What is PBC?

Primary biliary cirrhosis (PBC) is a chronic (long duration) disease characterized by progressive inflammation and destruction of the small bile ducts within the liver. What are the bile ducts and what do they do? Lined with cells named biliary epithelial cells, the bile ducts are tubules that make up a plumbing system for the liver. The bile ducts along with the gallbladder are part of what is called the biliary tract.

The plumbing system begins in the liver with very small caliber ducts that connect to increasingly larger caliber ducts, like a tree in which twigs connect to small branches that connect to larger branches. In fact, this system is often referred to as the biliary tree. The large right and left bile ducts, still within the liver, connect to an even larger common bile duct that runs outside the liver to the small intestine just beyond the stomach. The common bile duct connects by the cystic duct to the gallbladder. The gallbladder is a pear-shaped, expandable, sac-like organ in the biliary system. The branching bile ducts course through special tissue in the liver, called portal tracts, which act like conduits for the ducts. In fact, the branching portal tracts containing the bile ducts also contain the blood vessels that enter and leave the liver.

The bile ducts carry bile, a fluid that is produced by the liver cells (hepatocytes) and modified by the biliary lining (epithelial) cells as it flows through the ducts to the small intestine. Bile contains substances required for digestion and absorption of fat called bile acids, as well as other compounds that are waste products, such as the pigment bilirubin. (Bilirubin is a yellow-orange compound produced by the breakdown of hemoglobin from old red blood cells.) Bile is stored in the gallbladder between meals and discharged into the small intestine during digestion of the meals.

The inflammation in PBC starts in the liver's portal tracts and involves the small bile ducts in these areas. The destruction of the small bile ducts blocks the normal flow of bile into the gut. The medical term for decreased flow of bile is cholestasis. (Chole means bile and stasis means failure to flow.) Cholestasis is a very important aspect of this disease. As the inflammation continues to destroy more of these bile ducts, it spreads to destroy nearby liver cells (hepatocytes). As the inflammatory destruction of the hepatocytes proceeds, scar tissue (fibrosis) forms and spreads through the areas of destruction.

The combined effects of progressive inflammation, scarring, and toxicity of bile trapped within hepatocytes (liver cells) culminates in cirrhosis. Cirrhosis is defined as the stage of disease when there is both widespread scarring of the liver and clusters (nodules) of hepatocytes reproducing (regenerating) themselves within the scars. Since cirrhosis occurs only in the later stage of PBC, the name primary biliary cirrhosis is actually a misnomer for patients in the earlier stages of the illness. The more technically correct and ponderous term for PBC, chronic non-suppurative destructive cholangitis, however, has never been widely used and is unlikely to replace PBC.

What is the scope of the problem?

PBC is a disease that disproportionately affects women, with 10 women for every man having the disease. It is also a disease of adulthood that, rather curiously, has never been diagnosed in childhood. As a matter of fact, the diagnosis is made most frequently in middle-aged people, between the ages of about 30 and 60 years. PBC is considered to be an uncommon disease, but not rare. Studies indicate that the number of people with PBC at a given time (referred to as the prevalence of disease) ranges from 19 to 251 per million population in various countries. If these figures are adjusted to compensate for the fact that PBC is found only in adults and that 90% of the patients are women, then the calculated prevalence is approximately 25 to 335 per million women and 2.8 to 37 per million men.

The largest and best long-term studies of PBC have been conducted in northern England. Their findings indicate that the number of new cases of PBC over time (referred to as the incidence of disease) has increased steadily from 16 per million population in 1976 to 251 per million in 1994. Unfortunately, no similar studies have been conducted elsewhere to validate or refute the belief that the incidence and prevalence of PBC is rising worldwide.

One comprehensive study conducted in the north of England from 1987 to 1994 was designed specifically to find people with PBC. Using strict criteria for the diagnosis of PBC, they identified a total of 770 patients. Of these, the number of newly diagnosed people with PBC during just these 7 years was 468. Thus, clinical investigators interested in PBC had conducted extensive epidemiological (cause and distribution) studies of PBC over almost 20 years in this same geographic area. Such a concentrated focus of effort strongly supports the view that the apparent increase in the number of people with PBC is indeed a true increase.

