Primary Biliary Cirrhosis (PBC) Treatment

The risk of developing PBC is significantly greater for people who have had other autoimmune diseases.

Primary biliary cirrhosis (PBC) is a chronic disease characterized by progressive inflammation and destruction of small bile ducts within the liver. The bile ducts transport bile from the liver to the intestine for the absorption of fat and elimination of waste products.

The cause of PBC may involve autoimmunity, infection, or genetic predisposition, acting alone or in combination. The finding of autoantibodies called antimitochondrial antibodies (AMA) in most patients with PBC favors the concept of an autoimmune disease occurring in genetically predisposed individuals.

Medications used to treat PBC itself include most commonly ursodeoxycholic acid (UDCA), rarely colchicine (Colcrys), and sometimes certain immunosuppressive medications, such as corticosteroids. The UDCA is the most effective and safe treatment. In May 2016, the FDA approved another drug, obeticholic acid (Ocaliva) for the treatment of PBC.

Symptoms of PBC that can be treated include:

• Itching
• Osteoporosis
• Elevated serum cholesterol and xanthomas
• Malabsorption of fat and the fat-soluble vitamins A, D, E, and K

Complications of cirrhosis in PCB that can be treated include:

• Edema and ascites
• Bleeding from varices
• Hepatic encephalopathy
• Hypersplenism
• Liver cancer

Diseases associated with PBC that can be treated include:

• Low thyroid function (hypothyroidism)
• Sicca syndrome
• Raynaud's phenomenon
• Scleroderma
• Celiac sprue
• Urinary tract infections (UTIs)
• Gallstones

PBC patients with advanced complications of cirrhosis, severe osteoporosis, or intractable itching are eligible for liver transplantation. The results of liver transplantation are excellent in patients with PBC.

The treatments used in patients with PBC can be subdivided into:

• Medications to treat PBC itself
• Treatments for the symptoms of PBC
• Treatments for the complications of PBC
• Treatments for the diseases associated with PBC
• Medications to increase bile flow from the liver
• Liver transplantation

Most often, people will contact their primary care health-care professional with questions about the color of their stool. These include healthcare professionals who care for infants, children, and adults. Depending upon the cause of the stool color change, certain specialists may need to be involved. For example, for red or black stool due to bleeding, a gastroenterologist may be needed to perform endoscopy, to look for a bleeding source in the stomach or intestine. Patients with PBC are generally treated by gastroenterologists and/or hepatologists. Development of complications may require the need for other specialists. For example, an endocrinologist may be needed for the treatment of metabolic bone disease (osteoporosis). Patients who develop hepatocellular carcinoma may need the help of several specialists including an oncologist, interventional radiologist, and a liver surgeon. Patients with advanced liver disease including cirrhosis of the liver should be referred to a transplant center as they may need a liver transplant at some stage in the future.

The destruction of bile ducts in PBC leads to the retention of certain toxic bile acids in the liver cells (hepatocytes). These toxic bile acids are believed to cause the death of the hepatocytes and a gradual loss of liver function. Ursodeoxycholic acid (UDCA is an abbreviation for this chemical name) is a naturally occurring bile acid that is produced in small quantities by normal hepatocytes. UDCA is available to prescribe as ursodiol (Urso-250, Actigal, and generic preparations). When taken orally, UCDA is absorbed from the gut, taken up and processed by hepatocytes, and transported in bile back to the intestine.

UDCA has at least four beneficial effects in PBC:

• First, it increases the rate of bile flow from the hepatocytes, thereby combating cholestasis and diluting toxic bile acids in bile.
• Second, it inhibits the body's production of toxic bile acids, thereby preventing further injury to the hepatocytes.
• Third, it inhibits apoptosis (genetically programmed cell death), thereby preventing hepatocytes from dying.
• Fourth, it mildly inhibits the immune response in the liver, thereby possibly reducing immunological injury to the bile ducts and liver.

