Portal hypertension pathophysiology: Difference between revisions

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=== Physiology ===
=== Physiology ===
* [[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>
[[image:1111.jpg|center]]
<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>
[[image:1dffhdfg.jpg|center]]
<math display="inline">R = {8 \eta L\over \pi r^4}</math><small>
<br>
η= [[Viscosity index|Viscosity]]; L= Length of [[vessel]]; r= Radius of [[vessel]]; π=22/7</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>
[[image:1svsdfv.jpg|center]]
<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.  
* Blood [[viscosity]] (η) does not change, unless dramatic changes in [[hematocrit]] happen.
* Blood [[viscosity]] (η) does not change, unless dramatic changes in [[hematocrit]] happen.
Line 68: Line 62:
*** However, the resistance in [[collaterals]] is less than the normal liver.  
*** However, the resistance in [[collaterals]] is less than the normal liver.  
*** Thus, [[Portocaval anastomoses|portosystemic collaterals]] can not lead to a complete decompression.
*** Thus, [[Portocaval anastomoses|portosystemic collaterals]] can 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]] and the venous system of abdominal organs juxtaposed with the retroperitoneum and abdominal wall; the left renal vein and the splanchnic, adrenal, and the spermatic veins.<ref name="pmid1415713">{{cite journal |vauthors=Mosca P, Lee FY, Kaumann AJ, Groszmann RJ |title=Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium |journal=Am. J. Physiol. |volume=263 |issue=4 Pt 1 |pages=G544–50 |year=1992 |pmid=1415713 |doi= |url=}}</ref>
*** [[Portocaval anastomoses|Portosystemic collateraling]] occurs between the [[short gastric]], [[coronary]] veins, and the [[esophageal]] [[azygos]] and the [[intercostal veins]]; the superior, the middle, and the inferior [[Hemorrhoidal plexus|hemorrhoidal veins]]; the [[Paraumbilical veins|paraumbilical venous plexus]] and the venous system of abdominal organs juxtaposed with the retroperitoneum and abdominal wall; the left renal vein, the splanchnic, the adrenal, and the spermatic veins.<ref name="pmid1415713">{{cite journal |vauthors=Mosca P, Lee FY, Kaumann AJ, Groszmann RJ |title=Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium |journal=Am. J. Physiol. |volume=263 |issue=4 Pt 1 |pages=G544–50 |year=1992 |pmid=1415713 |doi= |url=}}</ref>