What is the cause of PBC?

The cause of PBC remains unclear. Current information suggests the cause may involve autoimmunity, infection, or genetic (hereditary) predisposition, acting either alone or in some combination. A complete understanding of the cause of PBC will require two types of information. One, referred to as the etiology, is identification of the initiating (triggering) events. The other, referred to as the pathogenesis, is a discovery of the ways (mechanisms) by which the triggering events lead to the inflammatory destruction of bile ducts and hepatocytes. Unfortunately, neither the etiology nor the pathogenesis of PBC has yet been defined.

The following topics relate to the cause of PBC:

• What is the role of autoimmunity?
• What are antimitochondrial antibodies (AMA)?
• Do the AMA react with the bile ducts?
• What causes destruction of the bile ducts in PBC?
• What is the role of infection?
• What is the role of genetics?

What is the role of autoimmunity?

PBC is presumed by most experts to be an autoimmune disease, which is an illness that occurs when the body's tissues are attacked by its own immune (defense) system. (Auto means self.) Childhood diabetes is one example of an autoimmune disease in which some type of transient infection (one that later goes away) triggers an immune reaction in a susceptible (genetically predisposed) person. This particular immune reaction in diabetes selectively destroys the cells in the pancreas that produce insulin.

Despite strong evidence to support the concept that PBC likewise is an autoimmune disease, some features of PBC are uncharacteristic of autoimmunity. For example, all other autoimmune diseases occur in both children and adults, while, as already mentioned, PBC has never been diagnosed in childhood. PBC and other autoimmune diseases, however, are associated with antibodies (small proteins found in the blood and bodily secretions) that react with the body's own proteins, which are referred to as autoantigens.

Table 1 shows a comparison between primary biliary cirrhosis and classic autoimmune diseases.

Feature	Primary Biliary Cirrhosis	Classic Autoimmunity
Predominantly females	Yes	Yes
Age at diagnosis	Adults only	Children and adults
Autoantibodies	Yes	Yes
Antigens recognized by autoantibodies	Restricted (few)	Diverse (many)
HLA (Human Lymphocyte Antigen) associations	Weak	Strong
Association with other autoimmune diseases	Yes	Yes
Response to drugs that suppress the immune system	Poor	Good

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)?

Between 95 and 98% of patients with PBC have autoantibodies in their blood that react with the inner lining of mitochondria. These autoantibodies are called antimitochondrial antibodies (AMA). Mitochondria are the energy factories present inside all of our cells, not just the cells of the liver or bile ducts. The mitochondria use the oxygen carried in the blood from the lungs as a fuel to generate energy. AMA bind to protein antigens that are contained in multienzyme complexes (packages of enzymes) within the inner lining of the mitochondria. The multienzyme complexes produce key chemical reactions necessary for life. These complexes are referred to as multienzyme because they are made up of multiple enzyme units.

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?

In as much as the bile ducts are the main targets of destruction in PBC, the question was asked whether the AMA reacts with the epithelial cell lining of the bile ducts. So, investigators prepared antibodies to PDC-E2. As expected, they found that these antibodies bound to the mitochondria within cells. But, sure enough, recent information suggests that these AMA autoantibodies also bind to PDC-E2 that lies outside the mitochondria yet within the epithelial cells lining the bile ducts. Indeed, these cells are the main targets of destruction in PBC.

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?

AMA are tremendously important as a diagnostic marker in patients with PBC. Despite that, no evidence exists that the AMA itself causes the destruction of the biliary epithelial cells lining the small bile ducts. Neither the presence nor the amount (titer) of AMA in the blood appears to be related to the inflammatory destruction of the bile ducts. Indeed, immunization of animals with PDC-E2 antigen results in production of AMA without any liver or bile duct damage (pathology).

