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. 

In This Article

Abstract and Introduction


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.


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.

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.

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]