Key Points
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Primary biliary cirrhosis (PBC) leads to progressive cholestasis, biliary fibrosis and cirrhosis and characteristic symptoms with a marked effect on life quality
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Ursodeoxycholic acid (UDCA) nonresponse or under-response has a major effect on outcome, substantially increasing the likelihood that liver transplantation will be required, or that patients will die of the disease
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Patients with high-risk, treatment-unresponsive or highly symptomatic disease need new treatment approaches; as yet, no agents demonstrating disease-modifying actions have been shown to improve systemic symptoms
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Excellent opportunities are offered by targeting the immune response, biliary injury and fibrotic processes
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Combination therapies with a stratified approach, in which specific treatments are targeted at the pathological processes at play, or single agents with multiple actions, are likely to be needed
Abstract
Primary biliary cirrhosis (PBC) is a chronic immune-mediated liver disease characterized by progressive cholestasis, biliary fibrosis and eventually cirrhosis. It results in characteristic symptoms with marked effects on life quality. The advent of large patient cohorts has challenged the view of PBC as a benign condition treated effectively by the single licensed therapy—ursodeoxycholic acid (UDCA). UDCA nonresponse or under-response has a major bearing on outcome, substantially increasing the likelihood that liver transplantation will be required or that patients will die of the disease. In patients with high-risk, treatment-unresponsive or highly symptomatic disease the need for new treatment approaches is clear. Evolution in our understanding of disease mechanisms is rapidly leading to the advent of new and re-purposed therapeutic agents targeting key processes. Notable opportunities are offered by targeting what could be considered as the 'upstream' immune response, 'midstream' biliary injury and 'downstream' fibrotic processes. Combination therapy targeting several pathways or the development of novel agents addressing multiple components of the disease pathway might be required. Ultimately, PBC therapeutics will require a stratified approach to be adopted in practice. This Review provides a current perspective on potential approaches to PBC treatment, and highlights the challenges faced in evaluating and implementing those treatments.
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References
Hirschfield, G. M. & Gershwin, M. E. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu. Rev. Pathol. 8, 303–330 (2013).
Griffiths, L., Dyson, J. K. & Jones, D. E. The new epidemiology of primary biliary cirrhosis. Semin. Liver Dis. 34, 318–328 (2014).
Mells, G. et al. The impact of primary biliary cirrhosis on perceived quality of life: the UK-PBC National Study. Hepatology 58, 273–283 (2013).
Carbone, M. et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastorenterology 144, 560–569 (2013).
Dyson, J. K. et al. Unmet clinical need in autoimmune liver diseases. J. Hepatol. 62, 208–218 (2014).
Corpechot, C. et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 48, 871–877 (2008).
Pares, A., Caballeria, L. & Rodes, J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology 130, 715–720 (2006).
Dhirapong, A. et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology 57, 708–715 (2013).
Tanaka, H. et al. Successful immunotherapy of autoimmune cholangitis by adoptive transfer of forkhead box protein 3+ regulatory T cells. Clin. Exp. Immunol. 178, 253–261 (2014).
Lammers, W. J. et al. Levels of alkaline phosphatase and bilirubin are surrogate endpoints of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology 147, 1338–1349 (2014).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Hirschfield, G. M. et al. Primary biliary cirrhosis associated with HLA, IL12A and IL12RB2 variants. N. Engl. J. Med. 360, 2544–2555 (2009).
Mells, G. F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 43, 329–332 (2011).
Yang, C. Y. et al. IL-12/Th1 and IL-23/Th17 biliary microenvironment in primary biliary cirrhosis: implications for therapy. Hepatology 59, 1944–1953 (2014).
US National Library of Medicine. ClinicalTrials.gov[online], (2012).
Manousou, P. et al. CXCR3 axis in patients with primary biliary cirrhosis: a possible novel mechanism of the effect of ursodeoxycholic acid. Clin. Exp. Immunol. 172, 9–15 (2013).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Afford, S. C. et al. CD40 activation-induced, Fas-dependent apoptosis and NKkB/AP1 signaling in human intrahepatic biliary epithelial cells. FASEB J. 15, 2345–2354 (2001).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Tsuda, M. et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 55, 512–521 (2012).
Myers, R. P., Swain, M. G., Lee, S. S., Shaheen, A. A. M. & Burak, K. W. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J. Gastroenterol. 108, 933–941 (2014).
