An Initial Attack of Urinary Stone Disease
Is Associated with an Increased Risk of
Developing New-Onset Irritable Bowel
Syndrome: Nationwide Population-Based Study
Wei-Yuan Lei1, Chih-Yu Chang1,2, Jr-Hau Wu1, Fei-Hung Lin1, Cheng Hsu Chen1, Chin-Fu Chang1, Yan-Ren Lin1,3,4☯*, Han-Ping Wu5,6☯*
1 Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan, 2 Department of Biological Science and Technology of Biochemical Engineering, National Chiao Tung University, Hsinchu, Taiwan, 3 School of Medicine, Chung Shan Medical University, Taichung, Taiwan, 4 School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, 5 Division of Pediatric General Medicine, Department of Pediatrics, Chang Gung Memorial Hospital at Linko, Kweishan, Taoyuan, Taiwan, 6 College of Medicine, Chang Gung University, Taoyuan, Taiwan
☯ These authors contributed equally to this work.
*[email protected](YRL);[email protected](HPW)
Abstract
Background
The neurotransmitter pathways in irritable bowel syndrome (IBS) and urinary stone attacks are both related to serotonin, and each disease may be influenced by viscero-visceral hyperalgesia. However, the relationship between urinary tract stone disease and IBS has never been addressed. We aimed to investigate the risk of suffering new-onset IBS after an initial urinary stone attack using a nationwide database.
Methods
A study group enrolled a total of 13,254 patients who were diagnosed with an initial urinary stone attack; a comparison group recruited 39,762 matched non-urinary stone participants during 2003 and 2007. We followed each patient for 3 years to determine new-onset IBS. We also used Cox proportional hazards models to analyze the risk of IBS between the study and comparison groups after modified by demographics, residence, patient charac-teristics and personal histories.
Results
The occurrence rates of IBS were 3.3% (n = 440) and 2.6% (n = 1,034) respectively in the study and comparison groups. A covariate-adjusted hazard ratio (HR) of IBS in the study group that was 1.28 times greater (HR = 1.29, 95% CI, 1.15–1.44) than that in the compari-son group was showed in the stratified Cox proportional analysis. The adjusted HRs of IBS did not decrease after considering demographics and past histories. The majority of IBS (30.5%) occurred within the first 6 months after the stone attack.
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OPEN ACCESS
Citation: Lei W-Y, Chang C-Y, Wu J-H, Lin F-H, Hsu Chen C, Chang C-F, et al. (2016) An Initial Attack of Urinary Stone Disease Is Associated with an Increased Risk of Developing New-Onset Irritable Bowel Syndrome: Nationwide Population-Based Study. PLoS ONE 11(6): e0157701. doi:10.1371/journal. pone.0157701
Editor: André Mouraux, Université catholique de Louvain, BELGIUM
Received: November 16, 2015 Accepted: April 19, 2016 Published: June 23, 2016
Copyright: © 2016 Lei et al. This is an open access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability Statement: All data are available from the National Health Insurance Research Database (NHIRD) of Taiwan (http://nhird.nhri.org.tw/ ). Requests for data can be sent as a formal proposal to the NHIRD.
Funding: The authors thank the National Chiao Tung University, Changhua Christian Hospital, and National Science Council (MOST 104-2314-B-371-010) for financially supporting this research.
Conclusion
Patients with an initial urinary stone attack are at increased risk of developing new-onset IBS. The HRs of IBS did not decrease even after adjusting for patient demographics and past histories. Most importantly, 30.5% of IBS occurred within the first 6 months after the uri-nary stone attack.
Introduction
Irritable bowel syndrome (IBS) has a high incidence worldwide and affects 10%-15% of popu-lation in Western countries. IBS is characterized by chronic, recurrent gastrointestinal upset followed by bowel dysfunction.[1–3] Additionally, it has a huge impact on healthcare costs and quality of life. In the United States, the annual cost of IBS treatment has been calculated to be $20 billion in indirect costs and range between $1.7 billion and $10 billion in direct medical costs.[4,5] In spite of its high prevalence rate, the exact pathophysiology of IBS is not yet clari-fied. Various mechanisms, such as gastrointestinal dysmotility[6,7], visceral hypersensitivity [8,9], intestinal mucosa activation[10–14], and increased intestinal permeability[8,9], have been implicated in the pathophysiology of IBS. Among these, visceral hypersensitivity is con-sidered to be the major cause of IBS.[15,16] Previous analyses of visceral hypersensitivity have identified serotonin (5-hydroxytryptophan, 5-HT) as an crucial neurotransmitter in the patho-genesis of IBS via purinergic mechanosensory transduction.[17–21]
Urinary stone disease is relatively common, with a lifetime risk of approximately 6% in women and 12% in men.[22] Urinary stones in the ureter or urinary bladder can induce disten-sion of tubes or sacs, leading to the release of adenosine triphosphate (ATP) from the epithe-lium lining the tube or sac, which triggers sensory nerves to convey information to the central nerve system (CNS), causing visceral pain. Similar to the neurotransmitter pathway of IBS, patients with urinary stone attacks also suffer visceral pain via purinergic mechanosensory transduction, and serotonin can be released from enterochromaffin cells.[21,23,24] In addition, certain previous studies reported that viscero-visceral hyperalgesia between two internal organs in the same patient might enhance pain symptoms, potentially via sensitization of viscero-vis-cero-somatic convergent neurons.[25–28] One of these studies further investigated the interac-tions between dysmenorrhea and urinary stone disease and between IBS and dysmenorrhea; they noted that treating one disease might reduce the symptoms of the other disease.[25]
Because of the similar neurotransmitter pathways linked to IBS and urinary stone attacks and the possibility of viscero-visceral hyperalgesia, we suspected that IBS could potentially be induced by urinary stone disease. However, the relationship between IBS and urinary stone dis-ease has never been discussed. In this study, we analyze the relationship between the diagnosis of an initial urinary stone attack and the risk of new-onset IBS during a three-year follow-up period by using a nationwide population database.
