Pathophysiology and Management of Variceal Bleeding (original) (raw)

• Bataller R, Brenner DA. Liver fibrosis. J Clin Investig. 2005;115(2):209–18. https://doi.org/10.1172/jci24282.
  Article CAS PubMed PubMed Central Google Scholar
• Popper H, Uenfriend S. Hepatic fibrosis. Correlation of biochemical and morphologic investigations. Am J Med. 1970;49:707–21. https://doi.org/10.1016/s0002-9343(70)80135-8.
  Article CAS PubMed Google Scholar
• Shackel NA, Patel K, McHutchison J. Chapter 50 - genomics in pathogenesis of cirrhosis. In: Ginsburg GS, Willard HF, editors. Essentials of genomic and personalized medicine. San Diego: Academic Press; 2010. p. 645–60.
  Chapter Google Scholar
• Collaborators GMaCoD. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (London, England). 2015;385(9963):117-71. https://doi.org/10.1016/s0140-6736(14)61682-2.
• Naveau S, Perlemuter G, Balian A. Epidemiology and natural history of cirrhosis. Rev Prat. 2005;55(14):1527–32.
  PubMed Google Scholar
• Collaborators GC. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(3):245–66. https://doi.org/10.1016/s2468-1253(19)30349-8.
  Article Google Scholar
• Bosch J, Abraldes JG, Fernández M, García-Pagán JC. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J Hepatol. 2010;53(3):558–67. https://doi.org/10.1016/j.jhep.2010.03.021.
  Article CAS PubMed Google Scholar
• Iwakiri Y. Pathophysiology of portal hypertension. Clin Liver Dis. 2014;18(2):281–91. https://doi.org/10.1016/j.cld.2013.12.001.
  Article PubMed PubMed Central Google Scholar
• Ginés P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology (Baltimore, MD). 1987;7(1):122–8. https://doi.org/10.1002/hep.1840070124.
  Article Google Scholar
• Zanetto A, Garcia-Tsao G. Management of acute variceal hemorrhage. F1000Res. 2019;8:F1000 Faculty Rev-966. https://doi.org/10.12688/f1000research.18807.1
• Romcea AA, Tanţău M, Seicean A, Pascu O. The etiology of upper gastrointestinal bleeding in cirrhotic patients. Clujul Med. 2013;86(1):21–3.
  PubMed PubMed Central Google Scholar
• Mansour D, McPherson S. Management of decompensated cirrhosis. Clin Med (Lond). 2018;18(Suppl 2):s60–5. https://doi.org/10.7861/clinmedicine.18-2-s60.
  Article PubMed PubMed Central Google Scholar
• D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217–31. https://doi.org/10.1016/j.jhep.2005.10.013.
  Article PubMed Google Scholar
• Parola M, Pinzani M. Hepatic wound repair. Fibrogenesis Tissue Repair. 2009;2(1):4. https://doi.org/10.1186/1755-1536-2-4.
  Article CAS PubMed PubMed Central Google Scholar
• Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia. 1971;27(5):549–50. https://doi.org/10.1007/bf02147594.
  Article CAS PubMed Google Scholar
• Jarnagin WR, Rockey DC, Koteliansky VE, Wang SS, Bissell DM. Expression of variant fibronectins in wound healing: cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol. 1994;127(6 Pt 2):2037–48. https://doi.org/10.1083/jcb.127.6.2037.
  Article CAS PubMed Google Scholar
• Blaner WS, O’Byrne SM, Wongsiriroj N, Kluwe J, D’Ambrosio DM, Jiang H, et al. Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage. Biochem Biophys Acta. 2009;1791(6):467–73. https://doi.org/10.1016/j.bbalip.2008.11.001.
  Article CAS PubMed Google Scholar
• Yin C, Evason KJ, Asahina K, Stainier DYR. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Investig. 2013;123(5):1902–10. https://doi.org/10.1172/JCI66369.
  Article CAS PubMed PubMed Central Google Scholar
• Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275(4):2247–50. https://doi.org/10.1074/jbc.275.4.2247.
  Article CAS PubMed Google Scholar
• Reynaert H, Thompson MG, Thomas T, Geerts A. Hepatic stellate cells: role in microcirculation and pathophysiology of portal hypertension. Gut. 2002;50(4):571–81. https://doi.org/10.1136/gut.50.4.571.
  Article CAS PubMed PubMed Central Google Scholar
• Lijnen HR. Matrix metalloproteinases and cellular fibrinolytic activity. Biochemistry Biokhimiia. 2002;67(1):92–8. https://doi.org/10.1023/a:1013908332232.
  Article CAS PubMed Google Scholar
• Dai WJ, Jiang HC. Advances in gene therapy of liver cirrhosis: a review. World J Gastroenterol. 2001;7(1):1–8. https://doi.org/10.3748/wjg.v7.i1.1.
  Article CAS PubMed PubMed Central Google Scholar
• Wiegand J, Berg T. The etiology, diagnosis and prevention of liver cirrhosis: part 1 of a series on liver cirrhosis. Dtsch Arztebl Int. 2013;110(6):85–91. https://doi.org/10.3238/arztebl.2013.0085.
  Article PubMed PubMed Central Google Scholar
• Ramadori G, Saile B. Portal tract fibrogenesis in the liver. Lab Investig J Tech Methods Pathol. 2004;84(2):153–9. https://doi.org/10.1038/labinvest.3700030.
  Article Google Scholar
• Bolognesi M, Di Pascoli M, Verardo A, Gatta A. Splanchnic vasodilation and hyperdynamic circulatory syndrome in cirrhosis. World J Gastroenterol. 2014;20(10):2555–63. https://doi.org/10.3748/wjg.v20.i10.2555.
  Article CAS PubMed PubMed Central Google Scholar
• Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet (London, England). 2014;383(9930):1749–61. https://doi.org/10.1016/s0140-6736(14)60121-5.
  Article Google Scholar
• Carneiro C, Brito J, Bilreiro C, Barros M, Bahia C, Santiago I, et al. All about portal vein: a pictorial display to anatomy, variants and physiopathology. Insights Imaging. 2019;10(1):38. https://doi.org/10.1186/s13244-019-0716-8.
  Article PubMed PubMed Central Google Scholar
• Blei AT. Portal hypertension and its complications. Curr Opin Gastroenterol. 2007;23(3):275–82. https://doi.org/10.1097/MOG.0b013e3280b0841f.
  Article PubMed Google Scholar
• Bosch J, García-Pagán JC. Complications of cirrhosis I. Portal hypertension. J Hepatol. 2000;32(1 Suppl):141–56. https://doi.org/10.1016/s0168-8278(00)80422-5.
  Article CAS PubMed Google Scholar
• Kaneda K, Ekataksin W, Sogawa M, Matsumura A, Cho A, Kawada N. Endothelin-1-induced vasoconstriction causes a significant increase in portal pressure of rat liver: localized constrictive effect on the distal segment of preterminal portal venules as revealed by light and electron microscopy and serial reconstruction. Hepatology (Baltimore, MD). 1998;27(3):735–47. https://doi.org/10.1002/hep.510270315.
  Article CAS Google Scholar
• Gracia-Sancho J, Marrone G, Fernández-Iglesias A. Hepatic microcirculation and mechanisms of portal hypertension. Nat Rev Gastroenterol Hepatol. 2019;16(4):221–34. https://doi.org/10.1038/s41575-018-0097-3.
