Pharmacological management of portal hypertension and its complications in children: lessons from adults and opportunities for the future

References

• Angeli P, Bernardi M, Villanueva C. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69(2):406–460. DOI:10.1016/j.jhep.2018.03.024.
   PubMed Web of Science ®Google Scholar
• Garcia-Tsao G, Abraldes JG, Berzigotti A, et al.. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017;65(1):310–335.
   PubMed Web of Science ®Google Scholar
• Shneider BL, de Ville de Goyet J, Leung DH, et al.. Primary prophylaxis of variceal bleeding in children and the role of MesoRex Bypass: summary of the Baveno VI Pediatric Satellite Symposium. Hepatology. 2016;63(4):1368–1380. DOI:10.1002/hep.28153.
   PubMed Web of Science ®Google Scholar
• Chapin CA, Bass LM. Cirrhosis and portal hypertension in the pediatric population. Clin Liver Dis. 2018;22(4):735–752.
   PubMed Web of Science ®Google Scholar
• Sathe MN, Patel AS. Update in pediatrics: focus on fat-soluble vitamins. Nutr Clin Pract. 2010;25(4):340–346.
   PubMed Web of Science ®Google Scholar
• Boyle JT. Gastrointestinal bleeding in infants and children. Pediatr Rev. 2008;29(2):39–52.
   PubMed Web of Science ®Google Scholar
• Kaufman RM, Djulbegovic B, Gernsheimer T, et al.. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2015;162(3):205–213. DOI:10.7326/M14-1589.
   PubMed Web of Science ®Google Scholar
• Moitinho E, Planas R, Banares R, et al. Multicenter randomized controlled trial comparing different schedules of somatostatin in the treatment of acute variceal bleeding. J Hepatol. 2001;35(6):712–718.
   PubMed Web of Science ®Google Scholar
• Kumar A, Jha SK, Mittal VV, et al.. Addition of Somatostatin after successful endoscopic variceal ligation does not prevent early rebleeding in comparison to placebo: a double blind randomized controlled trial. J Clin Exp Hepatol. 2015;5(3):204–212.
   PubMed Web of Science ®Google Scholar
• Heikenen JB, Pohl JF, Werlin SL, et al.. Octreotide in pediatric patients. J Pediatr Gastroenterol Nutr. 2002;35(5):600–609.
   PubMed Web of Science ®Google Scholar
• Bunchorntavakul C, Reddy KR. Pharmacologic management of portal hypertension. Clin Liver Dis. 2019;23(4):713–736.
   PubMed Web of Science ®Google Scholar
• Corley DA, Cello JP, Adkisson W, et al.. Octreotide for acute esophageal variceal bleeding: a meta-analysis. Gastroenterology. 2001;120(4):946–954.
   PubMed Web of Science ®Google Scholar
• Zou Z, Yan X, Lu H, et al. Comparison of drugs facilitating endoscopy for patients with acute variceal bleeding: a systematic review and network meta-analysis. Ann Transl Med. 2019;7(23):717.
   PubMed Web of Science ®Google Scholar
• Eroglu Y, Emerick KM, Whitingon PF, et al.. Octreotide therapy for control of acute gastrointestinal bleeding in children. J Pediatr Gastroenterol Nutr. 2004;38(1):41–47.
   PubMed Web of Science ®Google Scholar
• Gana JC, Valentino PL, Morinville V, et al.. Variation in care for children with esophageal varices: a study of physicians’, patients’, and families’ approaches and attitudes. J Pediatr Gastroenterol Nutr. 2011;52(6):751–755.
   PubMed Web of Science ®Google Scholar
• O’Meara M, Cicalese MP, Bordugo A, et al.. Successful use of long-acting octreotide for intractable chronic gastrointestinal bleeding in children. J Pediatr Gastroenterol Nutr. 2015;60(1):48–53.
   PubMed Web of Science ®Google Scholar
• Sarin SK, Sharma P. Terlipressin: an asset for hepatologists!. Hepatology. 2011;54(2):724–728.
