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Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?
Medical Hypotheses 81 (2013) 871–874
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis? Maja Thiele a,⇑,1, Reiner Wiest b, Lise Lotte Gluud c, Agustín Albillos d, Aleksander Krag a a
Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark University Hospital and Department of Visceral Surgery and Medicine, UVCM, Inselspital, Bern, Switzerland c Department of Medicine, Copenhagen University Hospital Gentofte, Hellerup, Denmark d Department of Gastroenterology and Hepatology, University Hospital Ramón y Cajal, University of Alcalá, IRYCIS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institute of Health Carlos III, Madrid, Spain b
a r t i c l e
i n f o
Article history: Received 17 June 2013 Accepted 23 August 2013
a b s t r a c t Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of b-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of b-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The metaanalytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Hepatocellular carcinoma (HCC) is the main liver-related cause of death in patients with compensated cirrhosis [1]. Seven-hundred thousand people die annually from HCC making it the third most common cause of cancer-related death worldwide [2]. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. Abbreviations: b-AR, beta-adrenoceptors; BT, bacterial translocation; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HVPG, hepatic venous pressure gradient; LPS, lipopolysaccharide; NSBB, non-selective beta-blockers; PAMP, pathogen-associated molecular pattern; TIPS, transjugular intrahepatic portosystemic shunt; TLR4, Toll Like Receptor 4; VEGF, vascular endothelial growth factor. ⇑ Corresponding author. Address: Department of Gastroenterology and Hepatology, Odense University Hospital, Sdr. Boulevard 29, Entrance 128, DK-5000 Odense C, Denmark. Tel.: +45 6541 2755. E-mail address: [email protected] (M. Thiele). 1 Support: M. Thiele is supported by a working grant from University of Southern Denmark. 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.08.026
Non-selective beta-blockers (NSBB) are recommended as prevention for variceal bleeding in patients with cirrhosis. A recent meta-analysis showed that NSBB decrease mortality in patients with cirrhosis beyond what can be explained by a reduced rate of gastrointestinal bleeding [3,4]. NSBB can in theory decrease the incidence of HCC, which could partly explain the findings in the meta-analysis. NSBB exhibit hemodynamic and non-hemodynamic effects [3,5]. The main non-hemodynamic effects consist of decreased bacterial translocation (BT) and a reduced portal load of proinflammatory bacterial products [6,7]. NSBB may also reduce intrahepatic inflammation, but results of individual studies are ambiguous. The anti-angiogenic effects of NSBB are well known and used in the treatment of hemangiomas [8,9]. The preventive effect of NSBB in cancer formation and growth has been tested in clinical studies on ovarian and breast cancer with promising results [10–13]. As gut-derived inflammation and angiogenesis are important factors in liver carcinogenesis [1,14], we hypothesize that NSBB
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M. Thiele et al. / Medical Hypotheses 81 (2013) 871–874
have the potential to decrease the HCC incidence and HCC growth in patients with cirrhosis (Fig. 1). The hypothesis NSBB antagonize b1- and b2-adrenoceptors (b-ARs), which are present in a variety of tissue such as hepatic cells, gut-associated lymphatic tissue, intestinal mucosa, blood vessels, and smooth muscle cells. The b-ARs main ligands are the catecholamines norepinephrine and epinephrine, which are neurotransmitters of the sympathetic nervous system. Catecholamines exhibit pro-carcinogenic effects [15] and NSBB antagonize catecholamine driven cell migration, tumor angiogenesis, invasiveness and proliferation in gastric, breast and pancreatic cancer [12,16,17]. The result is cancer cell apoptosis and reduced growth. Patients with cirrhosis exhibit increased levels of catecholamines with increasing severity of liver disease [18]. NSBB may therefore be especially potent for the inhibition of carcinogenesis in cirrhosis. Expression of b2-ARs