Moons, L.M.G.

Differential expression of the nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) for grading dysplasia in patients with Barrett's oesophagus (Article)

2011-01-01T00:00:00Z

Aims: To investigate expression of nuclear receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR) as a diagnostic tool to improve grading of dysplasia in Barrett's oesophagus patients. Methods and results: Immunostaining was analysed on a total of 192 biopsy samples of 22 Barrett's patients with no dysplasia (ND), 17 with low-grade dysplasia (LGD), 20 high-grade dysplasia (HGD) and 24 with adenocarcinoma (AC). Nuclear FXR expression was observed in 15 of 22 (68%) ND cases versus none of 19 HGD; 3 of 17 (18%); LGD; 5 of 60 (8%) patients with AC (P<0.001). FXR expression was highly specific for non-dysplastic tissue. Nuclear PXR was expressed in 16 of 20 (80%) HGD cases versus two of 16 (13%) LGD cases (PPV 89%). Upon examining adjacent tissue taken from HGD and AC patients, PXR expression was high in samples of all tissue types. Conclusions: Nuclear receptors are expressed differentially during neoplastic progression, with FXR positivity being useful to distinguish ND from dysplasia and AC. PXR nuclear expression is able to separate HGD from LGD and ND. The combination of FXR and PXR also appears to have diagnostic and possibly prognostic value, but future prospective studies are required to investigate their predictive power for neoplastic progression in Barret's oesophagus.

Histological changes in patients with chronic upper gastrointestinal ischaemia (Article)

2010-10-01T00:00:00Z

Aims: Diagnosing chronic upper gastrointestinal ischaemia (CUGI) remains a challenge in clinical practice. Histological examination of biopsy material currently plays no role in the diagnosis of transient CUGI, as little is known about gastrointestinal histology in these patients. The aim of this study was to investigate upper gastrointestinal histology in patients with well-defined CUGI.Methods and results: Consecutive patients suspected of CUGI were included prospectively and underwent a diagnostic work-up existing of upper endoscopy, gastrointestinal tonometry and computed tomography (CT) or magnetic resonance (MR) angiography. Results were discussed in a multidisciplinary team and a consensus diagnosis was made. Endoscopic biopsy samples were taken from the descending duodenum, gastric antrum and corpus, and scored using the Sydney, Vienna, Chiu, Marsh and Operative Link for Gastritis Assessment (OLGA) classifications. Gastropathy was scored present or absent. Seventy-nine patients were analysed in 8 months. CUGI was diagnosed in 41 patients (52%): 36 males, mean age 60 (17-86) years. Prevalence of gastropathy was significantly higher in patients with ischaemia (P = 0.025). No other differences were found between patients with and without ischaemia.Conclusions: Histological examination of biopsy samples plays no definitive role in diagnosing CUGI, but the presence of histological signs of reactive gastropathy can be used to support the clinical diagnosis of ischaemia.

Chronic gastrointestinal ischaemia: Shifting paradigms (Article)

2010-01-01T00:00:00Z

Chronic gastrointestinal ischaemia (CGI) is generally considered to be a rare disease entity. The majority of patients with CGI are only diagnosed after a long period of slowly progressive abdominal symptoms, in some cases with impressive weight loss. These patients may have a broad range of clinical signs and quite often undergo repeated extensive evaluation of their symptoms with negative outcome. The classical triad of symptoms, also known as 'abdominal angina', is defined as the combination of postprandial pain, weight loss due to fear of pain after eating, and an abdominal bruit during physical examination. Recent studies have shed new lights on these long unchallenged concepts. These studies first showed that CGI is more prevalent than previously thought and can occur in patients with both single- and multi-vessel disease. Second, the disease presents with a much wider range in symptoms, and only a minority of patients present with the classical triad. Third, long-term positive outcomes can be achieved after endovascular or surgical revascularisation therapy in large proportion of patients. This knowledge results from a combination of clinical research by dedicated focus groups, the current widespread availability of new imaging techniques such as CT-angiography, the development of new functional tests for assessment of mucosal perfusion, and the evolution of endovascular stenting options. Clinicians diagnosing and treating patients with acute and chronic abdominal conditions have to be aware of these new developments. We therefore here review the new insights on CGI with a focus on epidemiology, pathophysiology, current diagnostics and treatment.