   PubMed Web of Science ®Google Scholar
• Wang C, Han J, Xiao L, et al.. Efficacy of vasopressin/terlipressin and somatostatin/octreotide for the prevention of early variceal rebleeding after the initial control of bleeding: a systematic review and meta-analysis. Hepatol Int. 2015;9(1):120–129.
   PubMed Web of Science ®Google Scholar
• Zhou X, Tripathi D, Song T, 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. DOI:10.1097/MD.0000000000013437.
   PubMed Web of Science ®Google Scholar
• Zhang J, Liu J, Wu Y, et al.. Effect of terlipressin on renal function in cirrhotic patients with acute upper gastrointestinal bleeding. Ann Transl Med. 2020;8(6):340. DOI:10.21037/atm.2020.02.135.
   PubMed Web of Science ®Google Scholar
• Masarwa R, Paret G, Perlman A, et al.. Role of vasopressin and terlipressin in refractory shock compared to conventional therapy in the neonatal and pediatric population: a systematic review, meta-analysis, and trial sequential analysis. Crit Care. 2017;21(1):1.
   PubMedGoogle Scholar
• Rimola A, Bory F, Teres J, et al.. Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage. Hepatology. 1985;5(3):463–467.
   PubMed Web of Science ®Google Scholar
• Committee ASoP, Khashab MA, Chithadi KV, Acosta RD, et al. Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc. 2015;81(1):81–89.
   PubMed Web of Science ®Google Scholar
• Castillo L, Prachuapthunyachart S, Hall M, et al.. Antibiotic use in cirrhotic children with acute upper gastrointestinal bleeding: a retrospective study using the pediatric health information system (PHIS) database. Medicine (Baltimore). 2019;98(29):e16505.
   PubMed Web of Science ®Google Scholar
• Marti-Carvajal AJ, Vitamin SI. K for upper gastrointestinal bleeding in people with acute or chronic liver diseases. Cochrane Database Syst Rev. 2015;6:CD004792.
   Google Scholar
• Albanese G, Kondo KL. Pharmacology of sclerotherapy. Semin Intervent Radiol. 2010;27(4):391–399.
   PubMedGoogle Scholar
• Abd El-Hamid N, Taylor RM, Marinello D, et al.. Aetiology and management of extrahepatic portal vein obstruction in children: King’s College Hospital experience. J Pediatr Gastroenterol Nutr. 2008;47(5):630–634. DOI:10.1097/MPG.0b013e31817b6eea.
   PubMed Web of Science ®Google Scholar
• Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr Gastroenterol Rep. 2008;10(6):528–534.
   PubMedGoogle Scholar
• Lin L, Cui B, Deng Y, et al.. The efficacy of proton pump inhibitor in cirrhotics with variceal bleeding: a systemic review and meta-analysis. Digestion. 2020;1–11. DOI:10.1159/000505059
   PubMed Web of Science ®Google Scholar
• Zhu J, Qi X, Yu H, et al.. Acid suppression in patients treated with endoscopic therapy for the management of gastroesophageal varices: a systematic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2018;12(6):617–624.
   PubMed Web of Science ®Google Scholar
• Grammatikopoulos T, McKiernan PJ, Dhawan A. Portal hypertension and its management in children. Arch Dis Child. 2018;103(2):186–191.
   PubMed Web of Science ®Google Scholar
• Augustin S, Pons M, Maurice JB, et al. Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease. Hepatology. 2017;66(6):1980–1988.
   PubMed Web of Science ®Google Scholar
• Duche M, Ducot B, Ackermann O, et al.. Portal hypertension in children: High-risk varices, primary prophylaxis and consequences of bleeding. J Hepatol. 2017;66(2):320–327.
   PubMed Web of Science ®Google Scholar
• Gana JC, Cifuentes LI, Gattini D, et al.. Band ligation versus beta-blockers for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. Cochrane Database Syst Rev. 2019;9:CD010546.
