https://orcid.org/0000-0002-9142-5244
Abstract
Objective
The prevalence of functional gastrointestinal (FGI) symptoms and irritable bowel syndrome (IBS) is high in the society, but the etiology is mainly unknown. This population-based, cross-sectional study aimed to examine the associations between self-reported IBS or gastrointestinal (GI) symptoms within the past 2 weeks and concomitant diseases, drug consumption and family history of diseases.
Material and methods
Participants from the Malmö Offspring Study (MOS) answered a questionnaire about lifestyle habits, medical history and GI symptoms. Associations between self-reported IBS or GI symptoms and other diseases, drugs, and family history of diseases were calculated by logistic regression, adjusted for false discovery rate (FDR; q < 0.05).
Results
Of 2648 included patients, 316 had IBS and 459 had GI symptoms. There was an association between IBS and asthma (OR: 1.66; 95% confidence interval [CI]: 1.19–2.32; q = 0.018), and between IBS and using of prescription (OR: 1.44; 95% CI: 1.10–1.89; q = 0.028) and nonprescription drugs (OR: 1.92; 95% CI: 1.43–2.59; q < 0.001), specifically adrenergic beta-antagonists, antihistamines and hypnotics. Regarding family history, GI disease in the family (OR: 2.44; 95% CI: 1.78–3.35; q < 0.001) and the subgroups celiac disease, gastric ulcer, functional dyspepsia, IBS and reflux, as well as prostate cancer were associated with IBS, while GI diseases (OR: 2.56; 95% CI: 1.89–3.46; q < 0.001), joint diseases (OR: 1.61; 95% CI: 1.19–2.16; q = 0.009), and myocardial infarction (OR: 1.48; 95% CI: 1.09–2.99; q = 0.043) were associated with GI symptoms. Abdominal pain was the specific symptom with strongest associations.
Conclusions
IBS and GI symptoms were mainly associated with GI diseases in the family and drug consumption. To take a family and drug history is pertinent to all clinical history taking, irrespective of the symptomatology.
Introduction
Irritable bowel syndrome (IBS) is the most diagnosed functional gastrointestinal disorder (FGID), presenting itself with abdominal pain in relation to altered bowel habits without organic findings [Citation1]. The prevalence of any functional gastrointestinal (GI) symptoms in the community is up to 40%, but using Rome IV criteria [Citation1], IBS showed a global prevalence of 4.1% [Citation2]. IBS and other FGIDs generate a significant healthcare burden, impaired quality of life and direct and indirect costs due to healthcare costs and impairments in work [Citation3]. Self-reported IBS means that participants report whether they have IBS or not, after a short description of IBS, resembling the definition used by clinicians based on the long-standing presence of abdominal pain or discomfort associated with altered bowel habits [Citation1,Citation2].
Risk factors of IBS are female gender (14% prevalence in women and 9% in men), age <50 years, and a prior acute enteric infection [Citation4,Citation5]. Associated diseases include anxiety, depression, insomnia and functional somatic syndromes, such as fibromyalgia and chronic fatigue [Citation6,Citation7]. Patients with IBS are twice as likely as comparison groups to be diagnosed with a non-GI somatic disorder [Citation6]. Psychiatric stress and food hypersensitivity have also been shown to be associated with IBS [Citation8]. The society uses more drugs than ever before, which also leads to more adverse drug reactions. Side effects as constipation and diarrhea are common, and to start drug treatment increase the prevalence of these symptoms with more than 2% [Citation9]. Most likely, IBS represents numbers of diseases with various pathophysiology, where a biopsychosocial model of dysregulated communications between the gut and the brain may be one potential etiology [Citation10].
Our hypothesis was that development of IBS or GI symptoms could be caused by concomitant diseases or diseases in the family which contribute to stress, as well as be caused by medications. The primary aim of this study was to examine the association between comorbidity, medications, and family history of severe diseases and self-reported IBS or GI symptoms in the general population. The secondary aim was to examine associations with specific symptoms for variables associated with overall GI symptoms.
