Primary Biliary Cirrhosis Beyond Ursodeoxycholic Acid

Christophe Corpechot

doi:10.1055/s-0035-1571273

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2016; 36(01): 015-026
DOI: 10.1055/s-0035-1571273

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Primary Biliary Cirrhosis Beyond Ursodeoxycholic Acid

Authors

Christophe Corpechot

¹Hepatology Department, Reference Center for Chronic Inflammatory Biliary Diseases (MIVB), French Network for Pediatric and Adult Rare Liver Diseases (FILFOIE), INSERM UMR_S938, Saint-Antoine Hospital (Assistance Publique—Hôpitaux de Paris) and Faculty of Medicine Pierre et Marie Curie, Paris 6 University, Paris, France

Abstract

Although ursodeoxycholic acid remains the only approved pharmacotherapy for patients with primary biliary cirrhosis, the better characterization of factors responsible for the poor response to this drug and the emergence of several new putative therapeutic targets now offer significant opportunities to improve the management of patients and our capacity to treat them more efficiently. The availability of novel treatment options, such as fibrates, budesonide, and obeticholic acid, all capable of improving prognostic markers, invites us to reconsider our management and treatment strategies. Early identification of high-risk patients should remain a priority to deliver adjunctive therapies to appropriately selected populations and increase their chances of success. Given the absence of comparative trials, the choice between second-line treatments should be dictated by the biochemical, histological, and expected tolerance profiles. Here the author presents a brief overview of what should be known in this field and proposes a practical approach to facilitate decision making.

Keywords

budesonide - bezafibrate - fenofibrate - obeticholic acid - peroxisome proliferating-associated receptor - farnesoid X receptor - pregnane X receptor - fibroblast growth factor-19