Materials and Methods
Database
In this study, the data were randomly enrolled from the Longitudinal Health Insurance Data-base (LHID), which was developed by the National Health Insurance (NHI) program. As described previously [29], this program enrolled almost 99% of Taiwan’s population and obtained original data from one million people.
Competing Interests: The authors have declared that no competing interests exist.
Ethics statement
Because the data that we used is de-identified secondary data; therefore, our study was exempt from a full review by the Institutional Review Board (IRB). (IRB of Changhua Christian Hospi-tal, permission code: 150216). This manuscript has also followed the Strengthening the Report-ing of Observational Studies in Epidemiology (STROBE) guidelines.
Study setting and population
The data of this retrospective cohort study were collected from the LHID during the period from January 1, 2003 to December 31, 2007. The study group was defined as patients who suf-fered an initial urinary stone attack. The comparison group was defined as patients who never suffer any urinary stone attacks. In this analysis, the study patients (with an initial urinary stone attack) and the comparison patients (without urinary stones) were followed for 3 years. The chance of suffering a new-onset episode of IBS was analyzed for the two groups during the 3-year follow-up period.
Inclusion criteria
Definition of patients with an initial urinary stone attack. Patients who were diagnosed principally (the major reason for coming to the hospital) as urinary stone attack by an emergency or outpatient department using the International Classification of Diseases, 9th Revision, Clinical Modification codes (using ICD-9-CM; codes 592, 592.1 and 592.9) were enrolled in the study.
Definition of patients with irritable bowel syndrome. We defined IBS patients as those who were diagnosed according to the criteria of the International Classification of Diseases, 9th Revision, Clinical Modification (using ICD-9-CM; code 564.1) by an emergency or outpatient department.
Exclusion criteria
Patients with any of the following characteristics were excluded from this study: 1. Age<18 years.
2. Diagnosis of any form of urinary tract stone (including acute/chronic attack or no prior attack) or IBS before the study period.
3. Inability to be followed up during the study period (i.e., death or incomplete medical records).
4. Urinary stone disease was the co-diagnosis (not the major reason for the hospital visit).
Quality control
Overtreatment and ICD-9 over-coding were not permitted in the NHI program; these actions could result in fines. Specialists routinely and randomly inspected the treatments, diagnosis, and medications for each patient.
Study protocol
Our study group included 13,254 patients who suffered a first urinary stone attack. The com-parison group was chosen from the remaining NHI beneficiaries registered in the LHID. 39,762 comparison patients (three comparison patients for each urinary stone patient) who
were matched to the study group by age, gender, and number of hospital visits and years of index healthcare use were randomly enrolled. This study included a total of 53,016 patients.
Data analysis
The SAS program (SAS Institute Inc., Cary, NC, USA) was used to select the study and com-parison groups. We followed each patient (n = 53,016) for three years to identify those who experienced new-onset IBS. The independent variables, including personal history at baseline, patient characteristics, and demographics, are reported as percentages or the mean ± standard deviation (SD).
We used the X2test to analyze the differences between the study and comparison groups for demographics, including socioeconomic level (>$1,000 USD, $601–1,000 USD or <$600 USD, monthly income of the patient and guardian), the degree of urbanization in the patient’s city of residence, the location of the patient’s residence (eastern and western Taiwan; western Taiwan was further divided into northern, central and southern Taiwan), and personal disease history (diabetes, hypertension, liver cirrhosis, renal failure, stroke, osteoporosis and fibromyalgia). The degree of urbanization, which was classified by population and certain development-related con-ditions, (Level 1 urbanization: more than 1,250,000 people; level 2: 1,250,000~500,000 people; levels 3: 500,000~150,000 people; level 4: fewer than 150,000 people).[30] Moreover, the crude hazard ratio (HR) was calculated by creating age-stratified Cox proportional hazards models, which were used in the study and comparison groups to analyze the risk of experiencing new-onset IBS. Furthermore, the HR was analyzed after adjusting for demographics (mode 1), per-sonal disease history (mode 2), and all variables (mode 3).
Moreover, variables that were related or unrelated to the occurrence of IBS among the study and comparison patients were analyzed using the X2test. These variables included demograph-ics and personal disease history. Furthermore, multiple logistic regression analysis was respec-tively used to analyze the more important factors that associated with new-onset IBS for all patients, study patients and comparison patients.
We also used the log-rank test and the Kaplan-Meier method to estimate 3-year IBS-free survival rates for the study and comparison groups. Finally, among the patients with an initial urinary stone attack, the amount of time before the onset of IBS was recorded and further divided into 6 periods (<6, 6–12, 13–18, 19–24, 25–30, and 31–36 months). P<0.05 was con-sidered to indicate statistical significance.
