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Specific types of white blood cells called B-lymphocytes make antibodies. Antibodies recognize specific protein targets called antigens (substances that are capable of causing the production of antibodies.) To facilitate our discussion of autoimmunity, let us first look at what happens in the more common type of immunity. It takes new or foreign antigens to produce this usual type of immunity. Vaccines, infectious organisms (like viruses or bacteria), or surgically transplanted tissues contain such foreign antigens. So, for instance, when a person is first vaccinated to prevent tetanus , that person is newly exposed to tetanus proteins, which are foreign antigens. What happens then? First, specialized cells within tissues of the body take up and digest the tetanus proteins. Then the protein fragments are attached to special molecules called HLA molecules that are produced by the HLA complex. (HLA is an abbreviation for Human Leukocyte Antigen). The HLA complex is a group of inherited genes located on chromosome 6. The HLA molecules control a person's immune response. Next, the protein (antigen) fragments bound to the HLA molecules set into action (activate or stimulate) specialized white blood cells called T-lymphocytes. The T-lymphocytes then begin to multiply (reproduce) and secrete chemical signals into their environment. Another type of white blood cell, called B-lymphocytes, also enters the picture. B-lymphocytes have molecules on their surface, called immunoglobulins (Ig) that can bind directly to undigested tetanus antigens. An essential part of the body's immune system, immunoglobulins are antibodies that attach to foreign substances, such as bacteria, and assist in destroying them. This binding activates the B-lymphocytes, that is, gets them ready for action. Meanwhile, the above-mentioned secreted chemicals of the activated T-lymphocytes provide a helper signal for the B-lymphocytes. This signal tells the B-lymphocytes to begin secreting the immunoglobulins (specific antibodies) that precisely recognize the stimulating tetanus antigen. The bottom line here is that antibodies that specifically bind and inactivate tetanus proteins prevent an immunized person from developing tetanus. What is more, both the T- and B-lymphocytes reside in the body as memory cells. This means that they can remember to generate increased amounts of antibodies against tetanus antigens whenever a person has a booster shot of the vaccine. So, that's what happens in the common type of immunity. By contrast, in autoimmunity, autoantibodies, produced by B-lymphocytes react against self or auto antigens rather than against foreign antigens. In this reaction, the activated B-lymphocytes still require help from chemicals secreted by activated T-lymphocytes. Although the human immune system is capable of recognizing a nearly infinite number of antigens, normally it does not recognize or respond to autoantigens. The expected absence of immune responses against self is called tolerance. Thus, in all autoimmune diseases, including PBC, tolerance (absence of an immune response) becomes defective (is lost) for autoantigens recognized by both T- and B-lymphocytes. In other words, an immune response to autoantigens does occur. What's more, in autoimmune diseases, B-lymphocytes initially produce autoantibodies that recognize a single autoantigen. With time, however, B-lymphocytes produce new autoantibodies that recognize additional autoantigens that are distinct from the initial autoantigen. PBC, however, is the only allegedly autoimmune disease in which this sequence does not occur. In other words, in PBC, the autoantibodies recognize only the initial autoantigen. What are antimitochondrial antibodies (AMA)? AMA specifically react against a component of this multienzyme complex called E2. In PBC, AMA preferentially react with the E2 component of one of the multienzymes that is called the pyruvate dehydrogenase complex (PDC). Accordingly, the antigen is designated as PDC-E2. The practical importance of all of this is that the PDC-E2 antigen is now used, as will be discussed below, in a diagnostic test for detection of AMA. The PDC-E2 antigen is also referred to as M2, a term introduced to designate it as the second mitochondrial antigen discovered by researchers interested in PBC. Do the AMA react with the bile ducts? This accumulation of PDC-E2 within the biliary epithelial cells is observed exclusively in the livers of patients with PBC, and not in normal livers or in livers from patients with any other types of liver disease. Interestingly, it was also observed in the livers of those two to five percent of PBC patients who do not have AMA in their blood (AMA-negative PBC). Furthermore, intense binding of these antibodies to biliary epithelial cells was also found to be the earliest indication of recurrence of PBC in a transplanted liver. (PBC is sometimes treated by liver transplantation, which will be discussed later.) These observations led to a speculation that the antibodies were actually reacting with an antigen from an infectious agent. The idea was that the infectious agent was present in the biliary epithelial cells of patients with PBC and that the agent could also infect the biliary cells of a transplanted liver. (See the section below on the role of infection). What causes destruction of the bile ducts in PBC? What, then, causes the destruction of the bile ducts in PBC? Inspection of liver biopsies from