Introduction Barrett’s metaplasia (BM) is the main risk factor for oesophageal adenocarcinoma, a cancer which carries a mortality of >50% at 12 months. Refluxate containing gastric and bile acids seems to be causative for inflammation at the lower oesophagus, but it is not known how this induces replacement of stratified squamous epithelium (SSQE) with columnar epithelium at a molecular level.There is likely to be a progenitor cell population replacing denuded epithelium, although the origin of these cells has not been proven. Genes that play a role in gut tissue patterning during embryogenesis have received attention. One such ‘master switch’ our laboratory is investigating encodes the hepatocyte nuclear factor 4 alpha (HNF4α) transcription factor.

Methods We optimised an immunohistochemistry protocol for demonstrating HFN4α on formalin-fixed paraffin-embedded slides of human tissue. This protocol was applied to forceps biopsy specimens of normal oesophagus, gastro-oesophageal junction (GOJ), stomach, ileum, colon and BM (UK REC reference: 13/YH/0197). Tissues were examined from at least 3 different patients per anatomical site.

Results In healthy tissues, nuclear HNF4α positive immunostaining was demonstrated in stomach, ileum and colonic epithelium, but not in normal SSQE in the oesophagus. At the GOJ, there was clear delineation between HNF4α positive nuclei in the columnar gastric cardia mucosa, and negative HNF4α staining of SSQE. In contrast, the columnar epithelial nuclei in BM were consistently positive.

• Download figure
• Open in new tab
• Download powerpoint

Abstract PTU-156 Figure 1

Conclusion HNF4α transcription factor is demonstrable in BM, but not SSQE. We are not aware that this HNF4α gastrointestinal distribution has been previously published. HNF4α is likely to be a key transcription factor in the pathogenesis of BM.

Previous work in our laboratory with a mouse explant tissue culture model has shown that another candidate transcription factor responsible for BM (Cdx2) was insufficient to induce an intestinal phenotype, whereas HNF4α induced villin, K18, trefoil factor 3 and mucin 5AC. We propose a 2-hit hypothesis for the development of BM:

1. induction of HNF4α (which initially converts the oesophageal SSQE to columnar epithelium) and

2. Cdx2 (which causes intestinalisation of the columnar epithelium).

Demonstration of HNF4α in BM but not SSQE is supportive of this theory.

Disclosure of Interest None Declared.