본문 바로가기
KERD
논문KCI 등재

β-blockers in advanced cirrhosis: More friend than enemy

Ki Tae Yoon|Hongqun Liu|Samuel S. Lee
대한간학회 (The korean Association for the Study of the Liver)|2021.07|Clinical and Molecular Hepatology|제27권 제3호|pp. 425-436|DOI 10.3350/cmh.2020.0234

1

조회

0

다운로드

5

인용

0

참고문헌

키워드

CirrhosisPortal hypertensionVaricesRefractory ascites

초록

Nonselective beta-adrenergic blocker (NSBB) therapy for the prevention of initial and recurrent gastrointestinal bleeding in cirrhotic patients with gastroesophageal varices has been used for the past four decades. NSBB therapy is considered the cornerstone of treatment for varices, and has become the standard of care. However, a 2010 study from the group that pioneered β-blocker therapy suggested a detrimental effect of NSBBs in decompensated cirrhosis, especially in patients with refractory ascites. Since then, numerous additional studies have incompletely resolved whether NSBBs are deleterious, although more recent evidence weighs against a harmful effect. The possibility of a “therapeutic window” has also been raised. We aimed to review the literature to analyze the pros and cons of using NSBBs in patients with cirrhosis, not only with respect to bleeding or mortality but also to other potential benefits and risks. β-blockers are highly effective in preventing first bleeding and recurrent bleeding. Furthermore, NSBBs improve congestion/ischemia of the gut mucosa, decrease intestinal permeability, and therefore indirectly alleviate systemic inflammation. β-blockers shorten the electrocardiographic prolonged QTc interval and may also decrease the incidence of hepatocellular carcinoma. On the other hand, the possibility of deleterious effects in cirrhosis has not been completely eliminated. NSBBs may be associated with an increased risk of portal vein thrombosis, although this could be correlational artifact. Overall, we conclude that β-blockers in cirrhosis are much more of a friend than enemy.

Abstract

Nonselective beta-adrenergic blocker (NSBB) therapy for the prevention of initial and recurrent gastrointestinal bleeding in cirrhotic patients with gastroesophageal varices has been used for the past four decades. NSBB therapy is considered the cornerstone of treatment for varices, and has become the standard of care. However, a 2010 study from the group that pioneered β-blocker therapy suggested a detrimental effect of NSBBs in decompensated cirrhosis, especially in patients with refractory ascites. Since then, numerous additional studies have incompletely resolved whether NSBBs are deleterious, although more recent evidence weighs against a harmful effect. The possibility of a “therapeutic window” has also been raised. We aimed to review the literature to analyze the pros and cons of using NSBBs in patients with cirrhosis, not only with respect to bleeding or mortality but also to other potential benefits and risks. β-blockers are highly effective in preventing first bleeding and recurrent bleeding. Furthermore, NSBBs improve congestion/ischemia of the gut mucosa, decrease intestinal permeability, and therefore indirectly alleviate systemic inflammation. β-blockers shorten the electrocardiographic prolonged QTc interval and may also decrease the incidence of hepatocellular carcinoma. On the other hand, the possibility of deleterious effects in cirrhosis has not been completely eliminated. NSBBs may be associated with an increased risk of portal vein thrombosis, although this could be correlational artifact. Overall, we conclude that β-blockers in cirrhosis are much more of a friend than enemy.

참고문헌 (77)

