The biochemical hallmarks of PBC are elevated serum ALP and GGT. Mild elevation of serum aminotransferases and increased level of immunoglobulins (mainly IgM) is commonly observed16 while some patients with PBC may have high aminotransferase activities with hypergammaglobulinemia. The changes in biochemical tests reflect in part the severity of histology28,29 and the improvement of biochemical tests after UDCA administration is a strong predictor of long-term prognosis.30-33 In patients without cirrhosis, the degree of ALP elevation is related to the severity of ductopenia and inflammation on liver histology. The increase in aminotransferase and IgG levels reflects the degree of periportal and lobular necroinflammation. The level of serum bilirubin reflect the severity of ductopenia and biliary piecemeal necrosis.29 Hyperbilirubinemia, hypergammaglobulinemia, hypoalbuminemia, and thrombocytopenia are indicators of the development of liver cirrhosis and portal hypertension. As in other chronic cholestatic disease, serum cholesterol levels often elevated.28,29

AMA was described in a patient with PBC in 1965 for the first time,34 and has been regarded as a hallmark of PBC. Serum AMA is highly specific for the diagnosis of PBC and detected in nearly 95% of patients with PBC, while it is detected in normal population in about 1%.1 When AMA is detected in asymptomatic subjects with normal biochemical tests, PBC is already present histologically in 40% of cases,35 and in the remaining patients it is likely to develop in succeeding years.5,16,36,37 The antigenic target of AMA is the E2 subunits of 2-oxo acid dehydrogenase complexes, in particular the pyruvate dehydrogenase complex (PDC)-E2.38 AMA titer may differ by more than 200-fold among patients who have PBC, but in the single patient it remains stable over the years, and has no prognostic value in PBC.39 Therefore, presence of AMA itself rather than its titer is important for the diagnosis. The measurement of serum AMA is typically based on the immunofluorescent techniques (the criteria of positivity, above 1:40), however, with recognition of antigenic determinants, enzyme-linked immunosorbent assays (ELISA) or western blotting assays have been developed. Each assay uses different epitopes, so that interpretation of AMA result should be considered the different sensitivity and specificity of the specific assay. Moreover, 5-10% of PBC patients did not show AMA positivity in their sera, so that liver biopsy is required for the suspicious cases. However, the comparison of AMA-positive PBC and AMA-negative PBC did not show significant differences in terms of clinical features, treatment response or prognosis.40 Antinuclear antibodies (ANA) and anti-smooth muscle antibody (ASMA) are found in about half of PBC patients. ANAs such as anti-gp210 and possibly anti-p62 are detected in some of patients with PBC and may be associated with aggressive disease and poor prognosis.41-43

Histology of PBC is characterized by chronic, nonsuppurative cholangitis that affects interlobular and septal bile ducts. The term "florid duct lesion" is often used when focal lesions show intense inflammatory changes and necrosis around the small bile ducts. The inflammatory infiltrates are comprised of plasma cells, macrophages, polymorphonuclear cells (especially eosinophils) and sometimes epithelioid granulomas.1 The size of the specimen is important and at least 10-15 portal tracts should be present to adequately evaluate cholangitis and ductopenia.

Histologic lesions are classically divided into four stages. Stage I is characterized by portal inflammation with or without florid duct lesion and the inflammation is confined to the portal triads. Stage II is a progression of periportal lesions to involvement of the hepatic parenchyma, which is termed as interface hepatitis. Stage III is characterized by distortion of the hepatic architecture with numerous fibrous septa. Stage IV is defined as cirrhosis with the existence of regenerative nodules.44

The role of liver biopsy for the diagnosis of PBC is limited, when the biochemical liver tests and AMA results are compatible to PBC. However, the information on the stage of PBC and the exclusion of the possibility of overlap syndrome such as autoimmune hepatitis can be obtained from the liver biopsy results. For AMA-negative patients, liver biopsy is mandatory for the diagnosis of PBC. Therefore, balanced decision should be made to do or not to do liver biopsy for suspicious PBC patients after consideration of benefit and risk or cost related to the invasive procedure.

UDCA, the 7-beta epimer of chenodeoxycholic acid, comprised 2% of human bile acid and has several interrelated functions including direct choleretic, anti-inflammatory, and antiapoptotic properties.45 UDCA in a dose of 13-15 mg/kg /day is the only drug approved for PBC treatment by USA FDA (Table 2).27 It decreases serum levels of bilirubin, ALP, aminotransferase, cholesterol and IgM,46,47 and improves liver histology.12,46 A combined analysis of the three largest clinical trials shows that UDCA prolongs survival free of liver transplantation.48 The adequate dosing of UDCA is important. A dose of 13-15 mg/kg/day was superior to either a lower dose of 5-7 mg/kg/day or a higher dose of 23-25 mg/kg/day in biochemical responses and costs.49 A complete response occurs in about 30% of patients treated with PBC, which was defined by normalized biochemical tests and stabilized or improved liver histology.50,51 Serum ALP levels at 6 months after UDCA therapy can be helpful in predicting response to UDCA.30,32 The life expectancy of patients showing the complete response during treatment with UDCA was similar to that of age- and sex-matched healthy controls for up to 20 years.32 However, the disease progresses in many patients who do not show the complete response during UDCA therapy, for whom additional medical treatment is definitely required.

Other drugs for the treatment of PBC have been studied for the past decade as single agents or adjuvant medications. None of these drugs have been found beneficial as single agents, in which colchicines,52,53 methotraxate,54 penicillamine,55 cyclosporine,56 corticosteroid,57 azathioprine,58 mycophenolate mofetil were included.59 Many of these have been used in combination with UDCA to see if further improvement in liver disease can be achieved. Budesonide had been reported to improve liver histology and the biochemical tests of liver function when used with UDCA, but it may worsen osteopenia.60 However, studies were of too short treatment duration to show convincingly whether budesonide will improve survival or not. The additions of colchicines,61 methotraxate62 and silymarin63 to UDCA had no additional benefits compared with UDCA alone.

Bezafibrate and fenofibrate (fibric acid derivatives used to treat hypertriglyceridemia) improved liver biochemical tests in pilot studies.64,65 The proposed mechanism of action of fibric acid derivatives in treatment of PBC involves the regulation of expression of immunomodulatory proteins and lipids,66,67 downregulation of cholesterol 7 alpha-hydroxylase, an enzyme involved in the synthesis of bile acids68 and decrease of multi-drug resistance (MDR) gene through the activation of peroxisome proliferator-activated receptor alpha.69 Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor highly expressed in both the liver and gastrointestinal tract. It has a regulatory role in bile and cholesterol metabolism, and FXR agonists such as INT-747 may hold promise for the new therapeutic option in UDCA-refractory PBC.70 Modification of UDCA (nor-UDCA) with more potent choleretic property than UDCA improved liver biochemistry and histology in MDR2 knockout mouse, an animal model for slcerosing cholangitis, which suggests that translational studies in human are required.71 Tamoxifen decreased alkaline phosphatase levels in two women who were taking it after surgery for breast cancer.72 Although atorvastatin with many antiinflammatory properties was commonly used for control of hypercholesterolemia in PBC, it was not effective for PBC itself.73

Transplantation is the only effective treatment for those with decompensated cirrhosis or liver failure.74 The outcome of liver transplantation in patients with PBC is more favorable than for other liver diseases. The survival rates at one and five years are 92 percent and 85 percent, respectively. About 20-25% of patients with PBC who undergo transplantation have recurrent disease over 10 years. Fortunately, recurrent PBC does not affect patient or graft survival.75