Four large-scale, clinical trials have compared the effectiveness and safety of UDCA to that of an inactive drug (a placebo). These controlled trials were done in both symptomatic and asymptomatic patients with a spectrum of tissue abnormalities (pathology) on their liver biopsies, ranging from early disease to cirrhosis. UDCA treatment led to improvement in liver blood test abnormalities, significantly reducing elevated levels of bilirubin, alkaline phosphatase, gamma-glutamyl transferase (GGT), and cholesterol. UDCA, however, did not improve fatigue or prevent or improve osteoporosis and had a variable effect on itching. Three of the four trials used a similar dose of UDCA (13-15 mg per kg body weight per day) and were combined for an analysis of a total of 548 patients.

The results of the combined analysis showed that UDCA significantly increased survival after up to 4 years of therapy, without the need for liver transplantation. The fourth large-scale study used a lower dose of UDCA (10 to 12 mg per kg per day). The results of this study differed somewhat from those of the other three studies. This one showed the benefit of UDCA treatment primarily in patients with bilirubin levels of less than 2 mg/dL. The three other studies, analyzed alone or combined, however, did not confirm this observation about bilirubin. In fact, each of those studies actually demonstrated a benefit for patients with advanced disease and elevated bilirubin levels. Furthermore, the development of portal hypertension was reduced by the UDCA. It is important to note that despite producing clear benefits, UDCA treatment primarily retards progression and does not cure PBC.

All patients with PBC who have abnormal liver tests, regardless of the stage of the liver biopsy or the phase of the natural progression of the disease, probably should be treated with UDCA. The dose usually should be between 13 and 15 mg per kg body weight per day. Patients can take UDCA as either a single dose or a divided dose without affecting its clinical benefits. UDCA is very safe for long-term use. The primary side effect is diarrhea, which is due to failure to absorb all of the UDCA from the gut. Patients who experience diarrhea can take smaller doses more frequently, trying to maintain the recommended total daily dose. On the other hand, patients who do not have diarrhea can try taking larger amounts per dose, to take only one dose (again, the recommended total dose) per day at bedtime.

Colchicine, a drug that reduces inflammation and scarring, has been used primarily to treat arthritis caused by gout. Three randomized, controlled trials in PBC showed that colchicine, compared to placebo, modestly slowed the progression of abnormal blood tests, but did not reduce symptoms or prevent the progression of liver pathology (tissue abnormalities on the biopsy). One of the trials suggested that colchicine improved survival. This impression of better survival with colchicine, however, has not been substantiated. The seemingly improved survival appears to be due to an unexpectedly high death rate (mortality) among the patients receiving the inactive drug in that study. The benefits of colchicine are so small that it is rarely recommended.

Immunosuppressive medications, for example, corticosteroids, azathioprine, cyclosporine (Sandimmune, Neoral, Gengraf), and methotrexate (Rheumatrex, Trexall) suppress immune reactions. These medications are theoretically attractive agents to treat PBC, based on the concept that it is an autoimmune disease. Several randomized controlled studies have tested immunosuppressive drugs in PBC. However, none of these studies has demonstrated prolonged survival of patients.

Corticosteroids, for example, prednisone, prednisolone, and budesonide (Entocort) inhibit the initiation of immune responses, including those initial responses required for the perpetuation of autoimmunity reactions. A randomized (treatment assigned by chance) controlled trial was carried out comparing a placebo with a low dose of prednisolone over 3 years. This study showed that prednisolone improved liver function and did not significantly increase the rate of bone thinning or demineralization. (Osteoporosis is a potential side effect of steroids). Another randomized trial compared UDCA and placebo with UDCA and prednisolone in patients with early stages of PBC. Although improvement in liver function was similar for both groups, only the combination of UDCA and prednisolone resulted in markedly improved liver biopsies.

It is noteworthy that the principal benefits of corticosteroids were seen in patients with early stages of the disease on liver biopsy. Still, these treatments did not result in a full remission or cure. Moreover, neither the size nor duration of these trials was sufficient to determine an effect on survival without liver transplantation. Accordingly, more data are needed to confirm the benefit and safety of PBC of steroids alone or in combination with UDCA. Nevertheless, these studies disproved an earlier notion that corticosteroids would cause rapid progression of the bone disease osteoporosis in patients with PBC.

