This was a case-control study conducted at the Regional Hospital of Durres, the second main district in Albania after Tirana, the capital. Two hundred and forty-eight cases and 273 controls were enrolled in the study during the period 07 January 2013 – 30 June 2014. Controls were selected from Durres catchment areas. The study was approved by the Department of Biomedical Sciences of the Faculty of Medicine, Tirana, Albania and all participants gave written informed consent after being explained the aim and procedures of the study.
Cases consisted of consecutive new patients aged 18-70 years who presented with typical and/or atypical reflux symptoms and who were diagnosed with erosive reflux esophagitis by upper gastrointestinal endoscopy during 07 January 2013 – 30 June 2014 (N=248). The erosive reflux esophagitis was graded according to the Los Angeles (LA) classification criteria based on the extent of visible erosions: grade A, one or more mucosal breaks no longer than 5 mm, none of which extends between the tops of the mucosal folds; grade B, one or more mucosal breaks more than 5 mm long, none of which extends between the tops of the mucosal folds; grade C, mucosal breaks that extend between the tops of two or more mucosal folds, but which involve less than 75% of the esophageal circumference; and grade D, mucosal breaks which involve at least 75% of the esophageal circumference. The exclusion criteria for cases were as follows: (i) previous GERD; (ii) Barrett’s esophagus; (iii) history of gastrointestinal surgery and/or gastrointestinal malignancies; (iv) taking daily anticholinergics or prokinetics drugs; (v) using non-steroid or steroid anti-inflammatory drugs; (vi) pregnancy; (vii) history of asthma, heart or pulmonary diseases, and; (viii) severe diseases of other organs such as severe liver or kidney diseases, or other severe systemic conditions. Subjects who had received any acid-suppressive drugs within the last four weeks before endoscopy were also excluded. Patients were further divided into two groups according to the severity of esophagitis: LA grade A/B: mild erosive esophagitis, and severe erosive esophagitis: LA grade C/D. Hiatal hernia was recorded as the occurrence of the Z line more than 2 cm above the cardio-esophageal junction.
During the same time period (07 January 2013 – 30 June 2014), two controls for each case were targeted for recruitment among family members of the patients at Durres Hospital (overall N=496). Inclusion criteria (based on interview and medical history) consisted of individuals aged 18-70 years with no history of previous reflux diseases or use of medications against such diseases. Of the 496 targeted individuals, 51 did not meet the inclusion criteria. Furthermore, individuals unable to provide a clear medical history or who reported typical reflux symptoms more than once per week were excluded (N=48). In addition, 115 individuals refused to participate. No significant differences in socio-demographic characteristics were found between participants and non-participants in the control group. All the remaining controls (N=282) with no reflux symptoms agreed to undergo an upper endoscopy examination. Those with endoscopic findings related to GERD or hiatal hernia (N=9) were also excluded from the study. The final sample included 273 controls (overall response rate: 273/496=55%; response rate among eligible controls: 273/388=70%).
A physician (medical doctor) completed a standard questionnaire to cases and controls at the time of endoscopy. The questionnaire was designed to collect data on participants’ health conditions, socio-demographic characteristics and lifestyle habits [11, 12]. The socio-demographic data included age, sex, place of residence (urban vs. rural areas), marital status (dichotomized in the analysis into: married vs. not married), educational level (trichotomized into: low, middle and high), employment status (dichotomized into: employed/retired vs. unemployed) and income level (dichotomized into: low vs. average/high). The lifestyle factors included current smoking status (yes vs. no), alcohol consumption (<1drink/week, 1-6 drinks/week and ≥1 drink/day), dietary type (based on frequency of consumption of four main food items: traditional dishes, fruit and vegetables, olive oil, and fish [each item assessed in a scale ranging from ‘frequent’ to ‘no consumption’]; a summary score was calculated or each participant which in the analysis was dichotomized into: Mediterranean diet vs. non-Mediterranean diet)  and physical activity (low, moderate and high). In addition, height and weight were measured, based on which body mass index (BMI) was calculated for each participant (and subsequently trichotomized in the analysis into: normal weight, overweight and obesity).
All participants were asked to identify the presence of typical and/or extraesophageal symptoms of GERD. The typical gastroesophageal symptoms of GERD were defined as presence of heartburn or acid regurgitation. Heartburn was defined as a retrosternal burning sensation . Acid regurgitation was defined as the perception of flow of refluxed gastric content into the mouth or throat . Participants were also asked to self-assess individually the severity of their typical symptoms which were divided into three categories: no/mild, moderate, or severe. The extra-esophageal symptoms of GERD were defined as chronic cough, throat cleaning, sore throat and globus sensation. Chronic cough was defined as a cough that persists eight weeks or longer without having lung disorders. Throat clearing was defined as an instinctive attempt to remove an irritant in the throat. Sore throat was defined as a pain, scratchiness or irritation of the throat that often worsens when swallowing without bacterial or viral infection. Globus sensation was defined as the persistent feeling of a lump in the throat when not swallowing. In the analysis, throat clearing, sore throat and globus sensation were grouped into ‘laryngeal disorders’.
This study was approved by the Albanian Committee of Biomedical Ethics. All participants gave their consent after being informed about the aim and procedures of the study.
The statistical review of the study was performed by a biomedical statistician.
Student’s t-test was used to compare the distribution of age between cases with erosive esophagitis and controls. Conversely, Fisher’s exact test was used to compare the distribution of the other socio-demographic characteristics and lifestyle factors between cases with erosive esophagitis and controls. Similarly, Fisher’s exact test was employed to compare the distribution of typical gastroesophageal symptoms between cases with mild erosive esophagitis and those with severe erosive esophagitis.
Binary logistic regression was used to assess the association between erosive esophagitis (outcome variable) and extra-esophageal symptoms (independent variables alias “predictors”). More specifically, the three predictor variables included any extra-esophageal symptoms, chronic cough and laryngeal disorders. Crude (unadjusted) logistic regression models were initially run. Next, age-adjusted models were conducted. Subsequently, logistic regression models were adjusted for all socio-demographic characteristics of study participants (age, sex, marital status, residence, education, employment status and income). Finally, logistic regression models were additionally adjusted for lifestyle/behavioral factors (smoking, alcohol consumption, physical activity, BMI and dietary score). Odds ratios (ORs), their 95% confidence intervals (95%CIs) and p-values were calculated for all the logistic regression models. Hosmer-Lemeshow goodness-of-fit test was used to assess the validity of the logistic regression models.
In all cases, a p-value ≤0.05 was considered as statistically significant.
The statistical analysis was conducted in SPSS (Statistical Package for Social Sciences, version 17.0).