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* Cirrhosis leads to endothelial dysfunction<ref name="pmid9755227">{{cite journal |vauthors=Gupta TK, Toruner M, Chung MK, Groszmann RJ |title=Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats |journal=Hepatology |volume=28 |issue=4 |pages=926–31 |year=1998 |pmid=9755227 |doi=10.1002/hep.510280405 |url=}}</ref>
* Cirrhosis leads to endothelial dysfunction<ref name="pmid9755227">{{cite journal |vauthors=Gupta TK, Toruner M, Chung MK, Groszmann RJ |title=Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats |journal=Hepatology |volume=28 |issue=4 |pages=926–31 |year=1998 |pmid=9755227 |doi=10.1002/hep.510280405 |url=}}</ref>
* Increased production of prostanoids, most likely thromboxane  A2 (TXA2) has been known to be associated with endothelial dysfunction<ref name="pmid12971960">{{cite journal |vauthors=Graupera M, García-Pagán JC, Parés M, Abraldes JG, Roselló J, Bosch J, Rodés J |title=Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers |journal=J. Hepatol. |volume=39 |issue=4 |pages=515–21 |year=2003 |pmid=12971960 |doi= |url=}}</ref>
* Increased production of prostanoids, most likely thromboxane  A2 (TXA2) has been known to be associated with endothelial dysfunction<ref name="pmid12971960">{{cite journal |vauthors=Graupera M, García-Pagán JC, Parés M, Abraldes JG, Roselló J, Bosch J, Rodés J |title=Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers |journal=J. Hepatol. |volume=39 |issue=4 |pages=515–21 |year=2003 |pmid=12971960 |doi= |url=}}</ref>
'''Mechanism leading to variceal rupture'''
'''Mechanism leading to variceal hemorrhage'''
* The wall tension of the vessel determines if there will be rupture of the varices<ref name="pmid10425421">{{cite journal |vauthors=Jackson FW, Adrain AL, Black M, Miller LS |title=Calculation of esophageal variceal wall tension by direct sonographic and manometric measurements |journal=Gastrointest. Endosc. |volume=50 |issue=2 |pages=247–51 |year=1999 |pmid=10425421 |doi= |url=}}</ref>
* The wall tension of the vessel determines if there will be rupture of the varices<ref name="pmid10425421">{{cite journal |vauthors=Jackson FW, Adrain AL, Black M, Miller LS |title=Calculation of esophageal variceal wall tension by direct sonographic and manometric measurements |journal=Gastrointest. Endosc. |volume=50 |issue=2 |pages=247–51 |year=1999 |pmid=10425421 |doi= |url=}}</ref>
* The wall tension depends upon the variceal pressure, luminal pressure and radius of the vessel<ref name="pmid10425421">{{cite journal |vauthors=Jackson FW, Adrain AL, Black M, Miller LS |title=Calculation of esophageal variceal wall tension by direct sonographic and manometric measurements |journal=Gastrointest. Endosc. |volume=50 |issue=2 |pages=247–51 |year=1999 |pmid=10425421 |doi= |url=}}</ref>
* The wall tension depends upon the variceal pressure, luminal pressure and radius of the vessel<ref name="pmid10425421">{{cite journal |vauthors=Jackson FW, Adrain AL, Black M, Miller LS |title=Calculation of esophageal variceal wall tension by direct sonographic and manometric measurements |journal=Gastrointest. Endosc. |volume=50 |issue=2 |pages=247–51 |year=1999 |pmid=10425421 |doi= |url=}}</ref>
Line 59: Line 59:
=== Gastric varices ===
=== Gastric varices ===
Gastric varices may form secondary to chronic liver disease or splenic vein obstruction; splenic vein obstruction may be caused by pancreatitis, pancreatic pseudocysts, pancreatic carcinoma, other retroperitoneal tumors, or intrinsic thrombosis of the splenic vein
Gastric varices may form secondary to chronic liver disease or splenic vein obstruction; splenic vein obstruction may be caused by pancreatitis, pancreatic pseudocysts, pancreatic carcinoma, other retroperitoneal tumors, or intrinsic thrombosis of the splenic vein
* '''Vascular architecture and venous drainage of stomach'''