Results
1. Demographics and personal histories collected from patients with an
initial urinary stone attack
The characteristics of patients with an initial urinary stone attack (n = 13,254) and control patients (without any urinary stone history; n = 39,762) are showed inTable 1. Males comprised the preponderance in both groups. Most of the initial urinary stone attacks arose in the age groups of 30 to 39 years (24.1%) and 40 to 49 years (25.4%). Compared with the control patients, the economic and urbanization levels were significantly lower in those with urinary stones. Addi-tionally, patients with urinary stones had a higher prevalence of diseases, including hypertension, renal failure, osteoporosis and fibromyalgia (for all of the above findings, p<0.05).
2. Irritable bowel syndrome probability based on crude HR
We found that the risk of suffering new-onset IBS was significantly higher in the study patients than in the comparison patients during the 3-year follow-up period. We found that 3.3%
(n = 440) of patients experienced IBS after the occurrence of an initial urinary stone attack, whereas the percentage of IBS was only 2.6% (n = 1,034) in the comparison patients. The study patients had a crude HR 1.29 times greater than that of the comparison patients (95% CI, 1.15– 1.44; p<0.001) (Table 2), which is showed in the stratified Cox proportional hazards analysis. Furthermore, adjusting for likely influence factors, including patient geographic region, monthly income (mode 1), personal history at baseline (mode 2) and both modes 1 and 2 (mode 3), did not affect the HRs of suffering IBS, which all remained higher in patients with an initial stone attack compared with controls (for all of the above findings, p<0.05) (Table 3).
Table 1. Characteristics and personal histories between patients with urinary stone attack and comparison patients. Patients with Urinary Stone Attack (n = 13,254) Comparison Patients (n = 39,762)
No. % No. % p
Gender 1.000
Male 9,251 69.8 27,753 69.8
Mean age (y/o) (mean ±SD)
45.3±14.3 45.1±14.6 0.210
Age group (y/o) 1.000
30 2,052 15.5 6,156 15.5 30–39 3,197 24.1 9,591 24.1 40–49 3,363 25.4 10,089 25.4 50–59 2,515 19.0 7,545 19.0 60–69 1,310 9.9 3,930 9.9 70–79 657 5.0 1,971 5.0 80 133 1.1 465 1.2 Economic level (monthly income) (USD$)* <0.001 <600 3,547 26.8 10,419 26.2 601–1,000 6,609 49.9 18,816 47.3 >1,000 3,098 23.4 10,527 26.5 Urbanization* <0.001 1 (most) 3,584 27.1 11,003 29.0 2 1,539 11.7 4,741 12.5 3 3,920 29.4 10,708 28.3 4 4,211 31.8 11,815 29.7 Geographic regions of Taiwan* <0.001 Northern 6,927 52.3 20,502 51.6 Central 3,055 23.0 8,501 21.4 Southern 2,794 21.1 9,580 24.1 Eastern 478 3.6 1,179 3.0 Personal history Diabetes mellitus 950 7.2 2,762 6.9 0.387 Hypertension* 1,754 13.2 4,848 12.2 0.002 Renal failure* 342 2.6 861 2.2 0.006 Liver cirrhosis 1,065 8.0 3,052 7.7 0.183 Stroke 81 0.6 306 0.8 0.069 Osteoporosis* 2,292 17.3 6,575 16.5 0.044 Fibromyalgia* 4,503 34.0 11,742 29.5 <0.001 *Significant differences, p<0.05. doi:10.1371/journal.pone.0157701.t001
3. Clinical features associated with the occurrence of IBS in patients with
an initial urinary stone attack (n = 440)
The clinical features of patients in both the study and comparison groups who suffered new-onset IBS are shown inTable 4. We found that IBS was more predominant in the age group of 40 to 49 years and in those with a history of osteoporosis and fibromyalgia in both the study and comparison groups (all p<0.05). Furthermore, diabetes was significantly associated with IBS only in the study patients (p<0.05). The results of multiple logistic regression analysis of suffering new-onset IBS for all patients, study patients and comparison patients are shown in
Table 5.
4. IBS-free survival curves for patients
The IBS-free survival curves of study and comparison patients generated during the study period are shown inFig 1. Patients with an initial urinary stone attack had a significantly lower incidence of 3-year IBS-free survival than the comparison patients (p<0.05).
5. Time between the initial urinary stone attack and IBS onset
The time between experiencing an initial urinary stone attack and new-onset IBS in the study period is shown inFig 2. Most IBS cases (30.5%) occurred within the first 6 months after the urinary stone attack.
Discussion
Although the incidence of IBS and its impact on human life is high worldwide[1–3], its patho-physiological mechanisms remain unclear. Several studies have previously reported that the neurotransmitter pathways of IBS and urinary stone attack are similar, with serotonin-related visceral pain or viscero-visceral hyperalgesia [23,25,26,31–34]; therefore, we suspected that uri-nary stone attack may be a major cause of IBS. One previous study reported that the relative risk of developing IBS was 2.48-fold higher in patients with urinary stone disease than in those without urinary stone disease in a small sample size.[35] However, the relationship between IBS and urinary stone disease has never been well demonstrated in large papulation. In this study, we aimed to analyze the relationship between a diagnosis of first urinary stone attack and the risk of new-onset IBS within a 3-year follow-up period.