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?

The possibility that PBC is caused by an infection with a virus, bacterium, or fungus has generated a number of studies. To date, none has shown conclusively that PBC is an infectious disease or even that it is triggered by a self-limited (nonpersistent) infection. Clearly, PBC is not associated with infection by any of the known hepatitis viruses. Furthermore, none of the new viruses that may cause liver diseases have been found preferentially or exclusively in patients with PBC.

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?

PBC is not transmitted by heredity from parents with the disease to their children. Thus, PBC is not a classical hereditary (genetic) disease, as is diabetes, for example. Clearly, however, the genes of our immune system control human responses to infections with bacteria and viruses. The genes of the immune system also control the risk of developing autoimmune diseases. Studies have shown that there are some weak associations between PBC and certain specific inherited genes of the immune system. The fact that many people without PBC also have these identical immune genes indicates that the genes themselves do not determine if a patient develops the disease.

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?

The symptoms and physical signs (findings) in patients with PBC can be divided into those manifestations due to:

• PBC itself
• Complications of cirrhosis in PBC
• Diseases often associated with PBC

Table 2 lists the multiple signs and symptoms (manifestations) of primary biliary cirrhosis, its assciated diseases, and the complications of the cirrhosis.

Biliary Cirrhosis	Associated Diseases	Complications of Cirrhosis
Fatigue	Thyroid dysfunction	Edema and ascites
Itching	Sicca syndrome	Bleeding from varices
Metabolic bone disease	Raynaud's phenomenon	Hepatic Encephalopathy
Xanthomas	Scleroderma	Hypersplenism
Fat & vitamin malabsorption	Rheumatoid arthritis	Hepatocellular carcinoma
Jaundice	Celiac sprue
Hyperpigmentation	Inflammatory bowel disease
	Urinary tract infections

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 following manifestations (symptoms and findings) due to PBC will be discussed:

• Fatigue
• Itching
• Metabolic Bone Disease
• Xanthomas
• Jaundice
• Hyperpigmentation
• Malignancy

Fatigue

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:

• Fatigue is often absent in the morning
• Rapid decrease in energy later in the day
• Failure to rejuvenate with a rest period
• Occasional days without fatigue

Itching

Just about as common as fatigue in PBC, itching (pruritus) of the skin affects 66% of patients at some time during the disease. The itching tends to occur early in the course of the disease, when patients still have good liver function. As a matter of fact, itching can even be the initial symptom of PBC.

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

Patients with PBC may experience pain in the bones of their legs, pelvis, back (spine), or hips. This bone pain can come from one of two bone diseases, osteoporosis (sometimes referred to as thin bones) or osteomalacia (soft bones). Patients with PBC have a 440% increase in the likelihood of having poorly calcified bones compared to normal people of the same age and gender. Most people with osteoporosis or osteomalacia, however, do not have bone pain. Still, a minority do experience bone pain that can be severe, often due to bone fractures.

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

Cholesterol may deposit in the skin around the eyes or in skin creases of the palms, soles, elbows, knees, or buttocks. Collectively, these waxy, raised deposits are called xanthomas. Such deposits around the eyes are also referred to as xanthalasma. Xanthomas are more common in PBC than in any other liver diseases associated with cholestasis. Most xanthomas do not cause symptoms, but those on the palms sometimes can be painful. Rarely, xanthomas deposit in nerves and cause a neuropathy (disease of the nerve). This neuropathy is characterized by abnormal sensation in the parts of the body, most often the limbs, supplied by the affected nerves.

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

As the amount of bile acids entering the gut decrease with increasing cholestasis, patients can loose the ability to absorb all of the fat present in their diet. This reduction in fat absorption, called malabsorption, occurs because the bile acids are needed for the normal intestinal absorption of fat. So, when advanced cholestasis prevents adequate amounts of bile acids from reaching the small bowel, the absorption of dietary fat and of the vitamins A, D, E and K is reduced. As a result, undigested fat passing into the large intestine causes diarrhea, while continuing malabsorption of fat can lead to weight loss and vitamin deficiencies. A laboratory measurement of the amount of fat in the bowel movements can reveal whether the dietary fat is being absorbed normally or not.

