Alimentary Pharmacology and Therapeutics

Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis T. H. Karlsen*,†, M. Vesterhus*,‡ & K. M. Boberg*,§,¶

*Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway. † Department of Clinical Medicine, University of Bergen, Bergen, Norway. ‡ Department of Medicine, National Centre for Ultrasound in Gastroenterology, Haukeland University Hospital, Bergen, Norway. § Institute of Clinical Medicine, University of Oslo, Oslo, Norway. ¶ Section of Gastroenterology, Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Correspondence to: Prof. K. M. Boberg, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Postboks 4950 Nydalen, N-0424 Oslo, Norway. E-mail: [email protected]

Publication data Submitted 25 September 2013 First decision 9 October 2013 Resubmitted 18 November 2013 Accepted 18 November 2013 EV Pub Online 29 December 2013 This commissioned review article was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.

SUMMARY Background Despite considerable advances over the last two decades in the molecular understanding of cholestasis and cholestatic liver disease, little improvement has been made in diagnostic tools and therapeutic strategies. Aims To critically review controversial aspects of the scientific basis for common clinical practice in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and to discuss key ongoing challenges to improve patient management. Methods We performed a literature search using PubMed and by examining the reference lists of relevant review articles related to the clinical management of PBC and PSC. Articles were considered on the background of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) practice guidelines and clinical experience of the authors. Results Ongoing challenges in PBC mainly pertain to the improvement of medical therapy, particularly for patients with a suboptimal response to ursodeoxycholic acid. In PSC, development of medical therapies and sensitive screening protocols for cholangiocarcinoma represent areas of intense research. To rationally improve patient management, a better understanding of pathogenesis, including complications like pruritis and fatigue, is needed and there is a need to identify biomarker end-points for treatment effect and prognosis. Timing of liver transplantation and determining optimal regimens of immunosuppression post-liver transplantation will also benefit from better appreciation of pre-transplant disease mechanisms. Conclusion Controversies in the management of PBC and PSC relate to topics where evidence for current practice is weak and further research is needed. Aliment Pharmacol Ther 2014; 39: 282–301

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ª 2013 John Wiley & Sons Ltd doi:10.1111/apt.12581

Review: controversies in cholestatic diseases INTRODUCTION Cholestatic liver disease may arise due to defects at any level of bile formation. The aetiologies of these conditions range from molecular abnormities caused by genetic variation or drugs to structural changes due to developmental disorders, autoimmune bile duct injury, tumours and gallstones. In everyday clinical practice, the term is most often applied to primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Both these conditions pose major management challenges in adult hepatology. In addition to the general features associated with a broader syndrome of ‘cholestatic liver disease’ (e.g. development of cholestatic liver cirrhosis) (Figure 1), disease specific pathologies (e.g. malignancy risk in PSC) require attention. Considerable advances have been made over the last two decades regarding the molecular understanding of cholestasis and cholestatic liver disease.1–5 These advances have largely derived from the identification of the genes responsible for the progressive familial intrahepatic cholestasis (PFIC) syndromes throughout the 1990s6–9 and from the recent genome-wide association studies (GWAS) applications in PBC and PSC.10 Despite the new knowledge, little improvement has been made in diagnostic tools and therapeutic strategies. Primary biliary cirrhosis and PSC (Figure 2) are slowly progressive diseases with a course of one to two decades from the manifestations of early stages of disease until end-stage liver disease. This results in difficulties in establishing a robust level of evidence for the benefit of any management option, including surveillance for complications throughout the disease course. Prognostic modelling taking surrogate markers for disease stage [including alkaline phosphatase (ALP), bilirubin, model for end-stage liver disease (MELD) score, Child-Pugh score, histology and radiology] into account has, to some extent, assisted the assessment in treatment trials, but robust markers for disease activity and disease complications are missing. Interpretation of the present basis for patient management requires caution and awareness of such limitations. In this review, we aimed to critically summarise the evidence for clinical practice in PBC and PSC. The controversies that do exist arise on topics where evidence is weak or conflicting and a further and better research is needed. Therefore, we will highlight both controversies and important challenges. We will, to some extent, discuss general features of cholestatic liver disease (cirrhosis development, pruritus and fatigue) and associated

