Fibrate treatment for primary biliary cirrhosis

Purpose of review Primary biliary cirrhosis (PBC) can lead to end-stage liver disease and death. Ursodeoxycholic acid (UDCA) treatment can normalize serum liver enzymes in PBC, and such UDCA-responsive patients have a similar life expectancy as age and sex-matched controls. Nearly up to 50% of the patients with PBC, depending on sex and age at diagnosis, show an incomplete biochemical response to UDCA and require additional/alternative treatment. The purpose of this review is to critically evaluate the molecular mechanisms and clinical benefit of fibrate treatment in these patients. Recent findings Fibrates have anticholestatic, anti-inflammatory, and antifibrotic effects in animal and in-vitro studies. The mechanisms that underlie these effects are complementary, and largely mediated through activation of peroxisome proliferator activated receptors. Fibrate treatment ameliorated liver biochemical tests in UDCA unresponsive patients, either as mono-therapy or in combination with UDCA. These results, however, were obtained in case series and small pilot studies. The results of phase III studies, such as the Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis (BEZURSO) trial, are currently awaited. Summary A considerable body of observational evidence supports the safety and efficacy of fibrate treatment in PBC patients with an incomplete response to UDCA. These results encourage the evaluation of its effects on liver-related morbidity and mortality in larger clinical trials.

[1]  C. Ponsioen,et al.  Rising incidence and prevalence of primary biliary cirrhosis: a large population‐based study , 2014, Liver international : official journal of the International Association for the Study of the Liver.

[2]  J. Boyer,et al.  Peroxisome proliferator‐activated receptor α activates human multidrug resistance transporter 3/ATP‐binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion , 2014, Hepatology.

[3]  S. Lens,et al.  Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid , 2014, Liver international : official journal of the International Association for the Study of the Liver.

[4]  M. Swain,et al.  B-Cell Depletion With Rituximab in Patients With Primary Biliary Cirrhosis Refractory to Ursodeoxycholic Acid , 2013, The American Journal of Gastroenterology.

[5]  J. Boyer,et al.  Fibrates as adjuvant therapy for chronic cholestatic liver disease: Its time has come , 2013, Hepatology.

[6]  A. Baghdasaryan,et al.  Nuclear Receptors as Drug Targets in Cholestatic Liver Diseases , 2013, Clinics in liver disease.

[7]  G. Alexander,et al.  Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. , 2013, Gastroenterology.

[8]  R. Poupon.  Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases: an overview of their mechanisms of action. , 2012, Clinics and research in hepatology and gastroenterology.

[9]  B. Ludviksson,et al.  The epidemiology and natural history of primary biliary cirrhosis: a nationwide population-based study , 2012, European journal of gastroenterology & hepatology.

[10]  Xiong Ma,et al.  Efficacy of fenofibrate in Chinese patients with primary biliary cirrhosis partially responding to ursodeoxycholic acid therapy , 2012, Journal of digestive diseases.

[11]  K. Lindor,et al.  Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid , 2012, Hepatology.

[12]  O. Chazouilleres,et al.  Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. , 2011, Journal of hepatology.

[13]  A. Takaki,et al.  Additive improvement induced by bezafibrate in patients with primary biliary cirrhosis showing refractory response to ursodeoxycholic acid , 2011, Journal of gastroenterology and hepatology.

[14]  Y. Hiasa,et al.  Biochemical response to ursodeoxycholic acid predicts long‐term outcome in Japanese patients with primary biliary cirrhosis , 2011, Hepatology research : the official journal of the Japan Society of Hepatology.

[15]  R. Chapman,et al.  28 AN INTERNATIONAL STUDY EVALUATING THE FARNESOID X RECEPTOR AGONIST OBETICHOLIC ACID AS MONOTHERAPY IN PBC , 2011 .

[16]  K. Lindor,et al.  Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid , 2011, Alimentary pharmacology & therapeutics.

[17]  T. Arenovich,et al.  Baseline Ductopenia and Treatment Response Predict Long-Term Histological Progression in Primary Biliary Cirrhosis , 2010, The American Journal of Gastroenterology.

