Recent Advances in the Management of Primary Sclerosing Cholangitis

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree, typically in the setting of inflammatory bowel disease, with an increased risk of liver failure and cholangiocarcinoma. A complex pathophysiology, heterogeneity in clinical features, and the rare nature of the disease have contributed to the lack of effective therapy to date. However, recent innovations in the characterization and prognostication of patients with PSC, in addition to new tools for medical management and emerging pharmacologic agents, give rise to the potential for meaningful progress in the next several years. This review summarizes current concepts in PSC and highlights particular areas in need of further study. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree, typically in the setting of inflammatory bowel disease, with an increased risk of liver failure and cholangiocarcinoma. A complex pathophysiology, heterogeneity in clinical features, and the rare nature of the disease have contributed to the lack of effective therapy to date. However, recent innovations in the characterization and prognostication of patients with PSC, in addition to new tools for medical management and emerging pharmacologic agents, give rise to the potential for meaningful progress in the next several years. This review summarizes current concepts in PSC and highlights particular areas in need of further study. Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree.1Karlsen T.H. Folseraas T. Thorburn D. et al.Primary sclerosing cholangitis – a comprehensive review.J Hepatol. 2017; 67: 1298-1323Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar PSC can present in pediatric and adult populations, both men and women, and typically is associated with inflammatory bowel disease (IBD). Complications include progressive biliary fibrosis leading to cirrhosis, liver failure, and cholangiocarcinoma (CCA). Despite improvements in the understanding of pathogenesis (Figure 1), and the recent development of risk-stratification tools, progress to fundamentally alter the course of the disease has been lacking and no effective medical therapy exists. This review discusses relevant topics in the current understanding and management of patients with PSC through the lens of unmet therapeutic need and highlights the state of currently studied interventions and future directions for therapy. The understanding of PSC is challenged by heterogeneous clinical findings that vary between patients: some patients have progressive liver fibrosis and eventual cirrhosis while others have mild fibrosis but nonetheless suffer from recurrent complications such as biliary obstruction, acute bacterial cholangitis, and pruritus. Recently proposed definitions have provided clarity to patients, providers, industry, and regulators.2Ponsioen C.Y. Assis D.N. Boberg K.M. et al.Defining primary sclerosing cholangitis: results from an International Primary Sclerosing Cholangitis Study Group consensus process.Gastroenterology. 2021; 161: 1764-1775Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar The term PSC itself implies the absence of secondary causes of fibrotic biliary strictures. Secondary causes include those identified previously (eg, ischemic biliopathy, IgG4 sclerosing cholangitis) as well as newer considerations such as immune checkpoint inhibitor toxicity. In addition, mutations in the ABCB4 and other genes responsible for progressive familial intrahepatic cholestasis may be confused with PSC. Indeed, the role of genetic testing has been highlighted in recent society guidance documents.3Bowlus C.L. Arrive L. Bergquist A. et al.AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma.Hepatology. 2023; 77: 659-702Crossref PubMed Scopus (31) Google Scholar The ongoing addition of specific causes of secondary sclerosing cholangitis may further refine the characterization of true primary (idiopathic) sclerosing cholangitis. The standard PSC phenotype is defined as large-duct fibrotic strictures of the biliary tree detected on cholangiography by magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP). Although most patients have a cholestatic pattern of injury on liver tests such as alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT), this is not always found and levels can fluctuate over time. Given that 70% to 80% of patients with PSC have IBD, specifically a particular right-sided colitis in many patients, PSC with IBD should be viewed as the standard phenotype of a disease manifested in two organs. The impact of PSC therapies on IBD activity, and IBD activity on PSC, is critical in the assessment of specific interventions. A minority of patients (5%–10%) have small-duct PSC, defined as a recent (<1 year) normal high-quality ERCP or MRCP, with histologic features typical of PSC or with both concurrent overt or histologic features of IBD and increased ALP levels (GGT in pediatric cases).2Ponsioen C.Y. Assis D.N. Boberg K.M. et al.Defining primary sclerosing cholangitis: results from an International Primary Sclerosing Cholangitis Study Group consensus process.Gastroenterology. 2021; 161: 1764-1775Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Although the clinical course of small-duct PSC typically is benign and such patients have a much lower risk of CCA or progressive liver fibrosis, a subset of such patients will progress over time to the large-duct phenotype and become susceptible to its complications.4Ringe K.I. Bergquist A. Lenzen H. et al.Clinical features and MRI progression of small duct primary sclerosing cholangitis (PSC).Eur J Radiol. 2020; 129109101Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Another small percentage of patients (5%) have PSC overlapping with autoimmune hepatitis (AIH),5Boberg K.M. Chapman R.W. Hirschfield G.M. et al.Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue.J Hepatol. 2011; 54: 374-385Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar which is identified more frequently in pediatric populations. For these patients, prognosis is most affected by complications derived from large-duct strictures of PSC rather than AIH itself. The common practice of excluding patients with less-common phenotypes (eg, small-duct PSC, overlapping PSC and AIH) from clinical trials to focus on the standard phenotype (large-duct PSC with IBD) is understandable. However, a significant minority of patients therefore are ineligible for therapeutic trials, which also reduces the pool of available patients for enrollment. The incidence (1–1.5 per 100,000 person-years) and prevalence (6–16 per 100,000 person-years)6Bambha K. Kim W.R. Talwalkar J. et al.Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a Full Text Full Text PDF PubMed Scopus Google K.M. J. et and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a J PubMed Scopus Google Scholar of PSC vary the and may be over but this may be to the true in disease the the clinical of PSC with primary sclerosing cholangitis. A review of features and of and PubMed Scopus Google Scholar A to of patients with with to a L. et and in patients with primary sclerosing PubMed Scopus Google Scholar In with to MRCP, patients are and in the have been both of of medical and of the lack of International of specific to PSC, which of the term cholangitis The of a through by and such as PSC a has the for in the of and are risk of PSC. have that the of PSC is to of the C.L. T.H. et al.Primary sclerosing cholangitis in for liver clinical and PubMed Scopus Google K. et al.Primary sclerosing cholangitis is not rare in a Hepatol. Full Text Full Text PDF PubMed Scopus Google Scholar The understanding of PSC as a K. Kim W.R. Talwalkar J. et al.Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a Full Text Full Text PDF PubMed Scopus Google Scholar is by an of with PSC and A. et of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with inflammatory bowel Full Text Full Text PDF PubMed Scopus Google Scholar to have a risk of disease T. 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