Aliment Pharmacol Ther 2014; 39: 282-301 ª 2013 John Wiley & Sons Ltd

Diseases

Manifestation

Consequence

Primary biliary cirrhosis (PBC) Liver cirrhosis

Primary sclerosing cholangitis (PSC) Biliary atresia Hereditary cholestasis

Cholestatic liver disease

Intrahepatic cholestasis of pregnancy

Bile duct cancer Pruritus Fatigue

Gallstone disease

Osteoporosis

Polycystic liver disease Drug-induced liver disease

Hepatocellular cancer

Other liver affection (e.g. hepatitis)

Figure 1 | The term ‘cholestatic liver disease’ jointly denominates the manifestations of a wide variety of liver diseases. For most of the chronic cholestatic liver diseases, therapeutic opportunities are limited, resulting in progression to liver cirrhosis and risk of cancer development. Disease-associated symptoms (e.g. pruritus and fatigue) represent major clinical challenges. The focus of this review article is primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).

molecular and genetic aspects. We will not provide comprehensive discussions on drug-induced cholestasis and cholestatic liver disease in the context of developmental disorders and gallstone disease, for which the interested reader is guided elsewhere.11–13

METHODS A literature search was conducted 1st September 2013 on PubMed using a broad range of search terms including, but not limited to, ‘primary biliary cirrhosis’ and ‘primary sclerosing cholangitis’ along with ‘ursodeoxycholic acid’, ‘treatment’, ‘clinical trial’ and ‘prognostic score’. Articles were selected for discussion on the basis of the authors’ prior knowledge on controversial or challenging topics in the management of PBC and PSC. In addition, important review articles, meta-analyses and Cochrane Systematic Reviews were reviewed and examined for relevant references and practice guidelines. Randomised clinical trials involving a treatment group (UDCA for PSC, non-UDCA for PSC or PBC) vs. placebo or no treatment were included for full table

283

T. H. Karlsen et al.

PBC

PSC

Interlobular bile duct destruction

Intra-/extrahepatic bile ducts

Prevalence: 0.6–40 per 100.000

Prevalence: 0.2–14 per 100.000

Gender: F>M, 10:1

Gender F28 known risk genes

>16 known risk genes

Autoantibodies (AMA)

Autoantibodies (ANCA?)

Known T cell targets

Unknown T cell targets Shared hepatic features: Autoimmune hepatitis (~10%)

PBC

Autoimmunity

Cholestatic liver cirrhosis Pruritus Fatigue

Cancer PSC Autoimmunity

presentation irrespective of blinding or language. Observational studies or studies lacking a control group were excluded from full table presentation, but have been included in the main text to appropriately account for controversial aspects where appropriate. Evaluation of predictive models in PSC was limited to those assessing pre-transplant survival. Articles may have been missed by the adopted approach, and the presentation may also be biased as to the opinion of the authors.

Management of PBC Diagnosis of PBC. The diagnostic criteria for PBC rely on the fact that the targets of liver infiltrating T cells and the antibody production have been identified as lipoylated domains of three members of the 2-oxo-acid dehydrogenase complex family (mainly the E2 284

Inflammatory bowel disease

Figure 2 | Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) share features of an autoimmune affection targeting different levels of the biliary tree.14, 135 Cooccurring autoimmune manifestations outside the liver are common in both conditions. In PSC, the increased risk of biliary tractand colonic cancer poses particular challenges. The present review elaborates on clinical challenges in PBC and PSC, as well as each of the shared hepatic features shown in the figure. AMA, antimitochondrial antibodies; ANCA, anti-neutrophil cytoplasmic antibodies.

component of the pyruvate dehydrogenase complex; PDC-E2).14 The diagnosis can be made on the basis of two of three criteria: the presence of biochemical cholestasis (ALP elevation), detection of anti-mitochondrial antibodies (AMA) and typical histological findings. A liver biopsy is not essential in patients with ALP elevation and AMA, but may be required for the diagnosis of concurrent features of autoimmune hepatitis and disease stage. There is little controversy regarding the diagnostic criteria in PBC, but some discrepancy in the evaluation of the level of evidence supporting these. Depending on the assay employed,15–17 5–10% of patients with PBC present without detectable AMA, even by repeated measures at follow-up. There is little knowledge on the specific pathological features of AMA-negative PBC. Other mitochondrial epitopes than M2 may be Aliment Pharmacol Ther 2014; 39: 282-301 ª 2013 John Wiley & Sons Ltd

