Primary Biliary Cirrhosis

The gallbladder and the bile ducts. Also called biliary system or biliary tree. Source: National Digestive Diseases Information Clearinghouse

Primary biliary cirrhosis (PBC) is a chronic disease of the liver. The disease causes destruction of the medium-sized bile ducts of the liver. Early stages of the disease usually involve mild symptoms of itching and fatigue. Cirrhosis and liver failure occur later in the course of the disease. PBC, which is thought to be an autoimmune disorder, affects women more often than men and usually occurs between ages 30 and 60.

Other Names

• Autoimmune cholestatic liver disease

Signs and Symptoms

PBC is a chronic, slowly progressive disease. It is often detected in the early stage by routine laboratory tests before the patient has symptoms. As it progresses, symptoms begin to appear. Liver failure develops in the late stages and is identified by increased levels of bilirubin in the blood.

In early stages of PBC, blood tests done as part of a routine doctor's visit may detect elevated levels of the substances alkaline phosphatase and bilirubin, and/or an elevated total cholesterol.^[1] A high alkaline phosphatase by itself doesn't diagnose PBC, because bone damage and other liver diseases also result in elevated levels, but it does suggest disease in the bile ducts.

The first, and most common, symptoms of PBC are itchy skin (pruritus) and fatigue. The following are other symptoms may eventually develop.

• Jaundice, which leads to a yellowing of the eyes and skin (due to increased bilirubin levels)
• Fatty deposits under the skin, around the tendons and underneath the eyes
• Oily appearing stool, due to high-fat content
• Swelling of lower legs and ankles due to fluid retention
• Dry eyes and mouth

Osteoporosis,^[2] arthritis, and thyroid problems develop during the later stages of PBC. Osteoporosis or osteopenia (bone weakening that has not progressed to osteoporosis) increases the risk of bone fractures and breaks.

Causes

PBC is an autoimmune disorder. The body produces antibodies to fight substances in the body which it believes are foreign. These are called autoantibodies because they are attacking normal tissue. In PBC, it is the bile ducts that are being destroyed. These autoantibodies are found in 95% of patients with PBC. In addition, PBC is associated with a number of other autoimmune disorders, including the following:

• Hypothyroidism^[3]
• Celiac disease^[4]
• Sjogren syndrome
• Autoimmune thyroid disease
• Raynaud syndrome
• Scleroderma

As with most autoimmune diseases, the cause is not clear. One hypothesis suggests that an infection prompts the immune system to malfunction. For PBC, this is thought to be related to infection with certain microbes that cause "walking pneumonia," such as Chlamydia trachomatis.^[5] The disease may also be hereditary, as between 2% and 5% of cases have family members with the disease.

Diagnosis

Primary biliary cirrhosis is diagnosed by laboratory tests, x-rays, and liver biopsy. A liver biopsy also helps doctors follow the progression of the disease.

Laboratory tests

The first sign of PBC is often elevated alkaline phosphatase. Alkaline phosphatase is an enzyme that is found in high concentrations in the liver, particularly around the ducts where PBC is active. Two other liver enzymes, referred to as transaminases (ALT and AST), are often increased as well. Elevated liver enzymes give a general idea of liver tissue damage or inflammation and are not specific for PBC. More tests are needed to pin down why the transaminases are abnormal.

A more specific marker of PBC are anti-mitochondrial antibodies.^[1] These are present in more than 95% of patients with PBC. These are antibodies found in the blood that bind to an enzyme called pyruvate dehydroxygenase. These antibodies are probably involved in the progression of the disease. Another test detects levels of antinuclear antibodies (ANA). This test is fairly specific, but it is rarely done because a diagnosis can be made using elevated liver enzymes and a positive anti-mitochondrial antibody test.