Clinically, serotonin plays a key factor in colic pain via purinergic mechanosensory trans-duction, and it is also the most significant neurotransmitter in the pathogenesis of IBS. [21,31,32] Serotonin is a paracrine signaling molecule found widely throughout the gastroin-testinal tract, and it modulates governing functions, such as motility, secretion, sensation, and blood flow.[17–20] It can be released from enterochromaffin cells and the enteric motor system
Table 2. Crude HRs for new-onset irritable bowel syndrome among patients with urinary stone attack and comparison patients. New-Onset IBS Total Sample (n = 53,016) Patients with Urinary Stone Attack
(n = 13,254)
Comparison Patients (n = 39,762)
3-year follow-up No. % No. % No. %
Yes 1,474 2.8 440 3.3 1,034 2.6
No 51,542 97.2 12,814 96.7 38,728 97.4
Crude HR (95% CI)
- 1.29* (1.15–1.44) 1.00
*p<0.0001. HR, hazard ratio; IBS, irritable bowel syndrome. doi:10.1371/journal.pone.0157701.t002
by triggering by chemical signals, especially conducted by luminal distension.[23,34] Serotonin receptors modulate visceral pain and assist in peristalsis, and the emotional component of vis-ceral stimulation seems to be affected through these receptors within the CNS.[36–38] Urinary stones in the ureter or urinary bladder induce distension of tubes or sacs. This leads to the release of ATP from the epithelium lining the tube or sac, which then acts on purinoceptors (P2X3 and P2X2/3) on subepithelial sensory nerves to convey sensory/nociceptive information to the CNS. This neurotransmitter pathway also leads to visceral pain though serotonin release and purinergic mechanosensory transduction.[23,24] Because this neurotransmitter pathway is similar to IBS, we suspected that the IBS may be induced by increased serotonin released from patients with urinary stone attacks. In addition, viscero-visceral hyperalgesia might con-tribute to IBS in patients with urinary stones. Several previous studies reported that colon-blad-der cross-sensitization could induce painful symptoms. Patients with IBS often co-exhibit
Table 3. Adjusted-effect estimates for urinary stone attack.
Occurrence of new-onset irritable bowel syndrome
Mode 1 Mode 2 Mode 3
Variables HR 95% CI HR 95% CI HR 95% CI Groups Patients with urinary stone 1.29 1.15–1.44 1.26 1.13–1.41 1.28 1.13–1.42 Control* 1.00 - 1.00 - 1.00 -Geographic regions Northern* 1.00 - - - 1.00 -Central 0.99 0.86–1.14 - - 0.98 0.85–1.13 South 1.01 0.88–1.15 - - 0.99 0.87–1.14 Eastern 0.63 0.44–0.91 - - 0.62 0.43–0.89 Economic level (monthly income, USD$) >1,000* 1.00 - - - 1.00 -600–1,000 0.92 0.81–1.04 - - 0.92 0.81–1.05 <600 0.85 0.74–0.99 - - 0.87 0.75–1.01 Urbanization 1* 1.00 - - - 1.00 -2 1.10 0.92–1.31 - - 1.09 0.91–1.30 3 0.99 0.86–1.14 - - 0.98 0.85–1.13 4 1.11 0.95–1.28 - - 1.11 0.96–1.28 Personal history Diabetes - - 1.08 0.88–1.31 1.08 0.88–1.31 Hypertension - - 1.12 0.95–1.32 1.12 0.95–1.32 Renal failure - - 1.28 0.94–1.74 1.27 0.93–1.73 Liver cirrhosis - - 1.62 1.37–1.93 1.61 1.36–1.91 Stroke - - 1.84 1.19–2.85 1.86 1.20–2.88 Osteoporosis - - 1.36 0.18–1.57 1.36 1.18–1.57 Fibromyalgia - - 1.33 1.19–1.48 1.33 1.19–1.48
*Reference group. Mode 1: Adjusted by demographics (i.e., economic level of family, degree of urbanization and geographical location). Mode 2: Adjusted by personal disease histories (i.e., diabete, hypertension, renal failure, liver cirrhosis, stroke, osteoporosis andfibromyalgia). Mode 3: Adjusted by demographics and personal disease histories.
urinary hypersensitivity.[28,39,40] Moreover, some animal studies on colon-bladder sensitiza-tion demonstrated that acute or chronic colon irritasensitiza-tion could increase the frequency of blad-der contractions and alter micturition reflexes.[27,41] Drug-induced bladder inflammation not only causes bladder hypersensitivity but also induces colon distension.[42,43] Although the mechanisms of viscero-visceral hyperalgesia are not very clear, the most credited hypothesis is that this phenomenon derives from the sensitization of neurons that receiving convergent sen-sory input from the two affected visceral organs.[25] Sensory afferent information from the bowel and urinary bladder may converge at the level of the dorsal root ganglion (DRG).