Review: controversies in cholestatic diseases relevant.18 There are also slight differences in the cellular composition and severity of histological lesions between AMA-positive and -negative cases.19 Robust genetic determinants to differentiate between AMA-positive and -negative PBC patients have not been detected;20 however, the AMA-negative subset of patients is clearly too small to obtain conclusive statistical power in the analyses. Clinical presentation and behaviour of AMA negative PBC is largely similar to that of AMA-positive PBC,21 and collated anecdotal data suggest that there is also a similar response to ursodeoxycholic acid.22 Disease recurrence rates of PBC after liver transplantation also do not seem to be affected by AMA status.23 In clinical practice, the presence of non-M2 immunoreactivity in a patient with PBC means that a liver biopsy is required for diagnosis. Typically, considerations must also be made as to the presence of small-duct PSC and genetic cholangiopathies,24–26 and precise distinctions between these conditions may not always be feasible.

Current treatment of PBC. Therapeutic applications in PBC and other cholestatic liver diseases can broadly be divided into bile acid therapy and other approaches. Of bile acid preparations, doses of 13–15 mg/kg/day of ursodeoxycholic acid (UDCA) appear beneficial and are commonly used in PBC.27–30 AASLD advises in favour of UDCA therapy judging evidence unambiguously as class I (conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure or treatment is beneficial, useful and effective), level A (data derived from multiple randomised clinical trials or meta-analyses). The EASL guidelines evaluate the overall support for UDCA treatment at the same level, but suggest that the evidence for long-term treatment is less robust (category II-2; evidence for recommendation is derived from cohort or case–control analytic studies, grade B; further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate, recommendation strong). This slight discrepancy may partly be due to a still ongoing dispute as to the quality of trials performed and the true efficacy of UDCA,31 largely deriving from two negative Cochrane-based meta-analyses of survival benefit from UDCA.32, 33 Another meta-analysis,34 focusing on studies with long-term follow-up, however, claims a significant improvement in transplant-free survival in patients on UDCA and that duration of studies need to be taken into account when evaluating drug efficacy in PBC. UDCA therapy also appears to be associated with reduced costs compared with placebo/ Aliment Pharmacol Ther 2014; 39: 282-301 ª 2013 John Wiley & Sons Ltd

conservative treatment28, 35 and is by many authorities considered standard care. A favourable biochemical response to UDCA, incorporating specific improvements in ALP (‘Barcelona criteria’),30, 36 or in ALP, bilirubin and aspartate transaminase (AST) (‘Paris criteria’),37 seems to associate with improvement in transplant-free survival in PBC. In brief, the sum of these biochemical responses and related assessments (e.g. the Mayo risk score38 and baseline parameters like ductopenia39) strongly suggests that there is heterogeneity of the PBC patient population as to the efficacy of UDCA. The mechanism of action of UDCA is reviewed elsewhere,40 yet which aspects of the pathogenesis of PBC that are reflected by heterogeneity in the response to UDCA are unknown. For research purposes, the response-indices may serve useful in stratifying patients in studies aiming to determine the pathophysiology of such aspects. PBC patients with little or no improvement in suggested response-indices are also candidates for trials of supplementary or alternative therapies.

Future treatment of PBC. No other bile acids than UDCA are currently in use in clinical practice. Obeticholic acid, a derivative of chenodeoxycholic acid, has (unlike UDCA) strong activating effects on the nuclear receptor farnesoid X receptor (FXR) and is currently entering phase III clinical trials following promising phase II results (http://clinicaltrials.gov/ct2/show/ NCT01473524).41 A derivative of UDCA, nor-UDCA, is currently in phase II clinical trials for PSC (see below), but has not been tested in PBC. Of the nonbile acid therapies, bezafibrate combination therapy with UDCA has shown the most promising results42, 43 and is also at time of writing at the recruiting stage for phase III trials (http://www.clinicaltrials.gov/ct2/show/NCT01654731). Like obeticholic acid, bezafibrate exerts its likely main mechanism of action via nuclear receptors, targeting the pregnane X receptor (PXR; also called the steroid and xenobiotic receptor, SXR) and peroxisome proliferatoractivated receptor alpha (PPARa).43 The glucocorticoid receptor agonist budesonide also activates PXR.44 Budesonide has shown some efficacy, which so far has not translated into standard care,45–48 largely due to concerns on osteoporotic side effects.49 In our opinion, glucocorticoid receptor-centred adjuvancy to UDCA in PBC should be restricted to patients with features of autoimmune hepatitis (see below). In many ways, PBC is a prototypical autoimmune disease,14 with a well-defined autoantigen, a relatively 285

