The Intractable Hepato-Biliary Diseases Study Group in Japan, Health Labor Science Research Grants from Research on Measures for Intractable Diseases


Primary Biliary Cholangitis

Last Update: February 22, 2022

1. What kind of disease is it?

The liver performs such a wide variety of functions that it is sometimes referred to as the "body's factory." One of these functions is the production of the digestive juice known as bile. Liver cells are created within the liver due to the action of bile, and then the bile exits the liver via the bile duct and is temporarily stored in the gall bladder. It then flows into the duodenum.
Primary biliary cholangitis (PBC) is a disease that destroys the extremely small bile ducts within the liver. The destruction of these very small bile ducts within the liver causes bile flow to be slightly more delayed than normal. This, in turn, manifests higher than normal levels of biliary enzymes such as ALP and γGTP in blood test results. Another characteristic of PBC is the presence of the autoantibody known as the anti-mitochondrial antibody (AMA) in the blood.

Topic (1): The name PBC changed in 2016

Previously, PBC stood for primary biliary cirrhosis. When the illness was first identified, it was impossible to diagnose in its early stages, and thus by the time it was finally diagnosed, it had progressed to the stage at which liver cirrhosis occurred because cirrhosis triggers a variety of symptoms. Put another way, in the past, most patients who were diagnosed with PBC had already advanced to the stage at which cirrhosis of the liver had begun. Now, however, the disease can be diagnosed prior to the emergence of symptoms, and thus in most cases, the disease is identified before it advances to cirrhosis of the liver. Thus, the name "primary biliary cirrhosis" does not match the condition experienced by many patients. As a result, discussions began on whether the name of the disease should be changed, which led to its being changed to primary biliary cholangitis first in Europe and the United States in 2015. In the wake of this change, Japan also made the same change in 2016. When a patient applies for an Intractable Disease Certificate, the medical certificate now lists "Primary biliary cholangitis" with "primary biliary cirrhosis'" listed below.

2. How many PBC patients are there?

According to a survey conducted by our study group in 2018, it is estimated that 37,000 patients throughout Japan have been diagnosed with PBC. This figure shows annual increases. However, the increases are occurring among patients with relatively mild cases. Increases are not occurring among patients with severe cases.

3. What sort of people are susceptible to this disease?

This disease is common among middle-aged and older females. The male-to-female ratio is 1:4. Onset occurs after the age of 20, most commonly among those aged between 50 and 60 years. Onset has not been seen in children.

4. Is the cause of this disease known?

The cause of this disease is unknown, but the cause of the destruction of the bile ducts is an abnormal immune response, which implies that this disease is an autoimmune disease related to the autoimmune response. Investigations of this issue both in Japan and abroad are currently revealing new data. PBC is believed to attack the bile ducts as a result of an autoimmune response.

5. Is this disease hereditary?

There are almost no cases of the children of patients with PBC developing the disease. However, PBC patients within the same immediate family (e.g., parents, siblings) occur with relatively high frequency. Thus, as is the case with diabetes, hypertension, and cancer, PBC onset is also thought to be influenced by genetics. Investigations conducted both in Japan and abroad have found several genes that contribute to PBC onset.

6. What are the symptoms of this disease?

In many people diagnosed with PBC, the disease has not yet progressed and has not developed into liver cirrhosis. Although the bile flow in the liver may be somewhat delayed at this stage, it remains sufficient, and liver functions remain normal. As a result, there are nearly no subjective symptoms. However, approximately 30% of those who have mild cases experience skin itchiness ranging from moderate to severe.
If PBC is not diagnosed and treated at this stage, then it will advance further. Specifically, the small bile ducts within the liver will suffer further destruction, leading to worsening bile flow. Once this happens, the bile components begin to backflow into the bloodstream, causing intense systemic itchiness. Complications such as esophageal and gastric varices can also occur. Some patients also experience intense fatigue and listlessness. In addition to the bile ducts within the liver, liver cells are also destroyed, which gradually develops into cirrhosis of the liver. As the bile required for the body to absorb the vitamin D in food decreases, it becomes increasingly difficult for the body to absorb vitamin D, particularly in menopausal females, which can lead to osteoporosis. Another result of decreased amounts of bile is higher levels of cholesterol in the blood. In some cases, patients develop fat deposits around the eyes and suffer from xanthoma palpebrarum (yellowish plaque over the eyelids).
Once liver functions decline, the patient suffers from jaundice, edema, and ascites, followed by hepatic encephalopathy and liver failure, which can be a failure in the absence of liver transplantation. Some patients develop liver cancer.
Individuals with a predisposition to autoimmunity suffer autoimmune attacks on other tissues and cells in addition to the bile ducts, and thus PBC is known to be frequently associated with autoimmune disease comorbidities. In Japan, approximately 15% of patients with PBC experience difficulty in producing tears and saliva. Other notable comorbidities include Sjogren's syndrome, which causes the mouth and eyes to dry, rheumatoid arthritis or chronic thyroiditis (approximately 5% of patients), or other autoimmune diseases.

