Fibrate treatment for primary biliary cirrhosis.

REVIEW URRENT C OPINION

Fibrate treatment for primary biliary cirrhosis Frans J.C. Cuperus, Emina Halilbasic, and Michael Trauner

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. Keywords fibrate, multidrug resistance protein 3, peroxisome proliferator activated receptor, primary biliary cirrhosis, ursodeoxycholic acid

INTRODUCTION Primary biliary cirrhosis (PBC) is an autoimmunemediated liver disease that mainly affects middleaged women [1]. The disease has an estimated incidence that ranges between 0.7 and 49 cases per million, a prevalence between 7 and 402 per million, and a male:female ratio of 1 : 10 [2–4]. PBC clusters in certain geographical areas, such as northern Europe [5,6], where long-term observational studies suggest that its incidence is increasing [7–9]. PBC is characterized by a progressive granulomatous destruction of the small bile ducts, which can lead to biliary cirrhosis, portal hypertension, and eventually death. The cause of the bile duct destruction remains enigmatic, but is thought to involve genetic and environmental factors [4,10,11]. An environmental trigger (e.g., infection, chemical, toxin) may damage the bile ducts, which results in a T-cell-mediated destruction of bile duct epithelial cells in genetically susceptible individuals [12–15]. Antimitochondrial antibodies (AMAs), the serological hallmark of PBC, are found in 95%

of these patients and target mitochondrial autoantigens such as the E2 subunits of the pyruvate dehydrogenase complex [1,16]. Most PBC patients are initially asymptomatic, but are diagnosed by a cholestatic pattern of serum liver enzymes in the presence of positive AMAs, and after the exclusion of other causes of cholestasis [17].

URSODEOXYCHOLIC ACID TREATMENT The natural course of PBC is unpredictable, but generally progressive, in individual patients

Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Wien, Austria Correspondence to Michael Trauner, MD, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Wa¨hringergu¨rtel 18-20, 1090 Wien, Austria. Tel: +43 0 1 40400 4741; fax: +43 0 1 40400 4735; e-mail: michael.trauner@meduniwien. ac.at Curr Opin Gastroenterol 2014, 30:279–286 DOI:10.1097/MOG.0000000000000056

0267-1379 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

www.co-gastroenterology.com

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Biliary tract

KEY POINTS A substantial body of observational evidence has demonstrated that fibrate treatment ameliorated liver biochemical tests in patients with an incomplete response to UDCA treatment. Fibrate treatment has anticholestatic, anti-inflammatory, and antifibrotic properties in in-vitro and animal studies. These beneficial effects are mostly mediated via PPARa and PPARg, and possibly via PXR. The results of larger, multicenter, prospective, doubleblind studies of fibrates plus UDCA, such as the BEZURSO trial that is now being conducted in France, are eagerly anticipated.

[18,19]. Ursodeoxycholic acid (UDCA), the only Food and Drug Administration-approved therapy for PBC, should therefore be administered to all patients diagnosed with PBC [20]. UDCA is well tolerated by most patients in the recommended dose of 13–15 mg/kg/day, with diarrhea being the most reported side-effect [21]. A timely diagnosis and the early use of UDCA have improved the prognosis, and decreased the need for liver transplantation, in PBC patients over the last 20 years [22–25]. UDCA not only improves liver biochemical tests, but also delays the histological progression (i.e., fibrosis, periportal inflammation, ductular proliferation) and the development of esophageal varices in PBC [26–31]. Several key studies and two meta-analyses of large clinical trials showed that long-term (>2 years) and adequately dosed UDCA treatment resulted in an improved survival free of liver transplantation [32,33]. A retrospective analysis concluded that long-term administration of 13–15 mg/kg UDCA normalized survival rates in early-stage (stage 1 or 2), but not late-stage PBC [22]. UDCA exerts its beneficial effects via several mechanisms (reviewed in [34]). UDCA shifts the bile acid pool to a more hydrophilic (i.e., less toxic) composition, and promotes the biliary excretion of (toxic)

