Clinical Science (2014) 126, 631–632 (Printed in Great Britain) doi: 10.1042/CS20130810
Is it tea time for portal hypertension? Jordi GRACIA-SANCHO∗ and Jaime BOSCH∗ ∗
Clinical Science
www.clinsci.org
Barcelona Hepatic Hemodynamic Laboratory, Institut d’Investigacions Biom`ediques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Barcelona, Spain and Centro de Investigaci´on Biom´edica en Red de Enfermedades Hep´aticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
Abstract Portal hypertension is the main complication of cirrhosis and represents a leading cause of death in patients with chronic liver disease. Therapeutic agents to improve portal hypertension should ameliorate the underlying mechanisms of portal hypertension: the elevated hepatic resistance and the hyperdynamic circulation. In the present issue of Clinical Science, Hsu and co-workers show the beneficial effects of GTPs (green tea polyphenols) in improving portal hypertension. Long-term administration of GTPs inhibited the development of cirrhosis and portal hypertension by decreasing both hepatic resistance and splanchnic hyperdynamic circulation. The main underlying mechanism of the benefits of GTPs appears related to the down-regulation of splanchnic angiogenesis. The present study adds further evidence supporting the potential of natural compounds for an effective nutriceutical approach to the treatment of patients with cirrhosis of the liver. Key words: ( − )-epigallocatechin-3-gallate (EGCG), angiogenesis, green tea polyphenol (GTP), liver cirrhosis, portosystemic collateral
Cirrhosis, and its main complication PH (portal hypertension), represents a leading cause of mortality worldwide, accounting for over 170 000 deaths per year in Europe [1]. The primary factor contributing to the development of PH is a progressive increase in the hepatic vascular resistance due to both liver architectural distortion and de-regulation of the phenotype of sinusoidal cells [2]. In addition, an increase in portal blood flow and formation of portal–systemic collaterals further aggravate this syndrome [3]. Over the last decades, substantial research has focused on developing new therapeutic options for PH based on the use of natural compounds. In the present issue of Clinical Science, Hsu and co-workers [4] describe the possibility of ameliorating PH by administrating GTPs (green tea polyphenols) in an experimental model of liver cirrhosis. The study demonstrates that long-term administration of GTPs to rats with BDL (bile duct ligation)induced liver cirrhosis reduces the degree of liver fibrosis, and decreases intra- and extra-hepatic angiogenesis and portal–systemic shunting. Thus GTPs affect both the hepatic and the extrahepatic disturbances contributing to PH in cirrhosis. It is surprising in view of these findings that GTPs did not decrease portal pressure. Desirable future studies will elucidate why administration of GTPs did not result in a significant decrease in portal pressure. It could be hypothesized that GTPs, in addition to reducing hepatic vascular resistance (as suggested by reduced hepatic fibrosis), might promote an increase in portal blood inflow thus maintaining portal pressure. Unfortunately, this possibility was not investigated, as the authors did not assess portal (or splanchnic) blood flow in the rats included in the study.
It is important to note that the efficacy of GTPs depended on the timing of its administration during the disease course [4]. Although administration of GTPs had clear beneficial effects when administered as a prophylactic agent (in the early stages after BDL), they had no effect when administered once liver fibrosis was already established. It would be interesting to evaluate the efficacy of GTPs in other experimental models of liver cirrhosis, such as carbon tetrachloride intoxication, which more closely reflects human toxic and metabolic cirrhosis. BDL is a rapidly progressive model of biliary cirrhosis, a much less prevalent human disease. This would allow an assessment of whether the different effects of GTPs along the course of cirrhosis are inherent to the BDL model. Previous experimental studies employing natural compounds have shown that vitamin E [5] and resveratrol [6] markedly reduce liver fibrosis, inflammation and PH. In addition, clinical studies demonstrating the beneficial effects of vitamin C [7] and dark chocolate [8] in attenuating the post-prandial increase in portal pressure in patients with cirrhosis have reinforced further the potential of dietary supplementation in improving PH. These reports ascribed most of the beneficial effects of natural compounds to their ability to decrease hepatic oxidative stress, which is much increased in cirrhotic livers [9]. However, the present study [4] did not show any beneficial effects of GTPs on hepatic oxidative stress, but reported a downregulation of the angiogenic pathway including HIF-1α (hypoxiainducible factor-1α), VEGF (vascular endothelial growth factor) and Akt, thus suggesting that the mechanism by which GTPs
Abbreviations: BDL, bile duct ligation; GTPs, green tea polyphenols; PH, portal hypertension. Correspondence: Dr Jordi Gracia-Sancho (email [email protected]) or Professor Jaime Bosch (email [email protected]).