Material and methods
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation (Etikprövningslagen) and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committees (Ethical Review Board) in Lund (2012/594). All participants gave their written, informed consent before entering the study.
Study population
Malmö offspring study (MOS) started in 2013 and consists of children and grandchildren to participants in the Malmö diet and cancer study – cardiovascular cohort (MDCS-CC), which is a subgroup of the MDCS. MDCS was performed between 1991 and 1996 and included 28,098 individuals living in Malmö [Citation11]. MOS participants completed a web-based questionnaire, and a basic physical examination was performed. Study information was sent to all children and grandchildren along with a time point for an initial visit. A few days later, the participants were called to confirm the appointment. Those who did not answer or came to the visit were contacted once again. Totally, 4225 individuals were enrolled until June 2020 (inclusion rate 47%). Those who had not answered the questions about GI symptoms (n = 704) or had any organic bowel disease, i.e., celiac disease, Crohn’s disease, ulcerative colitis, gastric ulcer, lactose intolerance or reflux (n = 873) were excluded. Thus, 2648 participants were finally included in this study (Supplementary Figure 1).
Study questionnaire
An electronic link was given to the participants at the time point for their first visit to the Clinical Research Unit, Skåne University Hospital, Malmö, so they could log in to the questionnaire and answer the questions. If they did not complete the questionnaire, they were reminded twice. The questionnaire included questions about lifestyle factors, living conditions, education, occupation, medical health and family history of diseases. This questionnaire is similar to the questionnaires used in MDCS and MDCS-CC [Citation11]. The most common diseases in the society, e.g., hypertension, hyperlipidemia, myocardial diseases, joint diseases and pulmonary diseases, were listed, and the participants had to answer ‘yes’ or ‘no’ for each specific disease whether they had received the diagnosis from a physician. They had to answer whether they had received a diagnosis of specific GI diseases, i.e., celiac disease, Crohn’s disease, ulcerative colitis, gastric ulcer, functional dyspepsia, IBS, lactose intolerance or reflux. They also had to answer ‘yes’, ‘no’ or ‘do not know’ for each specific disease occurring in the family, separated for mother, father and siblings. In a free-writing form, they reported all medications prescribed or bought over the county. If they answered ‘yes’ to occurrence of GI disorder, they had to complete which subgroup of GI disorder they had in the family. They answered ‘yes’ or ‘no’ whether they had consumed antibiotics the past 6 months. Participants were asked ‘Have you several times during a month suffered from abdominal pain related to irregular bowel habits which is called IBS?’ The formulation was supposed to reflect the Rome III criteria for IBS [Citation12]. Second, they were asked if they had suffered from GI symptoms within the past 2 weeks. If they answered ‘yes’ to this question, they were encouraged to complete the validated visual analog scale for IBS (VAS-IBS) included in the study questionnaire, containing one VAS scale, 0–100 mm, for each of the symptoms abdominal pain, diarrhea, constipation, bloating and flatulence, and vomiting and nausea. The more symptoms and the higher score, the scales are inverted from the original version [Citation13]. Reference values from healthy volunteers are defined, and overall GI symptoms were classified as presence of one or more symptom [Citation14].
Data categorization and modification
Variables were not normally distributed and therefore divided into groups. Age was grouped into 10-year intervals. Body mass index (BMI) was sorted into <25, 25–30 and ≥30 kg/m2. Education was categorized into primary school, secondary school and higher education and occupation were into working, studying, sick leave, unemployed, retired or other. Marital status was grouped into living alone, living together or other. Smoking and snuff using were sorted into never, former or present use. Alcohol consumption was based on drinking frequency (never, ≤1 time/month, 2–4 times/months, 2–3 times/week or ≥ 4 times/week) and amount in standard glasses (12 g alcohol) per occasion (1–2, 3–4, 5–6, 7–9 or ≥10). Physical activity at work was divided into light (mostly sitting), intermediate (walking or doing laundry) and hard (gardening, timberwork or heavy lifting). Physical activity in leisure time was divided into sedentary to moderate (mostly sitting or moving without sweating) and training regularly (>30 min twice a week or sweating).