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

One of the principal signs of advanced PBC is jaundice, which is a yellow appearance of the whites of the eyes and skin. Jaundice is usually first noticeable as a yellowing of the whites of the eyes. The jaundice reflects increased levels of bilirubin in the blood. The bilirubin is a yellow waste product that is normally produced mostly in the liver, delivered in bile to the intestine, and passed out in the stools (bowel movements).

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

Cholestasis increases production of the dark pigment, melanin, which is found in the skin. The darkening of the skin is called hyperpigmentation. What is notable about the pigmentation is that it occurs in both sun-exposed and non-exposed areas of the body. Moreover, prolonged scratching because of severe itching in PBC may intensify the pigmentation, leading to darkened areas and a blotchy or mottled appearance of the skin.

Malignancy

Early reports indicated that women with PBC might have an increased risk of developing breast cancer. Subsequently, however, larger studies, did not confirm this possibility. Please see the section on liver cancer (hepatocellular cancer).

What are the manifestations of the complications of cirrhosis in PBC?

The manifestations of the following complications of cirrhosis will be discussed:

• Edema and ascites
• Bleeding from varices
• Hepatic encephalopathy
• Hypersplenism
• Hepatorenal syndrome
• Hepatopulmonary syndrome
• Liver Cancer (hepatocellular carcinoma)

Edema and ascites

As cirrhosis of the liver develops, signals are sent to the kidneys to retain salt and water. This excess fluid first accumulates in the tissue beneath the skin of the ankles and legs (due to the pressure of gravity). This accumulation of fluid is called edema or pitting edema. Pitting edema refers to the observation that pressing a fingertip against a swollen ankle or leg causes an indentation that persists for some time after release of the pressure. Actually, any type of sufficient pressure, such as from the elastic part of socks, can produce pitting edema. The swelling often is worse at the end of the day and may lessen overnight. As more salt and water are retained and liver function decreases, fluid may also accumulate in the abdomen. This accumulation of fluid (called ascites) causes swelling of the abdomen.

Bleeding from varices

In cirrhosis, the scar tissue (fibrosis) and the regenerating nodules of hepatocytes block (obstruct) blood flow in the portal vein in virtually all patients. The portal vein carries blood from the intestines, spleen, and other abdominal organs to the liver on the way back to the heart and lungs. The build-up of pressure caused by the blockage in the portal vein is called portal hypertension. When pressure in the portal vein becomes high enough, it causes blood to flow through alternative vessels (paths of lesser resistance.) Often, these vessels include veins in the lining of the lower part of the esophagus and the upper part of the stomach.

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

The protein in our diet is converted by bacteria normally present in the gut into substances that can alter the function of the brain. When these substances (ammonia, for example) accumulate in the body, they become toxic. Ordinarily, these potentially toxic compounds are carried in the portal vein to the normal liver where they are detoxified.

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

The spleen normally acts as a filter removing older red blood cells, white blood cells, and platelets (small particles that help stop bleeding from a cut surface) from the blood. As the portal pressure rises, it increasingly blocks blood flow from the spleen to the liver. The resulting backward pressure in the blood vessels coming from the spleen causes the organ to enlarge (splenomegaly). Sometimes, the spleen is stretched so large that it causes abdominal pain.

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

Patients with advanced liver disease and portal hypertension can sometimes develop the hepatorenal syndrome. This syndrome is a serious problem with the functioning of the kidneys without actual physical damage to the kidneys themselves. The hepatorenal syndrome is defined by progressive failure of the kidneys to clear substances from the blood and produce adequate volumes of urine even though some other kidney functions, such as retention of salt, are maintained. If liver function improves or a healthy liver is transplanted into a patient with hepatorenal syndrome, the kidneys often begin to work normally. This restoration of kidney function indicates that liver failure is associated with an inability of the liver to either produce or detoxify substances that affect kidney function.

