Authors: Rita Baron-Faust,Jill Buyon
Primary biliary cirrhosis
is another autoimmune disease that damages the liver, but it results from an autoimmune attack on the
bile ducts
rather than on liver cells.
Bile
, which helps break down fat during digestion, is stored in the gallbladder and released through the bile ducts into the
duodenum
, where fat enters the small intestine.
In PBC, the immune system attacks the smaller bile ducts and
ductules
, causing damage and leakage of bile acids into nearby tissues. Bile acids are toxic and injure liver cells, attracting T cells and causing small, granular inflammatory lesions (
granulomas
) to form as the liver attempts to contain bile seepage. Copper, normally excreted in bile, also accumulates in liver cells, as does
bilirubin
, the orange-yellow pigment that gives bile its color (bilirubin is normally excreted in stool). In PBC, cells in the small bile ducts overgrow, eventually replacing the ducts with hardened scar tissue.
17
Bile flow is reduced (
cholestasis
)
and may eventually be blocked.
Immune damage is concentrated around blood vessels of the liver and causes increased blood pressure (
portal hypertension
) in the network of veins that carry blood to the liver from the stomach and other organs of the digestive system. The increased pressure causes bulging of the veins (
varices
) and bleeding in the stomach and esophagus.
As tissue injury progresses in the liver, inflammation and scarring spread and liver function becomes impaired. PBC is slow, chronic, and progressive, eventually causing liver failure, and is a common reason for a liver transplant.
17
The cause of PBC is not known. Some research suggests that the immune system may mistake liver cells for bacteria, such as
Escherichia coli (E. coli)
, especially associated with recurrent urinary tract infections. In addition,
Epstein-Barr virus (EBV)
and
cytomegalovirus
are among the infectious agents associated with bile duct injury. Some drugs and environmental toxins have also been associated with PBC, but there’s little evidence of any direct cause and effect. Progression of the disease may be hastened by changes in bile composition, making the bile ductules more susceptible to injury.
Autoantibodies seen in PBC are not specific to the bile ducts, but attack the tiny energy-producing components within cells called mitochondria,
antimitochondrial antibodies (AMAs)
. Ninety percent of people with PBC have circulating AMAs.
A variant of the disease,
PBC-AIH overlap syndrome
, is characterized by damage from cholangitis and bile duct destruction, along with elevated serum
alanine aminotransferase
, elevated IgG, and
smooth muscle antibodies (SMA)
. A liver biopsy will also show patches of cell death (
necrosis
) around the bile ducts.
18
PBC is 10 times more common in women and mostly affects those ages 35 to 65. But PBC can also occur in young women and in the elderly, adds
Dr. Bodenheimer. There’s a genetic component, with a higher prevalence among first-degree relatives with the disease and among women with family members who have other autoimmune diseases. Notably, sisters of women with PBC may have as much as a fourteen fold greater risk of the disease.
17
Smoking may also increase the risk of PBC.
A majority of women with PBC also have another autoimmune disease, which may be present years before PBC is diagnosed. Between 50 and 75 percent of women with PBC may have
Sjögren’s syndrome. Scleroderma
is also common. About 6 percent of women with PBC also have rheumatoid arthritis, and another 6 percent have thyroid disease. Some experts recommend testing women with thyroid disorders for AMAs.
18
Other autoimmune diseases seen in women with PBC include
pernicious anemia
,
autoimmune thrombocytopenia
,
celiac disease
, and
polymyositis
. Women with PBC may also be at higher risk for liver and other cancers, including lymphoma and cancers of the breasts, ovaries, and thyroid.
17
As with AIH, fatigue may be one of the earliest symptoms of primary biliary cirrhosis, occurring in as many as 78 percent of patients. You may find that you’re unable to exert yourself physically, especially with exercise.
Another common symptom is intense itching (seen in over 60 percent of women), which may worsen at bedtime. The dry mouth of Sjögren’s syndrome can alter taste and hamper swallowing and even vocal cord function. Dry eyes are also common, and there may be enlargement of the parotid glands in women who also have Sjögren’s.
17
Women may also complain of upper abdominal pain on the right side. There may be weight loss and diarrhea with pale, bulky stools. Some women may have brownish hyperpigmentation of the skin. Signs of later disease and liver failure include fluid in the abdomen, gastric bleeding, and jaundice (caused by accumulation of bilirubin in the skin and other tissues).
Advanced PBC is also associated with bone loss (see
page 411
); in some cases, poor absorption of vitamin D (a fat-soluble vitamin) may contribute.
17
The degree of osteoporosis can be severe, with spinal
fractures and compression that result in back pain and muscle spasms. Older women may experience spontaneous (nontraumatic) fractures of the ribs and bone pain.
Up to 60 percent of people with PBC have no symptoms at all (some may even have normal aminotransferase levels). As with AIH, routine blood work may reveal abnormalities in liver test results that alert a woman’s doctor to a problem. In PBC, the red flag is an elevation in the enzyme
alkaline phosphatase
(an enzyme that increases in bile with cholestasis) over normal levels (20 to 70 units per liter, U/L). Cholesterol may also be mildly elevated, due to backflow of bile fats into the blood and increased cholesterol production by liver cells. However, some women may have normal liver enzymes and even in advanced disease may show no outward signs.