Comorbidity, medication and family history
The drugs were organized into groups based on the type of medication or pharmacodynamics, with the help of FASS (Pharmaceutical Specialties in Sweden) categorization with Anatomic Therapeutic Chemical classification system (ATC-codes) (see Supplementary Table 1) [Citation15]. All drugs used by less than 20 participants were excluded. Family history of diseases was merged into groups with a mother, father or sibling with the disease, except for breast cancer (mother or sister), and prostate cancer (father or brother). All type of GI disorders was both grouped together and separately; more than one subgroup could be present in the same family. For subgroups of GI diseases, all who had not filled in ‘yes’ were labeled as ‘no’.
Statistical analysis
The data were analyzed using SPSS version 27 for Mac (SPSS Inc., Chicago, IL). Spearman’s test was used to calculate correlations. Binary logistic regression was used to calculate crude odds ratio (OR) and 95% confidence interval (CI) for the association between basal characteristics (independent variables) and self-reported IBS or GI symptoms the past 2 weeks (dependent variables). Adjusted OR were then calculated for the significant factors in the crude calculation. Crude OR were calculated for associations between comorbidity, medication and family history (independent variables) and self-reported IBS or GI symptoms the past 2 weeks, and then adjusted for significantly different basal characteristics in the IBS group (sex, smoking, drinking frequency and drinking amount) and the GI symptoms group (age, sex, occupation and smoking). The reference was set to the absence of comorbidity, medication or family history. Data was not calculated for conditions present in less than 20 participants in the group with IBS or GI symptoms. To adjust for multiple comparisons, false discovery rate (FDR) of 5% was applied (q values) using the Benjamini–Hochberg method [Citation16]. The q values are considered the main result and only presented for the variables with p values < .05.
Variables associated with overall GI symptoms within the past 2 weeks (p < .05), were calculated by binary logistic regression regarding each specific GI symptom according to the VAS-IBS, adjusted for sex, age, occupation and smoking. p Values < .05 were considered statistically significant.
Results
Population characteristics
The median age of the participants was 45.2 years (range 18.4–73.6), and 52.5% were women. Of the included 2648 participants, 316 participants (11.9%) had self-reported IBS and 459 participants (17.3%) had GI symptoms in the past 2 weeks (). Both self-reported IBS and GI symptoms were found in 221 participants (8.3%); 69.9% of the IBS patients had GI symptoms the past 2 weeks, while 48.1% of the responders with GI symptoms the past 2 weeks also had IBS.
Table 1. Characteristics of the study population.
More IBS cases than controls were women and present or former smokers. IBS cases drank alcohol less frequently and at lesser amount per occasion than the controls. Participants with GI symptoms had a lower age and were more often women, were present or former smokers, and were studying or unemployed, compared to controls ().
The most common concomitant diseases were asthma, hypertension, chest pain and hyperlipidemia. Antibiotic treatment the past 6 months or non-steroidal anti-inflammatory drugs (NSAID) were the most used drugs (). Diabetes, GI disorders, joint diseases and myocardial infarction were the most common diseases in the family history ().
Table 2. Prevalence of concomitant diseases and drug treatment.
Table 3. Prevalence for family history of different diseases.
Self-reported IBS or GI symptoms and comorbidity and medication
There was an association between asthma (OR: 1.66; 95% CI: 1.19–2.32; p = .003) and chest pain > 30 min (OR: 1.66; 95% CI: 1.07–2.58; p = .024) and IBS. Asthma was also associated with having GI symptoms the past 2 weeks (OR: 1.50; 95% CI: 1.10–2.06; p = .012). The only significant association after FDR adjustment was between asthma and IBS (q = 0.018) ().
Table 4. Association between irritable bowel syndrome or gastrointestinal symptoms past 2 weeks and other diseases and drug treatment.