www.clinsci.org
631
Commentary
inhibited cirrhosis progression may be via anti-angiogenic properties. Angiogenesis, the process of new vessel formation from preexisting vessels, has been shown to play a key role in the pathophysiology of PH [3]. Indeed, angiogenesis is involved in the development and maintenance of the hyperdynamic splanchnic and portal–collateral circulations, contributing to increased portal inflow and thus worsening the increase in portal pressure [3,10]. Anti-angiogenic drugs, such as sorafenib or sunitinib, result in a significant improvement in liver fibrosis and portal hypertensive syndrome [11,12]. These findings lead to the hypothesis that angiogenesis might represent a new therapeutic target for PH. The results from the present study [4] further validate previous findings and demonstrate that natural anti-angiogenic molecules could also be applied to ameliorate cirrhosis-induced PH. Indeed, using GTPs as a new ‘nutriceutical’ approach for liver cirrhosis seems an excellent choice, since green tea production and consumption is markedly increasing worldwide, it is an affordable product and represents a tasteful pleasure. Nevertheless, special caution should be given when uncontrolled green tea extracts are consumed as cases of acute liver failure have been described [13]. Evidently, further studies characterizing the clinical effects of GTPs are required before they can be recommended for the treatment of human cirrhosis.
2
3
4
5
6
7
8
9 FUNDING
The authors’ work is supported by the Instituto de Salud Carlos III and co-funded by the FEDER (Fonds Europeos para el Desarrollo Regional) programme from the European Union. J.G.-S. is supported by a Ram´on y Cajal contract from the Ministerio de Econom´ıa and Competitividad. CIBEREHD is funded by the Instituto de Salud Carlos III.
10
11
12
REFERENCES 1
Blachier, M., Leleu, H., Peck-Radosavljevic, M., Valla, D. C. and Roudot-Thoraval, F. (2013) The burden of liver disease in Europe: a review of available epidemiological data. J. Hepatol. 58, 593–608
13
Garcia-Pagan, J. C., Gracia-Sancho, J. and Bosch, J. (2012) Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J. Hepatol. 57, 458–461 Bosch, J., Abraldes, J. G., Fernandez, M. and Garcia-Pagan, J. C. (2010) Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J. Hepatol. 53, 558–567 Hsu, S.-J., Wang, S.-S., Hsin, I.-F., Lee, F.-Y., Huang, H.-C., Huo, T.-I., Lee, W.-S., Lin, H.-C. and Lee, S.-D. (2014) Green tea polyphenol decreases the severity of portosystemic collaterals and mesenteric angiogenesis in rats with liver cirrhosis. Clin. Sci. 126, 633–644 Yang, Y. Y., Lee, T. Y., Huang, Y. T., Chan, C. C., Yeh, Y. C., Lee, F. Y., Lee, S. D. and Lin, H. C. (2012) Asymmetric dimethylarginine (ADMA) determines the improvement of hepatic endothelial dysfunction by vitamin E in cirrhotic rats. Liver Int. 32, 48–57 Di Pascoli, M., Divi, M., Rodriguez-Vilarrupla, A., Rosado, E., Gracia-Sancho, J., Vilaseca, M., Bosch, J. and Garc´ıa-Pag´an, J. C. (2013) Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats. J. Hepatol. 58, 904–910 Hernandez-Guerra, M., Garcia-Pagan, J. C., Turnes, J., Bellot, P., Deulofeu, R., Abraldes, J. G. and Bosch, J. (2006) Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology 43, 485– 491 De Gottardi, A., Berzigotti, A., Seijo, S., D’Amico, M., Thormann, W., Abraldes, J. G., Garc´ıa-Pag´an, J. C. and Bosch, J. (2012) 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. 96, 584–590 Gracia-Sancho, J., Lavina, B., Rodriguez-Vilarupla, A., Garc´ıa-Calder´o, H., Fern´andez, M., Bosch, J. and Garc´ıa-Pag´an, J. C. (2008) Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 47, 1248–1256 Fern´andez, M., Semela, D., Bruix, J., Colle, I., Pinzani, M. and Bosch, J. (2009) Angiogenesis in liver disease. J. Hepatol. 50, 604–620 Mejias, M., Garcia-Pras, E., Tiani, C., Miquel, R., Bosch, J. and Fernandez, M. (2009) Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 49, 1245–1256 Tugues, S., Fernandez-Varo, G., Munoz-Luque, J., Ros, J., Arroyo, V., Rod´es, J., Friedman, S. L., Carmeliet, P., Jim´enez, W. and Morales-Ruiz, M. (2007) Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 46, 1919–1926 Molinari, M., Watt, K. D., Kruszyna, T., Nelson, R., Walsh, M., Huang, W. Y., Nashan, B. and Peltekian, K. (2006) Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl. 12, 1892–1895
