While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein–coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

Abbreviations

AASLD: American Association for the Study of Liver Diseases
ACG: American College of Gastroenterology
AE2: Apical chloride/bicarbonate exchanger
ALP: Serum alkaline phosphatase
ALT: Alanine transaminase IL 12
AMA: Antimitochondrial antibody
ASBT: Apical sodium-dependent bile acid transporter
ATRA: All-trans retinoic acid
BSEP: Bile salt export pump
C4: 7a-hydroxy-4-cholesten-3-one
CD: Crohn's disease
CFTR: Cystic fibrosis transmembrane conductance regulator
CTLA-4: Cytotoxic T-lymphocyte antigen 4
CVC: Cenicriviroc
CYP3A4: Cytochrome P450 3A4
CYP7A1: Cytochrome P450 7A1-hydroxylase
FGF-19: Fibroblast growth factor 19
FXR: Farnesoid X nuclear receptor
GLP-1: glucagon-like peptide 1
HDL: High-density lipoprotein
IBD: Inflammatory bowel disease
LOXL2: Lysyl oxidase-like 2
MDR1: Multidrug resistance protein 1
MDR3: Multidrug resistance protein 3
MRP2: Multidrug resistance-associated protein 2
MRP3: Multidrug resistance-associated protein
MRS: Mayo Risk Score
NF-κB: Nuclear factor kappa B
norUDCA: 24 nor-ursodeoxycholic acid
NTCP: Sodium-taurocholate cotransporting polypeptide
OATP: Organic anion-transporting polypeptide
OCA: Obeticholic acid
OST: Organic solute transporter
PBC: Primary biliary cholangitis
PPAR: Peroxisome proliferator-activated receptor
PSC: Primary sclerosing cholangitis
PXR: Pregnane X receptor
QALY: Quality-adjusted life year
RXR: Retinoid X receptor
STAT: Signal transducer and activator of transcription
SULT2A1: Sulphotransferase family 2A member 1
TGR5: Transmembrane G-protein–coupled receptor 5
TUDCA: Tauroursodeoxycholate
UC: Ulcerative colitis
UDCA: Ursodeoxycholic acid
UGT1A1: UDP glucuronosyltransferase family 1 member A1
ULN: Upper limit of normal

Key points

Patients with primary biliary cholangitis (PBC) who do not respond to ursodeoxycholic acid (UDCA) have an increased risk of developing complications of cirrhosis, including clinical decompensation, hepatocellular carcinoma and death.
Obeticholic acid is approved as the second-line therapy for PBC and is indicated for non-responders to UDCA or patients who are intolerant to UDCA.
There is no approved medical therapy for primary sclerosing cholangitis.
Many novel therapies targeting nuclear and surface receptors involved in bile acid signalling are currently under evaluation for cholestatic liver diseases, including agonists of FXR, PPAR, PXR and TGR5, among others, with promising results.

1 INTRODUCTION

Cholestasis is defined as a condition where bile flow is decreased, either due to impaired secretion by hepatocytes or by obstruction to the bile flow. Primary cholestatic liver diseases affecting adults are mainly primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). PBC is a rare disease in which a chronic, immune-mediated injury to the small intrahepatic bile ducts leads to an imbalance between cholangiocyte proliferation and apoptosis, with resulting ductopaenia, fibrosis and eventually biliary cirrhosis.1 The diagnosis is made by a combination of unexplained biochemical cholestasis and a positive antimitochondrial antibody (AMA) titre, which is found in greater than 90% of patients.2 When AMAs are not detected, a PBC diagnosis can be confirmed by the presence of PBC-specific antinuclear antibodies or typical findings on histology. Only 2 drugs have received FDA approval for the treatment of PBC: ursodeoxycholic acid (UDCA), as the first-line therapy, and obeticholic acid (OCA), for UDCA non-responders or intolerance to UDCA. Approximately 40% of patients with PBC fail to respond to UDCA, and only half of those respond to OCA.3 Non-responders to treatment with UDCA and/or OCA are at risk for progression to biliary cirrhosis, end-stage liver disease and death or liver transplantation.4

Primary sclerosing cholangitis affects predominantly medium- to large-sized bile ducts, with progressive inflammation and fibrosis leading to multifocal biliary strictures. Effective medical therapy is not available for PSC; therefore, the disease invariably progresses towards biliary cirrhosis at variable rates. Moreover, patients with PSC may develop dominant strictures and bacterial cholangitis in addition to having an increased risk for malignancies. Liver transplantation is the only definitive treatment and its rates have remained stable since the 1990s.5 Identifying an effective medical therapy for PSC is one of the greatest unmet needs in hepatology. A comparison of the clinical features of PBC and PSC is highlighted in Table 1.

Table 1. Characteristics of PBC and PSC

	Primary biliary cholangitis1, 109, 110	Primary sclerosing cholangitis111, 112
Pathogenesis	Multifactorial; genetic susceptibility, immune mediated with loss of tolerance to self-antigen (pyruvate dehydrogenase complex), defective bicarbonate umbrella.1, 113	Multifactorial; genetic susceptibility, increased exposure to bacterial products, abnormal lymphocyte homing, toxic bile.111, 113
Disease hallmark	(+) Antimitochondrial antibodies	(+) Multifocal biliary strictures/beading of bile ducts on cholangiogram
Size of bile ducts involved	Small to medium	Medium to large
Classic histopathology	Florid duct lesion114	Onion skinning115
Gender predominance	Women >>> men	Men > women
Average age of onset (y)	40-50	30-40
Incidence (per 10 000 people)	0.33-5.8116	0-1.3116
Prevalence (per 10 000 people)	1.91-40116	0-16.2116
Association with IBD	No	Yes, in 50%-75%
Complications	Biliary cirrhosis, portal hypertension	Biliary cirrhosis, portal hypertension, dominant bile duct strictures (in 50%), bacterial cholangitis
Risk for malignancy	Hepatocellular carcinoma in cirrhotics, especially males and non-responders to UDCA.	Cholangiocarcinoma (lifetime risk up to 20%), gallbladder adenocarcinoma, colorectal neoplasia (in patients with PSC-IBD). Rarely, hepatocellular carcinoma.
Disease-modifying treatment	First line: UDCA Second line: OCA	No approved therapy
Transplant-free survival	UDCA-treated patients: 90% at 5 y, 78% at 10 y and 67% at 15 y.117, 118	10-21 y from diagnosis to transplant or PSC-related death.5, 119, 120
Ranking as indication for liver transplantation in the US (2016-2017)a	6^th	5^th
10-y patient survival after liver transplantation	76%-94%121, 122	83%123, 124
Disease recurrence after liver transplantation	Yes, 9.6%-34% at 5 y121	Yes, 20%-37% at 5 y121, 123

IBD, inflammatory bowel disease; OCA, obeticholic acid; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid.
^a Based on OPTN data as of 1 January 2018 (https://optn.transplant.hrsa.gov/data/view-data-reports/build-advanced/).

2 BILE ACID HOMOEOSTASIS, SIGNALLING PATHWAYS AND TARGETS FOR THERAPY

Given the liver involvement in their synthesis and transport, the liver is exposed to very high concentrations of bile acids. While their detergent-like properties help with digestion, leakage and accumulation of bile acids in hepatocytes at higher concentrations may lead to activation of cholangiocytes, causing chronic inflammation, proliferation, apoptosis and subsequently fibrosis.6-8 Bile acids are thought to play a key role in the progression of both PBC and PSC.

The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver from cholesterol by the rate limiting enzyme cytochrome P450 7A1-hydroxylase (CYP7A1). Prior to secretion into the bile canaliculi, they undergo conjugation with taurine or glycine to form bile salts which decrease passive reabsorption. Once in the bowel, these primary bile salts undergo dehydroxylation and deconjugation by the gut microbiota, forming the secondary acids deoxycholic acid, lithocholic acid and UDCA. Although a small amount of bile acids are reabsorbed passively in the upper intestine, 90%-95% of them are reabsorbed in the terminal ileum through the apical sodium-dependent bile acid transporter (ASBT).9, 10 Bile acids then enter the portal circulation via transport by organic solute transporter (OST) α/β and are subsequently taken back into the hepatocyte through the sodium-taurocholate cotransporting polypeptide (NTCP) or the organic anion-transporting polypeptide (OATP). This process is known as the enterohepatic circulation and it is tightly regulated by numerous feedback mechanisms to protect the hepatocytes from bile acid-induced cytotoxicity (Figure 1).

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Enterohepatic circulation (EC) involves the production and maintenance of bile flow from production through recycling in the liver, biliary system, and intestines. EC begins with the production of the primary BA, CA and CDCA, via the rate limiting enzyme CYP7A1. After conjugation the BA are secreted into the bile canaliculi, mainly through BSEP, where a portion of the bile undergoes re-uptake via the periductular capillary plexus and subsequent resecretion (cholehepatic shunting); this increases bile flow and augments the bicarbonate-rich choleresis (bicarbonate umbrella). After assisting with digestion in the intestines, BA are reabsorbed via ABST. BA bind FXR in both the intestines and liver causing subsequent downregulation of CYP7A1. BA make their way back to the liver by portal circulation and are recycled, completing EC. AE2, apical chloride/bicarbonate exchanger; ASBT, apical sodium-dependent bile acid transporter; BA, bile acid; BSEP, bile salt export pump; CA, cholic acid; CDCA, chenodeoxycholic acid; CFTR, cystic fibrosis transmembrane conductance regulator; Cl-, chloride; CYP7A1, cytochrome P450 7A1-hydroxylase; FGF4, fibroblast growth factor 14; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; HCO3-, bicarbonate; MDR1, multidrug resistance protein 1; MDR3, multidrug resistance protein 3; MRP2, multidrug resistance-associated protein 2; NTCP, sodium-taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; OST, organic solute transporter; PPAR, peroxisome proliferator-activated receptor

The main negative feedback mechanism regulating bile acid homoeostasis is via the farnesoid X nuclear receptor (FXR). In the enterocytes, bile acids bind FXR, triggering a signalling cascade which ultimately downregulates CYP7A1, thus decreasing the synthesis of bile acids. Importantly, one of the pathways to suppress CYP7A1 activity is through upregulation of the enteral hormone fibroblast growth factor 19 (FGF-19). Once secreted in the portal circulation, FGF-19 reaches the hepatocyte, where it binds to its receptor, the fibroblast growth factor 4/β klotho complex, to inhibit CYP7A1 gene transcription. Furthermore, FXR activation leads to downregulation of the intestinal bile acid transporter ASBT, the hepatic uptake transporters NTCP and OATP and upregulation of the hepatic efflux transporters bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2).11, 12

Other important defence mechanisms include (1) the bicarbonate umbrella, (2) cholehepatic shunting, and (3) anti-inflammatory signalling. The bicarbonate umbrella, thought to be defective in PBC and PSC, refers to the alkalinization of bile via increased bicarbonate secretion. The elevated pH shifts bile acids towards an ionized form, decreasing their ability to diffuse and lessening their cytotoxic effects.13, 14 Similarly, cholehepatic shunting occurs when bile acids are recirculated between hepatocytes and cholangiocytes through the periductular capillary plexus, thus increasing bile flow and augmenting bicarbonate-rich choleresis.11, 15 Finally, bile acids can modulate inflammatory pathways via binding to a variety of nuclear and surface receptors (ie FXR, TGR5 and PXR) throughout the intestines and bile ducts.16 By altering or overwhelming these defence mechanisms, PBC and PSC can further progress.