are increased on HCC cell membranes compared to healthy liver cells [19].The role of this remains unclear. It is more probable that NSBB exert anticarcinogenic effects via indirect mechanisms on extrahepatic and intrahepatic b1- and b2-ARs. NSBB would therefore in theory be more beneficial than selective beta-blockers. In the following, we discuss different molecular mechanisms by which NSBB can potentially reduce HCC by preventing carcinogenesis, delaying growth and improving outcomes. Preventing HCC by reducing gut-derived inflammation Inflammatory processes are key drivers of malignant transformation in hepatocytes [20–22]. As BT constitutes the main inflammatory load to the cirrhotic liver, it is a potential target for HCC prevention [23]. The evidence on NSBB and HCC is indirect: NSBB decrease BT and gut-derived inflammation, which promote HCC development and growth. Increased BT in cirrhosis is promoted by increased intestinal permeability, bacterial overgrowth, changes in gut microbiome and impaired host immunity. By blocking the effect of norepinephrine on b-ARs in the gut, NSBB have beneficial effects on the above mentioned parameters: Intestinal permeability is decreased in both hemodynamic responders and non-responders although the mechanism is still unknown [24]. Bacterial overgrowth is decreased by an acceleration of transit time and via modulation of iron acquisition [6,25]. Alterations in gut microbiome consists of reduced growth and adherence of Eschericia coli and other gram negative rods [25–27]. Improved immunologic barrier function
includes chemotaxis and phagocytosis [28–30]. As a result of reduced BT, NSBB lower the portal concentration of the bacterial products pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) [6,24]. Whether intrahepatic b-antagonism can reduce intrahepatic inflammation is debated. Increased levels of proinflammatory cytokines activate intrahepatic b1-ARs by norepinephrine. Adding NSBB do not modulate the result [31]. The interpretation of the results is complicated by the fact that catecholamines in the liver exert different effects depending on target cells, degree of sympathetic nervous system tone, sympathetic subtypes of a- and b-receptors, and receptor-affinity, -density and -stimulation [32–35]. The sympathetic nervous system has direct effects on hepatocytes, Kupffer cells and hepatic stellate cells increasing fibrosis. This may contribute to an intrahepatic preventive effect of NSBB on HCC [36]. In two studies on rodents [23,37], intestinal decontamination lead to reduced HCC tumor size and rate of metastasis. The effect was explained by a decrease in the portal concentration of PAMPs and concurrent downregulation of Toll Like Receptor 4 (TLR4). The same effect was seen in knock out mice without expression of TLR4. Gut-derived PAMPs and TLR4 activation lead to Kupfferand hepatic stellate cell activation and subsequent release of the proinflammatory cytokines Tumor Necrosis Factor-a and interleukine-6 [21,31]. The proinflammatory cytokines increase HCC thermotolerance and may thereby negatively impact treatment with radiofrequency ablation [38]. Levels of LPS are correlated to HCC development, whereas restoration of gut homeostasis (by decreasing the number of gram negative rods) reduces the LPS load to the portal vein [39]. Delaying HCC growth by blocking angiogenesis NSBB lead to regression of infantile hemangiomas through inhibitory effects on angiogenesis, one of which is downregulation of vascular endothelial growth factor (VEGF) [8,40]. The only approved therapy for advanced HCC (Sorafenib) is a multikinase inhibitor targeting pro-angiogenic factors including VEGF and NSBB could potentially exhibit similar effects, albeit less potent. In gastric cancer, NSBB reduce VEGF activity by decreasing the levels of nuclear factor-jb [16]. There is no direct evidence indicating that NSBB reduce HCC tumor growth by decreasing angiogenesis. How the hypothesis differs from current thinking Currently, NSBB are used for prevention of variceal bleeding in patients with high-risk varices. It is debated whether the indication for NSBB can be expanded to other patient groups, but this debate
Fig. 1. Proposed pathways by which non-selective beta-blockers may decrease incidence of hepatocellular carcinoma.