T. H. Karlsen et al. homogenous disease expression and a genetic susceptibility background similar to that of other autoimmune diseases (Figure 2).50 For this reason, the poor efficacy of immune-targeted therapies that have been tested so far (Table 1) remains somewhat of a paradox. There is little controversy as to this observation, yet there is renewed interest in immune-target therapies on the basis of specific pathways highlighted by GWAS findings. Phase II trials on ustekinumab (a monoclonal anti-p40 antibody, http:// www.clinicaltrials.gov/ct2/show/NCT01430429) are ongoing based on the prominent genetic associations with several components of the interleukin 12 (IL12) and IL23 signalling pathway in the study populations of European ancestry.51, 52 As a note of caution in this regard, the biological implications of these genetic associations are as of yet not understood. Moreover, they seem not to be a prerequisite for PBC development as shown by the absence of similar associations in Asian study populations.53 The efficacy of ustekinumab in other IL12/23-related diseases varies; e.g. in psoriasis, ustekinumab is part of the established treatment armamentarium,54 whereas in multiple sclerosis, it has been concluded to be of no benefit.55 As the relationship between this response heterogeneity and the genetic associations in implicated diseases is unknown, efficacy in PBC of ustekinumab and similar approaches is hard to predict. A definite controversy in PBC exists as to the possibility of an infectious aetiology.56, 57 It is beyond the scope of this article to review the scientific basis of this dispute, which has triggered the execution of completed58 and planned (http://clinicaltrials.gov/ct2/show/NCT01614405) anti-retroviral regimens. As of yet, there is no proven benefit of such approaches. In epidemiological data (reviewed elsewhere),59 associations have also been suggested between exposure to urinary tract pathogens (Novosphingobium aromaticivorans in particular) and other potential environmental co-factors for the ongoing immune response in PBC. Of particular interest is 2-Octynoic acid,60 which is present in commonly used cosmetic products and food flavourings and has the potential to modify PDC-E2 in an immunogenic direction. Elimination studies, like for gluten in coeliac disease, have not yet been performed to justify any particular advice on 2-Octynoic acid-related products for patients.61 Unlike the case in PSC, antibiotic therapy in PBC has not been attempted outside the context of pruritus (rifampicin).62, 63 Of the reported environmental risk factors in PBC,64 smoking seems to be the only one to be accounted for in clinical counselling so far, given associations with an increased rate of liver fibrosis.65, 66 286

Liver transplantation in PBC. In general, disease progression is more predictable in PBC than in PSC, and the utility of prognostic models (bilirubin, Mayo risk score and MELD, in particular) in the appropriate timing of liver transplantation is established.67–69 Pruritus may, in a few cases, serve as the sole indication for liver transplantation. The improvement of fatigue following liver transplantation is less predictable and pronounced than other symptoms,70, 71 and fatigue should, therefore, not trigger liver transplantation without the presence of other indications. There is little or no controversy as to incorporating symptomatic indications in the transplant assessments, even in areas with MELD-based graft allocation programmes. Hepatocellular carcinoma (HCC) may develop in PBC patients with advanced disease stages,72, 73 and may also be associated with nonresponse to UDCA.74 The patients should be followed accordingly.75–77 Disease recurrence occurs in up to 30–35% of liver allografts in PBC recipients.78 The variable frequencies between studies probably reflect differences in practice as to protocol biopsies and diagnostic criteria. There is no consensus as to treatment of UDCA in transplant recipients with recurrent PBC, but hepatic biochemistries improve upon administration like in the native liver disease.78–80 Whether the choice of calcineurin inhibitor influences recurrence rates is debated.81 Tacrolimus seems to associate with higher frequencies of recurrence and shorter recurrence-free survival than ciclosporine in many series.81 Meta-analysis of available data as of January 2006, however, did not support a significant difference in PBC recurrence rates according to immunosuppressive regimen. On this basis, and as short- to mediate-term impact on overall and graft survival from PBC recurrence is neglible,82 tacrolimus-based regimens remain standard at most centres. As very long-term (>10–20 years of follow-up) impact from PBC recurrence on re-transplantation rates is unknown, further considerations may become relevant as data accumulate. Management of PSC Diagnosis of PSC. There is emerging evidence that previous estimates of a frequency of PSC in IBD of 2–4% may be too low and that up to 10% of patients with IBD may show changes compatible with PSC on magnetic resonance cholangiography (MRC).83, 84 The association between IBD and PSC remains one of the key features of PSC for which the basis is still not established. Hypotheses range from endotoxin leakage,85 via pathogenic changes to the gut microbiota,86 to aberrant homing of intestinally activated lymphocytes to engage in biliary Aliment Pharmacol Ther 2014; 39: 282-301 ª 2013 John Wiley & Sons Ltd