patients with PBC indicates that T-lymphocytes surround and invade the small bile ducts. Thus, T-lymphocytes appear to be responsible for the death of the biliary epithelial cells lining the ducts and the destruction of the bile ducts. T-lymphocytes capable of directly killing target-cells (for example, biliary epithelial cells) are called cytotoxic T-lymphocytes, meaning that these T-cells are toxic to the target cells. And, in fact, cytotoxic T-lymphocytes have been observed in liver biopsies to invade the bile ducts and to be present in areas where biliary epithelial cells are dying. Other T-lymphocytes that surround the bile ducts are known to produce chemicals that can also cause biliary epithelial cells to die. Some of these chemicals actually stimulate the biliary epithelial cells themselves to secrete small proteins that attract more T-lymphocytes. Paradoxically, then, this response by the biliary epithelial cells might result in even greater injury to the bile ducts, in sort of a vicious cycle. Recent studies of T-lymphocytes isolated from the inflamed livers of patients with PBC have shown that these T-lymphocytes can, in fact, kill biliary epithelial cells. Moreover, many of the T-lymphocytes recognized the digested fragments of PDC-E2. These observations suggest the possibility (hypothesis) that the T-lymphocytes might attack the biliary epithelial cells because these cells display PDC-E2 antigens in their HLA (Human Lymphocyte Antigen) molecules to which the T lymphocytes react. No direct evidence, however, supports this hypothesis. The fact is that the actual antigens on biliary epithelial cells that are recognized by invading, destructive T-lymphocytes remain to be determined. However, the biliary epithelial cells do contain molecules, such as intercellular adhesion molecule-1, that are required for activated T lymphocytes to adhere to the cells that they kill. What is the role of infection? Investigators are currently pursuing leads suggesting that the biliary epithelial cells of patients with PBC may contain an infectious virus that belongs to the class of viruses called retroviruses. (The human immunodeficiency virus, HIV, is an example of a retrovirus.) These studies have identified genetic fragments of a retrovirus in the biliary epithelial cells of patients with PBC. Nevertheless, further research is required to answer the important question of whether PBC is caused by a retroviral infection. The possibility that PBC is caused by infection with bacteria has intrigued clinical investigators for decades. You see, the mitochondria in the cells of mammals were derived, during evolution, from bacteria. Thus, many bacteria contain antigens that react with the AMA found in patients with PBC. Some of these bacteria have been cultured from the urine of patients with PBC who have recurrent urinary tract infections. Interestingly enough, as discussed later, recurrent urinary tract infection has been recognized as a risk factor for developing PBC. This association between urinary tract infection and PBC led to the speculation that a bacterial infection might trigger an immune response that developed into an autoimmune reaction. Although this speculation is plausible, there is currently no direct evidence that this sequence of events occurs in PBC. As a matter of fact, molecular techniques now exist to screen livers for the presence of any type of bacteria. So far, these kinds of studies have found no evidence of a chronic bacterial infection in PBC. Another intriguing possibility is that an infection with a virus, bacterium, fungus or parasite might introduce foreign proteins that mimic the protein antigens of mitochondria. An immune response against these foreign proteins could develop antibodies and T lymphocytes that react with the mimicked self-proteins, thereby resulting in autoimmunity. In other words, the body's immune system responds to the foreign proteins but it reacts against its own mitochondrial proteins. This phenomenon is called molecular mimicry. One of the best examples of molecular mimicry is found in rheumatic fever. This condition is an autoimmune reaction involving the skin, joints, and heart muscle, that is caused by an immune response to a streptococcal bacterial infection. Now, rheumatic fever is usually diagnosed within a few weeks of having strep throat . Physicians, therefore, recognized the relationship between the two events (streptococcal infection and rheumatic fever) before molecular mimicry was understood. PBC, however, is usually a more subtle condition that might not be diagnosed for many years. Therefore, if a transient infection were to trigger molecular mimicry in PBC, causing an autoimmune reaction, the relationship between the infection and the autoimmune disease might be easily missed. What is the role of genetics? Accordingly, it appears likely that some immune genes create susceptibility for PBC, but the disease does not occur without additional events. Besides that, certain other immune genes may control progression of the disease. These genes are more common in patients with advanced PBC than in patients with the earlier stages of PBC. Indeed, recently, additional genes involved in immune signaling were found to be markers of both susceptibility and disease progression. Studies currently being conducted on patients whose close relatives also have PBC may clarify exactly which genes are associated with susceptibility and progression of PBC. What are the symptoms and physical findings in PBC?
