Review Article

Controversies in the Management of Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis

T. H. Karlsen; M. Vesterhus; K. M. Boberg

Aliment Pharmacol Ther. 2014;39(3):282-301.

Abstract and Introduction

Abstract

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.

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 1990s^[6–9] 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.

(Enlarge Image)

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).

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.

(Enlarge Image)

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} Co-occurring autoimmune manifestations outside the liver are common in both conditions. In PSC, the increased risk of biliary tract- and 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, anti-mitochondrial antibodies; ANCA, anti-neutrophil cytoplasmic antibodies.

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 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]

1 2 3

Next Section

Abstract and Introduction
Methods
Conclusions
References

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)
Study	Year	Treatment	N (treat/control)	Study duration	Lab	Histology	OLT-free survival	Outcome
Heathcote et al.¹	1976	Azathioprine	45 (22/23)	5 years	−	−	−	No effect on liver tests, histology or survival
Christensen et al.²	1985	Azathioprine	248 (127/121)	11 years	−	−	−	No effect on liver tests, histology or survival
Minuk et al.³	1988	Ciclosporine vs. placebo	12 (6/6)	1 year	+	ND	ND	Improved liver tests, but high incidence of side effects
Wiesner et al.⁴	1990	Ciclosporine vs. placebo	29 (19/10)	2 years	+	+	ND	Improved liver tests (ALP, bilirubin) and AMA, improved histology compared with placebo
Lombard et al.⁵	1993	Ciclosporine vs. placebo	349	6 years	+	−	−	Prolonged survival in Cox multivariate analysis was not confirmed in the univariate analysis Side effects (9% HT, 11% renal insufficiency)
Lindor et al.⁶	1995	Methotrexate/UDCA	32*	2 years	−	−	ND	Seven patients withdrawn because of side effects No effect on liver tests or histology
Gonzalez-Koch et al.⁷	1997	Methotrexate/UDCA vs. UDCA	25 (13/12)	48 weeks	−	−	ND	No effect on liver tests or histology
Leuschner et al.⁸	1999	Budesonide/UDCA vs. UDCA	39 (20/19)	2 years	+	+	ND	Improved liver tests, IgM, IgG, and histology
Nakai et al.⁹	2000	Bezafibrate/UDCA vs. UDCA	23 (10/13)	1 year	+	ND	ND	Combination therapy improved liver tests compared with UDCA
Kurihara et al.¹⁰	2000	Bezafibrate vs. UDCA	24 (12/12)	1 year	+	ND	ND	Improved liver tests more than UDCA
Itakura et al.¹¹	2004	Bezafibrate/UDCA vs. UDCA	16†	6 months	+	ND	ND	Improved liver tests
Combes et al.¹²	2005	Methotrexate/UDCA vs. UDCA	265	7.5 years (4.6–8.8 years)	−	−	−	No effect on death, OLT,varices encephalopathy, bilirubin, histological progression by two stages or to cirrhosis
Rautiainen et al.¹³	2005	Budesonide/UDCA vs. UDCA	77 (41/36)	3 years	−	+	ND	Budesonide improved histology, but did not result in additional improvement in liver tests
Iwasaki et al.¹⁴	2008	Bezafibrate vs. UDCA Bezafibrate/UDCA vs. UDCA	45 (20/25) 22 (12/10)	1 year 1 year	Equal +	ND ND	ND ND	Bezafibrate and UDCA monotherapy equally improved liver tests. Additional improvement with combination
Mason et al.¹⁵	2008	Lamivudine/zidovudine/UDCA vs. UDCA	59	6 months	+	ND	ND	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.