   PubMedGoogle Scholar
• Ling SC. Should children with esophageal varices receive beta-blockers for the primary prevention of variceal hemorrhage?. Can J Gastroenterol. 2005;19(11):661–666.
   PubMedGoogle Scholar
• Hobolth L, Bendtsen F, Hansen EF, et al.. Effects of carvedilol and propranolol on circulatory regulation and oxygenation in cirrhosis: a randomised study. Dig Liver Dis. 2014;46(3):251–256.
   PubMedGoogle Scholar
• Ling SC, Walters T, McKiernan PJ, et al.. Primary prophylaxis of variceal hemorrhage in children with portal hypertension: a framework for future research. J Pediatr Gastroenterol Nutr. 2011;52(3):254–261.
   PubMed Web of Science ®Google Scholar
• Shashidhar H, Langhans N, Grand RJ. Propranolol in prevention of portal hypertensive hemorrhage in children: a pilot study. J Pediatr Gastroenterol Nutr. 1999;29(1):12–17.
   PubMed Web of Science ®Google Scholar
• de Franchis R, Baveno VIF. 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):743–752.
   PubMed Web of Science ®Google Scholar
• Ozsoylu S, Kocak N, Yuce A. Propranolol therapy for portal hypertension in children. J Pediatr. 1985;106(2):317–321.
   PubMed Web of Science ®Google Scholar
• Zacharias AP, Jeyaraj R, Hobolth L, et al.. Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. Cochrane Database Syst Rev. 2018;10:CD011510.
   PubMedGoogle Scholar
• Hidaka H, Nakazawa T, Wang G, et al.. Long-term administration of PPI reduces treatment failures after esophageal variceal band ligation: a randomized, controlled trial. J Gastroenterol. 2012;47(2):118–126. DOI:10.1007/s00535-011-0472-0.
   PubMed Web of Science ®Google Scholar
• Zhu J, Qi X, Yu H, et al.. Association of proton pump inhibitors with the risk of hepatic encephalopathy during hospitalization for liver cirrhosis. United European Gastroenterol J. 2018;6(8):1179–1187. DOI:10.1177/2050640618773564.
   PubMed Web of Science ®Google Scholar
• Fasullo M, Rau P, Liu DQ, et al.. Proton pump inhibitors increase the severity of hepatic encephalopathy in cirrhotic patients. World J Hepatol. 2019;11(6):522–530. DOI:10.4254/wjh.v11.i6.522.
   PubMed Web of Science ®Google Scholar
• Janka T, Tornai T, Borbely B, et al.. Deleterious effect of proton pump inhibitors on the disease course of cirrhosis. Eur J Gastroenterol Hepatol. 2020;32(2):257–264. DOI:10.1097/MEG.0000000000001499.
   PubMed Web of Science ®Google Scholar
• De Bruyne P, Ito S. Toxicity of long-term use of proton pump inhibitors in children. Arch Dis Child. 2018;103(1):78–82.
   PubMed Web of Science ®Google Scholar
• Pose E, Cardenas A. Translating our current understanding of Ascites management into new therapies for patients with Cirrhosis and fluid retention. Dig Dis. 2017;35(4):402–410.
   PubMed Web of Science ®Google Scholar
• Matloff RG, Arnon R. The kidney in pediatric liver disease. Curr Gastroenterol Rep. 2015;17(9):36.
   PubMedGoogle Scholar
• Carey RG, Bucuvalas JC, Balistreri WF, et al.. Hyponatremia increases mortality in pediatric patients listed for liver transplantation. Pediatr Transplant. 2010;14(1):115–120.
   PubMed Web of Science ®Google Scholar
• Karnsakul W, Ingviya T, Seaberg E, et al.. Ascites in Children: A Single-Center Experience of 27 Years. J Pediatr Gastroenterol Nutr. 2017;64(1):83–88. DOI:10.1097/MPG.0000000000001209.