[18]  R. Poupon.  Primary biliary cirrhosis: a 2010 update. , 2010, Journal of hepatology.

[19]  M. Elisaf,et al.  Fenofibrate in Primary Biliary Cirrhosis: A Pilot Study , 2010, The open cardiovascular medicine journal.

[20]  R. D. de Man,et al.  Trends in liver transplantation for primary biliary cirrhosis in the Netherlands 1988-2008 , 2009, BMC gastroenterology.

[21]  R. Tur-kaspa,et al.  Bezafibrate Treatment of Primary Biliary Cirrhosis Following Incomplete Response to Ursodeoxycholic Acid , 2009, Journal of clinical gastroenterology.

[22]  M. Kaplan,et al.  Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma , 2009, Hepatology.

[23]  Y. Maehara,et al.  The state of cholesterol metabolism in the liver of patients with primary biliary cirrhosis: the role of MDR3 expression , 2009, Hepatology international.

[24]  Y. Hiasa,et al.  Early biochemical response to ursodeoxycholic acid predicts symptom development in patients with asymptomatic primary biliary cirrhosis , 2009, Journal of Gastroenterology.

[25]  K. V. van Erpecum,et al.  Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. , 2009, Gastroenterology.

[26]  J. Newton,et al.  Comment on biochemical response to ursodeoxycholic acid and long‐term prognosis in primary biliary cirrhosis , 2009, Hepatology.

[27]  C. Vincent,et al.  Portal hypertension and primary biliary cirrhosis: effect of long-term ursodeoxycholic acid treatment. , 2008, Gastroenterology.

[28]  B. Bacon,et al.  Clinical trial: randomized controlled study of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol , 2008, Alimentary pharmacology & therapeutics.

[29]  Y. Chrétien,et al.  Biochemical response to ursodeoxycholic acid and long‐term prognosis in primary biliary cirrhosis , 2008, Hepatology.

[30]  S. Kaneko,et al.  The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study , 2008, Hepatology research : the official journal of the Japan Society of Hepatology.

[31]  I. Mackay,et al.  The causes of primary biliary cirrhosis: Convenient and inconvenient truths , 2007, Hepatology.

[32]  S. Friedman,et al.  Transplantation trends in primary biliary cirrhosis. , 2007, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[33]  T. Saibara,et al.  Fibrate for treatment of primary biliary cirrhosis , 2007, Hepatology research : the official journal of the Japan Society of Hepatology.

[34]  J. Talwalkar,et al.  Clinical Epidemiology of Primary Biliary Cirrhosis: Incidence, Prevalence, and Impact of Therapy , 2007, Journal of clinical gastroenterology.

[35]  V. Salomaa,et al.  Prevalence and incidence of primary biliary cirrhosis are increasing in Finland , 2007, Scandinavian journal of gastroenterology.

[36]  R. Evans,et al.  Anatomical Profiling of Nuclear Receptor Expression Reveals a Hierarchical Transcriptional Network , 2006, Cell.

[37]  H. Kokuryu,et al.  Bezafibrate may attenuate biliary damage associated with chronic liver diseases accompanied by high serum biliary enzyme levels , 2006, Journal of Gastroenterology.

[38]  Liang Zhu,et al.  Long-Term Effects of Mid-Dose Ursodeoxycholic Acid in Primary Biliary Cirrhosis: A Meta-analysis of Randomized Controlled Trials , 2006, The American Journal of Gastroenterology.

[39]  Shinichiro Yamamoto,et al.  Long-term effect of bezafibrate on parameters of hepatic fibrosis in primary biliary cirrhosis , 2006, Journal of Gastroenterology.

[40]  A. Branch,et al.  Increased prevalence of primary biliary cirrhosis near superfund toxic waste sites , 2006, Hepatology.

[41]  J. Rodés,et al.  Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. , 2006, Gastroenterology.

