Portal hypertension pathophysiology: Difference between revisions

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* [[Ohm's law]] in vascular system defines the [[pressure gradient]] (ΔP) in [[blood vessels]] as equal to product of [[Blood flow|blood flow (Q)]] and [[Vascular resistance|vascular resistance (R)]]:
* [[Ohm's law]] in vascular system defines the [[pressure gradient]] (ΔP) in [[blood vessels]] as equal to product of [[Blood flow|blood flow (Q)]] and [[Vascular resistance|vascular resistance (R)]]:
<br>
<br>
<math display="block">\Delta P =P2-P1= Q\times R</math>
<math display="inline">\Delta P =P2-P1= Q\times R</math>


* Vascular resistance (R) has to be measured through Pouseuille’s law formula:
* Vascular resistance (R) has to be measured through Pouseuille’s law formula:
<br>
<br>
<math display="block">R = {8 \eta L\over \pi r^4}</math><small>η= [[Viscosity index|Viscosity]]; L= Length of [[vessel]]; r= Radius of [[vessel]]; π=22/7</small>
<math display="inline">R = {8 \eta L\over \pi r^4}</math><small>η= [[Viscosity index|Viscosity]]; L= Length of [[vessel]]; r= Radius of [[vessel]]; π=22/7</small>


* When the (R) measurement formula is integrated in [[Ohm's law]] it becomes as the following:
* When the (R) measurement formula is integrated in [[Ohm's law]] it becomes as the following:
<br>
<br>
<math display="block">\Delta P= P_2-P_1 = {Q\times 8 \eta L\over \pi r^4}</math>
<math display="inline">\Delta P= P_2-P_1 = {Q\times 8 \eta L\over \pi r^4}</math>


* Length of [[blood vessels]] (L) never differs in normal [[physiologic]] condition.  
* Length of [[blood vessels]] (L) never differs in normal [[physiologic]] condition.  
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|[[DNA replication]]
|[[DNA replication]]
|[[Point mutation]]
|[[Point mutation]]
|[[Mutation]] leads to:  
|[[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]]  
* [[Liver failure]]  
* [[Neurologic]] abnormalities
* [[Neurologic]] abnormalities
* [[Hypoglycemia]]
* [[Hypoglycemia]]
* Increased [[Lactic acid|lactate]] in [[body fluids]]
* 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]]
|-
|-
|'''[[Adenosine deaminase|Adenosine deaminase (ADA)]]'''
|'''[[Adenosine deaminase|Adenosine deaminase (ADA)]]'''
|608958  
|608958  
|20q13.12
|20q13.12
|Irreversible [[deamination]] of [[adenosine]] and [[deoxyadenosine]]  
|Irreversible [[deamination]] of [[adenosine]] and [[deoxyadenosine]] in the [[Purine metabolism|purine catabolic pathway]]  
|Reduced  
|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>
|Some roles in modulating tissue response to [[Interleukin 13|IL-13]]
|Some roles in modulating tissue response to [[Interleukin 13|IL-13]]


