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Primary Biliary Cirrhosis

Definition:
Your body has an intricate network of ducts designed specifically to transport bile, a fluid produced in your liver. Bile is essential for the proper digestion of fats and helps rid your body of worn-out red blood cells, cholesterol and potentially toxic metals. In primary biliary cirrhosis, the bile ducts are slowly destroyed, causing harmful substances to build up in your liver and sometimes leading to irreversible scarring of liver tissue (cirrhosis).

The cause of primary biliary cirrhosis remains a matter of debate. 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 further slow the progression of the disease, especially if treatment begins early. Advanced primary biliary cirrhosis can lead to life-threatening complications and liver failure. In that case, a liver transplant may be an option for improving and extending life.

Causes:
Bile is a greenish-yellow fluid produced in the cells of the liver. It's essential for digesting and absorbing fats and is one of the main avenues for eliminating drugs, cholesterol and metabolic byproducts from the body. Within the liver, bile is excreted into canal-like spaces (canaliculi) between the 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 the

liver, much like the branches of a tree.

Bile leaves the liver through the common hepatic duct — the "trunk" of the biliary tree — and enters the gallbladder, a small, pear-shaped organ just below the liver, through the cystic duct. The gallbladder stores bile in a highly concentrated form until you eat, when it's released into the common bile duct. From there, bile flows to the upper part of the small intestine (duodenum), where it begins to break down the fat in food.

Most of the bile that enters the small intestine is returned to the liver for reuse, sometimes recycling two or three times in a single meal. Ordinarily, nearly a quart of bile passes from the liver to the intestine every day, but primary biliary cirrhosis destroys the small ducts within the liver (intrahepatic ducts), slowing and sometimes blocking the normal flow of bile.

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

An immune system disorder?
Most evidence suggests that primary biliary cirrhosis is an immune system disorder. The initial inflammation begins when T lymphocytes (T cells) — white blood cells that normally recognize and help defend the body against bacteria and fungi — invade and destroy the epithelial cells lining the small bile ducts. The T cells also produce chemicals that stimulate the epithelial cells to secrete proteins that attract more T cells, thereby creating an ongoing cycle of damage.

This is a classic autoimmune scenario — a case in which the body's immune system turns against its own cells. But not everything about primary biliary cirrhosis is classic. For one thing, no cases of the disease have ever been diagnosed in children, even though autoimmune disorders usually begin in childhood. For another, unlike most autoimmune diseases, primary biliary cirrhosis doesn't usually respond to drugs that suppress the immune system. For these and other reasons, researchers suspect that other factors play a part in the disease, such as :

  • Genetics. Primary biliary cirrhosis isn't transmitted from parent to child and so isn't considered a hereditary disease. Yet because it seems to run in families, researchers suspect that some people may inherit certain immune system defects that make them more susceptible to the disorder. Other immune system genes may play a role in disease progression.
  • Infection. For decades, researchers have suspected that primary biliary cirrhosis might result from a bacterial, fungal or parasitic infection. That would explain the massing of T cells in the small bile ducts and why the disease has some anomalies that distinguish it from other autoimmune disorders. But no commonplace infections have been linked to primary biliary cirrhosis, and scientists are now focusing their attention on retroviruses, the same type of virus that causes HIV/AIDS.

Risk Factor :
The following factors, although nonspecific, may increase the risk of primary biliary cirrhosis :

  • Your sex. More than 90 percent of people with primary biliary cirrhosis are women. Immune system disorders in general affect far more women than men, but the reason for the gender disparity isn't known.
  • Age. Most people diagnosed with primary biliary cirrhosis are 30 to 60 years old. Although older adults can develop the disease, no cases have been found in children.
  • Family history. Primary biliary cirrhosis isn't hereditary, but having a family member with the disease increases your risk.

Symptoms:
Although some people with primary biliary cirrhosis remain symptom-free for years after they're diagnosed, others experience fatigue, itching, dry eyes and dry mouth early in the disease :

  • Fatigue. This is the most common, and often the most debilitating, symptom of primary biliary cirrhosis. In general, energy levels are normal in the morning, but fall precipitously later in the day and don't improve with rest. Doctors haven't found any correlation between the degree of exhaustion and the severity of the illness, which means that people with mild primary biliary cirrhosis and those with more serious disease may be equally fatigued.
  • Itching. Another common symptom, itching (pruritis) usually begins on the palms of the hands and soles of the feet but eventually can affect your entire body. The severity of itching may fluctuate, often becoming worse at night and improving somewhat during the day. Nighttime itching can disturb sleep, making exhaustion worse and sometimes leading to depression and even thoughts of suicide. 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. This can lead to difficulty swallowing, light sensitivity and corneal ulcers.

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 in old or damaged red blood cells. Normally, bile carries bilirubin out of the 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 the blood and eventually becomes visible in your skin and eyes.
  • Hyperpigmentation. Inadequate bile flow increases the production of the skin pigment, melanin, which 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 water accumulates mainly in your feet and ankles, which tend to become more swollen late in the day. In time, fluid can also collect in your abdomen.
  • Cholesterol deposits (xanthomas). Bile is the body's main route for eliminating excess cholesterol. When disease interferes with this process, the amount of cholesterol in the blood increases, and fatty deposits can form in the skin around the eyes, the eyelids, or in the creases in the palms, soles, elbows, knees or buttocks. These raised, waxy growths usually don't appear until blood cholesterol reaches very high levels, and even then, not everyone with primary biliary cirrhosis develops them. More important, the cholesterol in people with primary biliary cirrhosis is often high-density lipoprotein (HDL) cholesterol — the so-called "good" cholesterol — which doesn't appear to increase the risk of heart disease.
  • Digestive problems. Because bile is essential for the digestion and absorption of fats, primary biliary cirrhosis can cause intestinal problems, especially diarrhea and steatorrhea — greasy, malodorous stools that result from faulty fat digestion.
  • Urinary tract infections. About one in five women with primary biliary cirrhosis experiences recurring urinary tract infections. The relationship between these infections and bile duct destruction isn't well understood, but a few studies suggest that the same bacteria responsible for urinary tract infections may play a role in some cases of primary biliary cirrhosis.