Budesonide is a steroid that is more rapidly processed (metabolized) in the liver and, therefore, presumably would be less injurious to bone than other steroids. This drug was studied in selected patients with PBC who had had suboptimal (less than favorable) responses to UDCA. Unfortunately, budesonide was ineffective in this group. In fact, it significantly worsened osteoporosis and did not prevent the progression of the PBC. In contrast, a randomized trial comparing UDCA and placebo with a combination of budesonide and UDCA showed the combination to be more effective, while bone thinning (loss of mineral density) was comparable in the two groups. But here again, more data are needed to confirm the benefit and safety of this combination.

Imuran prevents the production of new lymphocytes (white blood cells that take part in immune responses) by blocking cell division (reproduction) of the lymphocytes. The consequence of this action is to reduce the number of new inflammatory cells entering the sites of inflammation. A large study comparing the effect of azathioprine with an inactive drug (placebo) in 248 patients with PBC, however, showed no benefit. Consequently, this drug is not currently recommended for use in PBC patients outside of research protocols.

Cyclosporine is a powerful immunosuppressive drug, cyclosporine (Sandimmune, Neoral, Gengraf) is used primarily to prevent rejection of transplanted organs. The drug prevents the production of an important signal required for lymphocytes to divide (reproduce) and generate inflammation. A large study of 349 PBC patients, comparing cyclosporine with an inactive drug, showed some benefit from the cyclosporine. The frequency of the side effects of high blood pressure and decreased kidney function, however, make this drug unacceptable for long-term use.

Methotrexate both suppresses the immune system and prevents cells from dividing. This drug has been used successfully in severe rheumatoid arthritis and an immunologic skin disease called psoriasis. Initial limited trials in patients with PBC did not show a benefit, and serious side effects included ulcerations of the mouth, hair loss, and pneumonia. Additionally, preliminary reports of randomized, controlled trials of methotrexate therapy of PBC in Europe noted a higher-than-expected rate of a form of pneumonia that scars the lungs. Moreover, a recently published randomized, controlled trial of low-dose methotrexate in PBC showed serious toxicity over six years. Currently, a large trial in the United States comparing UDCA alone to a combination of UDCA and methotrexate is underway. At present, it is premature to recommend the use of methotrexate to treat PBC outside of clinical trials.

Ocaliva was approved by the FDA in May 2016 for the treatment of PBC in combination with ursodeoxycholic acid (UDCA) in adults with inadequate response or are intolerant to UDCA, or as a single therapy in adults unable to tolerate UDCA. In such patients, nearly 50% showed an improvement in the liver tests. The most common adverse effect is pruritus, observed in over 50% of patients. The most common side effects include fatigue, abdominal pain and discomfort, joint pain, pain in the middle part of the throat, dizziness, constipation, and itching.

Cholestyramine is a drug taken orally that is not absorbed in the gut. The drug attaches (binds) to substances in the gut, including those that come from the bile, and then removes them from the body into the bowel movements. Presumably, cholestyramine is helpful because it binds both bile acids and unidentified substances that cause itching after they are absorbed from the gut into the bloodstream. Cholestyramine is the most effective therapy for most patients with cholestatic itching. For optimal effects, cholestyramine should be taken with meals when bile flow into the gut is highest. A somewhat larger dose with breakfast is recommended for patients with gallbladders since the bile stored overnight in the gallbladder is released at this time.

It is important to note that cholestyramine can also bind to medications. Therefore, other medicines must be taken one hour before or two hours after cholestyramine. The usual dosage is 8 grams with breakfast, 4 grams with lunch, and 4 grams with dinner. Cholestyramine does not dissolve well in liquids and often feels gritty as it is swallowed. Mixing it in carbonated beverages, however, can reduce this problem.

The principal side effect of cholestyramine is constipation. Constipation occurs because the drug binds the bile acids that otherwise would make more water available in the colon to soften the stool. Adverse reactions of cyclosporine include:

• Kidney dysfunction
• Tremor
• High blood pressure
• Gum hyperplasia

Another bile acid-binding medication that can be tried to relieve itching is colestipol (Colestid).

An antibiotic, rifampin (Rifidin) was initially found to improve itching due to cholestasis actually by chance. Then, a study of patients with PBC that included a cross-over between rifampin and an inactive compound (placebo) showed that rifampin did reduce itching at a dose of 150 mg taken two or three times per day. This drug may take up to one month to be effective, but should not take longer. Therefore, if the drug is not effective after one month, it should be discontinued. Not all patients with PBC benefit from this drug.

