What is primary sclerosing cholangitis (PSC)?

Primary sclerosing cholangitis (PSC) is a chronic (lasting years and decades), progressive (worsening over time) disease of the bile ducts that channel bile from the liver into the intestines. The liver performs many functions; one of them is manufacturing bile. Bile is a watery liquid made by the cells of the liver that is important for digesting food in the intestine, particularly fat, and ridding the body of toxins. Liver cells secrete the bile they make into small canals within the liver. The bile flows through the canals and into larger collecting canals (ducts) within the liver (the intra-hepatic bile ducts). The bile then flows within the intra-hepatic bile ducts out of the liver and into the extrahepatic bile ducts. From the extrahepatic bile ducts, the bile flows into the intestine where the bile mixes with food. In primary sclerosing cholangitis, the intra-hepatic and extra-hepatic bile ducts become inflamed, scarred and thickened (sclerotic), narrowed, and finally obstructed. Obstruction of the ducts can lead to abdominal pain, itching, jaundice, infection in the bile ducts (cholangitis), and liver scarring that leads to liver cirrhosis and liver failure.

How common is primary sclerosing cholangitis?

Primary sclerosing cholangitis is a rare disease. It is more common in men then in women. The mean age at diagnosis of primary sclerosing cholangitis is around 40 years of age. There is a strong association between primary sclerosing cholangitis and chronic ulcerative colitis. Primary sclerosing cholangitis can also occur alone or in association with Crohn's disease, a disease of the intestines that is related to ulcerative colitis.

What causes primary sclerosing cholangitis?

The cause of primary sclerosing cholangitis is not known. A small subset (approximately 10%) of primary sclerosing cholangitis patients has a rapidly progressive form of the disease with early onset of abdominal pain, fever, and itching that responds dramatically to treatment with corticosteroids. Since corticosteroids (such as prednisone) are medications for treating immune diseases such as ulcerative colitis, Crohn's disease, and systemic lupus erythematosus, this small subset of primary sclerosing cholangitis patients are believed to have an immune disorder causing their primary sclerosing cholangitis.

What are the symptoms of primary sclerosing cholangitis?

Most patients with early primary sclerosing cholangitis have no symptoms, and the presence of primary sclerosing cholangitis is recognized only because of abnormally elevated blood levels of liver enzymes (particularly alkaline phosphatase levels) that often are performed along with a routine physical examination.

Early symptoms of primary sclerosing cholangitis include:

• fatigue and
• bodily itching (pruritus)

As the disease progresses, patients may develop jaundice (yellowing of skin and darkening of urine). Jaundice is due to the accumulation of bilirubin in the body. The bilirubin accumulates because it is not able to be eliminated in the bile due to prolonged obstruction of the bile ducts. The accumulation of bilirubin turns the skin and whites of the eye (sclera) yellow. The reason for the pruritus is not entirely known. It may be due to accumulation of bile salts in the body, also as a result of obstruction of the bile ducts. As primary sclerosing cholangitis progresses, patients typically develop right upper abdominal pain, fever, fatigue, pruritus, and jaundice. These patients also are at risk of developing primary sclerosing cholangitis complications. The patients with the autoimmune form of primary sclerosing cholangitis have more rapid and early onset of symptoms of abdominal pain, jaundice and fever than the majority of patients with the more indolent form of primary sclerosing cholangitis.

What are the complications of primary sclerosing cholangitis?

Cholangiocarcinoma

Cholangiocarcinoma (cancer of the bile ducts) is more common among patients with primary sclerosing cholangitis. As far as estimation is concerned 9%-15% of patients with primary sclerosing cholangitis will develop cholangiocarcinoma, a very deadly type of cancer. Patients at highest risks for developing cholangiocarcinoma are primary sclerosing cholangitis patients with cirrhosis who also have long-standing ulcerative colitis.

Cirrhosis

As primary sclerosing cholangitis progresses, the disease causes cirrhosis of the liver (irreversible scarring of the liver) and liver failure; leading to the consideration of liver transplantation. Primary sclerosing cholangitis is, in fact, one of the more common reasons for liver transplantation. Patients with advanced cirrhosis may develop frequent infections, fluid in the ankles and the abdomen (ascites), internal bleeding from rupture of esophageal varices, and mental confusion with progression to coma (hepatic encephalopathy).

Colon cancer

Long-standing chronic ulcerative colitis alone is a risk factor for colon cancer. Patients with both primary sclerosing cholangitis and ulcerative colitis have an even higher risk for developing colon cancer than patients with ulcerative colitis alone.

Cholangitis

The narrowing of the bile ducts predisposes the bile to bacterial infection (cholangitis). Cholangitis is a serious and potentially life-threatening infection with fever, shaking chills (rigors), jaundice, and upper abdominal pain. Cholangitis can result in bacterial infection spreading to the blood stream (a condition called sepsis). Sepsis can cause damage to kidneys and lungs and even cause shock.

How is the diagnosis of primary sclerosing cholangitis made?

The diagnosis of primary sclerosing cholangitis is suspected from the symptoms (such as fatigue, itching, and jaundice) and abnormal laboratory tests (such as abnormally elevated blood levels of alkaline phosphatase and other liver enzymes); and is confirmed by demonstration of abnormally thickened bile ducts using special radiological tests. It is also important to exclude other diseases that can mimic primary sclerosing cholangitis. These diseases include primary biliary cirrhosis (PBC), gallstones in the bile ducts, bile duct cancers and strictures.

Blood tests

The blood level of alkaline phosphates is usually elevated in primary sclerosing cholangitis. The blood levels of other liver enzymes (AST and ALT) may also be mildly elevated. Except in those patients with the autoimmune form of primary sclerosing cholangitis, the bilirubin usually is normal but gradually increases as the disease progress. Anti-mitochondrial antibody (AMA), which is elevated in patients with PBC, is usually normal in patients with primary sclerosing cholangitis.