Table 4. Clinical features associated with new-onset irritable bowel syndrome in patients with urinary stone attack. Patients with Urinary Stone Attack (n = 13,254) Comparison Patients (n = 39,762) New-Onset IBS (n = 440) No. (%) p New-Onset IBS (n = 1,034) No. (%) p Gender 0.056 0.001 Male 289 (65.7) 674 (68.2) Mean age 47.9±14.8 49.1±15.6
Age group (y/o)* 0.003 <0.001
30 52 (11.8) 122 (11.8) 30–39 94 (21.4) 195 (18.9) 40–49 107 (24.3) 231 (22.3) 50–59 94 (21.4) 231 (22.3) 60–69 52 (11.8) 145 (14.0) 70–79 37 (8.4) 86 (8.3) 80 4 (0.9) 24 (2.3)
Economic level (monthly income) (USD$) 0.494 0.645 <600 107 (24.3) 259 (25.0) 600–1,000 228 (51.8) 492 (47.6) >1,000 105 (23.9) 283 (27.4) Geography regions of Taiwan 0.266 0.241 Northern 229 (52.2) 530 (51.3) Central 96 (21.9) 236 (22.8) Southern 103 (23.5) 247 (23.9) Eastern 11 (2.5) 21 (2.0) Urbanization 0.403 0.171 1 (most) 114 (25.9) 294 (28.4) 2 62 (14.1) 133 (12.9) 3 124 (28.2) 271 (26.2) 4 140 (31.8) 336 (32.5) Personal history Diabetes mellitus* 46 (10.5) 0.009 70 (6.8) 0.895 Hypertension 51 (11.6) 0.352 164 (15.9) <0.001 Renal failure 16 (3.6) 0.166 27 (2.6) 0.330 Liver cirrhosis 35 (8.0) 0.991 131 (12.7) <0.001 Stroke 6 (1.4) 0.052 15 (1.5) 0.018 Osteoporosis* 103 (23.4) <0.001 219 (21.2) <0.001 Fibromyalgia* 195(44.3) <0.001 388(37.5) <0.001
*Significant features associated with irritable bowel syndrome in study group, p<0.05. IBS, irritable bowel syndrome. doi:10.1371/journal.pone.0157701.t004
Table 5. Multiple logistic regression analysis of suffering new-onset IBS for all patients, study patients and comparison patients. All patients (n = 53,016) Patients with Urinary Stone Attack
(n = 13,254)
Comparison Patients (n = 39,762)
Variables OR 95% C.I. OR 95% C.I. OR 95% C.I.
Gender
Female* 1.00 - 1.00 - 1.00
-Male 0.87 0.78–0.98 0.91 0.74–1.12 0.86 0.75–0.98
Age group (y/o)
30* 1.00 - 1.00 - 1.00 -30–39 1.01 0.83–1.22 1.13 0.80–1.60 0.96 0.76–1.21 40–49 1.06 0.88–1.28 1.16 0.83–1.64 1.03 0.82–1.29 50–59 1.29 1.06–1.57 1.30 0.90–1.86 1.30 1.03–1.64 60–69 1.48 1.19–1.85 1.38 0.91–2.10 1.53 1.18–1.99 70–79 1.85 1.44–2.38 1.97 1.25–3.12 1.81 1.34–2.45 80 1.78 1.17–2.71 0.95 0.33–2.69 2.13 1.34–3.39 Economic level (monthly income, USD$) <600* 1.00 - 1.00 - 1.00 -601–1,000 1.05 0.93–1.20 1.11 0.87–1.40 1.02 0.88–1.20 >1,000 1.13 0.97–1.31 1.12 0.85–1.49 1.14 0.95–1.35 Geographic regions Northern* 1.00 - 1.00 - 1.00 -Central 0.98 0.84–1.13 0.88 0.67–1.15 1.02 0.86–1.22 Southern 0.98 0.86–1.12 1.08 0.85–1.39 0.96 0.82–1.12 Eastern 0.62 0.43–0.89 0.58 0.30–1.12 0.64 0.41–0.99 Urbanization 1 (most)* 1.00 - 1.00 - 1.00 -2 1.09 0.90–1.30 1.33 0.95–1.85 0.99 0.80–1.25 3 0.98 0.85–1.14 1.06 0.81–1.39 0.95 0.80–1.13 4 1.11 0.96–1.29 1.11 0.84–1.46 1.10 0.92–1.32 Diabetes mellitus Yes 1.08 0.88–1.33 1.46 1.04–2.04 0.92 0.71–1.19 No* 1.00 - 1.00 - 1.00 -Hypertension Yes 1.13 0.95–1.34 0.82 0.59–1.15 1.26 1.04–1.54 No* 1.00 - 1.00 - 1.00 -Renal failure Yes 1.29 0.94–1.76 1.41 0.84–2.38 1.21 0.81–1.80 No* 1.00 - 1.00 - 1.00 -Liver cirrhosis Yes 1.62 1.36–1.93 0.99 0.69–1.43 1.93 1.58–2.35 No* 1.00 - 1.00 - 1.00 -Stroke Yes 1.87 1.19–2.94 2.19 0.93–5.15 1.79 1.05–3.05 No* 1.00 - 1.00 - 1.00 -Osteoporosis Yes 1.37 1.19–1.59 1.34 1.03–1.74 1.37 1.16–1.63 No* 1.00 - 1.00 - 1.00 -(Continued)
Noxious stimulus from a directly affected organ to an adjacent non-irritated structure follow-ing an inflammatory insult may be transmitted through the hyperexcitability of convergent DRG neurons.[44] Thus, stimulation from urinary stone disease may affect bowel dysmotility via viscero-visceral hyperalgesia and increase the chance of experiencing IBS.
To demonstrate the relationship between urinary stone disease and IBS, we retrospectively reviewed 53,016 (13,254 patients with an initial urinary stone attack and 39,762 matched non-urinary stone participants) cases from LHID in Taiwan and followed each of them for 3 years. According to our results, patients with an initial urinary stone attack were at higher risk for suf-fering new-onset IBS. Additionally, patients with urinary stones had significantly lower rates of 3-year IBS-free survival compared with control patients. Furthermore, after adjusting for patient demographics (mode 1) and personal histories (mode 2), the HRs of suffering new-onset IBS remained significantly higher in stone attack patients compared with controls. Finally, we found that most IBS occurred within the first 6 months after the initial urinary stone attack. The age distributions were not the same in the groups of patients with an initial
Table 5. (Continued)
All patients (n = 53,016) Patients with Urinary Stone Attack (n = 13,254)
Comparison Patients (n = 39,762)
Variables OR 95% C.I. OR 95% C.I. OR 95% C.I.
