Portal hypertension pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Portal venous pressure is determined by portal blood flow and portal vascular resistance. Increased portal vascular resistance is often the main factor responsible for it. The consequences of portal hypertension are due to blood being forced down alternate channels by the increased resistance to flow through the portal system. Due to formation of alternate channels initially some of the portal blood and later most of it is shunted directly to the systemic circulation bypassing the liver.
Pathophysiology
- Portal hypertension is caused by conditions classified as pre-hepatic, intra-hepatic, and post-hepatic disorders.
- Intra-hepatic portal hypertension causes are classified as pre-sinusoidal, sinusoidal, and post-sinusoidal disorders.
- The exact pathogenesis in portal hypertension is disturbance in normal physiology of portocaval circulation.
Physiology
- Ohm's law in vascular system defines the pressure gradient (ΔP) in blood vessels as equal to product of blood flow (Q) and vascular resistance (R):<math display="block">\Delta P =P2-P1= Q\times R</math>
- Vascular resistance (R) has to be measured through Pouseuille’s law formula:<math display="block">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="block">\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.
- Blood viscosity (η) does not change, unless dramatic changes in hematocrit happen.
- Thus, 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.
| • 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
- Portal hypertension is related to elevation of portal vasculature resistance.
- Increased resistance in portal system can be due to both intra-hepatic and also portosystemic collaterals resistances.
- Intra-hepatic resistance
- The main factor in intra-hepatic resistance is hepatic vascular compliance, which is greatly decreased in various liver diseases, such as fibrosis or cirrhosis.
- Portal hypertension occurs when compliance is decreased and blood flow is increased in liver.[1]
- Pre-hepatic and post-hepatic portal hypertension are due to some secondary obstruction before or after liver vasculature, respectively.[2]
- Schistosomiasis causes both pre-sinusoidal and sinusoidal pathologies. The granulomas compress the pre-sinusoidal veins. In late stages sinusoidal resistance also increased.[3]
- Alcoholic hepatitis causes both sinusoidal and post-sinusoidal pathologies.[4][5]
- Hepatic vascular endothelium synthesizes and secretes both vasodilator (e.g., nitric oxide, prostacyclins) and vasoconstrictor (e.g., endothelin and prostanoids) chemicals.[6][7]
- Increased resistance due to the elevation of vascular tone can be caused by vasoconstrictors excess or vasodilators lack.
- It is postulated that in cirrhotic liver the nitric oxide level is lower and the response to endothelin response in myofibrils is higher than normal liver.[8]
- Portosystemic collateral resistance
- Collateral formation is the consequence of portal hypertension that is also the main contributor to esophageal varices.
- The main purpose of the collaterals is to decompress and bypass the portal blood flow.
- However, the resistance in collaterals is less than the normal liver.
- Thus, portosystemic collaterals can not lead to a complete decompression.