3 IMMUNOPATHOLOGY

Cholangiocytes recognize the presence of pathogens through pattern recognition receptors (PRR), such as the toll-like receptors, which are activated in the presence of pathogen-associated molecular patterns (PAMPs). Activation of these PRRs triggers a signalling cascade which results in the expression of various cytokines and chemokines, immunoglobulins and adhesion molecules.17 Histological samples from PBC and PSC patients show a strong lymphocytic predominance, with the majority being CD4+ T cells, along with the presence of CD8+ T cells, B cells, macrophages and natural killer cells. These immune cells are able to release a number of mediators with diverse activity including pro- and anti-inflammatory, angiogenic, fibrogenic and proliferative, which are directly affected by bile acids.18 For instance, accumulation of hydrophobic bile acids can blunt the inflammatory cytokine response, inhibit lymphocyte proliferation and impair clearance of apoptotic cholangiocytes. The ineffective removal of apoptotic bodies is important in the pathogenesis of immune-mediated liver diseases, since the exposure of intracellular components generates activation of the immune system by unrecognized self-antigens. This understanding remains the basis for consideration of immunomodulatory therapies for cholestatic liver diseases, including drugs that regulate T-cell activation, such as abatacept, or deplete the pool of B cells, such as rituximab.

4 EXISTING THERAPIES

4.1 Ursodeoxycholic acid

Ursodeoxycholic acid was approved in 1997 for use in PBC at a dose of 13-15 mg/kg/d. The beneficial effects of UDCA are due to an increase in the ratio of hydrophilic to hydrophobic bile acids, stimulation of bile flow through BSEP, stabilization of the bicarbonate umbrella and antiapoptotic as well as anti-inflammatory effects.16, 19, 20 In addition to improvement in liver biochemistries, studies have shown that UDCA delays histological progression, delays the development of oesophageal varices and improves survival free of liver transplantation.21-23 UDCA should be used as the first-line therapy for all patients with PBC.

The American Association for the Study of Liver Diseases (AASLD) recommends against the use of UDCA as medical therapy in PSC, as beneficial data regarding its long-term use are lacking and doses >28 mg/kg/d have been associated with worse outcomes compared to placebo.24, 25 However, some experts still use UDCA for PSC in dosages of 17-23 mg/kg/d in hopes of decreasing serum alkaline phosphatase (ALP),26 as studies have shown a survival benefit in patients who normalized ALP either spontaneously or as a result of treatment with UDCA.27-29 Notably, recent guidelines from the American College of Gastroenterology (ACG) emphasize that doses greater than 28 mg/kg/d should not be used, but defer to the treating physician whether or not to use median doses (17-23 mg/kg/d).30

4.2 Obeticholic acid

The natural ligand for FXR is chenodeoxycholic acid. Obeticholic acid (OCA), a 6-ethyl derivative of chenodeoxycholic acid with 100 times its potency, functions as a strong FXR agonist.31 In addition to modulation of bile acid homeostasis, as previously discussed, FXR also regulates lipid metabolism and gluconeogenesis as well as inflammation and fibrosis pathways.32

Obeticholic acid was granted conditional approval in May 2016 for use in PBC. It should be prescribed in conjunction with UDCA for patients with inadequate response to UDCA, or as monotherapy for those who are unable to tolerate UDCA. This approval was based on results of the POISE trial, where 216 patients with PBC and an inadequate response to UDCA received either placebo, OCA 10 mg/d or OCA 5 mg/d with the possibility to titrate to 10 mg/d, for 12 months. In this study, OCA or placebo was given in combination with UDCA in 93% of patients and as monotherapy in 7%. The primary endpoint was a composite of 3 criteria: ALP < 1.67× upper limit of normal (ULN), total bilirubin ≤ULN and an ALP reduction of at least 15%. Nearly half of OCA-treated patients met the primary endpoint compared to only 10% of patients on placebo.3 In a separate phase II study, ALP reductions of 53.9% and 37.2% were observed in patients receiving 10 mg/d and 50 mg/d of OCA monotherapy, respectively.33

The most common side effect of OCA is a dose-dependent development of itching. This is minimized by starting with the lowest recommended dose, 5 mg/d, and increasing to 10 mg/d after 3 months if the medication is well tolerated and the ALP remains elevated. Use of OCA has also been associated with a dose-dependent reduction in high-density lipoprotein (HDL) cholesterol and this should be monitored during treatment.34 Importantly, the recommended starting dose is reduced in cirrhotics with moderate or severe hepatic impairment. Hepatic decompensation, liver failure and death have been reported when Child B or C cirrhotics are dosed more frequently than recommended. As a result, the FDA issued a black box warning to the OCA label highlighting prescribing recommendations for patients with decompensated liver disease (https://www.fda.gov/Drugs/DrugSafety/ucm594941.htm). These recommendations are listed in Table 2.

Table 2. Recommended dosages for obeticholic acid (OCA) in PBC

OCA dose	Disease stage
OCA dose	Non-cirrhotic or compensated cirrhosis (Child-Pugh A)	Decompensated cirrhosis, child B or C (including prior decompensation)
Starting dose: 1^st 3 mo	5 mg/d	5 mg/wk
Dose titration at 3 mo	10 mg/d	5 mg twice a week, at least 3 d apart May increase to 10 mg twice a week, at least 3 d apart
Maximum dose	10 mg/d	10 mg twice a week

mg, milligramme; OCA, obeticholic acid.

Further studies are needed to examine the long-term effect of OCA therapy on mortality and liver transplantation as well as its adequacy for patients with more advanced liver disease. Using data from the POISE trial in a microsimulation model, Samur and colleagues determined that the combination of UDCA and OCA could decrease the 15-year cumulative incidence of decompensated cirrhosis, hepatocellular carcinoma, liver transplants and liver-related deaths, thus increasing transplant-free survival. However, adding OCA to UDCA led to an incremental cost-effectiveness ratio of $473 400/quality-adjusted life year (QALY) gained, which is deemed not cost effective when using a willingness-to-pay threshold of $100 000/QALY.35 While OCA is promising in terms of its ability to significantly decrease ALP levels in PBC patients and possibly improving survival free of liver transplantation, it is not economically feasible in the long term and a significant reduction in cost would be required to achieve cost-effectiveness.

In regard to the use of OCA in PSC, the phase II AESOP trial looked at the effect of OCA on 77 patients with PSC over 24 weeks (NCT02177136). Investigators noted a statistically significant decrease in baseline ALP of 22% in both the low-dose (1.5-3 mg) and high-dose (5-10 mg) groups,36 and a long-term extension phase is ongoing. While encouraging, further trials are needed to assess if these results translate into a clinically significant endpoint such as increased time to transplantation or death.

5 NOVEL THERAPIES

5.1 Bile acids: TUDCA and norUDCA

Tauroursodeoxycholate (TUDCA) is the taurine conjugated form of UDCA, which has increased hydrophilicity. TUDCA was evaluated in a non-inferiority phase III trial including 199 Chinese patients with PBC treated over a 24-week period with TUDCA or UDCA. A similar proportion of patients in both groups achieved a 25% or 40% reduction in ALP compared to baseline values. Likewise, rates of study-related adverse events were similar except for itching, which appeared to occur more frequently in UDCA-treated subjects.37 The study suffered from several limitations including a heterogeneous population, short treatment duration, lack of bioequivalence between doses of TUDCA and UDCA and lack of appropriate instruments to evaluate pruritus and other quality of life measures. Overall, the drug offers no advantage over the well-established use of UDCA.

Twenty four nor-ursodeoxycholic acid (norUDCA) is a side-chain shortened UDCA, which prevents it from undergoing amidation with glycine or taurine.16 This modification is thought to reinforce the bicarbonate umbrella via cholehepatic shunting. Since this molecule escapes conjugation with glycine or taurine, it is passively reabsorbed within the biliary canaliculi, augmenting the secretion of bile acids and bicarbonate.10 norUDCA is also more hydrophilic and therefore less toxic to the epithelial cells. A phase II study of 159 patients with PSC treated with placebo vs 500, 1000 or 1500 mg of norUDCA showed that, at 12 weeks, norUDCA reduced ALP levels in a dose-dependent manner.38 The dose reductions were 12.3%, 17.3%, and 26.0% in the 500, 1000, and 1500 mg groups, respectively, compared to a 1.2% ALP increase in the placebo group. Notably, this effect was independent of disease stage, duration of disease or prior use of UDCA. Adverse events and pruritus occurred at similar rates in all groups. NUC-5, a larger phase III randomized controlled trial with norUDCA, is in progress in Europe (EudraCT Number: 2016-003367-19).

