Erosions or not in GERD? The potential role of esophageal cell kinetics

Gastro-oesophageal reflux is an almost universal daily occurrence, but only a small percentage of the population develops gastro-oesophageal reflux disease (GORD) and, among them, a small number develop erosive oesophagitis (ERD) or one of its complications. It is well accepted that the pathophysiology of GORD is related to failure of antireflux mechanisms but several phenomena are not fully explained on the basis of this sequence. There is no apparent relation between damage and the amount and quality of refluxate. It is not known why the same amount of refluxate determines GORD in one patient and not in another.2 It is also unclear whether there is a relation between these unexplained questions and the possible influence of proliferative responses of epithelial proliferating cells to damage. Hence we evaluated cell proliferation of the oesophageal epithelium using Ki67 immunostaining in normal subjects and in patients with GORD, with or without erosions. Thirty five subjects were enrolled: nine were healthy voluntary controls with normal pH testing and normal endoscopic, histological, and ultrastructural patterns. Twenty six patients were affected by GORD, defined as frequent heartburn for at least a year, and abnormal 24 hour pH, histological, and ultrastructural parameters. Of these 26 patients, 13 had a normal appearing oesophageal mucosa at endoscopy (NERD) while 13 had ERD. All subjects underwent gastroscopy; six biopsies were obtained within the lower 5 cm of the oesophagus from areas of macroscopically intact oesophageal mucosa. The presence of oesophagitis was graded according to the Los Angeles classification. pH parameters were not statistically different between NERD and ERD. At transmission electron microscopy (TEM), all patients with GORD, with or without erosions, showed ultrastructural signs of damage, defined by the presence of dilation of intercellular spaces (>0.74 µm). No significant differences were observed between the two groups. For assessment of the proliferative activity of epithelial cells, we used the immunohistochemical approach based on the Ki67 marker of cell proliferation which provides an accurate estimate of the cell growth fraction. Ki67-labelling index (LI) ranged from 8.9% to 74.4% among all patients (mean (SD) 33.5 (19.7)%; median 27.8%). Mean Ki67-LI values for the three groups of patients (normal, NERD, and ERD) were 62.2%, 29.8%, and 17.2%, respectively, and the difference among the groups was significant (p<0.01). This study was carried out on biopsies taken only in normal appearing mucosa at endoscopy. In this way we studied the behaviour of the mucosa exposed to chronic acid insult but far from erosions, and in particular from reparative changes secondary to lack of superficial mucosa where basal cell hyperplasia and elongation of papillae have been reported.8 We found that in all patients, oesophageal epithelium exposed to chronic acid exposure in normal appearing mucosa had a proliferation rate inferior to that of normal subjects: GORD patients had cell kinetics that were reduced to 50% and 25% in NERD and ERD patients, respectively. In order to explain the reduced proliferation rate observed in GORD patients, two different pathogenetic mechanisms can be suggested. Cell proliferation changes could be a consequence of either chronic cell damage or an intrinsic reduced ability of cells to proliferate, the one mechanism not excluding the other. Regarding the first hypothesis, little is known of the behaviour of the oesophageal mucosa stressed by chronic acid and pepsin insult. The second pathogenetic hypothesis concerns the existence of an individual predisposition to stronger or weaker cell proliferative efficacy of epithelial mucosa to chronic insults. This concept supports the idea that in genetically susceptible individuals, chronic acid and pepsin exposure may trigger or accelerate the development of ERD while in others more efficient cell proliferative activity can repa...