[42]  A. Vercelli,et al.  Thiazolidinedione treatment inhibits bile duct proliferation and fibrosis in a rat model of chronic cholestasis. , 2005, World journal of gastroenterology.

[43]  K. Kotoh,et al.  Long-term fibrate treatment for PBC , 2005, Journal of Gastroenterology.

[44]  M. Färkkilä,et al.  Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: A three‐year randomized trial , 2005, Hepatology.

[45]  B. P. Kota,et al.  An overview on biological mechanisms of PPARs. , 2005, Pharmacological research.

[46]  F. Carrat,et al.  The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. , 2005, Gastroenterology.

[47]  M. Abe,et al.  Therapeutic efficacy of decreased nitrite production by bezafibrate in patients with primary biliary cirrhosis , 2005, Journal of Gastroenterology.

[48]  J. Neuberger,et al.  Pilot Studies of Single and Combination Antiretroviral Therapy in Patients with Primary Biliary Cirrhosis , 2004, The American Journal of Gastroenterology.

[49]  K. Okazaki,et al.  Multidrug resistance3 is in situ detected in the liver of patients with primary biliary cirrhosis, and induced in human hepatoma cells by bezafibrate. , 2004, Hepatology research : the official journal of the Japan Society of Hepatology.

[50]  Y. Sugiyama,et al.  Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARalpha-mediated redistribution of ABCB4. , 2004, Journal of lipid research.

[51]  M. Kurosaki,et al.  Prospective randomized crossover trial of combination therapy with bezafibrate and UDCA for primary biliary cirrhosis. , 2004, Hepatology research : the official journal of the Japan Society of Hepatology.

[52]  R. Gish,et al.  Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. , 2004, Gastroenterology.

[53]  Kyosuke Yamamoto,et al.  Fenofibrate for patients with asymptomatic primary biliary cirrhosis. , 2004, World journal of gastroenterology.

[54]  O. James,et al.  The epidemiology of primary biliary cirrhosis. , 2003, Clinics in liver disease.

[55]  T. Sauerbruch,et al.  Pharmacokinetics and pharmacodynamic action of budesonide in early‐ and late‐stage primary biliary cirrhosis , 2003, Hepatology.

[56]  K. Lindor,et al.  Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. , 2003, Journal of hepatology.

[57]  J. Neuberger,et al.  Does a betaretrovirus infection trigger primary biliary cirrhosis? , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[58]  K. Lam,et al.  Immunization with a Xenobiotic 6-Bromohexanoate Bovine Serum Albumin Conjugate Induces Antimitochondrial Antibodies1 , 2003, The Journal of Immunology.

[59]  B. Staels,et al.  Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. , 2003, The Biochemical journal.

[60]  T. Ueno,et al.  Fenofibrate treatment in patients with primary biliary cirrhosis , 2002, American Journal of Gastroenterology.

[61]  H. Ishibashi,et al.  Is bezafibrate histologically effective for primary biliary cirrhosis? , 2002, American Journal of Gastroenterology.

[62]  B Staels,et al.  Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-&agr;–Mediated Downregulation of Cholesterol 7&agr;-Hydroxylase and Sterol 27-Hydroxylase Expression , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[63]  A. Tanaka,et al.  Detection of antimitochondrial autoantibodies in immunofluorescent AMA‐negative patients with primary biliary cirrhosis using recombinant autoantigens , 2001, Hepatology.

[64]  Y. Mitsui,et al.  Effect of bezafibrate in primary biliary cirrhosis: a pilot study. , 2001, Liver.

[65]  J. Neuberger,et al.  Transplantation for primary biliary cirrhosis: Retrospective analysis of 400 patients in a single center , 2001, Hepatology.

[66]  H. Saito,et al.  A novel treatment for refractory primary biliary cirrhosis? , 2000, Hepato-gastroenterology.

[67]  B. Staels,et al.  Induction of IκBα Expression as a Mechanism Contributing to the Anti-inflammatory Activities of Peroxisome Proliferator-activated Receptor-α Activators* , 2000, The Journal of Biological Chemistry.