Received 10 December 2013/17 December 2013; accepted 18 December 2013 Published as Immediate Publication 20 December 2013, doi: 10.1042/CS20130810
632
C The Authors Journal compilation C 2014 Biochemical Society
Copyright of Clinical Science is the property of Portland Press Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Is it tea time for portal hypertension? Jordi GRACIA-SANCHO∗ and Jaime BOSCH∗ ∗
Clinical Science
www.clinsci.org
Barcelona Hepatic Hemodynamic Laboratory, Institut d’Investigacions Biom`ediques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, Barcelona, Spain and Centro de Investigaci´on Biom´edica en Red de Enfermedades Hep´aticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
Abstract Portal hypertension is the main complication of cirrhosis and represents a leading cause of death in patients with chronic liver disease. Therapeutic agents to improve portal hypertension should ameliorate the underlying mechanisms of portal hypertension: the elevated hepatic resistance and the hyperdynamic circulation. In the present issue of Clinical Science, Hsu and co-workers show the beneficial effects of GTPs (green tea polyphenols) in improving portal hypertension. Long-term administration of GTPs inhibited the development of cirrhosis and portal hypertension by decreasing both hepatic resistance and splanchnic hyperdynamic circulation. The main underlying mechanism of the benefits of GTPs appears related to the down-regulation of splanchnic angiogenesis. The present study adds further evidence supporting the potential of natural compounds for an effective nutriceutical approach to the treatment of patients with cirrhosis of the liver. Key words: ( − )-epigallocatechin-3-gallate (EGCG), angiogenesis, green tea polyphenol (GTP), liver cirrhosis, portosystemic collateral
Cirrhosis, and its main complication PH (portal hypertension), represents a leading cause of mortality worldwide, accounting for over 170 000 deaths per year in Europe [1]. The primary factor contributing to the development of PH is a progressive increase in the hepatic vascular resistance due to both liver architectural distortion and de-regulation of the phenotype of sinusoidal cells [2]. In addition, an increase in portal blood flow and formation of portal–systemic collaterals further aggravate this syndrome [3]. Over the last decades, substantial research has focused on developing new therapeutic options for PH based on the use of natural compounds. In the present issue of Clinical Science, Hsu and co-workers [4] describe the possibility of ameliorating PH by administrating GTPs (green tea polyphenols) in an experimental model of liver cirrhosis. The study demonstrates that long-term administration of GTPs to rats with BDL (bile duct ligation)induced liver cirrhosis reduces the degree of liver fibrosis, and decreases intra- and extra-hepatic angiogenesis and portal–systemic shunting. Thus GTPs affect both the hepatic and the extrahepatic disturbances contributing to PH in cirrhosis. It is surprising in view of these findings that GTPs did not decrease portal pressure. Desirable future studies will elucidate why administration of GTPs did not result in a significant decrease in portal pressure. It could be hypothesized that GTPs, in addition to reducing hepatic vascular resistance (as suggested by reduced hepatic fibrosis), might promote an increase in portal blood inflow thus maintaining portal pressure. Unfortunately, this possibility was not investigated, as the authors did not assess portal (or splanchnic) blood flow in the rats included in the study.