Full Text

References

References
1 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51 (2) 237-267
2 Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology 2009; 50 (1) 291-308
3 ter Borg PC, Schalm SW, Hansen BE, van Buuren HR ; Dutch PBC Study Group. Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol 2006; 101 (9) 2044-2050
4 Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology 2006; 130 (3) 715-720
5 Corpechot C, Abenavoli L, Rabahi N , et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008; 48 (3) 871-877
6 Lammers WJ, van Buuren HR, Hirschfield GM , et al; Global PBC Study Group. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology 2014; 147 (6) 1338-49.e5 , quiz e15
7 Trivedi PJ, Bruns T, Cheung A , et al. Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response. J Hepatol 2014; 60 (6) 1249-1258
8 Leuschner M, Maier KP, Schlichting J , et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 1999; 117 (4) 918-925
9 Iwasaki S, Ohira H, Nishiguchi S , et al; Study Group of Intractable Liver Diseases for Research on a Specific Disease, Health Science Research Grant, Ministry of Health, Labour and Welfare of Japan. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res 2008; 38 (6) 557-564
10 Hirschfield GM, Mason A, Luketic V , et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148 (4) 751-61.e8
11 Corpechot C, Chazouillères O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol 2011; 55 (6) 1361-1367
12 Floreani A, Cazzagon N, Martines D, Cavalletto L, Baldo V, Chemello L. Performance and utility of transient elastography and noninvasive markers of liver fibrosis in primary biliary cirrhosis. Dig Liver Dis 2011; 43 (11) 887-892
13 Corpechot C, Carrat F, Poujol-Robert A , et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology 2012; 56 (1) 198-208
14 Carbone M, Mells GF, Pells G , et al; UK PBC Consortium. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 2013; 144 (3) 560-569.e7 , quiz e13–e14
15 Quarneti C, Muratori P, Lalanne C , et al. Fatigue and pruritus at onset identify a more aggressive subset of primary biliary cirrhosis. Liver Int 2015; 35 (2) 636-641
16 Chazouillères O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 1998; 28 (2) 296-301
17 Heurgué A, Vitry F, Diebold MD , et al. Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis: a retrospective study of 115 cases of autoimmune liver disease. Gastroenterol Clin Biol 2007; 31 (1) 17-25
18 Joshi S, Cauch-Dudek K, Wanless IR , et al. Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid. Hepatology 2002; 35 (2) 409-413
19 Chazouillères O, Poupon R. Ursodeoxycholic acid and primary biliary cirrhosis with features of autoimmune hepatitis. Hepatology 2002; 36 (4 Pt 1) 1026-1027 , author reply 1027
20 Ozaslan E, Efe C, Akbulut S , et al. Therapy response and outcome of overlap syndromes: autoimmune hepatitis and primary biliary cirrhosis compared to autoimmune hepatitis and autoimmune cholangitis. Hepatogastroenterology 2010; 57 (99–100) 441-446
21 Corpechot C, Carrat F, Poupon R, Poupon RE. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol-treated patients. Gastroenterology 2002; 122 (3) 652-658
22 Carbone M, Sharpe SJ, Heneghan MA , et al. Histological stage is relevant for risk-stratification in primary biliary cirrhosis. J Hepatol 2015; 62: S805
23 Silveira MG, Brunt EM, Heathcote J, Gores GJ, Lindor KD, Mayo MJ. American Association for the Study of Liver Diseases endpoints conference: design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology 2010; 52 (1) 349-359
24 Kuiper EM, Hansen BE, de Vries RA , et al; Dutch PBC Study Group. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 2009; 136 (4) 1281-1287
25 Kumagi T, Guindi M, Fischer SE , et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol 2010; 105 (10) 2186-2194
26 Carbone M, Sharp SJ, Flack S , et al; and the members of the UK-PBC Consortium. The UK-PBC risk scores: derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cirrhosis. Hepatology 2015; ;Jul 29. doi:10.1002/hep.28017
27 Lammers WJ, Hirschfield GM, Corpechot C , et al; Global PBC Study Group. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology 2015; 149 (7) 1804-1812.e4
28 Angulo P, Lindor KD, Therneau TM , et al. Utilization of the Mayo Risk Score in patients with primary biliary cirrhosis receiving ursodeoxycholic acid. Liver 1999; 19 (2) 115-121
29 Azemoto N, Kumagi T, Abe M , et al. Biochemical response to ursodeoxycholic acid predicts long-term outcome in Japanese patients with primary biliary cirrhosis. Hepatol Res 2011; 41 (4) 310-317
30 Poupon RE, Bonnand AM, Chrétien Y, Poupon R ; The UDCA-PBC Study Group. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Hepatology 1999; 29 (6) 1668-1671
31 Prince MI, James OF, Holland NP, Jones DE. Validation of a fatigue impact score in primary biliary cirrhosis: towards a standard for clinical and trial use. J Hepatol 2000; 32 (3) 368-373
32 Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000; 31 (2) 318-323
33 Rautiainen H, Kärkkäinen P, Karvonen AL , et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 2005; 41 (4) 747-752
34 Rabahi N, Chrétien Y, Gaouar F , et al. Triple therapy with ursodeoxycholic acid, budesonide and mycophenolate mofetil in patients with features of severe primary biliary cirrhosis not responding to ursodeoxycholic acid alone. Gastroenterol Clin Biol 2010; 34 (4–5) 283-287
35 Parés A, Guañabens N. Osteoporosis in primary biliary cirrhosis: pathogenesis and treatment. Clin Liver Dis 2008; 12 (2) 407-424
36 Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology 2003; 38 (1) 196-202
37 Rautiainen H, Karvonen AL, Karkkainen P , et al. 6 year follow up of liver histology after budesonide + UDCA combination therapy in PBC compared with UDCA monoterapy. J Hepatol 2011; 54 (Suppl): S517
38 Rautiainen H, Färkkilä M, Neuvonen M , et al. Pharmacokinetics and bone effects of budesonide in primary biliary cirrhosis. Aliment Pharmacol Ther 2006; 24 (11–12) 1545-1552
39 Schade RW, Demacker PN, van T Laar A. Letter: Reduction of serum-alkaline-phosphatase by clofibrate. Lancet 1975; 1 (7911) 862-863
40 Schaffner F. Paradoxical elevation of serum cholesterol by clofibrate in patients with primary biliary cirrhosis. Gastroenterology 1969; 57 (3) 253-255