   PubMed Web of Science ®Google Scholar
• Sungaila I, Bartle WR, Walker SE, et al.. Spironolactone pharmacokinetics and pharmacodynamics in patients with cirrhotic ascites. Gastroenterology. 1992;102(5):1680–1685. DOI:10.1016/0016-5085(92)91730-R.
   PubMed Web of Science ®Google Scholar
• Li JS, Flynn JT, Portman R, et al.. The efficacy and safety of the novel aldosterone antagonist eplerenone in children with hypertension: a randomized, double-blind, dose-response study. J Pediatr. 2010;157(2):282–287. DOI:10.1016/j.jpeds.2010.02.042.
   PubMed Web of Science ®Google Scholar
• Giefer MJ, Murray KF, Colletti RB. Pathophysiology, diagnosis, and management of pediatric ascites. J Pediatr Gastroenterol Nutr. 2011;52(5):503–513.
   PubMed Web of Science ®Google Scholar
• Phakdeekitcharoen B, Boonyawat K. The added-up albumin enhances the diuretic effect of furosemide in patients with hypoalbuminemic chronic kidney disease: a randomized controlled study. BMC Nephrol. 2012;13:92.
   PubMed Web of Science ®Google Scholar
• Schrier RW, Gross P, Gheorghiade M, et al.. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355(20):2099–2112. DOI:10.1056/NEJMoa065181.
   PubMed Web of Science ®Google Scholar
• Tahara T, Mori K, Mochizuki M, et al. Tolvaptan is effective in treating patients with refractory ascites due to cirrhosis. Biomed Rep. 2017;7(6):558–562.
   PubMed Web of Science ®Google Scholar
• Wang S, Zhang X, Han T, et al.. Tolvaptan treatment improves survival of cirrhotic patients with ascites and hyponatremia. BMC Gastroenterol. 2018;18(1):137. DOI:10.1186/s12876-018-0857-0.
   PubMedGoogle Scholar
• Rodriguez-Roisin R, Krowka MJ. Hepatopulmonary Syndrome — A Liver-Induced Lung Vascular Disorder. N Engl J Med. 2008;358(22):2378–2387.
   PubMed Web of Science ®Google Scholar
• Lee WS, Wong SY, Ivy DD, et al.. Portopulmonary Hypertension in Children: Recent Advances in Diagnosis and Management. J Pediatr. 2018;196:14–21 e1.
   PubMed Web of Science ®Google Scholar
• Warner S, McKiernan PJ, Hartley J, et al.. Hepatopulmonary syndrome in children: a 20-year review of presenting symptoms, clinical progression, and transplant outcome. Liver Transpl. 2018;24(9):1271–1279. DOI:10.1002/lt.25296.
   PubMed Web of Science ®Google Scholar
• Raevens S, Fallon MB. Potential clinical targets in hepatopulmonary syndrome: lessons from experimental models. Hepatology. 2018;68(5):2016–2028.
   PubMed Web of Science ®Google Scholar
• Kawut SM, Ellenberg SS, Krowka MJ, et al. Sorafenib in hepatopulmonary syndrome: a randomized, double-blind, placebo-controlled trial. Liver Transpl. 2019;25(8):1155–1164.
   PubMed Web of Science ®Google Scholar
• Yang W, Zhang J, Hu B, et al.. The role of receptor tyrosine kinase activation in cholangiocytes and pulmonary vascular endothelium in experimental hepatopulmonary syndrome. Am J Physiol Gastrointest Liver Physiol. 2014;306(1):G72–80. DOI:10.1152/ajpgi.00178.2013.
   PubMed Web of Science ®Google Scholar
• Raevens S, Geerts A, Paridaens A, et al.. Placental growth factor inhibition targets pulmonary angiogenesis and represents a therapy for hepatopulmonary syndrome in mice. Hepatology. 2018;68(2):634–651. DOI:10.1002/hep.29579.
   PubMed Web of Science ®Google Scholar
• Gupta LB, Kumar A, Jaiswal AK, et al.. Pentoxifylline therapy for hepatopulmonary syndrome: a pilot study. Arch Intern Med. 2008;168(16):1820–1823. DOI:10.1001/archinte.168.16.1820.