The main effects of [[IL-13]] are:
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]]
* [[Inflammation]]
* [[Chemokine]] elaboration
* [[Chemokine]] elaboration
Line 118: Line 120:
|16p13.12
|16p13.12
|Catalyzing the release of [[Fatty acid|fatty acids]] from [[phospholipids]]
|Catalyzing the release of [[Fatty acid|fatty acids]] from [[phospholipids]]
|Reduced  
|Reduced<ref name="KotaniKawabe2015" />
|Identifier of PL2G10 expression:
|Identifier of PL2G10 expression:
* [[Arachidonic acid|Arachidonic acid (AA)]]
* [[Arachidonic acid|Arachidonic acid (AA)]]
Line 128: Line 130:
|19p13.12
|19p13.12
|Catalyzing the omega-[[hydroxylation]] of [[Leukotriene B4|leukotriene B4 (LTB4)]]
|Catalyzing the omega-[[hydroxylation]] of [[Leukotriene B4|leukotriene B4 (LTB4)]]
|Increased  
|Increased<ref name="KotaniKawabe2015" />
| -
| -
|-
|-
Line 134: Line 136:
|138321  
|138321  
|5q33.1
|5q33.1
|[[Glutathione]] reduction which reduce:
|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]]
* [[Hydrogen peroxide]]
* [[Organic peroxide|Organic hydroperoxide]]
* [[Organic peroxide|Organic hydroperoxide]]
* [[Lipid peroxidation|Lipid peroxides]]
* [[Lipid peroxidation|Lipid peroxides]]
|Increased  
|Increased<ref name="KotaniKawabe2015" />
|Protects various organs against [[oxidative stress]]:
|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]]
* [[Liver]]
* [[Kidney]]
* [[Kidney]]
Line 147: Line 149:
|601531  
|601531  
|14q12
|14q12
|
|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]]
* Increasing intra-cellular [[calcium]]
* Elevation of [[Inositol-3-phosphate synthase|inositol 3-phosphate (IP3)]]  
* Elevation of [[Inositol-3-phosphate synthase|inositol 3-phosphate (IP3)]]  
* Inhibition of [[Adenylate cyclase|adenylyl cyclase]]
* Inhibition of [[Adenylate cyclase|adenylyl cyclase]]
|Mutated
|Mutated
|Increase [[blood flow]] to target [[tissue]] (esp. [[heart]]) about 4 times more.
|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>
|-
|-
|'''[[Prostaglandin E2 receptor|Prostaglandin E receptor 2 (PTGER2)]]'''
|'''[[Prostaglandin E2 receptor|Prostaglandin E receptor 2 (PTGER2)]]'''
Line 158: Line 160:
|14q22.1
|14q22.1
|Various biological activities in diverse tissues
|Various biological activities in diverse tissues
|Reduced  
|Reduced<ref name="KotaniKawabe2015" />
| -
| -
|-
|-
Line 164: Line 166:
|131240  
|131240  
|6p24.1
|6p24.1
|[[Vasoconstriction]]
|[[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>
|Increased  
|Increased  
|The most powerful [[vasoconstrictor]] known
|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>
|-
|-
|'''[[Endothelin receptor type A|Endothelin receptor type A (EDNRA)]]'''
|'''[[Endothelin receptor type A|Endothelin receptor type A (EDNRA)]]'''
Line 172: Line 174:
|4q31.22-q31.23
|4q31.22-q31.23
|[[Vasoconstriction]] through binding to [[endothelin]]
|[[Vasoconstriction]] through binding to [[endothelin]]
|Reduced  
|Reduced<ref name="KotaniKawabe2015" />
|Directly related to [[hypertension]] in patients
|Directly related to [[hypertension]] in patients<ref name="pmid15148269" />
|-
|-
|'''[[Natriuretic peptides|Natriuretic peptide receptor 3 (NPR3)]]'''
|'''[[Natriuretic peptides|Natriuretic peptide receptor 3 (NPR3)]]'''
Line 181: Line 183:
* [[Blood pressure]]  
* [[Blood pressure]]  
* [[Extracellular fluid|Extracellular fluid volume]]
* [[Extracellular fluid|Extracellular fluid volume]]
|Increased  
|Increased<ref name="KotaniKawabe2015" />
|Released from [[heart muscle]] in response to increase in wall tension
|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>
|-
|-
|'''[[Cluster of differentiation|Cluster of differentiation 44 (CD44)]]'''
|'''[[Cluster of differentiation|Cluster of differentiation 44 (CD44)]]'''
Line 189: Line 191:
|
|
* [[Lymphocyte]] activation  
* [[Lymphocyte]] activation  
* [[Lymph node]] homing
* [[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>
|Reduced  
|Reduced<ref name="KotaniKawabe2015" />
|
|
* Related to [[Fibroblast growth factor|fibroblast growth factor (FGF)]]  
* 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]]  
* 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>
|-
|-
|'''[[Transforming growth factor-β|Transforming growth factor (TGF)-β]]'''
|'''[[Transforming growth factor-β|Transforming growth factor (TGF)-β]]'''
Line 200: Line 202:
|
|
* [[Transformation|Tissue transformation]]
* [[Transformation|Tissue transformation]]
* [[Apoptosis]] regulation
* [[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>
|Reduced  
|Reduced<ref name="KotaniKawabe2015" />