Table 2 lists the multiple signs and symptoms (manifestations) of primary biliary cirrhosis, its assciated diseases, and the complications of the cirrhosis.
Patients with PBC, however, very often do not have any symptoms. In the large study of 770 patients with PBC in northern England, 56% had no symptoms at the time of diagnosis. What manifestations are specifically due to PBC itself? The most common symptom of PBC is fatigue, which occurs in up to 70% of patients. The presence and severity of fatigue, however, does not correspond (correlate) with the severity of the liver disease. It should be noted that significant fatigue can be either the cause or the result of difficulty sleeping or depression . Fatigue associated with inflammation of the liver is often characterized by normal energy during the initial half to two thirds of the day followed by a profound loss of energy that requires rest or a substantial reduction in activity. Thus, when patients report being exhausted in the morning, it is likely that sleep deprivation and depression are the cause of the exhaustion rather than PBC. Most people with PBC report that a nap does not rejuvenate them. Conversely, many PBC patients inexplicably experience occasional days without a loss of energy. In summary, the main characteristics of fatigue due to liver inflammation in PBC are:
Itching It is interesting to note that some women with PBC experienced itching during the last trimester (three months) of a prior pregnancy, before they knew about their PBC. In a condition called cholestasis of pregnancy, some otherwise normal women during the last trimester develop cholestasis and itching that resolve following delivery. (Remember that cholestasis means decreased bile flow.) Of course, most women with cholestasis of pregnancy do not go on to develop PBC. Yet, it turns out that about 5% of women diagnosed with PBC give a history of having had such itching during a prior pregnancy. Characteristically, the itching in PBC begins in the palms of the hands and soles of the feet. Later, it may affect the entire body. The intensity fluctuates in a circadian rhythm, meaning that the itching can worsen at night and improve during the day. Nocturnal itching can disrupt sleep and lead to sleep deprivation, fatigue, and depression. Rarely, the itching is so severe and unresponsive to therapy that the person may become suicidal. Prolonged itching and scratching causes scratch marks (excoriations), thickening, and darkening of the skin. The cause (etiology and pathogenesis) of itching remains unclear. The bile acids, as previously mentioned, normally are transported in bile from the liver, through the bile ducts, to the intestine. Most of the bile acids are then reabsorbed in the intestine and go back to the liver for reprocessing and recycling. In cholestasis, therefore, the bile acids back up from the liver, accumulate in the blood, and, for some years, were presumed to be the cause of the itching. Modern studies, however, have just about refuted the notion that the itching in PBC and other cholestatic liver diseases is caused by bile acids. Recently, the itching was considered (postulated) to be due to accumulation of an endorphin, a natural substance that attaches (binds) to the natural receptors (acceptors) for morphine in nerves. You see, nerves in the skin carry the sensation of itching. Indeed, the finding that itching improved in some people treated with drugs that block the binding of morphine or endorphins to nerves supported this consideration. Yet, many patients do not respond to these blocking drugs, suggesting that other causes or mechanisms are involved in producing itching. Metabolic Bone Disease Poorly calcified bones (osteopenia) characterize both osteoporosis and osteomalacia. The cause of the osteopenia in osteoporosis, however, is not known, although the development of osteoporosis tends to speed up in women after the onset of menopause . In osteoporosis, there is chronic, accelerated loss of calcium and protein from the bones. By contrast, in osteomalacia, the osteopenia results from failure of the bones to calcify. The cause of osteomalacia is