Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management

Abstract

Primary sclerosing cholangitis (PSC), first described in the mid-1850s, is a complex liver disease that is heterogeneous in its presentation. PSC is characterized by chronic cholestasis associated with chronic inflammation of the biliary epithelium, resulting in multifocal bile duct strictures that can affect the entire biliary tree. Chronic inflammation leads to fibrosis involving the hepatic parenchyma and biliary tree, which can lead to cirrhosis and malignancy. The etiology of PSC is not fully understood, which in part explains the lack of effective medical therapy for this condition. However, we have begun to better understand the molecular pathogenesis of PSC. The recognition of specific clinical subtypes and their pattern of progression could improve phenotypic and genotypic classification of the disease. We review our current understanding of this enigmatic disorder and discuss important topics for future studies.

Keywords: AIH; AIP; Autoimmune Disease; CA; CCA; CFTR; CRN; Cholangiocarcinoma; Cholestatic Liver Disease; ERCP; FISH; FXR; GBN; HCC; IAC; IBD; IL; Ig; Inflammatory Bowel Disease; JAK; LGD; LPC; LT; MAdCAM-1; MDR; MR; MRCP; PSC; T-helper; TLR; TNF; Th; Toll-like receptor; UC; UDCA; VAP-1; autoimmune hepatitis; autoimmune pancreatitis; carbohydrate antigen; cholangiocarcinoma; colorectal neoplasia; cystic fibrosis transmembrane conductance regulator; endoscopic retrograde cholangiopancreatography; farnesoid X receptor; fluorescence in situ hybridization; gallbladder neoplasia; hepatocellular carcinoma; immunoglobulin; immunoglobulin G4–associated cholangitis; inflammatory bowel disease; interleukin; janus kinase; liver transplant; low-grade dysplasia; lymphoplasmacytic; magnetic resonance; magnetic resonance cholangiopancreatography; mucosal addressin cellular adhesion molecule 1; multidrug resistance protein; primary sclerosing cholangitis; tumor necrosis factor; ulcerative colitis; ursodeoxycholic acid; vascular adhesion protein 1.

Figure 1

A 3D Post-Processing Image From MR Cholangiography Diffusely dilated intrahepatic ducts with multifocal narrowing with diffuse ductal wall thickening and enhancement.

Figure 2

Histologic Features of PSC Concentric ductal fibrosis.

Figure 3

Survival of Patients with PSC with Polysomy, Trisomy 3/7 or Tetrasomy, or no Chromosome Amplifications, Based on FISH Analysis. Reused with permission from Lindor and colleagues.

Figure 4

Surveillance of Co-Morbid Conditions in Patients with PSC. Abbreviations: PSC (primary sclerosing cholangitis); IBD (inflammatory bowel disease); CRN (colorectal neoplasia); HCC (hepatocellular carcinoma); GBN (gallbladder neoplasia); CCA (cholangiocarcinoma); ERCP (endoscopic retrograde cholangiopancreatography); MRCP (magnetic resonance cholangiopancreatography); FISH (fluorescence in situ hybridization).