Review: controversies in cholestatic diseases Table 1 | Overview of clinical studies of non-ursodeoxycholic acid treatment in primary biliary cirrhosis (PBC). References for studies refer to the online supplementary reference list (Data S1 for tables 1–5) N (treat/ control)

Study duration

Year

Treatment

Heathcote et al.1 Christensen et al.2 Minuk et al.3

1976

Azathioprine

45 (22/23)

5 years

1985

Azathioprine

248 (127/121)

11 years

1988

Ciclosporine vs. placebo

12 (6/6)

1 year

+

ND

ND

Wiesner et al.4

1990

Ciclosporine vs. placebo

29 (19/10)

2 years

+

+

ND

Lombard et al.5

1993

Ciclosporine vs. placebo

6 years

+

Lindor et al.6

1995

Methotrexate/ UDCA

32*

2 years

ND

GonzalezKoch et al.7 Leuschner et al.8 Nakai et al.9

1997

Methotrexate/ UDCA vs. UDCA Budesonide/ UDCA vs. UDCA Bezafibrate/UDCA vs. UDCA

25 (13/12)

48 weeks

ND

39 (20/19)

2 years

+

+

ND

23 (10/13)

1 year

+

ND

ND

Kurihara et al.10 Itakura et al.11 Combes et al.12

2000

24 (12/12)

1 year

+

ND

ND

16†

6 months

+

ND

ND

Rautiainen et al.13

2005

Budesonide/ UDCA vs. UDCA

77 (41/36)

3 years

Iwasaki et al.14

2008

Bezafibrate vs. UDCA Bezafibrate/UDCA vs. UDCA

45 (20/25)

1 year

22 (12/10)

Lamivudine/ zidovudine/UDCA vs. UDCA

59

Mason et al.15

1999 2000

2004 2005

2008

Bezafibrate vs. UDCA Bezafibrate/UDCA vs. UDCA Methotrexate/ UDCA vs. UDCA

349

265

Lab

Histology

OLT-free survival

Study

7.5 years (4.6–8.8 years)

+

ND

Equal

ND

ND

1 year

+

ND

ND

6 months

+

ND

ND

Outcome No effect on liver tests, histology or survival No effect on liver tests, histology or survival Improved liver tests, but high incidence of side effects Improved liver tests (ALP, bilirubin) and AMA, improved histology compared with placebo Prolonged survival in Cox multivariate analysis was not confirmed in the univariate analysis Side effects (9% HT, 11% renal insufficiency) Seven patients withdrawn because of side effects No effect on liver tests or histology No effect on liver tests or histology Improved liver tests, IgM, IgG, and histology Combination therapy improved liver tests compared with UDCA Improved liver tests more than UDCA Improved liver tests No effect on death, OLT, varices encephalopathy, bilirubin, histological progression by two stages or to cirrhosis Budesonide improved histology, but did not result in additional improvement in liver tests Bezafibrate and UDCA monotherapy equally improved liver tests. Additional improvement with combination Improved ALP, but did not improve primary end-points

