Background Factors of Reflux Esophagitis and Non-Erosive Reflux Disease: A Cross-Sectional Study of 10,837 Subjects in Japan

<div><p>Background</p><p>Despite the high prevalence of gastroesophageal reflux disease (GERD), its risk factors are still a subject of controversy. This is probably due to inadequate distinction between reflux esophagitis (RE) and non-erosive reflux disease (NERD), and is also due to inadequate evaluation of adjacent stomach. Our aim is therefore to define background factors of RE and NERD independently, based on the evaluation of <i>Helicobacter pylori</i> infection and gastric atrophy.</p><p>Methods</p><p>We analyzed 10,837 healthy Japanese subjects (6,332 men and 4,505 women, aged 20–87 years) who underwent upper gastrointestinal endoscopy. RE was diagnosed as the presence of mucosal break, and NERD was diagnosed as the presence of heartburn and/or acid regurgitation in RE-free subjects. Using GERD-free subjects as control, background factors for RE and NERD were separately analyzed using logistic regression to evaluate standardized coefficients (SC), odds ratio (OR), and <i>p</i>-value.</p><p>Results</p><p>Of the 10,837 study subjects, we diagnosed 733 (6.8%) as RE and 1,722 (15.9%) as NERD. For RE, male gender (SC = 0.557, OR = 1.75), <i>HP</i> non-infection (SC = 0.552, OR = 1.74), higher pepsinogen I/II ratio (SC = 0.496, OR = 1.64), higher BMI (SC = 0.464, OR = 1.60), alcohol drinking (SC = 0.161, OR = 1.17), older age (SC = 0.148, OR = 1.16), and smoking (SC = 0.129, OR = 1.14) are positively correlated factors. For NERD, <i>HP</i> infection (SC = 0.106, OR = 1.11), female gender (SC = 0.099, OR = 1.10), younger age (SC = 0.099, OR = 1.10), higher pepsinogen I/II ratio (SC = 0.099, OR = 1.10), smoking (SC = 0.080, OR = 1.08), higher BMI (SC = 0.078, OR = 1.08), and alcohol drinking (SC = 0.076, OR = 1.08) are positively correlated factors. Prevalence of RE in subjects with chronic <i>HP</i> infection and successful <i>HP</i> eradication denotes significant difference (2.3% and 8.8%; <i>p</i><0.0001), whereas that of NERD shows no difference (18.2% and 20.8%; <i>p</i> = 0.064).</p><p>Conclusions</p><p>Significantly associated factors of NERD are considerably different from those of RE, indicating that these two disorders are pathophysiologically distinct. Eradication of <i>Helicobacter pylori</i> may have disadvantageous effects on RE but not on NERD.</p></div

Orders, directions, and standardized coefficients of associations between the 12 upper GI symptoms and 13 background factors among the 528 H₂RA users.

<p>Background factors are (F1) age, (F2) female gender, (F3) BMI, (F4A) <i>HP</i> IgG ≥10 U/ml, (F4B) 10 U/ml><i>HP</i> IgG ≥2 U/ml, (F5A) 2≥PG I/II, (F5B) 3≥PG I/II >2, (F6) use of NSAIDs, (F7) inadequate sleep, (F8) weight gain in adulthood, (F9) dinner just before bedtime, (F10) frequent skipping of breakfast, (F11) lack of habitual exercise, (F12) alcohol drinking, and (F13) smoking. (F4A) and (F4B) were compared with “2> <i>HP</i> IgG”, and (F5A) and (F5B) were compared with “PG I/II >3”. Orders of association among the 13 background factors are shown as the upper integers for the individual 12 symptoms, in which attached “P” and “N” denote positive and negative association respectively. Standardized coefficients are shown as the lower decimal fractions. The levels of significance in these multivariate analyses were set at <0.05. The difference of associated background factors between H₂RA users and digestive drug-free subjects were calculated; <i>p</i> scores below 0.05 were set for the level of significance.</p

Comparison between endoscopic reflux esophagitis (RE) patients and GERD-free subjects.

