Results from GWAS have the potential to be translated in biological knowledge and, hopefully, clinical application. There are a number of immune pathways highlighted in GWAS that may have therapeutic implications in PBC and in other autoimmune diseases, such as the anti-interleukin-12/interleukin-23, nuclear factor-kb, tumor necrosis factor, phosphatidylinositol LY2157299 order signaling
and hedgehog signaling pathways. Further areas in which GWAS findings are leading to clinical applications either in PBC or in other autoimmune conditions, include disease classification, risk prediction and drug development. In this review we outline the possible next steps that may help accelerate progress from genetic studies to the biological knowledge that would guide the development of predictive, preventive, or therapeutic measures in PBC. Primary
biliary cirrhosis (PBC) click here is the most common autoimmune liver disease and is considered a model of organ-specific autoimmune diseases . It is characterized by loss of tolerance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients, the development of fibrosis and cirrhosis. Patients with PBC may present with symptoms as fatigue, pruritus and/or jaundice, but the majority of them are asymptomatic at diagnosis. Glutamate dehydrogenase A diagnosis of PBC can be made with confidence in adult patients with otherwise unexplained elevation of alkaline phosphatase and presence of antimitochondrial antibodies (AMAs) at a titre of ≥1:40 and/or AMA type M2. A liver biopsy is not essential for the diagnosis of PBC in these patients, but allows activity and stage of the disease to be assessed. Progression of disease in PBC is variable with a substantial proportion of patients eventually developing cirrhosis and liver failure. The only licensed therapy for PBC is ursodeoxycholic acid (UDCA) which has been demonstrated to exert anticholestatic
effects in various cholestatic disorders. Several potential mechanisms and sites of action of UDCA have been unraveled in clinical and experimental studies which might explain its beneficial effects. These include protection of injured cholangiocytes against the toxic effects of bile acids, particularly at an early stage; stimulation of impaired hepatocellular secretion by mainly posttranscriptional mechanisms, including stimulation of synthesis, targeting and apical membrane insertion of key transporters, more relevant in the advanced cholestasis; stimulation of ductular alkaline choleresis and inhibition of bile acid-induced hepatocyte and cholangiocyte apoptosis.