Primary Biliary Cirrhosis — Claire Altschuler

Primary Biliary Cirrhosis: Management Strategies

By Richard M. Green MD

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver, which predominantly affects middle-aged women. The disease is slowly progressive and can result in the development of cirrhosis and end-stage liver disease. Although the diagnosis of PBC is often made when the patient is asymptomatic, common symptoms include fatigue, pruritus, fat-soluble vitamin deficiencies, osteoporosis, skin xanthomata, complications of portal hypertension and/or liver failure. Many autoimmune diseases including thyroid disease, Sjogren's syndrome, SICCA syndrome, Raynaud's phenomenon and celiac disease are associated with PBC and can cause significant co-morbidity.

Diagnosis

The diagnosis of PBC frequently follows the detection of an elevated serum alkaline phosphatase. The antimitochondrial antibody (AMA) is also elevated in 90-95 percent of patients. Serum immunoglobulin fractions in PBC are characterized by an elevation of IgM, but immunoglobulin testing is not routinely required.

Ultrasound examination or other imaging studies of the liver and biliary tree are typically normal in early PBC but may be useful in excluding other causes of cholestasis. Liver biopsy may reveal granulomatous destruction of the interlobular bile ducts, which leads to progressive ductopenia. The liver histopathology progresses to the development of fibrosis and cirrhosis. In addition, a subgroup of patients may have clinical and biochemical features of PBC and elevated anti-nuclear antibody (ANA) titers, an entity which has been termed "autoimmune cholangitis."

Pathogenesis

The pathogenesis of PBC is poorly understood, although autoimmune mechanisms seem to play an important role. T-cell lymphocyte infiltrates in the portal tract have led many investigators to focus on the role of these cells in the pathogenesis. As mentioned above, the AMA is frequently an early serologic marker for PBC. The autoantigen for the AMA is the E2 component of the mitochondrial PDC/OGDC/BCOADC multienzyme complex. (The natural history of AMA-positive and AMA-negative PBC appears to be similar.)

Other autoantibodies may also be present, although it is unclear whether these autoantibodies are of primary import for the pathogenesis of PBC or whether they represent an epiphenomenon.

Abnormalities of cytokine expression and environmental factors have also been hypothesized to be important for the pathogenesis of PBC. And there appears to be a significant geographical variation in the incidence of PBC, with an especially high prevalence in the north of England.

Therapy

The current goals of therapy are to slow disease progression, treat symptoms and avoid the systemic complications of PBC. The recommended treatment is the hydrophilic bile acid ursodeoxycholic acid (UDCA) 13-15 mg/kg daily. Although some studies question the effectiveness of UDCA, several randomized, controlled trials show that it improves liver function abnormalities and delays the time to liver transplantation or death. It also has a very safe side-effect profile. It may also be effective for treating the pruritis associated with PBC. UDCA does not lead to complete resolution of the disease, however; and, even with treatment, PBC may eventually progress to end-stage liver disease.

Pruritis associated with PBC may be treated with UDCA or oral anion-exchange resins such as cholestyramine. (Cholestyramine should not be taken within 4 hours of UDCA as it may bind the UDCA and prevent absorption.) Rifampicin has been shown to decrease pruritis, while naloxone, naltrexone, UV light exposure and plasmapheresis can been used for refractory patients.

Immunosuppressive therapies have been tried in PBC patients, but have not been proven to prolong survival and should be regarded as investigational at this time.

Severe osteoporosis is common in patients with PBC. Although patients' metabolism of vitamin D is normal, malabsorption of both calcium and vitamin D may result in decreased bone mass. The recommended treatment includes calcium supplementation, exercise and cessation of smoking. For patients who demonstrate malabsorption of fat-soluble vitamins, supplementation of vitamins A, D, E and K may be indicated. Hormonal replacement therapy (HRT) and bisphosphonates should also be considered.

Although the total serum cholesterol may be markedly elevated in patients with PBC and xanthomata may form, retrospective studies do not suggest an increase in atherosclerotic heart disease associate with PBC. Because of this, cholesterol-lowering agents should not be routinely administered to these patients.

Disease Progression

The most reliable determinants of prognosis in PBC are the height of the serum bilirubin and the Mayo risk score. Although the progression of PBC is quite variable, once evidence of liver failure develops, it can progress rapidly. Therefore, PBC is a common indication for liver transplantation, and is recommended for patients with liver failure. In rare cases, liver transplantation may also be required for patients with uncontrollable pruritus and severe osteoporosis.

A small number of patients with PBC can develop presinusoidal portal hypertension before becoming cirrhotic. These patients can be treated with shunt surgery, which has a lower morbidity and mortality rate than transplant surgery. The initial medical and endoscopic management of portal hypertension and variceal bleeding in this subgroup of patients is similar to that of cirrhotic patients, but medical failures can potentially be managed with shunt surgery.

PBC is a progressive liver disease, however, accurate diagnosis and appropriate medical therapy can slow disease progression, control some symptoms and prevent complications. In end-stage liver disease, timely evaluation for liver transplantation is essential for decreasing disease morbidity and mortality.

Primary Biliary Cirrhosis: Management Strategies

Diagnosis

Pathogenesis

Therapy

Disease Progression

Recommended Reading