'''Vascular architecture and venous drainage of stomach'''
* Gastric varices consist of dilated veins present in the submucosa of the stomach in areas of port-caval anastomosis (fundus and cardia)
* Gastric varices consist of dilated veins present in the submucosa of the stomach in areas of port-caval anastomosis (fundus and cardia)
* The splenic vein and superior mesenteric vein join together to form the portal vein. The anastomosis contributing to gastric varices consists of short gastric vein, left gastric vein and esophageal branches
* The splenic vein and superior mesenteric vein join together to form the portal vein. The anastomosis contributing to gastric varices consists of short gastric vein, left gastric vein and esophageal branches
Line 71: Line 71:
* First, through the right and left gastric veins, which drain varices around the distal esophagus and cardia (EV and GOV1) into the portal vein, or when flow is reversed the blood flows backwards into the azygous system
* First, through the right and left gastric veins, which drain varices around the distal esophagus and cardia (EV and GOV1) into the portal vein, or when flow is reversed the blood flows backwards into the azygous system
'''(b) Fundic varices'''
'''(b) Fundic varices'''
* The second pathway is via the short and posterior gastric veins, which under normal circumstances drain blood from the fundus into the splenic vein, but in PHT the flow often is reversed and blood drains from the spleen toward the stomach into fundal varices (GOV2 and IGV1).31 IGV2 often are caused by dilation of branches of the gastroepiploic veins.
* Blood from the fundus of the stomach is drained via the short gastric and posterior gastric veins, these veins give rise to the fundic varices
* In portal hypertension, the flow often is reversed and blood drains from the spleen toward the stomach into fundal varices (GOV2 and IGV1)
* IGV2 often are caused by dilation of branches of the gastroepiploic veins
'''Mechanism leading to variceal hemorrhage'''
* The wall tension of the vessel determines if there will be rupture of the varices<ref name="pmid10425421" />
* The wall tension depends upon the variceal pressure, luminal pressure and radius of the vessel<ref name="pmid10425421" />
* The wall tension is calculated by using the “Lapace's law”:
** Wall tension = (variceal pressure – luminal pressure) × radius/thickening of variceal wall.  
** The result is the force which is generated by the variceal wall opposing further dilation
* When the wall tension over comes the elastic limit of the varices, rupture occurs<ref name="pmid23193482" />
* The vessel wall of the varix is covered by a thinned out serosa and mucosa, and the varix comes to be seen through from the serosa as well as from the mucosa. When such a large varix ruptures, bleeding is profuse and difficult to manage, and the mortality rate is high


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

Revision as of 15:10, 22 November 2017

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

Overview

Pathophysiology

Varices arise from hemodynamic disturbance between the systemic and portal venous system. The majority of venous drainage of the gastrointestinal system occurs via the portal venous system. Whenever there is an interruption of drainage through the portal system (for example due to cirrhosis), the vessels contributing to the porto-caval shunts become more prominent due to increased pressure gradient. The interruption in blood flow leads to the creation collateral vessels that involve veins of the esophagus, stomach, pelvis (hemorrhoids), retroperitoneum, liver, abdominal wall, and other areas.[1][2]

Esophageal varices

Esophageal varices are a major complication of portal hypertension (increased blood pressure in the portal venous system). In order to understand the mechanism leading to the development of esophageal varices, it is important to understand the normal vascular architecture and venous drainage of the esophagus.[3]

Vascular architecture and venous drainage of esophagus

  • Vascular resistance increases against portal blood flow in cirrhosis, noncirrhotic portal fibrosis, idiopathic portal hypertension, extrahepatic portal vein obstruction, Budd-Chiari syndrome, and other portal hypertensive disorders, inducing congestion of blood in the splenic and mesenteric veins that lie upstream of the portal trunk[4][5][6]
  • The major vessels draining blood from the esophagus include, the left gastric (coronary) and less frequently short gastric veins[7][8]