5.2 FXR agonists: LJN-452, GS-9674, EDP-305

In addition to OCA, other FXR agonists are emerging as potential therapies for cholestatic liver diseases. In mouse models, 2 non-steroidal FXR agonists have shown promising results with reduction in liver biochemistries, improvement of inflammatory infiltrates and improvement in fibrosis (Figure 2).39 These FXR agonists, GS-9674 by Gilead Sciences and Tropifexor (otherwise known as LJN-452) by Novartis, are currently undergoing phase II trials for PBC. Both are non-bile acid formulations, thus expected to cause less pruritus and hyperlipidaemia compared to OCA.40 In addition, a newer non-bile acid FXR agonist, EDP-305, recently demonstrated a promising safety and tolerability profile in a phase I study including healthy individuals and patients with presumed non-alcoholic fatty liver disease.41 The drug is now under evaluation for patients with PBC (NCT03394924).

A proof-of-concept phase II trial assessing GS-9674 in patients with PSC in an open-label fashion is also ongoing (NCT02943460). All ongoing trials for PBC and PSC are summarized in Tables 3 and 4.

Table 3. Active clinical trials for PBCa

Mechanism	Drug	Primary outcomes	Phase	Clinical trial/EudraCT number
ASBT inhibitor	GSK2330672	Pruritus	II	NCT02966834
Bile acid	Median dose UDCA (18-22 mg/kg/d)	Biochemical	IV	NCT03345589
CX3CL1 monoclonal antibody	E6011	Biochemical	II	NCT03092765
FXR agonist	EDP-305	Biochemical	II	NCT03394924
FXR agonist	LJN452	Biochemical	II	NCT02516605
FXR agonist	OCA	Clinical outcomes	IV	NCT02308111
FXR agonist	GS 9674	Biochemical	II	NCT02943447
Kappa opioid receptor agonist	Nalfurafine Hydrochloride	Pruritus		NCT02659696
NADPH oxidase NOX1/NOX4 inhibitor	GKT137831	Biochemical	II	NCT03226067
PPAR-α and gamma agonist	Saroglitazar magnesium	Biochemical	II	NCT03112681
PPAR-α agonist	Fenofibrate	Biochemical	I/II	NCT02965911
PPAR-α agonist	Fenofibrate	Biochemical	III	NCT02823353
PPAR-α agonist	Fenofibrate	Biochemical	III	NCT02823366
PPAR-α, γ, & δ	Bezafibrate	Biochemical	III	NCT02937012
PPAR- α & δ agonist	Elafibranor	Biochemical	II	NCT03124108
PPAR-δ agonist	Seladelpar	Biochemical	II	NCT02955602
PPAR-δ agonist	Seladelpar	Biochemical	II/III	NCT03301506
Selective S1P receptor modulator	Etrasimod (APD334)	Biochemical	II	NCT03155932
PPAR- α, γ, & δ	Bezafibrate	Pruritus	III	NCT02701166
Corticosteroid	Budesonide	Clinical outcomes	III	2007-004040-70

ASBT, Apical sodium-dependent bile acid transporter; CX3CL1, chemokine (C-X3-C motif) ligand 1; CTLA-4, cytotoxic T-lymphocyte antigen 4; EudraCT, European clinical trials database; FXR, farnesoid X receptor; IgG1, immunoglobulin G1; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; OCA, obeticholic acid; PPAR, peroxisome proliferator-activated receptor; S1P, sphingosine 1-phosphate; UDCA, ursodeoxycholic acid.
^a From https://clinicaltrials.gov.

Table 4. Active clinical trials for PSCa

Mechanism	Drug	Primary outcomes	Phase	Clinical trial/EudraCT number
Retinoic acid receptor agonist	All-trans retinoic Acid	Biochemical	II	NCT03359174
FXR agonist	OCA	Biochemical	II	NCT02177136
FXR agonist	GS-9674	Biochemical	II	NCT02943460
Inhibitor of hyaluronan synthesis	Oral hymecromone	Safety, biochemical, MRCP changes	I/II	NCT02780752
VAP-1 monoclonal antibody	BTT1023	Biochemical	II	NCT02239211
PPAR- α, γ, & δ	Bezafibrate	Pruritus	III	NCT02701166
Altering the microbiome	Faecal microbiota transplantation	Biochemical	I/II	NCT02424175
Undefined	HTD1801	Biochemical	II	NCT03333928
Undefined	DUR-928	Biochemical	II	NCT03394781
Antibiotic	Vancomycin	Biochemical	IV	NCT02605213
Antibiotic	Vancomycin	Biochemical	III	NCT01802073
Bile acid derivative	NorUDCA	Biochemical	III	2016-003367-19

FXR, farnesoid X receptor; NorUDCA, 24 nor-ursodeoxycholic acid; OCA, obeticholic acid; PPAR, peroxisome proliferator-activated receptor.
^a From https://clinicaltrials.gov.

5.3 FGF-19 analogues: NGM282

As previously mentioned, FGF-19 expression results directly from FXR activation and leads to downregulation of CYP7A1.42 In a phase II multicenter randomized controlled trial of NGM282, a synthetic analogue of FGF-19 with a modified N terminus, 45 patients with PBC and an incomplete response to UDCA received UDCA plus NGM282 in doses of 0.3 mg or 3.0 mg vs placebo for 28 days. A dose-dependent reduction in ALP and other liver biochemistries was observed in treated patients at day 28: 15.2% in the 0.3 mg group, 19.2% in the 3.0 mg group and 1.2% in the placebo group. The ALP reduction was more pronounced in the subgroups where the baseline ALP was greater than 3× the ULN. Main side effects included diarrhoea, nausea and headaches.43 NGM282 was also evaluated in a randomized controlled trial including 62 patients with PSC (NCT02704364). A press release note from NGM states that the study did not meet the primary endpoint of a statistically significant change in ALP (http://www.ngmbio.com/media/press-releases/020518/).

5.4 PPAR agonists: Fibrates, Seladelpar

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) occurs in 3 different isoforms: α, γ and δ. PPAR agonists have different affinities for the various isoforms. For instance, fenofibrate binds PPAR-α with the greatest specificity, bezafibrate binds all 3 subtypes comparably, and seladelpar binds the δ isoform selectively. Furthermore, each isoform has variable expression in different organs, with PPAR-α being predominantly expressed in the liver and other organs participating in fatty acid catabolism, PPAR-γ is found in adipose tissues and immune cells and the δ isoform being ubiquitously expressed.44, 45 PPAR agonists will have different effects depending on which isoforms are activated.

Peroxisome proliferator-activated receptor agonists have a multitude of effects thought to be beneficial in cholestatic diseases. First, they upregulate MDR3, which promotes excretion of phosphatidylcholine in bile causing reduced bile salt cytotoxicity. Furthermore, they modulate expression of MRP2, MDR1, NTCP and ASBT and upregulate sulphotransferase family 2A member 1 (SULT2A1) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1), among other genes which help detoxify bile acids. Fibrates also suppress NF-κB transcription (Figure 2), thus interfering with inflammatory pathways, and cross-react with other receptors, including pregnane X receptor (PXR) and FXR, further enhancing its anticholestatic and anti-inflammatory properties.16, 46

5.4.1 Fibrates

Several studies evaluated the use of bezafibrate alone or in combination with UDCA for PBC and consistently showed improvement in serum liver biochemistries.47-56 Typically, these studies included a small sample size (10-30 patients) and were of relatively short duration. The recently completed BEZURSO trial, included a much larger sample size of 100 PBC patients (50 in each group), treated for 2 years with either UDCA/bezafibrate 400 mg/d or UDCA/placebo. Normalization of ALP and normalization of all liver chemistries were seen in 67% and 30% of bezafibrate-treated patients, respectively, compared to none on placebo. Additionally, liver stiffness by transient elastography and the itch scores also improved in treated patients.57

Similarly, Reig and colleagues reported their experience in treating 48 patients with PBC and an incomplete response to UDCA with the addition of bezafibrate 400 mg/d for a median of 38 months. Notably, 54% of patients normalized serum ALP. In this group of so-called responders, investigators observed significant improvement in pruritus, jaundice and liver stiffness measured by elastography. Predictors of non-response to bezafibrate included liver stiffness >7.3 kPa and younger age (<53 years). The drug was safe; serious adverse events were not reported; and the kidney function was stable. Side effects were infrequent and included mild gastrointestinal discomfort and myalgias.58

The long-term efficacy and safety of bezafibrate should be evaluated further. In that regard, a trial by Hosonuma and colleagues randomized 27 patients with PBC and incomplete response to UDCA to receive UDCA + bezafibrate (400 mg/d) vs UDCA alone for up to 8 years.59 Despite improvement in serum ALP and Mayo risk score, survival was not better in bezafibrate-treated patients. In addition, patients receiving bezafibrate were more likely to discontinue the study due to renal dysfunction or myalgias. However, one should recognize that this study enrolled only patients with PBC who also had dyslipidaemia; thus, the patient population may not be representative of all PBC patients.

While bezafibrate is not available in the United States, fenofibrate is available. Treatment of PBC patients refractory to UDCA monotherapy with the addition of fenofibrate 160 mg/d led to significant reductions in serum ALP and other liver biochemistries as well as improvement in serum IgM and inflammatory markers. Side effects included mostly heartburn, myalgias and transient transaminase elevation.60

In contrast to the growing experience with PPAR agonists in PBC, summarized in Table 5, our understanding of their effect on patients with PSC is just beginning. A Japanese open-label study prospectively evaluated use of bezafibrate 200 mg twice daily for 12 weeks in 11 patients with PSC.61 Serum ALP and ALT improved in 7 patients (64%). Use of fenofibrate was also evaluated for PSC in 2 small open-label studies from France and the US published only in abstract format, again showing improvement of serum liver biochemistries.62, 63 Additional studies including larger sample size and longer follow-up are warranted.