[68]  T. Willson,et al.  Peroxisome Proliferator-activated Receptors and Hepatic Stellate Cell Activation* , 2000, The Journal of Biological Chemistry.

[69]  J. Chiang,et al.  Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. , 2000, Journal of lipid research.

[70]  E. Dickson,et al.  Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid , 2000, Hepatology.

[71]  H. Ackermann,et al.  Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. , 1999, Gastroenterology.

[72]  S. Iwasaki.  Bezafibrate may have a beneficial effect in pre-cirrhotic primary biliary cirrhosis , 1999 .

[73]  D. Howel,et al.  Primary biliary cirrhosis once rare, now common in the United Kingdom? , 1999, Hepatology.

[74]  T. Therneau,et al.  Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial. , 1999, Journal of hepatology.

[75]  B. Balkau,et al.  Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression , 1999, Hepatology.

[76]  David C. Jones,et al.  Familial primary biliary cirrhosis reassessed: a geographically-based population study. , 1999, Journal of hepatology.

[77]  K. Lindor,et al.  Primary biliary cirrhosis , 1998, Springer Netherlands.

[78]  T. Therneau,et al.  Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis. , 1997, Mayo Clinic proceedings.

[79]  E. Dickson,et al.  Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. , 1997, Gastroenterology.

[80]  R. Bhopal,et al.  Incidence and prevalence of primary biliary cirrhosis in the city of Newcastle upon Tyne, England. , 1997, International journal of epidemiology.

[81]  B. Combes,et al.  Ursodeoxycholic Acid in Primary Biliary Cirrhosis , 1997, Seminars in liver disease.

[82]  David E. J. Jones,et al.  Natural history of early primary biliary cirrhosis , 1996, The Lancet.

[83]  M. Feher,et al.  The effect of bezafibrate treatment on serum alkaline phosphatase isoenzyme activities. , 1993, Metabolism: clinical and experimental.

[84]  M. Kaplan,et al.  Primary Biliary Cirrhosis , 1987, The New England journal of medicine.

[85]  S. Sherlock,et al.  Effects of clofibrate in primary biliary cirrhosis hypercholesterolemia and gallstones. , 1975, Gastroenterology.

[86]  G. Práctica,et al.  European Association for the Study of the Liver , 1971 .

[87]  F. Schaffner,et al.  Paradoxical elevation of serum cholesterol by clofibrate in patients with primary biliary cirrhosis. , 1969, Gastroenterology.

[88]  T. Miyazaki,et al.  AUTOIMMUNE , CHOLESTATIC , AND BILIARY DISEASE Anticholestatic Effects of Bezafibrate in Patients with Primary Biliary Cirrhosis Treated with Ursodeoxycholic Acid , 2013 .

[89]  Y. Maehara,et al.  Therapeutic effect of bezafibrate against biliary damage: a study of phospholipid secretion via the PPARalpha-MDR3 pathway. , 2010, International journal of clinical pharmacology and therapeutics.

[90]  F. Lammert,et al.  EASL Clinical Practice Guidelines: management of cholestatic liver diseases. , 2009, Journal of hepatology.

[91]  M. Trauner,et al.  Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases , 2008, Wiener Medizinische Wochenschrift.

[92]  O. Yokosuka,et al.  Bezafibrate treatment: a new medical approach for PBC patients? , 2003, Journal of Gastroenterology.

[93]  T. Kurihara,et al.  Investigation into the efficacy of bezafibrate against primary biliary cirrhosis, with histological references from cases receiving long term monotherapy , 2002, American Journal of Gastroenterology.

[94]  B. Staels,et al.  Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. , 2000, The Journal of biological chemistry.

[95]  T. Kurihara,et al.  Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid , 2000, American Journal of Gastroenterology.

[96]  T. Masaki,et al.  Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study , 2000, American Journal of Gastroenterology.

[97]  P. Katz,et al.  Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis , 1999, American Journal of Gastroenterology.

[98]  W. Wahli,et al.  Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. , 1996, Endocrinology.