Primary biliary cirrhosis

Definition

Primary biliary cirrhosis is a disease in which the bile ducts in your liver are slowly destroyed. Bile, a fluid produced in your liver, is essential for the proper digestion of fats. It also helps rid your body of worn-out red blood cells, cholesterol and toxins. In primary biliary cirrhosis, the destruction of your bile ducts can cause harmful substances to build up in your liver and sometimes lead to irreversible scarring of liver tissue (cirrhosis).

The cause of primary biliary cirrhosis remains unclear.  Many experts consider primary biliary cirrhosis an autoimmune disease in which the body turns against its own cells, although it's likely that genetic and environmental factors also play a part. Primary biliary cirrhosis develops slowly. Medication can slow the progression of the disease, especially if treatment begins early.

Symptoms

Early stage
Although some people with primary biliary cirrhosis remain symptom-free for years after they're diagnosed, others experience a number of symptoms early in the disease:

• Fatigue. A common symptom of primary biliary cirrhosis is fatigue, but doctors haven't found any correlation between the degree of exhaustion and the severity of the illness. This means that people with mild primary biliary cirrhosis and those with more serious disease may be equally fatigued.
• Itching. Another common symptom, itching (pruritus), is often most bothersome over your legs, arms and back. The severity of itching may change, often becoming worse at night and improving during the day. Nighttime itching can disturb sleep, making fatigue worse and sometimes leading to depression. The cause of this severe itching isn't clear.
• Dry eyes and mouth (sicca syndrome). Sicca syndrome often occurs in people with other autoimmune disorders. It causes inflammation in the moisture-secreting glands of the eyes and mouth, resulting in the decreased production of tears and saliva.

Later stage
As the destruction of bile duct and liver cells progresses, other signs and symptoms may develop, such as:

• Jaundice. A common sign of advanced liver disease, jaundice turns your skin and the whites of your eyes yellow. The discoloration is due to high blood levels of bilirubin, a byproduct of the breakdown of the hemoglobin from old or damaged red blood cells. Normally, bile carries bilirubin out of your liver so that it can be excreted from your body. But as more bile ducts are destroyed and the flow of bile slows, bilirubin begins to build up in your blood and eventually jaundice becomes visible in your skin and eyes.
• Hyperpigmentation. Inadequate bile flow increases the production of the skin pigment melanin. This causes your skin to become darker, even in areas that aren't exposed to the sun. Sometimes the deeper color isn't uniform, and your skin appears blotchy.
• Swollen feet (edema) and abdomen (ascites). As liver damage progresses, your body begins to retain salt and fluids. At first, the excess salt and water accumulate mainly in your feet and ankles (edema), which tend to become more swollen late in the day. In time, fluid can also collect in your abdomen.
• Cholesterol deposits (xanthomas). Your body uses bile as the main way of eliminating excess cholesterol. When disease interferes with this process, the amount of cholesterol in the blood increases. This can lead to the formation of fatty deposits in the skin around your eyes, your eyelids, or in the creases in your palms, soles, elbows or knees. These raised, waxy growths usually don't appear until blood cholesterol reaches very high levels. Even then, not everyone with primary biliary cirrhosis develops them.
• Digestive problems. Because bile is essential for the digestion and absorption of fats, primary biliary cirrhosis can cause intestinal problems. These include diarrhea and steatorrhea — greasy, bad-smelling stools that result from poor fat digestion.

Causes

The exact cause of primary biliary cirrhosis isn't known, but it appears to be an immune system disorder that slowly destroys the bile ducts in your liver. Genetics and the environment also likely play a role in this disease.

Normally, bile is excreted into canal-like spaces between your liver cells, which drain into an interconnected series of thin tubes (ducts). The initial ducts are quite small, but become progressively larger as they spread through your liver, much like the branches of a tree.

Origin of the condition
The problems in primary biliary cirrhosis begin with inflammation in the smallest ducts in your liver. In time, the inflammation spreads to and destroys nearby liver cells. As these cells are destroyed, they're replaced by scar tissue (fibrosis). Over a period of years, the combination of ongoing inflammation, scarring and toxicity from trapped bile can lead to cirrhosis. Cirrhosis involves irreversible scarring of liver tissue that makes it impossible for your liver to carry out essential functions.