<p>CI, confidence interval; <i>H. pylori</i>, <i>Helicobacter pylori</i>; PG, pepsinogen; BMI, body mass index; y.o., years old. Chi-square test was used for statistical evaluation, and the correlation of each background factor between RE patients and GERD-free subjects was calculated respectively. The level of significance in the univariate analyses was set at <i>p</i> value <0.05 (*).</p

Correlation between endoscopic reflux esophagitis (RE) and selected background factors.

<p>CI, confidence interval; <i>H. pylori</i>, <i>Helicobacter pylori</i>; PG, pepsinogen; BMI, body mass index. We evaluated age and BMI as continuous variables. Multiple logistic regression analysis was applied to calculate standardized coefficients and odds ratio for selected seven variables. The seven variables are shown in order of the absolute values of standardized coefficients. The level of significance was set at <i>p</i> value <0.05 (*).</p

Scores of the typical 12 upper GI symptoms among the 18,097 digestive drug-free subjects, 364 PPI users, and 528 H₂RA users.

<p>Scores of the 12 upper GI symptoms included in the FSSG range from 0 to 4 respectively. Consequently, total symptom scores range from 0 to 48.</p

Comparison between non-erosive reflux disease (NERD) patients and GERD-free subjects.

<p>CI, confidence interval; <i>H. pylori</i>, <i>Helicobacter pylori</i>; PG, pepsinogen; BMI, body mass index; y.o., years old. Chi-square test was used for statistical evaluation; the correlation of each subject background factor between NERD patients and GERD-free subjects was calculated respectively as an odds ratio (OR) with 95% confidence interval (CI). The level of significance in the univariate analyses was set at <i>p</i> value <0.05 (*).</p

Orders, directions, and standardized coefficients of associations between the 12 upper GI symptoms and 13 background factors among the 364 PPI users.

<p>Background factors are (F1) age, (F2) female gender, (F3) BMI, (F4A) <i>HP</i> IgG ≥10 U/ml, (F4B) 10 U/ml><i>HP</i> IgG ≥2 U/ml, (F5A) 2≥PG I/II, (F5B) 3≥PG I/II >2, (F6) use of NSAIDs, (F7) inadequate sleep, (F8) weight gain in adulthood, (F9) meals immediately prior to sleep, (F10) frequent skipping of breakfast, (F11) lack of habitual exercise, (F12) alcohol drinking, and (F13) smoking. (F4A) and (F4B) were compared with “2> <i>HP</i> IgG”, and (F5A) and (F5B) were compared with “PG I/II >3”. Orders of association among the 13 background factors are shown as the upper integers for the individual 12 symptoms, in which attached “P” and “N” denote positive and negative association respectively. Standardized coefficients are shown as the lower decimal fractions. The levels of significance in these multivariate analyses were set at <0.05. The differences of associated background factors between PPI users and digestive drug-free subjects were calculated; <i>p</i> scores below 0.05 were set for the level of significance.</p

Study recruitment flowchart.

<p>Study recruitment flowchart.</p

Orders, directions, and standardized coefficients of association between the 12 upper GI symptoms and 13 background factors among the 18,097 digestive drug-free subjects.

<p>Background factors are (F1) age, (F2) female gender, (F3) BMI, (F4A) <i>HP</i> IgG ≥10 U/ml, (F4B) 10 U/ml><i>HP</i> IgG ≥2 U/ml, (F5A) 2≥PG I/II, (F5B) 3≥PG I/II >2, (F6) use of NSAIDs, (F7) inadequate sleep, (F8) weight gain in adulthood, (F9) meals immediately prior to sleep, (F10) frequent skipping of breakfast, (F11) lack of habitual exercise, (F12) alcohol drinking, and (F13) smoking. (F4A) and (F4B) were compared with “2> <i>HP</i> IgG”, and (F5A) and (F5B) were compared with “PG I/II >3”. Orders of association among the 13 background factors are shown as the upper integers for the individual 12 symptoms, in which attached “P” and “N” denote positive and negative association respectively. Standardized coefficients are shown as the lower decimal fractions. The levels of significance in these multivariate analyses were set at <0.005.</p

The 12 questions for frequencies of various upper gastrointestinal symptoms (A) and 13 background factors derived from the questionnaire (B).

<p>The 12 questions for frequencies of various upper gastrointestinal symptoms (A) and 13 background factors derived from the questionnaire (B).</p