- Portosystemic collateraling occurs between the short gastric, coronary veins, and the esophageal azygos and the intercostal veins; superior and the middle and inferior hemorrhoidal veins; the 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 spermatic veins.[9]
- Intra-hepatic resistance
Hyperdynamic circulation in portal hypertension
- Peripheral vasodilatation is the basis for decreased systemic vascular resistance and mean arterial pressure, plasma volume expansion, elevated splanchnic blood flow, and elevated cardiac index.[10]
- Systemic vasodilation
- Three main mechanisms which contribute to the peripheral vasodilation are as following:
- Increased vasodilators production in systemic circulation[11]
- Increased vasodilators production in local endothelium[12]
- Decreased vascular response to local vasoconstrictors[13]
- Three main mechanisms which contribute to the peripheral vasodilation are as following:
- Plasma volume
- There are several events which contribute to the hyperdynamic circulation such as:
- Initial vasodilatation, induced by systemic and local endothelial factors
- Subsequent plasma volume expansion[14]
- There are several events which contribute to the hyperdynamic circulation such as:
Genetics
- Genes involved in the pathogenesis of portal hypertension include the following:
| Gene | OMIM number | Chromosome | Function | Gene expression in portal hypertension | Notes |
|---|---|---|---|---|---|
| Deoxyguanosine kinase (DGUOK) | 601465 | 2p13.1 | DNA replication | Point mutation | Mutation leads to:
|
| Adenosine deaminase (ADA) | 608958 | 20q13.12 | Irreversible deamination of adenosine and deoxyadenosine | Reduced | Some roles in modulating tissue response to IL-13
The main effects of IL-13 are:
|
| Phospholipase A2 (PL2G10) | 603603 | 16p13.12 | Catalyzing the release of fatty acids from phospholipids | Reduced | 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 | - |
| Glutathione peroxidase 3 (GPX3) | 138321 | 5q33.1 | Glutathione reduction which reduce:
|
Increased | Protects various organs against oxidative stress:
|
| Leukotriene B4 (LTB4) | 601531 | 14q12 |
|
Mutated | Increase blood flow to target tissue (esp. heart) about 4 times more. |
| Prostaglandin E receptor 2 (PTGER2) | 176804 | 14q22.1 | Various biological activities in diverse tissues | Reduced | - |
| Endothelin (EDN1) | 131240 | 6p24.1 | Vasoconstriction | Increased | The most powerful vasoconstrictor known |
| Endothelin receptor type A (EDNRA) | 131243 | 4q31.22-q31.23 | Vasoconstriction through binding to endothelin | Reduced | Directly related to hypertension in patients |
| Natriuretic peptide receptor 3 (NPR3) | 108962 | 5p13.3 | Maintenance of:
|
Increased | Released from heart muscle in response to increase in wall tension |
| Cluster of differentiation 44 (CD44) | 107269 | 11p13 |
|
Reduced |
|
| Transforming growth factor (TGF)-β | 190180 | 19q13.2 |
|
Reduced | Hyper-expressed in African-American hypertensive patients |
| Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) | 607577 | 8p21.3 | Increasing phosphatase activity in intracellular membrane-bound nucleosides | Reduced | - |
| ATP-binding cassette, subfamily C, member 1 (ABCC1) | 158343 | 16p13.11 | Multi-drug resistance in small cell lung cancer | Reduced | - |
Deoxyguanosine kinase (DGUOK) gene
- Deoxyguanosine kinase (DGUOK) gene with OMIM number of 601465 is on chromosome 2p13.1.
- Point mutation in deoxyguanosine kinase (DGUOK) gene causes progressive liver failure and neurologic abnormalities, hypoglycemia, and increased lactate in body fluids.[15]
- Homozygous missense mutation in DGUOK gene found to be related with non-cirrhotic portal hypertension.[16]
Adenosine deaminase (ADA) gene
- 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 catabolic pathway.
- It is postulated that ADA gene expression is reduced in portal hypertension.[17]
- Adenosine and adenosine signaling have some roles in modulating the tissue response to IL-13. The main effects of IL-13 are inflammation, chemokine elaboration, and fibrosis.[18]
Phospholipase A2 (PL2G10) gene
- Phospholipase A2 (PL2G10) gene with OMIM number of 603603 is on chromosome 16p13.12. PL2G10 gene is responsible for catalyzing the release of fatty acids from phospholipids.
- It is postulated that PL2G10 gene expression is reduced in portal hypertension.[17]
- Arachidonic acid (AA), prostaglandins (PG), and leukotrienes (LT) measurements in patients of portal hypertension show the level of PL2G10 expression.
Cytochrome P450, family 4, subfamily F, polypeptide 3 (CYP4F3) gene
- 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 (LTB4).