Porto-caval collaterals in esophagus

  • Portal hypertension develops due to the formation of porto-collateral circulation[9]
  • Dilatation and hypertrophy of preexisting vascular channels lead to the formation of these collateral channels[10]
  • Collaterals develop according to the increased portal pressure, and minimum threshold level of hepatic-venous portal geadient may be 10 mmHg for the development of portosystemic collaterals and esophageal varices[11]

Role of hepatic vasodilators

(a) Nitric Oxide (NO)

  • Nitric oxide (NO) acts as an intra-hepatic vasodilator[12][13]
  • The levels of NO are decreased in patients suffering from chronic liver disease[14]
  • This leads to an imbalance between the endogenous vasodilators and vasoconstrictors inside the hepatic vascular tree
  • Reduced levels of hepatic NO production may contribute to the increased intrahepatic vascular resistance in cirrhosis, thereby worsening portal hypertension[15]
  • NO-dependent apoptosis maintains the hepatic sinusoidal homeostasis
  • NO also leads to apoptosis of hepatic stellate cell through a signaling mechanism that involves mitochondria, and a decreased level of NO may lead to a disturbance of the intra-hepatic homeostasis[16]

(b) Glucagon

  • Glucagon is a hormonal vasodilator which is associated with increased blood flow in the splanchnic bed and portal hypertension[17]
  • Plasma glucagon levels are increased in cirrhotic patients due to decreased hepatic clearance of glucagon as well as an increased secretion of glucagon by pancreatic alpha cells[17][18] 
  • Hyperglucagonemia may play a part in splanchnic vasodilatation of chronic portal hypertension[19][20][21]

(c) Prostacyclin

  • Prostacyclin is an endogenous vasodilator[22][23]
  • Prostacyclin levels are inversely related to the size of varices[24][25]
  • Decreased prostacyclin levels are found in cirrhotic patients

Role of hepatic vasoconstrictors

(a) Endothelin

  • Endothelin is involved in changes in the vascular tone in cirrhotic patients[26]
  • Endothelin leads to increased vascular tone (vasocontriction)
  • Endothelin 1 and endothelin 3 are increased in cirrhosis[27][28]

(b) Angiotensin II

  • Angiotensin II leads to increased intraportal resistance via vasoconstriction[29]

(c) Norepinephrine

  • Norepinephrine is also a vasoconstrictor, which controls the intrahepatic vascular tone, including portal vessels[30][31]

Role of endothelial dysfunction

  • Vascular endothelium harbors a number of vasocontrictive substance such as, prostaglandin H2(PGH2), thromboxane A2 (TXA2) and anion superoxide,which contribute to portal hypertension[32]
  • Cirrhosis leads to endothelial dysfunction[33]
  • Increased production of prostanoids, most likely thromboxane A2 (TXA2) has been known to be associated with endothelial dysfunction[34]

Mechanism leading to variceal hemorrhage

  • The wall tension of the vessel determines if there will be rupture of the varices[35]
  • The wall tension depends upon the variceal pressure, luminal pressure and radius of the vessel[35]
  • The wall tension is calculated by using the “Lapace's law”:
    • Wall tension = (variceal pressure – luminal pressure) × radius/thickening of variceal wall.
    • The result is the force which is generated by the variceal wall opposing further dilation
  • When the wall tension over comes the elastic limit of the varices, rupture occurs[36]

Gastric varices

Gastric varices may form secondary to chronic liver disease or splenic vein obstruction; splenic vein obstruction may be caused by pancreatitis, pancreatic pseudocysts, pancreatic carcinoma, other retroperitoneal tumors, or intrinsic thrombosis of the splenic vein

  • Vascular architecture and venous drainage of stomach
  • Gastric varices consist of dilated veins present in the submucosa of the stomach in areas of port-caval anastomosis (fundus and cardia)
  • The splenic vein and superior mesenteric vein join together to form the portal vein. The anastomosis contributing to gastric varices consists of short gastric vein, left gastric vein and esophageal branches
  • Cardiac varices are supplied majorly by left gastric vein
  • Fundic varices are supplied by short gastric or posterior gastric veins[37]
  • Cardiac and fundic varices differ in the degree of anastomosis (more common in cardiac varices) and the caliber of the varicose veins