vitamin D deficiency. While the body's processing (metabolism) of dietary calcium and vitamin D is normal in PBC, bone metabolism is abnormal. Normal bone metabolism involves an ongoing balance among production of new bone, calcification of bone, and loss of bone. Vitamin D plays a key role in regulating the deposition of calcium in bone. What then, causes the deficiency of vitamin D in PBC? First of all, patients with PBC and advanced cholestasis, usually recognized by significant jaundice, can have a decreased ability to absorb dietary vitamin D from the gut. (Please see the section on fat malabsorption and jaundice.) Additionally, poor pancreatic function, celiac sprue, and scleroderma with bacterial overgrowth may be present in some patients with PBC. Each of these conditions can further impair the ability to absorb dietary vitamin D from the intestines. The resulting vitamin D deficiency is the cause of the decreased deposit of calcium in the bones in osteomalacia. All of this said, compared to osteoporosis, osteomalacia is rare, especially among patients who are exposed to sunlight throughout the year. That's because sunlight stimulates the production of vitamin D in the skin, which can compensate for the poor absorption of vitamin D from the diet. Xanthomas Although elevated levels of cholesterol in the blood are common in PBC and other liver diseases with cholestasis, xanthomas are found in only 25% of patients at the time of diagnosis. Xanthomas tend not to occur until the serum cholesterol rises to very high levels, for example, above 600 mg/dL. Xanthomas tend to spontaneously disappear in patients with advanced liver disease due to impaired production of cholesterol by the damaged liver. Importantly, the high levels of serum cholesterol in PBC do not seem to increase the risk of heart disease because the composition of the cholesterol is different from the usual cholesterol (atypical) and does not easily deposit in blood vessels. Malabsorption of fat and fat-soluble vitamins Vitamins A, D, E, and K, referred to collectively as the fat-soluble vitamins, are absorbed from the gut in the same way that dietary fat is absorbed. Therefore, deficiencies of these vitamins can occur in advanced cholestasis. Also, bear in mind that some of the other conditions associated with PBC, such as pancreatic insufficiency, celiac sprue, and scleroderma with bacterial overgrowth, can also lead to malabsorption of fat and of the fat-soluble vitamins. Prior to the development of jaundice, however, deficiencies of vitamins A and E actually occur in only a minority of PBC patients. Vitamin A deficiency causes decreased vision in the dark. Vitamin E deficiency can cause abnormal skin sensations or muscular weakness due to its effects on the nerves that extend from the spinal cord. As already noted, deficiency of vitamin D results in osteomalacia (bones with inadequate amounts of calcium deposited in them.) Deficiency of vitamin K reduces the liver's production of blood clotting proteins and consequently, causes a tendency to bleed easily. Also, the resulting deficiency of clotting factors makes a blood test called the prothrombin time (blood clotting test) to become abnormal. Prothrombin is a clotting factor that is produced in the liver and needed for the normal clotting of blood. It is important to recognize that the liver damage itself also can impair production of blood clotting factors and cause easy bleeding and an abnormal prothrombin time. Jaundice As cholestasis worsens as a result of destruction of the small bile ducts that carry bile from the liver, bilirubin levels rise in the blood resulting in jaundice. Subtle jaundice is detectable only in sunlight and not in artificial light. Still, the jaundice does not become visible until the bilirubin level in the blood (normally under about one mg%) gets up to about three mg%. The simultaneous onset of both jaundice and itching is less common than the onset of itching alone, but is more common than either jaundice preceding itching or jaundice without itching. Hyperpigmentation Malignancy What are the manifestations of the complications of cirrhosis in PBC?
