Medikamentöse Therapie der portalen Hypertension

Abstract

In western industrialized nations, liver cirrhosis is the most common cause of portal hypertension. Portal hypertension is defined by a persistent increase in portal pressure >7mmHg. An HVPG >10mmHg defines the presence of clinically significant portal hypertension. The presence of clinically significant portal hypertension (CSPH) in patients with liver cirrhosis is a key risk factor for the transition from a compensated to a decompensated stage of the disease. CPSH can be determined invasively by measuring HPVG or noninvasively by measuring liver stiffness, platelet count and spleen stiffness. If acute decompensation manifests itself (e.g. ascites, esophageal variceal bleeding), this is associated with a significant increase in patient morbidity and mortality. Non-selective beta blockers (NSBB) are the standard medical therapy for portal hypertension in the presence of CSPH. Due to the additional α1-antiadrenergic effects, carvedilol leads to a greater reduction in portal pressure compared to traditional NSBB (e.g. Propanolol). In patients with compensated liver cirrhosis, carvedilol is better than traditional NSBB at reducing the risk of variceal bleeding and the occurrence of hepatic decompensation. The early identification of CSPH and evaluation of drug therapy to reduce portal hypertension is therefore crucial to improve the prognosis of patients.

Das Vorliegen einer klinisch signifikanten portalen Hypertension (CSPH) bei Patienten mit Leberzirrhose ist ein Risikofaktor für den Übergang eines kompensierten in ein dekompensiertes Krankheitsstadium. Manifestiert sich eine akute Dekompensation, ist dies mit einer deutlichen Zunahme der Morbidität und Mortalität verbunden. Die frühzeitige Identifikation einer CSPH und Evaluation einer medikamentösen Therapie zur Senkung der portalen Hypertension ist entscheidend für die Prognose.

Kernaussagen

• In westlichen Industrienationen ist die Leberzirrhose die häufigste Ursache der portalen Hypertension.

• Ein HVPG >10mmHg definiert das Vorliegen einer klinisch signifikanten portalen Hypertension.

• Eine CPSH kann invasiv durch eine Messung des HVPG oder nicht invasiv durch eine Bestimmung der Lebersteifigkeit, Thrombozytenzahl und Milzsteifigkeit bestimmt werden.

• Nicht selektive Betablocker (NSBB) stellen die medikamentöse Standardtherapie der portalen Hypertension bei Vorliegen einer CSPH dar.

• Carvedilol führt aufgrund der zusätzlich α1-antiadrenergen Effekte im Vergleich zu traditionellen NSBB (z.B. Propanolol) zu einer höheren Senkung des portalen Drucks.

• Bei Patienten mit einer kompensierten Leberzirrhose reduziert Carvedilol besser als traditionelle NSBB das Risiko einer Varizenblutung sowie das Auftreten einer hepatischen Dekompensation.

Schlüsselwörter

Leberzirrhose - Dekompensation - Portale Hypertension - Carvedilol - Nicht-selektive Beta-Blocker

Keywords

liver cirrhosis - hepatic decompensation - portal hypertension - Carvedilol - non-selective beta-blockers