   PubMedGoogle Scholar
• Tanikella R, Philips GM, Faulk DK, et al.. Pilot study of pentoxifylline in hepatopulmonary syndrome. Liver Transpl. 2008;14(8):1199–1203.
   PubMed Web of Science ®Google Scholar
• Zhang J, Luo B, Tang L, et al.. Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome. Gastroenterology. 2009;136(3):1070–1080. DOI:10.1053/j.gastro.2008.12.001.
   PubMed Web of Science ®Google Scholar
• Gupta S, Faughnan ME, Lilly L, et al.. Norfloxacin therapy for hepatopulmonary syndrome: a pilot randomized controlled trial. Clin Gastroenterol Hepatol. 2010;8(12):1095–1098.
   PubMed Web of Science ®Google Scholar
• Rabiller A, Nunes H, Lebrec D, et al.. Prevention of gram-negative translocation reduces the severity of hepatopulmonary syndrome. Am J Respir Crit Care Med. 2002;166(4):514–517. DOI:10.1164/rccm.200201-027OC.
   PubMed Web of Science ®Google Scholar
• Tazi KA, Moreau R, Herve P, et al.. Norfloxacin reduces aortic NO synthases and proinflammatory cytokine up-regulation in cirrhotic rats: role of Akt signaling. Gastroenterology. 2005;129(1):303–314. DOI:10.1053/j.gastro.2005.04.016.
   PubMed Web of Science ®Google Scholar
• Schenk P, Madl C, Rezaie-Majd S, et al.. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med. 2000;133(9):701–706.
   PubMed Web of Science ®Google Scholar
• Fix OK, Bass NM, De Marco T, et al.. Long-term follow-up of portopulmonary hypertension: effect of treatment with epoprostenol. Liver Transpl. 2007;13(6):875–885.
   PubMed Web of Science ®Google Scholar
• Krowka MJ, Frantz RP, McGoon MD, et al.. Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology. 1999;30(3):641–648.
   PubMed Web of Science ®Google Scholar
• Safdar Z, Bartolome S, Sussman N. Portopulmonary hypertension: an update. Liver Transpl. 2012;18(8):881–891.
   PubMed Web of Science ®Google Scholar
• Cheng CH, Wang YC, Wu TH, et al.. Sildenafil monotherapy to treat portopulmonary hypertension before liver transplant. Transplant Proc. 2019;51(5):1435–1438. DOI:10.1016/j.transproceed.2019.01.139.
   PubMed Web of Science ®Google Scholar
• Vionnet J, Yerly P, Aubert JD, et al.. Management of severe portopulmonary hypertension with dual oral therapy before liver transplantation. Transplantation. 2018;102(5):e194. DOI:10.1097/TP.0000000000002142.
   PubMed Web of Science ®Google Scholar
• Kuang HY, Wu YH, Yi QJ, et al.. The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease: a systematic review and meta-analysis. Medicine (Baltimore). 2018;97(10):e0075. DOI:10.1097/MD.0000000000010075.
   PubMed Web of Science ®Google Scholar
• Savale L, Magnier R, Le Pavec J, et al.. Efficacy, safety and pharmacokinetics of bosentan in portopulmonary hypertension. Eur Respir J. 2013;41(1):96–103. DOI:10.1183/09031936.00117511.
   PubMed Web of Science ®Google Scholar
• Sitbon O, Bosch J, Cottreel E, et al.. Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial. Lancet Respir Med. 2019;7(7):594–604. DOI:10.1016/S2213-2600(19)30091-8.
   PubMed Web of Science ®Google Scholar
• Cartin-Ceba R, Halank M, Ghofrani HA, et al.. Riociguat treatment for portopulmonary hypertension: a subgroup analysis from the PATENT-1/-2 studies. Pulm Circ. 2018;8(2):2045894018769305. DOI:10.1177/2045894018769305.