The way in which rifampin works is poorly understood. It can induce biochemical pathways in hepatocytes that theoretically may alter the bile acid environment within these cells. The side effects of rifampin include elevation of bilirubin, dark urine, hepatitis (more rarely), reduced numbers of blood platelets (small elements that help stop bleeding from a cut surface), and kidney damage.

The fact that some patients who receive opiate narcotics (such as morphine) develop itching led to the hypothesis that itching in cholestasis may be caused by the body's natural opiates, called endorphins. To test this hypothesis, patients with PBC who had itching were treated with the oral drug nalmephene, an antagonist (acts against or blocks the action) of opiates. Itching improved over 9 months. Some patients treated with the opiate antagonist, however, developed very unpleasant symptoms of opiate withdrawal when their natural endorphins were inhibited. Therefore, this drug is not appropriate for long-term use in PBC. A controlled study comparing an intravenous opiate antagonist called naloxone (Narcan) with inactive intravenous fluids showed that the naloxone improved itching in PBC patients. Because it must be given intravenously, naloxone also is inappropriate for long-term use.

Recently, the oral opiate antagonist, naltrexone (Revia), was tested in a small, randomized, controlled trial in PBC patients with itching. It improved itching in 50% of patients and did not cause opiate withdrawal symptoms. Naltrexone also improved symptoms of fatigue and depression, possibly by restoring the ability to sleep at night when itching is most severe. However, future studies are needed to assess its safety, how long it can be given, and whether patients will eventually become unresponsive (refractory) to its effects.

In uncontrolled studies, patients with PBC who had severe itching underwent a procedure called plasmapheresis. (Uncontrolled studies are studies in which the treatment is not compared with other treatments or placebos.) In this procedure, the blood is removed from the body, and the fluid phase (called plasma) of the blood is separated from the blood cells and platelets. The plasma is then percolated through a column containing activated charcoal. Finally, the plasma is remixed with the blood cells and returned intravenously to the patient. The idea is that the charcoal would remove some compound or compounds (as yet unknown) from the plasma that caused the itching. Anecdotally, many patients had relief of itching for periods ranging from days to months. However, no controlled trials (compared with other treatments or placebos) were performed. Hence, this procedure is still considered experimental and is not often used.

Whether the usually recommended therapies for osteoporosis can satisfactorily treat or prevent osteoporosis in patients with PBC is not yet clear. It makes good sense, however, to provide adequate calcium and vitamin D in the diet. Vitamin D is needed for the absorption of calcium from the gut. Adequate amounts of calcium can be taken by eating dairy products such as milk or yogurt or by supplementing the diet with 1000 to 1500 mg of calcium carbonate. Calcium carbonate, prepared from powdered oyster shells, can be purchased over the counter. Usually, the extra vitamin D contained in a daily multivitamin is enough to satisfy the daily requirement. Exposure of the skin to sunlight also increases the production of vitamin D in the body.

For postmenopausal women with PBC, hormonal replacement therapy with estrogen can decrease the risk of osteoporosis. Estrogen, available in oral form or as a patch that allows absorption of estrogen through the skin, is safe for women with PBC. Remember, however, that there is controversy about the use of estrogen replacement therapy in postmenopausal women who have had breast cancer, because of a possible risk of recurrence of the cancer. There is also concern about the prolonged use of estrogens with progestin in increasing the risk of coronary heart diseases, strokes, and pulmonary embolism in healthy menopausal women. Therefore, whether to use estrogen or not should be individualized after consulting one's doctor. Another alternative to estrogen to protect bone density in patients with PBC is bisphosphonates, which are FDA-approved drugs for the prevention of osteoporosis. Too few studies have been performed using other drugs (for example, fluoride or calcitonin) for osteoporosis to recommend their use in PBC.

Elevated levels of cholesterol in the blood are common in patients with PBC, and xanthomas (fatty deposits that appear as yellowish firm nodules in the skin) occur in about 25% of those patients with elevated cholesterol. Diets with low cholesterol content do not consistently lower serum cholesterol in these patients because the production of cholesterol by the liver is stimulated in patients with PBC. Cholestyramine, the oral medication that is often used to treat itching, can, at the same time, reduce the levels of serum cholesterol to a modest degree.