  1. Lebrec D, "Propranolol--a medical treatment for portal hypertension?", Lancet, 2, pp.180~182 (1980)
  2. Hillon P, "Comparison of the effects of a cardioselective and a nonselective beta-blocker on portal hypertension in patients with cirrhosis", Hepatology, 2, pp.528~531 (1982)
  3. 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, 63, pp.743~752 (2015)
  4. Lebrec D, "Drug therapy for portal hypertension", Gut, 49, pp.441~442 (2001)
  5. Jakab SS, "Evaluation and management of esophageal and gastric varices in patients with cirrhosis", Clin Liver Dis, 24, pp.335~350 (2020)
  6. The Korean Association for the Study of the Liver, "KASL clinical practice guidelines for liver cirrhosis: Varices, hepatic encephalopathy, and related complications", Clinical and Molecular Hepatology, 26(2), pp.83~127 (2020), 대한간학회[DOI]
  7. Brunner F, "Prevention and treatment of variceal haemorrhage in 2017", Liver Int (2017)
  8. Kim MY, "Hemodynamic alterations in cirrhosis and portal hypertension", Korean J Hepatol, 16, pp.347~352 (2010)
  9. Sersté T, "Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites", Hepatology, 52, pp.1017~1022 (2010)
  10. Sersté T, "The use of beta-blockers is associated with the occurrence of acute kidney injury in severe alcoholic hepatitis", Liver Int, 35, pp.1974~1982 (2015)
  11. Qi XS, "Nonselective β-blockers may induce development of portal vein thrombosis in cirrhosis", World J Gastroenterol, 20, pp.11463~11466 (2014)
  12. Mookerjee RP, "All beta-blockers are created equal, but some beta-blockers are more equal than others", Liver Int, 33, pp.501~503 (2013)
  13. Poynard T, "Betaadrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-italian multicenter study group", N Engl J Med, 324, pp.1532~1538 (1991)
  14. 신종범, "Acute-on-chronic liver failure as a major predictive factor for mortality in patients with variceal bleeding", Clinical and Molecular Hepatology, 26(4), pp.540~553 (2020), 대한간학회[DOI]
  15. Kumar M, "Treatment with carvedilol improves survival of patients with acute‑on‑chronic liver failure : a randomized controlled trial", Hepatol Int, 13, pp.800~813 (2019)
  16. Reiberger T, "Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis", J Hepatol, 58, pp.911~921 (2013)
  17. Moreau R, "Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis", Gastroenterology, 144, pp.1426~1437 (2013)
  18. Jalan R, "Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure", J Hepatol, 61, pp.1038~1047 (2014)
  19. Cazzaniga M, "The systemic inflammatory response syndrome in cirrhotic patients : relationship with their in-hospital outcome", J Hepatol, 51, pp.475~482 (2009)
  20. Albillos A, "Cirrhosis-associated immune dysfunction : distinctive features and clinical relevance", J Hepatol, 61, pp.1385~1396 (2014)
  21. Seo YS, "The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension", Clin Mol Hepatol, 18, pp.337~346 (2012)
  22. Madsen BS, "Targeting the gut-liver axis in cirrhosis : antibiotics and non-selective β-blockers", Adv Ther, 30, pp.659~670 (2013)
  23. Pérez-Paramo M, "Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites", Hepatology, 31, pp.43~48 (2000)
  24. Yoon KT, "Cirrhotic cardiomyopathy", Curr Gastroenterol Rep, 22, pp.45~ (2020)
  25. Moctezuma-Velazquez C, "Beta-blockers in patients with advanced liver disease : has the dust settled?", Liver Transpl, 23, pp.1058~1069 (2017)
  26. Mookerjee RP, "Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure", J Hepatol, 64, pp.574~582 (2016)
  27. Zambruni A, "QT interval correction in patients with cirrhosis", J Cardiovasc Electrophysiol, 18, pp.77~82 (2007)
  28. Tsiompanidis E, "Liver cirrhosis-effect on QT interval and cardiac autonomic nervous system activity", World J Gastrointest Pathophysiol, 9, pp.28~36 (2018)
  29. Santeusanio AD, "The impact of cirrhosis and prescription medications on QTc interval before and after liver transplantation", J Pharm Pract, 32, pp.48~53 (2019)
  30. Bernardi M, "Q-T interval prolongation in cirrhosis : prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors", Hepatology, 27, pp.28~34 (1998)
  31. Kim SM, "QT prolongation is associated with increased mortality in end stage liver disease", World J Cardiol, 9, pp.347~354 (2017)
  32. Peter G, "QT interval prolongation : a risk factor for development of hepatorenal syndrome in cirrhotic patients with acute variceal bleeding", Trop Gastroenterol, 35, pp.157~163 (2014)
  33. Henriksen JH, "Acute non-selective beta-adrenergic blockade reduces prolonged frequency-adjusted Q-T interval(QTc)in patients with cirrhosis", J Hepatol, 40, pp.239~246 (2004)
  34. Zambruni A, "Effect of chronic beta-blockade on QT interval in patients with liver cirrhosis", J Hepatol, 48, pp.415~421 (2008)
  35. Ripoll C, "Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis", J Hepatol, 50, pp.923~928 (2009)
  36. Al-Wadei HA, "Prevention of pancreatic cancer by the beta-blocker propranolol", Anticancer Drugs, 20, pp.477~482 (2009)
  37. Liao X, "The β-adrenoceptor antagonist, propranolol, induces human gastric cancer cell apoptosis and cell cycle arrest via inhibiting nuclear factor κB signaling", Oncol Rep, 24, pp.1669~1676 (2010)
  38. Powe DG, "Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival", Oncotarget, 1, pp.628~638 (2010)
  39. Thiele M, "Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?", Med Hypotheses, 81, pp.871~874 (2013)
  40. Chim H, "Propranolol induces regression of hemangioma cells through HIF-1α-mediated inhibition of VEGF-A", Ann Surg, 256, pp.146~156 (2012)
  41. Herrera I, "The use of β-blockers is associated with a lower risk of developing hepatocellular carcinoma in patients with cirrhosis", Eur J Gastroenterol Hepatol, 28, pp.1194~1197 (2016)
  42. Thiele M, "Nonselective beta-blockers may reduce risk of hepatocellular carcinoma : a meta-analysis of randomized trials", Liver Int, 35, pp.2009~2016 (2015)