   Web of Science ®Google Scholar
• Spreemann T, Bertram H, Happel CM, et al.. First-in-child use of the oral soluble guanylate cyclase stimulator riociguat in pulmonary arterial hypertension. Pulm Circ. 2018;8(1):2045893217743123.
   Web of Science ®Google Scholar
• Gluud LL, Christensen K, Christensen E, et al.. Terlipressin for hepatorenal syndrome. Cochrane Database Syst Rev. 2012;9:CD005162.
   PubMed Web of Science ®Google Scholar
• Yousef N, Habes D, Ackermann O, et al.. Hepatorenal syndrome: diagnosis and effect of terlipressin therapy in 4 pediatric patients. J Pediatr Gastroenterol Nutr. 2010;51(1):100–102.
   PubMed Web of Science ®Google Scholar
• Nanjo S, Yamazaki J, Yoshikawa K, et al.. Carvedilol prevents myocardial fibrosis in hamsters. Int Heart J. 2006;47(4):607–616.
   PubMed Web of Science ®Google Scholar
• Silvestre OM, Farias AQ, Ramos DS, et al. beta-Blocker therapy for cirrhotic cardiomyopathy: a randomized-controlled trial. Eur J Gastroenterol Hepatol. 2018;30(8):930–937.
   PubMed Web of Science ®Google Scholar
• DuBrock HM, Krowka MJ. The myths and realities of portopulmonary hypertension. Hepatology. 2020. DOI:10.1002/hep.31415
   PubMed Web of Science ®Google Scholar
• Gines P, Sola E, Angeli P, et al.. Hepatorenal syndrome. Nat Rev Dis Primers. 2018;4(1):23.
   PubMedGoogle Scholar
• Salerno F, Gerbes A, Gines P, et al.. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut. 2007;56(9):1310–1318.
   PubMed Web of Science ®Google Scholar
• Zhang J, Rossle M, Zhou X, et al.. Terlipressin for the treatment of hepatorenal syndrome: an overview of current evidence. Curr Med Res Opin. 2019;35(5):859–868.
   PubMed Web of Science ®Google Scholar
• Deep A, Saxena R, Jose B. Acute kidney injury in children with chronic liver disease. Pediatr Nephrol. 2019;34(1):45–59.
   PubMed Web of Science ®Google Scholar
• Moller S, Lee SS. Cirrhotic cardiomyopathy. J Hepatol. 2018;69(4):958–960.
   PubMed Web of Science ®Google Scholar
• Celtik C, Durmaz O, Oner N, et al.. Investigation of cardiomyopathy in children with cirrhotic and noncirrhotic portal hypertension. J Pediatr Gastroenterol Nutr. 2015;60(2):177–181. DOI:10.1097/MPG.0000000000000580.
   PubMed Web of Science ®Google Scholar
• Gorgis NM, Kennedy C, Lam F, et al.. Clinical consequences of cardiomyopathy in children with biliary atresia requiring liver transplantation. Hepatology. 2019;69(3):1206–1218. DOI:10.1002/hep.30204.
   PubMed Web of Science ®Google Scholar
• Izzy M, Oh J, Watt KD. Cirrhotic cardiomyopathy after transplantation: neither the transient nor innocent bystander. Hepatology. 2018;68(5):2008–2015.
   PubMed Web of Science ®Google Scholar
• Campagna F, Montagnese S, Schiff S, et al.. Cognitive impairment and electroencephalographic alterations before and after liver transplantation: what is reversible?. Liver Transpl. 2014;20(8):977–986. DOI:10.1002/lt.23909.
   PubMed Web of Science ®Google Scholar
• Wijdicks EF, Longo DL. Hepatic encephalopathy. N Engl J Med. 2016;375(17):1660–1670.
   PubMed Web of Science ®Google Scholar
• Misel ML, Gish RG, Patton H, et al.. Sodium benzoate for treatment of hepatic encephalopathy. Gastroenterol Hepatol. 2013;9(4):219–227.