M. Thiele et al. / Medical Hypotheses 81 (2013) 871–874
does not yet include a potential preventive effect on HCC. NSBB reduce the risk of spontaneous bacterial peritonitis [5] and ascitic decompensation [41], but have detrimental effects in patients with refractory ascites [42,43]. Testing the hypothesis The hypothesis needs to be verified by clinical evidence. Only two retrospective cohort studies on NSBB have addressed the effect on HCC incidence [44,45]. One assessed 291 patients with compensated hepatitis C virus related cirrhosis [45]. Fifty patients received propranolol during a mean follow up period of 54 months. Propranolol decreased HCC incidence compared with untreated patients. The second study assessed low dose NSBB in 138 treated and 135 untreated patients with cirrhosis of mixed etiologies and severity [44]. The mean duration of follow up was 45 months. There was no effect of NSBB on HCC incidence or HCC-related mortality. The opposing results of the two studies can be explained by differences in study design, NSBB dose, disease severity and a higher a priori HCC risk in chronic hepatitis C patients. In addition, the risk of detection and attrition bias is high in retrospective studies. The best way to test our hypothesis would be a long-term randomized trial of NSBB versus placebo with HCC incidence and HCC related mortality as the primary outcome measures. The feasibility of such a trial is limited by considerable power challenges. Patients with high-risk varices, contraindications to NSBB and prior NSBB treatment would have to be excluded, limiting the number of eligible patients. The number of patients with side effects and refusals to participate is likely to result in dropouts and losses to follow up. The hypothesis could be tested using other study designs with varying levels of evidence. Our group found differences between HCC incidence rate estimates in randomized trials, prospective cohorts and case–control series [46]. Epidemiological studies using cancer registries and drug databases have a risk of detection bias and other biases. Any clinical study would need to consider that the incidence of HCC depends on the etiology ranging from 0.7% to 1.5% and 2.1% to 2.8% per year in precirrhotic and cirrhotic hepatitis B patients to 2.7–4.7% in cirrhotic hepatitis C patients [47] and a lower risk in alcoholic cirrhosis [48,49]. Meta-analyses of randomized trials can be used for valid assessments of treatment effects. A systematic review on NSBB for HCC should include randomized trials on NSBB for patients with cirrhosis an follow-up periods longer than 12 months (in order for new HCCs to develop). Prevalent cases of HCC would need to be excluded for assessment of incidence, but not for the assessment of HCC mortality. The main limitation of a systematic review is the lack of trials reporting HCC incidence, which increases the risk of reporting, detection and ascertainment bias. Discussion Due to beneficial effects on gut-derived inflammation and reduced angiogenesis, NSBB have the potential to reduce HCC incidence and growth, and to improve outcomes. The molecular results have not been translated into clinical evidence and well-designed investigative studies are missing. If this hypothesis holds true, the use of NSBB in chronic liver diseases could be extended beyond prevention of variceal bleeding. NSBB are cheap, widely used and have a favorable safety profile. Further, a dual effect on varices and HCC would reinforce the recommendation of NSBB as first line treatment in the primary prophylaxis of variceal bleeding. The prognosis of patients with cirrhosis has improved within the last decades due to improved treatments. Quality of life and adverse effects of therapy are therefore becoming increasingly important. Potential benefits of NSBB
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should outbalance potential side effects of long-term NSBB, especially in otherwise asymptomatic patients. A number of aspects regarding NSBB and HCC remain to be elucidated. Less than 50% of patients are hemodynamic responders to NSBB. Whether a possible anti-carcinogenic effect of NSBB depends on a hemodynamic response in unknown [50]. The hepatic venous pressure gradient (HVPG) predicts HCC incidence in cirrhosis, irrespective of disease severity [51]. If a reduction in the HVPG results in a decreased HCC incidence, other therapies directed at lowering the HVPG such as transjugular intrahepatic portosystemic shunting (TIPS) could be beneficial. It does however not seem to