Hepatopulmonary syndrome

Rarely, some patients with advanced cirrhosis can develop the hepatopulmonary syndrome. These patients can experience difficulty with breathing because certain hormones released in advanced cirrhosis cause abnormal functioning of the lungs. The basic lung problem in the hepatopulmonary syndrome is that the blood flowing through the small vessels in the lungs does not come in sufficient contact with the alveoli (air pockets) of the lungs. Therefore, the blood cannot pick up enough oxygen from the air that is breathed and the patient experiences difficulty breathing.

Liver cancer (hepatocellular carcinoma)

Patients with PBC that develop cirrhosis have an increased risk of developing a primary cancer of the liver cells (hepatocytes) called liver cancer (hepatocellular carcinoma). Primary refers to the fact that the tumor originates in the liver. A secondary tumor originates elsewhere in the body and can spread (metastasize) to the liver.

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?

The manifestations of the following diseases associated with PBC will be discussed:

• Thyroid dysfunction
• Sicca syndrome
• Raynaud's phenomenon
• Scleroderma
• Rheumatoid arthritis
• Celiac sprue
• Urinary tract infections
• Gallstones
• Other associated diseases

Thyroid dysfunction

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

Up to 70% of patients with PBC experience a sensation of dry eyes or dry mouth referred to as sicca syndrome or alternatively, as Sjogren's syndrome. This syndrome is caused by an autoimmune inflammation of the lining cells of the ducts that carry tears or saliva. Rarely, patients experience the consequences of dryness in other areas of the body including the windpipe or larynx (causing hoarseness) and the vagina. This autoimmune inflammation and drying of secretions can also occur, although even more rarely, in the ducts of the pancreas. The resulting poor pancreatic function (pancreatic insufficiency) can cause impaired absorption of fat and the fat-soluble vitamins.

Raynaud's phenomenon

Raynaud's phenomenon starts with an intense blanching (paling) of the skin of the fingers or toes when they are exposed to the cold. When the hands or feet are re-warmed, the blanching characteristically changes to a purplish discoloration and then to a bright red, often associated with throbbing pain. This phenomenon is due to the cold causing a constriction (narrowing) of the arteries that supply blood to the fingers or toes. Then, with re-warming of the hands or feet, the blood flow is restored and causes the redness and pain. Raynaud's phenomenon is often associated with scleroderma. For more information about this phenomenon, please read the Raynaud's phenomenon. article

Scleroderma

Approximately 17% of patients with PBC develop mild scleroderma, a condition in which the skin around the fingers, toes, and mouth becomes tight. In addition, scleroderma involves the muscles of the esophagus and small intestine. The esophagus connects the mouth to the stomach, and its muscles help to propel swallowed food into the stomach. In addition, a band of muscle (the lower esophageal sphincter), which is located at the junction of the esophagus and stomach, has two other functions. One is to open to let food pass into the stomach. The other is to close to prevent the stomach juices that contain acid from flowing back into the esophagus.

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

An abnormal type of antibody, called rheumatoid factor, is found in the blood of most patients with rheumatoid arthritis. This antibody also is found, however, in approximately 25% of patients with PBC. Although some PBC patients with the rheumatoid factor also have symptoms of joint pain and stiffness, most do not.

Celiac sprue

This autoimmune disease of the gut occurs in about 6% of patients with PBC. The disease impairs intestinal absorption of dietary fat and other nutrients, resulting in diarrhea and nutritional and vitamin deficiencies. Celiac sprue is caused by intolerance to gluten, a component of wheat, barley, and rye in the diet. As already mentioned, similar symptoms can occur in PBC itself as a result of fat malabsorption due to decreased bile flow into the gut. In any case, PBC patients with the signs or symptoms of fat malabsorption should be tested for celiac sprue. The diagnosis of celiac sprue is made by finding certain serum antibodies (for example, those called antigliadin or antiendomysial antibodies), characteristic intestinal biopsy features, and a usually dramatic response to dietary restriction of gluten.