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

Several tests can help diagnose primary biliary cirrhosis, 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 the body. Antibodies are proteins in the blood that help destroy bacteria and other harmful pathogens. The great majority of 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 an extremely 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 the small incision using a thin needle. A liver biopsy can cause some discomfort for a day or two, including tenderness where the needle was inserted and sometimes pain in the right shoulder. More serious risks of a liver biopsy, including puncture of the lungs or gallbladder, infection, and serious bleeding, are rare. Doctors may take more liver biopsies as time goes on to check the progression of the disease.

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

  • 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. Under normal circumstances, the pressure in this vein is considerably lower than the pressure in the arteries. But when scar tissue blocks normal circulation through the 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 the liver, hormones, drugs and other toxins aren't filtered properly before entering the bloodstream, making them more harmful to the body.
  • 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. Sometimes veins also form around your navel and at the rectum. The blood vessels are thin walled, and increased pressure in the veins can cause bleeding in the upper stomach or esophagus. This is a life-threatening emergency that requires immediate medical care.
  • Weak bones (osteoporosis). Liver scarring interferes with the 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, sometimes leading to deficiencies of these vitamins in advanced cases of primary biliary cirrhosis.
  • Cirrhosis. The term "primary biliary cirrhosis" isn't entirely accurate because cirrhosis develops only in the last stages of the disease — often many years after diagnosis. Yet when it does occur, cirrhosis can be life-threatening because it interferes with the 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 the liver is no longer able to function.
  • Liver cancer. The destruction of healthy liver tissue that occurs in cirrhosis greatly increases the risk of liver cancer, primarily hepatocellular carcinoma, which affects the hepatocytes, the main type of liver cell.

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

  • Thyroid disease. Thyroid problems not only are common in people with primary biliary cirrhosis, but often appear long before the bile duct damage is diagnosed.
  • 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 the blood vessels and esophagus, and sometimes the digestive tract, lungs and heart. People with primary biliary cirrhosis are more likely to have some, rather than all, of the signs and symptoms of CREST.
  • Raynaud's phenomenon. One of the symptoms of CREST, this disorder is common 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. Although not everyone with Raynaud's experiences the same symptoms during an attack, 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. Attacks of Raynaud's may last from a few minutes to several hours and tend to become worse over time.
  • Rheumatoid arthritis. Some people with primary biliary cirrhosis have the aching joints that typify rheumatoid arthritis, another classic autoimmune disorder. Other people may have markers for rheumatoid arthritis in their blood but no signs or symptoms of the disease.
  • Ulcerative colitis. This inflammatory bowel disease, which can cause profuse bloody diarrhea, cramping and abdominal pain, sometimes occurs with primary biliary cirrhosis.

Treatment:
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). Commonly used to treat gallstones, UDCA may work by affecting the body's bile acids and reducing inflammation. Although UDCA doesn't cure primary biliary cirrhosis, it may prolong life if started early in the disease. It's less likely to help people with advanced liver damage, and it doesn't improve fatigue, the most common and often the most disabling symptom of the disorder. The most frequent side effect of UDCA is diarrhea; other possible side effects include aches and pains and trouble swallowing.
  • 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. For example, some studies show that the drug methotrexate, which is normally used to treat arthritis, psoriasis and some types of cancer, may make primary biliary cirrhosis worse.
  • Liver transplant. When treatments no longer control primary biliary cirrhosis and the liver begins to fail, a liver transplant may help prolong life. Many doctors use a mathematical model to help determine who will benefit from a liver transplant. 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
No medication has been found to improve fatigue, but several therapies may be used to help control the intense itching that often occurs in primary biliary cirrhosis :

  • 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, and it can be severely constipating. What's more, these drugs bind UDCA and certain other medications, as well as hormones and some vitamins.
  • Rifampicin. This drug is often prescribed for people who can't tolerate the side effects of cholestyramine. Rifampicin doesn't work for everyone, and it's slow acting, sometimes taking about a month to take effect. It also can cause serious side effects or toxic reactions.
  • Opioid antagonists. Researchers are studying this class of drugs to relieve 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 intractable and intolerable itching.

Preventing complications
Working together, you and your doctor can help prevent some of the many 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.
  • Weak bones (osteoporosis). Although it's not certain that osteoporosis can always be prevented in cases of primary biliary cirrhosis, treatment with bisphosphonates, a group of drugs that can inhibit bone breakdown and even increase bone mass, can prevent steroid-induced osteoporosis. Taking at least 1,500 milligrams of calcium and 1,000 international units of vitamin D every day also may be of benefit. 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; autogenic training, a type of progressive muscle relaxation; and hypnosis all can 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.
Please be aware that this information is provided to supplement the care provided by your physician. It is neither intended nor implied to be a substitute for professional medical advice. CALL YOUR HEALTHCARE PROVIDER IMMEDIATELY IF YOU THINK YOU MAY HAVE A MEDICAL EMERGENCY. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with any questions you may have regarding a medical condition.
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