ALP, alkaline phosphatase; AMA, anti-mitochondrial antibodies; HT, hypertension; ND, not done; UDCA, ursodeoxycholic acid; OLT, orthotopic liver transplantation. The interested reader is guided to the following references for treatment reports not fulfilling the criteria for Table presentation, i.e. randomized allocation to either a treatment group or a control group receiving placebo, no treatment or UDCA.16–34 * No controls included, but comparison with 180 patients in a UDCA vs. placebo study conducted during the same period. † No controls, cross-over design with exchange of treatment protocols between the two groups after 6 months. Aliment Pharmacol Ther 2014; 39: 282-301 ª 2013 John Wiley & Sons Ltd

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T. H. Karlsen et al. inflammatory processes.87, 88 If the pathological processes involved can be dissected, it may be possible to develop diagnostic tools for early, potentially pre-clinical, detection of PSC in IBD patients. On the other hand, it is currently not known to what extent failure of medical therapy in PSC can be ascribed to an advanced disease stage with manifest strictures already at the time of diagnosis. As of yet, procedures to diagnose PSC are restricted to IBD patients in whom abnormal regular biochemical tests suggest the presence of liver disease. There is now consensus in both AASLD and EASL guidelines that MRC is the method of choice, unless endoscopic interventions or sampling is called for and endoscopic retrograde cholangiography (ERC) is indicated. Likely, the practice is sound, but IBD patients with normal biochemistries in whom an intensified colorectal screening programme could be justified if they proved to have PSC will be missed by this approach.83 The topic of elevated levels of immunoglobulin G4 (IgG4) in 10–20% of patients with PSC has received much attention over the last years.89–93 An unknown fraction of these patients is likely to have cholangitis in the context of autoimmune pancreatitis (AIP) as determined by the HISORt criteria94 first reported in Asian populations.95, 96 Modified criteria have been adopted for the application in patients with PSC, i.e. accounting also for patients with two or more main manifestations (elevated serum IgG4, suggestive pancreatic imaging findings, other organ involvement and bile duct or papilla Vateri biopsy with >10 IgG4 positive cells/hpf) in combination with a significant corticosteroid treatment response defined as markedly improved biliary strictures allowing stent removal, liver enzymes 3 months, hepatomegaly, splenomegaly, dominant bile duct stenosis, intra- and extrahepatic bile duct changes (‘PSC score’)

AST, aspartate aminotransferase; IBD, inflammatory bowel disease; INR, international normalised ratio; MELD, model of end-stage liver disease.

Immunosuppressive regimens in liver-transplanted PSC patients are now mainly tacrolimus-based.149, 150 There is no firm evidence that the choice of immunosuppressive regimen directly affects risk of PSC recurrence.81, 149 However, there is an, as of yet not fully understood, interrelationship between post-transplant Aliment Pharmacol Ther 2014; 39: 282-301 ª 2013 John Wiley & Sons Ltd

IBD activity (requiring intensified corticosteroid treatment) and increased PSC recurrence rates.149, 151 A cause–effect relationship between IBD activity and PSC occurrence (or, more appropriately, re-occurrence) is adopted by most authors as the most likely explanation, but alternative mechanisms (e.g. intrinsically high disease 293

T. H. Karlsen et al. activity of both bile duct and colonic inflammation) may also prove correct. There is also a relationship between acute cellular rejection (against which corticosteroids would protect) and PSC recurrence.152 The topic is of considerable interest as long-term follow-up indicates that PSC recurrence does increase re-transplantation rates.153 Interpreting the relationship between disease recurrence and immunosuppression is further complicated by associations between tacrolimus-based regimens and IBD flares following liver transplantation in PSC.154–156 As of yet, evidence does not allow for firm recommendations either on timing of colectomy (pre-transplant in patients with high-activity IBD pre-transplant?) or choice of immunosuppression (ciclosporine-based regimens in patients with high-activity IBD post-transplant?). Likely, on a more comprehensive appreciation of disease mechanisms in PSC and IBD in PSC, immunosuppression regimens post-liver transplantation in PSC that accounts not only for allograft rejection issues but also for PSC immunopathology can be designed.