Urinary tract infections

Recurrent bacterial infections of the urine occur in 19% of women with PBC. These infections may be without symptoms or cause a sense of a frequent, urgent need to urinate with a burning feeling while passing urine.

Gallstones

Patients with PBC can develop two types of gallstones in the gallbladder. One type (called cholesterol gallstones) contains mostly cholesterol, and is by far the most common type of gallstone found in the general population. The other type (called pigment gallstones) contains mostly bile pigments (including bilirubin) and calcium. This type of gallstone occurs with increased frequency in all types of cirrhosis, including PBC.

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

Rarely, an inflammatory bowel disease (ulcerative colitis or Crohn's disease), a kidney problem (renal tubular acidosis), poor pancreatic function (pancreatic insufficiency), as mentioned earlier, or a lung condition (pulmonary interstitial fibrosis) can be associated with PBC.

What are risk factors for PBC?

Identification of risk factors for developing PBC should be an important priority, but astonishingly little research has been done in this area. A recent survey used questions from the National Health and Nutrition Examination Survey of the U.S. government. This survey compared the answers of 199 patients with PBC with those of 171 siblings and 141 friends of the patients. As anticipated, the patients with PBC were predominantly women (10 to 1 women to men), and the average age was 53 years.

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:

• 492% greater for having had other autoimmune diseases
• 204% greater for having smoked cigarettes
• 186% greater for having had tonsillectomy
• 212% greater among women for having had urinary tract infections or vaginal infections.

Similar increased risks were found for the PBC patients when they were compared to siblings without PBC.

How is PBC diagnosed?

The diagnosis of PBC is established by the results of several types of tests. These include blood tests, serum autoantibody testing, ultrasound imaging of the liver, and liver biopsy.

What is the role of blood tests?

The key blood test abnormality in PBC and all liver diseases associated with cholestasis is an elevated alkaline phosphatase enzyme level in the blood. The finding of a concurrent elevation of the gamma glutamyl transpeptidase (ggt) blood level proves that the elevated alkaline phosphatase is from the liver, rather than from bone (another source of alkaline phosphatase). Other liver enzymes, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), may be either normal or only slightly elevated at the time of diagnosis. As the duration of disease increases, both of these liver enzymes (the aminotransferases) usually become elevated to a mild to moderate degree, while the alkaline phosphatase can become very high. For more information about liver blood tests, please read the Liver Blood Tests article.

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?

AMA are detectable in the serum in 95 to 98% of patients with PBC, as noted earlier. The most economical test for AMA applies diluted samples of a patient's serum onto tissue sections from rat stomach or kidney in the laboratory. (Remember that the mitochondria are present in all cells, not just the cells of the liver and bile ducts.) Serum antibodies that attach (bind) to mitochondrial membranes within the tissue cells can then be observed with a microscope. The most dilute sample of serum showing this binding reaction is reported, using the term titer. The titer indicates the most dilute serum sample that reacts with the tissue mitochondria. A higher titer means there is a greater amount of AMA in the serum.

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?

Ultrasound imaging of the liver is recommended for patients whose blood tests show cholestasis. Cholestatic blood tests feature a disproportionately elevated alkaline phosphatase and ggt, compared to the ALT and AST. The purpose of the ultrasound exam is to visualize the bile ducts to exclude mechanical blockage (obstruction) of larger bile ducts as the cause of the cholestasis. Gallstones or tumors, for example, may cause mechanical obstruction of bile ducts. The blockage can cause increased pressure in the bile ducts that leads to dilation (widening) of the upstream bile ducts.

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?

The benefits of doing a liver biopsy (taking a tissue sample) include:

• Confirmation of the diagnosis
• Determination of the stage of disease
• Identification of any other concurrent liver disease

Pathologists (physicians who analyze tissue samples) have divided the evolution of PBC into four stages recognizable by the microscopic appearance of the liver biopsy.

