Diseases

Primary Biliary Cirrhosis Treatment (PBC) Information

Azathioprine (Imuran)

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.

Budesonide (Entocort)

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 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.

Charcoal hemoperfusion for itching

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.

Cholestyramine (Questran) for 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 came 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 blood stream. 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, it is important that other medicines 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. The 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

Colchicine (Colcrys)

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 progression of abnormal blood tests, but did not reduce symptoms or prevent progression of liver pathology (tissue abnormalities on the biopsy). One of the trials actually suggested that colchicine improved survival. This impression of better survival with colchicine, however, has not been substantiated. In fact, 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.

Corticosteroids

Corticosteroids, for example, prednisone, prednisolone, and budesonide (Entocort) inhibit the initiation of immune responses, including those initial responses required for 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 a 3-year period. 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 in 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.

Cyclosporine (Sandimmune, Neoral, Gengraf)

Cyclosporine is a powerful immunosuppressive drug, cyclosporine (Sandimmune, Neoral, Gengraf) is used primarily to prevent rejection of transplanted organs. The drug prevents 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.

Immunosuppressive medications

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.

Methotrexate (Rheumatrex, Trexall)

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 a six-year period. 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.

Obeticolic acid (Ocaliva)

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% 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.

Opiod antagonists for itching

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 a 9-month period. 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.

Osteoporosis medications

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. The vitamin D is needed for 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 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 the 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.

PBC facts

• 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.
• A disease of adults, PBC affects women more often than men.
• 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.
• The symptoms and physical findings in patients with PBC can be divided into those due to the PBC itself, the complications of cirrhosis in PBC, and the diseases associated with PBC.
• The risk of developing PBC is significantly greater for people who have had other autoimmune diseases, smoked cigarettes, had a tonsillectomy as a child, or for women who have had urinary tract or vaginal infections.
• The criteria for a definitive diagnosis of PBC include the presence of cholestatic liver blood tests, a positive AMA with a titer equal to or greater than 1:40, and a liver biopsy consistent with the diagnosis.
• The natural history of untreated PBC extends for decades and goes through four phases. Sequentially, there is a pre-clinical phase with a positive AMA in the absence of liver blood test abnormalities or symptoms, an asymptomatic phase when liver tests become abnormal, a symptomatic phase, and an advanced phase with the complications of cirrhosis.
• The outcome (prognosis) of individual patients can be estimated using a mathematical equation to calculate a Mayo risk score.
• Pregnancy occurs infrequently in women with PBC, but most pregnant women with PBC have delivered normal babies. The chance that treatment with ursodeoxycholic acid during pregnancy will cause fetal harm is remote but possible.
• 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, and
  • 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, and
  • 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), and
  • 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 goal of research in PBC is to better understand the ways in which the inflammation that destroys small bile ducts and later produces cirrhosis is initiated and perpetuated. More research funding from both the public and private sectors is necessary to achieve results that lead to more effective therapies.

Rifampin for itching

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.

Treatment of bleeding from varices

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, sclerotherapy or 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.

Treatment of edema and ascites

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 retention of fluid by eliminating salt and water into 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).

Treatment of elevated serum cholesterol and xanthomas

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 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 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 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.

Treatment of enlarged spleen

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 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.

Treatment of gallstones

Cholesterol gallstones may be prevented by the UDCA used for the long-term treatment of the PBC itself. (UDCA taken orally can actually 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.

Treatment of hepatic encephalopathy

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. The lactulose, which is a liquid medication, traps the toxic compounds in the colon. Consequently, they cannot be absorbed into the blood stream 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, the oral antibiotics, neomycin or metronidazole (Flagyl), can be added to the treatment regimen.

Treatment of malabsorption of fat and fat-soluble vitamins (A, D, E and K)

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 actually 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 in 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.

Treatment of Raynaud's phenomenon

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.

Treatment of 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 esophagus and stomach.

Treatment of Sicca syndrome

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 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. It is imperative that all patients with dry mouth 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.

Ursodeoxycholic acid (UDCA)

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 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.