Clofibrate (Atromid) should not be used for treating elevated serum cholesterol in PBC because it elevates (rather than lowers) the cholesterol levels in these patients. Moreover, this drug may worsen xanthomas and cause the formation of gallstones containing cholesterol. Two studies indicate that UDCA therapy significantly reduces serum levels of cholesterol and is recommended for use in patients with xanthomas. A new class of drugs called statins inhibits the formation of cholesterol and, to a lesser degree, triglycerides. The safety and effectiveness of the statins, however, have not been adequately studied in PBC. One of the common side effects of statins is liver injury. Thus, their use in a person with liver disease requires careful monitoring by a physician.

Reduction of dietary fat is the treatment of choice for fat malabsorption (poor absorption of fat in the gut). The idea is that if the dietary intake of fat is decreased, more of this fat will be absorbed. The goal of the low-fat diet would be to alleviate the diarrhea caused by the fat malabsorption, while still providing enough fat for adequate nutrition. If this diet does not help, a supplement of special fats called medium-chain triglycerides (MCT) can be ingested. MCT can replace as much as 60% of the calories provided by ordinary dietary fat, which is mostly long-chain triglycerides. MCT is a special type of fat preparation that does not require bile acids for its absorption and is absorbed more easily than the usual dietary fat. As noted earlier, PBC patients with malabsorption of fat should also be tested for celiac sprue.

It is recommended that patients with PBC take a multivitamin supplement without minerals to increase the dietary intake of fat-soluble vitamins. If the quantities of bile acids flowing through the bile ducts to the gut are marginal, intestinal absorption of the fat-soluble vitamins may not be adequate, even with supplements. Two strategies exist for this situation. First, patients can take Liqui-E with meals. Liqui-E is an over-the-counter liquid preparation of vitamin E that also increases the absorption of other fat-soluble vitamins in the diet or multivitamin preparations. Second, the fat-soluble vitamins A and K can be given by injection into the muscle once a month. Remember, however, that women who might become pregnant, should not receive injections of vitamin A, because it can cause birth defects.

Retention of salt and water can lead to swelling of the ankles and legs (edema) or abdomen (ascites) in patients with cirrhosis. Diuretics are medications that work in the kidneys to combat the retention of fluid by eliminating salt and water in the urine. A combination of the diuretics spironolactone (Aldactone) and furosemide (Lasix) can reduce or eliminate the swelling in most people. During treatment with diuretics, it is important to monitor kidney function by measuring serum levels of blood urea nitrogen (BUN) and creatinine to determine if the doses of the diuretics are safe. Sometimes, when the diuretics do not work, a long needle is used to draw out the fluid directly from the abdomen (a procedure called paracentesis).

If large varices (distended veins) develop in the esophagus or upper stomach or any episodes of bleeding from varices have occurred, physicians should consider specific therapy for the varices. Treatment with propranolol (Inderal), a drug in a class called beta-blockers, is effective in preventing initial bleeding or rebleeding from varices in patients with cirrhosis. This drug, however, has not been proven to prevent bleeding in patients with portal hypertension who do not have cirrhosis.

Other methods are available to prevent or treat varices. These methods include:

• Procedures done during upper endoscopy (for example band ligation of the varices)
• Other drugs, for example, octreotide (Sandostatin)
• Other non-surgical procedures (for example, a procedure called TIPS to decrease the portal pressure)
• A surgical operation to create a shunt (passage) from the high-pressure portal vein to veins with lower pressure can eliminate blood flow into the varices. It is appropriate to consider such a surgical shunt for patients with PBC and portal hypertension who do not have cirrhosis or have only early cirrhosis. The hazards of shunt surgery in these patients would be less than those in patients with advanced cirrhosis.

PBC patients with an abnormal sleep cycle, impaired thinking, odd behavior, or other signs of hepatic encephalopathy usually should be treated with a low protein diet and oral lactulose. Dietary protein is restricted because it is a source of the toxic compounds present in hepatic encephalopathy. Lactulose, which is a liquid medication, traps the toxic compounds in the colon. Consequently, they cannot be absorbed into the bloodstream and cause the symptoms of encephalopathy. To be sure that adequate lactulose is present in the colon at all times, the patient should adjust the dose to produce 2 to 3 semiformed bowel movements a day. If symptoms of encephalopathy persist, oral antibiotics, such as rifaximin, can be added to the treatment regimen.

