Crohns Colitis. 5 (1): 48–53. doi:10.1016/j.crohns.2010.08.007. PMID 21272804.
  13. ↑ Nevens F, Fevery J, Van Steenbergen W, Sciot R, Desmet V, De Groote J (1990). "Arsenic and non-cirrhotic portal hypertension. A report of eight cases". J. Hepatol. 11 (1): 80–5. PMID 2398270.
  14. ↑ Geubel AP, De Galocsy C, Alves N, Rahier J, Dive C (1991). "Liver damage caused by therapeutic vitamin A administration: estimate of dose-related toxicity in 41 cases". Gastroenterology. 100 (6): 1701–9. PMID 2019375.
  15. ↑ Girard M, Amiel J, Fabre M, Pariente D, Lyonnet S, Jacquemin E (2005). "Adams-Oliver syndrome and hepatoportal sclerosis: occasional association or common mechanism?". Am. J. Med. Genet. A. 135 (2): 186–9. doi:10.1002/ajmg.a.30724. PMID 15832360.
  16. ↑ Roulot D (2013). "Liver involvement in Turner syndrome". Liver Int. 33 (1): 24–30. doi:10.1111/liv.12007. PMID 23121401.
  17. ↑ de Lonlay P, Seta N (2009). "The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib". Biochim. Biophys. Acta. 1792 (9): 841–3. doi:10.1016/j.bbadis.2008.11.012. PMID 19101627.
  18. ↑ Sarin SK, Mehra NK, Agarwal A, Malhotra V, Anand BS, Taneja V (1987). "Familial aggregation in noncirrhotic portal fibrosis: a report of four families". Am. J. Gastroenterol. 82 (11): 1130–3. PMID 3499813.
  19. ↑ 19.0 19.1 19.2 Bayan K, Tüzün Y, Yilmaz S, Canoruc N, Dursun M (2009). "Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension". J. Thromb. Thrombolysis. 28 (1): 57–62. doi:10.1007/s11239-008-0244-8. PMID 18685811.
  20. ↑ Kumar S, Joshi R, Jain AP (2007). "Portal hypertension associated with sickle cell disease". Indian J Gastroenterol. 26 (2): 94. PMID 17558079.
  21. ↑ <CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)>
  22. ↑ "www.meddean.luc.edu".
  23. ↑ 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
  24. ↑ <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">
  25. ↑ Pathology atlas, "cirrhosis".
  26. ↑ Mitchell, Richard (2012). Pocket companion to Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier Saunders. ISBN 978-1416054542.
  27. ↑ "File:Cirrhosis high mag.jpg - Libre Pathology".
  28. ↑ "Esophageal varices - Libre Pathology".
  29. ↑ "File:Hepatic amyloidosis - high mag.jpg - Libre Pathology".
  30. ↑ "File:2 CEN NEC 1 680x512px.tif - Libre Pathology".

Template:WS Template:WH

the end

-

Portal HTN results from the combination of the following:

  • Structural disturbances associated with advanced liver disease account for 70% of total hepatic vascular resistance.
  •  Functional abnormalities such as endothelial dysfunction and increased hepatic vascular tone account for 30% of total hepatic vascular resistance.

Pathogenesis of Cirrhosis due to Alcohol:

  • More than 66 percent of all American adults consume alcohol.
  • Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
  • Mechanisms of alcohol-induced damage include:
    • Impaired protein synthesis, secretion, glycosylation
  • Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
    • Lipoprotein secretion
    • Decreased fatty acid oxidation
    • Increased fatty acid uptake
  • Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
  • Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
    • Trafficking of hepatic proteins
    • Interrupting microtubule formation
    • Interfering with enzyme activities
  • Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.[1]
  • Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
  • Stellate cell activation leads to the production of extracellular matrix and collagen.
  • Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
  • Shrinkage of the liver occurs over years due to repeated insults that lead to:
    • Loss of hepatocytes
    • Increased production and deposition of collagen


Pathology

  • There are four stages of Cirrhosis as it progresses:
    • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading 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 leading to regenerative nodule formation.


Causes

Drugs and Toxins Infections Autoimmune Metabolic Biliary obstruction(Secondary bilary cirrhosis) Vascular Miscellaneous
Alcohol Hepatitis B Primary Biliary Cirrhosis Wilson's disease Cystic fibrosis Chronic RHF Sarcoidosis
Methotrexate Hepatitis C Autoimmune hepatitis Hemochromatosis Biliary atresia Budd-Chiari syndrome Intestinal

bypass operations for obesity

Isoniazid Schistosoma japonicum Primary Sclerosing Cholangitis Alpha-1 antitrypsin deficiency Bile duct strictures Veno-occlusive disease Cryptogenic: unknown
Methyldopa Porphyria Gallstones
Glycogen storage diseases (such as Galactosaemia, Abetalipoproteinaemia)

Cirrhosis

Pathophysiology [2][3][4][5][6][1]