   PubMedGoogle Scholar
• Bajaj JS. Review article: potential mechanisms of action of rifaximin in the management of hepatic encephalopathy and other complications of cirrhosis. Aliment Pharmacol Ther. 2016;43(Suppl 1):11–26.
   PubMed Web of Science ®Google Scholar
• Ahmad I, Khan AA, Alam A, et al. L-ornithine-L-aspartate infusion efficacy in hepatic encephalopathy. J Coll Physicians Surg Pak. 2008;18(11):684–687.
   PubMed Web of Science ®Google Scholar
• Mock CM, Schwetschenau KH. Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy. Am J Health Syst Pharm. 2012;69(1):35–39.
   PubMed Web of Science ®Google Scholar
• Sharma P, Sharma BC, Agrawal A, et al.. Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose. J Gastroenterol Hepatol. 2012;27(8):1329–1335.
   PubMed Web of Science ®Google Scholar
• Bass NM, Mullen KD, Sanyal A, et al.. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362(12):1071–1081. DOI:10.1056/NEJMoa0907893.
   PubMed Web of Science ®Google Scholar
• Goh ET, Stokes CS, Sidhu SS, et al.. L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev. 2018;5:CD012410.
   PubMedGoogle Scholar
• Sushma S, Dasarathy S, Tandon RK, et al.. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology. 1992;16(1):138–144.
   PubMed Web of Science ®Google Scholar
• Henkel SAF, McKiernan PJ. Bye Bye Benzoate: what next for hyperammonemia in liver disease?. J Pediatr Gastroenterol Nutr. 2020;70(2):158.
   PubMed Web of Science ®Google Scholar
• Snehavardhan P, Lal BB, Sood V, et al.. Safety of sodium benzoate in the management of hyperammonemia in decompensated chronic liver disease of the childhood-a double-blind randomized controlled trial. J Pediatr Gastroenterol Nutr. 2020;70(2):165–170.
   PubMed Web of Science ®Google Scholar
• Weiss N, Tripon S, Lodey M, et al.. Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study. Fundam Clin Pharmacol. 2018;32(2):209–215. DOI:10.1111/fcp.12340.
   PubMedGoogle Scholar
• Berry SA, Vockley J, Vinks AA, et al. Pharmacokinetics of glycerol phenylbutyrate in pediatric patients 2months to 2years of age with urea cycle disorders. Mol Genet Metab. 2018;125(3):251–257.
   PubMed Web of Science ®Google Scholar
• Shiraki M, Shimizu M, Moriwaki H, et al.. Carnitine dynamics and their effects on hyperammonemia in cirrhotic Japanese patients. Hepatol Res. 2017;47(4):321–327.
   PubMed Web of Science ®Google Scholar
• Marti-Carvajal AJ, Gluud C, Arevalo-Rodriguez I, et al.. Acetyl-L-carnitine for patients with hepatic encephalopathy. Cochrane Database Syst Rev. 2019;1:CD011451.
   PubMedGoogle Scholar
• Simon-Talero M, Garcia-Martinez R, Torrens M, et al. Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: a randomized double-blind study. J Hepatol. 2013;59(6):1184–1192.
   PubMed Web of Science ®Google Scholar
• Bai Z, Bernardi M, Yoshida EM, et al.. Albumin infusion may decrease the incidence and severity of overt hepatic encephalopathy in liver cirrhosis. Aging (Albany NY). 2019;11(19):8502–8525. DOI:10.18632/aging.102335.
   PubMedGoogle Scholar
• Mehta G, Gustot T, Mookerjee RP, et al.. Inflammation and portal hypertension - the undiscovered country. J Hepatol. 2014;61(1):155–163. DOI:10.1016/j.jhep.2014.03.014.
   PubMed Web of Science ®Google Scholar
• Kang SH, Lee YB, Lee JH, et al.. Rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients experiencing hepatic encephalopathy. Aliment Pharmacol Ther. 2017;46(9):845–855. DOI:10.1111/apt.14275.