A rare cause of large liver cysts (Article)

2009-04-01T00:00:00Z

Bile acid-stimulated expression of the farnesoid X receptor enhances the immune response in Barrett esophagus (Article)

2008-06-01T00:00:00Z

OBJECTIVES: Barrett's esophagus (BE) is a premalignant condition of the esophagus. It is a consequence of mucosal injury from chronic gastroesophageal reflux in which bile acids are an important toxic component. The farnesoid X receptor (FXR) is a nuclear receptor involved in the regulation of bile acid synthesis, transport, and absorption. FXR activation is also involved in the induction of the innate immune response. This suggests that FXR is involved in the pathogenesis and the inflammation seen in BE. METHODS: mRNA levels of FXR and the FXR-regulated genes, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and chemokines interleukin (IL)-8 and macrophage inflammatory protein 3α (MIP3α), were determined by real time-polymerase chain reaction (RT-PCR). Protein expression was determined by immunohistochemistry. RESULTS: FXR was not expressed in squamous epithelium of healthy subjects (N = 7), but was present in both squamous and columnar epithelium of BE patients. Compared to the squamous epithelium of BE patients, their columnar epithelium displayed a 2.3-fold (P = 0.02) increase in FXR mRNA. Also, IBABP (2.2-fold; P = 0.0029), SHP (2.7-fold; P = 0.007), IL-8 (1.5-fold; P = 0.04), and MIP3α (1.7-fold; P = 0.019) transcription levels were increased. Exposure of esophageal cell line TE7 to deoxycholic acid (DCA) resulted in a similar induction. The induction was abolished by the FXR antagonist guggulsterone. CONCLUSIONS: Expression levels of the bile acid receptor FXR, the bile acid metabolism genes IBABP and SHP, and the chemokines IL-8 and MIP3α are increased in Barrett's epithelium. The in vitro induction of FXR by DCA suggests that bile acids can actively induce the inflammatory response in BE by recruiting immune cells.

Predisposing Role of Immunologic determinants in the Etiology of Barrett’s Esophagus (Doctoral Thesis)

2008-02-22T00:00:00Z

Gastroesophageal reflux disease (GERD) is defined as the presence of symptoms or lesions that can be attributed to reflux of gastric contents into the esophagus. In the Western world, GERD represent one of the most common gastrointestinal problems [1,2]. Cardinal manifestations of GERD are the presence of reflux symptoms such as heartburn, and the presence of gastroesophageal reflux. Heartburn is very common in Western populations with over 40% of the general population having monthly symptoms, and approximately 20% having symptoms on at least a weekly basis [1]. GERD is a spectrum encompassing a broad range of conditions. Of all patients referred for upper GI endoscopy for heartburn as their major symptom, 20-40 % have a reflux esophagitis, 6-12% have a Barrett’s esophagus (BE), and the remaining have endoscopynegative GERD [3-10]. The diagnosis of severe reflux esophagitis is important as treatment can prevent the development of reflux related complications such as bleeding, stricture, and ulcers. Another important complication of chronic exposure to gastroesophageal reflux is the development of esophageal adenocarcinoma (EAC). Gastroesophageal reflux is considered to be the key element in the development of EAC since severe, longstanding, and frequent episodes of gastroesophageal reflux is associated with a seven- to eightfold increased risk of EAC.

The homeodomain protein CDX2 is an early marker of Barrett's oesophagus (Article)

2004-01-01T00:00:00Z

BACKGROUND: In Barrett's oesophagus (BO), squamous epithelium is replaced by specialised intestinal epithelium (SIE). Transcription factors associated with intestinal differentiation, such as CDX2, may be involved in BO development. AIM: To investigate CDX2 expression in BO, squamous epithelium, and oesophageal adenocarcinoma (ADC). METHODS: CDX2 expression was assessed in 245 samples-167 biopsies of the columnar lined segment and 38 squamous epithelial biopsies of 39 patients with histologically confirmed BO (10 with ADC). Forty biopsies from 20 patients with reflux oesophagitis (RO) without BO were also evaluated. CDX2 protein was investigated immunohistochemically in 138 biopsies from 16 patients with BO, four with ADC, and 20 with RO. Cdx2 and Muc2 mRNA were detected semiquantitatively using 88 BO biopsies and squamous epithelium from 19 BO patients, and when present from ADC. RESULTS: SIE was present in 53/79 biopsies from the columnar lined segment; CDX2 protein was seen in all epithelial cells, but not in biopsies containing only gastric metaplastic epithelium (26/79), or in squamous epithelium (0/40) of patients with RO. Cdx2 mRNA was detected in all biopsies with goblet cell specific Muc2 transcription-indicative of SIE. Low Cdx2 mRNA expression was seen in 6/19 squamous epithelium samples taken 5 cm above the squamocolumnar junction of BO patients. CONCLUSION: CDX2 protein/mRNA is strongly associated with oesophageal SIE. Cdx2 mRNA was present in the normal appearing squamous epithelium of one third of BO patients, and may precede morphological changes seen in BO. Therefore, pathways that induce Cdx2 transcription in squamous epithelial cells may be important in BO development.