It is important to note that the efficacy of GTPs depended on the timing of its administration during the disease course [4]. Although administration of GTPs had clear beneficial effects when administered as a prophylactic agent (in the early stages after BDL), they had no effect when administered once liver fibrosis was already established. It would be interesting to evaluate the efficacy of GTPs in other experimental models of liver cirrhosis, such as carbon tetrachloride intoxication, which more closely reflects human toxic and metabolic cirrhosis. BDL is a rapidly progressive model of biliary cirrhosis, a much less prevalent human disease. This would allow an assessment of whether the different effects of GTPs along the course of cirrhosis are inherent to the BDL model. Previous experimental studies employing natural compounds have shown that vitamin E [5] and resveratrol [6] markedly reduce liver fibrosis, inflammation and PH. In addition, clinical studies demonstrating the beneficial effects of vitamin C [7] and dark chocolate [8] in attenuating the post-prandial increase in portal pressure in patients with cirrhosis have reinforced further the potential of dietary supplementation in improving PH. These reports ascribed most of the beneficial effects of natural compounds to their ability to decrease hepatic oxidative stress, which is much increased in cirrhotic livers [9]. However, the present study [4] did not show any beneficial effects of GTPs on hepatic oxidative stress, but reported a downregulation of the angiogenic pathway including HIF-1α (hypoxiainducible factor-1α), VEGF (vascular endothelial growth factor) and Akt, thus suggesting that the mechanism by which GTPs
Abbreviations: BDL, bile duct ligation; GTPs, green tea polyphenols; PH, portal hypertension. Correspondence: Dr Jordi Gracia-Sancho (email [email protected]) or Professor Jaime Bosch (email [email protected]).
www.clinsci.org
631
Commentary
inhibited cirrhosis progression may be via anti-angiogenic properties. Angiogenesis, the process of new vessel formation from preexisting vessels, has been shown to play a key role in the pathophysiology of PH [3]. Indeed, angiogenesis is involved in the development and maintenance of the hyperdynamic splanchnic and portal–collateral circulations, contributing to increased portal inflow and thus worsening the increase in portal pressure [3,10]. Anti-angiogenic drugs, such as sorafenib or sunitinib, result in a significant improvement in liver fibrosis and portal hypertensive syndrome [11,12]. These findings lead to the hypothesis that angiogenesis might represent a new therapeutic target for PH. The results from the present study [4] further validate previous findings and demonstrate that natural anti-angiogenic molecules could also be applied to ameliorate cirrhosis-induced PH. Indeed, using GTPs as a new ‘nutriceutical’ approach for liver cirrhosis seems an excellent choice, since green tea production and consumption is markedly increasing worldwide, it is an affordable product and represents a tasteful pleasure. Nevertheless, special caution should be given when uncontrolled green tea extracts are consumed as cases of acute liver failure have been described [13]. Evidently, further studies characterizing the clinical effects of GTPs are required before they can be recommended for the treatment of human cirrhosis.