Mechanism of development of gastric varices

  • Increased pressure in two main venous pathways are responsible development of gastric varices:

(a) Cardiac varices

  • First, through the right and left gastric veins, which drain varices around the distal esophagus and cardia (EV and GOV1) into the portal vein, or when flow is reversed the blood flows backwards into the azygous system

(b) Fundic varices

  • Blood from the fundus of the stomach is drained via the short gastric and posterior gastric veins, these veins give rise to the fundic varices
  • In portal hypertension, the flow often is reversed and blood drains from the spleen toward the stomach into fundal varices (GOV2 and IGV1)
  • IGV2 often are caused by dilation of branches of the gastroepiploic veins

Mechanism leading to variceal hemorrhage

  • The wall tension of the vessel determines if there will be rupture of the varices[35]
  • The wall tension depends upon the variceal pressure, luminal pressure and radius of the vessel[35]
  • The wall tension is calculated by using the “Lapace's law”:
    • Wall tension = (variceal pressure – luminal pressure) × radius/thickening of variceal wall.
    • The result is the force which is generated by the variceal wall opposing further dilation
  • When the wall tension over comes the elastic limit of the varices, rupture occurs[36]
  • The vessel wall of the varix is covered by a thinned out serosa and mucosa, and the varix comes to be seen through from the serosa as well as from the mucosa. When such a large varix ruptures, bleeding is profuse and difficult to manage, and the mortality rate is high