Fibromyalgia
Yes 1.35 1.21–1.50 1.46 1.20–1.78 1.29 1.13–1.47
No* 1.00 - 1.00 - 1.00
-*Reference group. OR, Adjusted odds ratio; C.I., confidence interval. doi:10.1371/journal.pone.0157701.t005
Fig 1. Time-related factors associated with new-onset irritable bowel syndrome occurrence. Irritable bowel syndrome-free survival curves for patients with urinary stone attack and comparison patients during the 3-year follow-up period (p = 0.001).
urinary stone and those with IBS. We suspect two possible reasons for the slight difference in age distribution: one, sampling bias (this study randomly selected patients from a database); and two, study design (urinary stone was always prior to IBS). Among patients with IBS, a his-tory of osteoporosis and fibromyalgia was more predominant in both the study and control groups. We suspect that malabsorption and inflammation related to IBS are two possible major causes of bone loss and may even induce osteoporosis.[45,46] Otherwise, a disrupted mucosal barrier and altered gut microbiota were observed in patients with IBS, which indicated the rela-tionship between IBS and fibromyalgia may partially reflect disorders in gastrointestinal per-meability. [47] In this study, diabetes was associated with IBS only in the study group. We suspect that insulin resistance is associated with defects in renal ammonium production, and acidic urine, which may cause uric acid stones, was more predominant among diabetes patients.[48–51]
According to the results mentioned above, we suggest that physicians consider urinary stone disease before or when IBS is diagnosed. This is especially important for patients previ-ously diagnosed with IBS, as they should be assessed to rule out the likelihood of urinary stone disease. A significant treatment challenge for patients and practitioners remains due to the complex nature of IBS. Antispasmodics, antidepressants, and bulking agents are frequently prescribed for IBS traditionally. Once urinary stone diseases are diagnosed in patients with IBS, passing urinary stones (i.e., extracorporeal shockwave lithotripsy or ureteroscopy [52]) may be considered rather than prescribing the symptomatic treatment for IBS. Otherwise, we suspect that the distension of tubes or sacs (caused by stones) will prolong serotonin release and puri-nergic mechanosensory transduction; therefore, the symptoms of IBS may not improve.
Fig 2. Most irritable bowel syndrome (30.5%) occurred within the first 6 months after the initial urinary stone attack.
In conclusion, patients with a first urinary stone attack are at increased risk of developing new-onset IBS. The HRs of suffering IBS did not decrease even after adjusting for patient demographics and prior histories. Most importantly, 30.5% of IBS occurred within the first 6 months after the initial urinary stone attack.
Limitations
A natural limitation for researchers who analyze data using the LHID database cannot be avoided is that diagnoses made before 1995 were not included since the LHID began in 1995. [53–54] Consequently, we cannot clearly exclude several patients had diagnoses of IBS or uri-nary stone diseases before 1995. To decrease this limitation, patients who had any medical record of IBS or urinary stone diseases from 1995 to 2003 were excluded. Moreover, ICD-9 over- or miscoding was another limitation. The codes sent to the National Health Database were made by the attending physicians in emergency/outpatient departments. The treating physicians in Taiwan must make and confirm all of the codes by following Taiwan law. Although the Rome criteria (criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis) are commonly used to diagnose IBS, physicians may overdiagnose this syndrome because of its various clinical presentations and uncertain pathophysiology. In this study, some patients (30.5%) were diagnosed with IBS within the first 6 months after initial stone attack. We suspect two possible reasons for this result: one, some of these patients might have had symptoms of IBS (but no IBS diagnosis or presentation at the hospital) before the uri-nary stone attack; and two, physicians might overdiagnose IBS (not following the Rome crite-ria). The first issue is a natural limitation of a database-based study, but the second issue has been improved by the government-supported NHI program (see themethodssection: quality control). The number of fibromyalgia patients might have been overestimated because the par-ticular ICD-9 code, 729.1, could be easily used to code common myalgia or myositis (natural limitation of the ICD-9). Finally, patients with an initial urinary stone attack may have been over-excluded. We excluded patients if their urinary stone diseases were only the co-diagnosis (or not the major reason for their hospital visit) because they may not be suffering a stone attack.
Acknowledgments
We appreciated the National Changhua Christian Hospital, Chiao Tung University and National Science Council (MOST 104-2314-B-371-010) for financially supporting this research.
Author Contributions
Conceived and designed the experiments: WYL CYC YRL. Performed the experiments: YRL HPW FHL CYC CFC. Analyzed the data: YRL WYL JHW. Contributed reagents/materials/ analysis tools: HPW YRL CHC CYC. Wrote the paper: WYL HPW YRL.