  Article PubMed Google Scholar
• Loureiro-Silva MR, Cadelina GW, Groszmann RJ. Deficit in nitric oxide production in cirrhotic rat livers is located in the sinusoidal and postsinusoidal areas. Am J Physiol Gastrointest Liver Physiol. 2003;284(4):G567–74. https://doi.org/10.1152/ajpgi.00452.2002.
  Article CAS PubMed Google Scholar
• Gupta TK, Toruner M, Chung MK, Groszmann RJ. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology (Baltimore, MD). 1998;28(4):926–31. https://doi.org/10.1002/hep.510280405.
  Article CAS Google Scholar
• Safka V, Moreau R, Gadano A, Lebrec D. Vascular hyporesponsiveness to vasodilators in rats with cirrhosis. J Hepatol. 1997;26(2):382–6. https://doi.org/10.1016/s0168-8278(97)80056-6.
  Article CAS PubMed Google Scholar
• Sieber CC, Lopez-Talavera JC, Groszmann RJ. Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats. Gastroenterology. 1993;104(6):1750–4. https://doi.org/10.1016/0016-5085(93)90655-v.
  Article CAS PubMed Google Scholar
• Møller S, Gülberg V, Henriksen JH, Gerbes AL. Endothelin-1 and endothelin-3 in cirrhosis: relations to systemic and splanchnic haemodynamics. J Hepatol. 1995;23(2):135–44. https://doi.org/10.1016/0168-8278(95)80327-0.
  Article PubMed Google Scholar
• Moore K, Wendon J, Frazer M, Karani J, Williams R, Badr K. Plasma endothelin immunoreactivity in liver disease and the hepatorenal syndrome. N Engl J Med. 1992;327(25):1774–8. https://doi.org/10.1056/nejm199212173272502.
  Article CAS PubMed Google Scholar
• Yokomori H, Oda M, Yasogawa Y, Nishi Y, Ogi M, Takahashi M, et al. Enhanced expression of endothelin B receptor at protein and gene levels in human cirrhotic liver. Am J Pathol. 2001;159(4):1353–62. https://doi.org/10.1016/s0002-9440(10)62522-9.
  Article CAS PubMed PubMed Central Google Scholar
• Yokomori H, Oda M, Ogi M, Kamegaya Y, Tsukada N, Nakamura M, et al. Enhanced expression of endothelin receptor subtypes in cirrhotic rat liver. Liver. 2001;21(2):114–22. https://doi.org/10.1034/j.1600-0676.2001.021002114.x.
  Article CAS PubMed Google Scholar
• Witte CL, Witte MH, Bair G, Mobley WP, Morton D. Experimental study of hyperdynamic vs stagnant mesenteric blood flow in portal hypertension. Ann Surg. 1974;179(3):304–10. https://doi.org/10.1097/00000658-197403000-00010.
  Article CAS PubMed PubMed Central Google Scholar
• Vorobioff J, Bredfeldt JE, Groszmann RJ. Increased blood flow through the portal system in cirrhotic rats. Gastroenterology. 1984;87(5):1120–6.
  Article CAS PubMed Google Scholar
• Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: from peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol. 2015;63(5):1272–84. https://doi.org/10.1016/j.jhep.2015.07.004.
  Article CAS PubMed Google Scholar
• Bauer TM, Schwacha H, Steinbrückner B, Brinkmann FE, Ditzen AK, Aponte JJ, et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol. 2002;97(9):2364–70. https://doi.org/10.1111/j.1572-0241.2002.05791.x.
  Article PubMed Google Scholar
• Bauer TM, Steinbrückner B, Brinkmann FE, Ditzen AK, Schwacha H, Aponte JJ, et al. Small intestinal bacterial overgrowth in patients with cirrhosis: prevalence and relation with spontaneous bacterial peritonitis. Am J Gastroenterol. 2001;96(10):2962–7. https://doi.org/10.1111/j.1572-0241.2001.04668.x.
  Article CAS PubMed Google Scholar
• Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology. 2014;146(6):1513–24. https://doi.org/10.1053/j.gastro.2014.01.020.
  Article CAS PubMed Google Scholar
• Such J, Francés R, Muñoz C, Zapater P, Casellas JA, Cifuentes A, et al. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology (Baltimore, MD). 2002;36(1):135–41. https://doi.org/10.1053/jhep.2002.33715.
  Article CAS Google Scholar
• Kubes P, Mehal WZ. Sterile inflammation in the liver. Gastroenterology. 2012;143(5):1158–72. https://doi.org/10.1053/j.gastro.2012.09.008.
  Article CAS PubMed Google Scholar
• de Franchis R. Expanding consensus in portal hypertension: report of the Baveno VI consensus workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743–52. https://doi.org/10.1016/j.jhep.2015.05.022.
  Article PubMed Google Scholar
• Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;133(2):481–8. https://doi.org/10.1053/j.gastro.2007.05.024.
  Article CAS PubMed Google Scholar
• Maruyama H, Yokosuka O. Pathophysiology of portal hypertension and esophageal varices. Int J Hepatol. 2012;2012:895787. https://doi.org/10.1155/2012/895787.
  Article PubMed PubMed Central Google Scholar
• Sharma M, Rameshbabu CS. Collateral pathways in portal hypertension. J Clin Exp Hepatol. 2012;2(4):338–52. https://doi.org/10.1016/j.jceh.2012.08.001.
  Article PubMed PubMed Central Google Scholar
• Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology (Baltimore, MD). 2007;46(3):922–38. https://doi.org/10.1002/hep.21907.
  Article CAS Google Scholar
• D’Amico G, Morabito A. Noninvasive markers of esophageal varices: another round, not the last. Hepatology (Baltimore, MD). 2004;39(1):30–4. https://doi.org/10.1002/hep.20018.
  Article Google Scholar
• Roberts LR, Kamath PS. Pathophysiology and treatment of variceal hemorrhage. Mayo Clin Proc. 1996;71(10):973–83. https://doi.org/10.1016/s0025-6196(11)63772-5.
  Article CAS PubMed Google Scholar
• Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology (Baltimore, MD). 1985;5(3):419–24. https://doi.org/10.1002/hep.1840050313.
  Article CAS Google Scholar
• Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med. 2005;353(21):2254–61. https://doi.org/10.1056/NEJMoa044456.
  Article CAS PubMed Google Scholar
• Abraldes JG, Iwakiri Y, Loureiro-Silva M, Haq O, Sessa WC, Groszmann RJ. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol. 2006;290(5):G980–7. https://doi.org/10.1152/ajpgi.00336.2005.
  Article CAS PubMed Google Scholar
• Huang H-C, Haq O, Utsumi T, Sethasine S, Abraldes JG, Groszmann RJ, et al. Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure. J Cell Mol Med. 2012;16(5):1125–33. https://doi.org/10.1111/j.1582-4934.2011.01399.x.
  Article CAS PubMed PubMed Central Google Scholar
• Fernandez M, Vizzutti F, Garcia-Pagan JC, Rodes J, Bosch J. Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice. Gastroenterology. 2004;126(3):886–94. https://doi.org/10.1053/j.gastro.2003.12.012.
