Abstract
Progressive hepatic fibrosis in combination with nodular regeneration dominates the increased intrahepatic vascular resistance to portal flow and thus portal hypertensive syndrome (PHT), which is one of the major driving forces in the development of clinical complications associated with cirrhosis. From this perspective, attempts to prevent, halt, or reverse liver fibrosis have logically been pursued for decades. At present, successful antiviral treatment serves as the best example for antifibrotic strategies and has encouraged the interest herein given the clinical trade-off of improved clinical outcomes, reduced portal pressure, and decreased all-cause mortality. This chapter serves the purpose of briefly pointing out some of the most far-advanced molecules, including FXR agonists, anticoagulation, angiotensin blockage, and modulating dysbiosis, in their transition from the bench to the bedside.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bosch J, GarcÃa-Pagán JC (2000) Complications of cirrhosis. I. Portal hypertension. J Hepatol 32(1 Suppl):141–156
Laleman W, Landeghem L, Wilmer A, Fevery J, Nevens F (2005) Portal hypertension: from pathophysiology to clinical practice. Liver Int 25:1079–1090
Lee YA, Wallace MC, Friedman SL (2015) Pathobiology of liver fibrosis: a translational success story. Gut 64(5):830–841
Mehal WZ, Iredale J, Friedman SL (2011) Scraping fibrosis: expressway to the core of fibrosis. Nat Med 17:552–553
Torok N, Dranoff JA, Schuppan D, Friedman SL (2015) Strategies and endpoints of antifibrotic drug trials: summary and recommendations from the AASLD Emerging Trends Conference, Chicago, June 2014. Hepatology 62(2):627–634
Karsdal MA, Manon-Jensen T, Genovese F et al (2015) Novel insights into the function and dynamics of extracellular matrix in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 308(10):G807–G830
Marcellin P, Gane E, Buti M et al (2013) Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381:468–475
D’Ambrosio R, Aghemo A, Rumi MG et al (2012) A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 56:532–543
Lefebvre P, Cariou B, Lien F et al (2009) Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89:147–191
Pellicciari R, Costantino G, Camaioni E et al (2004) Bile acid derivatives as ligands of the farnesoid X receptor. Synthesis, evaluation, and structure-activity relationship of a series of body and side chain modified analogues of chenodeoxycholic acid. J Med Chem 47:4559–4569
Fan M, Wang X, Xu G et al (1849) Bile acid signaling and liver regeneration. Biochim Biophys Acta 2015:196–200
Wang YD, Chen WD, Wang M et al (2008) Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48:1632–1643
Wolfe A, Thomas A, Edwards G et al (2011) Increased activation of the Wnt/beta-catenin pathway in spontaneous hepatocellular carcinoma observed in farnesoid X receptor knockout mice. J Pharmacol Exp Ther 388:12–21
Verbeke L, Farre R, Trebicka J et al (2014) Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 59:2286–2298
Lutz P, Berger C, Langhans B et al (2014) A farnesoid X receptor polymorphism predisposes to spontaneous bacterial peritonitis. Dig Liver Dis 46:1047–1050
Fickert P, Fuchsbichler A, Moustafa T et al (2009) Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol 175:2392–2405
Fiorucci S, Antonelli E, Rizzo B et al (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127:1497–1512
Albanis E, Alvarez CE, Pruzansky M et al (2005) INT-747, a novel FXR activator, reverses hepatic fibrosis and cirrhosis in thioacetamide-induced liver injury in rats. Hepatology 42(4, Suppl 1):1040
Verbeke L, Mannaerts I, Schierwagen R et al (2015) Obeticholic acid, a farnesoid X-receptor agonist, reduces hepatic fibrosis in a rat model of toxic cirrhosis. J Hepatol 2015; Suppl 2: 62: P0445
Fiorucci S, Antonelli E, Rizzo B et al (2005) A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther 314:584–595
Verbeke L, Farre R, Verbinnen B et al (2015) The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats. Am J Pathol 185:409–419
Ubeda M, Borrero MJ, Lario M et al (2014) The Farnesoid X receptor agonist, obeticholic acid, improves intestinal antibacterial defense and reduces gut bacterial translocation and hepatic fibrogenesis in CCl4 cirrhotic rats with ascites. J Hepatol 60(Suppl):S63
Hirschfield GM, Mason A, Luketic V et al (2014) Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148:751–761
Neuschwander-Ttri BA, Loomba R, Sanyal AJ, on behalf of NASH Clinical Research Network et al (2015) Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385:956–965
Mookerje R, Rosselli M, Pieri G et al (2014) Effects of the FXR agonist obeticholic acid on hepatic venous pressure gradient in alcoholic cirrhosis: a proof of concept phase 2A study. J Hepatol 60(Suppl):S7