References
1. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syn-drome. Gastroenterology. 2002; 123: 2108–2131. PMID:12454866
2. Cremonini F, Talley NJ. Irritable bowel syndrome: epidemiology, natural history, health care seeking and emerging risk factors. Gastroenterol Clin North Am. 2005; 34: 189–204. PMID:15862929 3. Drossman DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Thompson WG, et al. U.S. householder survey
of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci. 1993; 38: 1569–1580. PMID:8359066
4. Hulisz D. The burden of illness of irritable bowel syndrome: current challenges and hope for the future. J Manag Care Pharm. 2004; 10: 299–309. PMID:15298528
5. Leong SA, Barghout V, Birnbaum HG, Thibeault CE, Ben-Hamadi R, Frech F, et al. The economic con-sequences of irritable bowel syndrome: a US employer perspective. Arch Intern Med. 2003; 163: 929– 935. PMID:12719202
6. Stanghellini V, Tosetti C, Barbara G, De Giorgio R, Cogliandro L, Cogliandro R, et al. Dyspeptic symp-toms and gastric emptying in the irritable bowel syndrome. Am J Gastroenterol. 2002; 97: 2738–2743. PMID:12425541
7. Cann PA, Read NW, Brown C, Hobson N, Holdsworth CD. Irritable bowel syndrome: relationship of dis-orders in the transit of a single solid meal to symptom patterns. Gut. 1983; 24: 405–411. PMID: 6840614
8. Tillisch K, Labus JS. Advances in imaging the brain-gut axis: functional gastrointestinal disorders. Gastroenterology. 2011; 140: 407–411.e1. doi:10.1053/j.gastro.2010.12.014PMID:21167161 9. Tillisch K, Mayer EA, Labus JS. Quantitative meta-analysis identifies brain regions activated during
rec-tal distension in irritable bowel syndrome. Gastroenterology. 2011; 140: 91–100. doi:10.1053/j.gastro. 2010.07.053PMID:20696168
10. Mearin F, Perello A, Balboa A. Irritable bowel syndrome and inflammatory bowel disease: Is there a connection? Gastroenterol Hepatol. 2009; 32: 364–372. doi:10.1016/j.gastrohep.2008.12.007PMID: 19442413
11. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, et al. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology. 2002; 122: 1778–1783. PMID:12055584 12. Cremon C, Gargano L, Morselli-Labate AM, Santini D, Cogliandro RF, De Giorgio R, et al. Mucosal
immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol. 2009; 104: 392–400. doi:10.1038/ajg.2008.94PMID:19174797 13. Barbara G. Mucosal barrier defects in irritable bowel syndrome. Who left the door open? Am J
Gastro-enterol. 2006; 101: 1295–1298. PMID:16771952
14. Camilleri M, Lasch K, Zhou W. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012; 303: G775–85. doi:10.1152/ajpgi.00155.2012PMID: 22837345
15. Wang WF, Yang YS, Peng LH, Sun G. Alternation of substance P-containing neural pathways in a rat model of irritable bowel syndrome with rectal distension. Chin J Dig Dis. 2006; 7: 211–8. PMID: 17054583
16. Gaudreau G, Plourde V. Involvement of N-methyl-d-aspartate (NMDA) receptors in a rat model of vis-ceral hypersensitivity. Behav Brain Res. 2004; 150: 185–189. PMID:15033291
17. Greenwood-van Meerveld B. Importance of 5-hydroxytryptamine receptors on intestinal afferents in the regulation of visceral sensitivity. Neurogastroenterol Motil. 2007; 19 Suppl 2: 13–18. PMID:17620083 18. Gershon MD. Review article: serotonin receptors and transporters—roles in normal and abnormal
gas-trointestinal motility. Aliment Pharmacol Ther. 2004; 20 Suppl 7: 3–14. PMID:15521849
19. Gershon M. Review article: roles played by 5‐hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther. 1999; 13: 15–30.
20. Crowell MD. Role of serotonin in the pathophysiology of the irritable bowel syndrome. Br J Pharmacol. 2004; 141: 1285–1293. PMID:15100164
21. Burnstock G. Purinergic mechanosensory transduction and visceral pain. Mol Pain. 2009; 5: 69-8069-5-69.
22. Curhan GC. Epidemiology of stone disease. Urol Clin North Am. 2007; 34: 287–293. PMID:17678980 23. Burnstock G. Release of vasoactive substances from endothelial cells by shear stress and purinergic
mechanosensory transduction. J Anat. 1999; 194 (Pt 3): 335–342. PMID:10386771 24. Burnstock G. Expanding field of purinergic signaling. Drug Dev Res. 2001; 52: 1–10.
25. Giamberardino MA, Costantini R, Affaitati G, Fabrizio A, Lapenna D, Tafuri E, et al. Viscero-visceral hyperalgesia: characterization in different clinical models. Pain. 2010; 151: 307–322. doi:10.1016/j. pain.2010.06.023PMID:20638177
26. Lopopolo M, Affaitati G, Fabrizio A, Massimini F, Lapenna D, Giamberardino MA, et al. Effects of trama-dol on viscero-visceral hyperalgesia in a rat model of endometriosis plus ureteral calculosis. Fundam Clin Pharmacol. 2014; 28: 331–341. doi:10.1111/fcp.12038PMID:23786290
27. Lamb K, Zhong F, Gebhart GF, Bielefeldt K. Experimental colitis in mice and sensitization of converging visceral and somatic afferent pathways. Am J Physiol Gastrointest Liver Physiol. 2006; 290: G451–7. PMID:16195421
28. Bielefeldt K, Lamb K, Gebhart GF. Convergence of sensory pathways in the development of somatic and visceral hypersensitivity. Am J Physiol Gastrointest Liver Physiol. 2006; 291: G658–65. PMID: 16500917
29. Chang CY, Chen WL, Liou YF, Ke CC, Lee HC, Huang HL, et al. Increased risk of major depression in the three years following a femoral neck fracture—a national population-based follow-up study. PLoS One. 2014; 9: e89867. doi:10.1371/journal.pone.0089867PMID:24626193
30. Kuo CL, Chen CY, Huang HL, Chen WL, Lee HC, Chang CY, et al. Increased risk of major depression subsequent to a first-attack and non-infection caused urticaria in adolescence: a nationwide popula-tion-based study. BMC Pediatr. 2014; 14: 181-2431-14-181.