As the liver disease progresses, and liver failure begins to become a problem, the liver stops functioning properly. A patient will have increased levels of bilirubin (hyperbilirubinemia). In addition, glucose levels (blood sugar) will be decreased, as a major function of the liver is to store and process glucose for use as energy. The liver manufactures the blood's clotting factors, which means that the ability to form clots is decreased and the patient will have more of a tendency to bleed. The tests used are the prothrombin time and INR ("International Normalized Ratio") and partial thromboplastin time (PTT). The liver also produces protein called albumin, which keeps water in the blood. Progressive liver damage reduces albumin levels and causes fluid to leak into tissues. This collection of fluid is called edema. It causes swelling and fluid accumulation. It can be seen in the abdomen (ascites) as well as other parts of the body such as the lower legs.

Imaging tests

The main purpose of imaging tests is to rule out other causes of elevated liver enzymes. Alkaline phosphatase is produced around the liver ducts, and swelling of the ducts from any cause—for example, gallstones and cancers of the bile duct—will elevate enzyme levels. The ducts can be seen on a CT scan or a specialized MRI scan called the MRCP (magnetic resonance cholangiopancreatography).

Liver biopsy

A liver biopsy is used to determine the progression of PBC. The biopsy involves a thin needle that removes a small sample of liver tissue under local anesthetic (numbing medicine). The sample is examined with a microscope. The disease can be categorized into one of four stages of progression, depending on the appearance of the liver cells under the microscope. Staging helps guide treatment and predict prognosis, or the outcome, of the disease.

Treatment

Initial treatment of PBC is usually aimed at relieving symptoms. Vitamin replacement therapy, calcium supplements, and drugs to treat itching are usually prescribed.

Itching is caused by the accumulation of bile salts in the blood. Usually these salts are excreted through the bile ducts of the liver. In PBC, these ducts are blocked. Drugs that treat the itch reduce the level of salts in the body by dissolving them. Drugs often used for this purpose include cholestyramine and colestipol. Other drugs that help relieve itch include naloxone or naltrexone.

Since lack of bile function may prevent absorption of fatty substances, certain fat-soluble vitamins may be lacking in people with PBC. For this reason, supplements of Vitamins A, D and K are often given. Osteoporosis may be treated by calcium supplements.

Celiac disease, or gluten enteropathy, may be linked to PBC. In these patients, a gluten-free diet is the treatment.

For treatment of the PBC itself, many patients benefit from the drug ursodeoxycholic acid (Urso 250 and Urso Forte), which is the only drug approved by the U.S. Food and Drug Administration for the treatment of PBC. It is particularly effective in people with early stage disease. Ursodiol (Actigall) has also helped some patients by increasing bile flow. Neither of these drugs cure the disease, but they can help delay its progression. Colchicine and methotrexate may be used to delay the disease in some individuals.

Once scarring of the liver (cirrhosis) occurs, the disease is in its end stages. If the liver becomes severely damaged, a transplant may be necessary. This involves the removal of the entire diseased liver in replacement with a liver from an organ donor. There is a very limited supply of donor livers, and liver transplantation is major surgery. It also requires the lifelong use of immune suppressant drugs to prevent the liver from being rejected by the patient's body.

Prevention

To date, PBC cannot be prevented.

Living with PBC

Living with PBC requires a number of adjustments to day-to-day living. The key factor is to avoid worsening liver damage, which translates to avoiding alcohol consumption and certain medications, including acetaminophen. In its early stages, PBC can cause severe, irritating pruritus. The itching may respond to treatment. The fatigue can be severe. In its late stages, patients require frequent medical follow up and may eventually require liver transplantation when end stage liver disease is diagnosed. Living with a liver transplant is far preferable to living the end stage PBC but does require a number of lifestyle changes. These changes include taking immune suppressant drugs and making recurrent visits to transplant physicians.

According the American Liver Foundation, some helpful lifestyle changes include:

• A reduced sodium diet
• Drinking ample water
• Taking calcium and Vitamin D supplements
• Avoiding or reducing the consumption of alcohol
• Reducing stress
• Exercising, particularly walking
• Skin care
• Regular dental examinations
• Artificial tears for dry eyes

Chances of Developing PBC

The majority of patients with PBC are women aged between 40 and 60. Primary biliary cirrhosis is seven times more common in women than men. The diagnosis is made in about 5 per 100,000 women every year and 1 per 150,000 men per year. Also at risk are people with other autoimmune conditions.

