Primary Biliary Cirrhosis (cont.)
John M. Vierling, MD, FACP
John M. Vierling, MD, FACP
John M. Vierling M.D. is Professor of Medicine and Surgery at the Baylor College of Medicine in Houston, Texas, where he also serves as Director of Baylor Liver Health and Chief of Hepatology. In addition, he is the Director of Advanced Liver Therapies, a center devoted to clinical research in hepatobiliary diseases at St. Luke's Episcopal Hospital. Dr. Vierling is board certified in internal medicine and gastroenterology and a Fellow of the American College of Physicians.
Leslie J. Schoenfield, MD, PhD
Leslie J. Schoenfield, MD, PhD
Dr. Schoenfield served as associate professor of medicine and consultant in gastroenterology on the faculty of the Mayo Clinic for seven years. He became a professor of medicine in residence at UCLA from 1972 to 1999 (now emeritus). He was the director of gastroenterology at Cedars-Sinai Medical Center in Los Angeles for 25 years, where he received the chief resident's teaching award, the president's award, and the pioneer of medicine award.
In this Article
What manifestations are specifically due to PBC itself?
The following manifestations (symptoms and findings) due to PBC will be discussed:
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:
Just about as common as fatigue in PBC, itching (pruritus) of the skin affects a majority 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 some 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 greater 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.
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 develop in less than 5% of patients diagnosed with PBC. 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.
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.
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.
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).
Medically Reviewed by a Doctor on 1/9/2014
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