bile acids. UDCA also protects against toxic stress, and inhibits bile acid or cytokine-induced cellular injury. UDCA has, finally, various beneficial immune-modulatory, anti-inflammatory, and antibacterial effects [34]. The response to UDCA treatment is monitored through liver biochemical tests, and can be defined with the use of several published criteria (Table 1) [26,35–40]. UDCA-responsive patients will generally show biochemical improvement within 6–9 months, and have a similar life expectancy as age and sex-matched controls [22]. In spite of its beneficial effects, UDCA remains ineffective in up to 50% of patients, depending on sex and age at diagnosis, and liver transplantation remains the only definitive treatment option for end-stage PBC [22,41,42]. Male sex and a young age proved to be independent predictors of UDCA non-response in a recent cross-sectional study of 2353 PBC patients in the United Kingdom [41]. These considerations have prompted the development of alternative and complementary treatment strategies, most of which are currently undergoing phase II and III clinical trials.

NOVEL TREATMENT STRATEGIES IN UDCA NON-RESPONDERS The treatment of patients with an incomplete biochemical response to UDCA remains a major clinical challenge, which is reflected by the numerous treatment regimens that were evaluated in these patients. Among these, only budesonide, a nonhalogenated glucocorticoid with a high receptorbinding affinity and a high first pass metabolism, is recommended by European Association for the Study of the Liver guidelines as a second-line therapy in UDCA non-responders [20]. Two clinical trials showed that budesonide (6 or 9 mg/day) combined with UDCA improved liver histology in PBC patients (stage I-III), whereas the effect of UDCA alone was limited to liver biochemical tests [43,44]. These trials, however, were not conducted in UDCA non-responders. Notably, an observational study in

Table 1. Various criteria of a biochemical response to UDCA treatment in PBC patients Criteria

Evaluation time

Definition

Barcelona [35]

1 year

#ALP >40% or ALP normalization

Paris I [26]

1 year

ALP 3 ULN, AST 2 ULN, and bilirubin 1 mg/dl

Paris II [36]

1 year

ALP and AST 1.5 ULN and normal bilirubin level

Rotterdam [37]

1 year

Normalization of abnormal serum bilirubin and/or albumin

Toronto [38]

2 years

ALP 70%

ALP, alkaline phosphatase; GGT, gamma-glutamyltransferase; ULN, upper limit of normal.

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non-responders showed that budesonide only transiently improved liver biochemical tests and led to a significant worsening of osteoporosis [45]. Budesonide treatment, in addition, is contraindicated in late-stage cirrhotic disease with portal hypertension because of severe side-effects such as portal vein thrombosis and death [46]. Obeticholic acid (6E-CDCA, INT747), a synthetic activator of the farnesoid X receptor (FXR), has also shown promising results in recent clinical trials. Activation of FXR, a key regulator in bile acid metabolism, promotes bile formation, decreases the hepatocellular bile acid load, decreases biliary toxicity, and has anti-inflammatory and antimicrobial effects (reviewed in [47]). Accordingly, FXR activation by obeticholic acid ameliorated the biochemical markers of liver damage in PBC patients that were non-responsive to UDCA alone in phase II trials [48–50]. Obeticholic acid treatment, however, induced a dose-dependent itching, which led to a substantial discontinuation rate, or to dose reduction, in the high-dose (50 mg) treatment groups. A phase III trial with a lower dosage of obeticholic acid (5–10 mg) is currently underway. Several other treatments, such as antiretrovirals and rituximab, have also been evaluated in PBC patients with an incomplete response to UDCA. Treatment with the antiretrovirals lamivudine and zidovudine, which was based upon the hypothesis of a possible retroviral cause of PBC, led to a normalization of liver biochemical tests in a pilot study [51]. This initial result, however, was not corroborated by a subsequent randomized placebo-controlled clinical trial in patients with an incomplete response to UDCA [52] and results with more potent antiretroviral regimens are awaited. Preliminary studies with rituximab, a monoclonal antibody against the CD 20 phosphoprotein (expressed mainly at the cell surface of B cells), have found an improvement of liver biochemistry in PBC patients with an incomplete response to UDCA. Although rituximabinduced selective B-cell depletion holds promise for the treatment of these patients, larger controlled clinical trials are warranted to study its long-term efficacy and safety [53,54]. Taken together, the above-mentioned results illustrate that the optimal management of UDCA-nonresponsive PBC patients remains an area of intense investigation.

