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Erosions or not in GORD? The potential role of oesophageal cell proliferation
  1. C Calabrese1,
  2. G Cenacchi2,
  3. D Trerè3,
  4. A Fabbri4,
  5. M Derenzini5,
  6. M Miglioli6,
  7. G Di Febo6
  1. 1Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna, Italia
  2. 2Dipartimento Clinico di Scienze Radiologiche e Istocitopatologiche, Università di Bologna, Italia
  3. 3Dipartimento di Patologia Sperimentale, Università di Bologna, Italia
  4. 4Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna, Italia
  5. 5Dipartimento di Patologia Sperimentale, Università di Bologna, Italia
  6. 6Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna, Italia
  1. Correspondence to:
    Dr C Calabrese
    Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna, Policlinico S Orsola-Malpighi, Via Massarenti n 9, 40138 Bologna, Italy; calabrese.c{at}

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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.1,2 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.3 There is no apparent relation between damage and the amount and quality of refluxate.4 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.

Patients gave written informed consent to participate in the study which was approved by the ethics committee. The design was blinded for epithelial cell kinetic evaluation. 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 (table.1).

Table 1

 Demographic, endoscopic, pH monitoring, histological, and ultrastructural data of the studied population (normal healthy controls, and gastro-oesophageal reflux disease patients with erosive oesophagitis (ERD) and those with a normal appearing oesophageal mucosa (NERD))

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.5 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).6 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.7 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) (fig 1).

Figure 1

 Box plots of Ki67-labelling index (LI), LI median (bold line in the box), and interquartile range (upper and lower lines of the box) in human oesophageal mucosa of healthy controls and of patients with erosive oesophagitis (ERD) and a normal appearing oesophageal mucosa (NERD). Whiskers indicate lowest and highest values.

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 repair the damage due to acid and pepsin insults. We believe that the second hypothesis is worth considering in future studies, also because cell replication of basal layers has been hypothesised to be one of the causes implicated in the resistance of the mucosa and in structural epithelial defence. To date, this concept has not been taken into account.



  • Conflict of interest: None declared.