  Article CAS PubMed Google Scholar
• Pinter M, Sieghart W, Reiberger T, Rohr-Udilova N, Ferlitsch A, Peck-Radosavljevic M. The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma–a pilot study. Aliment Pharmacol Ther. 2012;35(1):83–91. https://doi.org/10.1111/j.1365-2036.2011.04896.x.
  Article CAS PubMed Google Scholar
• Jensen DM. Endoscopic screening for varices in cirrhosis: findings, implications, and outcomes. Gastroenterology. 2002;122(6):1620–30. https://doi.org/10.1053/gast.2002.33419.
  Article PubMed Google Scholar
• Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology (Baltimore, MD). 1992;16(6):1343–9. https://doi.org/10.1002/hep.1840160607.
  Article CAS Google Scholar
• Kang HK, Jeong YY, Choi JH, Choi S, Chung TW, Seo JJ, et al. Three-dimensional multi-detector row CT portal venography in the evaluation of portosystemic collateral vessels in liver cirrhosis. Radiographics. 2002;22(5):1053–61. https://doi.org/10.1148/radiographics.22.5.g02se011053.
  Article PubMed Google Scholar
• Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol. 2003;38(3):266–72. https://doi.org/10.1016/s0168-8278(02)00420-8.
  Article PubMed Google Scholar
• Boregowda U, Umapathy C, Halim N, Desai M, Nanjappa A, Arekapudi S, et al. Update on the management of gastrointestinal varices. World J Gastrointest Pharmacol Ther. 2019;10(1):1–21. https://doi.org/10.4292/wjgpt.v10.i1.1.
  Article PubMed PubMed Central Google Scholar
• Müting D, Kalk JF, Fischer R, Wiewel D. Spontaneous regression of oesophageal varices after long-term conservative treatment. Retrospective study in 20 patients with alcoholic liver cirrhosis, posthepatitic cirrhosis and haemochromatosis with cirrhosis. J Hepatol. 1990;10(2):158–62. https://doi.org/10.1016/0168-8278(90)90045-s.
  Article PubMed Google Scholar
• Vorobioff J, Groszmann RJ, Picabea E, Gamen M, Villavicencio R, Bordato J, et al. Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study. Gastroenterology. 1996;111(3):701–9. https://doi.org/10.1053/gast.1996.v111.pm8780575.
  Article CAS PubMed Google Scholar
• Lampertico P, Invernizzi F, Viganò M, Loglio A, Mangia G, Facchetti F, et al. The long-term benefits of nucleos(t)ide analogs in compensated HBV cirrhotic patients with no or small esophageal varices: a 12-year prospective cohort study. J Hepatol. 2015;63(5):1118–25. https://doi.org/10.1016/j.jhep.2015.06.006.
  Article CAS PubMed Google Scholar
• Jwa HY, Cho Y-K, Choi EK, Kim HU, Song HJ, Na S-Y, et al. Regression of esophageal varices during entecavir treatment in patients with hepatitis-B-virus-related liver cirrhosis. Clin Mol Hepatol. 2016;22(1):183–7. https://doi.org/10.3350/cmh.2016.22.1.183.
  Article PubMed PubMed Central Google Scholar
• Abby Philips C, Sahney A. Oesophageal and gastric varices: historical aspects, classification and grading: everything in one place. Gastroenterol Rep (Oxf). 2016;4(3):186–95. https://doi.org/10.1093/gastro/gow018.
  Article PubMed PubMed Central Google Scholar
• Vianna A, Hayes PC, Moscoso G, Driver M, Portmann B, Westaby D, et al. Normal venous circulation of the gastroesophageal junction. A route to understanding varices. Gastroenterology. 1987;93(4):876–89. https://doi.org/10.1016/0016-5085(87)90453-7.
  Article CAS PubMed Google Scholar
• Chiva LM, Magrina J. Chapter 2 - Abdominal and Pelvic Anatomy. In: Ramirez PT, Frumovitz M, Abu-Rustum NR, editors. Principles of Gynecologic Oncology Surgery. Elsevier; 2018. p. 3-49.
• Luketic VA, Sanyal AJ. Esophageal varices. I. Clinical presentation, medical therapy, and endoscopic therapy. Gastroenterol Clin N Am. 2000;29(2):337–85. https://doi.org/10.1016/s0889-8553(05)70119-9.
  Article CAS Google Scholar
• Gaba RC, Couture PM, Lakhoo J. Gastroesophageal variceal filling and drainage pathways: an angiographic description of afferent and efferent venous anatomic patterns. J Clin Imaging Sci. 2015;5:61. https://doi.org/10.4103/2156-7514.170730.
  Article PubMed PubMed Central Google Scholar
• Chikamori F, Kuniyoshi N, Shibuya S, Takase Y. Correlation between endoscopic and angiographic findings in patients with esophageal and isolated gastric varices. Dig Surg. 2001;18(3):176–81. https://doi.org/10.1159/000050126.
  Article CAS PubMed Google Scholar
• Kiyosue H, Ibukuro K, Maruno M, Tanoue S, Hongo N, Mori H. Multidetector CT anatomy of drainage routes of gastric varices: a pictorial review. Radiographics. 2013;33(1):87–100. https://doi.org/10.1148/rg.331125037.
  Article PubMed Google Scholar
• Tripathi D, Stanley AJ, Hayes PC, Patch D, Millson C, Mehrzad H, et al. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015;64(11):1680–704. https://doi.org/10.1136/gutjnl-2015-309262.
  Article PubMed Google Scholar
• Angels Escorsell JB. Pathophysiology of Variceal Bleeding. In: Bosch RJGaJ, editor. Portal Hypertension in the 21st Century. Springer Netherlands; 2004. p. 155–66.
• D’Amico G, Pasta L, Morabito A, D’Amico M, Caltagirone M, Malizia G, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther. 2014;39(10):1180–93. https://doi.org/10.1111/apt.12721.
  Article CAS PubMed Google Scholar
• Christensen E, Fauerholdt L, Schlichting P, Juhl E, Poulsen H, Tygstrup N. Aspects of the natural history of gastrointestinal bleeding in cirrhosis and the effect of prednisone. Gastroenterology. 1981;81(5):944–52.
  Article CAS PubMed Google Scholar
• Calès P, Pascal JP. Natural history of esophageal varices in cirrhosis (from origin to rupture). Gastroenterol Clin Biol. 1988;12(3):245–54.
  PubMed Google Scholar
• Rigau J, Bosch J, Bordas JM, Navasa M, Mastai R, Kravetz D, et al. Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage. Gastroenterology. 1989;96(3):873–80.
  Article CAS PubMed Google Scholar
• Varices NIECftSaToE. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med. 1988;319(15):983–9. https://doi.org/10.1056/nejm198810133191505.
• Organisation WG. Esophageal varices. 2014. https://www.worldgastroenterology.org/UserFiles/file/guidelines/esophageal-varices-english-2014.pdf. Accessed 04 May 2020.
• Dennis M Jensen TOK, Disaya Chavalitdhamrong. Variceal Bleeding: Surgery and Radiology. In: Joseph J. Y. Sung EJK, Alan N. Barkun, editor. Variceal Bleeding: Surgery and Radiology. 2012.
• D’Amico G, Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding. Bailliere’s Clin Gastroenterol. 1997;11(2):243–56. https://doi.org/10.1016/s0950-3528(97)90038-5.