FIBRATE TREATMENT IN PRIMARY BILIARY CIRRHOSIS: MECHANISM OF ACTION Fibrate treatment, which is traditionally used to treat hyperlipidemia, has been associated with a decrease in serum alkaline phosphatase (ALP) [55]. This decrease suggested that fibrates could also

benefit patients with chronic cholestatic disease, and led to their evaluation in PBC, which is associated with hyperlipidemia, and primary sclerosing cholangitis (PSC). Several case reports and pilot studies have indeed shown that fibrate treatment benefits these patients, albeit via mechanisms that are only partly understood. The current consensus is that fibrates exert their effects through activation of peroxisome proliferator-activated receptors (PPARs), which constitute their pharmacological targets. PPARs are ligand-activated nuclear receptors that play a central role in lipid and energy homeostasis [56,57]. Three PPAR isoforms exist: PPARa, PPARg, and PPARd. PPARa is mainly expressed in the liver, PPARg in adipose tissue and in the immune system, and PPARd is ubiquitously expressed [56,58]. An important rationale for the use of fibrates is their ability to stimulate the transcription and the canalicular insertion of multidrug resistance protein 3 (MDR3, Mdr2 in rodents) [59,60]. This stimulation, which was demonstrated in human hepatoma cell lines and in rodents [59–61], occurs via the binding of PPARa to response elements in the MDR3 promoter [62 ]. The resulting transactivation of MDR3 protects the hepatobiliary system by inducing phosphatidylcholine (PC) transport across the bile canalicular membrane, which renders the bile less toxic [63]. Bezafibrate, a PPARa/g/d agonist, promoted biliary phospholipid excretion in patients undergoing a percutaneous trans-hepatic biliary drainage, which provided functional evidence for fibrate-induced MDR3 activation. Interestingly, this study also showed that fibrate treatment did not increase MDR3 expression in PBC patients, likely because MDR3 was already significantly up-regulated in these patients before treatment [64,65]. This last result indicates that non-MDR3-dependent mechanisms may also contribute to the beneficial effects of fibrates in PBC. Indeed, bezafibrate treatment exerts various anticholestatic effects that are independent of MDR3 [61,66,67,68 ]. Bezafibrate treatment of a human hepatoma cell line inhibited cholesterol 7a-hydroxylase (CYP7A1), sterol 27-hydroxylase (CYP27A1), and the sodium/taurocholate co-transporting polypeptide (NTCP), which decreases bile acid synthesis (CYP7A1/CYP27A1) and uptake (NTCP) [68 ]. Repression of bile acid synthesis, however, may also be linked to known side-effects such as an increased risk of gallstone formation [67]. Bezafibrate treatment also induced cytochrome P450 3A4 (CYP3A4) in these cell lines, which promotes bile acid detoxification. These anticholestatic effects were confirmed in bezafibrate and UDCA-treated patients with early-stage PBC, who showed a reduction of 7a-hydroxy-4-cholesten-3-one (C4), a marker of bile acid synthesis, and of 4b-hydroxycholesterol, a


&&

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marker of CYP3A4 activity, as compared with patients treated with UDCA alone [68 ]. This study also suggested that bezafibrate might induce other anticholestatic nuclear receptors, such as the pregnane X receptor (PXR) [68 ], although this remains to be confirmed [69]. PPARa also had anti-inflammatory effects, and down-regulated pro-inflammatory genes in hepatocytes by antagonizing nuclear factorkB signaling [70]. PPARg, finally, did not directly interfere with bile acid metabolism, but repressed the transactivation of inflammatory response genes, and had antifibrotic effects on hepatic stellate cells [71]. The specific PPARg agonist troglitazone decreased fibrosis in a rat model of obstructive cholestasis [72]. Troglitazone, however, has currently been withdrawn from the market because of hepatotoxic side-effects. Taken together, these results show that fibrates exert their anticholestatic, anti-inflammatory, and antifibrotic effects mainly via PPARa and PPARg, and possibly via PXR. The relative contribution of these pathways, however, remains to be elucidated and may well differ between diseases, according to their underlying disease. &&