  43. Xu X, "Nonselective beta-blockers and development of portal vein thrombosis in liver cirrhosis : a systematic review and meta-analysis", Hepatol Int, 13, pp.468~481 (2019)
  44. Kirnake V, "Hemodynamic response to carvedilol is maintained for long periods and leads to better clinical outcome in cirrhosis : a prospective study", J Clin Exp Hepatol, 6, pp.175~185 (2016)
  45. Sinha R, "Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites", J Hepatol, 67, pp.40~46 (2017)
  46. Bossen L, "Nonselective β-blockers do not affect mortality in cirrhosis patients with ascites : post hoc analysis of three randomized controlled trials with 1198patients", Hepatology, 63, pp.1968~1976 (2016)
  47. de Souza AR, "Prognosis of acute variceal bleeding : is being on betablockers an aggravating factor? A short-term survival analysis", Hepatology, 62, pp.1840~1846 (2015)
  48. Sersté T, "Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites : a cross-over study", J Hepatol, 55, pp.794~799 (2011)
  49. Maharaj S, "Severe carvedilol toxicity without overdose-caution in cirrhosis", Clin Hypertens, 23, pp.25~ (2017)
  50. Chirapongsathorn S, "Nonselective β-blockers and survival in patients with cirrhosis and ascites : a systematic review and metaanalysis", Clin Gastroenterol Hepatol, 14, pp.1096~1104.e9 (2016)
  51. Wong RJ, "Assessing the safety of beta-blocker therapy in cirrhosis patients with ascites : a meta-analysis", Liver Int, 39, pp.1080~1088 (2019)
  52. Villanueva C, "β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension(PREDESCI) : a randomised, double-blind, placebo-controlled, multicentre trial", Lancet, 393, pp.1597~1608 (2019)
  53. Mandorfer M, "Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis", Gastroenterology, 146, pp.1680~1690.e1 (2014)
  54. Kim SG, "Beneficial and harmful effects of nonselective beta blockade on acute kidney injury in liver transplant candidates", Liver Transpl, 23, pp.733~740 (2017)
  55. Scheiner B, "Non-selective beta-blocker treatment does not impact on kidney function in cirrhotic patients with varices", Scand J Gastroenterol, 52, pp.1008~1015 (2017)
  56. Ngwa T, "Non-selective beta blocker use is associated with improved short-term survival in patients with cirrhosis referred for liver transplantation", BMC Gastroenterol, 20, pp.4~ (2020)
  57. Ferrarese A, "Hemodynamic evaluation of nonselective β-blockers in patients with cirrhosis and refractory ascites", Gastroenterol Res Pract, 2018, pp.4098210~ (2018)
  58. Krag A, "The window hypothesis : haemodynamic and non-haemodynamic effects of β-blockers improve survival of patients with cirrhosis during a window in the disease", Gut, 61, pp.967~969 (2012)
  59. D’Amico G, "Natural history and prognostic indicators of survival in cirrhosis : a systematic review of 118 studies", J Hepatol, 44, pp.217~231 (2006)
  60. Garcia-Tsao G, "Beta blockers in cirrhosis : the window re-opens", J Hepatol, 64, pp.532~534 (2016)
  61. Leithead JA, "Non-selective β-blockers are associated with improved survival in patients with ascites listed for liver transplantation", Gut, 64, pp.1111~1119 (2015)
  62. Kim SG, "A randomized, multi-center, open-label study to evaluate the efficacy of carvedilol vs. propranolol to reduce portal pressure in patients with liver cirrhosis", Am J Gastroenterol, 111, pp.1582~1590 (2016)
  63. Tripathi D, "Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension", Aliment Pharmacol Ther, 16, pp.373~380 (2002)
  64. Sinagra E, "Systematic review with meta-analysis : the haemodynamic effects of carvedilol compared with propranolol for portal hypertension in cirrhosis", Aliment Pharmacol Ther, 39, pp.557~568 (2014)
  65. European Association for the Study of the Liver, "EASL clinical practice guidelines for the management of patients with decompensated cirrhosis", J Hepatol, 69, pp.406~460 (2018)
  66. Garcia-Tsao G, "Portal hypertensive bleeding in cirrhosis : risk stratification, diagnosis, and management : 2016 practice guidance by the american association for the study of liver diseases", Hepatology, 65, pp.310~335 (2017)
  67. Tripathi D, "Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed", Hepatology, 50, pp.825~833 (2009)
  68. Zacharias AP, "Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices", Cochrane Database Syst Rev, 10, pp.CD011510~ (2018)
  69. Sharma M, "Comparison of therapies for primary prevention of esophageal variceal bleeding : a systematic review and network meta-analysis", Hepatology, 69, pp.1657~1675 (2019)
  70. Tripathi D, "Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis(CALIBRE trial)", BMJ Open Gastroenterol, 6, pp.e000290~ (2019)
  71. Premkumar M, "Carvedilol combined with ivabradine improves left ventricular diastolic dysfunction, clinical progression, and survival in cirrhosis", J Clin Gastroenterol, 54, pp.561~568 (2020)
  72. Thorup L, "Ivabradine : current and future treatment of heart failure", Basic Clin Pharmacol Toxicol, 121, pp.89~97 (2017)
  73. de Souza AR, "Patients whose first episode of bleeding occurs while taking a β-blocker have high long-term risks of rebleeding and death", Clin Gastroenterol Hepatol, 10, pp.670~676 (2012)
  74. Kalambokis GN, "Propranolol use beyond 6 months increases mortality in patients with Child-Pugh C cirrhosis and ascites", Hepatology, 64, pp.1806~1808 (2016)
  75. Sarin SK, "Early primary prophylaxis with beta-blockers does not prevent the growth of small esophageal varices in cirrhosis : a randomized controlled trial", Hepatol Int, 7, pp.248~256 (2013)
  76. Bhutta AQ, "Beta-blockers in hospitalised patients with cirrhosis and ascites : mortality and factors determining discontinuation and reinitiation", Aliment Pharmacol Ther, 47, pp.78~85 (2018)
  77. Onali S, "Non-selective beta-blockers are not associated with increased mortality in cirrhotic patients with ascites", Liver Int, 37, pp.1334~1344 (2017)

