OBJECTIVES: Objectively diagnosing non-erosive refl ux disease (NERD) is still a challenge. We aimed to evaluate the use of in-vivo confocal laser endomicroscopy (CLE) to examine the microalterations of the esophagus in patients with NERD and its relationship with refl ux episodes monitored by multiple intraluminal impedance-pH (MII-pH). METHODS: Patients with gastroesophageal refl ux symptoms completed refl ux disease questionnaires. NERD was de- termined by negative gastroscopy. Patients without refl ux symptoms were recruited as controls. Pilot clini- cal study was followed by prospective controlled blinded study. All subjects were examined by white-light mode of the endoscopy followed by the standard CLE mode and then MII-pH monitoring. The microalter- ations seen on CLE images and the correlation between CLE features and refl ux episodes were evaluated, the correlation between CLE and transmission electron microscope (TEM) data was also analyzed. RESULTS: On CLE images, NERD patients had more intrapapillary capillary loops (IPCLs) per image than did controls (8.29 ± 3.52 vs. 5.69 ± 2.31, P = 0.010), as well as the diameter of IPCLs (19.48 ± 3.13 vs. 15.87 ± 2.21 μ m, P = 0.041) and intercellular spaces of squamous cells (3.40 ± 0.82 vs. 1.90 ± 0.53 μ m, P = 0.042). The receiver operating characteristic analysis indicated that IPCLs number (optimal cut- off > 6 per image, area under the curve (AUC ) 0.722, 95 % confi dence interval (CI) 0.592 – 0.853, sensitivity 67.7 % , specifi city 71.6 % ), IPCLs diameter (optimal cutoff > 17.2 μ m, AUC 0.847, 95 % CI 0.747 – 0.947, sensitivity 81 % , specifi city 76 % ), and the intercellular spaces of squamous cells (optimal cutoff > 2.40 μ m, AUC 0.935, 95 % CI 0.875 – 0.995, sensitivity 85.7 % , specifi city 90.5 % ) diagnosed NERD with reasonable accuracy. Combined features of dilatation of intercellular space plus increased IPCLs provided 100 % specifi city in the diagnosis of NERD patients. The intercellular spaces of squamous cells observed on CLE were highly related to that on TEM fi ndings ( r = 0.75, P < 0.001). Multivariate progressive regression analysis showed that acidic refl ux, especially in the supine position, was related to the increased number and dilation of IPCLs in the squamous epithelium ( b = 0.063, t = 2.895, P = 0.038 and b = 0.156, t = 1.023, P = 0.04). CONCLUSIONS: CLE represents a useful and potentially signifi cant improvement over standard endoscopy to examine the microalterations of the esophagus in vivo . Acidic refl ux is responsible for the microalterations in the esophagus of patients with NERD.

第一署名医院：山东大学齐鲁医院；山东省济南市中心医院