The blood filtration function of an enlarged spleen usually results in only mild reductions of red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia) that do not require treatment. Severe anemia, however, may require blood transfusions or treatment with erythropoietin or epoetin alfa (Epogen, Procrit), a hormone that stimulates the production of red blood cells. If the numbers of white blood cells are severely reduced, another hormonal drug, called granulocyte-colony stimulating factor (G-CSF) is available to increase the white blood cells. An example of an available G-CSF drug is filgrastim (Neupogen).

No FDA-approved medication is available yet to increase the number of platelets. As a necessary precaution, patients with low platelets should not use aspirin or other non-steroidal anti-inflammatory drugs (NSAIDS) since these drugs can hinder the function of platelets. If a low number of platelets is associated with significant bleeding, transfusions of platelets usually should be given. Surgical removal of the spleen (called splenectomy) should be avoided, if possible, because of the risk of excessive bleeding during the operation and the risk of anesthesia in advanced liver disease.

Dry eyes

For chronically dry eyes, use artificial tears containing methylcellulose without preservatives. These artificial tears can prevent the complications of dry eyes, such as ulcers of the cornea.

Dry mouth

Patients with dry mouth have a reduced amount of watery saliva but maintain the production of thick saliva. Chewing gum or sucking on a small object can stimulate more watery saliva. Others may need to moisten the mouth with fluids. All patients with dry mouth must take adequate amounts of fluids to help with swallowing during meals or when taking oral medications. It is also recommended that these patients have frequent dental appointments to check for cavities.

Dry vagina

Lubricating jelly is suggested to prevent painful sexual intercourse. If a woman is postmenopausal, estrogen creams are also recommended to improve the function of the cells lining the vagina.

PBC patients with Raynaud's phenomenon should restrict exposure to the cold. They can wear warm clothing, gloves, and shoes when they must be in cold environments. Some patients find that using gloves also helps avoid problems when they handle ice-cold articles, for example, frozen food packages and cold cans of soda. All patients with Raynaud's phenomenon should stop smoking cigarettes because smoking causes reduced blood flow in the blood vessels of the hands and feet. Drugs called calcium channel blockers help the symptoms in the hands and feet of some patients. At the same time, unfortunately, however, these drugs may worsen swallowing difficulties associated with scleroderma.

Skin tightening, calcification, or telangiectasia

There is no known therapy to prevent or reverse skin tightening, calcium deposits, or telangiectasias in patients with scleroderma.

Swallowing problems and heartburn

As previously mentioned, patients with scleroderma may experience heartburn or difficulty swallowing. It is recommended that patients with these symptoms or other evidence of scleroderma or the CREST syndrome:

• Take drugs called proton pump inhibitors (PPIs) to reduce stomach acid.
• Avoid eating or drinking within 2 hours of lying down or going to bed.
• Elevate the head of the bed about 6 to 8 inches. This gentle slope helps prevent stomach acid from flowing up into the esophagus.
• Consult a gastroenterologist (a specialist in diseases of the esophagus and stomach) to undergo an upper endoscopy to assess the interior of the esophagus and stomach.

Cholesterol gallstones may be prevented by the UDCA used for the long-term treatment of the PBC itself. (UDCA taken orally can dissolve cholesterol gallstones in a minority of patients.) No treatment is necessary for patients who have gallstones that are not causing symptoms. These patients should usually just be observed because they will probably never develop symptoms from their gallstones.

An operation (cholecystectomy) to remove the gallbladder and its gallstones should be considered if the gallstones have been causing symptoms. These symptoms ordinarily are bouts of rather characteristic abdominal pain. This surgery usually should not be done, however, if a patient has advanced cirrhosis because of the increased risk of complications from both the surgery and the PBC. In this situation, less risky procedures can be considered or, if the gallstones are the cholesterol type, UDCA (if not already being used to treat the PBC) can be given reasonably safely to try to dissolve the gallstones.