|Hyper-expressed in African-American hypertensive patients
|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>
|-
|-
|'''Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4)'''
|'''Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4)'''
Line 208: Line 210:
|8p21.3
|8p21.3
|Increasing [[phosphatase]] activity in [[intracellular]] membrane-bound [[nucleosides]]
|Increasing [[phosphatase]] activity in [[intracellular]] membrane-bound [[nucleosides]]
|Reduced  
|Reduced<ref name="KotaniKawabe2015" />
| -
| -
|-
|-
Line 214: Line 216:
|158343
|158343
|16p13.11
|16p13.11
|[[Multidrug resistance|Multi-drug resistance]] in [[small cell lung cancer]]
|[[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>
|Reduced  
|Reduced  
| -
| -
|}
|}
=== Deoxyguanosine kinase (DGUOK) gene ===
* [[DGUOK|Deoxyguanosine kinase (DGUOK)]] [[gene]] with [[OMIM]] number of 601465 is on [[chromosome]] 2p13.1.
* [[Point mutation]] in [[DGUOK|deoxyguanosine kinase (DGUOK)]] [[gene]] causes progressive [[liver failure]] and [[neurologic]] abnormalities, [[hypoglycemia]], and increased [[lactate]] in [[body fluids]].<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>
* [[Homozygous]] [[missense mutation]] in [[DGUOK]] gene found to be related with [[non-cirrhotic portal hypertension]].<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>
=== Adenosine deaminase (ADA) gene ===
*[[Adenosine deaminase|Adenosine deaminase (ADA)]] [[gene]] with [[OMIM]] number of 608958 is on [[chromosome]] 20q13.12. ADA [[gene]] is responsible for irreversible [[deamination]] of [[adenosine]] and [[deoxyadenosine]] in the [[Purine metabolism|purine catabolic pathway]].
*It is postulated that [[Adenosine deaminase|ADA]] gene expression is reduced in portal hypertension.<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>
*[[Adenosine]] and [[adenosine]] signaling have some roles in modulating the tissue response to [[Interleukin 13|IL-13]]. The main effects of [[Interleukin 13|IL-13]] are [[inflammation]], [[chemokine]] elaboration, and [[fibrosis]].<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>
=== Phospholipase A2 (PL2G10) gene ===
* [[Phospholipase A2|Phospholipase A2 (PL2G10)]] [[gene]] with [[OMIM]] number of 603603 is on [[chromosome]] 16p13.12. PL2G10 [[gene]] is responsible for catalyzing the release of [[Fatty acid|fatty acids]] from [[phospholipids]].
* It is postulated that [[Phospholipase A2|PL2G10]] [[gene]] expression is reduced in portal hypertension.<ref name="KotaniKawabe2015" />
* [[Arachidonic acid|Arachidonic acid (AA)]], [[Prostaglandins|prostaglandins (PG)]], and [[Leukotrienes|leukotrienes (LT)]] measurements in patients of portal hypertension show the level of [[Phospholipase A2|PL2G10]] expression.
=== Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3) gene ===
*[[CYP4F3|Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3)]] [[gene]] with [[OMIM]] number of 601270 is on [[chromosome]] 19p13.12. [[CYP4F3]] [[gene]] is responsible for catalyzing the omega-[[hydroxylation]] of [[Leukotriene B4|leukotriene B4 (LTB4)]].
*It is postulated that [[CYP4F3]] [[gene expression]] is increased in portal hypertension.<ref name="KotaniKawabe2015" />
=== Glutathione peroxidase 3 (GPX3) gene ===
*[[Glutathione peroxidase|Glutathione peroxidase 3 (GPX3)]] [[gene]] with [[OMIM]] number of 138321 is on [[chromosome]] 5q33.1. [[Glutathione peroxidase|GPX3]] [[gene]] is responsible for catalyzing [[glutathione]] reduction; through which [[hydrogen peroxide]], [[Organic peroxide|organic hydroperoxide]], and lipid [[peroxides]] are reduced.<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>
*It is postulated that [[Glutathione peroxidase|GPX3]] [[gene expression]] is increased in portal hypertension.<ref name="KotaniKawabe2015" />
*[[Glutathione peroxidase|Glutathione peroxidase 3]] protects various organs against [[oxidative stress]], such as [[liver]], [[kidney]], and [[breast]].<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>
=== Leukotriene B4 (LTB4) gene ===
* [[Leukotriene B4|Leukotriene B4 (LTB4)]] [[gene]] with [[OMIM]] number of 601531 is on [[chromosome]] 14q12. [[Leukotriene B4|LTB4]] [[gene]] is responsible for increasing intra-cellular [[calcium]], elevation of [[Inositol triphosphate|inositol 3-phosphate (IP3)]] concentration, and inhibition of [[adenylyl cyclase]].<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>
* [[Leukotriene B4|LTB4]] treatment for [[smooth muscle cells]] makes the [[blood flow]] to target tissue (esp. [[heart]]) about 4 times more. [[Leukotriene B4|LTB4]] also increase the [[smooth muscle cells]] migration in response to [[chemotaxis]].<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>