  Article CAS Google Scholar
• Jairath V, Rehal S, Logan R, Kahan B, Hearnshaw S, Stanworth S, et al. Acute variceal haemorrhage in the United Kingdom: patient characteristics, management and outcomes in a nationwide audit. Dig Liver. 2014;46(5):419–26. https://doi.org/10.1016/j.dld.2013.12.010.
  Article Google Scholar
• Abraldes JG, Trebicka J, Chalasani N, D’Amico G, Rockey DC, Shah VH, et al. Prioritization of therapeutic targets and trial design in cirrhotic portal hypertension. Hepatology (Baltimore, MD). 2019;69(3):1287–99. https://doi.org/10.1002/hep.30314.
  Article Google Scholar
• Lens S, Alvarado-Tapias E, Mariño Z, Londoño MC, E LL, Martinez J et al. Effects of All-Oral Anti-Viral Therapy on HVPG and Systemic Hemodynamics in Patients With Hepatitis C Virus-Associated Cirrhosis. Gastroenterology. 2017;153(5):1273-83. https://doi.org/10.1053/j.gastro.2017.07.016.
• Glass LM, Dickson RC, Anderson JC, Suriawinata AA, Putra J, Berk BS, et al. Total body weight loss of ≥ 10 % is associated with improved hepatic fibrosis in patients with nonalcoholic steatohepatitis. Dig Dis Sci. 2015;60(4):1024–30. https://doi.org/10.1007/s10620-014-3380-3.
  Article CAS PubMed Google Scholar
• Berzigotti A, Albillos A, Villanueva C, Genescá J, Ardevol A, Augustín S, et al. Effects of an intensive lifestyle intervention program on portal hypertension in patients with cirrhosis and obesity: the SportDiet study. Hepatology (Baltimore, MD). 2017;65(4):1293–305. https://doi.org/10.1002/hep.28992.
  Article Google Scholar
• Lund-Johansen P. The influence of vasodilating beta-blockers on cardiac function and vascular resistance in essential hypertension. Clin Nephrol. 1992;38(Suppl 1):S78-86.
  CAS PubMed Google Scholar
• Price HL, Cooperman LH, Warden JC. Control of the splanchnic circulation in man. Role of beta-adrenergic receptors. Circ Res. 1967;21(3):333–40. https://doi.org/10.1161/01.res.21.3.333.
  Article CAS PubMed Google Scholar
• Lebrec D, Poynard T, Hillon P, Benhamou JP. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med. 1981;305(23):1371–4. https://doi.org/10.1056/nejm198112033052302.
  Article CAS PubMed Google Scholar
• Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: evidence-based indications and limitations. JHEP Rep. 2019;2(1):100063. https://doi.org/10.1016/j.jhepr.2019.12.001.
  Article PubMed PubMed Central Google Scholar
• Villanueva C, Albillos A, Genescà J, Garcia-Pagan JC, Calleja JL, Aracil C, et al. β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet (London, England). 2019;393(10181):1597–608. https://doi.org/10.1016/s0140-6736(18)31875-0.
  Article CAS Google Scholar
• Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: evidence-based indications and limitations. JHEP Rep. 2020;2(1):100063. https://doi.org/10.1016/j.jhepr.2019.12.001.
  Article PubMed Google Scholar
• Lebrec D, Nouel O, Corbic M, Benhamou JP. Propranolol–a medical treatment for portal hypertension? Lancet (London, England). 1980;2(8187):180–2. https://doi.org/10.1016/s0140-6736(80)90063-x.
  Article CAS Google Scholar
• Pascal JP, Cales P. Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med. 1987;317(14):856–61. https://doi.org/10.1056/nejm198710013171403.
  Article CAS PubMed Google Scholar
• Bleeding TIMPfPiPo. Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients. Final report of a multicenter randomized trial. The Italian Multicenter Project for Propranolol in Prevention of Bleeding. J Hepatol. 1989;9(1):75–83.
• Conn HO, Grace ND, Bosch J, Groszmann RJ, Rodés J, Wright SC et al. Propranolol in the prevention of the first hemorrhage from esophagogastric varices: A multicenter, randomized clinical trial. The Boston-New Haven-Barcelona Portal Hypertension Study Group. Hepatology (Baltimore, Md). 1991;13(5):902–12.
• Cheng J-W, Zhu L, Gu M-J, Song Z-M. Meta analysis of propranolol effects on gastrointestinal hemorrhage in cirrhotic patients. World J Gastroenterol. 2003;9(8):1836–9. https://doi.org/10.3748/wjg.v9.i8.1836.
  Article CAS PubMed PubMed Central Google Scholar
• Merkel C, Marin R, Angeli P, Zanella P, Felder M, Bernardinello E, et al. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology. 2004;127(2):476–84. https://doi.org/10.1053/j.gastro.2004.05.004.
  Article CAS PubMed Google Scholar
• Merkel C, Marin R, Sacerdoti D, Donada C, Cavallarin G, Torboli P, et al. Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Hepatology (Baltimore, MD). 2000;31(2):324–9. https://doi.org/10.1002/hep.510310210.
  Article CAS Google Scholar
• García-Pagán JC, Morillas R, Bañares R, Albillos A, Villanueva C, Vila C, et al. Propranolol plus placebo versus propranolol plus isosorbide-5-mononitrate in the prevention of a first variceal bleed: a double-blind RCT. Hepatology (Baltimore, MD). 2003;37(6):1260–6. https://doi.org/10.1053/jhep.2003.50211.
  Article CAS Google Scholar
• Frishman WH. Nadolol: a new beta-adrenoceptor antagonist. N Engl J Med. 1981;305(12):678–82. https://doi.org/10.1056/nejm198109173051206.
  Article CAS PubMed Google Scholar
• PImenta JR, Ferreira AR, Bittencourt PFS, ResendE CBd, Fagundes EDT, Silva IMLd. Evaluation of primary prophylaxis with propranolol and elastic band ligation in variceal bleeding in cirrhotic children and adolescents. Arquivos de Gastroenterologia. 2016;53:257–61.
• Miñano C, Garcia-Tsao G. Clinical pharmacology of portal hypertension. Gastroenterol Clin North Am. 2010;39(3):681–95. https://doi.org/10.1016/j.gtc.2010.08.015.
  Article PubMed PubMed Central Google Scholar
• Yoshikawa T, Port JD, Asano K, Chidiak P, Bouvier M, Dutcher D, et al. Cardiac adrenergic receptor effects of carvedilol. Eur Heart J. 1996;17(Suppl B):8–16. https://doi.org/10.1093/eurheartj/17.suppl_b.8.
  Article CAS PubMed Google Scholar
• Al-Ghamdi H. Carvedilol in the treatment of portal hypertension. Saudi J Gastroenterol. 2011;17(2):155–8. https://doi.org/10.4103/1319-3767.77251.
  Article PubMed PubMed Central Google Scholar
• Li T, Ke W, Sun P, Chen X, Belgaumkar A, Huang Y, et al. Carvedilol for portal hypertension in cirrhosis: systematic review with meta-analysis. BMJ open. 2016;6(5):e010902. https://doi.org/10.1136/bmjopen-2015-010902.
  Article PubMed PubMed Central Google Scholar
• Wong SY, Lee J, Anile Sule A. Is carvedilol better than propranolol in portal hypertension? AME Medical Journal. 2017;2(7).
• Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology (Baltimore, MD). 2017;65(1):310–35. https://doi.org/10.1002/hep.28906.
  Article Google Scholar
• Liver EAftSot. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406-60. https://doi.org/10.1016/j.jhep.2018.03.024.
• Njei B, McCarty TR, Garcia-Tsao G. Beta-blockers in patients with cirrhosis and ascites: type of beta-blocker matters. Gut. 2016;65(8):1393–4. https://doi.org/10.1136/gutjnl-2016-312129.
  Article PubMed Google Scholar
• Poza CJ, Froilan TC, Burgos GA, Gea RF, Suárezde PJM. Endoscopic management of esophageal varices. World J Gastrointest Endosc. 2012;4(7):312–22. https://doi.org/10.4253/wjge.v4.i7.312.
  Article Google Scholar
• Garcia-Pagán JC, Bosch J. Endoscopic band ligation in the treatment of portal hypertension. Nat Clin Pract Gastroenterol Hepatol. 2005;2(11):526–35. https://doi.org/10.1038/ncpgasthep0323.
  Article PubMed Google Scholar
• Funakoshi N, Duny Y, Valats JC, Ségalas-Largey F, Flori N, Bismuth M, et al. Meta-analysis: beta-blockers versus banding ligation for primary prophylaxis of esophageal variceal bleeding. Ann Hepatol. 2012;11(3):369–83.
  Article PubMed Google Scholar
• Li L, Yu C, Li Y. Endoscopic band ligation versus pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis. Can J Gastroenterol. 2011;25(3):147–55. https://doi.org/10.1155/2011/346705.
  Article PubMed PubMed Central Google Scholar
• Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed). 1997;315(7109):629–34. https://doi.org/10.1136/bmj.315.7109.629.
  Article CAS PubMed Central Google Scholar
• Merkel C, Montagnese S, Amodio P. Primary prophylaxis of bleeding from esophageal varices in cirrhosis. J Clin Exp Hepatol. 2013;3(3):198–203. https://doi.org/10.1016/j.jceh.2013.08.002.
  Article PubMed PubMed Central Google Scholar
• Andreani T, Poupon RE, Balkau BJ, Trinchet JC, Grange JD, Peigney N, et al. Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: results of a controlled trial comparing propranolol, endoscopic sclerotherapy and placebo. Hepatology (Baltimore, MD). 1990;12(6):1413–9. https://doi.org/10.1002/hep.1840120624.
  Article CAS Google Scholar
• Group TPS. Prophylaxis of first hemorrhage from esophageal varices by sclerotherapy, propranolol or both in cirrhotic patients: a randomized multicenter trial. The PROVA Study Group. Hepatology (Baltimore, Md). 1991;14(6):1016–24.
• Helmy A, Hayes PC. Review article: current endoscopic therapeutic options in the management of variceal bleeding. Aliment Pharmacol Ther. 2001;15(5):575–94. https://doi.org/10.1046/j.1365-2036.2001.00950.x.
  Article CAS PubMed Google Scholar
• Kim YD. Management of acute variceal bleeding. Clin Endosc. 2014;47(4):308–14. https://doi.org/10.5946/ce.2014.47.4.308.
  Article PubMed PubMed Central Google Scholar
• Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013;368(1):11–21. https://doi.org/10.1056/NEJMoa1211801.
  Article CAS PubMed Google Scholar
• Soriano G, Guarner C, Tomás A, Villanueva C, Torras X, González D, et al. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology. 1992;103(4):1267–72. https://doi.org/10.1016/0016-5085(92)91514-5.
  Article CAS PubMed Google Scholar
• Blaise M, Pateron D, Trinchet JC, Levacher S, Beaugrand M, Pourriat JL. Systemic antibiotic therapy prevents bacterial infection in cirrhotic patients with gastrointestinal hemorrhage. Hepatology (Baltimore, MD). 1994;20(1 Pt 1):34–8. https://doi.org/10.1016/0270-9139(94)90131-7.
  Article CAS Google Scholar
• Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila F, Soares-Weiser K, Mendez-Sanchez N, Gluud C, et al. Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding—an updated Cochrane review. Aliment Pharmacol Ther. 2011;34(5):509–18. https://doi.org/10.1111/j.1365-2036.2011.04746.x.
  Article CAS PubMed Google Scholar
• Fernández J, Ruizdel AL, Gómez C, Durandez R, Serradilla R, Guarner C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology. 2006;131(4):1049–56. https://doi.org/10.1053/j.gastro.2006.07.010 ((quiz 285)).
  Article CAS PubMed Google Scholar
• Caly WR, Strauss E. A prospective study of bacterial infections in patients with cirrhosis. J Hepatol. 1993;18(3):353–8. https://doi.org/10.1016/s0168-8278(05)80280-6.
  Article CAS PubMed Google Scholar
• Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis. 2008;28(1):26–42. https://doi.org/10.1055/s-2008-1040319.
  Article CAS PubMed Google Scholar
• Tandon P, Abraldes JG, Keough A, Bastiampillai R, Jayakumar S, Carbonneau M, et al. Risk of bacterial infection in patients with cirrhosis and acute variceal hemorrhage, based on child-pugh class, and effects of antibiotics. Clin Gastroenterol Hepatol. 2015;13(6):1189-96.e2. https://doi.org/10.1016/j.cgh.2014.11.019.
  Article PubMed Google Scholar
• Mallet M, Rudler M, Thabut D. Variceal bleeding in cirrhotic patients. Gastroenterol Rep (Oxf). 2017;5(3):185–92. https://doi.org/10.1093/gastro/gox024.
  Article PubMed PubMed Central Google Scholar
• Ready JB, Robertson AD, Goff JS, Rector WG Jr. Assessment of the risk of bleeding from esophageal varices by continuous monitoring of portal pressure. Gastroenterology. 1991;100(5 Pt 1):1403–10.
  Article CAS PubMed Google Scholar
• Armonis A, Patch D, Burroughs A. Hepatic venous pressure measurement: an old test as a new prognostic marker in cirrhosis? Hepatology (Baltimore, MD). 1997;25(1):245–8. https://doi.org/10.1053/jhep.1997.v25.ajhep0250245.
  Article CAS Google Scholar
• Goulis J, Burroughs AK. Role of vasoactive drugs in the treatment of bleeding oesophageal varices. Digestion. 1999;60(Suppl 3):25–34. https://doi.org/10.1159/000051486.
  Article CAS PubMed Google Scholar
• Zhou X, Tripathi D, Song T, Shao L, Han B, Zhu J, et al. Terlipressin for the treatment of acute variceal bleeding: a systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore). 2018;97(48):e13437-e. https://doi.org/10.1097/MD.0000000000013437.
  Article CAS Google Scholar
• Lo G-H. The use of vasoconstrictors in acute variceal bleeding: how long is enough? Clin Endosc. 2019;52(1):36–9. https://doi.org/10.5946/ce.2018.084.
  Article PubMed PubMed Central Google Scholar
• Fortune BE, Jackson J, Leonard J, Trotter JF. Vapreotide: a somatostatin analog for the treatment of acute variceal bleeding. Expert Opin Pharmacother. 2009;10(14):2337–42. https://doi.org/10.1517/14656560903207019.