  • When an injured issue is replaced by a collagenous scar, it is termed as fibrosis.
  • 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 cellular mechanisms responsible for cirrhosis are similar regardless of the type of initial insult and site of injury within the liver lobule.
  • Viral hepatitis involves the periportal region, whereas involvement in alcoholic liver disease is largely pericentral.
  • If the damage progresses, panlobular cirrhosis may result.
  • Cirrhosis involves the following steps: [7]
    • Inflammation
    • Hepatic stellate cell activation
    • Angiogenesis
    • Fibrogenesis
  • Kupffer cells are hepatic macrophages responsible for Hepatic Stellate cell activation during injury.
  • The hepatic stellate cell (also known as the perisinusoidal cell or Ito cell) plays a key role in the pathogenesis of liver fibrosis/cirrhosis.
  • Hepatic stellate cells(HSC) are usually located in the subendothelial space of Disse and become activated to a myofibroblast-like phenotype in areas of liver injury.
  • Collagen and non collagenous matrix proteins responsible for fibrosis are produced by the activated Hepatic Stellate Cells(HSC).
  • Hepatocyte damage causes the release of lipid peroxidases from injured cell membranes leading to necrosis of parenchymal cells.
  • Activated HSC produce numerous cytokines and their receptors, such as PDGF and TGF-f31 which are responsible for fibrogenesis.
  • The matrix formed due to HSC activation is deposited in the space of Disse and leads to loss of fenestrations of endothelial cells, which is a process called capillarization.
  • Cirrhosis leads to hepatic microvascular changes characterised by [8]
    •  formation of intra hepatic shunts (due to angiogenesis and loss of parenchymal cells) 
    • hepatic endothelial dysfunction
  • The endothelial dysfunction is characterised by [9]
    • insufficient release of vasodilators, such as nitric oxide due to oxidative stress
    • increased production of vasoconstrictors (mainly adrenergic stimulation and activation of endothelins and RAAS)
  • Fibrosis eventually leads to formation of septae that grossly distort the liver architecture which includes both the liver parenchyma and the vasculature. A cirrhotic liver compromises hepatic sinusoidal exchange by shunting arterial and portal blood directly into the central veins (hepatic outflow). Vascularized fibrous septa connect central veins with portal tracts leading to islands of hepatocytes surrounded by fibrous bands without central veins.[10][11][12]
  • The formation of fibrotic bands is accompanied by regenerative nodule formation in the hepatic parenchyma.
  • Advancement of cirrhosis may lead to parenchymal dysfunction and development of portal hypertension.
  • Portal HTN results from the combination of the following:
    • Structural disturbances associated with advanced liver disease account for 70% of total hepatic vascular resistance.
    •  Functional abnormalities such as endothelial dysfunction and increased hepatic vascular tone account for 30% of total hepatic vascular resistance.

Pathogenesis of Cirrhosis due to Alcohol:

  • More than 66 percent of all American adults consume alcohol.
  • Cirrhosis due to alcohol accounts for approximately forty percent of mortality rates due to cirrhosis.
  • Mechanisms of alcohol-induced damage include:
    • Impaired protein synthesis, secretion, glycosylation
  • Ethanol intake leads to elevated accumulation of intracellular triglycerides by:
    • Lipoprotein secretion
    • Decreased fatty acid oxidation
    • Increased fatty acid uptake
  • Alcohol is converted by Alcohol dehydrogenase to acetaldehyde.
  • Due to the high reactivity of acetaldehyde, it forms acetaldehyde-protein adducts which cause damage to cells by:
    • Trafficking of hepatic proteins
    • Interrupting microtubule formation
    • Interfering with enzyme activities
  • Damage of hepatocytes leads to the formation of reactive oxygen species that activate Kupffer cells.[1]
  • Kupffer cell activation leads to the production of profibrogenic cytokines that stimulates stellate cells.
  • Stellate cell activation leads to the production of extracellular matrix and collagen.
  • Portal triads develop connections with central veins due to connective tissue formation in pericentral and periportal zones, leading to the formation of regenerative nodules.
  • Shrinkage of the liver occurs over years due to repeated insults that lead to:
    • Loss of hepatocytes
    • Increased production and deposition of collagen


Pathology

  • There are four stages of Cirrhosis as it progresses:
    • Chronic nonsuppurative destructive cholangitis - inflammation and necrosis of portal tracts with lymphocyte infiltration leading 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 leading to regenerative nodule formation.

Video codes

Normal video

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Video in table

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Floating video

Title
https://https://www.youtube.com/watch?v=ypYI_lmLD7g%7C350}}

Redirect

  1. REDIRECTEsophageal web

synonym website

https://mq.b2i.sg/snow-owl/#!terminology/snomed/10743008

Image

Normal versus Abnormal Barium study of esophagus with varices


Image to the right

C. burnetii, the Q fever causing agent
C. burnetii, the Q fever causing agent

Image and text to the right

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Gallery

References

  1. ↑ 1.0 1.1 1.2 Arthur MJ (2002). "Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C". Gastroenterology. 122 (5): 1525–8. PMID 11984538.
  2. ↑ Arthur MJ, Iredale JP (1994). "Hepatic lipocytes, TIMP-1 and liver fibrosis". J R Coll Physicians Lond. 28 (3): 200–8. PMID 7932316.
  3. ↑ 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.
  4. ↑ Iredale JP (1996). "Matrix turnover in fibrogenesis". Hepatogastroenterology. 43 (7): 56–71. PMID 8682489.
  5. ↑ Gressner AM (1994). "Perisinusoidal lipocytes and fibrogenesis". Gut. 35 (10): 1331–3. PMC 1374996. PMID 7959178.
  6. ↑ 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.
  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. ↑ 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.
  9. ↑ 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.
  10. ↑ Schuppan D, Afdhal NH (2008). "Liver cirrhosis". Lancet. 371 (9615): 838–51. doi:10.1016/S0140-6736(08)60383-9. PMC 2271178. PMID 18328931.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 13.0 13.1 13.2 Neuroendocrine tumor of the pancreas. Libre Pathology. http://librepathology.org/wiki/index.php/Neuroendocrine_tumour_of_the_pancreas

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REFERENCES

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