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The aim of this study was to assess the yield of endoscopic evaluation in isolated unintentional weight loss (UWL) patients compared with patients with weight loss and additional symptoms or signs.A retrospective review of all patients who underwent an endoscopic evaluation for the investigation of UWL at Soroka University Medical Center between 2006 and 2012. Data on clinical indication, endoscopic, and laboratory finding were retrieved. Severe inflammation, ulcers, achalasia, and neoplasias were considered clinically significant endoscopic findings (CSEF) that could explain weight loss. Detection rates of CSEF were compared between endoscopic studies for which UWL was the sole indication (group 1) and those performed for UWL and at least one other indication (group 2).During the study period, 1843 patients with UWL were evaluated with 2098 endoscopic procedures. Of these, 1540 underwent esophagogastroduodenoscopy (EGD) and 558 underwent colonoscopy. EGD was performed in 229 (14.8%) patients in group 1 (mean age: 60.9±16.4, 43.3% men), and in 1311 (85.2%) patients in group 2 (mean age: 60.5±18.5, 45% men). Pathological endoscopic findings were identified in 712 (46%) EGDs. Of these, 155 (10%) studies detected significant outcomes: six (3.9%) in group 1 and 149 (96.1%) in group 2. Of the 558 colonoscopies performed, 105 (18.8%) were performed in group 1 (mean age: 61.7±17.5, 43% men) and 453 (82.2%) in group 2 patients (mean age: 62.9±14.6, 49% men). Abnormal findings were found in 190 (33.8%) of the procedures. CSEF were found in 34 (6%) patients: two in group 1 and 32 in group 2.The diagnostic yield of endoscopy for investigation of patients with UWL is non-negligible, and should be considered as part of its baseline evaluation, especially in older individuals and those who present with other gastrointestinal manifestations.