Dhirapong, A. L. et al. B-cell depletion therapy exacerbates murine primary biliary cirrhosis. Hepatology 53, 527–535 (2011).
Freeman, H. J. Colitis associated with biological agents. World J. Gastroenterol. 28, 1871–1874 (2012).
Nevens, F. et al. The first primary biliary cirrhosis (PBC) phase 3 trial in two decades—an international study of the FXR agonist obeticholic Acid. J. Hepatol. 60 (Suppl.) S525–S526 (2014).
Hirschfield, G. M. et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2014.12.005.
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Levy, C. et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxyxcholic acid. Aliment. Pharmacol. Ther. 33, 235–242 (2011).
Lens, S., Leoz, M., Nazal, L., Bruguera, M. & Pares, A. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int. 34, 197–203 (2014).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Marschall, H. U. et al. The farnesoid X receptor (FXR) agonist (OCA) increases plasma FGF-19 concentrations and decreases bile acid synthesis in primary biliary cirrhosis (PBC). J. Hepatol. 56, S377 (2012).
Liaskou, E., Hirschfield, G. M. & Gershwin, M. E. Mechanisms of tissue injury in autoimmune liver diseases. Semin. Immunopathol. 36, 553–568 (2014).
Yeaman, S. J., Kirby, J. A. & Jones, D. E. Autoreactive responses to pyruvate dehydrogenase complex in the pathogenesis of primary biliary cirrhosis. Immunol. Rev. 174, 238–249 (2000).
Kita, H. et al. Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J. Clin. Invest. 109, 1231–1240 (2002).
Van de Water, J. et al. Heterogeneity of autoreactive T-cell clones specific for the E2 component of the pyruvate dehydrogenase complex in primary biliary cirrhosis. J. Exp. Med. 181, 723–733 (1995).
Kita, H. et al. Identification of HLA-A2-restricted CD8+ cytotoxic T-cell responses in primary biliary cirrhosis: T-cell activation is augmented by immune complexes cross-presented by dendritic cells. J. Exp. Med. 195, 113–123 (2002).
Oo, Y. H. et al. CDCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver. J. Hepatol. 57, 1044–1051 (2012).
Joplin, R. et al. Membrane dihydrolipoamide acetyltransferase (E2) on human biliary epithelial cells in primary biliary cirrhosis. Lancet 339, 93–94 (1992).
Wang, J. et al. Animal models of primary biliary cirrhosis. Semin. Liver Dis. 34, 285–296 (2014).
Leung, P. S. et al. Immunization with a xenobiotic 6-bromohexanoate bovine serum albumin conjugate induces anti-mitochondrial antibodies. J. Immunol. 170, 5326–5332 (2003).
Walden, H. R. et al. Xenobiotic incorporation into pyruvate dehydrogenase complex can occur via the exogenous lipoylation pathway. Hepatology 48, 1874–1884 (2008).
Wakabayashi, K. et al. Loss of tolerance in C57BL/6 mice to the autoantigen E2 subunit of pyruvate dehydrogenase by a xenobiotic with ensuing biliary ductular disease. Hepatology 48, 531–540 (2008).
Chang, C. H. et al. Innate immunity drives xenobiotic-induced murine autoimmune cholangitis. Clin. Exp. Immunol. 177, 273–280 (2014).
Hirschfield, G. M. et al. Variants at IRF5-TNPO3, 17q12–21 and MMEL1 are associated with primary biliary cirrhosis. Nat. Genet. 42, 655–657 (2010).
Liu, J. Z. et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat. Genet. 44, 1137–1141 (2012).
Hirschfield. G. M. et al. P367 Phase 2 study evaluating the efficacy and safety of ustekinumab in patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid. J. Hepatol. 60 (Suppl.), S189–S190 (2014).
Suzuki, A. et al. Oral tolerance and pyruvate dehydrogenase in patients with primary biliary cirrhosis. Dev. Immunol. 9, 55–61 (2002).
Jones, D. E. Pathogenesis of primary biliary cirrhosis. Gut 56, 1615–1624 (2007).
Lamireau, T. et al. Effects of bile acids on biliary epithelial cells: proliferation, cytotoxicity and cytokine secretion. Life Sci. 72, 1401–1411 (2003).
Sasaki, M., Ikeda, H., Haga, H., Manabe, T. & Nakanuma, Y. Frequent cellular senescence in small bile ducts in primary biliary cirrhosis: a possible role in bile duct loss. J. Pathol. 205, 451–459 (2005).