Both prescription of drugs the past week (OR: 1.44; 95% CI: 1.10–1.89; p = .008; q = 0.028) or using a nonprescription drug the past week (OR: 1.92; 95% CI: 1.43–2.59; p < .001; q < 0.001) were significantly associated with IBS. Specifically, medication with antihistamines (n = 14; p = .014), beta blockers (n = 9; p = .044) and hypnotics (n = 7; p = .009) were associated with IBS (Supplementary Figure 2).
Nonprescription drugs were associated with GI symptoms the past 2 weeks (OR: 1.43; 95% CI: 1.07–1.91; p = .017), which was not significant after FDR correction (). Regarding prescribed drugs, medication with beta blockers (n = 15; p = .003) and proton pump inhibitors (PPIs) (n = 8; p = .017) were associated with reported GI symptoms the past 2 weeks (Supplementary Figure 3).
Self-reported IBS or GI symptoms and family history of diseases
A family history of prostate cancer was associated with IBS (OR: 1.74; 95% CI: 1.18–2.55; p = .005; q = 0.015). Additionally, there was an association between self-reported IBS and a GI disease in the family (OR: 2.44; 95% CI: 1.78–3.35; p < .001; q < 0.001) and the subgroups celiac disease (q = 0.033), gastric ulcer (q = 0.004), functional dyspepsia (q < 0.001), IBS (q < 0.001) and reflux (q < 0.001) (, ).
Figure 1. (a) Forest plot showing OR and CI for associations between self-reported irritable bowel syndrome (IBS) and family history of diseases. The red line is a reference line located at 1.00. Celiac disease, lactose intolerance, reflux, gastric ulcer, functional dyspepsia, IBS, Crohn’s disease and ulcerative colitis are subgroups of GI disease in the family. (b) Forest plot showing OR and CI for associations between gastrointestinal (GI) symptoms past 2 weeks and family history of diseases. GI symptoms were assessed by the validated visual analog scale for irritable bowel syndrome (VAS-IBS) [Citation13]. The red line is a reference line located at 1.00. Celiac disease, lactose intolerance, reflux, gastric ulcer, functional dyspepsia, IBS, Crohn’s disease and ulcerative colitis are subgroups of GI disease in the family.
![Figure 1. (a) Forest plot showing OR and CI for associations between self-reported irritable bowel syndrome (IBS) and family history of diseases. The red line is a reference line located at 1.00. Celiac disease, lactose intolerance, reflux, gastric ulcer, functional dyspepsia, IBS, Crohn’s disease and ulcerative colitis are subgroups of GI disease in the family. (b) Forest plot showing OR and CI for associations between gastrointestinal (GI) symptoms past 2 weeks and family history of diseases. GI symptoms were assessed by the validated visual analog scale for irritable bowel syndrome (VAS-IBS) [Citation13]. The red line is a reference line located at 1.00. Celiac disease, lactose intolerance, reflux, gastric ulcer, functional dyspepsia, IBS, Crohn’s disease and ulcerative colitis are subgroups of GI disease in the family.](/cms/asset/d42422e8-7200-4978-a01c-01d943790435/igas_a_2031281_f0001_c.jpg)
Table 5. Association between IBS or gastrointestinal symptoms the past 2 weeks and a family history of diseases.
There was an association between GI symptoms and a family history of GI disease (OR: 2.56; 95% CI: 1.89–3.46; p < .001; q < 0001), joint diseases (OR: 1.61; 95% CI: 1.19–2.16; p = .002; q = 0.009), and myocardial infarction (OR: 1.48; 95% CI: 1.09–2.00; p = .012; q = 0.043), with a tendency of association for diabetes (OR: 1.37; 95% CI: 1.03–1.81; p = .030; q = 0.077). The subgroups reflux (q < 0.001), functional dyspepsia (q = 0.051) and IBS (q < 0.001) showed significant association with GI symptoms (, ).
Specific GI symptoms and associations
When considering each specific symptom, the symptoms abdominal pain and constipation (rs = 0.479), abdominal pain and bloating and flatulence (rs = 0.535) and constipation and bloating (rs = 0.464) were the symptoms with highest degree of correlations. These three symptoms were associated with asthma, and abdominal pain and vomiting and nausea were associated with nonprescription drugs (). Regarding prescription drugs, no significant associations were found (data not shown).