41 Nakai S, Masaki T, Kurokohchi K, Deguchi A, Nishioka M. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study. Am J Gastroenterol 2000; 95 (1) 326-327
42 Kurihara T, Niimi A, Maeda A, Shigemoto M, Yamashita K. Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid. Am J Gastroenterol 2000; 95 (10) 2990-2992
43 Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients?. J Gastroenterol 2003; 38 (6) 573-578
44 Itakura J, Izumi N, Nishimura Y , et al. Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. Hepatol Res 2004; 29 (4) 216-222
45 Levy C, Peter JA, Nelson DR , et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther 2011; 33 (2) 235-242
46 Lens S, Leoz M, Nazal L, Bruguera M, Parés A. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int 2014; 34 (2) 197-203
47 Cuperus FJ, Halilbasic E, Trauner M. Fibrate treatment for primary biliary cirrhosis. Curr Opin Gastroenterol 2014; 30 (3) 279-286
48 Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology 2015; 62 (2) 635-643
49 Honda A, Ikegami T, Nakamuta M , et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 2013; 57 (5) 1931-1941
50 Tanaka A, Hirohara J, Nakanuma Y, Tsubouchi H, Takikawa H. Biochemical responses to bezafibrate improve long-term outcome in asymptomatic patients with primary biliary cirrhosis refractory to UDCA. J Gastroenterol 2015; 50 (6) 675-682
51 Hosonuma K, Sato K, Yamazaki Y , et al. A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol 2015; 110 (3) 423-431
52 Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 2003; 83 (2) 633-671
53 Trauner M. The nuclear bile acid receptor FXR as a novel therapeutic target in cholestatic liver diseases: hype or hope?. Hepatology 2004; 40 (1) 260-263
54 Pellicciari R, Fiorucci S, Camaioni E , et al. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002; 45 (17) 3569-3572
55 Fiorucci S, Clerici C, Antonelli E , et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther 2005; 313 (2) 604-612
56 Kowdley KV, Jones D, Luketic V , et al. An international study evaluating the farnesoid X receptor agonist obeticholic acid as monotherapy in PBC. J Hepatol 2011; 54: S13
57 Nevens F, Andreone P, Mazzella G , et al. The first primary biliary cirrhosis (PBC) phase 3 trial in two decades – an international study of the FXR agonist obeticholic acid in PBC patients. J Hepatol 2014; 60: S525
58 Mason A, Luketic VA, Lindor K , et al. Farnesoid - X receptor agonists: a new class of drugs for the treatment of PBC? An international study evaluating the addition of obeticholic acid (INT - 747) to ursodeoxycholic acid. Hepatology 2010; 52: 357A
59 Neuschwander-Tetri BA, Loomba R, Sanyal AJ , et al; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972) 956-965
60 Efe C, Ozaslan E, Kav T , et al. Liver fibrosis may reduce the efficacy of budesonide in the treatment of autoimmune hepatitis and overlap syndrome. Autoimmun Rev 2012; 11 (5) 330-334
61 Ballot E, Bandin O, Chazouilleres O, Johanet C, Poupon R. Immune response to lipopolysaccharide in primary biliary cirrhosis and autoimmune diseases. J Autoimmun 2004; 22 (2) 153-158
62 Calmus Y, Gane P, Rouger P, Poupon R. Hepatic expression of class I and class II major histocompatibility complex molecules in primary biliary cirrhosis: effect of ursodeoxycholic acid. Hepatology 1990; 11 (1) 12-15
63 Koga H, Sakisaka S, Ohishi M, Sata M, Tanikawa K. Nuclear DNA fragmentation and expression of Bcl-2 in primary biliary cirrhosis. Hepatology 1997; 25 (5) 1077-1084
64 Miura T, Ouchida R, Yoshikawa N , et al. Functional modulation of the glucocorticoid receptor and suppression of NF-kappaB-dependent transcription by ursodeoxycholic acid. J Biol Chem 2001; 276 (50) 47371-47378
65 Ikegami T, Matsuzaki Y, Fukushima S , et al. Suppressive effect of ursodeoxycholic acid on type IIA phospholipase A2 expression in HepG2 cells. Hepatology 2005; 41 (4) 896-905
66 Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014; 11 (1) 55-67
67 Luo J, Ko B, To C , et al. Hepatoprotective effects of NGM282 compared to obeticholic acid and bezafibrate in mouse models of cholestasis. J Hepatol 2014; 60 (Suppl): S531
68 Mayo M, Wigg A, Roberts S , et al. NGM282, a novel variant of FGF-19, demonstrates biologic activity in primary biliary cirrhosis patients with an incomplete response to ursodeoxycholic acid: results of a phase 2 multicenter, randomized, double blinded, placebo controlled trial. Hepatology 2015; 62: 263A
69 Baker A, Kelly D, McClean P , et al. LO4: a phase 2, randomized, placebo-controlled study (IMAGO) of LUM001, a novel inhibitor of the apical sodium-dependent bile acid transporter (ASBT), in paediatric patients with Alagille syndrome (ALGS). J Hepatol 2015; 62 (Suppl): S259
70 Baghdasaryan A, Claudel T, Gumhold J , et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO⁻ ₃ output. Hepatology 2011; 54 (4) 1303-1312
71 Hofmann AF, Zakko SF, Lira M , et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology 2005; 42 (6) 1391-1398
72 Hirschfield G, Gershwin M, Strauss R , et al. Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid: a proof-of-concept study. Hepatology 2015; ; doi:10.1002/hep.28359
73 Tsuda M, Moritoki Y, Lian ZX , et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 2012; 55 (2) 512-521
74 Myers RP, Swain MG, Lee SS, Shaheen AA, Burak KW. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol 2013; 108 (6) 933-941
75 Hochrath K, Stokes CS, Geisel J , et al. Vitamin D modulates biliary fibrosis in ABCB4-deficient mice. Hepatol Int 2014; 8 (3) 443-452
76 Guo GY, Shi YQ, Wang L , et al. Serum vitamin D level is associated with disease severity and response to ursodeoxycholic acid in primary biliary cirrhosis. Aliment Pharmacol Ther 2015; 42 (2) 221-230
77 Corpechot C, Gaouar F, Chazouilleres O , et al. Is biochemical response to ursodeoxycholic acid therapy impacted by vitamin D plasma level in patients with pri- mary biliary cirrhosis?. Hepatology 2012; 56: 1137A
78 Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman SL, Schuppan D. Inhibition of integrin alphavbeta6 on cholangiocytes blocks transforming growth factor-beta activation and retards biliary fibrosis progression. Gastroenterology 2008; 135 (2) 660-670