2
3
4
5
6
7
8
9 FUNDING
The authors’ work is supported by the Instituto de Salud Carlos III and co-funded by the FEDER (Fonds Europeos para el Desarrollo Regional) programme from the European Union. J.G.-S. is supported by a Ram´on y Cajal contract from the Ministerio de Econom´ıa and Competitividad. CIBEREHD is funded by the Instituto de Salud Carlos III.
10
11
12
REFERENCES 1
Blachier, M., Leleu, H., Peck-Radosavljevic, M., Valla, D. C. and Roudot-Thoraval, F. (2013) The burden of liver disease in Europe: a review of available epidemiological data. J. Hepatol. 58, 593–608
13
Garcia-Pagan, J. C., Gracia-Sancho, J. and Bosch, J. (2012) Functional aspects on the pathophysiology of portal hypertension in cirrhosis. J. Hepatol. 57, 458–461 Bosch, J., Abraldes, J. G., Fernandez, M. and Garcia-Pagan, J. C. (2010) Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J. Hepatol. 53, 558–567 Hsu, S.-J., Wang, S.-S., Hsin, I.-F., Lee, F.-Y., Huang, H.-C., Huo, T.-I., Lee, W.-S., Lin, H.-C. and Lee, S.-D. (2014) Green tea polyphenol decreases the severity of portosystemic collaterals and mesenteric angiogenesis in rats with liver cirrhosis. Clin. Sci. 126, 633–644 Yang, Y. Y., Lee, T. Y., Huang, Y. T., Chan, C. C., Yeh, Y. C., Lee, F. Y., Lee, S. D. and Lin, H. C. (2012) Asymmetric dimethylarginine (ADMA) determines the improvement of hepatic endothelial dysfunction by vitamin E in cirrhotic rats. Liver Int. 32, 48–57 Di Pascoli, M., Divi, M., Rodriguez-Vilarrupla, A., Rosado, E., Gracia-Sancho, J., Vilaseca, M., Bosch, J. and Garc´ıa-Pag´an, J. C. (2013) Resveratrol improves intrahepatic endothelial dysfunction and reduces hepatic fibrosis and portal pressure in cirrhotic rats. J. Hepatol. 58, 904–910 Hernandez-Guerra, M., Garcia-Pagan, J. C., Turnes, J., Bellot, P., Deulofeu, R., Abraldes, J. G. and Bosch, J. (2006) Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology 43, 485– 491 De Gottardi, A., Berzigotti, A., Seijo, S., D’Amico, M., Thormann, W., Abraldes, J. G., Garc´ıa-Pag´an, J. C. and Bosch, J. (2012) 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. 96, 584–590 Gracia-Sancho, J., Lavina, B., Rodriguez-Vilarupla, A., Garc´ıa-Calder´o, H., Fern´andez, M., Bosch, J. and Garc´ıa-Pag´an, J. C. (2008) Increased oxidative stress in cirrhotic rat livers: a potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 47, 1248–1256 Fern´andez, M., Semela, D., Bruix, J., Colle, I., Pinzani, M. and Bosch, J. (2009) Angiogenesis in liver disease. J. Hepatol. 50, 604–620 Mejias, M., Garcia-Pras, E., Tiani, C., Miquel, R., Bosch, J. and Fernandez, M. (2009) Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats. Hepatology 49, 1245–1256 Tugues, S., Fernandez-Varo, G., Munoz-Luque, J., Ros, J., Arroyo, V., Rod´es, J., Friedman, S. L., Carmeliet, P., Jim´enez, W. and Morales-Ruiz, M. (2007) Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 46, 1919–1926 Molinari, M., Watt, K. D., Kruszyna, T., Nelson, R., Walsh, M., Huang, W. Y., Nashan, B. and Peltekian, K. (2006) Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl. 12, 1892–1895
Received 10 December 2013/17 December 2013; accepted 18 December 2013 Published as Immediate Publication 20 December 2013, doi: 10.1042/CS20130810
632
C The Authors Journal compilation C 2014 Biochemical Society
Copyright of Clinical Science is the property of Portland Press Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