&&

FIBRATE TREATMENT IN PRIMARY BILIARY CIRRHOSIS: CLINICAL STUDIES Since the late 1990s, more than 20 studies have evaluated the effect of fibrate treatment in PBC patients, mostly in combination with UDCA (Table 2) [68 ,73 ,74–95]. Very few of these studies, however, were randomized or double-blinded, and the majority was conducted in a small number of patients over a limited period of time. Therefore, current evidence does not yet allow a recommendation for the clinical use of fibrates in PBC. Most of the studies in Table 2 investigated the effects of fibrates in patients with an incomplete or absent biochemical response to UDCA. Defining who is a biochemical responder is obviously important, as non-responders are most likely to benefit from additional fibrate treatment. The definition of an ‘UDCA nonresponder’, however, has been the subject of debate, which is reflected in the availability of published criteria (Tables 1 and 2) [26,35–40], and in the various definitions that were used in the published studies (Table 2). A uniformly accepted definition of an UDCA (non) responder is thus urgently needed, and would facilitate both the design and the interpretation of future clinical studies. So far, independent of the study design, all published studies and case series have demonstrated the efficacy of fibrates in reducing liver enzymes in patients with PBC. This decrease occurred relatively early (e.g., after 4 weeks for ALP and gamma-glutamyltransferase [74]), and was sustained during &&

282

&


long-term fibrate treatment. ALP was invariably decreased, and several studies reported ALP normalization [73 ,74,77,79,80,89,91]. However, hard evidence for the beneficial effects of fibrates, especially in patients with a higher risk of disease progression, is still missing. Several studies investigated the long-term effects of fibrate treatment, but the small number of patients precluded a survival analysis [82,83,89,90]. The impact of fibrates on histological disease progression (i.e., inflammation, fibrosis) also remains to be elucidated. Only three studies, with a total of eight patients, evaluated liver histology before and after fibrate treatment [89,90,96]. The results from these studies were mixed, and reported a mild histological improvement in half of these few cases, and a significant deterioration in one fibrate-treated patient. A recent study by Lens et al. [73 ] measured liver stiffness as a non-invasive marker for liver fibrosis, but did not find differences after 1 year of UDCA plus bezafibrate treatment. The lack of response in this study, however, may well be because of the relatively short observational period or because of variations in the applied measuring technique. Ohmoto et al. [82], in contrast, demonstrated a decrease in serum markers of liver cirrhosis (7 s collagen, IV collagen, hyaluronic acid) and a reduced aspartate transaminase platelet ratio index score in bezafibrate-treated PBC patients. As discussed in the previous section, there is a noticeable difference in ligand activity between fibrates. Although the results with respect to liver enzymes were similar, the effects on cholestasis, fibrosis, and inflammation between fenofibrate, a PPARa agonist, and bezafibrate, a PPARa/g/d agonist may certainly be diverse. It must also be noted that there is a lack of clinical studies with a mechanistic approach, and the few studies that investigate the anticholestatic mechanisms of bezafibrate in PBC have already been discussed above [65,68 ]. In addition, some individual reports addressed the anti-inflammtory properties of fibrates in PBC, and demonstrated a decreased nitrite production from dendritic cells isolated from bezafibratetreated PBC patients and reduced serum cytokines [76,84]. Finally, one should emphasize that fenofibrate treatment and bezafibrate treatment are well tolerated in PBC. Only a few of the recently performed studies reported side-effects, such as heartburn [76], pruritus [74], and a transient elevation of transaminases [88]. In addition, gallstone formation (possibly due to repression of bile acid synthesis) and paradoxical hypercholesterolemia, which were reported in PBC patients on clofibrate [97,98], were not confirmed during fenofibrate or bezafibrate &

&

&&



Fibrate treatment for primary biliary cirrhosis Cuperus et al. Table 2. Clinical studies testing fibrate treatment in PBC patients Fibrate (daily dose)

Patient number (treatment)

Tested in UDCA nonresponders?