be the case. TIPS may even have a detrimental effect on HCC incidence [52]. Some drugs such as statins reduce HCC incidence and lowers the HVPG [53,54]. Statins also decrease fibrosis [55], which is one of the mechanisms by which antiviral treatment decrease HCC incidence in chronic viral hepatitis B and C [56]. An antifibrotic effect of NSBB is not established in humans, but animal models suggest that reduced gut-derived inflammation leads to reduced fibrogenesis independently of the HVPG [57]. We hypothesize that the effect of NSBB on HCC is the result of non-hemodynamic effects. Accordingly, NSBB may also prevent HCC in HVPG non-responders. Whether a possible anticarcinogenic effect of NSBB is dosedependent and/or time-dependent and whether polymorphisms of the b-ARs play a role for the anticarcinogenic effect are also areas of interest for future research [58]. Conflict of interest statement The authors have nothing to disclose. Author contribution R. Wiest, L.L. Gluud, A. Albillos and A. Krag developed the hypothesis. M. Thiele and A. Krag obtained the scientific support of the hypothesis. M. Thiele drafted the manuscript. R. Wiest, L.L. Gluud, A. Albillos and A. Krag revised the manuscript for important intellectual content. All authors have approved of the final manuscript. References [1] Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012;379:1245–55. [2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 10.. Lyon, France: International Agency for Research on Cancer; 2010. [3] Krag A, Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic and non-haemodynamic effects of b-blockers improve survival of patients with cirrhosis during a window in the disease. Gut 2012;61:967–9. [4] Krag A, Wiest R, Gluud LL. Reduced mortality with non-selective betablockers compared to banding is not related to prevention of bleeding or bleeding related mortality: systematic review of randomized trials. J Hepatol 2011;54:S72. [5] Senzolo M, Cholongitas E, Burra P, et al. Beta-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009;29:1189–93. [6] Pérez-Paramo M, Muñoz J, Albillos A, et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 2000;31:43–8. [7] Wiest R, Krag A, Gerbes A. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut 2012;61:297–310. [8] Chim H, Armijo BS, Miller E, Gliniak C, Serret MA, Gosain AK. Propranolol induces regression of hemangioma cells through HIF-1alpha-mediated inhibition of VEGF-A. Ann Surg 2012;256:146–56. [9] Phillips CB, Pacha O, Biliciler-Denkta G, Hebert AA. A review of beta antagonist treatment for infantile hemangioma. J Drugs Dermatol 2012;11:826–9. [10] Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324168 participants from randomised trials. Lancet Oncol 2011;12:65–82. [11] Diaz ES, Karlan BY, Li AJ. Impact of beta blockers on epithelial ovarian cancer survival. Gynecol Oncol 2012;127:375–8.
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[36] Hamdy N, El-Demerdash E. New therapeutic aspect for carvedilol: antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage. Toxicol Appl Pharmacol 2012;261:292–9. [37] Yu LX, Yan HX, Liu Q, et al. Endotoxin accumulation prevents carcinogeninduced apoptosis and promotes liver tumorigenesis in rodents. Hepatology 2010;52:1322–33. [38] Yoshida, S, Kornek, M, Ikenaga, N, et al. Sub-lethal heat treatment promotes epithelial–mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma. Hepatology (2013). http://dx.doi.org/10.1002/ hep.26526. [Epub ahead of print]. [39] Zhang HL, Yu LX, Yang W, et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol 2012;57:803–12. [40] Lamy S, Lachambre MP, Lord-Dufour S, Beliveau R. Propranolol suppresses angiogenesis in vitro: inhibition of proliferation, migration, and differentiation of endothelial cells. Vascul Pharmacol 2010;53:200–8. [41] Hernandez-Gea V, Aracil C, Colomo A, et al. Development of ascites in compensated cirrhosis with severe portal hypertension treated with betablockers. Am J Gastroenterol 2012;107:418–27. [42] Serste T, Melot C, Francoz C, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010;52:1017–22. [43] Krag A, Bendtsen F, Moller S. Does cardiac dysfunction explain deleterious effects of beta-blockers in cirrhosis and refractory ascites? Hepatology 2011;53:370–1. [44] Kim TW, Kim HJ, Chon CU, et al. Is there any vindication for low dose nonselective beta-blocker medication in patients with liver cirrhosis? Clin Mol Hepatol 2012;18:203–12. [45] Nkontchou G, Aout M, Mahmoudi A, et al. Effect of long-term propranolol treatment on hepatocellular