However, two physical signs are the hallmarks of PBC: One is yellow, fatty nodules in the skin, caused by abnormal cholesterol metabolism. When these nodules appear around the eyes, they are called
xanthelasmas
, and when they arise in folds or creases of the skin (such as on the hands, elbows, or knees) they are termed
xanthomas
. People with PBC may also display abrasions and breaks in the skin caused by scratching to relieve intense itching (
excoriations
); these scratch marks can often bleed.
17
It’s often difficult to tell PBC from autoimmune hepatitis, because both cause the death of liver cells (necrosis). Blood tests and liver biopsy can help distinguish PBC from other
cholestatic
liver disorders and reveal the extent of damage to bile ducts, granulomas, and fibrosis, along with infiltration of inflammatory cells.
Diagnostic criteria include AMA titers, levels of
alkaline phosphatase
one and a half times the upper limit of normal over a six-month period, and liver histology showing
nonsuppurative destructive cholangitis (CNDC, or syndrome of primary biliary cirrhosis)
and destruction of the
interlobular bile ducts (Canals of Hering)
.
19
A liver biopsy also helps to “stage” PBC to evaluate the progression and extent of liver and bile duct damage, and whether there’s liver cirrhosis. In early disease, with diagnostic blood test results, a liver biopsy may not be needed to diagnose or manage PBC.
AMAs are detected in blood or liver cells using
immunofluorescence
. The amount of AMA does not indicate how severe PBC is or predict how rapidly it will progress. Unlike
antinuclear antibodies (ANAs)
, which often decline after treatment for other autoimmune diseases, AMAs do not respond to treatment.
Cholesterol can also be elevated in PBC; it can top 1,000 mg per deciliter of blood (mg/dl) in late-stage disease.
A majority of women with PBC have other autoimmune disorders (see list), which must be treated separately. Because of the overlap with autoimmune hepatitis, some patients are given a trial of prednisone to help distinguish between the two; PBC does not respond to corticosteroids, but AIH does.
Ursodeoxycholic acid (UDCA)
, or
ursodiol (Actigall, URSO 250, URSO Forte)
is the most common treatment for PBC. Taken orally, it improves symptoms, prolongs survival, and postpones the need for a liver transplant.
Ursodiol lowers levels of alkaline phosphatase, bilirubin, and other liver enzymes and is also prescribed to dissolve certain kinds of gallstones. Side effects may include abdominal pain, indigestion, nausea, chest pain, and itching.
20
Ursodiol can interact with cholesterol-lowering medications, aluminum-based antacids (such as
Rolaids
), and estrogens.
Ursodiol may also be given in combination with corticosteroids, especially budesonide (which is highly absorbed into the liver). PBC-AIH overlap syndrome is treated with corticosteroids or azathioprine.
Newer treatments for PBC are being tested, including
obeticholic acid
, which reduces bile acid synthesis and aids excretion of bile.
“The therapies we have do not cure the disease, and patients not adequately controlled by medication may progress to needing a liver transplant,” says Dr. Bodenheimer.
A liver transplant is the only definitive treatment for end-stage PBC, improving the course of the disease as well as survival. However, it doesn’t eradicate the underlying problem. PBC can also recur after a transplant. One-year survival after transplant is 85 to 90 percent and five-year survival is about 75 percent, with many patients going on to live 20 and more years.
The itching associated with PBC is treated with
cholestyramine resin (Questran, Questran Light)
taken three times a day. Questran is a bile-acid binder that comes in powder form and must be mixed with water or other liquids. The main side effect is constipation. It can also interact with estrogens and progestins, as well as thyroid medications such as
Synthroid
. Questran can also interfere with the normal digestion and absorption of fats and fat-soluble vitamins. The effects of Questran during pregnancy have not been well studied, so women need to take it under a doctor’s supervision.
Ursodiol can interfere with the estrogens in oral contraceptives, so women may need to use a second form of birth control or another method of contraception.
An estimated 25 percent of women with PBC are of childbearing age, and most available evidence indicates they have uneventful pregnancies.
21
In one retrospective study, researchers at a liver center in Toronto assessed outcomes in women who were pregnant at the time of PBC diagnosis or became pregnant after being diagnosed. In 80 percent of patients, liver biochemistry remained normal during pregnancy, and 72 percent had a postpartum biochemical flare. However, no adverse events were seen during pregnancy and postpartum, and risks to the baby don’t seem to be influenced by biochemical disease activity.
21
Biochemical disease activity and severe itching can increase during or after pregnancy.
While there’s no evidence to indicate that ursodiol can harm an unborn baby, it’s not recommended during pregnancy unless clearly needed. It’s not known whether the drug passes into breast milk, so caution is advised for those women who are breast-feeding.
Ursodiol can also interfere with the effectiveness of oral estrogen in hormone therapy, so women are advised to use estrogen patches or cream (see
pages 53
to
54
).
Osteoporosis is a serious concern for postmenopausal women in general, but women with PBC may have a greatly accelerated course. Older women with PBC can have vertebral fractures, spinal compression, loss of height, and sudden rib fractures. Women with PBC may need to be put on drugs such as alendronate to slow bone loss.
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