  Article CAS PubMed Google Scholar
• Yan P, Tian X, Li J. Is additional 5-day vasoactive drug therapy necessary for acute variceal bleeding after successful endoscopic hemostasis? a systematic review and meta-analysis. Medicine (Baltimore). 2018;97(41):e12826. https://doi.org/10.1097/md.0000000000012826.
  Article CAS PubMed PubMed Central Google Scholar
• Henderson KK, Byron KL. Vasopressin-induced vasoconstriction: two concentration-dependent signaling pathways. J Appl Physiol (Bethesda, Md: 1985). 2007;102(4):1402-9. https://doi.org/10.1152/japplphysiol.00825.2006.
• Iwao T, Toyonaga A, Oho K, Shigemori H, Sakai T, Tayama C, et al. Effect of vasopressin on esophageal varices blood flow in patients with cirrhosis: comparisons with the effects on portal vein and superior mesenteric artery blood flow. J Hepatol. 1996;25(4):491–7. https://doi.org/10.1016/s0168-8278(96)80208-x.
  Article CAS PubMed Google Scholar
• D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology (Baltimore, MD). 1995;22(1):332–54. https://doi.org/10.1002/hep.1840220145.
  Article CAS Google Scholar
• Kam PC, Williams S, Yoong FF. Vasopressin and terlipressin: pharmacology and its clinical relevance. Anaesthesia. 2004;59(10):993–1001. https://doi.org/10.1111/j.1365-2044.2004.03877.x.
  Article CAS PubMed Google Scholar
• Rodríguez-Pérez F, Groszmann RJ. Pharmacologic treatment of portal hypertension. Gastroenterol Clin North Am. 1992;21(1):15–40.
  Article PubMed Google Scholar
• Freeman JG, Cobden I, Lishman AH, Record CO. Controlled trial of terlipressin ('Glypressin’) versus vasopressin in the early treatment of oesophageal varices. Lancet (London, England). 1982;2(8289):66–8. https://doi.org/10.1016/s0140-6736(82)91689-0.
  Article CAS Google Scholar
• D'Amico G, Traina M, Vizzini G, Tinè F, Politi F, Montalbano L et al. Terlipressin or vasopressin plus transdermal nitroglycerin in a treatment strategy for digestive bleeding in cirrhosis. A randomized clinical trial. Liver Study Group of V. Cervello Hospital. J Hepatol. 1994;20(2):206-12. https://doi.org/10.1016/s0168-8278(05)80059-5
• Villanueva C, Ortiz J, Miñana J, Soriano G, Sàbat M, Boadas J, et al. Somatostatin treatment and risk stratification by continuous portal pressure monitoring during acute variceal bleeding. Gastroenterology. 2001;121(1):110–7. https://doi.org/10.1053/gast.2001.25536.
  Article CAS PubMed Google Scholar
• Samnegård H, Tydén G, Thulin L, Friman L, Udén R. Effect of somatostatin on regional splanchnic blood flows in man. Angiographic studies. Acta Chir Scand Suppl. 1980;500:71–3.
  PubMed Google Scholar
• Cirera I, Feu F, Luca A, García-Pagán JC, Fernández M, Escorsell A, et al. Effects of bolus injections and continuous infusions of somatostatin and placebo in patients with cirrhosis: a double-blind hemodynamic investigation. Hepatology (Baltimore, MD). 1995;22(1):106–11.
  CAS Google Scholar
• Katz MD, Erstad BL. Octreotide, a new somatostatin analogue. Clin Pharm. 1989;8(4):255–73.
  CAS PubMed Google Scholar
• Reynaert H, Geerts A. Pharmacological rationale for the use of somatostatin and analogues in portal hypertension. Aliment Pharmacol Ther. 2003;18(4):375–86. https://doi.org/10.1046/j.1365-2036.2003.01657.x.
  Article CAS PubMed Google Scholar
• Chatila R, Ferayorni L, Gupta T, Groszmann RJ. Local arterial vasoconstriction induced by octreotide in patients with cirrhosis. Hepatology (Baltimore, MD). 2000;31(3):572–6. https://doi.org/10.1002/hep.510310304.
  Article CAS Google Scholar
• Hanisch E, Doertenbach J, Usadel KH. Somatostatin in acute bleeding oesophageal varices. Pharmacology and rationale for use. Drugs. 1992;44 Suppl 2:24–s35. https://doi.org/10.2165/00003495-199200442-00005 (discussion 70-2)
• Wells M, Chande N, Adams P, Beaton M, Levstik M, Boyce E, et al. Meta-analysis: vasoactive medications for the management of acute variceal bleeds. Aliment Pharmacol Ther. 2012;35(11):1267–78. https://doi.org/10.1111/j.1365-2036.2012.05088.x.
  Article CAS PubMed Google Scholar
• Seo YS, Park SY, Kim MY, Kim JH, Park JY, Yim HJ, et al. Lack of difference among terlipressin, somatostatin, and octreotide in the control of acute gastroesophageal variceal hemorrhage. Hepatology (Baltimore, MD). 2014;60(3):954–63. https://doi.org/10.1002/hep.27006.
  Article CAS Google Scholar
• Lo GH, Lai KH, Cheng JS, Lin CK, Huang JS, Hsu PI, et al. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology (Baltimore, MD). 1997;25(5):1101–4. https://doi.org/10.1002/hep.510250509.
  Article CAS Google Scholar
• Villanueva C, Piqueras M, Aracil C, Gomez C, Lopez-Balaguer JM, Gonzalez B, et al. A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding. J Hepatol. 2006;45(4):560–7. https://doi.org/10.1016/j.jhep.2006.05.016.
  Article PubMed Google Scholar
• Bañares R, Albillos A, Rincón D, Alonso S, González M, Ruiz-del-Arbol L, et al. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: a meta-analysis. Hepatology (Baltimore, MD). 2002;35(3):609–15. https://doi.org/10.1053/jhep.2002.31354.
  Article Google Scholar
• Parvinian A, Gaba RC. Outcomes of TIPS for treatment of gastroesophageal variceal hemorrhage. Semin Interv Radiol. 2014;31(3):252–7. https://doi.org/10.1055/s-0034-1382793.
  Article Google Scholar
• Tripathi D, Stanley AJ, Hayes PC, Travis S, Armstrong MJ, Tsochatzis EA, et al. Transjugular intrahepatic portosystemic stent-shunt in the management of portal hypertension. Gut. 2020. https://doi.org/10.1136/gutjnl-2019-320221.
  Article PubMed Google Scholar
• García-Pagán JC, Caca K, Bureau C, Laleman W, Appenrodt B, Luca A, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362(25):2370–9. https://doi.org/10.1056/NEJMoa0910102.
  Article PubMed Google Scholar
• Khan S, Tudur Smith C, Williamson P, Sutton R. Portosystemic shunts versus endoscopic therapy for variceal rebleeding in patients with cirrhosis. Cochrane Database Syst Rev. 2006;2006(4):Cd000553. https://doi.org/10.1002/14651858.CD000553.pub2.
• Sauerbruch T, Mengel M, Dollinger M, Zipprich A, Rössle M, Panther E, et al. Prevention of rebleeding from esophageal varices in patients with cirrhosis receiving small-diameter stents versus hemodynamically controlled medical therapy. Gastroenterology. 2015;149(3):660-8.e1. https://doi.org/10.1053/j.gastro.2015.05.011.
