Primary Sclerosing Cholangitis (PSC)

Primary sclerosing cholangitis is a rare disease that affects the intra- and extrahepatic bile ducts. These structures are responsible for transporting bile, which is continuously produced by liver cells called hepatocytes.

Bile is a solution containing bile salts, which are necessary for the digestion of fats and fat-soluble vitamins and for the elimination of bilirubin and cholesterol.

The structures just described are affected by an inflammatory process that slowly causes scar tissue to form around the bile ducts. This fibrotic process causes progressive narrowing and hardening of the ducts, which then obstructs the flow of bile. This can lead to infections of the bile ducts (cholangitis), and scarring of the liver tissue can lead to cirrhosis. Primary sclerosing cholangitis is an important risk factor for the development of liver and bile duct cancer.

The cause of primary sclerosing cholangitis is not fully understood. Evidence suggests that in genetically predisposed individuals, damage to the biliary tract may be caused by immune system dysfunction triggered by a toxic agent or infectious event. The frequent association with chronic inflammatory bowel diseases (Crohn’s disease and ulcerative rectocolitis) suggests a common pathogenesis and a role for the gut-liver axis. It can also be associated with autoimmune hepatitis to define the pathological spectrum known as the Overlap Syndrome.

Onset is most common in men between 25 and 45 years of age, but can also occur in childhood. The prevalence appears to be 5-10 per 100000

Unlike viral hepatitis, primary sclerosing cholangitis is not transmissible from person to person.

Initial symptoms may be subtle or absent, but common signs include itching and debilitating fatigue. As the disease progresses, biliary tract infections manifest with jaundice (yellow eyes and skin), fever with shaking chills, and abdominal pain. The advancing disease shows signs of itself, in particular, infections starting in the biliary tract are very common, as mentioned above, manifesting with jaundice (yellow eyes and skin), fever with shaking chills, and abdominal pain.

Advanced stages bring additional symptoms due to further worsening of biliary tract narrowing may appear and include:

• Increasingly frequent infectious episodes with jaundice and fever with shaking chills
• Abdominal pain
• Increasingly intense itching
• Lack of appetite
• Undernutrition and weight loss.

When the fibrosis worsens to the point where the liver develops cirrhosis, the typical signs and symptoms common to all forms of chronic damage appear:

• Swelling of the ankles and feet (edema)
• Accumulation of fluid in abdomen (ascites)
• Gastrointestinal bleeding caused by rupture of esophageal veins secondary to increased pressure in the venous system upstream of the liver
• Mental confusion and motor slowing (porto-systemic encephalopathy), caused by the accumulation of circulating waste in the blood and secondary to liver malfunction.

In addition to the manifestations directly related to liver dysfunction and biliary obstruction, because of the association of primary sclerosing cholangitis with other diseases, symptoms indicative of chronic bowel disease may be present: bloody or mucous diarrhoea, weight loss or abdominal pain. Osteoporosis is also common.

The disease is diagnosed by blood tests: liver function tests (transaminases, gammaGT, alkaline phosphatase, bilirubin), inflammation indices (PCR) and blood counts; autoantibody tests (ANA, AMA, ANCA, LKM, ASMA).

Instrumental examinations are also carried out: magnetic resonance imaging to study the biliary tract (cholangioRMN). This allows the status of the bile ducts to be visualised, in particular any major stenoses. If procedural manoeuvres are useful, ERCP is performed, which allows direct visualisation of the biliary tree by direct injection of contrast medium into the main biliary tree, with access to the biliary tree outlet and the duodenum (first part of the small intestine) by gastroscopy. This manoeuvre allows dilators to be placed if the bile duct is narrow.

A liver biopsy may be needed to assess the degree of fibrosis and to define the pathological picture.

Once the diagnosis has been made, the specialist can issue a specific orphan drug exemption (code RI0050). The patient is then entitled to all diagnostic tests free of charge, according to the system in place for those with RIxxx rare disease exemption codes.

There is no specific targeted therapy for primary sclerosing cholangitis. The only possible and definitive treatment is liver transplantation, which is offered to patients with advanced liver disease.

The therapies used are designed to prevent complications. Infections that start in the bile ducts are treated promptly with antibiotics.

Ursodeoxycholic acid is used at 13-15 mg/kg, but its efficacy is controversial.

Antihistamines and cholestyramine (a drug that can bind bile acids in the intestine and promote their excretion) are used to treat pruritus. The antibiotic rifampin, which for unknown reasons is effective in treating this symptom, may be used in the most severe cases. Recent data show that the drug bezafibrate is very useful in controlling cholestatic pruritus.

As mentioned above, the risk of fibrosis is that the bile ducts become so narrow that they obstruct the passage of bile, requiring the intervention of an endoscopist who can use ERCP to insert dilators (stents) to maintain patency. If the endoscopist fails, the surgeon or interventional radiologist may be able to help by placing percutaneous drains through the abdominal wall into the obstructed bile duct.

As there are no specific drugs for this condition, a number of drugs are being tested, including:
– Nurocholic Acid
– IBAT Inhibitor A3907
– Oral Vancomycin
– IBAT Inhibitor VLX-301

Due to its unclear aetiopathogenesis, the disease cannot be prevented. However, as soon as the diagnosis is made, it is advisable to avoid further insult to the liver: limit or avoid alcohol consumption and avoid obesity.