==== Hyperdynamic circulation in portal hypertension ====
==== Hyperdynamic circulation in portal hypertension ====
Line 84: Line 78:
==Genetics==
==Genetics==
*[[Genes]] are involved in the [[pathogenesis]] of portal hypertension include the following:
*[[Genes]] are involved in the [[pathogenesis]] of portal hypertension include the following:
{| class="wikitable"
{|
!Gene
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Gene
!OMIM number
! style="background:#4479BA; color: #FFFFFF;" align="center" + |OMIM number
!Chromosome
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Chromosome
!Function
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Function
!Gene expression in portal hypertension
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Gene expression in portal hypertension
!Notes
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Notes
|-
|-
|'''[[DGUOK|Deoxyguanosine kinase (DGUOK)]]'''  
| style="background:#DCDCDC;" align="center" + |'''[[DGUOK|Deoxyguanosine kinase (DGUOK)]]'''  
|601465  
| style="background:#F5F5F5;" align="center" + |601465  
|2p13.1
| style="background:#F5F5F5;" align="center" + |2p13.1
|[[DNA replication]]
| style="background:#F5F5F5;" + |[[DNA replication]]
|[[Point mutation]]
| style="background:#F5F5F5;" + |[[Point mutation]]
|[[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>  
| 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]]  
* [[Liver failure]]  
* [[Neurologic]] abnormalities
* [[Neurologic]] abnormalities
Line 105: Line 99:
* [[Non-cirrhotic portal hypertension]]
* [[Non-cirrhotic portal hypertension]]
|-
|-
|'''[[Adenosine deaminase|Adenosine deaminase (ADA)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Adenosine deaminase|Adenosine deaminase (ADA)]]'''
|608958  
| style="background:#F5F5F5;" align="center" + |608958  
|20q13.12
| style="background:#F5F5F5;" align="center" + |20q13.12
|Irreversible [[deamination]] of [[adenosine]] and [[deoxyadenosine]] in the [[Purine metabolism|purine catabolic pathway]]  
| style="background:#F5F5F5;" + |Irreversible [[deamination]] of [[adenosine]] and [[deoxyadenosine]] in the [[Purine metabolism|purine catabolic pathway]]  
|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;" + |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]]
| 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>
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>
Line 117: Line 111:
* [[Fibrosis]]
* [[Fibrosis]]
|-
|-
|'''[[Phospholipase A2|Phospholipase A2 (PL2G10)]]'''  
| style="background:#DCDCDC;" align="center" + |'''[[Phospholipase A2|Phospholipase A2 (PL2G10)]]'''  
|603603  
| style="background:#F5F5F5;" align="center" + |603603  
|16p13.12
| style="background:#F5F5F5;" align="center" + |16p13.12
|Catalyzing the release of [[Fatty acid|fatty acids]] from [[phospholipids]]
| style="background:#F5F5F5;" + |Catalyzing the release of [[Fatty acid|fatty acids]] from [[phospholipids]]
|Reduced<ref name="KotaniKawabe2015" />  
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />  
|Identifier of PL2G10 expression:
| style="background:#F5F5F5;" + |Identifier of PL2G10 expression:
* [[Arachidonic acid|Arachidonic acid (AA)]]
* [[Arachidonic acid|Arachidonic acid (AA)]]
* [[Prostaglandins|Prostaglandins (PG)]]
* [[Prostaglandins|Prostaglandins (PG)]]
* [[Leukotrienes|Leukotrienes (LT)]]
* [[Leukotrienes|Leukotrienes (LT)]]
|-
|-
|'''[[CYP4F3|Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[CYP4F3|Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3)]]'''
|601270  
| style="background:#F5F5F5;" align="center" + |601270  
|19p13.12
| style="background:#F5F5F5;" align="center" + |19p13.12
|Catalyzing the omega-[[hydroxylation]] of [[Leukotriene B4|leukotriene B4 (LTB4)]]
| style="background:#F5F5F5;" + |Catalyzing the omega-[[hydroxylation]] of [[Leukotriene B4|leukotriene B4 (LTB4)]]
|Increased<ref name="KotaniKawabe2015" />  
| style="background:#F5F5F5;" + |Increased<ref name="KotaniKawabe2015" />  
| -
| style="background:#F5F5F5;" + | -
|-
|-
|'''[[Glutathione peroxidase|Glutathione peroxidase 3 (GPX3)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Glutathione peroxidase|Glutathione peroxidase 3 (GPX3)]]'''
|138321  
| style="background:#F5F5F5;" align="center" + |138321  
|5q33.1
| style="background:#F5F5F5;" align="center" + |5q33.1
|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>
| 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]]
* [[Hydrogen peroxide]]
* [[Organic peroxide|Organic hydroperoxide]]
* [[Organic peroxide|Organic hydroperoxide]]
* [[Lipid peroxidation|Lipid peroxides]]
* [[Lipid peroxidation|Lipid peroxides]]
|Increased<ref name="KotaniKawabe2015" />  
| style="background:#F5F5F5;" + |Increased<ref name="KotaniKawabe2015" />  
|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>
| 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]]
* [[Liver]]
* [[Kidney]]
* [[Kidney]]
* [[Breast]]
* [[Breast]]
|-
|-
|'''[[Leukotriene B4|Leukotriene B4 (LTB4)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Leukotriene B4|Leukotriene B4 (LTB4)]]'''
|601531  
| style="background:#F5F5F5;" align="center" + |601531  
|14q12
| style="background:#F5F5F5;" align="center" + |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>
| 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]]
* 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
| style="background:#F5F5F5;" + |Mutated
|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:#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>
|-
|-
|'''[[Prostaglandin E2 receptor|Prostaglandin E receptor 2 (PTGER2)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Prostaglandin E2 receptor|Prostaglandin E receptor 2 (PTGER2)]]'''
|176804  
| style="background:#F5F5F5;" align="center" + |176804  
|14q22.1
| style="background:#F5F5F5;" align="center" + |14q22.1
|Various biological activities in diverse tissues
| style="background:#F5F5F5;" + |Various biological activities in diverse tissues
|Reduced<ref name="KotaniKawabe2015" />  
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />  
| -
| style="background:#F5F5F5;" + | -
|-
|-
|'''[[Endothelin|Endothelin (EDN1)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Endothelin|Endothelin (EDN1)]]'''
|131240  
| style="background:#F5F5F5;" align="center" + |131240  
|6p24.1
| style="background:#F5F5F5;" align="center" + |6p24.1
|[[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;" + |[[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  
| style="background:#F5F5F5;" + |Increased  
|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:#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>
|-
|-
|'''[[Endothelin receptor type A|Endothelin receptor type A (EDNRA)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Endothelin receptor type A|Endothelin receptor type A (EDNRA)]]'''
|131243  
| style="background:#F5F5F5;" align="center" + |131243  
|4q31.22-q31.23
| style="background:#F5F5F5;" align="center" + |4q31.22-q31.23
|[[Vasoconstriction]] through binding to [[endothelin]]
| style="background:#F5F5F5;" + |[[Vasoconstriction]] through binding to [[endothelin]]
|Reduced<ref name="KotaniKawabe2015" />  
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />  
|Directly related to [[hypertension]] in patients<ref name="pmid15148269" />
| style="background:#F5F5F5;" + |Directly related to [[hypertension]] in patients<ref name="pmid15148269" />
|-
|-
|'''[[Natriuretic peptides|Natriuretic peptide receptor 3 (NPR3)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Natriuretic peptides|Natriuretic peptide receptor 3 (NPR3)]]'''
|108962  
| style="background:#F5F5F5;" align="center" + |108962  
|5p13.3
| style="background:#F5F5F5;" align="center" + |5p13.3
|Maintenance of:
| style="background:#F5F5F5;" + |Maintenance of:
* [[Blood pressure]]  
* [[Blood pressure]]  
* [[Extracellular fluid|Extracellular fluid volume]]
* [[Extracellular fluid|Extracellular fluid volume]]
|Increased<ref name="KotaniKawabe2015" />  
| style="background:#F5F5F5;" + |Increased<ref name="KotaniKawabe2015" />  
|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:#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>
|-
|-
|'''[[Cluster of differentiation|Cluster of differentiation 44 (CD44)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Cluster of differentiation|Cluster of differentiation 44 (CD44)]]'''
|107269  
| style="background:#F5F5F5;" align="center" + |107269  
|11p13
| style="background:#F5F5F5;" align="center" + |11p13
|
| style="background:#F5F5F5;" + |
* [[Lymphocyte]] activation  
* [[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>
* [[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<ref name="KotaniKawabe2015" />  
| 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>  
* 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>  
* 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]]'''
| style="background:#DCDCDC;" align="center" + |'''[[Transforming growth factor-β|Transforming growth factor (TGF)-β]]'''
|190180  
| style="background:#F5F5F5;" align="center" + |190180  
|19q13.2
| style="background:#F5F5F5;" align="center" + |19q13.2
|
| style="background:#F5F5F5;" + |
* [[Transformation|Tissue transformation]]
* [[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>
* [[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<ref name="KotaniKawabe2015" />  
| style="background:#F5F5F5; + |Reduced<ref name="KotaniKawabe2015" />  
|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:#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>
|-
|-
|'''Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4)'''
| style="background:#DCDCDC;" align="center" + |'''Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4)'''
|607577  
| style="background:#F5F5F5;" align="center" + |607577  
|8p21.3
| style="background:#F5F5F5;" align="center" + |8p21.3
|Increasing [[phosphatase]] activity in [[intracellular]] membrane-bound [[nucleosides]]
| style="background:#F5F5F5;" + |Increasing [[phosphatase]] activity in [[intracellular]] membrane-bound [[nucleosides]]
|Reduced<ref name="KotaniKawabe2015" />  
| style="background:#F5F5F5;" + |Reduced<ref name="KotaniKawabe2015" />  
| -
| style="background:#F5F5F5;" + | -
|-
|-
|'''[[ABCC1|ATP-binding cassette, subfamily C, member 1 (ABCC1)]]'''
| style="background:#DCDCDC;" align="center" + |'''[[ABCC1|ATP-binding cassette, subfamily C, member 1 (ABCC1)]]'''
|158343
| style="background:#F5F5F5;" align="center" + |158343
|16p13.11
| style="background:#F5F5F5;" align="center" + |16p13.11
|[[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;" + |[[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  
| style="background:#F5F5F5;" + |Reduced  
| -
| style="background:#F5F5F5;" + | -
|}
|}


