1 Introduction
Gastroesophageal reflux disease (GERD) is a condition that develops when reflux of stomach contents causes troublesome symptoms and/or complications.[1] [2] [3] [4] [4] [5,6] [7]
Appendicitis is one of the most common emergencies, and it requires an appendectomy.[8] [9] [10] [11] [11]
Based on these finding, it could be possible that appendicitis is related with GERD, as both gastrointestinal track disease might be affected by diet and autonomic imbalance. We hypothesized that appendicitis might be more prevalent in the patient with GERD. To complement our hypothesis, we reviewed the PubMed and Embase databases for studies using the keywords ‘(gastroesophageal reflux) AND ([appendicitis] OR [appendectomy] OR [appendix])’ and limited the results to human-based studies published in English before Dec. 2017. Only one study reported an association between GERD and appendicitis.[12] proton pump inhibitors (PPIs) are a possible factor underlying the etiology between GERD and appendicitis, but they did not confirm their hypothesis. The purpose of this study is to evaluate the risk of appendectomy in patients with GERD using a national sample cohort of the Korean population. The results of this study extend previous findings on PPI use.
2 Materials and methods
2.1 Study population and data collection
The ethics committee of Hallym University (2014-I148) approved the use of these data. The Institutional Review Board exempted the requirement for written informed consent.
This national cohort study used data from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC). The Korean NHIS selects samples directly from the entire population database to prevent non-sampling errors. Approximately 2% of the samples (1 million) were selected from the entire Korean population (50 million). The selected data were classified into 1476 levels (age [18 categories], sex [2 categories], and income level [41 categories]) using randomized stratified systematic sampling methods via proportional allocation to represent the entire population. A previous study verified the appropriateness of the sample after data selection.[13] [14]
1. personal information,
2. health insurance claim codes (procedures and prescriptions),
3. diagnostic codes using the International Classification of Disease-10 (ICD-10),
4. death records from the Korean National Statistical Office (using the Korean Standard Classification of disease),
5. socio-economic data (residence and income), and
6. medical examination data for each participant from 2002 to 2013.
All Korean citizens are recognized by a 13-digit resident registration number from birth to death. Therefore, exact population statistics have been determined using this database. All Koreans are required to enroll in the NHIS. All Korean hospitals and clinics use the 13-digit resident registration number to register individual patients in the medical insurance system. Therefore, the risk of overlapping medical records is minimal, even if a patient moves from one place to another. All medical treatments in Korea are tracked without exception using the Health Insurance Review & Assessment (HIRA) system. In Korea, the law states that a notice of death must be provided to an administrative entity before a funeral can be held. Medical doctors record the date and cause of death on a death certificate.
2.2 Participant selection
Out of 1,125,691 cases with 114,369,638 medical claim codes, we only included participants who had received an appendectomy, as identified using operation codes (Q2860-Q2863). Among appendectomy cases, we included appendectomies performed solely for appendicitis (ICD-10: K35) (n = 22,047).
GERD was defined using the ICD-10 code K21 from 2002 through 2013. We identified participants who were treated for GERD ≥ 2 times and were prescribed PPIs for ≥ 2 weeks (n = 137,807).
Participants who received an appendectomy were matched at a 1:4 ratio with participants in the control group, who did not undergo an appendectomy from 2002 through 2013 among this cohort. Participants in the control group were selected among total participants who were not categorized as appendectomy group (n = 1,103,644). Subject were matched on age group, sex, income group, region of residence, and medical histories (eg, hypertension, diabetes, and dyslipidemia). Participants in the control group were sorted using a random number order and selected from top to bottom to prevent selection bias when selecting the matched participants. The matched control participants were presumed to have been treated at the same time as each matched participant who received an appendectomy based on the index date. Therefore, subjects in the control group who died before the index date were excluded. Participants who received an appendectomy were excluded (n = 58) if we could not identify a sufficient number of matching participants. We excluded participants aged less than 20 years (n = 6927). The 1:4 matching resulted in the inclusion of 15,602 participants who had received an appendectomy and 60,248 control participants. However, subjects were not matched for ischemic heart disease, cerebral stroke, or depression histories because strict matching increased the exclusion of participants due to the lack of control participants. We analyzed previous histories of GERD before the index date in the appendectomy and control groups after matching (Fig. 1 ).
Figure 1: Schematic illustration of the participant selection process used in the present study. Of 1,125,691 participants, 15,062 participants who received an appendectomy were matched with 60,248 control participants for age group, sex, income group, region of residence, and medical histories.
2.3 Variables
Fourteen age groups were designated and classified by 5-year intervals as follows: 20–24, 25–29, 30–34… and 85+ years old. Income groups were initially divided into 41 classes (one health aid class, 20 self-employment health insurance classes, and 20 employment health insurance classes). These groups were re-categorized into 11 classes 1 (lowest income) -11 (highest income). They included one class of the lowest income group (heath aid) and other 10 classes by insurance premium. The region of residence was divided into 16 areas according to administrative district. These regions were regrouped into urban (Seoul, Busan, Daegu, Incheon, Gwangju, Daejeon, and Ulsan) and rural (Gyeonggi, Gangwon, Chungcheongbuk, Chungcheongnam, Jeollabuk, Jeollanam, Gyeongsangbuk, Gyeongsangnam, and Jeju) areas.