Publication History

Received: 15 October 2023

Accepted after revision: 18 December 2023

Article published online:
13 March 2024

• Literatur

• 1 D’Amico G, Pasta L, Morabito A. et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther 2014; 39: 1180-1193 DOI: 10.1111/apt.12721. (PMID: 24654740)
• 2 Ripoll C, Groszmann R, Garcia-Tsao G. et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007; 133: 481-488 DOI: 10.1053/j.gastro.2007.05.024.
• 3 de Franchis R, Bosch J, Garcia-Tsao G. et al. Baveno VII – Renewing consensus in portal hypertension. J Hepatol 2022; 76: 959-974 DOI: 10.1016/j.jhep.2021.12.022. (PMID: 35120736)
• 4 Bosch J, Groszmann RJ, Shah VH. Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments. J Hepatol 2015; 62: S121-130 DOI: 10.1016/j.jhep.2015.01.003. (PMID: 25920081)
• 5 Engelmann C, Claria J, Szabo G. et al. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021; 75: S49-S66 DOI: 10.1016/j.jhep.2021.01.002. (PMID: 34039492)
• 6 Sturm L, Reincke M, Bettinger D. Current pathophysiological concepts of acute decompensation in patients with liver cirrhosis and prognostic scores in different stages of disease. Dtsch Med Wochenschr 2022; 147: 662-669 DOI: 10.1055/a-1671-9114. (PMID: 35636416)
• 7 Costa D, Simbrunner B, Jachs M. et al. Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality. J Hepatol 2021; 74: 819-828 DOI: 10.1016/j.jhep.2020.10.004.
• 8 Bochnakova T. Hepatic Venous Pressure Gradient. Clin Liver Dis (Hoboken) 2021; 17: 144-148 DOI: 10.1002/cld.1031. (PMID: 33868655)
• 9 Baffy G, Bosch J. Overlooked subclinical portal hypertension in non-cirrhotic NAFLD: Is it real and how to measure it?. J Hepatol 2022; 76: 458-463 DOI: 10.1016/j.jhep.2021.09.029. (PMID: 34606912)
• 10 Ferrusquia-Acosta J, Bassegoda O, Turco L. et al. Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis. J Hepatol 2021; 74: 811-818 DOI: 10.1016/j.jhep.2020.10.003.
• 11 Miao L TG, Byrne C. D., Valenti L, Qi X, Zhen M-H. Portal hypertension in nonalcoholic fatty liver disease: Challenges and perspectives. Port Hypertens Cirrhos 2022; 1: 57-65 DOI: 10.1002/poh2.8.
• 12 Nababan SHH, Lesmana CRA. Portal Hypertension in Nonalcoholic Fatty Liver Disease: From Pathogenesis to Clinical Practice. J Clin Transl Hepatol 2022; 10: 979-985 DOI: 10.14218/JCTH.2021.00593. (PMID: 36304507)
• 13 Kaplan DE, Bosch J, Ripoll C. et al. AASLD practice guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology 2023; DOI: 10.1097/HEP.0000000000000647. (PMID: 37870298)
• 14 Dajti E, Ravaioli F, Marasco G. et al. A Combined Baveno VII and Spleen Stiffness Algorithm to Improve the Noninvasive Diagnosis of Clinically Significant Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease. Am J Gastroenterol 2022; 117: 1825-1833 DOI: 10.14309/ajg.0000000000001887.
• 15 Jachs M, Hartl L, Simbrunner B. et al. The Sequential Application of Baveno VII Criteria and VITRO Score Improves Diagnosis of Clinically Significant Portal Hypertension. Clin Gastroenterol Hepatol 2023; 21: 1854-1863 e1810 DOI: 10.1016/j.cgh.2022.09.032. (PMID: 36244661)
• 16 Reiberger T, Ulbrich G, Ferlitsch A. et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013; 62: 1634-1641 DOI: 10.1136/gutjnl-2012-304038.
• 17 Turco L, Reiberger T, Vitale G. et al. Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension. Liver Int 2023; 43: 1183-1194 DOI: 10.1111/liv.15559.
• 18 Villanueva C, Albillos A, Genesca J. et al. beta blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2019; 393: 1597-1608 DOI: 10.1016/S0140-6736(18)31875-0.
• 19 Villanueva C, Torres F, Sarin SK. et al. Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis. J Hepatol 2022; 77: 1014-1025 DOI: 10.1016/j.jhep.2022.05.021.
• 20 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: 406-460 DOI: 10.1016/j.jhep.2018.03.024.
• 21 Arora V, Choudhary SP, Maiwall R. et al. Low-dose continuous terlipressin infusion is effective and safer than intravenous bolus injections in reducing portal pressure and control of acute variceal bleeding. Hepatol Int 2023; 17: 131-138 DOI: 10.1007/s12072-022-10416-6.