Associated Conditions

Genetics

Gross Pathology

Microscopic Pathology

  1. ↑ "Anatomy - The Gastrointestinal Circulation - NCBI Bookshelf".
  2. ↑ Mahl TC, Groszmann RJ (1990). "Pathophysiology of portal hypertension and variceal bleeding". Surg. Clin. North Am. 70 (2): 251–66. PMID 2181704.
  3. ↑ Maruyama H, Yokosuka O (2012). "Pathophysiology of portal hypertension and esophageal varices". Int J Hepatol. 2012: 895787. doi:10.1155/2012/895787. PMC 3362051. PMID 22666604.
  4. ↑ Moreno AH, Burchell AR, Rousselot LM, Panke WF, Slafsky F, Burke JH (1967). "Portal blood flow in cirrhosis of the liver". J. Clin. Invest. 46 (3): 436–45. doi:10.1172/JCI105545. PMC 297064. PMID 6023778.
  5. ↑ Ponziani FR, Zocco MA, Campanale C, Rinninella E, Tortora A, Di Maurizio L, Bombardieri G, De Cristofaro R, De Gaetano AM, Landolfi R, Gasbarrini A (2010). "Portal vein thrombosis: insight into physiopathology, diagnosis, and treatment". World J. Gastroenterol. 16 (2): 143–55. PMC 2806552. PMID 20066733.
  6. ↑ Tanaka M, Wanless IR (1998). "Pathology of the liver in Budd-Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, veno-portal cirrhosis, and large regenerative nodules". Hepatology. 27 (2): 488–96. doi:10.1002/hep.510270224. PMID 9462648.
  7. ↑ Adithan S, Venkatesan B, Sundarajan E, Kate V, Kalayarasan R (2010). "Color Doppler evaluation of left gastric vein hemodynamics in cirrhosis with portal hypertension and its correlation with esophageal varices and variceal bleed". Indian J Radiol Imaging. 20 (4): 289–93. doi:10.4103/0971-3026.73541. PMC 3056627. PMID 21423905.
  8. ↑ Rebibo L, Chivot C, Fuks D, Sabbagh C, Yzet T, Regimbeau JM (2012). "Three-dimensional computed tomography analysis of the left gastric vein in a pancreatectomy". HPB (Oxford). 14 (6): 414–21. doi:10.1111/j.1477-2574.2012.00468.x. PMC 3384867. PMID 22568419.
  9. ↑ Sikuler E, Groszmann RJ (1986). "Interaction of flow and resistance in maintenance of portal hypertension in a rat model". Am. J. Physiol. 250 (2 Pt 1): G205–12. PMID 3953799.
  10. ↑ Sharma M, Rameshbabu CS (2012). "Collateral pathways in portal hypertension". J Clin Exp Hepatol. 2 (4): 338–52. doi:10.1016/j.jceh.2012.08.001. PMC 3940321. PMID 25755456.
  11. ↑ Kumar A, Sharma P, Sarin SK (2008). "Hepatic venous pressure gradient measurement: time to learn!". Indian J Gastroenterol. 27 (2): 74–80. PMID 18695309.
  12. ↑ Simmonds MJ, Detterich JA, Connes P (2014). "Nitric oxide, vasodilation and the red blood cell". Biorheology. 51 (2–3): 121–34. doi:10.3233/BIR-140653. PMID 24819865.
  13. ↑ González-Abraldes J, García-Pagán JC, Bosch J (2002). "Nitric oxide and portal hypertension". Metab Brain Dis. 17 (4): 311–24. PMID 12602508.
  14. ↑ Wiest R, Groszmann RJ (1999). "Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance". Semin. Liver Dis. 19 (4): 411–26. doi:10.1055/s-2007-1007129. PMID 10643626.
  15. ↑ "Nitric Oxide - Hepatic Circulation - NCBI Bookshelf".
  16. ↑ Langer DA, Das A, Semela D, Kang-Decker N, Hendrickson H, Bronk SF, Katusic ZS, Gores GJ, Shah VH (2008). "Nitric oxide promotes caspase-independent hepatic stellate cell apoptosis through the generation of reactive oxygen species". Hepatology. 47 (6): 1983–93. doi:10.1002/hep.22285. PMC 2562502. PMID 18459124.
  17. ↑ 17.0 17.1 Martell M, Coll M, Ezkurdia N, Raurell I, Genescà J (2010). "Physiopathology of splanchnic vasodilation in portal hypertension". World J Hepatol. 2 (6): 208–20. doi:10.4254/wjh.v2.i6.208. PMC 2999290. PMID 21160999.
  18. ↑ Gomis R, Fernández-Alvarez J, Pizcueta P, Fernández M, Casamitjana R, Bosch J, Rodés J (1994). "Impaired function of pancreatic islets from rats with portal hypertension resulting from cirrhosis and partial portal vein ligation". Hepatology. 19 (5): 1257–61. PMID 8175150.
  19. ↑ Hansen JS, Clemmesen JO, Secher NH, Hoene M, Drescher A, Weigert C, Pedersen BK, Plomgaard P (2015). "Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans". Mol Metab. 4 (8): 551–60. doi:10.1016/j.molmet.2015.06.001. PMC 4529499. PMID 26266087.