Trauner, M., Meier, P. J. & Boyer, J. L. Molecular pathogenesis of cholestasis. N. Engl. J. Med. 339, 1217–1227 (1998).
Maillette de Buy Wenniger, L. J., Oude Elferink, R. P. & Beuers, U. Molecular targets for the treatment of fibrosing cholangiopathies Clin. Pharmacol. Ther. 92, 381–387 (2012).
Beuers, U. et al. EASL practice guidelines on management of cholestatic liver diseases. J. Hepatol. 51, 237–267 (2009).
Lindor, K. D. et al. Primary biliary cirrhosis. Hepatology 50, 291–308 (2009).
Beuers, U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 318–328 (2006).
Dilger, K. et al. Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health. J. Hepatol. 57, 133–140 (2012).
Beuers, U., Thiel, M., Bardenheuer, H. & Paumgartner, G. Tauroursodeoxycholic acid inhibits the cytosolic Ca++ increase in human neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine. Biochem. Biophys. Res. Commun. 171, 1115–1121 (1990).
Bouscarel, B., Fromm, H. & Nussbaum, R. Ursodeoxycholate mobilizes intracellular Ca++ and activates phosphorylase a in isolated hepatocytes. Am. J. Physiol. 264, G243–G251 (1993).
Beuers, U., Nathanson, M. H. & Boyer, J. L. Effects of tauroursodeoxycholic acid on cytosolic Ca++ signals in isolated rat hepatocytes. Gastroenterology 104, 604–612 (1993).
Bouscarel, B., Gettys, T. W., Fromm, H. & Dubner, H. Ursodeoxycholic acid inhibits glucagon-induced cAMP formation in hamster hepatocytes: a role for PKC. Am. J. Physiol. 268, G300–G310 (1995).
Beuers, U. et al. Tauroursodeoxycholic acid activates protein kinase C in isolate hepatocytes. Gastroenterology 110, 1553–1563 (1996).
Stravitz, R. T. et al. Hepatocellular protein kinase C activation by bile acids: implications for regulation of cholesterol 7 alpha-hydroylase. Am. J. Physiol. 27, G293–G303 (1996).
Schliess, F., Kurz, A. K., vom Dahl, S. & Haussinger, D. Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver. Gastroenterology 113, 1306–1314 (1997).
Kurz, A. K., Graf, D., Schmitt, M., Vom Dahl, S. & Haussinger, D. T. Tauroursodesoxycholate-induced choleresis involves p38(MAPK) activation and translocation of the bile salt export pump in rats. Gastroenterology 121, 407–419 (2001).
Häussinger, D. et al. Involvement of integrins and Src in tauroursodeoxycholate-induced and swelling-induced choleresis. Gastroenterology 124, 1476–1487 (2003).
Gohlke, H., Schmitz, B., Sommerfeld, A., Reinehr, R. & Haussinger, D. α5 β1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes Hepatology 57, 1117–1129 (2013).
Dombrowski, F., Stieger, B. & Beuers, U. Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver. Lab. Invest. 86, 166–174 (2006).
Beuers, U. et al. Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology 33, 1206–1216 (2001).
Haussinger, D., Saha, N., Hallbrucker, C., Lang, F. & Gerok, W. Involvement of microtubules in the swelling-induced stimulation of transcellular taurocholate transport in perfused rat liver. Biochem. J. 291, 355–360 (1993).
Beuers, U., Nathanson, M. H., Isales, C. M. & Boyer, J. L. Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis. J. Clin. Invest. 92, 2984–2993 (1993).
Wimmer, R. et al. Tauroursodeoxycholic acid exerts anticholestatic effects by a cooperative cPKCα-/PKA-dependent mechanism in rat liver. Gut 57, 1448–1454 (2008).
Cruz, L. N. et al. Regulation of multidrug resistance-associated protein 2 by calcium signaling in mouse liver. Hepatology 52, 327–337 (2010).
Beuers, U. β1-Integrin is a long-sought sensor for tauroursodeoxycholic acid. 57, 867–869 (2013).
Beuers, U. et al. The biliary HCO3− umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 52, 1489–1496 (2010).
Hohenester, S. et al. A biliary HCO3− umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology 55, 173–183 (2012).
Prieto, J. et al. Assessment of biliary bicarbonate secretion in humans by positron emission tomography. Gastroenterology 117, 167–172 (1999).