=== Prostaglandin E receptor 2 (PTGER2) gene ===
*[[Prostaglandin E2 receptor|Prostaglandin E receptor 2 (PTGER2)]] [[gene]] with [[OMIM]] number of 176804 is on [[chromosome]] 14q22.1. [[Prostaglandin E2 receptor|PTGER2]] [[gene]] is responsible for various biological activities in diverse [[tissues]].
*It is postulated that [[PTGER2]] [[gene expression]] is reduced in portal hypertension.<ref name="KotaniKawabe2015" />
=== Endothelin (EDN1) gene ===
*[[Endothelin|Endothelin (EDN1)]] [[gene]] with [[OMIM]] number of 131240 is on [[chromosome]] 6p24.1. [[Endothelin 1|EDN1]] [[gene]] is responsible for [[vasoconstriction]] and is secreted from [[endothelium]].
*[[Endothelin]] is 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>
*Increased [[Gene expression|expression]] of [[EDN1]] is directly related to [[hypertension]] in patients.<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>
=== Endothelin receptor type A (EDNRA) gene ===
*[[Endothelin receptor type A|Endothelin receptor type A (EDNRA)]] [[gene]] with [[OMIM]] number of 131243 is on [[chromosome]] 4q31.22-q31.23. [[Endothelin receptor type A|EDNRA]] [[gene]] is responsible for [[vasoconstriction]] through binding to [[endothelin]].
*It is postulated that [[Endothelin receptor type A|EDNRA]] [[gene]] expression is reduced in portal hypertension.<ref name="KotaniKawabe2015" />
*Decreased [[Gene expression|expression]] of [[Endothelin receptor type A|EDNRA]] is directly related to [[hypertension]] in patients.<ref name="pmid15148269" />
=== Natriuretic peptide receptor 3 (NPR3) gene ===
*[[Natriuretic peptides|Natriuretic peptide receptor 3 (NPR3)]] [[gene]] with [[OMIM]] number of 108962 is on [[chromosome]] 5p13.3. NPR3 [[gene]] is responsible for maintenance of [[blood pressure]] and [[Extracellular fluid|extracellular fluid volume]].
*It is postulated that NPR3 [[gene expression]] is elevated in portal hypertension.<ref name="KotaniKawabe2015" />
*[[Atrial natriuretic peptide|Atrial natriuretic peptide (ANP)]] released from [[heart muscle]] in response to increase in wall tension. When [[Atrial natriuretic peptide|ANP]] binds to NPR3, it can modulate [[blood pressure]].<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>
=== Cluster of differentiation 44 (CD44) gene ===
*[[Cluster of differentiation|Cluster of differentiation 44 (CD44)]] [[gene]] with [[OMIM]] number of 107269 is on [[chromosome]] 11p13. [[CD44]] [[gene]] is responsible for [[lymphocyte]] activation and [[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>
*It is postulated that [[CD44]] [[gene expression]] is reduced in portal hypertension.<ref name="KotaniKawabe2015" />
*It is thought that [[CD44]] is related to [[Fibroblast growth factor|fibroblast growth factor (FGF)]] and can lead to [[fibrosis]] in various [[tissue]].<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>
*[[CD44]] [[Gene expression|expression]] is increased during [[collateral]] [[arteriogenesis]] in mice.<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>
=== Transforming growth factor (TGF)-β gene ===
*[[Transforming growth factor-β|Transforming growth factor (TGF)-β]] [[gene]] with [[OMIM]] number of 190180 is on [[chromosome]] 19q13.2. [[TGF-β]] [[gene]] is responsible for tissue [[transformation]] and its dysregulation may lead to [[apoptosis]].<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>
*It is postulated that [[TGF-β]] [[gene expression]] is reduced in portal hypertension.<ref name="KotaniKawabe2015" />
*[[TGF-β]] is 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>
=== Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) gene ===
* Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) [[gene]] with [[OMIM]] number of 607577 is on [[chromosome]] 8p21.3. [[ENTPD6|ENTPD4]] [[gene]] is responsible for increasing [[phosphatase]] activity in [[intracellular]] membrane-bound [[nucleosides]].
* It is postulated that [[TGF-β]] [[gene expression]] is reduced in portal hypertension.<ref name="KotaniKawabe2015" />
=== ATP-binding cassette, subfamily C, member 1 (ABCC1) gene ===
* [[ABCC1|ATP-binding cassette, subfamily C, member 1 (ABCC1)]] [[gene]] with [[OMIM]] number of 158343 is on [[chromosome]] 16p13.11. [[ABCC1]] [[gene]] is responsible for [[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>
* It is postulated that [[ABCC1]] [[gene expression]] is reduced in portal hypertension.<ref name="KotaniKawabe2015" />