Participants’ medical histories were evaluated using ICD-10 codes. Hypertension (I10 and I15), diabetes (E10-E14), and dyslipidemia (E78) were examined for diagnostic accuracy if the participants were treated ≥ 2 times. Ischemic heart disease (I24 and I25) and cerebral stroke (I60-I66) were examined if the participants were treated ≥ 1 time. Depression was defined using the ICD-10 codes F31 (bipolar affective disorder) through F39 (unspecified mood disorder) assigned by a psychiatrist from 2002 through 2013. We selected participants who were treated for depression ≥ 2 times. We selected these variables as confounders in that these diseases are relatively common, and we think that they could reflect the general health status of participants.
2.4 Statistical analyses
An conditional logistic regression analysis was used to analyze the odd ratio (OR) of GERD in appendectomy patients. Crude (simple) and adjusted (age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression histories) models were used in this analysis, and a 95% confidence interval (CI) was calculated.
We stratified participants by age and sex for subgroup analyses (< 40 years old, ≥ 40 years old & < 60 years old, ≥ 60 years old; men and women).
In other analyses, we analyzed the ORs for GERD with of ≥ 30 days, and ≥ 60 days of PPI prescription before appendectomy
Two-tailed analyses were performed, and P values less than .05 were considered significant. The results were statistically analyzed using SPSS v. 22.0 (IBM, Armonk, NY, USA).
3 Results
A higher GERD rate was observed in the appendectomy group (11.4% [1,713/15,062]) than in the control group (8.2% [4,947/60,248], P < .001, Table 1 ). The general characteristics (age, sex, income, region of residence, and histories of hypertension, diabetes, and dyslipidemia) of participants were identical due to matching (P = 1.000). Higher rates of histories of ischemic heart disease, cerebral stroke, and depression were observed in the appendectomy group (all P values < .05). The adjusted OR for GERD was 1.37 (95% CI = 1.30–1.45 (P values < .001, Table 2 ).
Table 1: General characteristics of participants.
Table 2: Crude and adjusted odd ratios (95% confidence interval) of GERD for appendectomy (n = 75,310).
In the subgroup analyses, higher crude and adjusted Odds for GERD were observed in the appendectomy group (all P values < .05, Table 3 ). Adjusted ORs were 1.37 (95% CI = 1.18–1.61) in < 40-year-old men, 1.45 (95% CI = 1.26–1.67) in < 40-year-old women, 1.35 (95% CI = 1.20–1.52) in 40–59-year-old men, 1.36 (95% CI = 1.22–1.53) in 40 to 59-year-old women, 1.23 (95% CI = 1.08–1.42) in ≥ 60-year-old men, and 1.41 (95% CI = 1.25–1.59) in ≥ 60-year-old women.
Table 3: Subgroup analyses of crude and adjusted odd ratios (95% confidence interval) of GERD for appendectomy according to age and sex.
In other analyses, the adjusted OR for GERD with prescription of PPIs for ≥ 30 days was 1.31 (95% CI = 1.20–1.43), and the adjusted OR for GERD with prescription of PPIs for ≥ 60 days was 1.30 (95% CI = 1.15–1.48) (all P values < .001, Table 4 ).
Table 4: Analyses of crude and adjusted odd ratios (95% confidence interval) of GERD for appendectomy according to the dates of PPI prescription (n = 75,310).
4 Discussion
In the present study, higher Odds for GERD were observed in participants who received an appendectomy than in the control group. We obtained consistent results from different age groups and both sexes. The ORs for GERD with longer administration of PPI prescriptions was not higher than ORs for GERD with shorter administration of PPI prescriptions. These findings confirm and complement the results of a previous study[12]
PPI is the most common treatment for GERD, but it might cause appendicitis. The shared pathogenesis between GERD and appendectomy is not clear. PPI may alter the microbiome in the gastrointestinal (GI) tract,[15] [16] [17]
Both GERD and appendicitis could be affected by autonomic imbalance. Low sphincter pressure, transient lower esophageal sphincter relaxation, problem of esophageal clearance could result in GERD.[4] [18] [11,19]
Dietary factors may act as confounders between appendicitis and GERD. A low fiber and high carbohydrate diet may be responsible for appendicitis,[20] [21] [11] [22] [22]
The hygiene hypothesis may contribute to both GERD and appendicitis. The hygiene hypothesis was proposed as a trigger for appendicitis because epidemic appendicitis appears in development.[20] [20] [23] [20]
The advantages of this study are consistent with those of our previous studies using the national sample cohort.[24–26] [12] [3]
This study has several limitations. We did not analyze the severity of GERD in participants. Patients with GERD might have been overlooked if these patients did not visit a clinic. We used appendectomy rather than appendicitis itself to obtain an accurate diagnosis. However, appendectomy may be a surrogate marker of appendicitis. We did not analyze the possible confounding factors, such as obesity, smoking, and dietary habits, between GERD and appendicitis. Microbiology, such as bacterial or viral infections of the GI tract, was not evaluated.
5 Conclusions
The Odds for GERD increased in participants who received an appendectomy. This relationship was consistent in all age groups and in both genders. Patients with GERD and long-term PPI use did not exhibit higher ORs than the total sample of participants with GERD.
Acknowledgments
The manuscript was edited for proper English language, grammar, punctuation, spelling, and overall style by the highly qualified native English-speaking editors at American Journal Experts (C5D4–51E1-FC90-FDAF-CBCP).
Author contributions
Conceptualization: Hyo Geun Choi.
Formal analysis: Hyung-Jong Kim, Hyun Lim, Man Sup Lim.
Supervision: Hyo Geun Choi.
Writing – original draft: So Young Kim, Hyo Geun Choi.
Writing – review & editing: So Young Kim, Hyung-Jong Kim, Man Sup Lim, Miyoung Kim, Hyo Geun Choi.
Hyo Geun Choi orcid: 0000-0003-1655-9549.
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