Baghdasaryan, A. et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2−/− (Abcb4−/−) mouse cholangiopathy model by promoting biliary HCO3− output. Hepatology 54, 1303–1312 (2011).
Angulo, P. et al. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 31, 318–323 (2000).
Arenas, F. et al. Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells. J. Clin. Invest. 118, 695–709 (2008).
Hofmann, A. F. et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology 42, 1391–1398 (2005).
Fickert, P. et al. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 130, 465–481 (2006).
Denk, G. U. et al. Conjugation is essential for the anticholestatic effect of NorUrsodeoxycholic acid in taurolithocholic acid-induced cholestasis in rat liver. Hepatology 52, 1758–1768 (2010).
Ghonem, N. S., Ananthanarayanan, M., Soroka, C. J. & Boyer, J. L. Peroxisome proliferator-activated receptor alpha activates human multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion. Hepatology 59, 1030–1042 (2014).
Lunz, J. G. et al. Replicative senescence of biliary epithelial cells precedes bile duct loss in chronic liver allograft rejection: increased expression of p21(WAF1/Cip1) as a disease marker and the influence of immunosuppressive drugs. Am. J. Pathol. 158, 1379–1390 (2001).
Rygiel, K. A. et al. Epithelial-mesenchymal transition contributes to portal tract fibrogenesis during human chronic liver disease. Lab. Invest. 88, 112–123 (2008).
Rygiel, K. A. et al. T cell-mediated biliary epithelial-to-mesenchymal transition in liver allograft rejection. Liver Transpl. 16, 567–576 (2010).
Brain, J. G. et al. Biliary epithelial senescence and plasticity in acute cellular rejection. Am. J. Transplant. 13, 1688–1702 (2013).
Sasaki, M., Miyakoshi, M., Sato, Y. & Nakanuma, Y. Modulation of the microenvironment by senescent biliary epithelial cells may be involved in the pathogenesis of primary biliary cirrhosis. J. Hepatol. 53, 318–325 (2010).
Kinnman, N. et al. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab. Invest. 83, 163–173 (2003).
Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Invest. 115, 209–218 (2005).
Cassiman, D., Libbrecht, L., Desmet, V., Denef, C. & Roskams, T. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J. Hepatol. 36, 200–209 (2002).
Iredale, J. P. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J. Clin. Invest. 117, 539–548 (2007).
Georgiev, P. et al. Characterization of time-related changes after experimental bile duct ligation. Br. J. Surg. 95, 646–656 (2008).
Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).
Iwaisako, K. et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc. Natl Acad. Sci. USA 111, E3297–E3305 (2014).
Popov, Y., Patsenker, E., Fickert, P., Trauner, M. & Schuppan, D. Mdr2 (Abcb4)−/− mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J. Hepatol. 43, 1045–1054 (2005).
Strack, I. et al. β-adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotis effects in a model of nonsinusoidal fibrosis. Lab. Invest. 91, 252–261 (2011).
Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).
Popov, Y. et al. Integrin αvβ6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J. Hepatol. 48, 453–464 (2008).
Patsenker, E. et al. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 135, 660–670 (2008).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
US National Library of Medicine. ClinicalTrials.gov[online], (2011).
Lo, D. J. et al. Inhibition of αvβ6 promotes acute renal allograft rejection in non-human primates. Am. J. Transplant. 13, 3085–3093 (2013).
Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Poupon, R. Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. Clin. Res. Hepatol. Gastroenterol. 36, S3–S12 (2012).
Odin, J. A., Huebert, R. C., Casciola-Rosen, L., LaRusso, N. F. & Rosen, A. Bcl-2-dependent oxidation of pyruvate dehydrogenase-E2, a primary biliary cirrhosis autoantigen, during apoptosis. J. Clin. Invest. 108, 223–232 (2001).
Matsumura, S. et al. Contribution to antimitochondrial antibody production: cleavage of pyruvate dehydroganse complex-E2 by apoptosis-related proteases. Hepatology 35, 14–22 (2002).
Fickert, P. et al. Differential effects of norUDCA and UDCA in obstructive cholestasis in mice. J. Hepatol. 58, 1201–1208 (2013).
Sombetzki, M. et al. 24-nor-ursodeoxycholic acid ameliorates inflammatry response and liver fibrosis in a murine model of schistosomiasis. J. Hepatol. http://dx.doi.org/10.1016/j.jhep.2014.11.020.