• 22 Gillespie SL, Hanrahan TP, Rockey DC. et al. Review article: controversies surrounding the use of carvedilol and other beta blockers in the management of portal hypertension and cirrhosis. Aliment Pharmacol Ther 2023; 57: 454-463 DOI: 10.1111/apt.17380. (PMID: 36691947)
• 23 Nicoara-Farcau O, Han G, Rudler M. et al. Effects of Early Placement of Transjugular Portosystemic Shunts in Patients With High-Risk Acute Variceal Bleeding: a Meta-analysis of Individual Patient Data. Gastroenterology 2021; 160: 193-205 e110 DOI: 10.1053/j.gastro.2020.09.026.
• 24 Praktiknjo M, Götz M, Trebicka J. Management variköser Blutungen. Die Gastroenterologie 2022; 17: 268-277 DOI: 10.1007/s11377-022-00618-7.
• 25 Jachs M, Hartl L, Simbrunner B. et al. Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis. Clin Gastroenterol Hepatol 2023; 21: 2318-2326 e2317 DOI: 10.1016/j.cgh.2022.06.007.
• 26 Paternostro R, Jachs M, Hartl L. et al. Diabetes impairs the haemodynamic response to non-selective betablockers in compensated cirrhosis and predisposes to hepatic decompensation. Aliment Pharmacol Ther 2023; 58: 805-813 DOI: 10.1111/apt.17653. (PMID: 37519146)
• 27 Albillos A, Krag A. Beta-blockers in the era of precision medicine in patients with cirrhosis. J Hepatol 2023; 78: 866-872 DOI: 10.1016/j.jhep.2022.12.005. (PMID: 36529293)
• 28 Kim HY, So YH, Kim W. et al. Non-invasive response prediction in prophylactic carvedilol therapy for cirrhotic patients with esophageal varices. J Hepatol 2019; 70: 412-422 DOI: 10.1016/j.jhep.2018.10.018.
• 29 Marasco G, Dajti E, Ravaioli F. et al. Spleen stiffness measurement for assessing the response to beta-blockers therapy for high-risk esophageal varices patients. Hepatol Int 2020; 14: 850-857 DOI: 10.1007/s12072-020-10062-w. (PMID: 32557193)
• 30 Danielsen KV, Hove JD, Nabilou P. et al. Using MR elastography to assess portal hypertension and response to beta-blockers in patients with cirrhosis. Liver Int 2021; 41: 2149-2158 DOI: 10.1111/liv.14981.
• 31 Nicoara-Farcau O, Lozano JJ, Alonso C. et al. Metabolomics as a tool to predict the risk of decompensation or liver-related death in patients with compensated cirrhosis. Hepatology 2023; 77: 2052-2062 DOI: 10.1097/HEP.0000000000000316. (PMID: 36934740)
• 32 Reverter E, Lozano JJ, Alonso C. et al. Metabolomics discloses potential biomarkers to predict the acute HVPG response to propranolol in patients with cirrhosis. Liver Int 2019; 39: 705-713 DOI: 10.1111/liv.14042.
• 33 Abraldes JG, Albillos A, Banares R. et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009; 136: 1651-1658 DOI: 10.1053/j.gastro.2009.01.043.
• 34 Cerini F, Vilaseca M, Lafoz E. et al. Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2016; 64: 834-842 DOI: 10.1016/j.jhep.2015.12.003. (PMID: 26686269)
• 35 Vilaseca M, Garcia-Caldero H, Lafoz E. et al. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017; 65: 2031-2044 DOI: 10.1002/hep.29084.
• 36 Villa E, Camma C, Marietta M. et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143: 1253-1260 e1254 DOI: 10.1053/j.gastro.2012.07.018.
• 37 Schwabl P, Hambruch E, Seeland BA. et al. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 2017; 66: 724-733 DOI: 10.1016/j.jhep.2016.12.005. (PMID: 27993716)
• 38 Mookerjee R RM, Pieri G, Beecher-Jones T. et al. Effects of the FXR agonist obeticholic acid on hepatic venous pressure gradient (HVPG) in alcoholic cirrhosis: a proof of concept phase 2A study. J Hepatol 2014; 60 (Suppl. 01) S7-S8 DOI: 10.1016/S0168-8278(14)60017-9.
• 39 John BV, Schwartz K, Levy C. et al. Impact of Obeticholic acid Exposure on Decompensation and Mortality in Primary Biliary Cholangitis and Cirrhosis. Hepatol Commun 2021; 5: 1426-1436 DOI: 10.1002/hep4.1720. (PMID: 34430786)
• 40 de Mesquita FC, Guixe-Muntet S, Fernandez-Iglesias A. et al. Liraglutide improves liver microvascular dysfunction in cirrhosis: Evidence from translational studies. Sci Rep 2017; 7: 3255 DOI: 10.1038/s41598-017-02866-y.