(HEPATOLOGY selleck compound 2013) Primary biliary cirrhosis (PBC) is a chronic liver disease that is presumably caused by autoimmunity. The detection of serum antimitochondrial antibodies (AMA) and increased levels

of immunoglobulin M (IgM) are biochemical features of this disease. Histopathologically, it is characterized by portal inflammation and the slow progressive destruction of the portal interlobular bile ducts due to chronic nonsuppurative cholangitis. The loss of bile ducts leads to cholestasis, which leads to further hepatic damage, fibrosis, cirrhosis, and ultimately, liver failure.1 Ursodeoxycholic acid (UDCA) is the only Food and Drug Administration (FDA)-approved drug and the first-line medicine for the treatment of PBC.2 UDCA has been shown to improve serum levels of biliary enzymes and IgM, and may slow the histologic progression to liver cirrhosis.3-6 The mechanisms of the anticholestatic and antiinflammatory effects of UDCA have been reported to be due to the activation of the canalicular bile salt export pump (BSEP), canalicular

multidrug resistance protein 3 (MDR3; ATP-binding cassette transporter B4 [ABCB4]) and basolateral multidrug resistance-associated protein 4 (MRP4 [ABCC4]).7 In addition, the replacement of hydrophobic bile acids with hydrophilic UDCA appears to attenuate the damage to hepatocytes and biliary cells.2 It has been reported that about two-thirds of patients treated with UDCA in the early stage of the disease could have a normal life

expectancy without additional therapies.8 However, the remaining patients are not sufficiently controlled MDV3100 with UDCA monotherapy and additional therapeutic approaches have been necessary. Immunosuppressive medication is not recommended as the first-line, MCE alternative drug for PBC, but budesonide, a nonhalogenated glucocorticoid with a high first-pass metabolism, and/or mycophenolate mofetil, an inhibitor of the purine biosynthetic pathway which is critical to lymphocytic proliferation and activation, are sometimes used in patients who fail to respond to UDCA.9, 10 However, the effects of these immunosuppressive agents remain controversial.11, 12 The farnesoid X receptor (FXR; NR1H4) agonist, 6-ethyl-chenodeoxycholic acid, has been administered to PBC patients that exhibit incomplete responses to UDCA in a phase II clinical trial. This trial exhibited anticholestatic effects and serum alkaline phosphatase (ALP) levels were reduced, but pruritus occurs at the higher doses.13 In 1999, Iwasaki et al.14 introduced the effectiveness of a hypolipidemic agent, bezafibrate, on the reduction of serum ALP and IgM levels in precirrhosis PBC patients, and recently, combination therapy with UDCA and bezafibrate is being recognized as a beneficial treatment for PBC that is refractory to UDCA monotherapy.