- It is postulated that CYP4F3 gene expression is increased in portal hypertension.[17]
Glutathione peroxidase 3 (GPX3) gene
- Glutathione peroxidase 3 (GPX3) gene with OMIM number of 138321 is on chromosome 5q33.1. GPX3 gene is responsible for catalyzing glutathione reduction; through which hydrogen peroxide, organic hydroperoxide, and lipid peroxides are reduced.[19]
- It is postulated that GPX3 gene expression is increased in portal hypertension.[17]
- Glutathione peroxidase 3 protects various organs against oxidative stress, such as liver, kidney, and breast.[20]
Leukotriene B4 (LTB4) gene
- Leukotriene B4 (LTB4) gene with OMIM number of 601531 is on chromosome 14q12. LTB4 gene is responsible for increasing intra-cellular calcium, elevation of inositol 3-phosphate (IP3) concentration, and inhibition of adenylyl cyclase.[21]
- LTB4 treatment for smooth muscle cells makes the blood flow to target tissue (esp. heart) about 4 times more. LTB4 also increase the smooth muscle cells migration in response to chemotaxis.[22]
Prostaglandin E receptor 2 (PTGER2) gene
- Prostaglandin E receptor 2 (PTGER2) gene with OMIM number of 176804 is on chromosome 14q22.1. PTGER2 gene is responsible for various biological activities in diverse tissues.
- It is postulated that PTGER2 gene expression is reduced in portal hypertension.[17]
Endothelin (EDN1) gene
- Endothelin (EDN1) gene with OMIM number of 131240 is on chromosome 6p24.1. EDN1 gene is responsible for vasoconstriction and is secreted from endothelium.
- Endothelin is the most powerful vasoconstrictor known.[23]
- Increased expression of EDN1 is directly related to hypertension in patients.[24]
Endothelin receptor type A (EDNRA) gene
- Endothelin receptor type A (EDNRA) gene with OMIM number of 131243 is on chromosome 4q31.22-q31.23. EDNRA gene is responsible for vasoconstriction through binding to endothelin.
- It is postulated that EDNRA gene expression is reduced in portal hypertension.[17]
- Increased expression of EDNRA is directly related to hypertension in patients.[24]
Natriuretic peptide receptor 3 (NPR3) gene
- 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 volume.
- It is postulated that NPR3 gene expression is elevated in portal hypertension.[17]
- Atrial natriuretic peptide (ANP) released from heart muscle in response to increase in wall tension. When ANP binds to NPR3, it can modulate blood pressure.[25]
Cluster of differentiation 44 (CD44) gene
- 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.[26]
- It is postulated that CD44 gene expression is reduced in portal hypertension.[17]
- It is thought that CD44 is related to fibroblast growth factor (FGF) and can lead to fibrosis in various tissue.[27]
- CD44 expression is increased during collateral arteriogenesis in mice.[28]
Transforming growth factor (TGF)-β gene
- 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.[29]
- It is postulated that TGF-β gene expression is reduced in portal hypertension.[17]
- TGF-β is hyper-expressed in African-American hypertensive patients.[30]
Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) gene
- Ectonucleoside triphosphate diphosphohydrolase 4 (ENTPD4) gene with OMIM number of 607577 is on chromosome 8p21.3. 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.[17]
ATP-binding cassette, subfamily C, member 1 (ABCC1) gene
- ATP-binding cassette, subfamily C, member 1 (ABCC1) gene with OMIM number of 158343 is on chromosome 16p13.11. ABCC1 gene is responsible for multi-drug resistance in small cell lung cancer.[31]
- It is postulated that ABCC1 gene expression is reduced in portal hypertension.[17]
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ Greenway CV, Stark RD (1971). "Hepatic vascular bed". Physiol. Rev. 51 (1): 23–65. PMID 5543903.
- ↑ Schiff, Eugene (2012). Schiff's diseases of the liver. Chichester, West Sussex, UK: John Wiley & Sons. ISBN 9780470654682.
- ↑ 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.
- ↑ SCHAFFNER F, POPER H (1963). "Capillarization of hepatic sinusoids in man". Gastroenterology. 44: 239–42. PMID 13976646.
- ↑ 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.
- ↑ Rubanyi GM (1991). "Endothelium-derived relaxing and contracting factors". J. Cell. Biochem. 46 (1): 27–36. doi:10.1002/jcb.240460106. PMID 1874796.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 17.00 17.01 17.02 17.03 17.04 17.05 17.06 17.07 17.08 17.09 17.10 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 24.0 24.1 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.