Zhang, S., Wang, J., Liu, Q. & Harnish, D. C. Farnesoid X receptor agonist WAY-362450 attenuates liver inflammation and fibrosis in murine model of non-alcoholic steatohepatitis. J. Hepatol. 51, 380–388 (2009).
Fausther, M. & Dranoff, J. A. New insights on the pathogenesis of biliary cirrhosis provided by studies in FXR knockout mice. J. Hepatol. 55, 939–940 (2011).
Mason, A. et al. Farnesoid-X receptor agonists: a new class of drug for the treatment of PBC? An international study evaluating the addition of INT-747 to ursodeoxycholic acid. J. Hepatol. 52, S1–S2 (2010).
Prince, M. I., Burt, A. D. & Jones, D. E. J. Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis. Gut 50, 436–439 (2002).
Newton, J. L., Gibson, J. G., Tomlinson, M., Wilton, K. & Jones, D. E. J. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology 44, 91–98 (2006).
Beuers, U., Kremer, A. E., Bolier, R. & Elferink, R. P. Pruritus in cholestasis: facts and fiction. Hepatology 60, 399–407 (2014).
Bergasa, N. & Jones, E. A. in Primary Biliary Cirrhosis: From Pathogenesis to Clinical Treatment (eds Lindor, K. D., Heathcote, E. J. & Poupon, R. E.) 108–114 (Springer, 2012).
Podesta, A. L. et al. Treatment of pruritus in primary biliary cirrhosis with rifampicin. Results of a double-blind, cross-over, randomized trial. Gastroenterology 94, 488–493 (1991).
Tandon, P., Rowe, B. H., Vandermeer, B. & Bain, V. G. The efficacy and safety of bile acid binding agents, opioid antagonists or rifampicin in the treatment of cholestasis-associated pruritus. Am. J. Gastroenterol. 102, 1528–1536 (2007).
Montero, J. L. et al. Treatment of refractory cholestatic pruritus with molecular adsorbent recirculating system (MARS). Transplant. Proc. 38, 2511–2513 (2006).
Leckie, P. et al. 'Out-patient' albumin dialysis for cholestatic patients with intractable itch. Aliment. Pharmacol. Ther. 35, 696–704 (2012).
Datta, D. V. & Sherlock, S. Cholestyramine for long term relief of the priritus complicating intrahepatic cholestasis. Gastroenterology 50, 323–332 (1966).
Hofmann, A. F. & Huet, P. M. Nasobiliary drainage for cholestatic pruritus. Hepatology 43, 1170–1171 (2006).
Beuers, U., Gerken, G. & Pusl, T. Biliary drainage transiently relieves intractable pruritus in primary biliary cirrhosis. Hepatology 44, 280–281 (2006).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Wolfhagen, F. H. J. et al. Oral naltrexone for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 113, 1264–1269 (1997).
Kremer, A. E. et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 139, 1008–1018 (2010).
Kremer, A. E. et al. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin and responds to therapeutic interventions. Hepatology 56, 1391–1400 (2012).
Lieu, T. et al. The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 147, 1417–1428 (2014).
Alemi, F. et al. The TGR5 receptor mediated bile acid-induce itch and analgesia. J. Clin. Invest. 123, 1513–1530 (2013).
Keitel, V., Reich, M. & Haussinger, D. TGR5: pathogenetic role and/or therapeutic target in fibrosing cholangitis. Clin. Rev. Allergy Immunol. http://dx.doi.org/10.1007/s12016-014-8443-x.
Goldblatt, J. et al. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology 122, 1235–1241 (2002).
Pells, G. et al. The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC Cohort. J. Hepatol. 59, 67–73 (2013).
Newton, J. L. et al. Population prevalence and symptom associations of autonomic dysfunction in primary biliary cirrhosis. Hepatology 45, 1496–1505 (2007).
Dyson, J. K. et al. Fatigue in primary sclerosing cholangitis is associated with sympathetic over-activity and increased cardiac output. Liver Int. http://dx.doi.org/10.1111/liv.12709.
Swain, M. G. & Maric, M. Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment. Hepatology 25, 492–494 (1997).
Burak, K. W., Le, T. & Swain, M. G. Increased sensitivity to the locomotor-activating effects of corticotrophin-releasing hormone in cholestatic rats. Gastroenterology 122, 681–688 (2002).
Kerfoot, S. M. et al. TNF-α secreting monocytes are recruited into the brain of cholestatic mice. Hepatology 43, 154–162 (2006).