Table 5. Effects of specific PPAR agonists in patients with cholestatic liver diseases

Drug	PPAR isoforms affected	Mechanism	Summary of findings
Fenofibrate	α; expressed predominantly hepatocytes only80	Downregulation HNF4→ decreased CYP7A1 activity125 Downregulation NF-KB→ decrease in TNF- α126, 127 Upregulation MDR3→ Increased secretion of phospholipids128	Decreases markers of cholestasis60, 129 Decreases IgM60 Lowers TNF- α levels130 Lowers TG130
Bezafibrate	Pan-PPAR; expressed in adipose tissue and immune system45	As above + PXR agonist→ further downregulation of CYP7A166, 50 PPAR γ activation modulates lipid metabolism→ insulin sensitization131, 45	Decreases markers of cholestasis and inflammation58 Improvement of pruritus58 Improvement in liver stiffness58, 132
Seladelpar	δ; expressed in hepatocytes, cholangiocytes, macrophages and stellate cells45, 80	Improves insulin sensitivity131 →decreased lipid accumulation in the liver133 Induces weight loss133 Reduces markers of inflammation65 Reduces stellate cell activation134	Improves markers of cholestasis65 Improves markers of inflammation65 Improves LDL-C65
Elafibranor (NCT03124108)	α and δ; expressed in hepatocytes, cholangiocytes, macrophages and stellate cells⁸⁰	Improves insulin sensitivity→decreased lipid accumulation in the liver131, 135 Induces weight loss135 Reduces markers of inflammation135 Reduces stellate cell activation134	To be determined

CYP7A1, cholesterol 7 alpha-hydroxylase; HNF4, hepatocyte nuclear factor 4; IgM, immunoglobulin M; LDL-C, low-density lipoprotein cholesterol; MDR3, multidrug resistance protein 3; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; TG, triglycerides; TNF-α, tumor necrosis factor α.

5.4.2 Other PPAR agonists

Seladelpar is a selective PPAR-δ agonist. It was recently evaluated in a multicenter trial for PBC patients with an incomplete response to UDCA, where addition of seladelpar 50 mg/d or 200 mg/d was compared to placebo. The study showed a significant reduction in ALP of 53% and 63% in the 50 and 200 mg groups, respectively, compared to 2% in the placebo group. However, the trial was stopped early after 1 patient in the 50 mg group and 2 in the 200 mg group developed grade 3 increases in aminotransferases.64 An ongoing phase II/III trial is testing seladelpar at lower doses of 2, 5 and 10 mg (NCT03301506 & NCT02955602). Interim analyses suggest maintained efficacy at these lower doses, without the previously observed elevation in transaminases.65

Elafibranor (GFT505), a dual PPAR-α and PPAR-γ agonist, is thought to have antifibrotic activity and is currently being evaluated in non-alcoholic fatty liver disease and in PBC (NCT03124108).

5.5 PXR agonists: Budesonide

The main role of PXR is in detoxification and metabolism of bile acids via CYP3A4 and SULT2A1, decreasing bile acid synthesis through CYP7A1, and upregulation of MRP3, MRP2 and MDR1 (Figure 2).16, 66 Glucocorticoids are thought to possibly improve liver chemistries and histology in PBC but are not recommended given their extensive side effect profile.67 However, budesonide, a steroid with greater than 90% first-pass hepatic metabolism, may be a more tolerable alternative. In vitro, use of budesonide in combination with UDCA caused stimulation of the apical chloride/bicarbonate exchanger (AE2), producing a bicarbonate-rich choleresis and strengthening the bicarbonate umbrella.68 Three small studies have evaluated the use of budesonide in PBC and suggest that budesonide + UDCA may be slightly superior to UDCA alone in non-cirrhotic patients with respect to improvement in inflammation and fibrosis.67, 69, 70 Despite the high first-pass metabolism, side effects are still reported after long-term use of budesonide, including bone mass loss, hyperglycaemia and cosmetic changes.69 Furthermore, increased rates of portal vein thrombosis have been reported in cirrhotic patients receiving budesonide.71 Results of an European phase III multicentre randomized controlled trial comparing UDCA + budesonide to UDCA + placebo are awaited (Eudra CT number 2007-004040-70).

Budesonide has been previously evaluated in patients with PSC and found not to be beneficial at doses of 3 mg/d or 9 mg/d.72, 73

5.6 TGR5 agonists: INT-767 & INT-777

Transmembrane G-protein–coupled receptor 5 (TGR5) is a cell surface receptor which is widely distributed in the gastrointestinal tract, especially in the submucosal nervous plexus in the small and large intestine.74 In the liver, we find TGR5 in the sinusoidal endothelial cells, cholangiocytes and Kupffer cells, but not in the hepatocytes. Bile acid binding to TGR5 results in activation of intracellular cAMP signalling and other cell-specific signalling cascades. Among other effects, there are inhibition of NF-kB pathway, secretion of glucagon-like peptide 1 (GLP-1) and activation of iodothyronine deiodinase, which result in anti-inflammatory properties, improvement of diabetes control and enhancement of basal metabolism.75 In the biliary epithelial cell, TGR5 also mediates increased bicarbonate secretion through the cystic fibrosis transmembrane conductance regulator (CFTR), thus protecting against bile cytotoxicity. Furthermore, activation of TGR5 has been linked to the known immunosuppressive effect that bile acids exert on immune cells.74

In mice, TGR5 was found in dorsal root neurons that mediate itch and pain, and mice overexpressing TGR5 have spontaneous itching. Bile acids can activate TGR5 and induce secretion of neuropeptides that transmit itch and analgesia.76 Therefore, modulating TGR5 could represent a novel approach to treat itching in cholestatic diseases. Mouse models with overexpression of TGR5 have shown protective effects in 3,5-diethoxycarbonyl-1,4-dihydrocollidine induced sclerosing cholangitis, and likewise, mice with lower levels of TGR5 expression showed worsening fibrosis.16

The wide ranging and favourable activity of TGR5 makes it a potential treatment target, with 2 drugs currently being investigated. INT-767, a 23-sulphate derivative of OCA, is an agonist of both FXR and TGR5, and is 3 times as potent an FXR agonist as OCA. INT-767 has been shown to decrease bile acid synthesis, increase bicarbonate excretion and inhibit NF-kB.77 INT-777, α-ethyl-23(S)-methylcholic acid, is specific for TGR5. Both molecules have shown promising results in animal studies.78 However, while TGR5 agonists are potentially beneficial to their anti-apoptotic and proliferative effects in cholangiocytes, certain cancerous cells including cholangiocarcinoma tissue have increased expression of TGR5 receptors. Consequently, activation by TGR5 agonists may promote cholangiocarcinoma progression, thus making these drugs less attractive for patients with PSC.79

5.7 All trans retinoic acid (ATRA)

As FXR, PPAR and PXR all work via forming heterodimers with retinoid X receptor (RXR), with subsequent binding to promoter regions on DNA,80 retinoic acid has been evaluated as potential therapy for PSC. A pilot study treated 15 patients with PSC who failed UDCA monotherapy with combination UDCA + ATRA (45 mg/m²/d divided into 2 doses) for 12 weeks. Investigators observed a significant decrease in the bile acid precursor C4 as well as in ALT levels, but no significant change was noted in ALP levels. Additionally, 63% and 26% of patients experienced headaches and tinnitus respectively.81 A phase II study is ongoing to evaluate lower dose ATRA (10 mg twice daily) over 24 weeks in 20 PSC patients (NCT03359174).

5.8 Immunomodulatory Therapies

5.8.1 Ustekinumab

Genome-wide association studies found significant associations with the interleukin 12 (IL 12)—signal transducer and activator of transcription (STAT) 4 signalling pathway in PBC.82 Furthermore, mouse models with deletion of IL-12p40 have marked reduction of pro-inflammatory Th1 cytokines in the liver and less pronounced destructive cholangitis.83 With that in mind, a phase II open-label trial evaluated the effect of ustekinumab, an IL12/23 monoclonal antibody, in 20 patients with PBC and failed to demonstrate a sizable improvement in ALP after 28 weeks of treatment.84 Ustekinumab is not being evaluated further for PBC.

5.8.2 Abatacept

Abatacept is a fusion protein of the Fc region of IgG1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4), where CTLA-4 is required for costimulatory activation of T cells via CD80/CD86. In a mouse model of PBC, pretreatment with a CTLA-4 antibody abrogated development of cholangitis, and treatment after cholangitis had already developed led to reduction of the intrahepatic T-cell infiltrates and bile duct damage.85 A phase II study of abatacept 125 mg weekly for 24 weeks in 20 patients with PBC failed to meet the primary endpoint of either normalization or a decrease >40% in ALP from baseline.86

5.8.3 Rituximab

Rituximab is an anti-CD20 monoclonal antibody which has been evaluated in 2 small studies for PBC, unfortunately with only modest effect on serum ALP.87, 88 Nevertheless, the drug was overall safe and well tolerated.87 While Rituximab may not be beneficial in preventing disease progression, a study was recently completed in the UK exploring the use of rituximab for the treatment of fatigue in PBC (NCT02376335) and results are awaited.

5.8.4 Cenicriviroc

Cenicriviroc (CVC) is an antagonist of chemokine receptor 2 and chemokine receptor 5, which acts by blocking the recruitment of monocytes and macrophages. CVC has shown anti-inflammatory and antifibrotic effects in animal models of fibrosis and NASH.89 A phase II trial (PERSEUS) evaluating the effect of a 24-week treatment with CVC 150 mg/d in patients with PSC (NCT02653625) was completed December 2017, but results are yet to be published.

5.8.5 Vedoluzimab

The aberrant homing theory asserts that extraintestinal manifestations of IBD, including PSC, are secondary to atypically expressed adhesion molecules. The mucosal addressin cell adhesion molecule-1 (MADCAM-1), usually confined to the gut, can be found in the hepatic endothelium in patients with IBD-associated liver disease. MADCAM-1 is bound by α₄β₇ integrin (found on T cells) causing migration of gut-primed, mucosally activated T cells to the liver.90, 91 These are long-lived memory cells, which can explain why liver disease can occur years apart from the bowel disease and run a separate disease course.

