Primary Biliary Cholangitis (PBC)

Primary biliary cholangitis is an autoimmune disease of the liver with a chronic course that affects the biliary tract, particularly the small intrahepatic ducts. These structures are a dense network of canaliculi devoted to the transport of bile that is continuously produced by the liver cells, the hepatocytes.

From here, just through the small ducts, the bile reaches the major bile ducts and then the gallbladder, where it is stored, before being secreted into the intestines. 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 first descriptions of the condition date back to the mid-1800s. At that time, diagnoses were late and most patients had advanced disease, to the point that the disease picture was called Primary Biliary Cirrhosis (even earlier referred to by the terms “chronic non-suppurative cholangitis” or “autoimmune cholangitis”). However, with the advancement of diagnostic techniques, the condition is recognized early, when the picture has not yet evolved into cirrhosis, a complication that occurs only in a subset of patients.

In light of this, the world scientific community of hepatology, with a particular contribution from Italian scholars, since November 2015, has changed the name to Primary Biliary Cholangitis.

Studies in recent years have been aimed at finding the cause of the disease. The findings showed that some genetic factors, such as female sex but also some environmental factors such as previous infections, may play a role in determining this pathology. To date, however, a single causative agent has not yet been identified. Liver damage is caused by the immune system attacking, for as yet unknown causes, the cells of the small bile ducts (cholangiocytes) causing inflammation and fibrosis. A population of white blood cells, T lymphocytes, cells of acquired immunity responsible for defending the body against infection recognize cholangiocytes as foreign and attack them until they are destroyed. The inflammatory process involves, slowly also the neighboring cells, and slowly a fibrotic scar is generated to replace the liver tissue.

As already mentioned, the female sex is most affected by the disease and in particular the most affected individuals, are women between 40 and 60 years old. The ratio of affected females to affected males is 10:1. The frequency, however, is not yet well defined: it has been estimated that about 20-40 individuals per 100000 are affected.

Primary biliary cholangitis has a very slow evolution, and with therapy if nor can further slow the progression. Only a small proportion of patients present at diagnosis or evolve later to cirrhosis, or an advanced stage of fibrosis that impairs proper liver function.

It is important to say that unlike viral diseases, primary biliary cholangitis is not transmissible from individual to individual.

The most common symptoms at the onset of primary biliary cholangitis are itching, fatigue, and dry mouth and eyes. However, the disease presents asymptomatically in a high percentage of patients. In patients in whom the disease progresses to cirrhosis, symptoms common to all chronic diseases affecting the liver appear, leading to an advanced stage:

• Small periocular cholesterol deposits (xanthelasmas) and at the joints and palms of the feet and hands (xanthomas)
• Yellow discoloration of the skin and eyes (jaundice)
• Swelling of the ankles and feet (edema)
• Accumulation of fluid in the 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 accumulation of circulating waste in the blood and secondary to liver malfunction

As is often the case in autoimmune diseases, in primary biliary cholangitis several autoimmune diseases may be associated in the same individual such as Sjogren’s syndrome (a condition that affects salivary and lacrimal gland cells) and autoimmune thyroid disorders, which are the most common. In addition, a frequent complication is osteoporosis. One of the classic findings on laboratory tests is high cholesterol (hypercholesterolemia), however, it remains unclear how this affects a patient’s cardiovascular risk.

Very often the diagnosis of primary biliary cholangitis is suspected by the presence of altered liver biochemical indices, in blood tests performed routinely or for other reasons, precisely because in the early stages the disease is often asymptomatic.

The disease is diagnosed using:

• Autoantibody blood tests: in particular, AMA (anti-mitochondrial antibodies), and some subtypes of ANA (anti-nuclear antibodies) that are highly specific for this disease are sought.
• Liver function tests: transaminases, alkaline phosphatase, gamma GT, bilirubin), immunoglobulins IgG, IgM and IgA, serum-protein electrophoresis and cholesterol.
• Ultrasound of the abdomen.
• Liver biopsy. This examination is now rarely needed for diagnosis, although it is used in atypical cases, in the case of suspected overlap with autoimmune hepatitis or steatohepatitis, or more generally in all those cases in which experienced clinicians deem it necessary by discussing the indication with the patient.

To complement them, they can be used:

• MRI of the abdomen aimed at studying the biliary tract, for staging purposes and to rule out primary sclerosing cholangitis
• Bone densitometry given the frequent association with osteoporosis
• If dry eye is present, Schirmer test (test used to study tear quantity).
• When the diagnosis is made, the medical specialist can apply for a disease-specific exemption (code 008.571.6). This will entitle the patient to ultrasound of the abdomen, gastroscopy, and some blood tests used for monitoring primary biliary cholangitis at no charge.

The first therapy approved in Italy for primary biliary cholangitis was ursodesoxycholic acid, a bile acid naturally found in bile, which has been shown to be effective in preventing the progression of fibrosis when taken in the early stages of the disease. The drug has an excellent tolerability profile and is taken daily orally in varying doses depending on the patient’s weight.

Obeticolic Acid (OCA) OCA is a bile acid, just like Ursodesoxycholic acid, with the added ability to bind to a nuclear receptor (FXR) and whose efficacy has been proven in PBC patients. The drug is reimbursed by the National Health System (NHS) for patients who have alkaline phosphatase > 1.5 times normal limits despite 12 months of continuous therapy with ursodesoxycholic acid at a dosage of 13-15 mg/kg or in those (a very small minority) unable to tolerate ursodesoxycholic acid.

Several drugs are currently under investigation for patients who do not show adequate response to ursodesoxycholic acid. Although not yet recorded as an indication in the drug’s package insert, there is now solid scientific evidence that Bezafibrate 400 mg daily reduces cholestasis, improves pruritus, and improves the prognosis of patients with primary biliary cholangitis and incomplete response to ursodeoxycholic acid. This drug, like second-line therapies for the disease in general, must be prescribed in experienced centres for the treatment of autoimmune liver diseases.

In advanced stages of the disease, treatment for complications of cirrhosis becomes necessary. In advanced cirrhosis, liver transplantation may also be necessary, which proves useful in a very small percentage of patients.

There are also symptomatic therapies to alleviate the symptoms: for itching, the most commonly used drugs are antihistamines and cholestyramine (a bile acid chelator); dry eyes are counteracted with the use of artificial tears; for osteoporosis, vitamin D and calcium are administered; finally, it is not useful to use any remedy for hypercholesterolaemia because, as already mentioned, it does not increase cardiovascular risk.

The disease cannot be prevented, precisely because of its unclear aetiopathogenesis. However, it is a good idea to avoid further insult to the liver when the diagnosis is made: avoid alcohol consumption and avoid fattening up.