Common features in PBC and PSC Autoimmune hepatitis. A consensus document from the International Autoimmune Hepatitis Group (IAIHG) deals thoroughly with the controversy as to whether ‘overlap syndrome’ (Figure 2) should be considered a separate disease entity.157 If the patients fulfil a diagnosis of PBC or PSC, this should, according to this consensus document, be the primary diagnosis and co-occurring features of autoimmune hepatitis should be determined using general considerations (ALT at least 59 ULN, IgG at least 29 ULN, histological features of autoimmune hepatitis) rather than the IAIHG scoring systems.158 Identification of patients for corticosteroid therapy is not straightforward. Treatment response to corticosteroids in PSC and PBC patients with concomitant features of autoimmune hepatitis is generally less pronounced than in patients with autoimmune hepatitis as the primary diagnosis,159, 160 and more so in PSC than in PBC.161, 162 It is thus important to be aware of the risk of side effects (osteoporosis in particular) and to assess treatment response regularly, as well as to consider steroid sparing agents for patients requiring long-term treatments.67 Cholestatic liver cirrhosis. To what extent defects of bile acid homoeostasis involve in the primary insult in PBC and PSC is still debated.163 Regardless of the aetiological basis of bile duct injury in PBC and PSC, development of liver fibrosis throughout the disease course 294

most likely involves bile acid toxicity at some level.1 The hepatocyte initiates adaptive responses during cholestasis (Figure 3), including the (i) downregulation of bile acid synthesis and hepatocellular bile acid uptake, (ii) increased hydroxylation and conjugation to make bile acids more water soluble and (iii) induction of bile acid efflux pumps on the sinusoidal membrane leading to export of metabolised bile acids to the systemic circulation for renal elimination. Together with FXR and PXR, the constitutive androstane receptor (CAR) is a major determinant of the expression of the genes involved in this adaption.164, 165 The concept of directing or augmenting these adaptive mechanisms during cholestasis forms the basis of several ongoing treatment trials (e.g. obeticholic acid), but so far remains to be proven. At the level of the cholangiocyte, several lines of evidence converge on the importance of apical bicarbonate secretion (the bicarbonate ‘umbrella’ hypothesis) in preventing the protonation of luminal bile acids and thus reducing cellular injury.163, 166 The bile acid receptor TGR5 is involved in these mechanisms, but so far therapeutic efficacy for TGR5 agonism in cholestatic liver disease seems to occur in conjunction with FXR effects.167 Importantly, the risk of accelerating cholangiocarcinoma development argues against human applications of TGR5 agonists in PSC.167 The role of the gut microbiota in modifying the cholestatic bile acid pool within the enterohepatic circulation and vice versa also needs to be defined (Figure 3).130–133

Pruritus. The large number of candidate pruritogens in cholestatic liver disease launched over the years is reviewed elsewhere.168–170 More recently, two groups have reported on slightly differing aspects of cholestatic pruritus.171, 172 An Amsterdam group identified lysophosphatidic acid (LPA) as a pruritogen produced by autotaxin171 and associating with itching behaviour in mice. In humans, the serum activity of autotaxin correlated with itch intensity and was reduced upon treatment with nasobiliary drainage. Similar correlations were not observed for bile salts, in contrast to findings recently reported from a San Francisco group, which detected correlations with itching behaviour and TGR5 activation status.172 Intradermal injection of bile acids and a TGR5-agonist induced itch behaviour in the experimental setup, which also included detection of reduced itch behaviour in tgr5-/- mice and spontaneous itching behaviour in TGR5 overexpressing mice. The main criticism against the TGR5 data pertains to the doses of deoxycholic acid used in the experiAliment Pharmacol Ther 2014; 39: 282-301 ª 2013 John Wiley & Sons Ltd

Review: controversies in cholestatic diseases Liver - detoxification De novo synthesis