Edema and ascites Bleeding from varices When these veins distend (dilate) because of the increased blood flow and pressure, they are referred to as esophageal or gastric varices, depending on where they are located. So, portal hypertension and varices develop in PBC after cirrhosis is established. Only a minority of patients with PBC develops portal hypertension and varices before cirrhosis occurs. The higher the portal pressure, the larger are the varices (distended veins). Accordingly, patients with large varices are at risk for the varices to burst and bleed into the gut. It is recommended, therefore, that patients with PBC have an upper endoscopy done at the time of diagnosis and approximately every three years thereafter to detect and then, if necessary, treat the varices. An upper endoscopy is a direct look with a tubular instrument (an upper endoscope) into the esophagus and stomach. Hepatic encephalopathy When cirrhosis and portal hypertension are present, part of the blood flow in the portal vein, as already described, bypasses the liver by flowing through alternative blood vessels. Some of the toxic compounds take this bypass route and, thereby escape detoxification by the liver. The rest of the toxic compounds travel with the rest of the portal blood flow to the liver. However, a damaged liver may be functioning so poorly that it cannot detoxify the toxic compounds present in the portal blood. In this situation, the toxic compounds can go right through the liver and escape detoxification. Thus, in these two ways, in variable proportions - going around (bypassing) the liver and going right through the liver -- the toxic compounds accumulate in the blood. When the accumulated toxic compounds in the blood stream impair the function of the brain, the condition is called hepatic encephalopathy. Sleeping during the day rather than at night (reversal of the normal sleep pattern) is among the earliest symptoms of hepatic encephalopathy. Other symptoms include irritability, inability to concentrate or perform calculations, loss of memory, confusion, or depressed levels of consciousness. Ultimately, severe hepatic encephalopathy causes coma. Hypersplenism As the spleen enlarges, it filters out more and more of the blood elements. Hypersplenism is the term used to describe splenomegaly associated with a low red blood cell count ( anemia ), low white blood cell count (leucopenia), and/or low platelet count (thrombocytopenia). The anemia can cause weakness, the leucopenia contributes to susceptibility to infections, and the thrombocytopenia can impair the clotting of blood. Hepatorenal syndrome Hepatopulmonary syndrome Liver cancer (hepatocellular carcinoma) Cirrhosis due to any cause increases the risk of liver cancer. Therefore, the development of a primary liver cancer in an individual with PBC is not unexpected. However, the risk of hepatocellular carcinoma in PBC appears to be lower than the risk in cirrhosis caused by some other liver diseases, such as chronic viral hepatitis . A recent report indicated that hepatocellular carcinoma might be more common in men than women with PBC. Indeed, this one series of 273 patients with advanced PBC found hepatocellular carcinoma in 20% of the men compared to only 4.1% of the women. The way hepatocellular cancer develops in PBC, however, is not understood. The most common symptoms and signs of primary liver cancer are abdominal pain and swelling, an enlarged liver, weight loss, and fever. In addition, these liver tumors can produce and release a number of substances, including ones that cause an increase in red blood cells (erythrocytosis), low blood sugar ( hypoglycemia ), and high blood calcium (hypercalcemia). The most useful diagnostic tests for hepatocellular carcinoma are a blood test called an alpha-fetoprotein and an imaging study of the liver (either a CT Scan or an MRI with intravenous dye/contrast). The best screening tests for early detection of hepatocellular carcinoma in patients with cirrhosis are serial alpha-fetoprotein levels and ultrasound examinations of the liver every 6 to 12 months. It is important to note that about 40% of hepatocellular cancers do not produce elevated levels of alpha-fetoprotein. What are the manifestations of diseases associated with PBC?
Up to 25% of patients with PBC develop an autoimmune reaction against the thyroid gland. This reaction results in an inflammation of the gland, called thyroiditis. When the thyroid gland is first inflamed, only a minority of these individuals experience thyroid tenderness or pain. This pain is usually mild and located over the gland in the front of the lower neck. In fact, most people do not experience symptoms from the thyroiditis until some months or years after the autoimmune reaction began. By then, the slow and gradual decrease in thyroid function resulting from the inflammation can cause an underproduction of thyroid hormone, called hypothyroidism . It should be noted that the symptoms and signs of hypothyroidism, which include fatigue, weight gain, and elevated cholesterol, develop gradually and can be quite subtle. Further, they can easily be confused with those of PBC itself. Thus, physicians should periodically test thyroid function in all patients with PBC to detect hypothyroidism and to initiate treatment by replacement of thyroid hormone. Often, however, the thyroiditis occurs and the indications of hypothyroidism are found well before the diagnosis of PBC is made. Sicca syndrome Raynaud's phenomenon