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[[image:Cirrosi micronodular.1427.jpg|thumb|200px|Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons<ref><CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)></ref>]]
[[image:Cirrosi micronodular.1427.jpg|thumb|200px|Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons<ref><CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)></ref>]]
|
|
[[image:Fig78x.jpg|thumb|200px|Macronodular cirrhosis<ref name="urlwww.meddean.luc.edu">{{cite web |url=http://www.meddean.luc.edu/lumen/MedEd/orfpath/images/fig78x.jpg |title=www.meddean.luc.edu |format= |work= |accessdate=}}</ref>]]
[[image:Fig78x.jpg|thumb|200px|Macronodular cirrhosis- By Amadalvarez (Own work), via Wikimedia Commons<ref name="urlwww.meddean.luc.edu">{{cite web |url=http://www.meddean.luc.edu/lumen/MedEd/orfpath/images/fig78x.jpg |title=www.meddean.luc.edu |format= |work= |accessdate=}}</ref>]]
|-
|-
|
|
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On gross pathology, prominent, congested, and tortoise [[veins]] in the lower parts of [[esophagus]] are characteristic findings of [[esophageal varices]].
On gross pathology, prominent, congested, and tortoise [[veins]] in the lower parts of [[esophagus]] are characteristic findings of [[esophageal varices]].
|colspan="2"|
|colspan="2"|
[[image:F21. Venous enlargement in hepatic cirrhosis. Alfred Kast Wellcome L0074357.jpg|thumb|200px|center|Esophageal varices<ref><http://wellcomeimages.org/indexplus/obf_images/29/b4/13f38971164f946a97f9d32ddd93.jpg>Gallery: <"http://wellcomeimages.org/indexplus/image/L0074357.html"><"http://creativecommons.org/licenses/by/4.0> CC BY 4.0, <"https://commons.wikimedia.org/w/index.php?curid=36297209"></ref>]]
[[image:F21. Venous enlargement in hepatic cirrhosis. Alfred Kast Wellcome L0074357.jpg|thumb|200px|center|Esophageal varices- By Amadalvarez (Own work), via Wikimedia Commons<ref><http://wellcomeimages.org/indexplus/obf_images/29/b4/13f38971164f946a97f9d32ddd93.jpg>Gallery: <"http://wellcomeimages.org/indexplus/image/L0074357.html"><"http://creativecommons.org/licenses/by/4.0> CC BY 4.0, <"https://commons.wikimedia.org/w/index.php?curid=36297209"></ref>]]
|}
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==References==
==References==
{{Reflist|2}}
{{Reflist|2}}