carcinoma incidence in patients with HCVassociated cirrhosis. Cancer Prev Res 2012;5:1007–14. [46] Thiele, M, Gluud, LL, Dahl, E, Krag, A. Antiviral therapy for prevention of hepatocellular carcinoma and mortality in chronic hepatitis B: systematic review and meta-analysis. BMJ Open 2013;3(8): http://dx.doi.org/10.1136. [47] Thiele M, Gluud LL, Kimer N, Dahl E, Krag A. Incidence of hepatocellular carcinoma in precirrhotic and cirrhotic chronic B and C hepatitis: systematic review with data from 39 trials and 10.231 patients. Hepatology 2012;56:447. abstract 524. [48] Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Risk for hepatocellular carcinoma in patients with alcoholic cirrhosis: a Danish nationwide cohort study. Ann Intern Med 2012;156:841–7. W295. [49] Mancebo A, González-Diéguez ML, Cadahía V, et al. Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups. Clin Gastroenterol Hepatol 2013;11:95–101. [50] Augustin S, González A, Badia L, et al. Long-term follow-up of hemodynamic responders to pharmacological therapy after variceal bleeding. Hepatology 2012;56:706–14. [51] Ripoll C, Groszmann RJ, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol 2009;50:923–8. [52] Bañares R, Núñez O, Escudero M, et al. Patients with cirrhosis and bare-stent TIPS may have increased risk of hepatocellular carcinoma. Hepatology 2005;41:566–71. [53] Abraldes JG, Albillos A, Bañares R, et al. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009;136:1651–8. [54] Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and metaanalysis. Gastroenterology 2013;144:323–32. [55] Trebicka J, Hennenberg M, Odenthal M, et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. J Hepatol 2010;53:702–12. [56] Lok AS. Does antiviral therapy for hepatitis B and C prevent hepatocellular carcinoma? J Gastroenterol Hepatol 2011;26:221–7. [57] Strack I, Schulte S, Varnholt H, et al. Beta-adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis. Lab Invest 2011;91:252–61. [58] Turnes J, Hernández-Guerra M, Abraldes JG, et al. Influence of beta-2 adrenergic receptor gene polymorphism on the hemodynamic response to propranolol in patients with cirrhosis. Hepatology 2006;43:34–41.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis? Maja Thiele a,⇑,1, Reiner Wiest b, Lise Lotte Gluud c, Agustín Albillos d, Aleksander Krag a a
Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark University Hospital and Department of Visceral Surgery and Medicine, UVCM, Inselspital, Bern, Switzerland c Department of Medicine, Copenhagen University Hospital Gentofte, Hellerup, Denmark d Department of Gastroenterology and Hepatology, University Hospital Ramón y Cajal, University of Alcalá, IRYCIS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institute of Health Carlos III, Madrid, Spain b
a r t i c l e
i n f o
Article history: Received 17 June 2013 Accepted 23 August 2013
a b s t r a c t Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of b-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of b-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The metaanalytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Hepatocellular carcinoma (HCC) is the main liver-related cause of death in patients with compensated cirrhosis [1]. Seven-hundred thousand people die annually from HCC making it the third most common cause of cancer-related death worldwide [2]. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. Abbreviations: b-AR, beta-adrenoceptors; BT, bacterial translocation; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HVPG, hepatic venous pressure gradient; LPS, lipopolysaccharide; NSBB, non-selective beta-blockers; PAMP, pathogen-associated molecular pattern; TIPS, transjugular intrahepatic portosystemic shunt; TLR4, Toll Like Receptor 4; VEGF, vascular endothelial growth factor. ⇑ Corresponding author. Address: Department of Gastroenterology and Hepatology, Odense University Hospital, Sdr. Boulevard 29, Entrance 128, DK-5000 Odense C, Denmark. Tel.: +45 6541 2755. E-mail address: [email protected] (M. Thiele). 1 Support: M. Thiele is supported by a working grant from University of Southern Denmark. 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.08.026