31. Burnstock G, Wood JN. Purinergic receptors: their role in nociception and primary afferent neurotrans-mission. Curr Opin Neurobiol. 1996; 6: 526–532. PMID:8794102
32. Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev. 2007; 87: 659–797. PMID:17429044
33. Cooke HJ, Wunderlich J, Christofi FL. "The force be with you": ATP in gut mechanosensory transduc-tion. News Physiol Sci. 2003; 18: 43–49. PMID:12644618
34. Burnstock G. Expanding field of purinergic signaling. Drug Dev Res. 2001; 52: 1–10.
35. Erdem E, Akbay E, Sezgin O, Doruk E, Canpolat B, Cayan S. Is there a relation between irritable Bowel syndrome and urinary stone disease? Dig Dis Sci. 2005; 50: 605–608. PMID:15810650
36. Gershon MD. 5-HT (serotonin) physiology and related drugs. Curr Opin Gastroenterol. 2000; 16: 113– 120. PMID:17024028
37. Bardhan KD, Bodemar G, Geldof H, Schutz E, Heath A, Mills JG, et al. A double-blind, randomized, pla-cebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther. 2000; 14: 23–34.
38. Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther. 2000; 14: 775– 782. PMID:10848662
39. Pezzone MA, Liang R, Fraser MO. A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology. 2005; 128: 1953–1964. PMID: 15940629
40. Whorwell PJ, McCallum M, Creed FH, Roberts CT. Non-colonic features of irritable bowel syndrome. Gut. 1986; 27: 37–40. PMID:3949235
41. Peng HY, Chen GD, Tung KC, Lai CY, Hsien MC, Chiu CH, et al. Colon mustard oil instillation induced cross-organ reflex sensitization on the pelvic-urethra reflex activity in rats. Pain. 2009; 142: 75–88. doi: 10.1016/j.pain.2008.11.017PMID:19167822
42. Laird JM, Souslova V, Wood JN, Cervero F. Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J Neurosci. 2002; 22: 8352–8356. PMID:12351708
43. Korkmaz A, Oter S, Seyrek M, Topal T. Molecular, genetic and epigenetic pathways of peroxynitrite-induced cellular toxicity. Interdiscip Toxicol. 2009; 2: 219–228. doi:10.2478/v10102-009-0020-4PMID: 21217858
44. Malykhina AP, Qin C, Greenwood-van Meerveld B, Foreman RD, Lupu F, Akbarali HI. Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross-talk. Neurogastroenterol Motil. 2006; 18: 936–948. PMID:16961697
45. Bianchi ML. Inflammatory bowel diseases, celiac disease, and bone. Arch Biochem Biophys. 2010; 503: 54–65. doi:10.1016/j.abb.2010.06.026PMID:20599670
46. Yen CM, Muo CH, Lin MC, Chang SN, Chang YJ, Kao CH. A nationwide population cohort study: irrita-ble bowel syndrome is a risk factor of osteoporosis. Eur J Intern Med. 2014; 25: 87–91. doi:10.1016/j. ejim.2013.10.009PMID:24183216
47. Yang TY, Chen CS, Lin CL, Lin WM, Kuo CN, Kao CH. Risk for irritable bowel syndrome in fibromyalgia patients: a national database study. Medicine (Baltimore). 2015; 94: e616.
48. Pak CY, Sakhaee K, Moe O, Preminger GM, Poindexter JR, Peterson RD, et al. Biochemical profile of stone-forming patients with diabetes mellitus. Urology. 2003; 61: 523–527. PMID:12639639
49. Abate N, Chandalia M, Cabo-Chan AV,Jr, Moe OW, Sakhaee K. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int. 2004; 65: 386– 392. PMID:14717908
50. Sakhaee K, Adams-Huet B, Moe OW, Pak CY. Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int. 2002; 62: 971–979. PMID:12164880
51. Nerli R, Jali M, Guntaka AK, Patne P, Patil S, Hiremath MB. Type 2 diabetes mellitus and renal stones. Adv Biomed Res. 2015; 4: 180–9175.164012. eCollection 2015.
52. Türk C, Petřík A, Sarica K, Seitz C, Skolarikos A, Straub M, et al. EAU guidelines on interventional treat-ment for urolithiasis. Eur Urol. 2015; 4: S0302–2838
53. Hsu CS, Huang CJ, Kao JH, Lin HH, Chao YC, Fan YC, et al. Interferon-based therapy decreases risks of hepatocellular carcinoma and complications of cirrhosis in chronic hepatitis C patients. PLoS One. 2013; 8: e70458. doi:10.1371/journal.pone.0070458PMID:23894660
54. Chen YH, Kang JH, Lin HC. Patients with traumatic brain injury: population-based study suggests increased risk of stroke. Stroke. 2011; 42: 2733–2739. doi:10.1161/STROKEAHA.111.620112PMID: 21799162