Year

Duration (months)

2014

12

Bezafibrate (400 mg)

30 (UDCA þ bezafibrate)

Yesa

# or ALP normalization, #ALT, #GGT, #cholesterol, #TG, #pruritus, liver stiffness unchanged

Honda et al. [68 ]

2013

3



Yesb

#ALP, #ALT, #GGT, #IgM, #cholesterol, #TG, #C4, #FGF19

Han et al. [74]

2012

3–6

Fenofibrate (200 mg)

22 (UDCA þ fenofibrate)

Yesa

# or ALP normalization, #AST, #ALT, #GGT, #cholesterol, #TG

Takeuchi et al. [75]

2011

12



Yesa

# or ALP normalization, #IgM, #cholesterol, #TG

Levy et al. [76]

2011

12

Fenofibrate (160 mg)


Yesc

#ALP, #AST, #IgM, #IL1,6, "ApoAII, "ApoCII

Hazzan and Tur-Kaspa [77] Liberopoulos et al. [78]

2010

4–12


Yesb

# or ALP normalization, #GGT

2010

2

Bezafibrate (400 mg) Fenofibrate (200 mg)

6 (UDCA þ fenofibrate), 4 (UDCA), randomized

Yesd

#ALP, #ALT, #GGT, #cholesterol, #TG, #HDL

Walker et al. [79]

2009

23

Fenofibrate (134–200 mg)


Yesa

# or ALP normalization,#IgM

Iwasaki et al. [80]

2008

12


20 (Bezafibrate), 25 (UDCA), randomized

Naive

#ALP, #ALT, #GGT, #IgM, no difference between bezafibrate or UDCA monotherapy

Iwasaki et al. [80]

2008

12


12 (UDCA þ bezafibrate), 10 (UDCA), randomized

Yese

# or ALP normalization, #GGT, #IgM

Iwasaki et al. [96]

2007

not stated



Yesb

# or liver enzymes normalization (68%), progressive course of disease (32%), liver biopsy: improvement in 2 out of 3 cases

Kita et al. [81]

2006

6


22 (UDCA þ bezafibrate or bezafibrate monotherapy)

#ALP, #GGT, #IgM

Ohmoto et al. [82]

2006

24–88



5 Naive, 17 not stated 6 Naive, 11 not stated

Nakamuta et al. [83]

2005

25–53

5 (UDCA þ bezafibrate or fenofibrate)

Not stated

#ALP, #ALT, #GGT, #IgM, #AMA

Akbar et al. [84]

2005

12

Bezafibrate (400 mg) or fenofibrate (150 mg) Bezafibrate (400 mg)

16 (10 UDCA þ bezafibrate, 6 bezafibrate monotherapy)

10 Yesb, 6 naive

#ALP, #GGT, #cholesterol, #IgM, #nitrite production in isolated dendritic cells (as a measure for autoimmune disease progression)

Itakura et al. [85]

2004

12


9 (UDCA þ bezafibrate), 7 (UDCA), randomized cross–over

Not stated

#ALP, #GGT, #IgM, #TG

Dohmen et al. [86]

2004

3


Yesf

#ALP, #IgM, and partially # in AMA titer

Kanda et al. [87]

2003

6

Fenofibrate (100 or 150 mg) Bezafibrate (400 mg)

11 (UDCA þ bezafibrate), 11 (UDCA), randomized

Yesb

#ALP, #GGT, bile acids unchanged

Author Lens et al. [73 ] &

&&


Outcome

#serum markers of fibrosis (7s collagen, IV collagen, HA), #APRI score


283


Biliary tract Table 2 (Continued)

Author

Year

Duration (months)

Ohira et al. [88]

2002

6

Yano et al. [89]

2002

Kurihara et al. [90]

Fibrate (daily dose)

Patient number (treatment)

Tested in UDCA nonresponders? b

Outcome

Fenofibrate (150–200 mg)


Yes

#ALP, #GGT, #IgM

72–78


1 (UDCA þ bezafibrate), 1 (bezafibrate)

1 Naive, 1 yesf

Normalization of ALP, progression of disease in liver histology in case 1 and stabilization in case 2

2002

36–60


3 (Bezafibrate)

Not stated

Case 1 and 2: #portal inflammation, case 3: no deterioration in liver histology (yearly biopsies during 3–5 years of bezafibrate treatment)

Ohmoto et al. [91]

2001

12



Yesf

# or normalization of ALP, GGT, ALT, and IgM, #fatigue and pruritus

Kurihara et al. [92]

2000

12


12 (Bezafibrate), 12 (UDCA), randomized

Naive

#ALP, #GGT, #IgM, bezafibrate monotherapy more effective than UDCA

Nakai et al. [93]