7. How is this disease treated?

PBC treatment can be broadly divided into treatments of PBC itself, which includes improving the flow of bile and controlling progression to cirrhosis of the liver, and treating the symptoms and comorbidities that occur because of PBC.
1) Treatments for PBC itself include ursodeoxycholic acid, which is known to suppress the progression of the disease by promoting the flow of bile. Currently, this drug is utilized throughout the world for PBC. In cases in which ursodeoxycholic acid alone does not result in sufficient improvement in liver dysfunction, a drug known as bezafibrate is frequently used in Japan. Bezafibrate is not formally recognized for use on PBC, but our research group has found that the concurrent use of bezafibrate and ursodeoxycholic acid may improve the long-term prognosis of PBC.
2) Treatments of the symptoms and comorbidities associated with PBC include antihistamines for intense itchiness. A new drug (nalfurafine hydrochloride) for the itchiness that occurs due to liver disease has been developed. This drug has shown some degree of effectiveness on the itchiness associated with PBC. Drugs such as bisphosphonate and denosumab have been developed for osteoporosis due to vitamin D absorption disorder.
3) In cases in which PBC progresses to the point at which cirrhosis of the liver develops, the same drugs used to treat cirrhosis of the liver due to other causes (see the section on esophageal and gastric varices, ascites, and hepatic encephalopathy) are used. However, in cases in which these medical treatments are not effective, liver transplantation is considered. If a donor among the patient's relatives is available, a living donor segmental liver transplant is performed. While brain-dead donor liver transplantation is becoming slightly more common, it is necessary to be registered for brain-dead liver donor transplantation in such cases. In either case, it is recommended that patients discuss the liver transplantation option carefully with their attending physician and obtain a referral to a medical facility that specializes in such procedures. In the case of PBC, the postoperative course is good after liver transplantation.

Topic (2): Drugs other than ursodeoxycholic acid for PBC

The only drug that has been clearly shown to be effective on PBC is ursodeoxycholic acid. However, ursodeoxycholic acid is not sufficiently effective when used on approximately 30% of patients with PBC. The issue of how to treat these patients has been a global problem for several years. More than ten types of novel drugs are either undergoing or are scheduled to undergo trials. In 2016, the drug obeticholic acid was found to be effective in the USA and Europe, and thus it was officially approved for use in those regions. However, in Japan, there are no plans for trials of this drug. As indicated above, in Japan, the combined use of bezafibrate is common. In 2018, a great deal of attention was paid to the results of a French group that showed that bezafibrate is effective. There are also trials underway designed to identify treatments that improve the itchiness experienced by patients with PBC.

8. What is the course of this disease?

Since ursodeoxycholic acid came to be used, the course of PBC has markedly improved. Continuous use of the various available drugs allows asymptomatic patients with PBC who experience almost no symptoms to lead the same daily lives and enjoy the same lifespan as individuals not afflicted by the disease. Even in cases in which ursodeoxycholic acid is not sufficiently effective, the combined use of bezafibrate, as described above, controls the progression and worsening of the disease to a considerable degree.

9. What precautions related to daily life are required for people with this disease?

In the case of individuals with asymptomatic PBC, in which there are almost no symptoms and the only abnormalities appear in blood test results, there are no particular precautions as long as they continue with their course of drugs. They do not require rest, and they may contain with their jobs normally. Because there has recently been increased concern about obesity, the number of people who require restrictions in their dietary caloric intakes and require appropriate exercise is increasing. Since the disease may progress if a patient stops taking drugs, patients should regularly visit a medical facility and continue on their course of drugs.
In cases in which the disease has progressed to the liver cirrhosis stage, careful precautions in daily life, for example, regarding diet and exercise, are required. In such cases, patients should consult with their attending physician.

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