Table 6. Association between specific gastrointestinal symptoms within past 2 weeks and asthma and nonprescription drugs.
A family history of GI diseases was the only association found between family history and specific GI symptoms, and it was associated with abdominal pain, diarrhea, bloating and flatulence and vomiting and nausea (Supplementary Table 2).
Discussion
The main results of this study were that self-reported IBS and GI symptoms the past 2 weeks in the general population were associated with a family history of GI disorders. There was also an association between IBS and asthma, drug consumption and a family history of prostate cancer, and an association between GI symptoms and a family history of joint diseases and myocardial infarction. The associations were observed for the specific GI symptoms abdominal pain, diarrhea, constipation, bloating and flatulence and vomiting and nausea.
No previous research about IBS and family history of severe diseases could be found, but the present results indicate a need for future research. The association between IBS/GI symptoms and a family history of reflux and other FGID diseases overlapping with IBS is understandable [Citation1,Citation6]. However, associations between IBS and prostate cancer and between GI symptoms and a family history of diabetes, joint disease, and myocardial infarction are harder to understand. A possible explanation could be increased psychiatric stress due to sick family members or anxiety of getting this disease yourself [Citation8,Citation17], which could in turn lead to aggravated GI symptoms or IBS [Citation8]. The association with joint diseases can be explained by the well-known overlapping between FGID and fibromyalgia and arthralgia [Citation6]. The specific GI symptoms abdominal pain, constipation, and bloating and flatulence were the symptoms with strongest correlations, in accordance with previous literature [Citation18]. Abdominal pain was the specific symptom with strongest associations. Diarrhea may have another pathophysiology [Citation19].
Genetic studies have shown that IBS is more common in monozygotic than in dizygotic twins, indicating that genes are important [Citation20]. Furthermore, a Swedish study demonstrated an association between IBS and their biological parents but not adoptive parents [Citation21]. However, having a parent with IBS has been shown to be a stronger predictor than having a dizygotic twin, demonstrating that environmental factors as learned behavior could be more important than genetic factors [Citation20]. Children of parents with IBS had significantly more ambulatory care visits, even after excluding GI visits [Citation22]. Parents could transmit a pattern of social learning and illness behavior to their children if the children are rewarded when sick [Citation22]. Moreover, chronic illness behavior (more somatic complaints, more visits to physicians and more disability related to the physical findings) is a learned behavior found to be increased in patients with IBS [Citation23], which could explain the associations with the most prevalent family diseases.
IBS was associated both with using prescription and nonprescription drugs, whereas GI symptoms only tended to be associated with using nonprescription drugs. Previous studies have shown that drug treatment may increase the prevalence of constipation and diarrhea with 2.5 and 2.3%, respectively [Citation9]. A huge number of drugs may evoke diarrhea, and polypharmacy increased the prevalence of diarrhea significantly [Citation9]. The time between treatment start and symptom onset may be long, and since GI symptoms are common in the general population, causality may be difficult to ensure [Citation24]. It might also be hard to distinguish side effects of a drug and disease-related symptoms, especially as patients with IBS have more comorbidity, for example psychiatric disorders [Citation6,Citation8]. Moreover, the prevalence of drug intolerance was significantly higher in IBS patients than in patients without IBS (41% compared to 7%) [Citation25]. The present findings are not explaining the etiology of the IBS disease but strengthen the importance to take a proper anamnesis and drug history when meeting patients with functional GI symptoms, before giving the diagnosis IBS.
The low frequency of NSAID users may be due to under-reporting and could explain the absence of association between GI symptoms and NSAID although NSAID have well-established GI side effects, particularly constipation or diarrhea and stomach cramps or pain [Citation26].
IBS and GI symptoms in the past 2 weeks were associated with using adrenergic beta-antagonists, although very few users were found. According to FASS, GI symptoms are common adverse effects to beta-blocking drugs [Citation15], through their enhanced colonic motility with suppression of sympathetic nervous activity, which could lead to aggravated symptoms, such as pain and change in bowel habits [Citation27]. On the contrary, a systematic review concluded that 82 out of 100 participants with diarrhea would have had diarrhea also on placebo [Citation28].