The inflammation begins when T lymphocytes (T cells) begin accumulating in your liver. T cells are white blood cells that are part of your immune system response. Normally, T cells recognize and help defend against bacteria and fungi. But in primary biliary cirrhosis, the T cells invade and destroy the cells lining the small bile ducts. The T cells also produce chemicals that stimulate liver cells to secrete proteins that attract more T cells, thereby creating an ongoing cycle of damage.

Researchers suspect that a genetic susceptibility coupled with an environmental trigger, such as infection, may be at the root of this abnormal immune response:

• Genetics. Primary biliary cirrhosis seems to run in families, and scientists believe that some people may inherit certain immune system defects that make them more susceptible to the disorder. Research has identified three genetic variations associated with primary biliary cirrhosis. This finding may eventually help researchers narrow in on the cause of primary biliary cirrhosis.
• Infection. For decades, researchers have suspected that primary biliary cirrhosis might result from a bacterial, fungal or parasitic infection, which would explain the massing of T cells in the small bile ducts. Some women reported having urinary tract infections, primarily those caused by the Escherichia coli bacterium, prior to the development of primary biliary cirrhosis. However, no commonplace infections have yet been consistently linked to primary biliary cirrhosis.

Bile duct damage

Bile duct damage

The bile ducts carry bile from your liver to your small intestine. When bile ducts become damaged, bile can back up into the liver, causing damage to liver cells. This damage can lead to liver ...

Risk factors

The following factors may increase your risk of primary biliary cirrhosis:

• Your sex. More than 90 percent of people with primary biliary cirrhosis are women.
• Your age. Most people diagnosed with primary biliary cirrhosis are 35 to 60 years old. Although older adults can develop the disease, it's rare in children.
• Family history. Having a family history of primary biliary cirrhosis increases your risk of developing the disease.

Complications

As liver damage progresses, people with primary biliary cirrhosis may develop a number of serious problems, including:

• Cirrhosis. The term "primary biliary cirrhosis" isn't entirely accurate because cirrhosis develops only in the later stages of the disease — often many years after diagnosis. Yet when it does occur, cirrhosis can be life-threatening because it interferes with your liver's ability to carry out essential functions. Cases of primary biliary cirrhosis are divided into four stages. The first stage — inflammation of the bile ducts — is the least serious, and stage 4 — cirrhosis — the most serious. Ongoing cirrhosis can lead to liver failure, which occurs when your liver is no longer able to function.
• Increased pressure in the portal vein (portal hypertension). Blood from your intestine, spleen and pancreas enters your liver through a large blood vessel called the portal vein. When scar tissue blocks normal circulation through your liver, blood backs up, much like water behind a dam, leading to increased pressure within the vein. And because blood doesn't flow normally through your liver, hormones, drugs and other toxins aren't filtered properly before entering your bloodstream.
• Enlarged veins (varices). When circulation through the portal vein is slowed or blocked, blood may back up into other veins — mainly those in your stomach and esophagus. The blood vessels are thin walled, and increased pressure in your veins can cause bleeding in your upper stomach or esophagus. This bleeding is a life-threatening emergency that requires immediate medical care.
• Liver cancer. The destruction of healthy liver tissue that occurs in cirrhosis increases your risk of liver cancer.
• Weak bones (osteoporosis). Liver scarring interferes with your liver's ability to process vitamin D and calcium, both of which are essential for bone growth and health. As a result, weak, brittle bones and bone loss may be complications of late-stage primary biliary cirrhosis, and your doctor may order a bone density test to look for osteoporosis.
• Vitamin deficiencies. A lack of bile affects the absorption of fats and of the fat-soluble vitamins, A, D, E and K. This sometimes leads to deficiencies of these vitamins in advanced cases of primary biliary cirrhosis.
• Cognitive impairment. Some people with primary biliary cirrhosis have problems with memory and concentration. Cognitive difficulties don't seem to correlate directly to the amount of liver damage, however.