Vedoluzimab is an anti-α₄β₇ integrin monoclonal antibody. Conceptually, this drug could prevent abnormal lymphocyte trafficking from the gut to the liver and mitigate inflammation, cell death and the eventual development of fibrosis in PSC. A retrospective study of 34 PSC patients receiving vedoluzimab for concomitant IBD [16 with Crohn's disease (CD) and 8 with ulcerative colitis (UC)] did not demonstrate a decline in liver chemistries or Mayo PSC risk score at 30 weeks. However, 55% and 29% of CD and UC patients, respectively, reached clinical remission of their IBD symptoms.92

5.9 Manipulation of gut microbiome

The strong association between PSC and IBD as well as the growing evidence suggesting a role for the microbiome on the pathogenesis of PSC has led many investigators to pursue the use of antibiotics in PSC.93 Several antibiotics have been tested including vancomycin, metronidazole, minocycline and rifaximin. All but the latter have demonstrated at least some beneficial effect on liver biochemistries.94-97 Among the antibiotics in use, vancomycin is the most promising.97 It has been shown to improve liver biochemistries and markers of inflammation, lower the prognostic index mayo risk score (MRS), reduce symptoms and exert immunomodulatory effects on regulatory T cells, especially in the paediatric population without cirrhosis. Vancomycin is also better tolerated, with a significant proportion of patients on metronidazole or minocycline having dropped out of studies due to adverse events. However, long-term use of vancomycin induces drastic changes in the microbiome and prompts concerns about infections with resistant bacteria.98 Furthermore, nephrotoxicity, neutropaenia and ototoxicity are notorious side effects of vancomycin.

Small randomized controlled trials of both low and high doses of vancomycin for PSC over 12 weeks have shown a decrease in baseline ALP of 18%-43%, improvement of the MRS and improvement in symptoms including pruritus, fatigue, diarrhoea and anorexia.99, 100 These results show promise and larger trials over longer periods are needed to assess the efficacy of vancomycin. Currently, 2 clinical trials looking at vancomycin in patients with PSC are underway (NCT02605213 & NCT01802073).

Finally, in an ongoing open-label trial examining the safety and efficacy of faecal microbiota transplant in 6 PSC patients, 5 having concomitant ulcerative colitis, an interim analysis showed that 50% reached the primary endpoint of a decline in ALP ≥50% from baseline, without reported adverse events (NCT02424175).101

5.10 Antifibrotic therapies: Simtuzumab

Lysyl oxidase-like 2 is a copper-dependent amine oxidase which plays an important role in fibrosis by catalyzing the cross links in both collagen and elastin. Simtuzumab is an IgG4 monoclonal antibody directed against lysyl oxidase like-2 (LOXL2). In a phase 2b study which included 234 PSC patients (51% of patients at baseline had bridging fibrosis or cirrhosis), simtuzumab was administered at dosages of 75 mg or 125 mg vs placebo over 96 weeks. After 96 weeks, there was no significant difference in hepatic collagen content, Ishak fibrosis stage, decrease in ALP or adverse event rate compared to placebo. Despite simtuzumab being well tolerated, there was no overall benefit in patients with PSC and there are no other clinical trials evaluating this drug for PBC or PSC.102

6 TREATMENT OF PRURITUS

6.1 ASBT inhibitors: GSK2330672 & Marilixibat

Apical sodium-dependent bile acid transporter (ASBT) is a transporter on the apical border of the terminal ileum which reclaims about 90% of the bile acids.103 ASBT inhibitors decrease absorption of bile acids, hindering intra-ileal activation of FXR and subsequently preventing the FXR induced downstream inhibition of CYP7A1. Also, by blocking ASBT, the overall size of the BA pool decreases causing less of a buildup and decreased toxicity in the bile canaliculi.16, 104 The 2 ASBT inhibitors currently being studied are maralixibat and GSK2330672.

In a phase II trial of maralixibat + UDCA (CLARITY study), 66 PBC patients were treated for 13 weeks to determine the effect on itching. Despite improvement from baseline itching scores, no significant difference was observed in the magnitude of effect between the drug and placebo. Side effects included diarrhoea (61.9%), abdominal pain (23.8%) and nausea (23.8%).105

A phase IIa 14-day crossover study of GSK2330672 in 22 patients with PBC showed a significant reduction in pruritic symptoms. Besides the increased incidence of diarrhoea (7 patients in the GSK2330672 group vs one in the placebo group), there is concern for downstream effects such as vitamin deficiencies, gallstone formation and colonic inflammation.106, 107 A larger phase II study including 118 PBC patients is ongoing to confirm the beneficial effect on itching and further examine drug tolerability (NCT02966834).

Maralixibat was also evaluated in 27 patients with PSC (CAMEO study; NCT02061540). Data published on clinicaltrials.gov shows 25 of 27 patients experiencing adverse events, with the majority of the events being diarrhoea and other gastrointestinal symptoms. While secondary outcomes such as change in bilirubin (from 1.22 to 0.98), ALP (from 471.6 to 434.9) and ItchRO scores (from 15.00 to 7.23) all improved, these do not appear to be clinically meaningful. However, further analysis of the results is warranted.

6.2 Bezafibrate

Currently, underway in the Netherlands is the phase III FITCH trial, comparing placebo vs bezafibrate 400 mg daily over 3 weeks for the treatment of itching in 84 PBC patients (NCT02701166).108

7 CONCLUSION

As animal models and human studies continue to elucidate bile acid physiology, their associated nuclear and surface receptors, transporters and role in cholestatic diseases, the emergence of new therapeutic targets for PBC and PSC is rapidly growing. In addition to bile acid derivatives and FXR agonists, drugs targeting a variety of other signalling pathways are under evaluation, with PPAR agonists possibly showing the most promise so far. The BEZURSO trial and additional studies out of Spain showed pronounced biochemical and symptom improvement in bezafibrate-treated patients with PBC, and, likewise, use of seladelpar led to major improvement in liver biochemistries. Smaller studies suggest biochemical benefit of fibrates and FXR agonists in PSC as well. Unfortunately, experimental therapies which show benefit in PBC have not been as effective for PSC; the lack of adequate animal models and biomarkers in PSC precludes well-designed, hypothesis-driven, trial development. Despite this and other challenges in the design and conduct of clinical trials for cholestatic diseases, much progress has been made. Future trials are likely to evaluate combination therapies of drugs with synergistic mechanisms of action to halt disease progression and improve symptom control.

CONFLICT OF INTEREST

JG none. CL received research grants from Gilead, Intercept, Shire, Tobira, GSK, Cyma Bay, Genfit, Genkyotek, Novartis, High Tide, Durect and Enanta. She participates in advisory boards for Intercept and is a consultant for GSK, Novartis and Intercept.