The pooled prevalence of sleeping disorders in IBS patients was 37.6% [Citation7]. This could explain the observed association between IBS and hypnotics, which may thus not be a drug effect.
Patients with dyspepsia have an 8-fold risk of also having IBS, and 25% of IBS patients have gastroesophageal reflux [Citation29,Citation30]. This might contribute to the association between GI symptoms and PPI, although all participants with organic GI diseases were excluded. However, PPI treatment may trigger the onset of bowel symptoms, and 20% of the patients with PPI treatment had bowel symptoms after 6 months that could be classified as IBS [Citation31].
A systematic review stated that 20–65% of IBS patients attribute their symptoms to food intake and food reactions, such as food allergy or food intolerance, and generalized immune hypersensitivity is suggested to be one factor contributing to the development of IBS [Citation32]. The bidirectional association between asthma and IBS suggests that atopy could be a shared pathophysiology underlying the association [Citation33], in line with a high incidence of IBS among patients with allergic rhinitis, allergic eczema or asthma [Citation34]. Although a consistent association between IBS and asthma has been described, no studies have further tried to explain the pathophysiological mechanisms behind the association [Citation35]. This association between IBS and allergy might explain the present results of association between IBS and taking antihistamines.
The strength of this large study was that it included participants from the general population, which may be more representative for IBS than inclusion of selected patients from tertiary healthcare centers [Citation36]. A limitation of the study was that the participation rate in MOS was only 47%, which reflects the difficulties to attract healthy young or middle-aged subjects to participate in surveys [Citation11]. Further, there were many missing answers which gave incomplete data with few ‘yes’ and wide CIs. The drug groups were formed with help of ATC codes, which could result in groups hard to compare with other studies and groups with different ATC levels. The questions about heredity for subgroups of GI disease were answered by yes or missing, which means that the ones not answering automatically were categorized as ‘no’ in the calculation. The questionnaire did not ask for psychiatric disorders, which could be a confounder due to its close relation to IBS [Citation6,Citation7]. The Rome questionnaire was not completed depending on its size and depending on varying Rome criteria over time [Citation37,Citation38]. However, IBS is a well-known description of GI symptoms in the society, and people are familiar with the symptoms and criteria [Citation39]. Furthermore, there was a strong correlation between self-reported IBS and functional GI symptoms [Citation19], which are assessed by the validated VAS-IBS questionnaire [Citation13].
With a p value of .05, there is a 5% chance of getting significant results despite the null hypothesis being true [Citation16]. If you make 20 tests on the same material, the risk of getting a false positive (type I error) is 64%. FDR was calculated to adjust for multiple testing. However, a risk of adjusting for FDR is many false-negative results (type II error), and the significance of a true association is reduced [Citation16]. FDR and q values are mostly used in research with hundreds or thousands of analyses, and to use it on this study might result in too many false-negative results instead of positive [Citation16]. The true associations could thus be somewhere in between p values and q values, and both original p values and q values are therefore presented.
In conclusion, these results prove the importance of being aware of a family history of chronic organic disorders in patients presenting with self-reported IBS and functional GI symptoms. Further, side effects of medication must be considered in this entity. IBS is a group of diseases with similar symptoms but different pathogenesis and needs to be managed in different ways, depending on the etiology. The inheritance of illness behavior is important to consider and exclude before analysis of advanced technical methods. More research is needed to better understand the pathogenesis of IBS and what could contribute to GI symptoms.
Author contributions
HR analyzed and interpreted the patient data and wrote the initial draft. BO revised the draft and both authors read and approved the final manuscript.
Supplemental Material
Download MS Word (26.7 KB)Acknowledgments
The authors thank the staff at the Clinical Research Unit, Skåne University Hospital, for recruitment of participants and Anders Dahlin for data management.
Disclosure statement
There are no conflicts of interest.
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