Pares A, Caballeria L, Rodes J (2006) Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 130:715–720
Lisman T, Caldwell SH, Burroughs AK, Northup PG, Senzolo M, Stravitz RT et al (2010) Hemostasis and thrombosis in patients with liver disease: the ups and downs. J Hepatol 53:362–371
Wanless IR, Wong F, Blendis LM et al (1995) Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 21:1238–1247
Wright M, Goldin R, Hellier S et al (2003) Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection. Gut 52:1206–1210
Papatheodoridis GV, Papakonstantinou E, Andrioti E et al (2003) Thrombotic risk factors and extent of liver fibrosis in chronic viral hepatitis. Gut 52:404–409
Yee TT, Griffioen A, Sabin CA et al (2000) The natural history of HCV in a cohort of haemophilic patients infected between 1961 and 1985. Gut 47:845–851
Fiorucci S, Antonelli E, Distrutti E et al (2004) PAR1 antagonism protects against experimental liver fibrosis. role of proteinase receptors in stellate cell activation. Hepatology 39:365–375
Marra F, DeFranco R, Grappone C et al (1998) Expression of the thrombin receptor in human liver: up-regulation during acute and chronic injury. Hepatology 27:462–471
Friedman SL (2003) Liver fibrosis — from bench to bedside. J Hepatol 38(Suppl 1):S38–S53
Villa E, Camma C, Marietta M et al (2012) Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 143:1253–1260
Dhar A, Tschotazis E, Brown R et al (2015) Warfarin anticoagulation for liver fibrosis in patients transplanted for hepatitis C (WAFT-C): results at one year. J Hepatol 2015; Suppl 2: 62: LP11
Arroyo V, Bosch J, Mauri M et al (1981) Effects of angiotensin II blockade on systemic and hepatic hemodynamics and on the renin-angiotensin-aldosterone system in cirrhosis with ascites. Eur J Clin Invest 11:221–229
Tandon P, Abraldes JG, Berzigotti A et al (2010) Renin-angiotensin-aldosterone inhibitors in the reductio of portal pressure: a systematic review and meta-analysis. J Hepatol 53:273–282
Bataller R, Gines P, Lora J et al (2001) Evidence for a local renin-angiotensin system in human liver: expression in activated hepatic stellate cells. Hepatology 34:399A
Bataller R, Schwabe RF, Choi YH et al (2003) NADPH oxidase signal trans- duces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 112:383–394
Colmenero J, Bataller R, Sancho-Bru P et al (2009) Effects of losartan on hepatic expression of non-phagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol 297:G726–G734
Kim MY, Cho MY, Baik SK et al (2012) Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis – a randomized open-label controlled study. Liver Int 32:977–987
Hidaka H, Nakazawa T, Shibuya A et al (2011) Effects of 1-year administration of olmesartan on portal pressure and TGF-beta1 in selected patients with cirrhosis: a randomized controlled trial. J Gastroenterol 46:1316–1323
Debernardi-Venon W, Martini S, Biasi F et al (2007) AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol 46:1026–1033
Corey KE, Shah N, Misdraji J et al (2009) The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int 29:748–753
Abu Dayyeh BK, Yang M, Dienstag JL et al (2011) The effects of angiotensin blocking agents on the progression of liver fibrosis in the HALT-C Trial cohort. Dig Dis Sci 56:564–568
van Beuge MM, Prakash J, Lacombe M et al (2011) Reduction of fibrogenesis by selective delivery of a Rho kinase inhibitor to hepatic stellate cells in mice. J Pharmacol Exp Ther 337:628–635
Klein S, van Beuge M, Granzow M et al (2012) Inhibition or Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects. J Hepatol 57:1220–1227
Granzow M, Schierwagen R, Klein S et al (2014) Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology 60:334–348
Chassaing B, Etienne-Mesmin L, Gewirtz A (2014) Microbiota-liver axis in hepatic disease. Hepatology 59:328–339
Dhiman RK, Rana B, Agrawal S et al (2014) Probiotic VSL#3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial. Gastroenterology 147:1327–1337
Vlachogiannakos J, Viazis N, Vasianopoulou P et al (2013) Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol 28:450–455
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer International Publishing Switzerland
About this paper
Cite this paper
Laleman, W. (2016). Potential Antifibrotic Therapies: Approaching the Bedside: Proof-of-Concept Studies (Part 1). In: de Franchis, R. (eds) Portal Hypertension VI. Springer, Cham. https://doi.org/10.1007/978-3-319-23018-4_15
Download citation
DOI: https://doi.org/10.1007/978-3-319-23018-4_15
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-23017-7
Online ISBN: 978-3-319-23018-4
eBook Packages: MedicineMedicine (R0)