D'Mello, C. et al. P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors. J. Neurosci. 33, 14878–14888 (2013).
McDonald, C., Newton, J. L., Ming Lai, H., Baker, S. N. & Jones, D. E. J. Central nervous system dysfunction in primary biliary cirrhosis patients and its relationship to symptoms. J. Hepatol. 53, 1095–1100 (2010).
Newton, J. L. et al. Cognitive impairment in primary biliary cirrhosis: symptom impact and potential aetiology. Hepatology 48, 541–549 (2008).
Hollingsworth, K. G. et al. Impaired cerebral autoregulation in primary biliary cirrhosis: implications for the pathogenesis of cognitive decline. Liver Int. 30, 878–885 (2010).
Dionisio, P. A. et al. Amyloid-β pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset. Neurobiol. Aging 36, 228–240 (2015).
Hollingsworth, K. G. et al. A pilot study of peripheral muscle function in primary biliary cirrhosis: potential implications for fatigue pathogenesis. Clin. Gastroenterol. Hepatol. 6, 1041–1048 (2008).
European Medicines Agency. EU Clinical Trial Register [online].
Wilson, M. C. et al. Lactic acid efflux from white skeletal muscle is catalysed by the monocarboxylate transporter isoform MCT4. J. Biol. Chem. 273, 15920–15926 (1998).
Juel, C. & Holten, M. K. Effects of strength training on muscle lactate release and MCT1 and MCT4 content in healthy and type 2 diabetic humans. J. Physiol. 556, 297–304 (2004).
Pares, A. Old and novel therapies for primary biliary cirrhosis. Semin. Liver Dis. 34, 341–351 (2014).
US National Library of Medicine. ClinicalTrials.gov[online], (2013).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Dall'Era, M. & Davis, J. CTLA4Ig: a novel inhibitor of costimulation. Lupus 13, 372–376 (2004).
US National Library of Medicine. ClinicalTrials.gov[online], (2014).
Mason, A. L., Farr, G. H., Xu, L., Hubscher, S. G. & Neuberger, J. M. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis. Am. J. Gastroenterol. 99, 2348–2355 (2004).
Mason, A. L. & Zhang, G. Linking human beta retrovirus infection with primary biliary cirrhosis. Gastroenterol. Clin. Biol. 34, 359–366 (2010).
Sharon, D. et al. Impact of combination antiretroviral therapy in the NOD.c3c4 mouse model of autoimmune biliary disease. Liver Int. http://dx.doi.org/10.1111/liv.12699.
Mason, A., Xu, L. & Neuberger, J. Proof of principal studies to assess the role of the human betaretrovirus in patients with primary biliary cirrhosis. Am. J. Gastroenterol. 99, 2499–2500 (2004).
US National Library of Medicine. ClinicalTrials.gov[online], (2012).
US National Library of Medicine. ClinicalTrials.gov[online], (2013).
Acknowledgements
The work of the authors is supported by grant L001489 from the UK Medical Research Council (D.E.J.J.). The authors thanks Dr E. Liaskou for her help in developing Figure 3.
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G.M.H. is an investigator and/or consultant for Biotie Therapies, Bristol–Myers Squibb, Falk Pharma, FF Pharma, Gilead, GlaxoSmithKline, Intercept, Johnson & Johnson, NGM Biopharmaceuticals; he is a co-investigator for UK PBC, supported by a stratified medicine award from the UK Medical Research Council. U.H.B has consultant agreements via the University of Amsterdam with Intercept and Novartis, and receives lectures fees from the Falk Foundation. D.A.M. is a consultant and collaborator with GlaxoSmithKline, Medimmune, Novartis, UCB. K.D.L. is an unpaid member of the advisory board for Intercept and Lumena and a paid consultant for Abbvie and Gilead. D.E.J.J. receives UK PBC research and trial funding from GlaxoSmithKline, Intercept and Lumena, and acts as a consultant via Newcastle University for Intercept, Johnson & Johnson and Novartis. The other authors declare no competing interests.
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Supplementary Table 1
Summary of previous therapeutic trials in PBC (PDF 94 kb)
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Dyson, J., Hirschfield, G., Adams, D. et al. Novel therapeutic targets in primary biliary cirrhosis. Nat Rev Gastroenterol Hepatol 12, 147–158 (2015). https://doi.org/10.1038/nrgastro.2015.12
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DOI: https://doi.org/10.1038/nrgastro.2015.12
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