1. Progressive inflammation of the portal tracts and their small bile ducts
2. The inflammation causes destruction of the small bile ducts and spreads to also involve the nearby liver cells (hepatocytes)
3. Extensive scars (fibrosis) protrude from the inflamed portal tracts into the region of liver cells
4. Cirrhosis

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?

The criteria for a definitive diagnosis of PBC were established for the purpose of conducting clinical research, including therapeutic trials, on the disease. The criteria were designed to identify all patients with classic PBC and exclude any patient with a questionable diagnosis. A definitive diagnosis of PBC is established in a patient who has all three of the following:

• Cholestatic liver tests (alkaline phosphatase and ggt elevated more than ALT and AST)
• AMA positive at a titer of greater than or equal to 1:40
• Diagnostic or compatible liver biopsy

What is the course of natural progression in PBC?

The course of natural progression (the natural history) in PBC can be divided into four clinical phases (preclinical, asymptomatic, symptomatic, and advanced). What's more, based on our knowledge of the clinical findings in patients with PBC, mathematical models have been developed that can predict the outcome (prognosis) for individual patients.

What are the sequential clinical phases of PBC?

The four sequential clinical (symptoms and tests) phases of PBC are:

• Preclinical
• Asymptomatic
• Symptomatic
• Advanced

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.

Phase	Characteristics	Duration
Preclinical	Absence of symptoms Normal liver tests AMA positive	Poorly defined, estimated as 2 to 10 years
Asymptomatic	Absence of symptoms Abnormal liver tests AMA positive	Indefinite in some patients, 2 to 20 years in others
Symptomatic	Symptoms Abnormal liver tests AMA positive	3 to 11 years
Advanced	Symptoms Complications of cirrhosis and liver failure Abnormal liver tests AMA positive	0 to 2 years, without liver transpl

Preclinical phase

The first phase is characterized by the presence of AMA at a titer of greater than or equal to 1:40 in an adult without any abnormality of liver blood tests or any symptoms of liver disease. This phase is referred to as preclinical because there is usually no reason for people in this phase of the disease to see a physician or have testing. Furthermore, since screening tests for AMA are not routinely performed, only small numbers of such people have been identified. So, people with an AMA without symptoms or abnormal liver blood tests have been identified only as the result of research studies of autoantibodies in apparently healthy people.

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

This phase is characterized by a positive AMA and cholestatic liver blood tests in a person without symptoms of liver disease. The incidental discovery of an elevated alkaline phosphatase is what most commonly leads to the diagnosis of PBC in this phase. The elevated alkaline phosphatase is usually discovered after testing the blood routinely or for another clinical reason.

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

This phase is defined by a positive AMA, persistently abnormal liver blood tests, and the presence of symptoms of PBC. The duration of this phase among patients is also quite variable, lasting from 3 to 11 years.

Advanced phase

In this phase, symptomatic patients develop the complications of cirrhosis and progressive liver failure. The duration of this phase ranges from months to 2 years. These patients are at risk of dying unless they undergo successful liver transplantation.

What is the role of mathematical models in predicting the outcome (prognosis) in PBC?

Investigators at the Mayo Clinic performed statistical analyses of many variables (different types of data) among a large group of patients with PBC followed for many years. They used the results to derive a mathematical equation to calculate a so-called Mayo Risk Score (MRS). It turns out that the calculation is based on the results of three of the patient's blood tests (total bilirubin, albumin, and prothrombin time), the age of the patient, and the presence of enough fluid retention to swell the legs (edema) or abdomen (ascites). The Mayo Risk Score provides accurate information about the outcome (prognosis) of individual patients over time. It has been validated and is currently used to determine which patients with PBC need to be put on a liver transplant waiting list.

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?

As discussed earlier, some women experience itching during their last trimester of pregnancy when the hormone levels of estrogens are high. A minority of these women may have a predisposition to develop PBC or may actually have early PBC that has not yet been diagnosed.

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.

sourceLast Editorial Review: 9/17/2005

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