Liver transplantation is a life-saving operation for patients with PBC who are at risk of premature death due to liver failure or the complications of cirrhosis and portal hypertension. The Mayo Risk Score provides an accurate estimate of the future outcome (prognosis) for patients, regardless of whether they are being treated with ursodeoxycholic acid. The United Network for Organ Sharing (UNOS) permits patients with PBC to be listed for a liver transplant once their estimated survival with PBC for an additional year is 95% or less. It is recommended that physicians calculate the Mayo Risk Score at least yearly in all patients with PBC who have cirrhosis.

Most PBC candidates for transplantation have advanced cirrhosis with decompensated liver disease, which also is referred to as liver failure. Decompensated liver disease means that the patients have low levels of serum albumin and blood clotting factors made in the liver and complications of portal venous hypertension such as ascites, variceal bleeding, encephalopathy, or hypersplenism. Patients are classified as having decompensated cirrhosis whether or not the complications respond to medical therapy.

Rarely, before advanced cirrhosis develops, transplantation of the liver is warranted in a few clinically disastrous situations in PBC. Examples of such situations include recurrent fractures due to advanced osteoporosis or severe, debilitating itching unrelieved by any medical therapy, and even more rarely hepatopulmonary syndrome (breathing difficulty in advanced cirrhosis). The regional review committees of UNOS accept applications for transplantation in these special circumstances and decide on a patient-by-patient basis if liver transplantation is indicated.

The outcome of liver transplantation in PBC is excellent. The survival of patients two or more years after transplantation is generally 80%. This impressive survival rate is greater than the survival of patients transplanted for most other types of liver diseases. The titers of AMA fall following successful liver transplantation, but they do not usually disappear. A minority of patients, however, develop recurrent PBC in the transplanted liver. Studies are being performed to see if reducing the maintenance doses of immunosuppressive drugs more slowly after transplantation can prevent the recurrence of PBC. Once recurrent PBC is diagnosed, ursodeoxycholic acid therapy is started to retard progression. Patients with recurrent PBC rarely will need a second liver transplant.

The goal of ongoing and future research in PBC is to better understand the processes (mechanisms) that initiate and perpetuate the inflammation that destroys first the small caliber bile ducts and later the hepatocytes. Logically, a more complete understanding of these mechanisms will reveal new strategies for therapy, designed to block specific crucial steps in the progression of disease.

PBC is such a slowly progressive disease that it is often initially diagnosed after the development of cirrhosis. Future therapies will probably include strategies that differ for patients with early disease compared to those with advanced disease. Presumably, patients with early phases of PBC would benefit more from therapies that block immunologic mechanisms of bile duct destruction than would patients whose bile ducts have already been destroyed. Conversely, patients whose bile ducts have already been destroyed may benefit more from therapies that prevent the formation of scar tissue and the toxic consequences of cholestasis.

The key to success is the support of both basic science and clinical research in PBC, which have not been adequately funded in the past. Several promising research strategies are being pursued to reveal the mechanisms involved in developing PBC. For example, studies are in progress to evaluate the genetic (hereditary) characteristics of patients with PBC who have close relatives with the disease. By studying all of these patients with PBC and comparing them with other family members without PBC, it may be possible to better understand the predispositions to this disease. In addition, a large-scale study is underway in the United States that will compare PBC patients with healthy people of the same age and gender. The points of comparison will include their life experiences, habits, diet, medical and surgical histories, childbearing history, and exposures to environmental toxins and medications. This study likewise should provide important clues regarding predispositions to PBC.

Studies also are in progress to see if PBC may be initiated (triggered) by an infection with either bacteria or viruses. For example, studies are ongoing to confirm or disprove the notion that proteins of infectious organisms stimulate AMA autoantibodies (and the autoantibodies just happen to react to antigens present in the mitochondria). Other studies are dissecting the mechanisms involved in the lymphocyte migration toward small bile ducts and the lymphocyte killing of bile duct epithelial cells. These studies involve not only patients with PBC but also several animal models in which T-lymphocytes identically destroy small bile ducts to that seen in PBC. These studies ultimately should identify new ways to treat PBC by, for example, blocking the killing of bile ducts by T-lymphocytes.

Finally, the issue of scar tissue formation in PBC and other diseases associated with cholestasis is now being researched in the hope of finding a way to prevent the development of cirrhosis. If cirrhosis can be prevented, even if ongoing inflammation of the liver continues, many patients might not develop the complications of portal venous hypertension and the progression to liver failure.