Scleroderma Scleroderma, therefore, can also cause esophageal and intestinal symptoms. Thus, involvement of the esophageal muscles that propel food through the esophagus results in difficulty swallowing. Most often, patients experience this difficulty as a sensation of solid food sticking in the chest after swallowing. Involvement of the lower esophageal sphincter muscle prevents the closure of the lower end of the esophagus and thereby, allows reflux of stomach acid, causing the symptom of heartburn. The heartburn, which is not caused by a heart problem, is usually experienced as a sensation of burning in the center of the chest. Involvement of the muscles of the small intestine in scleroderma can cause a condition called bacterial overgrowth, which can lead to malabsorption of fat and diarrhea. For more about this condition, please read the Scleroderma article. Finally, a minority of PBC patients has a variant of scleroderma referred to as CREST syndrome. The term CREST refers to Calcium deposits in the skin, Raynaud's phenomenon, muscle dysfunction of the Esophagus, tightening of the skin of the fingers called Sclerodactyly, and dilated small blood vessels beneath the skin called Telangiectasias. Rheumatoid arthritis Celiac sprue Urinary tract infections Gallstones Gallstones occur in about 30% of adults in the general population and are at least twice as common in women as in men. It is not surprising, therefore, that gallstones are especially frequent in individuals having other conditions that tend to afflict women more than men, such as PBC. The most common symptom of gallstones is abdominal pain. Sometimes, they can cause nausea, fever, and/or jaundice. But the majority of gallstones do not cause any symptoms. The diagnosis of gallstones is usually made by ultrasound imaging of the gallbladder. Other associated diseases What are risk factors for PBC? The patients reported having had a high frequency of other autoimmune diseases, including sicca syndrome in 17.4% and Raynaud's phenomenon in 12.5%. Interestingly, 6% reported that at least one other family member had PBC. Statistical analysis showed that the risks of developing PBC for patients compared to friends as controls were:
Similar increased risks were found for the PBC patients when they were compared to siblings without PBC. How is PBC diagnosed? What is the role of blood tests? Other blood tests may also be helpful in the diagnosis of PBC. For example, serum immunoglobulin M (IgM) is frequently elevated. Also, just about all patients with cholestasis develop increased cholesterol levels (as noted previously), and some also develop elevated triglycerides. Moreover, testing the levels of these fats (lipids) can identify patients who might form cholesterol deposits in the skin or nerves. (See the section on xanthomas above.) What is the role of testing for antimitochondrial antibodies? The AMA titers in PBC are almost universally greater than or equal to 1 to 40. This means that a serum sample diluted with 40 times its original volume still contains enough antimitochondrial antibodies to be detected in the binding reaction. A positive AMA with a titer of at least 1:40 in an adult with an elevated alkaline phosphatase is highly specific for a diagnosis of PBC. The antigen recognized by AMA in patients with PBC is now known to be PDC-E2 and is also often referred to as the M2 antigen, as discussed earlier. So, newly developed tests for antibodies that bind to PDC-E2 are more specific and are now available to confirm the diagnosis of PBC. It is noteworthy that approximately 20% of patients with AMA also have antinuclear (ANA) and/or anti-smooth muscle (SMA) autoantibodies in their blood. The ANA and SMA are more characteristically found in a disease called chronic autoimmune hepatitis. It turns out that patients who have persistently undetectable AMA but otherwise have clinical, laboratory, and liver biopsy evidence of PBC, all have either ANA or SMA. These patients have been referred to as having AMA-negative PBC, autoimmune cholangiopathy, or autoimmune cholangitis. The natural history, associated diseases, laboratory test abnormalities, and liver pathology are indistinguishable between the AMA-positive and AMA-negative patients. Thus, it seems inappropriate, for now at least, to classify this AMA-negative disease as different from PBC. Accordingly, this situation should be referred to as AMA-negative PBC. Rarely, some other patients appear to concurrently have features of both PBC and chronic autoimmune hepatitis. Such patients are said to have an overlap syndrome. What is the role of imaging tests? Dilated bile ducts caused by mechanical obstruction can usually be visualized on the ultrasonogram. The dilated bile ducts can also be seen using other imaging techniques such as computerized tomographic (CT) scanning, Magnetic Resonance Imaging (MRI), or an endoscopic procedure called ERCP. On the other hand, in PBC, the ducts that are being destroyed are so small that any dilation of upstream ducts cannot be seen with any of the imaging techniques. For the diagnosis of PBC in patients with cholestatic liver tests, a positive AMA and a normal ultrasound examination usually is sufficient. In this situation, other imaging studies of the bile ducts are usually not required. What is the role of liver biopsy?
Pathologists (physicians who analyze tissue samples) have divided the evolution of PBC into four stages recognizable by the microscopic appearance of the liver biopsy.