REFERENCES

1Hirschfield GM, Gershwin ME. The immunobiology and pathophysiology of primary biliary cirrhosis. Annu Rev Pathol. 2013; 8: 303-330.
10.1146/annurev-pathol-020712-164014
CAS PubMed Web of Science® Google Scholar
2Bowlus CL, Gershwin ME. The diagnosis of primary biliary cirrhosis. Autoimmun Rev. 2014; 13: 441-444.
10.1016/j.autrev.2014.01.041
CAS PubMed Web of Science® Google Scholar
3Nevens F, Andreone P, Mazzella G, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016; 375: 631-643.
10.1056/NEJMoa1509840
CAS PubMed Web of Science® Google Scholar
4Harms MH, Lammers WJ, Thorburn D, et al. Major hepatic complications in ursodeoxycholic acid-treated patients with primary biliary cholangitis: risk factors and time trends in incidence and outcome. Am J Gastroenterol. 2018; 113: 254-264.
10.1038/ajg.2017.440
PubMed Web of Science® Google Scholar
5Boonstra K, Weersma RK, van Erpecum KJ, et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology (Baltimore, MD). 2013; 58: 2045-2055.
10.1002/hep.26565
CAS PubMed Web of Science® Google Scholar
6Pinto C, Giordano DM, Maroni L, Marzioni M. Role of inflammation and proinflammatory cytokines in cholangiocyte pathophysiology. Biochem Biophys Acta. 2018; 1864 (4 Pt B): 1270-1278.
Web of Science® Google Scholar
7Li M, Cai S-Y, Boyer JL. Mechanisms of bile acid mediated inflammation in the liver. Mol Aspects Med. 2017; 56: 45-53.
10.1016/j.mam.2017.06.001
CAS PubMed Web of Science® Google Scholar
8Jansen PL, Ghallab A, Vartak N, et al. The ascending pathophysiology of cholestatic liver disease. Hepatology (Baltimore, MD). 2017; 65: 722-738.
10.1002/hep.28965
CAS PubMed Web of Science® Google Scholar
9Chiang JYL, Ferrell JM. Bile acid metabolism in liver pathobiology. Gene Expr. 2018; 18: 71-87. https://doi.org/10.3727/105221618X15156018385515.
10.3727/105221618X15156018385515
CAS PubMed Google Scholar
10Arab JP, Cabrera D, Arrese M. Bile acids in cholestasis and its treatment. Ann Hepatol. 2017; 16(Suppl. 1): 53-57.
Google Scholar
11Trauner M, Fuchs CD, Halilbasic E, Paumgartner G. New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology (Baltimore, MD). 2017; 65: 1393-1404.
10.1002/hep.28991
PubMed Web of Science® Google Scholar
12Wagner M, Trauner M. Recent advances in understanding and managing cholestasis. F1000Res. 2016; 5. F1000 Faculty Rev-705.
10.12688/f1000research.8012.1
PubMed Google Scholar
13Beuers U, Hohenester S, de Buy Wenniger LJM, Kremer AE, Jansen PL, Elferink RP. The biliary HCO3− umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology (Baltimore, MD). 2010; 52: 1489-1496.
10.1002/hep.23810
CAS PubMed Web of Science® Google Scholar
14Beuers U, Maroni L, Elferink RO. The biliary HCO(3)(-) umbrella: experimental evidence revisited. Curr Opin Gastroenterol. 2012; 28: 253-257.
10.1097/MOG.0b013e328352aab2
CAS PubMed Web of Science® Google Scholar
15Yoon YB, Hagey LR, Hofmann AF, Gurantz D, Michelotti EL, Steinbach JH. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents. Gastroenterology. 1986; 90: 837-852.
10.1016/0016-5085(86)90859-0
CAS PubMed Web of Science® Google Scholar
16Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol. 2015; 62: S25-S37.
10.1016/j.jhep.2015.02.023
CAS PubMed Web of Science® Google Scholar
17Kawata K, Kobayashi Y, Gershwin ME, Bowlus CL. The immunophysiology and apoptosis of biliary epithelial cells: primary biliary cirrhosis and primary sclerosing cholangitis. Clin Rev Allergy Immunol. 2012; 43: 230-241.
10.1007/s12016-012-8324-0
CAS PubMed Web of Science® Google Scholar
18Calmus Y, Poupon R. Shaping macrophages function and innate immunity by bile acids: mechanisms and implication in cholestatic liver diseases. Clin Res Hepatol Gastroenterol. 2014; 38: 550-556.
10.1016/j.clinre.2014.07.007
CAS PubMed Web of Science® Google Scholar
19Vries E, Beuers U. Management of cholestatic disease in 2017. Liver Int. 2017; 37(S1): 123-129.
10.1111/liv.13306
PubMed Web of Science® Google Scholar
20Kagawa T, Orii R, Hirose S, et al. Ursodeoxycholic acid stabilizes the bile salt export pump in the apical membrane in MDCK II cells. J Gastroenterol. 2014; 49: 890-899.
10.1007/s00535-013-0833-y
CAS PubMed Web of Science® Google Scholar
21Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014b; 147: 1338-1349.
10.1053/j.gastro.2014.08.029
CAS PubMed Web of Science® Google Scholar
22Poupon RE, Bonnand AM, Chretien Y, Poupon R. Ten-year survival in ursodeoxycholic acid-treated patients with primary biliary cirrhosis. The UDCA-PBC Study Group. Hepatology (Baltimore, MD). 1999; 29: 1668-1671.
10.1002/hep.510290603
CAS PubMed Web of Science® Google Scholar
23Poupon RE, Lindor KD, Cauch-Dudek K, Dickson ER, Poupon R, Heathcote E. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology. 1997; 113: 884-890.
10.1016/S0016-5085(97)70183-5
CAS PubMed Web of Science® Google Scholar
24Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology (Baltimore, MD). 2010; 51: 660-678.
10.1002/hep.23294
CAS PubMed Web of Science® Google Scholar
25Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology (Baltimore, MD). 2009; 50: 808-814.
10.1002/hep.23082
CAS PubMed Web of Science® Google Scholar
26Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology. 2005; 129: 1464-1472.
10.1053/j.gastro.2005.08.017
CAS PubMed Web of Science® Google Scholar
27Al Mamari S, Djordjevic J, Halliday JS, Chapman RW. Improvement of serum alkaline phosphatase to< 1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol. 2013; 58: 329-334.
10.1016/j.jhep.2012.10.013
CAS PubMed Web of Science® Google Scholar
28Stanich PP, Björnsson E, Gossard AA, Enders F, Jorgensen R, Lindor KD. Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. Dig Liver Dis. 2011; 43: 309-313.
10.1016/j.dld.2010.12.008
CAS PubMed Web of Science® Google Scholar
29Lindström L, Hultcrantz R, Boberg KM, Friis–Liby I, Bergquist A. Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2013; 11: 841-846.
10.1016/j.cgh.2012.12.032
CAS PubMed Web of Science® Google Scholar
30Lindor KD, Kowdley KV, Harrison ME. ACG clinical guideline: primary sclerosing cholangitis. Am J Gastroenterol. 2015; 110: 646-659.
10.1038/ajg.2015.112
CAS PubMed Web of Science® Google Scholar
31Pellicciari R, Fiorucci S, Camaioni E, et al. 6α-Ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem. 2002; 45: 3569-3572.
10.1021/jm025529g
CAS PubMed Web of Science® Google Scholar
32Kliewer SA, Mangelsdorf DJ. Bile acids as hormones: the FXR-FGF15/19 pathway. Dig Dis. 2015; 33: 327-331.
10.1159/000371670
PubMed Web of Science® Google Scholar
33Kowdley KV, Luketic V, Chapman R, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology (Baltimore, MD). 2018; 67: 1890-1902.
10.1002/hep.29569
CAS PubMed Web of Science® Google Scholar
34Hirschfield 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: 751-761.
10.1053/j.gastro.2014.12.005
CAS PubMed Web of Science® Google Scholar
35Samur S, Klebanoff M, Banken R, et al. Long-term clinical impact and cost-effectiveness of obeticholic acid for the treatment of primary biliary cholangitis. Hepatology (Baltimore, MD). 2017; 65: 920-928.
10.1002/hep.28932
PubMed Web of Science® Google Scholar
36Kowdley KV, Bowlus CL, Levy C, et al. The AESOP trial: a randomized, double-blind, placebo-controlled, phase 2 study of obeticholic acid in patients with primary sclerosing cholangitis. Hepatology (Baltimore, MD). 2017; 66: 1254A-1255A.
Google Scholar
37Ma H, Zeng M, Han Y, et al. A multicenter, randomized, double-blind trial comparing the efficacy and safety of TUDCA and UDCA in Chinese patients with primary biliary cholangitis. Medicine (Baltimore). 2016; 95: e5391.
10.1097/MD.0000000000005391
CAS PubMed Web of Science® Google Scholar
38Fickert P, Hirschfield GM, Denk G, et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol. 2017; 67: 549-558.
10.1016/j.jhep.2017.05.009
CAS PubMed Web of Science® Google Scholar
39Liles J, Karnik S, Hambruch E, et al. FXR agonism by GS-9674 decreases steatosis and fibrosis in a murine model of NASH. J Hepatol. 2016; 64: S169.
10.1016/S0168-8278(16)01682-2
Web of Science® Google Scholar
40Silveira MG, Lindor KD. Investigational drugs in phase II clinical trials for primary biliary cholangitis. Expert Opin Investig Drugs. 2017; 26: 1115-1121.
10.1080/13543784.2017.1371135
CAS PubMed Web of Science® Google Scholar
41Ahmad A, Sanderson K, Dickerson D, Adda N. Pharmacokinetics (PK), Pharmacodynamics (PD), and Safety/Tolerability Effects of EDP-305, a Novel Once-Daily Oral Farnesoid X Receptor (FXR) Agonist in Healthy Subjects and in Subjects with Presumptive Nonalcoholic Fatty Liver Disease (NAFLD). Paper presented at: NASH-TAG2018Park City, Utah; Jan 4–6th 2018.
Google Scholar
42Floreani A, Mangini C. Primary biliary cholangitis: old and novel therapy. Eur J Intern Med. 2018; 47: 1-5.
10.1016/j.ejim.2017.06.020
CAS PubMed Web of Science® Google Scholar
43Mayo MJ, Wigg AJ, Roberts SK, 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 (Baltimore, MD). 2015; 62: 263-264.
Web of Science® Google Scholar
44Levy C. Fibrates for primary biliary cholangitis: what's all the hype? Ann Hepatol. 2017; 16: 704-706.
10.5604/01.3001.0010.2709
CAS PubMed Web of Science® Google Scholar
45Halilbasic E, Baghdasaryan A, Trauner M. Nuclear receptors as drug targets in cholestatic liver diseases. Clin Liver Dis. 2013; 17: 161-189.
10.1016/j.cld.2012.12.001
PubMed Web of Science® Google Scholar
46Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology (Baltimore, MD). 2015; 62: 635-643.
10.1002/hep.27744
CAS PubMed Web of Science® Google Scholar
47Kurihara T, Furukawa M, Tsuchiya M, et al. Effect of bezafibrate in the treatment of primary biliary cirrhosis. Current Ther Res. 2000; 61: 74-82.
10.1016/S0011-393X(00)88530-6
CAS Web of Science® Google Scholar
48Ohmoto K, Mitsui Y, Yamamoto S. Effect of bezafibrate in primary biliary cirrhosis: a pilot study. Liver Int. 2001; 21: 223-224.
10.1034/j.1600-0676.2001.021003223.x
CAS Web of Science® Google Scholar
49Nakai 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: 326-327.
