Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as jaundice, itching, and abdominal pain. The bile duct scarring that occurs in PSC narrows the ducts of the biliary tree and impedes the flow of bile to the duodenum. Eventually, it can lead to cirrhosis of the liver and liver failure. PSC increases the risk of various cancers, including liver cancer, gallbladder carcinoma, colorectal cancer, and cholangiocarcinoma. The underlying cause of PSC is unknown. Genetic susceptibility, immune system dysfunction, and abnormal composition of the gut flora may play a role. This is further suggested by the observation that around 75% of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis. No effective medical treatment for primary sclerosing cholangitis is known. Its most definitive treatment is a liver transplant, but disease recurrence can occur in 25–30% of cases. For patients unable or unwilling to receive a transplant, therapy primarily focuses on relieving symptoms, rather than stopping disease progression. If the sclerosing cholangitis is a secondary effect of a different disease, treatment is directed towards the underlying cause. PSC is a rare disease and most commonly affects people with IBD. About 3.0 to 7.5% of people with ulcerative colitis have PSC, and 80% of people with PSC have some form of IBD. Diagnosis usually occurs in people in their 30s or 40s. Individuals of Northern European ancestry are affected more often than people of Southern European or Asian descent. Men are affected more often than women. The disease was initially described in the mid-1800s, but was not fully characterized until the 1970s. The advent of improved medical-imaging techniques, such as endoscopic retrograde cholangiopancreatography, enabled more complete description and understanding.
Signs and symptoms Nearly half of people with PSC do not have symptoms, and are often incidentally discovered to have PSC due to abnormal liver function tests; however, a substantial proportion have debilitating signs and symptoms of the disease. Signs and symptoms of PSC may include severe itching and nonspecific fatigue. Jaundice may also be seen. Enlargement of the liver and spleen are seen in roughly 40% of affected individuals. Abdominal pain affects about 20% of people with PSC. Multiple episodes of life-threatening acute cholangitis (infection within the bile ducts) can be seen due to impaired drainage of the bile ducts, which increases 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. Alternatively, some experts have suggested that the reason immunosuppressant medications are ineffective is because PSC almost always remains undiagnosed until a very advanced stage, at which point damage may be irreversible or require more aggressive treatment than other autoimmune diseases. Data have provided novel insights suggesting:
an important association between the intestinal microbiota and PSC (reduced diversity of gut bacteria, an increased abundance of pathobionts and altered microbial metabolism, i.e. reduced production of short-chain fatty acids and B-Vitamins) 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:
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