==Associated Conditions==
==Associated Conditions==

Revision as of 20:43, 9 November 2017

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

Overview

The exact pathogenesis in portal hypertension is disturbance in normal physiology of portocaval circulation. The main factors that affect the pressure gradient in blood vessels are blood flow (Q) and vessel radius (r) in a direct and inverse way, respectively. Portal hypertension is related to elevation of portal vasculature resistance. 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. Fourteen different genes are involved in the pathogenesis of portal hypertension. Homozygous missense mutation in DGUOK gene found to be related with non-cirrhotic portal hypertension. On gross pathology, cirrhotic liver, splenomegaly, and esophageal varices are characteristic findings in portal hypertension. 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.

Pathophysiology

Physiology


<math display="inline">\Delta P =P2-P1= Q\times R</math>

  • Vascular resistance (R) has to be measured through Pouseuille’s law formula:


<math display="inline">R = {8 \eta L\over \pi r^4}</math>η= Viscosity; L= Length of vessel; r= Radius of vessel; π=22/7

  • When the (R) measurement formula is integrated in Ohm's law it becomes as the following:


<math display="inline">\Delta P= P_2-P_1 = {Q\times 8 \eta L\over \pi r^4}</math>



 
 
• Anatomical (irreversible component)
• Functional/vascular tone (reversible component)
 
 
 
 
 
• Opening of pre-existing vascular channels
• Formation of new vascular channels
 
• Systemic vasodilation (r)
• Increasing plasma volume (Q)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
lntra-hepatic resistance (r)
 
 
 