Other complications
In addition to bile duct and liver damage, people with primary biliary cirrhosis are likely to have other metabolic or immune system disorders, including:

• Thyroid disease. Thyroid problems are common in people with primary biliary cirrhosis. They may appear long before bile duct damage is diagnosed, or thyroid disorders may develop after you've received a diagnosis of primary biliary cirrhosis.
• Limited scleroderma (CREST syndrome). This immune system disorder is a subset of scleroderma, a disease that leads to thickening, tightening and hardening of connective tissue. CREST syndrome can affect many body systems, including your blood vessels and esophagus, and sometimes your digestive tract, lungs and heart. People with primary biliary cirrhosis generally have some, rather than all, of the signs and symptoms of CREST.
• Raynaud's phenomenon. One of the components of CREST, Raynaud's phenomenon may also occur in people with primary biliary cirrhosis. It occurs when small blood vessels (capillaries) spasm in response to cold or emotional stress, blocking the flow of blood. The areas of affected skin generally turn white before becoming blue, cold and numb. When circulation improves, the skin usually reddens and may throb or tingle.
• Rheumatoid arthritis. Some people with primary biliary cirrhosis have the aching joints that typify rheumatoid arthritis, another autoimmune disorder.

Preparing for your appointment

You're likely to start by first seeing your family doctor or a general practitioner. However, you may then be referred to a doctor who specializes in disorders of the digestive system (gastroenterologist).

Because there's often a lot of ground to cover during your appointment, it's a good idea to arrive well prepared. Here's some information to help you get ready for your appointment, and what to expect from your doctor.

What you can do

• Be aware of any pre-appointment restrictions. At the time you make the appointment, be sure to ask if there's anything you need to do in advance, such as restrict your diet.
• Write down any symptoms you're experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment.
• Write down key personal information, including any major stresses or recent life changes.
• Make a list of all medications, vitamins and supplements that you're taking.
• Ask a family member or friend to come with you, if possible. Sometimes it can be difficult to remember all of the information provided to you during an appointment. Someone who accompanies you may remember something that you missed or forgot.
• Write down questions to ask your doctor.

Preparing a list of questions can help you make the most of your time with your doctor. For primary biliary cirrhosis, some basic questions to ask your doctor include:

• What's the most likely cause of my symptoms?
• Are there any other possible causes for my symptoms?
• What kinds of tests do I need to confirm the diagnosis? Do these tests require any special preparation?
• How severe is the damage to my liver?
• What treatments are available, and which do you recommend for me?
• What types of side effects can I expect from treatment?
• Are there any alternatives to the primary approach that you're suggesting?
• What's my prognosis?
• I have other health conditions. How can I best manage them together?
• Are there any dietary or activity restrictions that I need to follow?
• Is there a generic alternative to the medicine you're prescribing me?
• Are there any brochures or other printed material that I can take home with me? What Web sites do you recommend visiting?

In addition to the questions that you've prepared to ask your doctor, don't hesitate to ask questions during your appointment at any time that you don't understand something.

What to expect from your doctor
Your doctor is likely to ask you a number of questions. Being ready to answer them may reserve time to go over any points you want to spend more time on. Your doctor may ask:

• What types of symptoms have you been experiencing?
• When did you first begin experiencing symptoms?
• Have your symptoms been continuous or occasional?
• How severe are your symptoms?
• Does anything seem to improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Has anyone in your family ever been diagnosed with primary biliary cirrhosis?
• Do you have any chronic health conditions?

Tests and diagnosis

Many people with primary biliary cirrhosis have no symptoms of the disease when they're initially diagnosed. Instead, doctors often become aware of a problem during routine blood tests or an evaluation for another condition.

If your doctor suspects primary biliary cirrhosis, several tests can help make the diagnosis, including:

• Liver function tests. These blood tests check the levels of enzymes that may indicate liver disease in general and bile duct injury in particular. Certain liver enzymes are elevated in most people with primary biliary cirrhosis, especially alkaline phosphatase, which is produced in the bile ducts.
• Ultrasound imaging. This noninvasive test uses high-frequency sound waves to create precise images of structures within the body, including the bile ducts. It's sometimes used to rule out other causes of bile flow blockage, such as gallstones or tumors.
• Anti-mitochondrial antibodies (AMAs). Found in every cell, mitochondria are the prime energy producers of your body. Antibodies are proteins in your blood that help destroy bacteria and other harmful pathogens. Most people with primary biliary cirrhosis have anti-mitochondrial antibodies — antibodies that target enzymes in the mitochondria. These antibodies almost never occur in people who don't have primary biliary cirrhosis, even if they have other liver disorders. For that reason, a positive AMA test is considered a very reliable indicator of the disease. At the same time, a small percentage of people with primary biliary cirrhosis don't have AMAs. False-positive tests, which indicate a problem where none exists, also can occur. Because an AMA test isn't entirely foolproof, doctors usually perform a liver biopsy, which can definitively confirm the presence or absence of the disease.
• Liver biopsy. In this test, a small sample of liver tissue (biopsy) is removed and examined in a laboratory, either to confirm the diagnosis or to determine the extent (stage) of the disease. Doctors withdraw the tissue through a small incision using a thin needle. Doctors may take more liver biopsies as time goes on to check the progression of the disease.
• Magnetic resonance imaging (MRI) and magnetic resonance elastography (MRE). MRI is a frequently used imaging test that uses a powerful magnetic field and radio waves to produce detailed images inside your body. When diagnosing primary biliary cirrhosis, MRI can be used to detect abnormalities of your liver. MRE is a relatively new test that may help your doctor diagnose primary biliary cirrhosis and may help avoid the need for a liver biopsy, which is more invasive. MRE technology works by combining traditional magnetic resonance imaging with low-frequency sounds waves. The MRI component shows the size and structure of your tissues and organs. The low-frequency sound waves then help reveal physical properties of those tissues and organs — such as tissue stiffness. Stiffness of your liver may indicate cirrhosis.

Early screening
In some cases, doctors may be able to discover if a person is at risk of primary biliary cirrhosis early. Some research has shown that first-degree relatives of people with primary biliary cirrhosis are more likely to have antibodies in their blood that increase their risk of the disease. If you have a first-degree relative — a parent, sibling or child — who has primary biliary cirrhosis, your doctor can screen your blood for these antibodies. By knowing whether you have them, your doctor can more closely monitor you and may be able to provide treatment earlier, should you develop the disease. Early treatment is important and can help slow the progression of the disease.

Treatments and drugs

Because no cure exists for primary biliary cirrhosis, treatment focuses on slowing the progress of the disease, relieving symptoms and preventing complications.

Treating the disease
Treatments aimed at slowing the disease and prolonging life include:

• Ursodeoxycholic acid (UDCA). Also known as ursodiol (Actigall), UDCA is a bile acid that helps move bile through your liver. Although UDCA doesn't cure primary biliary cirrhosis, it may prolong life if started early in the disease and is commonly considered the first line of therapy. It's less likely to help people with advanced liver damage. Side effects of UDCA may include weight gain, hair loss and diarrhea.
• Other drugs. Sometimes other drugs are used off-label or in clinical trials to treat primary biliary cirrhosis, but many have proved to have serious side effects or haven't been effective. For example, some studies show that the drug methotrexate, which is normally used to treat arthritis, psoriasis and some types of cancer, isn't helpful in primary biliary cirrhosis, whereas others show it to be somewhat effective.
• Liver transplant. When treatments no longer control primary biliary cirrhosis and the liver begins to fail, a liver transplant may help prolong life. People with primary biliary cirrhosis who have liver transplants often do very well, although the disease may recur in the new liver.

Treating the symptoms
The only medication that may help treat the fatigue that often accompanies primary biliary cirrhosis is modafinil (Provigil). Early research on this medication has shown promise in treating fatigue, but more research is needed to determine its role in primary biliary cirrhosis.

Several therapies may be used to help control the intense itching that often occurs in primary biliary cirrhosis, including:

• Cholestyramine and colestipol. These cholesterol-lowering drugs can provide marked relief of itching in some people, but they have several drawbacks. Cholestyramine is an unpleasant-tasting powder that must be mixed with food or liquids. Both drugs interfere with how your body metabolizes UDCA and certain other medications, as well as hormones and some vitamins. And, they may interact with other medications you are taking. Check with your doctor before combining medications, hormones or vitamins.
• Rifampin. This drug may be prescribed for people who can't tolerate the side effects of cholestyramine. Rifampin doesn't work for everyone, and it's slow acting, sometimes taking about a month before it starts working.
• Opioid antagonists. Researchers are studying whether this class of drugs relieves severe itching in people with primary biliary cirrhosis. Although some of these medications seem very effective, they must be administered intravenously and may cause withdrawal symptoms.
• Liver transplant. This may be the only option for some people with unrelieved and intolerable itching.