Table 2. Results of studies on the diagnostic utility of biliary brush cytology with and without DNA analysis [by fluorescence *in situ* hybridisation (FISH), digital image analysis (DIA) or flow cytometry] in primary sclerosing cholangitis. Differences in classification algorithms, brush cytology specimen collection procedures, as well as operator variability make direct comparisons difficult and are likely to underlie parts of the differences. Implementation of DNA analysis in the diagnostic protocols has a growing amount of scientific basis, but there is controversy as to the management of detected abnormities. References for studies refer to the online supplementary reference list (Data S1 for tables 1–5)
Author	Time period	Country	PSC patients (n)	Brush samples (n)	Cytology classification	Method	Sensitivity (%)	Specificity (%)	Comment
Ponsioen et al.³⁵	1987–1996	Amsterdam, The Netherlands	43	47	No abnormalities Reactive changes Some atypia Suspicious Adenocarcinoma	Cytology Suspicious or adenoca	60	89
Siqueira et al.³⁶	1984–1987	Pittsburgh, PA, US	151	318	Negative Suspicious Highly atypical Positive	Cytology Positive	46.4	100
Lindberg et al.³⁷	1997–2001	Stockholm, Sweden	20		Insufficient Benign Abnormal, but probably benign Suspicious, but inconclusive Probably malignant Malignant	Cytology Flow cytometric DNA analysis	71 29	100 92
Lal et al.³⁸	1995–2000	Chicago, Illinois, US	21	64	Benign Atypical Malignant	Cytology	n.d.	94
Moff et al.³⁹	2001–2004	Baltimore, MD, US	47	101	Unsatisfactory Benign/reactive Atypical Malignant	Cytology	n.d.	n.d.
Furmanczyk et al.⁴⁰	1995–2004	Seattle, WA, US	51 (37 with follow-up)	107	Negative Atypical Suspicious Positive	Cytology Positive Positive or suspicious	62.5 87.5	100 86.2
Moreno Luna et al.⁴¹	2003–2004	Mayo Clinic, MN, US	86		Benign Atypical Suspicious Malignant	Cytology Positive Positive or suspicious DIA Aneuploid or tetraploid FISH Polysomy or trisomy 7 or 3 Polysomy Cytology neither positive nor suspicious: DIA Aneuploid or tetraploid FISH Polysomy or trisomy 7 or 3 Polysomy DIA + FISH Aneuploidy/tetraploid + polysomy/trisomy	18 41 43 70 47 14 60 20 14	100 97 87 86 100 88 87 100 98
Boberg et al.⁴²	2000–2004	Oslo, Norway	61	121	Insufficient Normal Indefinite for dysplasia Low-grade dysplasia High-grade dysplasia –adenocarcinoma	Cytology High-grade dysplasia Low-grade + high-grade dysplasia	73 100	95 84
Levy et al.⁴³		Mayo Clinic, MN, US	34		Inadequate Negative Atypical Suspicious Positive	Cytology Positive Positive or suspicious DIA FISH Trisomy 7 benign Trisomy 7 malignant DIA + FISH Trisomy 7 benign Trisomy 7 malignant Cytology neither positive nor suspicious: DIA FISH Trisomy 7 benign Trisomy 7 malignant DIA + FISH Trisomy 7 benign Trisomy 7 malignant	7 29 21 29 64 36 64 14 14 57 29 71	100 100 95 100 70 100 70 95 100 71 95 67
Charatcharoenwitthaya et al.⁴⁴	2000–2006	Mayo Clinic, MN, US	117	216	Benign Atypical Suspicious Malignant	Cytology Positive Positive or suspicious DIA Aneuploid or tetraploid FISH Polysomy or trisomy Polysomy DIA + FISH Aneuploidy/tetraploid + polysomy/trisomy	8 46 63 88 38 63	100 97 80 73 98 90
Bangarulingam et al.⁴⁵	2003–2008	Mayo Clinic, MN, US	235		Negative Atypical Suspicious Positive	FISH Polysomy Trisomy/tetrasomy	46 25	88 67	Patients with FISH polysomy had outcome similar to patients with CCA Patients with FISH trisomy/tetrasomy had outcome similar to patients with negative FISH Conclusion: FISH should be interpreted with caution
Halme et al.⁴⁶	2004–2007	Helsinki, Finland	102	186	Benign Suspicious Malignant	Cytology Suspicious DNA content DNA + cytology for patients with end-point DNA + cytology for whole cohort	48 48 72 50	88 94 82 77	5 aneuploid cases with benign cytology had dysplasia or cancer on histology
Barr Fritcher et al.⁴⁷	2003–2009	Mayo Clinic, MN, US	30		Selected patients (n = 30) with FISH polysomy, but no definite CCA for follow-up				Patients with serial FISH polysomy are more likely to have CCA on follow-up than those with subsequent non-polysomy FISH
Barr Fritcher et al.⁴⁸	2003–2010	Mayo Clinic, MN, US	102		Selected only equivocal cytology: Atypical Suspicious	Univariate Cox model: Suspicious cytology: HR 1.90 (0.95–3.81)(P = 0.066) FISH polysomy: HR 8.70 (3.79–19.99)(P < 0.001) Multivariate Cox model: FISH polysomy: HR 6.96 (2.97–16.34)(P < 0.001)

CCA, cholangiocarcinoma; HR, hazard ratio; ND, not done.