2000

12

#ALP, #GGT, #IgM

2000

6

10 (UDCA þ bezafibrate), 13 (UDCA), randomized 13 (UDCA þ bezafibrate)

Not stated

Miyaguchi et al. [94]

Bezafibrate (400 mg) Bezafibrate (not stated)

Yesb

#ALP, #ALT, #GGT, #IgM, #IgG

Iwasaki et al. [95]

1999

12–21


11 (7 UDCA þ bezafibrate, 4 bezafibrate)

9 Yesf, 2 naive

#ALP, #ALT, #GGT, #IgM #fatigue and pruritus

ALP, alkaline phosphatase; ALT, alanine transaminase; AMA, antimitochondrial antibody; APRI, aspartate transaminase platelet ratio index; AST, aspartate transaminase; GGT, gamma-glutamyltransferase; HDL, high-density lipoprotein; PBC, primary biliary cirrhosis; TG, triglycerides; UDCA, ursodeoxycholic acid. a Barcelona criteria. b ALP > ULN. c Toronto criteria. d Paris I criteria. e Paris II criteria. f Not clearly stated.

treatment in PBC, although it must be noted that the sample size of the original studies was very small.

CONCLUSION A large number of pilot studies and case reports have now convincingly demonstrated that fenofibrate treatment and bezafibrate treatment are well tolerated and ameliorate the liver biochemistry of PBC patients with an incomplete response to UDCA. Its mechanism of action is likely multifactorial and mediated via PPARa, PPARg, and possibly PXR. Animal and in-vitro data have, in addition, shown not only anticholestatic, but also anti-inflammatory and antifibrotic effects of fibrate treatment. Whether fibrate treatment improves the survival free of liver transplantation in PBC patients remains to be investigated. Taken together, these observations demonstrate the need for double-blind multicenter phase III trials for fibrate treatment in PBC patients. Such a study could significantly alter 284


the therapeutic approach to PBC and is, as remarked by others, already overdue. The results of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis (BEZURSO) phase III trial (clinicaltrails.gov, NCT01654731), which is expected to end in 2015, are therefore eagerly anticipated. Acknowledgements This work was supported by funding from the Austrian Science Fund (FWF) project ‘Transmembrane Transporters in Health and Disease’ (F3517; to Michael Trauner), and by an EASL Dame Sheila Sherlock short-term fellowship (to Frans Cuperus). M.T. has received consultancy fees from Falk Phrama and Phenex; unrestricted research grants from Falk Pharma, Intercept and MSD; lecture fees (speaker’s bureau) from Falk Foundation, MSD, Gilead and Roche; travel support from Falk Founation, Gilead and Roche and acts as an advisor for Phenex. The Medical University of Graz has filed a patent on the medical use of norUDCA and M.T. is listed as co-inventor. Volume 30 Number 3 May 2014


Fibrate treatment for primary biliary cirrhosis Cuperus et al.

Conflicts of interest For the remaining authors, no potential conflicts of interest were declared.

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Primary biliary cirrhosis. Foreword.

Primary biliary cirrhosis.

New therapies for primary biliary cirrhosis.

Primary Biliary Cirrhosis: Challenges for the Future.

Women and primary biliary cirrhosis.

Primary biliary cirrhosis in 2014.

Primary biliary cirrhosis in adults.

Pregnancy in primary biliary cirrhosis.

Primary biliary cirrhosis in brothers.

Cyclosporine in primary biliary cirrhosis.

Arthritis and primary biliary cirrhosis.

Arthritis and primary biliary cirrhosis.

Susceptibility to primary biliary cirrhosis.

[Successful treatment of primary biliary cirrhosis with cyclosporin].

Prednimustin treatment in primary biliary cirrhosis: a preliminary study.

Treatment of pruritus of primary biliary cirrhosis with rifampin.

Environmental factors in primary biliary cirrhosis.

Primary biliary cirrhosis: new therapeutic directions.

Polymyalgia rheumatica and primary biliary cirrhosis.

Polymyalgia rheumatica and primary biliary cirrhosis.

Primary biliary cirrhosis in mother and daughter.

Lymphadenopathy in primary biliary cirrhosis: CT observations.

Primary biliary cirrhosis and adult celiac disease.

Diagnosis and management of primary biliary cirrhosis.