Clinical Trials

For a list of American government-sponsored clinical trials related to primary biliary cirrhosis, visit this link.

National Institutes of Health: S-Adenosyl Methionine for Symptomatic Treatment of primary biliary cirrhosis

Mayoclinic.com: Understanding the Genetic Predisposition to the Development of Primary Biliary Cirrhosis (PBC)

Expected Outcome

Primary biliary cirrhosis has no cure. Not all patients with asymptomatic disease will develop liver failure. Of those patients who do, liver transplantation long-term survival rates are higher than 90%. The disease may recur in 15% of patients within five years of transplantation.

The outcome of PBC depends on the stage at which it is diagnosed. Once a patient has symptoms of pruritus or fatigue, survival is usually about 7-10 years. Patients who are older at diagnosis or have signs of end stage liver disease usually have a worse outlook. The outcome is much better if PBC is detected with blood tests before symptoms appear. In this case, only one-third of patients will have symptomatic illness within 20 years. If patients undergo transplant, the success rate is high. Liver transplant has a 10% mortality within the first year, but after that survival rate improves. Primary biliary cirrhosis, however, does sometimes recur in transplanted livers, and retransplantation is possible.

Mathematical models have also been developed to estimate lifespan in patients with PBC to asssit patients and physicians.A risk score is calculated from 6 variables (age, albumin,bilirubin, protime,peripheral edema and use of diuretics) and the probability of survival for 24 months is calculated ^[6]

• Conducting a PBC twin study. Any twins with PBC are encouraged to contact megershwin@ucdavis.edu.
• Identifying families in whom two sisters or a brother/sister both have PBC (family study) (same contact as above)
• Studying the possibility that primary biliary cirrhosis is caused by a chemical exposure. In particular, they are currently screening several hundred chemical compounds that might 'imitate' compounds normally found in the body, thus producing an autoimmune response.
• Studying the possibility that primary biliary cirrhosis is caused by a bacterium. In particular, research is ongoing to determine if Novosphingobium aromaticivorans is potentially able to trigger AMA production and PBC onset.
• Trying to develop an animal model for PBC—that is, a mouse or guinea pig manifesting all the signs of the human disease. Producing such a model would provide a way to further study PBC mechanisms and future therapies for the disease.
• Recently completed an epidemiologic study identifying common factors found in 1032 patients and 1041 healthy controls who have PBC. Many other institutions are collaborating.
• Trying to find novel ways to interrupt PBC.

Mayo Clinic

References

1. ↑ ^{1.0 1.1} Kumagi T, Heathcote EJ. Primary biliary cirrhosis. Orphanet J Rare Dis. 2008 Jan 23;3:1. Abstract | Full Text
2. ↑ Parés A, Guañabens N. Osteoporosis in primary biliary cirrhosis: pathogenesis and treatment. Clin Liver Dis. 2008 May;12(2):407-24; x. Abstract
3. ↑ Elta GH, Sepersky RA, Goldberg MJ, Connors CM, Miller KB, Kaplan MM. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci. 1983 Nov;28(11):971-5. Abstract
4. ↑ Lawson A, West J, Aithal GP, Logan RF. Autoimmune cholestatic liver disease in people with coeliac disease: a population-based study of their association. Aliment Pharmacol Ther. 2005 Feb 15;21(4):401-5. Abstract
5. ↑ Abdulkarim AS, Petrovic LM, Kim WR, Angulo P, Lloyd RV, Lindor KD. Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae? J Hepatol. 2004 Mar;40(3):380-4. Abstract
6. ↑ Murtaugh PA et al. Primary biliary cirrhosis: prediction of short-term survival based on repeated patient visits. Hepatology 1994;20:126-134

   Notable Experts

   University of California at Davis

   UC Davis has a number of ongoing studies related to PBC. Per their website, they are/have:<ref> UC Davis Department of Internal Medicine: [http://www.ucdmc.ucdavis.edu/internalmedicine/rheumatology/immunolab_goals.html Autoimmune diseases and clinical immunology] </li></ol></ref>

E. Jenny Heathcote Management of primary biliary cirrhosis.Hepatology 2000;31:1005-13

External Links

PBCers Organization