관련 논문AI추천

Is there any vindication for low dose nonselective β-blocker medication in patients with liver cirrhosis?김병익, 김홍주, 박동일, 박정호, 손정일, 전우규, 조용균, Chang Uk Chon, Hyun Sun Won, Tae Wan Kim대한간학회 · Clinical and Molecular Hepatology2012 · 제18권 제2호Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patientsAnoop Saraya, Chan Yiong Huak, Chen Zhaojin, Elisabetta Degasperi, Guilia Tosetti, Li Jia, Liu Chuan, Massimo Primignani, Qi Xiaolong, Samagra Agarwal, Sanchit Sharma, Yu Jun Wong대한간학회 · Clinical and Molecular Hepatology2023 · 제29권 제1호Liver volume index predicts the risk of esophageal variceal hemorrhage in cirrhotic patients on propranolol prophylaxis김나영, 김범희, 김진욱, 이충섭, 장은선, 정숙향, 정정화대한내과학회 · The Korean Journal of Internal Medicine2019 · 제34권 제6호Rifaximin and Propranolol Combination Therapy Is More Effective than Propranolol Monotherapy for the Reduction of Portal Pressure: An Open Randomized Controlled Pilot Study권상옥, 김문영, 백순구, 임유리, 장윤옥거트앤리버 소화기연관학회협의회 · Gut and Liver2017 · 제11권 제5호The comparison of esophageal variceal ligation plus propranolol versus propranolol alone for the primary prophylaxis of esophageal variceal bleedi고광철, 곽금연, 백승운, 백용한, 유병철, 이준혁, 제동모, 최문석대한간학회 · Clinical and Molecular Hepatology2014 · 제20권 제3호Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension강혜원, 권상옥, 김문영, 김영주, 김재현, 김정민, 김현식, 김현아, 나지훈, 백순구, 조윤주, 차승환대한간학회 · Clinical and Molecular Hepatology2014 · 제20권 제4호

이 간행물의 다른 논문 (13건)

KASL clinical practice guidelines: Management of nonalcoholic fatty liver diseaseDo Seon Song, 이혜원, 조유리, 정수진, 고홍, 김승업, Won Kim, Jeong-Ju Yoo, Tae Hee Lee, 최준일, Sang Bong Ahn, Soung Won Jeong, Sang Gyune Kim, Haeryoung Kim, Dae Won Jun, Byoung Kuk Jang, Yong Kyun Cho, The Korean Association for the Study of the Liver (KASL), 김문영, 강성희, Jin Woo Leepp. 363-401Entecavir versus tenofovir in patients with chronic hepatitis B: Enemies or partners in the prevention of hepatocellular carcinoma김승업, Sung Won Lee, Jonggi Choi, Young-Suk Limpp. 402-412Anti-fibrotic treatments for chronic liver diseases: The present and the futureNaoshi Odagiri, Norifumi Kawada, Misako Sato-Matsubara, Tsutomu Matsubara, Masaru Enomoto, Hideki Fujiipp. 413-424Changes in the epidemiology and management of bacterial infections in cirrhosisMarta Tonon, Salvatore Piano, Paolo Angelipp. 437-445An analysis of polygenic risk scores for non-alcoholic fatty liver diseaseDae Won Junpp. 446-447
원문 보기