A stunning year for advances in biliary tract disease

Abstract

For the last several years, I have had the privilege of editing the biliary section for Current Opinion in Gastroenterology. However, this has been my favorite year. The year has shed light on many clinical and scientific problems in biliary tract pathobiology. I am excited to share these discoveries with you, as highlighted in the following paragraphs. Perhaps the most significant advance was the publication by Bridgewater et al. (pp. 258–261) establishing a new platform of care for patients with advanced biliary tract cancer, namely administration of cisplatin and gemcitabene. For the first time in medical oncology, we now have a standard of care for these cancers. The authors not only highlight this study but also point out that the data cannot be extrapolated to the adjuvant setting. Hopefully, the success of this study will spur additional clinical trials in this disease. Baron (pp. 262–267) describes a unique experience with removable, covered metallic stents for benign biliary tract disease. Heretofore, metallic stents were only used for malignant biliary strictures because they were ‘permanent’. With the advent of these removable covered stents, we now have new armamentarium to attack recalcitrant and problematic benign biliary strictures. The author’s success with these stents is described in detail. We are beginning to realize that cholangiocytes have an ‘activated phenotype’ that contributes to liver disease progression, especially biliary fibrosis. Furthermore, this phenotype is retained by cholangiocarcinoma cells explaining the highly desmoplastic nature of these cancers. Omenetti and Diehl (pp. 268–275) in their pioneering work suggest that Hedgehog and platelet-derived growth factor signaling pathways contribute to the activated cholangiocyte phenotype and associated periductular fibrosis. The fibrosis is due to cross talk between activated cholangiocytes and myofibroblasts. Al Sirica (pp. 276–284) explores similar cross talk between cholangiocarcinoma cells and cancer-associated fibroblasts as a key process in biliary tract cancer progression. These mediators are potential therapeutic targets for the treatment of benign and malignant biliary tract disease. Although ursodeoxycholic acid is effective for the treatment of primary biliary cirrhosis (PBC), not all patients respond. Thus, there is an unmet need for new therapy. Following identification of the farnesoid X receptor (FXR) nuclear receptor in biliary physiology, studies in humans employing an FXR agonist have been long awaited. Lindor (pp. 285–288) summarizes the role of FXR agonists in liver physiology relevant to the biliary tract and the initial results of a clinical trial in PBC employing the FXR agonist obeticholic. The results are promising, displaying a significant reduction in serum cholestatic biomarkers. These biomarkers, such as the serum alkaline phosphatase, have been verified as indicators of disease activity in PBC. We await further trials, but FXR-directed therapy with obeticholic appears to be disease modifying in this liver disease population. All clinicians are aware that cholestasis is associated with pruritus. However, the nature of the pruritus mediator has remained elusive. Elferink et al. (pp. 289–293) provides compelling data that lysophosphatidic acid (LPA) is the serum mediator of pruritus. A serum enzyme autotoxin is responsible for the generation of LPA from lysophosphatidyl choline. This is as an extremely exciting observation. We now have a molecule that we can measure and, hopefully, therapeutically modulate to relieve pruritus in patients with cholestasis. Polycystic liver disease and polycystic liver kidney disease are unique forms of biliary tract disease characterized by numerable hepatic cysts lined by biliary epithelium. The cysts progressively enlarge over time, causing mass-like symptoms in a subset of patients. The genotypes for these diseases have been defined, but an established medical therapy is unavailable. Drenth et al. (pp. 294–300) describe the use of somatostatin analogues for these patients, which appear to be successful by decreasing biliary epithelial cell secretion into these cysts. The failure of mammalian target of rapamycin inhibitors to modify disease progression is also reviewed. Finally, an emerging controversy has arisen regarding the risk of recurrent primary sclerosing cholangitis (PSC) in patients undergoing liver donor transplantation for this disease. The reported data from Japan suggest a high rate for recurrent PSC. Graziadei (pp. 301–305) reviews the existing literature and notes the limitations of the data. Clearly, there is yet insufficient information to alter clinical practice, and PSC patients should continue to be acceptable candidates for live donor liver transplantation.