  Article PubMed Google Scholar
• Holster IL, Tjwa ET, Moelker A, Wils A, Hansen BE, Vermeijden JR, et al. Covered transjugular intrahepatic portosystemic shunt versus endoscopic therapy + β-blocker for prevention of variceal rebleeding. Hepatology (Baltimore, MD). 2016;63(2):581–9. https://doi.org/10.1002/hep.28318.
  Article CAS Google Scholar
• Magaz M, Baiges A, Hernández-Gea V. Precision medicine in variceal bleeding: are we there yet? J Hepatol. 2020;72(4):774–84. https://doi.org/10.1016/j.jhep.2020.01.008.
  Article PubMed Google Scholar
• Abraldes JG, Villanueva C, Bañares R, Aracil C, Catalina MV, Garci APJC, et al. Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy. J Hepatol. 2008;48(2):229–36. https://doi.org/10.1016/j.jhep.2007.10.008.
  Article PubMed Google Scholar
• Moitinho E, Escorsell A, Bandi JC, Salmerón JM, García-Pagán JC, Rodés J, et al. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology. 1999;117(3):626–31. https://doi.org/10.1016/s0016-5085(99)70455-5.
  Article CAS PubMed Google Scholar
• Conejo I, Guardascione MA, Tandon P, Cachero A, Castellote J, Abraldes JG, et al. Multicenter external validation of risk stratification criteria for patients with variceal bleeding. Clin Gastroenterol Hepatol. 2018;16(1):132-9.e8. https://doi.org/10.1016/j.cgh.2017.04.042.
  Article PubMed Google Scholar
• Rudler M, Bureau C, Carbonell N, Mathurin P, Saliba F, Mallat A, et al. Recalibrated MELD and hepatic encephalopathy are prognostic factors in cirrhotic patients with acute variceal bleeding. Liver Int. 2018;38(3):469–76. https://doi.org/10.1111/liv.13632.
  Article PubMed Google Scholar
• Monescillo A, Martínez-Lagares F, Ruiz-del-Arbol L, Sierra A, Guevara C, Jiménez E, et al. Influence of portal hypertension and its early decompression by TIPS placement on the outcome of variceal bleeding. Hepatology (Baltimore, MD). 2004;40(4):793–801. https://doi.org/10.1002/hep.20386.
  Article Google Scholar
• Lv Y, Zuo L, Zhu X, Zhao J, Xue H, Jiang Z, et al. Identifying optimal candidates for early TIPS among patients with cirrhosis and acute variceal bleeding: a multicentre observational study. Gut. 2019;68(7):1297–310. https://doi.org/10.1136/gutjnl-2018-317057.
  Article CAS PubMed Google Scholar
• Thabut D, Pauwels A, Carbonell N, Remy AJ, Nahon P, Causse X, et al. Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: a large multicentre audit with real-life results. J Hepatol. 2017;68(1):73–81. https://doi.org/10.1016/j.jhep.2017.09.002.
  Article PubMed Google Scholar
• Garcia-Pagán JC, Di Pascoli M, Caca K, Laleman W, Bureau C, Appenrodt B, et al. Use of early-TIPS for high-risk variceal bleeding: results of a post-RCT surveillance study. J Hepatol. 2013;58(1):45–50. https://doi.org/10.1016/j.jhep.2012.08.020.
  Article PubMed Google Scholar
• Garcia-Tsao G, Bosch J. Varices and variceal hemorrhage in cirrhosis: a new view of an old problem. Clin Gastroenterol Hepatol. 2015;13(12):2109–17. https://doi.org/10.1016/j.cgh.2015.07.012.
  Article PubMed PubMed Central Google Scholar
• D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis. 1999;19(4):475–505. https://doi.org/10.1055/s-2007-1007133.
  Article CAS PubMed Google Scholar
• Chen Y-I, Ghali P. Prevention and management of gastroesophageal varices in cirrhosis. Int J Hepatol. 2012;2012:750150. https://doi.org/10.1155/2012/750150.
  Article PubMed PubMed Central Google Scholar
• Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T. Beta-adrenergic antagonists in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis. Hepatology (Baltimore, MD). 1997;25(1):63–70. https://doi.org/10.1053/jhep.1997.v25.pm0008985266.
  Article CAS Google Scholar
• Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP. Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding. Hepatology (Baltimore, MD). 2000;31(6):1239–45. https://doi.org/10.1053/jhep.2000.8106.
  Article CAS Google Scholar
• Laine L. Ligation: endoscopic treatment of choice for patients with bleeding esophageal varices? Hepatology (Baltimore, MD). 1995;22(2):663–5.
  Article CAS Google Scholar
• Gonzalez R, Zamora J, Gomez-Camarero J, Molinero LM, Banares R, Albillos A. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med. 2008;149(2):109–22. https://doi.org/10.7326/0003-4819-149-2-200807150-00007.
  Article PubMed Google Scholar
• Ravipati M, Katragadda S, Swaminathan PD, Molnar J, Zarling E. Pharmacotherapy plus endoscopic intervention is more effective than pharmacotherapy or endoscopy alone in the secondary prevention of esophageal variceal bleeding: a meta-analysis of randomized, controlled trials. Gastrointest Endosc. 2009;70(4):658-64.e5. https://doi.org/10.1016/j.gie.2009.02.029.
  Article PubMed Google Scholar
• Cheung J, Zeman M, van Zanten SV, Tandon P. Systematic review: secondary prevention with band ligation, pharmacotherapy or combination therapy after bleeding from oesophageal varices. Aliment Pharmacol Ther. 2009;30(6):577–88. https://doi.org/10.1111/j.1365-2036.2009.04075.x.
  Article CAS PubMed Google Scholar
• Lin L-L, Du S-M, Fu Y, Gu H-Y, Wang L, Jian Z-Y, et al. Combination therapy versus pharmacotherapy, endoscopic variceal ligation, or the transjugular intrahepatic portosystemic shunt alone in the secondary prevention of esophageal variceal bleeding: a meta-analysis of randomized controlled trials. Oncotarget. 2017;8(34):57399–408. https://doi.org/10.18632/oncotarget.18143.
  Article PubMed PubMed Central Google Scholar
• Albillos A, Zamora J, Martínez J, Arroyo D, Ahmad I, De-la-Peña J, et al. Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis. Hepatology (Baltimore, MD). 2017;66(4):1219–31. https://doi.org/10.1002/hep.29267.
  Article CAS Google Scholar
• Abraldes JG, Villanueva C, Aracil C, Turnes J, Hernandez-Guerra M, Genesca J, et al. Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology. 2016;150(5):1160-70.e3. https://doi.org/10.1053/j.gastro.2016.01.004.
  Article CAS PubMed Google Scholar
• Wan S, Huang C, Zhu X. Systematic review with a meta-analysis: clinical effects of statins on the reduction of portal hypertension and variceal haemorrhage in cirrhotic patients. BMJ Open. 2019;9(7):e030038. https://doi.org/10.1136/bmjopen-2019-030038.
  Article PubMed PubMed Central Google Scholar
• Vilaseca M, Guixé-Muntet S, Fernández-Iglesias A, Gracia-Sancho J. Advances in therapeutic options for portal hypertension. Therap Adv Gastroenterol. 2018;11:1756284818811294. https://doi.org/10.1177/1756284818811294.