10.1111/j.1572-0241.2000.01667.x
CAS PubMed Web of Science® Google Scholar
50Honda A, Ikegami T, Nakamuta M, et al. Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology (Baltimore, MD). 2013; 57: 1931-1941.
10.1002/hep.26018
CAS PubMed Web of Science® Google Scholar
51Iwasaki S, Ohira H, Nishiguchi S, et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study. Hepatol Res. 2008; 38: 557-564.
10.1111/j.1872-034X.2007.00305.x
CAS PubMed Web of Science® Google Scholar
52Akbar SMF, Furukawa S, Nakanishi S, Abe M, Horiike N, Onji M. Therapeutic efficacy of decreased nitrite production by bezafibrate in patients with primary biliary cirrhosis. J Gastroenterol. 2005; 40: 157-163.
10.1007/s00535-004-1518-3
CAS PubMed Web of Science® Google Scholar
53Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol. 2003; 38: 573-578.
10.1007/s00535-002-1102-7
CAS PubMed Web of Science® Google Scholar
54Lens 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: 197-203.
10.1111/liv.12290
CAS PubMed Web of Science® Google Scholar
55Hazzan R, Tur-Kaspa R. Bezafibrate treatment of primary biliary cirrhosis following incomplete response to ursodeoxycholic acid. J Clin Gastroenterol. 2010; 44: 371-373.
10.1097/MCG.0b013e3181c115b3
CAS PubMed Web of Science® Google Scholar
56Itakura 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: 216-222.
10.1016/j.hepres.2004.04.001
CAS PubMed Web of Science® Google Scholar
57Corpechot C, Chazouilleres O, Rousseau A, et al. A 2-year multicenter, double-blind, randomized, placebo-controlled study of bezafibrate for the treatment of primary biliary cholangitis in patients with inadequate biochemical response to ursodeoxycholic acid therapy (Bezurso). J Hepatol. 2017; 66: S89.
10.1016/S0168-8278(17)30442-7
Web of Science® Google Scholar
58Reig A, Sesé P, Parés A. Effects of bezafibrate on outcome and pruritus in primary biliary cholangitis with suboptimal ursodeoxycholic acid response. Am J Gastroenterol. 2018; 113: 49-55.
10.1038/ajg.2017.287
CAS PubMed Web of Science® Google Scholar
59Hosonuma 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: 423-431.
10.1038/ajg.2015.20
CAS PubMed Web of Science® Google Scholar
60Levy C, Peter J, Nelson D, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther. 2011; 33: 235-242.
10.1111/j.1365-2036.2010.04512.x
CAS PubMed Web of Science® Google Scholar
61Mizuno S, Hirano K, Isayama H, et al. Prospective study of bezafibrate for the treatment of primary sclerosing cholangitis. J Hepatobiliary Pancreat Sci. 2015; 22: 766-770.
10.1002/jhbp.281
PubMed Web of Science® Google Scholar
62Dejman A, Clark V, Martin P, Levy C. Fenofibrate improves alkaline phosphatase in primary sclerosing cholangitis. Gastroenterology. 2013; 144: S1028-S1029.
10.1016/S0016-5085(13)63825-1
Web of Science® Google Scholar
63Chazouilleres O, Corpechot C, Gaouar F, Poupon R. Fenofibrate improves liver tests in primary sclerosing cholangitis with incomplete biochemical response to ursodeoxycholic acid. Hepatology (Baltimore, MD). 2010; 52: 488-488.
Web of Science® Google Scholar
64Jones D, Boudes PF, Swain MG, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol. 2017; 2: 716-726.
10.1016/S2468-1253(17)30246-7
PubMed Web of Science® Google Scholar
65Hirschfield GM, Bowlus CL, Harrison SA, et al. Treatment efficacy and safety of low dose Seladelpar, a selective PPAR-delta agonist, in patients with primary biliary cholangitis: twelve-week interim analysis of an international, randomized, dose ranging, phase 2 study. Hepatology (Baltimore, MD). 2017; 66: 1256A-1257A.
Web of Science® Google Scholar
66Li T, Chiang JY. Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7 alpha-hydroxylase gene transcription. Am J Physiol Gastrointest Liver Physiol. 2005; 288: G74-G84.
10.1152/ajpgi.00258.2004
CAS PubMed Web of Science® Google Scholar
67Leuschner 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: 918-925.
10.1016/S0016-5085(99)70351-3
CAS PubMed Web of Science® Google Scholar
68Arenas F, Hervias I, Úriz M, Joplin R, Prieto J, Medina JF. Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells. J Clin Invest. 2008; 118: 695-709.
CAS PubMed Web of Science® Google Scholar
69Angulo 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 (Baltimore, MD). 2000a; 31: 318-323.
10.1002/hep.510310209
CAS PubMed Web of Science® Google Scholar
70Rautiainen 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 (Baltimore, MD). 2005; 41: 747-752.
10.1002/hep.20646
CAS PubMed Web of Science® Google Scholar
71Hempfling 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 (Baltimore, MD). 2003; 38: 196-202.
10.1053/jhep.2003.50266
CAS PubMed Web of Science® Google Scholar
72van Hoogstraten HJ, Vleggaar FP, Boland GJ, et al. Budesonide or prednisone in combination with ursodeoxycholic acid in primary sclerosing cholangitis: a randomized double-blind pilot study. Am J Gastroenterol. 2000; 95: 2015-2022.
10.1111/j.1572-0241.2000.02267.x
PubMed Web of Science® Google Scholar
73Angulo P, Batts KP, Jorgensen RA, LaRusso NA, Lindor KD. Oral budesonide in the treatment of primary sclerosing cholangitis. Am J Gastroenterol. 2000b; 95: 2333-2337.
10.1111/j.1572-0241.2000.02323.x
CAS PubMed Web of Science® Google Scholar
74Duboc H, Tache Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis. 2014; 46: 302-312.
10.1016/j.dld.2013.10.021
CAS PubMed Web of Science® Google Scholar
75Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol. 2014; 11: 55-67.
10.1038/nrgastro.2013.151
CAS PubMed Web of Science® Google Scholar
76Alemi F, Kwon E, Poole DP, et al. The TGR5 receptor mediates bile acid–induced itch and analgesia. J Clin Invest. 2013; 123: 1513-1530.
10.1172/JCI64551
CAS PubMed Web of Science® Google Scholar
77Baghdasaryan 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 (Baltimore, MD). 2011; 54: 1303-1312.
10.1002/hep.24537
CAS PubMed Web of Science® Google Scholar
78Hegade VS, Speight RA, Etherington RE, Jones DE. Novel bile acid therapeutics for the treatment of chronic liver diseases. Ther Adv Gastroenterol. 2016; 9: 376-391.
10.1177/1756283X16630712
CAS PubMed Web of Science® Google Scholar
79Reich M, Deutschmann K, Sommerfeld A, et al. TGR5 is essential for bile acid-dependent cholangiocyte proliferation in vivo and in vitro. Gut. 2016; 65: 487-501.
10.1136/gutjnl-2015-309458
CAS PubMed Web of Science® Google Scholar
80Gonzalez-Sanchez E, Firrincieli D, Housset C, Chignard N. Nuclear receptors in acute and chronic cholestasis. Dig Dis. 2015; 33: 357-366.
10.1159/000371688
PubMed Web of Science® Google Scholar
81Assis DN, Abdelghany O, Cai S-Y, et al. Combination therapy of all-trans retinoic acid with ursodeoxycholic acid in patients with primary sclerosing cholangitis: a human pilot study. J Clin Gastroenterol. 2017; 51: e11-e16.
10.1097/MCG.0000000000000591
CAS PubMed Web of Science® Google Scholar
82Hirschfield GM, Liu X, Xu C, et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med. 2009; 360: 2544-2555.
10.1056/NEJMoa0810440
CAS PubMed Web of Science® Google Scholar
83Yoshida K, Yang GX, Zhang W, et al. Deletion of interleukin-12p40 suppresses autoimmune cholangitis in dominant negative transforming growth factor beta receptor type II mice. Hepatology (Baltimore, MD). 2009; 50: 1494-1500.
10.1002/hep.23132
CAS PubMed Web of Science® Google Scholar
84Hirschfield GM, Gershwin ME, 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 (Baltimore, MD). 2016; 64: 189-199.
10.1002/hep.28359
PubMed Web of Science® Google Scholar
85Dhirapong A, Yang GX, Nadler S, et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology (Baltimore, MD). 2013; 57: 708-715.
10.1002/hep.26067
CAS PubMed Web of Science® Google Scholar
86Liu CH, Yang G-X, Johnson CR, et al. An open-label study of abatacept in patients with primary biliary cholangitis with an incomplete biochemical response to ursodeoxycholic acid. Hepatology (Baltimore, MD). 2017; 66: 160A-160A.
Web of Science® Google Scholar
87Myers RP, Swain MG, Lee SS, Shaheen AAM, Burak KW. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol. 2013; 108: 933-941.
10.1038/ajg.2013.51
CAS PubMed Web of Science® Google Scholar
88Tsuda 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 (Baltimore, MD). 2012; 55: 512-521.
10.1002/hep.24748
CAS PubMed Web of Science® Google Scholar
89Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016; 11: e0158156.
10.1371/journal.pone.0158156
PubMed Web of Science® Google Scholar
90Grant AJ, Lalor PF, Salmi M, Jalkanen S, Adams DH. Homing of mucosal lymphocytes to the liver in the pathogenesis of hepatic complications of inflammatory bowel disease. Lancet. 2002; 359: 150-157.
10.1016/S0140-6736(02)07374-9
PubMed Web of Science® Google Scholar
91Aron JH, Bowlus CL. The immunobiology of primary sclerosing cholangitis. Semin Immunopathol. 2009; 31: 383-397.
10.1007/s00281-009-0154-7
CAS PubMed Web of Science® Google Scholar
92Christensen B, Micic D, Gibson P, et al. Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease. Aliment Pharmacol Ther. 2018; 47: 753-762.
10.1111/apt.14525
CAS PubMed Web of Science® Google Scholar
93Tabibian JH, Talwalkar JA, Lindor KD. Role of the microbiota and antibiotics in primary sclerosing cholangitis. Biomed Res Int. 2013a; 2013: 389537.
10.1155/2013/389537
CAS PubMed Web of Science® Google Scholar
94Farkkila M, Karvonen AL, Nurmi H, et al. Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology (Baltimore, MD). 2004; 40: 1379-1386.
10.1002/hep.20457
CAS PubMed Web of Science® Google Scholar
95Silveira MG, Torok NJ, Gossard AA, et al. Minocycline in the treatment of patients with primary sclerosing cholangitis: results of a pilot study. Am J Gastroenterol. 2009; 104: 83-88.
10.1038/ajg.2008.14
CAS PubMed Web of Science® Google Scholar
96Tabibian JH, Gossard A, El-Youssef M, et al. Prospective clinical trial of rifaximin therapy for patients with primary sclerosing cholangitis. Am J Ther. 2017; 24: e56-e63.
10.1097/MJT.0000000000000102
PubMed Web of Science® Google Scholar
97Damman J, Rodriguez E, Ali A, et al. The evidence that vancomycin is a therapeutic option for primary sclerosing cholangitis. Aliment Pharmacol Ther. 2018; 47: 886-895.