Canalicular export

Cyp7A

Hydroxylation Sinusoidal export

Cyp3A

BSEP Conjugation

Sinusoidal uptake

MRP2

UGT

MDR3

SULT

MRP3 MRP4 OST

OATP

NTCP

GST

Enterohepatic circulation

Bile duct - bicarbonate protection

CFTR AE2 TGR5

Figure 3 | Traditions of bile acid research and the concept of ‘bile acid toxicity’ serve as the main basis for present therapies in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), as well as for most of the ongoing treatment trials. At the level of the liver, protective mechanisms in a context of cholestatic liver disease involve regulation of bile acid transport and metabolism (red, downregulation generally beneficial; blue, upregulation generally beneficial). At the level of the bile ducts, protective mechanisms involve apical bicarbonate secretion by the cholangiocytes (blue). There is emerging evidence that the gut microbiota, during the intestinal phase of the enterohepatic circulation, influences these mechanisms and serves additional regulatory mechanisms. There is an ongoing controversy in PBC and PSC as to the importance of these mechanisms as compared with primarily immunemediated liver and bile duct injury. Cyp (cytochrome P450), UGT (uridine diphosphate glucuronosyltransferase), SULT (sulfotransferase), GST (glutathione S-transferase), BSEP (bile salt export pump), MRP2, 3 and 4 (multidrug resistance-associated protein 2, 3 and 4), MDR3 (multidrug resistance protein 3), OST (organic solute transporter, OSTa-OSTb heterodimer), ASBT (apical sodium-dependent bile acid transporter), IBABP (ileal bile acid-binding protein), NTCP (Na+-taurocholate cotransporting polypeptide), OATP (several organic anion transporting polypeptides), CFTR (cystic fibrosis transmembrane conductance regulator), AE2 (anionic exchanger 2), TGR5 (Takeda G-protein coupled receptor 5).

ments,170 which range far above physiological concentrations in cholestasis.173 Furthermore, the concentrations used to elicit itching in vivo may also induce mast cell degranulation and thus cause itching via non-TGR5 mechanisms.174 Further studies are likely to elaborate on both TGR5 and autotaxin-associated aspects of pruritus and thus potentially open up for novel treatment options. Aliment Pharmacol Ther 2014; 39: 282-301 ª 2013 John Wiley & Sons Ltd

Fatigue. The pathogenetic basis for fatigue in cholestatic liver disease, sometimes pronounced and debilitating, is not known. The most pronounced affections occur in PBC, where more than half of the patients have been reported to suffer from fatigue.175, 176 Many of these patients report fatigue to represent the predominant cause of reduced quality of life.177–179 The range of causes proposed to cause fatigue in PBC is large and 295

T. H. Karlsen et al. reviewed elsewhere.180 Like in pruritus, a consensus biological explanation of fatigue is as of yet lacking. In neither PBC nor PSC is there a correlation of fatigue with severity or stage of liver disease.176, 181 The cause vs. effect relationship between fatigue and social and psychological complications to the disease burden is hard to dissect.178, 181 In lack of therapeutic means, appropriate recognition and handling of such complications are likely to be the most efficient management option.

CONCLUSIONS There are several scientific traditions running in parallel within the topic of cholestatic liver diseases, predominantly represented by research involving bile acids, liver immunology and luminal gastroenterology. The strategic priorities for research over the years are coloured by these traditions, sometimes emerging as controversies on topics where traditions and research outcomes point in different directions. Often, however, discussions are also flavoured by personal preferences and experience that may contrast that of frequently limited scientific evidence. The topics in lack of a consensus should serve as focus areas for further research. The discussions should translate into better study designs and renewed efforts to dissect these topics. As to clinical practice in areas of uncertainty, and even controversy, pragmatic considerations are often required. Rational guidance has now also been provided by the EASL and AASLD practice guidelines.67, 68, 102 Major challenges for future research relate to the accurate assessment of disease activity and progression to allow for evaluation of the treatment effect in clinical trials. Still, PBC and PSC patients account for almost 10% of the European liver transplant programme, highlighting the need for intense

research into disease pathophysiology as a basis for novel treatment options. Cholangiocarcinoma represents the cause of death in up to half of the PSC patients, and biomarkers for early detection are sorely needed in this population. Multiple initiatives in the international community are presently acting upon these topics, and there is also increased appreciation from the broader community (EASL and AASLD) as to the importance of improving patient management in cholestatic liver disease. We anticipate that some of the hurdles will soon be overcome, but as of yet, we have to care for the patients on the basis of sometimes conflicting or even lacking scientific evidence.

AUTHORSHIP Guarantor of the article: Kirsten Muri Boberg. Author contributions: T. H. Karlsen wrote the first draft of the manuscript and prepared the figures. M. Vesterhus and K. M. Boberg revised the manuscript for critical content and prepared the tables. All authors approved the final version of the manuscript. ACKNOWLEDGEMENTS Declaration of personal interests: We thank Tor Halland for assistance in preparing the figures. Declaration of funding interests: Prof. Boberg is involved in the nor-UDCA trial from the FALK pharmaceutical company. SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Data S1. References to Tables 1–5.

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