Table 3. Overview of clinical studies of treatment with ursodeoxycholic acid in primary sclerosing cholangitis (PSC). References for studies refer to the online supplementary reference list (Data S1 for tables 1–5)
Study	Year	Dose (mg/kg bw/day)	N (treat/control)	Study duration	Lab	Histology	CCA	OLT-free survival	Outcome
O'Brien et al.⁴⁹	1991	10	12*	2.5 years	+	ND	ND	ND	Improvement of liver tests in treatment periods and worsening in nontreatment periods
Beuers et al.⁵⁰	1992	13–15	14 (6/8)	1 year	+	+	ND	ND	Significant improvement in liver biochemistry
Stiehl et al.⁵¹	1994	750/day†	20 (10/10)	3 months	+	ND	ND	ND	Significant improvement in liver tests
De Maria et al.[52]a	1996	300 b.d.†	40 (20/20)	2 years					No effect on liver tests or cholangiography
Lindor et al.⁵³	1997	13–15	102 (51/51)	2.2 years	+	−	ND	−	No significant effect on primary end-points (death, OLT, histology, lab)
Mitchell et al.⁵⁴	2001	20	26 (13/13)	2 years	+	+	ND	ND	UDCA group had improved liver test results, histology and cholangiography
Harnois et al.⁵⁵	2001	25–30	30‡	1 year	+		ND	ND	Improved Mayo Risk Score for UDCA vs. placebo and for high-dose vs. low-dose UDCA Improved liver test results
Olsson et al.⁵⁶	2005	17–23	198 (97/101)	5 years	(+)	ND	−	−	No effect on death, OLT, CCA or liver tests
Lindor et al.⁵⁷	2009	28–30	149 (76/73)	6 years	+		ND	−	Terminated at 6 years as worse outcome in treatment group for death or OLT Improved liver tests in UDCA group

UDCA, ursodeoxycholic acid; ND, not determined; CCA, cholangiocarcinoma; 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. randomised allocation to either a treatment group receiving UDCA or a control group receiving placebo or no treatment.^58–74
*Cross-over design: 3 months pre-treatment, 6 months treatment, 3 months withdrawal, 18 months re-treatment.
†Uniform dose not adjusted to body weight.
‡Controls were 52 placebo/52 low-dose UDCA using data from Lindor et al.⁵⁷

Table 4. Overview of clinical studies of non-ursodeoxycholic acid treatment in primary sclerosing cholangitis. References for studies refer to the online supplementary reference list (Data S1 for tables 1–5)
Study	Year	Treatment	N (treat/placebo)	Study duration	Lab	Histology	OLT-free survival	Outcome
La Russo et al.⁷⁵	1988	Penicillamine	70 (39/31)	3 years	−	−	−	No effect on liver tests, histology or survival
Knox et al.⁷⁶	1994	Methotrexate	24 (12/12)	2 years	+ (ALP only)	−	−	Improved ALP. No effect on histology, cholangiography or outcome
Olsson et al.⁷⁷	1995	Colchicine	84 (44/40)	3 years	−	−	−	No effect on liver tests, histology or survival
Sterling et al.⁷⁸	2004	Mycophenolate mofetil/UDCA vs. UDCA	25 (12/13)	2 years	−	−	−	No effect on liver tests, histology, cholangiography or Mayo Risk Score
Farkkila et al.⁷⁹	2004	Metronidazole/UDCA	80 (39/41)	36 months	+	(+)		Improved liver tests and Mayo Risk Score, but no improvement in histology or cholangiography
Hommes et al.⁸⁰	2008	Infliximab	10 (6/4)	12 months	−	−	ND	Patient enrolment was prematurely stopped when interim analysis showed no treatment benefit. No effect on liver tests, histology

ALP, alkaline phosphatase; UDCA, ursodeoxycholic acid; ND, not done; 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. randomised allocation to either a treatment group or a control group receiving placebo or no treatment with the aim of evaluating effect on pre-transplant PSC.^81–98

Table 5. Predictive models for primary sclerosing cholangitis (PSC) progression. References for studies refer to the online supplementary reference list (Data S1 for tables 1–5)
Study	Year	Variables in predictive model
Pugh et al.⁹⁹	1973	Bilirubin, albumin, INR, encephalopathy, ascites (Child-Pugh score)
Wiesner et al.¹⁰⁰	1989	Age, bilirubin, histological stage, haemoglobin, IBD (Mayo risk score)
Farrant et al.¹⁰¹	1991	Age, histological stage, hepatomegaly, splenomegaly, alkaline phosphatase (King's College Hospital)
Dickson et al.¹⁰²	1992	Age, bilirubin, histological stage, splenomegaly
Broome et al.¹⁰³	1996	Age, bilirubin, histological stage
Kim et al.¹⁰⁴	2000	Age, bilirubin, albumin, AST, variceal bleeding (revised Mayo risk score)
Kamath et al.¹⁰⁵	2001	Bilirubin, creatinine, INR (MELD score)
Boberg et al.¹⁰⁶	2002	Age at diagnosis, bilirubin, albumin
Ponsioen et al.¹⁰⁷	2002	Age, cholangiographic score
Tischendorf et al.¹⁰⁸	2007	Age, albumin, bilirubin elevation >3 months, hepatomegaly, splenomegaly, dominant bile duct stenosis, intra- and extrahepatic bile duct changes ('PSC score')