Colonoscopy

Patients with primary sclerosing cholangitis have a high likelihood of also having ulcerative colitis, and, as mentioned previously, patients with primary sclerosing cholangitis and ulcerative colitis have higher risks of developing colon cancer. Thus, colonoscopy is important to both diagnose ulcerative colitis and for early detection of cancer or precancerous conditions.

Radiologic tests

Endoscopic retrograde cholangio-pancreatography (ERCP) and magnetic resonance cholangio-pancreatography (MRCP) are commonly performed to visualize the intra-hepatic and extrahepatic ducts. These ducts are typically normal in appearance in patients with PBC, but in primary sclerosing cholangitis patients, these ducts have a beaded appearance (multiple narrowings along the ducts with areas of widening in between). MRCP is noninvasive and safe. ERCP is more invasive and carries a 5%-6% chance of causing an attack of acute pancreatitis. However, ERCP has the advantage of obtaining cell samples (a process called brush cytology) from the bile ducts. Brush cytology is not very accurate, but sometimes can help to diagnose cholangiocarcinoma. Also, during ERCP, doctor can also insert balloons and stents across major areas of narrowing (dominant strictures) to relieve obstruction and treat infection.

How is primary sclerosing cholangitis treated?

The treatment of primary sclerosing cholangitis includes:

• cholestyramine (Questran) or rifampin (Rifadin) to diminish itching
• Antibiotics for infection, specifically cholangitis
• Vitamin D and calcium to prevent bone loss (osteoporosis)
• Medications such as ursodiol (UDCA) to retard the progression of primary sclerosing cholangitis
• ERCP with balloon dilatation and/or stenting (a procedure in which the bile ducts are stretched open) for primary sclerosing cholangitis patients with dominant extra-hepatic duct strictures
• Liver transplantation for patients with advanced cirrhosis

Medications

Many medications [such as ursodiol (UDCA), prednisone, methotrexate (Rheumatrex, Trexall), colchicine, 6 mercaptopurine, tacrolimus (Prograf), cyclosporine (Neoral, Gengraf)] have been studied to treat primary sclerosing cholangitis. Except in the case of prednisone for autoimmune form of primary sclerosing cholangitis, none of the other medications have shown a consistent benefit on survival or decreased need for liver transplantation.

UDCA

Ursodiol (UDCA) is a bile acid that is given orally and replaces other bile acids in the body. UDCA is believed to protect against damaging effects of other bile acids on the liver cells and also induce formation of antioxidants. UDCA is the most extensively studied medication for primary sclerosing cholangitis. At standard doses (15 mg/kg/day), it has been shown to improve fatigue, and improve blood levels of liver enzymes in patients with primary sclerosing cholangitis. In higher doses (20-30 mg/kg/day) UDCA has been shown to improve blood liver enzymes, decrease bile duct inflammation, and decrease liver scarring. However, there is still no conclusive evidence that UDCA actually prolongs life or decreases the need for liver transplantation in primary sclerosing cholangitis patients. Meanwhile, most doctors are treating primary sclerosing cholangitis patients with high dose UDCA (20-30 mg/kg/day) since UDCA is safe and well tolerated, and it may improve bile duct disease and retard the development of liver cirrhosis.

Treatment of dominant strictures

Dominant strictures are major narrowings in the extrahepatic bile ducts. Dominant strictures of the extrahepatic bile ducts occur in primary sclerosing cholangitis patients. In selected primary sclerosing cholangitis patients with dominant strictures, ERCP and balloon dilatation (stretching) of the stricture can improve symptoms and abnormal blood levels of liver enzymes and bilirubin. Some doctors also believe that successful dilatation of dominant strictures decreases the risk of developing cholangitis. However, ERCP and dilatation of dominant strictures should be done in centers with highly experienced physicians. During ERCP, doctors often also perform brush cytology of the dominant strictures to exclude cholangiocarcinoma.

Surgery is another treatment for dominant extrahepatic strictures in primary sclerosing cholangitis patients. In carefully selected patients, surgical resection of the stricture followed by creation of a choledocho-jejunostomy (an artificial passage for bile formed by attaching the bile duct from above the stricture directly into the small intestine) can improve symptoms, delay liver transplantation, and lower the risk of cholangiocarcinoma. However, few surgeons recommend surgical resection of dominant strictures because they are concerned that scarring around the liver from such surgery may complicate future liver transplantation.

Liver transplantation

Even with modern management, most primary sclerosing cholangitis patients will die within 11 years of the time of diagnosis without liver transplantation. Transplantation is now the definitive treatment in primary sclerosing cholangitis patients with advanced cirrhosis and liver failure. Reasons for liver transplant in primary sclerosing cholangitis patients are similar to those in other forms of end-stage liver disease. They are:

• Internal bleeding due to rupture of esophageal varices
• Severe ascites that are refractory to medical treatment
• Frequent episodes of bacterial cholangitis
• Hepatic encephalopathy

Primary Sclerosing Cholangitis at a Glance

• Primary sclerosing cholangitis is a chronic, progressive disease of the liver.
• The cause of primary sclerosing cholangitis is not known though an immune cause is suspected in at least a minority of patients.
• Primary sclerosing cholangitis has a strong association with ulcerative colitis and cancer of the bile ducts.
• The primary symptoms of primary sclerosing cholangitis are due to obstruction of the bile ducts and cirrhosis of the liver.
• Primary sclerosing cholangitis is diagnosed on the basis of abnormal blood tests and radiologic imaging of the bile ducts.
• Primary sclerosing cholangitis is treated with medications, endoscopy, and liver transplantation.