Activation of Wnt signalling promotes development of dysplasia in Barrett's oesophagus.

Barrett's oesophagus is a precursor of oesophageal adenocarcinoma, via intestinal metaplasia and dysplasia. Risk of cancer increases substantially with dysplasia, particularly high-grade dysplasia. Thus, there is a clinical need to identify and treat patients with early-stage disease (metaplasia and low-grade dysplasia) that are at high risk of cancer. Activated Wnt signalling is critical for normal intestinal development and homeostasis, but less so for oesophageal development. Therefore, we asked whether abnormally increased Wnt signalling contributes to the development of Barrett's oesophagus (intestinal metaplasia) and/or dysplasia. Forty patients with Barrett's metaplasia, dysplasia or adenocarcinoma underwent endoscopy and biopsy. Mice with tamoxifen- and ß-naphthoflavone-induced expression of activated ß-catenin were used to up-regulate Wnt signalling in mouse oesophagus. Immunohistochemistry of ß-catenin, Ki67, a panel of Wnt target genes, and markers of intestinal metaplasia was performed on human and mouse tissues. In human tissues, expression of nuclear activated ß-catenin was found in dysplasia, particularly high grade. Barrett's metaplasia did not show high levels of activated ß-catenin. Up-regulation of Ki67 and Wnt target genes was also mostly associated with high-grade dysplasia. Aberrant activation of Wnt signalling in mouse oesophagus caused marked tissue disorganization with features of dysplasia, but only selected molecular indicators of metaplasia. Based on these results in human tissues and a mouse model, we conclude that abnormal activation of Wnt signalling likely plays only a minor role in initiation of Barrett's metaplasia but a more critical role in progression to dysplasia.

Improvement of parenteral nutrition-associated cholestasis in an adult using fish oil-based parenteral nutrition.

Parenteral nutrition-associated cholestasis (PNAC) is a severe complication of parenteral nutrition. Standard feed preparations contain soybean and olive oil that are rich in ω-6 polyunsaturated fats, and which studies suggest can be hepatotoxic. Preparations containing fish oil, rich in ω-3 polyunsaturated fats, may be hepatoprotective and have been used in the critical care setting as immunotherapy. A case demonstrating dramatic improvement in liver function and overall clinical condition in an adult with PNAC and intestinal failure within 8 weeks of changing to a fish oil-based parenteral feed is reported. As far as is known, this is the first report of an adult patient whose parenteral nutrition-associated liver disease resolved after a parenteral nutrition lipid emulsion was changed to the fish oil-containing emulsion, SMOFlipid.