 
 
Portosystemic collaterals (Q)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Increased resistance to portal blood flow (R)
 
 
 
 
 
Increased systemic/splanchnic blood flow (Q)
(hyperdynamic circulation)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Elevated portal pressure (P)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Portal hypertension
 
 
 
 
 
 

Pathogenesis

Increased resistance

Hyperdynamic circulation in portal hypertension

Genetics

Gene OMIM number Chromosome Function Gene expression in portal hypertension Notes
Deoxyguanosine kinase (DGUOK) 601465 2p13.1 DNA replication Point mutation Mutation leads to:[15]

Homozygous missense mutation leads to:[16]

Adenosine deaminase (ADA) 608958 20q13.12 Irreversible deamination of adenosine and deoxyadenosine in the purine catabolic pathway Reduced[17] Some roles in modulating tissue response to IL-13

The main effects of IL-13 are:[18]

Phospholipase A2 (PL2G10) 603603 16p13.12 Catalyzing the release of fatty acids from phospholipids Reduced[17] Identifier of PL2G10 expression:
Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3) 601270 19p13.12 Catalyzing the omega-hydroxylation of leukotriene B4 (LTB4) Increased[17] -
Glutathione peroxidase 3 (GPX3) 138321 5q33.1 Reduction of glutathione which reduce:[19] Increased[17] Protects various organs against oxidative stress:[20]
Leukotriene B4 (LTB4) 601531 14q12 Include:[21] Mutated Increase blood flow to target tissue (esp. heart) about 4 times more.[22]
Prostaglandin E receptor 2 (PTGER2) 176804 14q22.1 Various biological activities in diverse tissues Reduced[17] -
Endothelin (EDN1) 131240 6p24.1 Vasoconstriction[23] Increased The most powerful vasoconstrictor known[24]
Endothelin receptor type A (EDNRA) 131243 4q31.22-q31.23 Vasoconstriction through binding to endothelin Reduced[17] Directly related to hypertension in patients[23]
Natriuretic peptide receptor 3 (NPR3) 108962 5p13.3 Maintenance of: Increased[17] Released from heart muscle in response to increase in wall tension. ANP can modulate blood pressure by binding to NPR3[25]
Cluster of differentiation 44 (CD44) 107269 11p13 Reduced[17]
Transforming growth factor (TGF)-β 190180 19q13.2 Reduced[17] Hyper-expressed in African-American hypertensive patients[30]
Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) 607577 8p21.3 Increasing phosphatase activity in intracellular membrane-bound nucleosides Reduced[17] -
ATP-binding cassette, subfamily C, member 1 (ABCC1) 158343 16p13.11 Multi-drug resistance in small cell lung cancer[31] Reduced -

Associated Conditions

 
 
 
 
 
 
 
 
 
 
Portal Hypertension
associated conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunological disorders
 
Infections
 
Medication and toxins
 
Genetic disorders
 
Prothrombotic conditions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Common variable immunodeficiency syndrome[32]
• Connective tissue diseases[33]
• Crohn’s disease[34]
• Solid organ transplant
•• Renal transplantation[35]
•• Liver transplantation[36]
• Hashimoto's thyroiditis[37]
• Autoimmune disease[38]
 
• Bacterial intestinal infections
• Recurrent E.coli infection[39]
• Human immunodeficiency virus (HIV) infection[40]
• Antiretroviral therapy[41]
 
• Thiopurine derivatives
•• Didanosine
•• Azathioprine[42]
•• Cis-thioguanine[43]
• Arsenicals[44]
• Vitamin A[45]
 
• Adams-Olivier syndrome[46]
• Turner syndrome[47]
• Phosphomannose isomerase deficiency[48]
• Familial cases[49]
 
• Inherited thrombophilias [50]
• Myeloproliferative neoplasm[50]
• Antiphospholipid syndrome[50]
• Sickle cell disease[51]
 
 

Gross Pathology

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[52]
Macronodular cirrhosis[53]
Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[54]
Esophageal varices[55]