[[Category:Gastroenterology]]
[[Category:Gastroenterology]]
[[Category:Hepatology]]
[[Category:Hepatology]]
[[Category:Disease]]
[[Category:Disease]]
[[Category:Needs content]]
[[Category:Emergency medicine]]
 
[[Category:Up-To-Date]]
{{WS}}
{{WS}}
{{WH}}
{{WH}}

Latest revision as of 14:15, 23 February 2018

https://www.youtube.com/watch?v=6Mf_8TawJ9w%7C500}}

Portal Hypertension Microchapters

Home

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Overview

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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 is 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

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

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:



 
 
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

Cirrhosis

On gross pathology there are two types of cirrhosis:

Micronodular cirrhosis - By Amadalvarez (Own work), via Wikimedia Commons[52]
Macronodular cirrhosis- By Amadalvarez (Own work), via Wikimedia Commons[53]

Splenomegaly

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

Splenomegaly - By Amadalvarez (Own work), via Wikimedia Commons[54]

Esophageal Varices

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

Esophageal varices- By Amadalvarez (Own work), via Wikimedia Commons[55]

Microscopic Pathology

Cirrhosis

Robbins definition of microscopic histopathological findings in cirrhosis includes (all three is needed for diagnosis):[56]

Cirrhosis with bridging fibrosis (yellow arrow) and nodule (black arrow) - By Nephron, via Librepathology.org[57]

Esophageal varices

The main microscopic histopathological findings in esophageal varices are:

Esophageal varices with submucosal vein (black arrow), via Librepathology.org[58]

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[59]

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[60]

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.
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