Non-selective beta-blockers (NSBB) are recommended as prevention for variceal bleeding in patients with cirrhosis. A recent meta-analysis showed that NSBB decrease mortality in patients with cirrhosis beyond what can be explained by a reduced rate of gastrointestinal bleeding [3,4]. NSBB can in theory decrease the incidence of HCC, which could partly explain the findings in the meta-analysis. NSBB exhibit hemodynamic and non-hemodynamic effects [3,5]. The main non-hemodynamic effects consist of decreased bacterial translocation (BT) and a reduced portal load of proinflammatory bacterial products [6,7]. NSBB may also reduce intrahepatic inflammation, but results of individual studies are ambiguous. The anti-angiogenic effects of NSBB are well known and used in the treatment of hemangiomas [8,9]. The preventive effect of NSBB in cancer formation and growth has been tested in clinical studies on ovarian and breast cancer with promising results [10–13]. As gut-derived inflammation and angiogenesis are important factors in liver carcinogenesis [1,14], we hypothesize that NSBB
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have the potential to decrease the HCC incidence and HCC growth in patients with cirrhosis (Fig. 1). The hypothesis NSBB antagonize b1- and b2-adrenoceptors (b-ARs), which are present in a variety of tissue such as hepatic cells, gut-associated lymphatic tissue, intestinal mucosa, blood vessels, and smooth muscle cells. The b-ARs main ligands are the catecholamines norepinephrine and epinephrine, which are neurotransmitters of the sympathetic nervous system. Catecholamines exhibit pro-carcinogenic effects [15] and NSBB antagonize catecholamine driven cell migration, tumor angiogenesis, invasiveness and proliferation in gastric, breast and pancreatic cancer [12,16,17]. The result is cancer cell apoptosis and reduced growth. Patients with cirrhosis exhibit increased levels of catecholamines with increasing severity of liver disease [18]. NSBB may therefore be especially potent for the inhibition of carcinogenesis in cirrhosis. Expression of b2-ARs are increased on HCC cell membranes compared to healthy liver cells [19].The role of this remains unclear. It is more probable that NSBB exert anticarcinogenic effects via indirect mechanisms on extrahepatic and intrahepatic b1- and b2-ARs. NSBB would therefore in theory be more beneficial than selective beta-blockers. In the following, we discuss different molecular mechanisms by which NSBB can potentially reduce HCC by preventing carcinogenesis, delaying growth and improving outcomes. Preventing HCC by reducing gut-derived inflammation Inflammatory processes are key drivers of malignant transformation in hepatocytes [20–22]. As BT constitutes the main inflammatory load to the cirrhotic liver, it is a potential target for HCC prevention [23]. The evidence on NSBB and HCC is indirect: NSBB decrease BT and gut-derived inflammation, which promote HCC development and growth. Increased BT in cirrhosis is promoted by increased intestinal permeability, bacterial overgrowth, changes in gut microbiome and impaired host immunity. By blocking the effect of norepinephrine on b-ARs in the gut, NSBB have beneficial effects on the above mentioned parameters: Intestinal permeability is decreased in both hemodynamic responders and non-responders although the mechanism is still unknown [24]. Bacterial overgrowth is decreased by an acceleration of transit time and via modulation of iron acquisition [6,25]. Alterations in gut microbiome consists of reduced growth and adherence of Eschericia coli and other gram negative rods [25–27]. Improved immunologic barrier function
includes chemotaxis and phagocytosis [28–30]. As a result of reduced BT, NSBB lower the portal concentration of the bacterial products pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) [6,24]. Whether intrahepatic b-antagonism can reduce intrahepatic inflammation is debated. Increased levels of proinflammatory cytokines activate intrahepatic b1-ARs by norepinephrine. Adding NSBB do not modulate the result [31]. The interpretation of the results is complicated by the fact that catecholamines in the liver exert different effects depending on target cells, degree of sympathetic nervous system tone, sympathetic subtypes of a- and b-receptors, and receptor-affinity, -density and -stimulation [32–35]. The sympathetic nervous system has direct effects on hepatocytes, Kupffer cells and hepatic stellate cells increasing fibrosis. This may contribute to an intrahepatic preventive effect of NSBB on HCC [36]. In two studies on rodents [23,37], intestinal decontamination lead to reduced HCC tumor size and rate of metastasis. The effect was explained by a decrease in the portal concentration of PAMPs and concurrent downregulation of Toll Like Receptor 4 (TLR4). The same effect was seen in knock out mice without expression of