  Article PubMed PubMed Central Google Scholar
• Schwabl P, Laleman W. Novel treatment options for portal hypertension. Gastroenterol Rep (Oxf). 2017;5(2):90–103. https://doi.org/10.1093/gastro/gox011.
  Article PubMed PubMed Central Google Scholar
• Rockey DC, Weisiger RA. Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Hepatology (Baltimore, MD). 1996;24(1):233–40. https://doi.org/10.1002/hep.510240137.
  Article CAS Google Scholar
• Feng HQ, Weymouth ND, Rockey DC. Endothelin antagonism in portal hypertensive mice: implications for endothelin receptor-specific signaling in liver disease. Am J Physiol Gastrointest Liver Physiol. 2009;297(1):G27-33. https://doi.org/10.1152/ajpgi.90405.2008.
  Article CAS PubMed PubMed Central Google Scholar
• Tripathi D, Therapondos G, Ferguson JW, Newby DE, Webb DJ, Hayes PC. Endothelin-1 contributes to maintenance of systemic but not portal haemodynamics in patients with early cirrhosis: a randomised controlled trial. Gut. 2006;55(9):1290–5. https://doi.org/10.1136/gut.2005.077453.
  Article CAS PubMed PubMed Central Google Scholar
• Heller J, Schepke M, Neef M, Woitas R, Rabe C, Sauerbruch T. Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension. J Hepatol. 2002;37(6):767–72. https://doi.org/10.1016/s0168-8278(02)00295-7.
  Article CAS PubMed Google Scholar
• Kemp W, Krum H, Colman J, Bailey M, Yandle T, Richards M, et al. Urotensin II: a novel vasoactive mediator linked to chronic liver disease and portal hypertension. Liver Int. 2007;27(9):1232–9. https://doi.org/10.1111/j.1478-3231.2007.01539.x.
  Article CAS PubMed Google Scholar
• Zhang R, Chen J, Liu D, Wang Y. Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl(4)-induced cirrhotic rats. Front Med. 2019;13(3):398–408. https://doi.org/10.1007/s11684-019-0689-5.
  Article PubMed Google Scholar
• Trebicka J, Leifeld L, Hennenberg M, Biecker E, Eckhardt A, Fischer N, et al. Hemodynamic effects of urotensin II and its specific receptor antagonist palosuran in cirrhotic rats. Hepatology (Baltimore, MD). 2008;47(4):1264–76. https://doi.org/10.1002/hep.22170.
  Article CAS Google Scholar
• Di Pascoli M, La Mura V. Renin-angiotensin-aldosterone system in cirrhosis: there’s room to try! Digest Liver Dis. 2019;51(2):297–8. https://doi.org/10.1016/j.dld.2018.07.038.
  Article Google Scholar
• Annicchiarico BE, Santonocito C, Siciliano M, Scapaticci M, Guarino D, Di Stasi C, et al. ACE I allele is associated with more severe portal hypertension in patients with liver cirrhosis: a pilot study. Digest Liver Dis. 2019;51(2):293–6. https://doi.org/10.1016/j.dld.2018.08.005.
  Article CAS Google Scholar
• Baik SK, Park DH, Kim MY, Choi YJ, Kim HS, Lee DK, et al. Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity. J Gastroenterol. 2003;38(12):1150–4. https://doi.org/10.1007/s00535-003-1222-8.
  Article PubMed Google Scholar
• Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J. Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol. 2010;53(2):273–82. https://doi.org/10.1016/j.jhep.2010.03.013.
  Article CAS PubMed Google Scholar
• Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012;33(7):829–37. https://doi.org/10.1093/eurheartj/ehr304.
  Article CAS PubMed Google Scholar
• Fiorucci S, Antonelli E, Brancaleone V, Sanpaolo L, Orlandi S, Distrutti E, et al. NCX-1000, a nitric oxide-releasing derivative of ursodeoxycholic acid, ameliorates portal hypertension and lowers norepinephrine-induced intrahepatic resistance in the isolated and perfused rat liver. J Hepatol. 2003;39(6):932–9. https://doi.org/10.1016/s0168-8278(03)00393-3.
  Article CAS PubMed Google Scholar
• Liu J, Li C, Waalkes MP, Clark J, Myers P, Saavedra JE, et al. The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. Hepatology (Baltimore, MD). 2003;37(2):324–33. https://doi.org/10.1053/jhep.2003.50063.
  Article CAS Google Scholar
• Berzigotti A, Bellot P, De Gottardi A, Garcia-Pagan JC, Gagnon C, Spénard J, et al. NCX-1000, a nitric oxide-releasing derivative of UDCA, does not decrease portal pressure in patients with cirrhosis: results of a randomized, double-blind, dose-escalating study. Am J Gastroenterol. 2010;105(5):1094–101. https://doi.org/10.1038/ajg.2009.661.
  Article CAS PubMed Google Scholar
• Biecker E, Trebicka J, Kang A, Hennenberg M, Sauerbruch T, Heller J. Treatment of bile duct-ligated rats with the nitric oxide synthase transcription enhancer AVE 9488 ameliorates portal hypertension. Liver Int. 2008;28(3):331–8. https://doi.org/10.1111/j.1478-3231.2008.01664.x.
  Article CAS PubMed Google Scholar
• Matei V, Rodríguez-Vilarrupla A, Deulofeu R, García-Calderó H, Fernández M, Bosch J, et al. Three-day tetrahydrobiopterin therapy increases in vivo hepatic NOS activity and reduces portal pressure in CCl4 cirrhotic rats. J Hepatol. 2008;49(2):192–7. https://doi.org/10.1016/j.jhep.2008.04.014.
  Article CAS PubMed Google Scholar
• Reverter E, Mesonero F, Seijo S, Martínez J, Abraldes JG, Peñas B, et al. Effects of sapropterin on portal and systemic hemodynamics in patients with cirrhosis and portal hypertension: a bicentric double-blind placebo-controlled study. Am J Gastroenterol. 2015;110(7):985–92. https://doi.org/10.1038/ajg.2015.185.
  Article CAS PubMed Google Scholar
• Vadera S, Yong CWK, Gluud LL, Morgan MY. Band ligation versus no intervention for primary prevention of upper gastrointestinal bleeding in adults with cirrhosis and oesophageal varices. Cochrane Database Syst Rev. 2019;6(6):012673. https://doi.org/10.1002/14651858.CD012673.pub2.
  Article Google Scholar
• Jaspersen D, Schwacha H, Sauer B, Wzatek J, Schorr W, Graf zu Dohna P et al. [Complications of endoscopic sclerotherapy of esophageal varices]. Leber, Magen, Darm. 1995;25(4):171–4.
• Augustin S, González A, Genescà J. Acute esophageal variceal bleeding: current strategies and new perspectives. World J Hepatol. 2010;2(7):261–74. https://doi.org/10.4254/wjh.v2.i7.261.
  Article PubMed PubMed Central Google Scholar
• Qin JP, Jiang MD, Tang W, Wu XL, Yao X, Zeng WZ, et al. Clinical effects and complications of TIPS for portal hypertension due to cirrhosis: a single center. World J Gastroenterol. 2013;19(44):8085–92. https://doi.org/10.3748/wjg.v19.i44.8085.
  Article PubMed PubMed Central Google Scholar