Cirrhosis

On gross pathology there are two types of cirrhosis:



Splenomegaly

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


Esophageal Varices

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


Microscopic Pathology

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[56]
Hepatic amyloidosis with amorphous amyloids (black arrow) and normal hepatocytes (blue arrow), via Librepathology.org[57]
Congestive hepatopathy with central vein (yellow arrowhead), inflammatory cells, Councilman body (green arrowhead), and hepatocyte with mitotic figure (red arrowhead), via Librepathology.org[58]
Esophageal varices with submucosal vein (black arrow), via Librepathology.org[59]


Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[60]


Esophageal varices

The main microscopic histopathological findings in esophageal varices are:


Hepatic amyloidosis

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

Congestive hepatopathy

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

References

  1. ↑ Greenway CV, Stark RD (1971). "Hepatic vascular bed". Physiol. Rev. 51 (1): 23–65. PMID 5543903.
  2. ↑ Schiff, Eugene (2012). Schiff's diseases of the liver. Chichester, West Sussex, UK: John Wiley & Sons. ISBN 9780470654682.
  3. ↑ Beker, Simón G.; Valencia-Parparcén, Joel (1968). "Portal hypertension syndrome". The American Journal of Digestive Diseases. 13 (12): 1047–1054. doi:10.1007/BF02233549. ISSN 0002-9211.
  4. ↑ SCHAFFNER F, POPER H (1963). "Capillarization of hepatic sinusoids in man". Gastroenterology. 44: 239–42. PMID 13976646.
  5. ↑ 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.
  6. ↑ Rubanyi GM (1991). "Endothelium-derived relaxing and contracting factors". J. Cell. Biochem. 46 (1): 27–36. doi:10.1002/jcb.240460106. PMID 1874796.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Mandel H, Szargel R, Labay V, Elpeleg O, Saada A, Shalata A, Anbinder Y, Berkowitz D, Hartman C, Barak M, Eriksson S, Cohen N (2001). "The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA". Nat. Genet. 29 (3): 337–41. doi:10.1038/ng746. PMID 11687800.
  16. ↑ Vilarinho S, Sari S, Yilmaz G, Stiegler AL, Boggon TJ, Jain D, Akyol G, Dalgic B, Günel M, Lifton RP (2016). "Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension". Hepatology. 63 (6): 1977–86. doi:10.1002/hep.28499. PMC 4874872. PMID 26874653.
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 17.8 17.9 Kotani, Kohei; Kawabe, Joji; Morikawa, Hiroyasu; Akahoshi, Tomohiko; Hashizume, Makoto; Shiomi, Susumu (2015). "Comprehensive Screening of Gene Function and Networks by DNA Microarray Analysis in Japanese Patients with Idiopathic Portal Hypertension". Mediators of Inflammation. 2015: 1–10. doi:10.1155/2015/349215. ISSN 0962-9351.
  18. ↑ Blackburn MR, Lee CG, Young HW, Zhu Z, Chunn JL, Kang MJ, Banerjee SK, Elias JA (2003). "Adenosine mediates IL-13-induced inflammation and remodeling in the lung and interacts in an IL-13-adenosine amplification pathway". J. Clin. Invest. 112 (3): 332–44. doi:10.1172/JCI16815. PMC 166289. PMID 12897202.
  19. ↑ Chambers I, Frampton J, Goldfarb P, Affara N, McBain W, Harrison PR (1986). "The structure of the mouse glutathione peroxidase gene: the selenocysteine in the active site is encoded by the 'termination' codon, TGA". EMBO J. 5 (6): 1221–7. PMC 1166931. PMID 3015592.
  20. ↑ Chu FF, Esworthy RS, Doroshow JH, Doan K, Liu XF (1992). "Expression of plasma glutathione peroxidase in human liver in addition to kidney, heart, lung, and breast in humans and rodents". Blood. 79 (12): 3233–8. PMID 1339300.
  21. ↑ Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T (1997). "A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis". Nature. 387 (6633): 620–4. doi:10.1038/42506. PMID 9177352.