TLR4. Gut-derived PAMPs and TLR4 activation lead to Kupfferand hepatic stellate cell activation and subsequent release of the proinflammatory cytokines Tumor Necrosis Factor-a and interleukine-6 [21,31]. The proinflammatory cytokines increase HCC thermotolerance and may thereby negatively impact treatment with radiofrequency ablation [38]. Levels of LPS are correlated to HCC development, whereas restoration of gut homeostasis (by decreasing the number of gram negative rods) reduces the LPS load to the portal vein [39]. Delaying HCC growth by blocking angiogenesis NSBB lead to regression of infantile hemangiomas through inhibitory effects on angiogenesis, one of which is downregulation of vascular endothelial growth factor (VEGF) [8,40]. The only approved therapy for advanced HCC (Sorafenib) is a multikinase inhibitor targeting pro-angiogenic factors including VEGF and NSBB could potentially exhibit similar effects, albeit less potent. In gastric cancer, NSBB reduce VEGF activity by decreasing the levels of nuclear factor-jb [16]. There is no direct evidence indicating that NSBB reduce HCC tumor growth by decreasing angiogenesis. How the hypothesis differs from current thinking Currently, NSBB are used for prevention of variceal bleeding in patients with high-risk varices. It is debated whether the indication for NSBB can be expanded to other patient groups, but this debate
Fig. 1. Proposed pathways by which non-selective beta-blockers may decrease incidence of hepatocellular carcinoma.
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does not yet include a potential preventive effect on HCC. NSBB reduce the risk of spontaneous bacterial peritonitis [5] and ascitic decompensation [41], but have detrimental effects in patients with refractory ascites [42,43]. Testing the hypothesis The hypothesis needs to be verified by clinical evidence. Only two retrospective cohort studies on NSBB have addressed the effect on HCC incidence [44,45]. One assessed 291 patients with compensated hepatitis C virus related cirrhosis [45]. Fifty patients received propranolol during a mean follow up period of 54 months. Propranolol decreased HCC incidence compared with untreated patients. The second study assessed low dose NSBB in 138 treated and 135 untreated patients with cirrhosis of mixed etiologies and severity [44]. The mean duration of follow up was 45 months. There was no effect of NSBB on HCC incidence or HCC-related mortality. The opposing results of the two studies can be explained by differences in study design, NSBB dose, disease severity and a higher a priori HCC risk in chronic hepatitis C patients. In addition, the risk of detection and attrition bias is high in retrospective studies. The best way to test our hypothesis would be a long-term randomized trial of NSBB versus placebo with HCC incidence and HCC related mortality as the primary outcome measures. The feasibility of such a trial is limited by considerable power challenges. Patients with high-risk varices, contraindications to NSBB and prior NSBB treatment would have to be excluded, limiting the number of eligible patients. The number of patients with side effects and refusals to participate is likely to result in dropouts and losses to follow up. The hypothesis could be tested using other study designs with varying levels of evidence. Our group found differences between HCC incidence rate estimates in randomized trials, prospective cohorts and case–control series [46]. Epidemiological studies using cancer registries and drug databases have a risk of detection bias and other biases. Any clinical study would need to consider that the incidence of HCC depends on the etiology ranging from 0.7% to 1.5% and 2.1% to 2.8% per year in precirrhotic and cirrhotic hepatitis B patients to 2.7–4.7% in cirrhotic hepatitis C patients [47] and a lower risk in alcoholic cirrhosis [48,49]. Meta-analyses of randomized trials can be used for valid assessments of treatment effects. A systematic review on NSBB for HCC should include randomized trials on NSBB for patients with cirrhosis an follow-up periods longer than 12 months (in order for new HCCs to develop). Prevalent cases of HCC would need to be excluded for assessment of incidence, but not for the assessment of HCC mortality. The main limitation of a systematic review is the lack of trials reporting HCC incidence, which increases the risk of reporting, detection and ascertainment bias. Discussion Due to beneficial effects on gut-derived inflammation and reduced angiogenesis, NSBB have the