  20. ↑ Tibblin, Sten (1970). "Splanchnic Hemodynamic Responses to Glucagon". Archives of Surgery. 100 (1): 84. doi:10.1001/archsurg.1970.01340190086020. ISSN 0004-0010.
  21. ↑ García-Pagán JC, Escorsell A, Moitinho E, Bosch J (1999). "Influence of pharmacological agents on portal hemodynamics: basis for its use in the treatment of portal hypertension". Semin. Liver Dis. 19 (4): 427–38. PMID 10643627.
  22. ↑ Zardi EM, Dobrina A, Amoroso A, Afeltra A (2007). "Prostacyclin in liver disease: a potential therapeutic option". Expert Opin Biol Ther. 7 (6): 785–90. doi:10.1517/14712598.7.6.785. PMID 17555364.
  23. ↑ Graupera M, García-Pagán JC, Abraldes JG, Peralta C, Bragulat M, Corominola H, Bosch J, Rodés J (2003). "Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers". Hepatology. 37 (1): 172–81. doi:10.1053/jhep.2003.50004. PMID 12500202.
  24. ↑ Bahde R, Kapoor S, Bandi S, Bhargava KK, Palestro CJ, Gupta S (2013). "Directly acting drugs prostacyclin or nitroglycerine and endothelin receptor blocker bosentan improve cell engraftment in rodent liver". Hepatology. 57 (1): 320–30. doi:10.1002/hep.26005. PMC 3524382. PMID 22899584.
  25. ↑ Potenza MA, Botrugno OA, De Salvia MA, Lerro G, Nacci C, Marasciulo FL, Andriantsitohaina R, Mitolo-Chieppa D (2002). "Endothelial COX-1 and -2 differentially affect reactivity of MVB in portal hypertensive rats". Am. J. Physiol. Gastrointest. Liver Physiol. 283 (3): G587–94. doi:10.1152/ajpgi.00391.2001. PMID 12181171.
  26. ↑ García-Pagán JC, Bosch J, Rodés J (1995). "The role of vasoactive mediators in portal hypertension". Semin. Gastrointest. Dis. 6 (3): 140–7. PMID 7551971.
  27. ↑ Møller S, Gülberg V, Henriksen JH, Gerbes AL (1995). "Endothelin-1 and endothelin-3 in cirrhosis: relations to systemic and splanchnic haemodynamics". J. Hepatol. 23 (2): 135–44. PMID 7499784.
  28. ↑ Leivas A, Jiménez W, Bruix J, Boix L, Bosch J, Arroyo V, Rivera F, Rodés J (1998). "Gene expression of endothelin-1 and ET(A) and ET(B) receptors in human cirrhosis: relationship with hepatic hemodynamics". J. Vasc. Res. 35 (3): 186–93. PMID 9647333.
  29. ↑ Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J (2010). "Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis". J. Hepatol. 53 (2): 273–82. doi:10.1016/j.jhep.2010.03.013. PMID 20570385.
  30. ↑ Ballet F, Chretien Y, Rey C, Poupon R (1988). "Differential response of normal and cirrhotic liver to vasoactive agents. A study in the isolated perfused rat liver". J. Pharmacol. Exp. Ther. 244 (1): 283–9. PMID 3336005.
  31. ↑ Lautt WW, Greenway CV, Legare DJ (1987). "Effect of hepatic nerves, norepinephrine, angiotensin, and elevated central venous pressure on postsinusoidal resistance sites and intrahepatic pressures in cats". Microvasc. Res. 33 (1): 50–61. PMID 3561267.
  32. ↑ Wiest R, Groszmann RJ (1999). "Nitric oxide and portal hypertension: its role in the regulation of intrahepatic and splanchnic vascular resistance". Semin. Liver Dis. 19 (4): 411–26. doi:10.1055/s-2007-1007129. PMID 10643626.
  33. ↑ Gupta TK, Toruner M, Chung MK, Groszmann RJ (1998). "Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats". Hepatology. 28 (4): 926–31. doi:10.1002/hep.510280405. PMID 9755227.
  34. ↑ Graupera M, García-Pagán JC, Parés M, Abraldes JG, Roselló J, Bosch J, Rodés J (2003). "Cyclooxygenase-1 inhibition corrects endothelial dysfunction in cirrhotic rat livers". J. Hepatol. 39 (4): 515–21. PMID 12971960.
  35. ↑ 35.0 35.1 35.2 35.3 Jackson FW, Adrain AL, Black M, Miller LS (1999). "Calculation of esophageal variceal wall tension by direct sonographic and manometric measurements". Gastrointest. Endosc. 50 (2): 247–51. PMID 10425421.
  36. ↑ 36.0 36.1 Hilzenrat N, Sherker AH (2012). "Esophageal varices: pathophysiology, approach, and clinical dilemmas". Int J Hepatol. 2012: 795063. doi:10.1155/2012/795063. PMC 3501997. PMID 23193482.
  37. ↑ Kimura K, Ohto M, Matsutani S, Furuse J, Hoshino K, Okuda K (1990). "Relative frequencies of portosystemic pathways and renal shunt formation through the "posterior" gastric vein: portographic study in 460 patients". Hepatology. 12 (4 Pt 1): 725–8. PMID 2210674.
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