  22. ↑ Bäck M, Bu DX, Bränström R, Sheikine Y, Yan ZQ, Hansson GK (2005). "Leukotriene B4 signaling through NF-kappaB-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia". Proc. Natl. Acad. Sci. U.S.A. 102 (48): 17501–6. doi:10.1073/pnas.0505845102. PMC 1297663. PMID 16293697.
  23. ↑ 23.0 23.1 Campia U, Cardillo C, Panza JA (2004). "Ethnic differences in the vasoconstrictor activity of endogenous endothelin-1 in hypertensive patients". Circulation. 109 (25): 3191–5. doi:10.1161/01.CIR.0000130590.24107.D3. PMID 15148269.
  24. ↑ Inoue A, Yanagisawa M, Takuwa Y, Mitsui Y, Kobayashi M, Masaki T (1989). "The human preproendothelin-1 gene. Complete nucleotide sequence and regulation of expression". J. Biol. Chem. 264 (25): 14954–9. PMID 2670930.
  25. ↑ Lopez MJ, Wong SK, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers DL, Beuve A (1995). "Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide". Nature. 378 (6552): 65–8. doi:10.1038/378065a0. PMID 7477288.
  26. ↑ Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B (1990). "CD44 is the principal cell surface receptor for hyaluronate". Cell. 61 (7): 1303–13. PMID 1694723.
  27. ↑ Nedvetzki S, Golan I, Assayag N, Gonen E, Caspi D, Gladnikoff M, Yayon A, Naor D (2003). "A mutation in a CD44 variant of inflammatory cells enhances the mitogenic interaction of FGF with its receptor". J. Clin. Invest. 111 (8): 1211–20. doi:10.1172/JCI17100. PMID 12697740.
  28. ↑ 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 (2004). "CD44 regulates arteriogenesis in mice and is differentially expressed in patients with poor and good collateralization". Circulation. 109 (13): 1647–52. doi:10.1161/01.CIR.0000124066.35200.18. PMID 15023889.
  29. ↑ Derynck R, Akhurst RJ, Balmain A (2001). "TGF-beta signaling in tumor suppression and cancer progression". Nat. Genet. 29 (2): 117–29. doi:10.1038/ng1001-117. PMID 11586292.
  30. ↑ Suthanthiran M, Li B, Song JO, Ding R, Sharma VK, Schwartz JE, August P (2000). "Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage". Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3479–84. doi:10.1073/pnas.050420897. PMC 16265. PMID 10725360.
  31. ↑ Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, Stewart AJ, Kurz EU, Duncan AM, Deeley RG (1992). "Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line". Science. 258 (5088): 1650–4. PMID 1360704.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ 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.
  37. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ 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.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ Roulot D (2013). "Liver involvement in Turner syndrome". Liver Int. 33 (1): 24–30. doi:10.1111/liv.12007. PMID 23121401.
  48. ↑ 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.
  49. ↑ 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.
  50. ↑ 50.0 50.1 50.2 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.
  51. ↑ Kumar S, Joshi R, Jain AP (2007). "Portal hypertension associated with sickle cell disease". Indian J Gastroenterol. 26 (2): 94. PMID 17558079.
  52. ↑ <CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)>
  53. ↑ "www.meddean.luc.edu".
  54. ↑ 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
  55. ↑ <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">
  56. ↑ "File:Cirrhosis high mag.jpg - Libre Pathology".
  57. ↑ "File:Hepatic amyloidosis - high mag.jpg - Libre Pathology".
  58. ↑ "File:2 CEN NEC 1 680x512px.tif - Libre Pathology".
  59. ↑ "Esophageal varices - Libre Pathology".
  60. ↑ Mitchell, Richard (2012). Pocket companion to Robbins and Cotran pathologic basis of disease. Philadelphia, PA: Elsevier Saunders. ISBN 978-1416054542.

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