Snapshot A 34-year-old man presents to his gastroenterologist's office complaining of worsening fatigue, jaundice, and pruritis over the last 2 months. He was diagnosed with ulcerative colitis 8 years ago. The physician ordered labs which came back with an elevated ALP, GGT, and bilirubin. She then scheduled the patient for magnetic resonance cholangiography and pancreatography which revealed multifocal stricturing of both the intrahepatic and extrahepatic biliary system. He is prescribed ursodeoxycholic acid. Introduction Clinical definition primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disorder characterized by multifocal biliary strictures and progressive liver disease Genetics significant genetic component but multifactorial siblings at ↑ risk Associated conditions ulcerative colitis Epidemiology Demographics young to middle-aged men mean age of 30-40 Risk factors inflammatory bowel disease (IBD) primarily ulcerative colitis up to 2/3 of PSC patients may have IBD ETIOLOGY Pathogenesis inflammation leads to multifocal fibrosis, sclerosis, and eventual stricturing and occlusion of both the extra- and intrahepatic bile ducts the etiology of the inflammation is unknown theorized to be caused by inflammatory mediators brought from the GI tract through the portal circulation Presentation Symptoms usually insidious onset, presenting with cholestatic symptoms fatigue jaundice pruritis +/- IBD symptoms later, symptoms resulting from chronic bile stasis steatorrhea symptoms of fat-soluble vitamin deficiencies episodes of cholangitis (RUQ pain and fever) Physical exam jaundice signs of fat soluble vitamin deficiencies in late disease signs of cirrhosis and/or liver failure e.g. ascites imaging Magnetic resonance cholangiography/pancreatography (MRCP) first-line modality for diagnosis shows segmental stricturing and dilation of the bile duct resulting in a "bead-like" appearance Endoscopic retrograde cholangiography/pancreatography (ERCP) gold standard similar appearance as on MRCP Studies Diagnostic testing diagnostic approach requires a radiological diagnosis with exclusion of causes of secondary sclerosing cholangitis studies cholestatic liver labs ↑ alkaline phosphatase (ALP) and ↑ GGT +/- ↑ bilirubin ALT and AST may be normal p-ANCA not specific nor required for diagnosis liver biopsy shows concentric periductal sclerosis (AKA "onion-skinning") Differential Primary biliary cirrhosis commonly confused distinguishing factors typically no extrahepatic disease typically female positive anti-mitochondrial antibody (AMA) Secondary cirrhosis history of causative disease (e.g. alcohol use, hepatitis, etc.) Primary cholangiocarcinoma typically older presence of mass without duct strictures on imaging Treatment Management approach symptomatic treatment until liver transplant no level 1 evidence of disease-altering treatments First-line ursodeoxycholic acid (cholestyramine) relief of cholestatic symptoms (e.g., pruritus) liver transplant the only definitive/curative treatment may recur even after transplant Other treatments endoscopic balloon dilatation and/or stenting relieves symptoms via bile duct dilatation and improved bile flow antibiotics during episodes of ascending cholangitis vitamin supplementation Complications Cirrhosis and end-stage liver disease inevitable in the majority of patients GI and hepatobiliary Mmalignancy ↑↑ risk for cholangiocarcinoma up to ~400x normal or around 10% of PSC patients ↑ risk for colorectal cancer ~5x risk ↑ risk for several others including liver and gallbladder cancers Ascending cholangitis increased susceptibility because of bile stasis Fat-soluble vitamin deficiencies from the inability to release bile acid