From a practical perspective, physicians most often divide the disease into prefibrotic (before scarring) and fibrotic (scarring or cirrhosis) stages, still usually using the biopsy findings. Patients often ask if a liver biopsy is mandatory. The answer usually depends on the level of confidence in establishing the diagnosis of PBC using the liver tests, autoantibodies, and ultrasound. In the presence of cholestatic liver tests, high levels of AMA, and an ultrasound showing no bile duct obstruction in a middle-aged woman, the diagnosis of PBC can be made rather confidently without a biopsy. Treatment then can often be started, for example, with ursodeoxycholic acid (UDCA, a naturally occurring bile acid that is produced in small quantities by normal liver cells). Without a biopsy, however, the stage (extent) of the disease would remain undefined. A biopsy helps the patient know where they are in the natural history of the disease. Furthermore, knowing the stage of PBC can help physicians decide about prescribing certain medications (for example corticosteroids) that may be effective in the early stages and less valuable in later stages. On the other hand, PBC patients who already have the complications of cirrhosis (for example, ascites, varices, or hepatic encephalopathy) are presumed to have advanced liver disease. In these PBC patients the imaging studies alone are usually sufficient to exclude dilated ducts and a biopsy is not needed for staging the disease. Otherwise, the presence or absence of other symptoms (apart from the presence of those clearly due to the complications of cirrhosis) is not an accurate guide to the stage of PBC on a liver biopsy. For example, in one large series of patients, approximately 40% of those without symptoms had cirrhosis on liver biopsy. What are the criteria for a definitive diagnosis of PBC?
What is the course of natural progression in PBC? What are the sequential clinical phases of PBC? It is important to realize that the time required to evolve from one clinical phase to another varies substantially among individuals. Also, be aware that these clinical phases are different from the pathological stages determined by the liver biopsy. Most importantly, since the diagnosis is often first made between the ages of 30 and 60 years and progression of the disease is usually so slow, PBC does not result in a reduced life expectancy in all patients. Table 3 shows the sequential phases in the natural progression of PBC without therapy.
Preclinical phase However, even with only the isolated positive AMA, these people do appear to have PBC. This conclusion is based on the presence of diagnostic or compatible features on a liver biopsy and subsequent findings or clinical events during long-term observation. Thus, more than 80% of these individuals with only a positive AMA ultimately develop cholestatic liver blood tests followed by the typical symptoms of PBC. After discovery of an isolated positive AMA test, the time before development of cholestatic liver tests ranged from 11 months to 19 years. The median time (the time at which 50% of the people had developed cholestatic liver tests) was 5.6 years. During 11 to 24 years of observation starting in the preclinical phase of 29 patients, 5 died. However, none of the five died as a result of liver disease and the median age at death was 78. Asymptomatic phase The results of three large studies indicate that 40% of these asymptomatic patients will develop symptoms of liver disease within the next 6 years. Over and above that, another 33% of patients will likely develop symptoms between 6 and 12 years. Longer follow up is not available, but this asymptomatic phase may persist indefinitely in a minority of patients with PBC. Symptomatic phase Advanced phase What is the role of mathematical models in predicting the outcome (prognosis) in PBC? Physicians can rather easily calculate a Mayo Risk Score for their patients by going to the Internet site of the Mayo Clinic. There is no charge. The results provide an estimated survival for the patient over the next several years. Patients with an estimated life expectancy of 95% or less over one year meet the minimal listing criteria set by the United Network of Organ Sharing (UNOS) for liver transplant candidates. What about pregnancy in PBC? In the medical literature, pregnancy in women with an established diagnosis of PBC has not been reported frequently. While early reports suggested that the outcome was suboptimal for both fetus and mother, later reports indicated that women with PBC can deliver healthy babies. However, these women may develop itching or jaundice during the last trimester. Otherwise, the clinical course of PBC does not tend to worsen or improve during most pregnancies. Although some babies may be born several weeks prematurely, only one miscarriage has been reported. Furthermore, the risk of fetal abnormalities does not appear to increase in the pregnancies of PBC women. Since advanced cirrhosis interferes with the processing (metabolism) of sex hormones, the likelihood of a woman with advanced liver disease becoming pregnant is small. Nevertheless, it is important to know that PBC patients who might become pregnant should not receive injections of vitamin A because it can cause birth defects (See the section on treatment of fat malabsorption). The chance that ursodeoxycholic acid therapy causes fetal harm is classified as remote but possible since adequate studies have not been done in pregnant women. The safety of ursodeoxycholic acid therapy taken by PBC mothers for their breast-feeding infants is unknown and considered controversial. Click here to go to Primary Biliary Cirrhosis Part II
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