potential to reduce HCC incidence and growth, and to improve outcomes. The molecular results have not been translated into clinical evidence and well-designed investigative studies are missing. If this hypothesis holds true, the use of NSBB in chronic liver diseases could be extended beyond prevention of variceal bleeding. NSBB are cheap, widely used and have a favorable safety profile. Further, a dual effect on varices and HCC would reinforce the recommendation of NSBB as first line treatment in the primary prophylaxis of variceal bleeding. The prognosis of patients with cirrhosis has improved within the last decades due to improved treatments. Quality of life and adverse effects of therapy are therefore becoming increasingly important. Potential benefits of NSBB
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should outbalance potential side effects of long-term NSBB, especially in otherwise asymptomatic patients. A number of aspects regarding NSBB and HCC remain to be elucidated. Less than 50% of patients are hemodynamic responders to NSBB. Whether a possible anti-carcinogenic effect of NSBB depends on a hemodynamic response in unknown [50]. The hepatic venous pressure gradient (HVPG) predicts HCC incidence in cirrhosis, irrespective of disease severity [51]. If a reduction in the HVPG results in a decreased HCC incidence, other therapies directed at lowering the HVPG such as transjugular intrahepatic portosystemic shunting (TIPS) could be beneficial. It does however not seem to be the case. TIPS may even have a detrimental effect on HCC incidence [52]. Some drugs such as statins reduce HCC incidence and lowers the HVPG [53,54]. Statins also decrease fibrosis [55], which is one of the mechanisms by which antiviral treatment decrease HCC incidence in chronic viral hepatitis B and C [56]. An antifibrotic effect of NSBB is not established in humans, but animal models suggest that reduced gut-derived inflammation leads to reduced fibrogenesis independently of the HVPG [57]. We hypothesize that the effect of NSBB on HCC is the result of non-hemodynamic effects. Accordingly, NSBB may also prevent HCC in HVPG non-responders. Whether a possible anticarcinogenic effect of NSBB is dosedependent and/or time-dependent and whether polymorphisms of the b-ARs play a role for the anticarcinogenic effect are also areas of interest for future research [58]. Conflict of interest statement The authors have nothing to disclose. Author contribution R. Wiest, L.L. Gluud, A. Albillos and A. Krag developed the hypothesis. M. Thiele and A. Krag obtained the scientific support of the hypothesis. M. Thiele drafted the manuscript. R. Wiest, L.L. Gluud, A. Albillos and A. Krag revised the manuscript for important intellectual content. All authors have approved of the final manuscript. References [1] Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet 2012;379:1245–55. [2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v2.0, Cancer incidence and mortality worldwide: IARC CancerBase No. 10.. Lyon, France: International Agency for Research on Cancer; 2010. [3] Krag A, Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic and non-haemodynamic effects of b-blockers improve survival of patients with cirrhosis during a window in the disease. Gut 2012;61:967–9. [4] Krag A, Wiest R, Gluud LL. Reduced mortality with non-selective betablockers compared to banding is not related to prevention of bleeding or bleeding related mortality: systematic review of randomized trials. J Hepatol 2011;54:S72. [5] Senzolo M, Cholongitas E, Burra P, et al. Beta-Blockers protect against spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. Liver Int 2009;29:1189–93. [6] Pérez-Paramo M, Muñoz J, Albillos A, et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatology 2000;31:43–8. [7] Wiest R, Krag A, Gerbes A. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut 2012;61:297–310. [8] Chim H, Armijo BS, Miller E, Gliniak C, Serret MA, Gosain AK. Propranolol induces regression of hemangioma cells through HIF-1alpha-mediated inhibition of VEGF-A. Ann Surg 2012;256:146–56. [9] Phillips CB, Pacha O, Biliciler-Denkta G, Hebert AA. A review of beta antagonist treatment for infantile hemangioma. J Drugs Dermatol 2012;11:826–9. [10] Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324168 participants from randomised trials. Lancet Oncol 2011;12:65–82. [11] Diaz ES, Karlan BY, Li AJ. Impact of beta blockers on epithelial ovarian cancer survival. Gynecol Oncol 2012;127:375–8.
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