   PubMed Web of Science ®Google Scholar
• Vlachogiannakos J, Saveriadis AS, Viazis N, et al.. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment Pharmacol Ther. 2009;29(9):992–999. DOI:10.1111/j.1365-2036.2009.03958.x.
   PubMed Web of Science ®Google Scholar
• Zhu Q, Zou L, Jagavelu K, et al.. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol. 2012;56(4):893–899. DOI:10.1016/j.jhep.2011.11.013.
   PubMed Web of Science ®Google Scholar
• Verbeke L, Mannaerts I, Schierwagen R, et al. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep. 2016;6:33453.
   PubMed Web of Science ®Google Scholar
• Tripathi DM, Vilaseca M, Lafoz E, et al.. Simvastatin prevents progression of Acute on chronic liver failure in rats with Cirrhosis and portal hypertension. Gastroenterology. 2018;155(5):1564–1577. DOI:10.1053/j.gastro.2018.07.022.
   PubMed Web of Science ®Google Scholar
• De Gottardi A, Berzigotti A, Seijo S, et al. Postprandial effects of dark chocolate on portal hypertension in patients with cirrhosis: results of a phase 2, double-blind, randomized controlled trial. Am J Clin Nutr. 2012;96(3):584–590.
   PubMed Web of Science ®Google Scholar
• Hernandez-Guerra M, Garcia-Pagan JC, Turnes J, et al.. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology. 2006;43(3):485–491. DOI:10.1002/hep.21080.
   PubMed Web of Science ®Google Scholar
• Barreyro FJ, Holod S, Finocchietto PV, et al.. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35(3):953–966. DOI:10.1111/liv.12570.
   PubMed Web of Science ®Google Scholar
• Garcia-Tsao G, Fuchs M, Shiffman M, et al.. Emricasan (IDN-6556) lowers portal pressure in patients with compensated Cirrhosis and severe portal hypertension. Hepatology. 2019;69(2):717–728. DOI:10.1002/hep.30199.
   PubMed Web of Science ®Google Scholar
• Tripathi DM, Erice E, Lafoz E, et al.. Metformin reduces hepatic resistance and portal pressure in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol. 2015;309(5):G301–9. DOI:10.1152/ajpgi.00010.2015.
   PubMed Web of Science ®Google Scholar
• Dhiman RK, Rana B, Agrawal S, et al.. Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology. 2014;147(6):1327–37 e3. DOI:10.1053/j.gastro.2014.08.031.
   PubMed Web of Science ®Google Scholar
• Rincon D, Vaquero J, Hernando A, et al.. Oral probiotic VSL#3 attenuates the circulatory disturbances of patients with cirrhosis and ascites. Liver Int. 2014;34(10):1504–1512. DOI:10.1111/liv.12539.
   PubMed Web of Science ®Google Scholar
• Shneider BL, Bosch J, de Franchis R, et al.. Portal hypertension in children: expert pediatric opinion on the report of the Baveno v consensus workshop on methodology of diagnosis and therapy in portal hypertension. Pediatr Transplant. 2012;16(5):426–437. DOI:10.1111/j.1399-3046.2012.01652.x.
   PubMed Web of Science ®Google Scholar
• D’Antiga L. Medical management of esophageal varices and portal hypertension in children. Semin Pediatr Surg. 2012;21(3):211–218.
   PubMed Web of Science ®Google Scholar
• Sharma M, Singh S, Desai V, et al.. Comparison of therapies for primary prevention of Esophageal variceal bleeding: a systematic review and network meta-analysis. Hepatology. 2019;69(4):1657–1675. DOI:10.1002/hep.30220.
   PubMed Web of Science ®Google Scholar
• Kianifar HR, Khalesi M, Mahmoodi E, et al.. Pentoxifylline in hepatopulmonary syndrome. World J Gastroenterol. 2012;18(35):4912–4916.
   PubMed Web of Science ®Google Scholar
• Abraldes JG, The G-TG. Design of Clinical Trials in Portal Hypertension. Semin Liver Dis. 2017;37(1):73–84.
   PubMed Web of Science ®Google Scholar