the risk of infection. Dark urine due to excess conjugated bilirubin, which is water-soluble and excreted by the kidneys (i.e. choluria) Malabsorption, especially of fat, and steatorrhea (fatty stool), due to an inadequate amount of bile reaching the small intestine, leading to decreased levels of the fat-soluble vitamins, A, D, E, and K. Portal hypertension, a complication of cirrhosis, which can manifest with esophageal and parastomal varices as well as hepatic encephalopathy (mental status alteration/disturbance caused by liver dysfunction and shunting of blood away from the scarred liver; such that ammonia detoxification is reduced with concomitant encephalopathy) or ascites. Cause The exact cause of primary sclerosing cholangitis is unknown, and its pathogenesis is improperly understood. Although PSC is thought to be caused by autoimmune disease, it does not demonstrate a clear response to immunosuppressants. Thus, many experts believe it to be a complex, multifactorial (including immune-mediated) disorder and perhaps one that encompasses several different hepatobiliary diseases. Data have provided novel insights suggesting: an important association between the intestinal microbiota and PSC and a process referred to as cellular senescence and the senescence-associated secretory phenotype in the pathogenesis of PSC. In addition, longstanding, well-recognized associations are seen between PSC and human leukocyte antigen alleles (A1, B8, and DR3). Pathophysiology PSC is characterized by inflammation of the bile ducts (cholangitis) with consequent stricturing (i.e., narrowing) and hardening (sclerosis) of these ducts due to scar formation, be it inside and/or outside the liver. The resulting scarring of the bile ducts obstructs the flow of bile, which further perpetuates bile duct and liver injury. Chronic impairment of bile flow due to blockage and dysfunctional bile transport (cholestasis) causes progressive biliary fibrosis and ultimately biliary cirrhosis and liver failure. The primary physiological function of bile is to assist in the breakdown and absorption of fat in the intestinal tract; a relative deficiency of bile can lead to fat malabsorption and deficiencies of fat-soluble vitamins (A, D, E, K). Liver enlargement is seen due to portal hypertension caused by compression of portal veins by the proximate sclerosed intrahepatic bile ducts, and leads to right upper quadrant abdominal pain. Diagnosis PSC is generally diagnosed on the basis of having at least two of three clinical criteria after secondary causes of sclerosing cholangitis have been ruled out: serum alkaline phosphatase (ALP) > 1.5x the upper limit of normal for longer than 6 months cholangiography demonstrating biliary strictures or