Primary biliary cirrhosis (PBC) is an autoimmune liver disorder characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis, cirrhosis, and liver failure. Patients usually are asymptomatic at presentation but may experience fatigue or have symptoms of cholestasis (eg, pruritus, steatorrhea) or cirrhosis (eg, portal hypertension, ascites). Laboratory tests reveal cholestasis, increased IgM, and, characteristically, antimitochondrial antibodies in the serum. Liver biopsy may be necessary for diagnosis and staging. Treatment includes ursodeoxycholic acid, cholestyramine (for pruritus), supplementary fat-soluble vitamins, and, ultimately for advanced disease, liver transplantation.
PBC is the most common liver disease associated with chronic cholestasis in adults. Most (95%) cases occur in women aged 35 to 70. PBC also clusters in families. A genetic predisposition, perhaps involving the X chromosome, probably contributes. There may be an inherited abnormality of immune regulation. An autoimmune mechanism has been implicated; antibodies to antigens located on the inner mitochondrial membranes occur in > 95% of cases. These antimitochondrial antibodies (AMAs), the serologic hallmarks of PBC, are not cytotoxic and are not involved in bile duct damage. PBC is associated with other autoimmune disorders, such as RA, systemic sclerosis, Sjögren's syndrome, CREST syndrome, autoimmune thyroiditis, and renal tubular acidosis.
T cells attack the small bile ducts. CD4 and CD8 T lymphocytes directly target biliary epithelial cells. The trigger for the immunologic attack on bile ducts is unknown. Exposure to foreign antigens, such as an infectious (bacterial or viral) or toxic agent, may be the instigating event. These foreign antigens might be structurally similar to endogenous proteins (molecular mimicry); then the subsequent immunologic reaction would be autoimmune and self-perpetuating. Destruction and loss of bile ducts lead to impaired bile formation and secretion (cholestasis). Retained toxic materials such as bile acids then cause further damage, particularly to hepatocytes. Chronic cholestasis thus leads to liver cell inflammation and scarring in the periportal areas. Eventually, hepatic inflammation decreases as hepatic fibrosis progresses to cirrhosis.
Autoimmune cholangitis is sometimes considered to be a separate disorder. It is characterized by autoantibodies, such as antinuclear antibodies (ANAs), anti–smooth muscle antibodies, or both and has a clinical course and response to treatment that are similar to PBC. However, in autoimmune cholangitis, AMAs are absent.
Symptoms and Signs
About half of patients present without symptoms. Symptoms or signs may develop during any stage of the disease and may include fatigue or reflect cholestasis (and the resulting fat malabsorption, which may lead to vitamin deficiencies and osteoporosis), hepatocellular dysfunction, or cirrhosis.
Symptoms usually develop insidiously. Pruritus, fatigue, and dry mouth and eyes are the initial symptoms in > 50% of patients and can precede other symptoms by months or years. Other initial manifestations include right upper quadrant discomfort (10%); an enlarged, firm, nontender liver (25%); splenomegaly (15%); hyperpigmentation (25%); xanthelasmas (10%); and jaundice (10%). Eventually, all the features and complications of cirrhosis occur. Peripheral neuropathy and other autoimmune disorders associated with PBC may also develop.
In asymptomatic patients, PBC is detected incidentally when liver function tests detect abnormalities, typically elevated levels of alkaline phosphatase and γ-glutamyl transpeptidase (GGT). PBC is suspected in middle-aged women with classic symptoms (eg, unexplained pruritus, fatigue, right upper quadrant discomfort, jaundice) or laboratory results suggesting cholestatic liver disease: elevated alkaline phosphatase and GGT but minimally abnormal aminotransferases (ALT, AST). Serum bilirubin is usually normal in the early stages; elevation indicates disease progression and a worsening prognosis.
If PBC is suspected, liver function tests and tests to measure serum IgM (increased in PBC) and AMA should be done. ELISA tests are 95% sensitive and 98% specific for PBC; false-positive results can occur in autoimmune hepatitis (type 1). Other autoantibodies (eg, ANAs, anti–smooth muscle antibodies, rheumatoid factor) may be present. Extrahepatic biliary obstruction should be ruled out. Ultrasonography is often done first, but ultimately MRCP and sometimes ERCP are necessary. Unless life expectancy is short or there is a contraindication, liver biopsy is usually done. Liver biopsy confirms the diagnosis; it may detect pathognomonic bile duct lesions, even in early stages. As PBC progresses, it becomes morphologically indistinguishable from other forms of cirrhosis. Liver biopsy also helps stage PBC, which has 4 histologic stages:
Autoimmune cholangitis is diagnosed when AMAs are absent in a patient who otherwise would be diagnosed with PBC.
Usually, PBC progresses to terminal stages over 15 to 20 yr, although the rate of progression varies. PBC may not diminish quality of life for many years. Patients who present without symptoms tend to develop symptoms over 2 to 7 yr but may not do so for 10 to 15 yr. Once symptoms develop, median life expectancy is 10 yr. Predictors of rapid progression include the following:
The prognosis is ominous when pruritus disappears, xanthomas shrink, jaundice develops, and serum cholesterol decreases.
All alcohol use and hepatotoxic drugs should be stopped. Ursodeoxycholic acid (15 mg/kg po once/day) decreases liver damage, prolongs survival, and delays the need for liver transplantation. About 20% of patients do not have biochemical improvement after ≥ 4 mo; they may have advanced disease and require liver transplantation in a few years. Other drugs proposed to decrease liver damage have not improved overall clinical outcomes or are controversial.
Pruritus may be controlled with cholestyramine 6 to 8 g po bid. This anionic-binding drug binds bile salts and thus may aggravate fat malabsorption. If cholestyramine is taken long-term, supplements of fat-soluble vitamins should be considered. Cholestyramine can decrease absorption of ursodeoxycholic acid, so these drugs should not be given simultaneously.
Some patients with pruritus respond to ursodeoxycholic acid and ultraviolet light; others may warrant a trial of rifampin or an opioid antagonist, such as naltrexone. Patients with fat malabsorption due to bile salt deficiency should be treated with vitamins A, D, E, and K. For osteoporosis, weight-bearing exercises, bisphosphonates, or raloxifene may be needed in addition to Ca and vitamin D supplements. In later stages, portal hypertension (see Approach to the Patient With Liver Disease: Portal Hypertension) or complications of cirrhosis (see Fibrosis and Cirrhosis: Complications) require treatment.
Liver transplantation has excellent results. The general indication is decompensated liver disease (uncontrolled variceal bleeding, refractory ascites, intractable pruritus, and hepatic encephalopathy). Survival rates after liver transplantation are > 90% at 1 yr, > 80% at 5 yr, and > 65% at 10 yr. AMAs tend to persist after transplantation. PBC recurs in 15% of patients in the first few years and in > 30% by 10 yr. So far, recurrent PBC after liver transplantation has a benign course. Cirrhosis rarely occurs.
Last full review/revision August 2007 by Eldon A. Shaffer, MD