Preventing complications
Working together, you and your doctor can help prevent some of the complications that can occur with primary biliary cirrhosis:

• Increased pressure in the portal vein (portal hypertension). Your doctor is likely to screen for portal hypertension and enlarged veins when you're first diagnosed and every few years thereafter. You'll need more frequent screening if enlarged veins are found, if you have cirrhosis or if you've had gastrointestinal bleeding.
• Weak bones (osteoporosis). Although it's not certain that osteoporosis can always be prevented in cases of primary biliary cirrhosis, treatment with bisphosphonates may help increase bone mineral density. Bisphosphonates are a group of drugs that can inhibit bone breakdown and even increase bone mass. Taking at least 1,500 milligrams of calcium, along with a vitamin D supplement every day, may be of benefit. Ask your doctor what amount of vitamin D you need. Equally important are lifestyle measures such as stopping smoking and getting regular weight-bearing exercise.
• Vitamin deficiencies. Your doctor may recommend injections of vitamin K and water-based oral supplements of vitamins A, D and E.
• Raynaud's phenomenon. Although drug and even surgical options exist for treating Raynaud's, self-care measures are often highly successful and are usually tried first. These measures include keeping your body's core temperature elevated and protecting your hands and feet from cold, both indoors and out. Biofeedback, a technique that teaches you to control certain body responses, may help. Autogenic training, a type of progressive muscle relaxation and hypnosis, also may help improve blood flow to the extremities. If these methods fail, your doctor may prescribe a vasodilator such as a long-acting calcium channel blocker, a drug that can open small blood vessels and increase circulation.

Lifestyle and home remedies

Taking good care of your overall health may help you feel better and improve some of the symptoms of primary biliary cirrhosis:

• Eat a reduced-sodium diet, because sodium increases your risk of tissue swelling and of accumulating fluid in your abdominal cavity (ascites).
• Exercise and take calcium and vitamin D supplements to help reduce your risk of developing osteoporosis.
• Avoid alcohol consumption, because it speeds the progression of liver disease.
• Practice good skin care to reduce itching. Avoid scratching. Use cool, wet compresses. Try cool baking soda or oatmeal baths. Avoid irritating clothes, soaps and detergents.
• Use artificial tears to help reduce dry eyes.
• If you're a smoker, quit. Smoking may speed up the rate of liver scarring.
• Check with your doctor before starting new medications or dietary supplements. Because you're liver isn't working normally, you'll likely be more sensitive to the effects of over-the-counter and prescription medications, as well as some dietary supplements, so check with your doctor before taking anything new.

Coping and support

Although the prognosis for people with primary biliary cirrhosis is far better than it was in the past, it can still be difficult and frustrating to live with a chronic liver disease. When symptoms of the disease develop, such as fatigue and itching, they can seriously affect your quality of life.

Following are some strategies that may make dealing with primary biliary cirrhosis easier:

• Educate yourself. Find out everything you want to know about primary biliary cirrhosis. The more you understand about what's going on in your body, the more active you can be in your own care. In addition to talking with your doctor, look for information at your local library and on Web sites affiliated with reputable organizations, such as the American Liver Foundation.
• Take time for yourself. Eating well, exercising and getting enough rest can help you feel better. Try to plan ahead for times when you may need more rest.
• Get help. If you have friends or family who want to help, take them up on their offer and let them know what would be most useful to you. Primary biliary cirrhosis can be exhausting, so if someone wants to do your grocery shopping, wash a load of laundry or cook your dinner, accept the help.
• Seek support. Strong relationships can play an important role in helping you maintain a positive attitude. If friends or family have a hard time understanding your illness, you may find that a support group can be helpful. Ask your doctor if there are any local support groups for people with primary biliary cirrhosis, or call the American Liver Foundation at 800-GO-LIVER (800-465-4837).