10.1111/apt.14540
CAS PubMed Web of Science® Google Scholar
98Isaac S, Scher JU, Djukovic A, et al. Short- and long-term effects of oral vancomycin on the human intestinal microbiota. J Antimicrob Chemother. 2017; 72: 128-136.
10.1093/jac/dkw383
CAS PubMed Web of Science® Google Scholar
99Tabibian J, Weeding E, Jorgensen R, et al. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis-a pilot study. Aliment Pharmacol Ther. 2013b; 37: 604-612.
10.1111/apt.12232
CAS PubMed Web of Science® Google Scholar
100Rahimpour S, Nasiri-Toosi M, Khalili H, et al. A triple blinded, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of oral vancomycin in primary sclerosing cholangitis: a pilot study. J Gastrointestin Liver Dis. 2016; 25: 457-464.
10.15403/jgld.2014.1121.254.rah
PubMed Web of Science® Google Scholar
101Allegretti J, Kassam Z, Carrellas M, et al. Fecal microbiota transplantation improves microbiome diversity and liver enzyme profile in primary sclerosing cholangitisPoster 1425. Poster presented at: World Congress of Gastroenterology at ACG2017. Orlando, FL; Oct 13-182017.
Google Scholar
102Muir A, Goodman Z, Levy C, et al. Efficacy and safety of simtuzumab for the treatment of primary sclerosing cholangitis: results of a phase 2b, dose-ranging, randomized, placebo-controlled trial. J Hepatol. 2017; 66: S73.
10.1016/S0168-8278(17)30408-7
Web of Science® Google Scholar
103Wong MH, Oelkers P, Craddock AL, Dawson PA. Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J Biol Chem. 1994; 269: 1340-1347.
10.1016/S0021-9258(17)42263-0
CAS PubMed Web of Science® Google Scholar
104Hegade VS, Jones DE, Hirschfield GM. Apical sodium-dependent transporter inhibitors in primary biliary cholangitis and primary sclerosing cholangitis. Dig Dis. 2017a; 35: 267-274.
10.1159/000450988
PubMed Web of Science® Google Scholar
105Mayo M, Pockros P, Jones D, et al. CLARITY: a phase 2, randomized, double-blind, placebo-controlled study of lopixibat chloride (formerly Lum001), a novel apical sodium-dependent bile acid transporter inhibitor, in the treatment of primary biliary cirrhosis associated with itching. J Hepatol. 2016; 64: S197.
10.1016/S0168-8278(16)00146-X
Web of Science® Google Scholar
106Poupon R. ASBT inhibitors in cholangiopathies–Good for mice, good for men? J Hepatol. 2016; 64: 537-538.
10.1016/j.jhep.2015.12.007
CAS PubMed Web of Science® Google Scholar
107Hegade VS, Kendrick SF, Dobbins RL, et al. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet. 2017b; 389: 1114-1123.
10.1016/S0140-6736(17)30319-7
CAS PubMed Web of Science® Google Scholar
108Bolier R, de Vries ES, Parés A, et al. Fibrates for the treatment of cholestatic itch (FITCH): study protocol for a randomized controlled trial. Trials. 2017; 18: 230.
10.1186/s13063-017-1966-8
PubMed Web of Science® Google Scholar
109Jones DE, Donaldson PT. Genetic factors in the pathogenesis of primary biliary cirrhosis. Clin Liver Dis. 2003; 7: 841-864.
10.1016/S1089-3261(03)00095-3
PubMed Google Scholar
110Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005; 353: 1261-1273.
10.1056/NEJMra043898
CAS PubMed Web of Science® Google Scholar
111Karlsen TH, Folseraas T, Thorburn D, Vesterhus M. Primary sclerosing cholangitis - a comprehensive review. J Hepatol. 2017; 67: 1298-1323.
10.1016/j.jhep.2017.07.022
PubMed Web of Science® Google Scholar
112Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. Primary sclerosing cholangitis. Lancet. 2013; 382: 1587-1599.
10.1016/S0140-6736(13)60096-3
PubMed Web of Science® Google Scholar
113Hirschfield GM, Heathcote EJ, Gershwin ME. Pathogenesis of cholestatic liver disease and therapeutic approaches. Gastroenterology. 2010; 139: 1481-1496.
10.1053/j.gastro.2010.09.004
CAS PubMed Web of Science® Google Scholar
114Nakanuma Y, Harada K. Florid duct lesion in primary biliary cirrhosis shows highly proliferative activities. J Hepatol. 1993; 19: 216-221.
10.1016/S0168-8278(05)80574-4
CAS PubMed Web of Science® Google Scholar
115Desmet VJ. Histopathology of chronic cholestasis and adult ductopenic syndrome. Clin Liver Dis. 1998; 2: 249-264, viii.
10.1016/S1089-3261(05)70006-4
CAS PubMed Google Scholar
116Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012; 56: 1181-1188.
10.1016/j.jhep.2011.10.025
PubMed Web of Science® Google Scholar
117Lammers WJ, Kowdley KV, van Buuren HR. Predicting outcome in primary biliary cirrhosis. Ann Hepatol. 2014a; 13: 316-326.
10.1016/S1665-2681(19)30838-5
PubMed Web of Science® Google Scholar
118Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009; 136: 1281-1287.
10.1053/j.gastro.2009.01.003
CAS PubMed Web of Science® Google Scholar
119Wiesner RH, Grambsch PM, Dickson ER, et al. Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology (Baltimore, MD). 1989; 10: 430-436.
10.1002/hep.1840100406
CAS PubMed Web of Science® Google Scholar
120Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology. 2003; 125: 1364-1369.
10.1016/j.gastro.2003.07.011
PubMed Web of Science® Google Scholar
121Montano-Loza AJ, Bhanji RA, Wasilenko S, Mason AL. Systematic review: recurrent autoimmune liver diseases after liver transplantation. Aliment Pharmacol Ther. 2017; 45: 485-500.
10.1111/apt.13894
CAS PubMed Web of Science® Google Scholar
122Bosch A, Dumortier J, Maucort-Boulch D, et al. Preventive administration of UDCA after liver transplantation for primary biliary cirrhosis is associated with a lower risk of disease recurrence. J Hepatol. 2015; 63: 1449-1458.
10.1016/j.jhep.2015.07.038
CAS PubMed Web of Science® Google Scholar
123Martin EF, Levy C. Timing, management, and outcomes of liver transplantation in primary sclerosing cholangitis. Semin Liver Dis. 2017; 37: 305-313.
10.1055/s-0037-1608655
PubMed Web of Science® Google Scholar
124Singal AK, Guturu P, Hmoud B, Kuo Y-F, Salameh H, Wiesner RH. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation. 2013; 95: 755-760.
10.1097/TP.0b013e31827afb3a
PubMed Web of Science® Google Scholar
125Marrapodi M, Chiang JY. Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. J Lipid Res. 2000; 41: 514-520.
CAS PubMed Web of Science® Google Scholar
126Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem. 2000; 275: 36703-36707.
10.1074/jbc.M004045200
CAS PubMed Web of Science® Google Scholar
127Lee J, Hong EM, Byun HW, et al. The effect of PPARα and PPARγ ligands on inflammation and ABCA1 expression in cultured gallbladder epithelial cells. Dig Dis Sci. 2008; 53: 1707-1715.
10.1007/s10620-007-0029-5
CAS PubMed Web of Science® Google Scholar
128Ghonem NS, Ananthanarayanan M, Soroka CJ, Boyer JL. 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 (Baltimore, MD). 2014; 59: 1030-1042.
10.1002/hep.26894
CAS PubMed Web of Science® Google Scholar
129Cheung A, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther. 2016; 43: 283-293.
10.1111/apt.13465
CAS PubMed Web of Science® Google Scholar
130Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000; 43: 527-550.
10.1021/jm990554g
CAS PubMed Web of Science® Google Scholar
131Lee CH, Olson P, Hevener A, et al. PPARdelta regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci USA. 2006; 103: 3444-3449.
10.1073/pnas.0511253103
CAS PubMed Web of Science® Google Scholar
132Reig A, Sese P, Pares A. P1201: long-term therapy with bezafibrate and ursodeoxycholic acid is insufficient for preventing disease progression in patients with advanced primary biliary cirrhosis. J Hepatol. 2015; 62: S806.
10.1016/S0168-8278(15)31397-0
Web of Science® Google Scholar
133Haczeyni F, Wang H, Barn V, et al. The selective peroxisome proliferator–activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. Hepatol Commun. 2017; 1: 663-674.
10.1002/hep4.1072
CAS PubMed Web of Science® Google Scholar
134Iwaisako K, Haimerl M, Paik YH, et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor δ agonist. Proceedings of the National Academy of Sciences. 2012; 109(21): E1369-76.
10.1073/pnas.1202464109
CAS PubMed Web of Science® Google Scholar
135Staels B, Rubenstrunk A, Noel B, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology (Baltimore, MD). 2013; 58: 1941-1952.
10.1002/hep.26461
CAS PubMed Web of Science® Google Scholar
136Chen WD, Wang YD, Zhang L, et al. Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription. Hepatology (Baltimore, MD). 2010; 51: 953-962.
10.1002/hep.23390
CAS PubMed Web of Science® Google Scholar
137Suraweera D, Rahal H, Jimenez M, Viramontes M, Choi G, Saab S. Treatment of primary biliary cholangitis non-responders: a systematic review. Liver Int. 2017; 37: 1877-1886.
10.1111/liv.13477
PubMed Web of Science® Google Scholar
138Post SM, Duez H, Gervois PP, Staels B, Kuipers F, Princen HM. Fibrates suppress bile acid synthesis via peroxisome proliferator–activated receptor-α–mediated downregulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol. 2001; 21: 1840-1845.
10.1161/hq1101.098228
CAS PubMed Web of Science® Google Scholar
139Barbier O, Duran-Sandoval D, Pineda-Torra I, Kosykh V, Fruchart J-C, Staels B. Peroxisome proliferator-activated receptor α induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme. J Biol Chem. 2003; 278: 32852-32860.
10.1074/jbc.M305361200
CAS PubMed Web of Science® Google Scholar
140Jung D, Fried M, Kullak-Ublick GA. Human apical sodium-dependent bile salt transporter gene (SLC10A2) is regulated by the peroxisome proliferator-activated receptor α. J Biol Chem. 2002; 277: 30559-30566.
10.1074/jbc.M203511200
CAS PubMed Web of Science® Google Scholar
141Kast HR, Goodwin B, Tarr PT, et al. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem. 2002; 277: 2908-2915.
10.1074/jbc.M109326200
CAS PubMed Web of Science® Google Scholar
142Ihunnah CA, Jiang M, Xie W. Nuclear receptor PXR, transcriptional circuits and metabolic relevance. Biochem Biophys Acta. 2011; 1812: 956-963.
10.1016/j.bbadis.2011.01.014
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume38, Issue9

September 2018

Pages 1520-1535

Novel and emerging therapies for cholestatic liver diseases

Abstract