Colonic diverticulosis (CD) is the herniation of the colonic mucosa through the circular muscle layer at various points. The underlying pathological mechanisms that cause the formation of colonic diverticula remain unknown.1 The prevalence of CD is estimated 13.5% in Taiwan and even higher in older people (up to 71.4% for age > 80 years in USA).2,3 The common complications of CD include abdominal pain, diverticulitis, peritonitis, obstruction, fistulization, or abscess formation.4,5 In addition to these recurrent acute complications and chronic abdominal pain, model theories suggested that CD can cause some chronic disease and effect qualities of life.6 Chronic inflammation and microbiome shifts are potential etiologic factors for CD.7–11 Chronic inflammation plays a role in the pathogenesis of cardiovascular disease, venous thromboembolism, and arterial atherosclerosis.12 Therefore, CD may increase relevant diseases associated with this condition. For example, CD was recently found to increase the risk of arterial and venous thromboembolic events.13
Erectile dysfunction (ED) is a consistent or recurrent inability to obtain or maintain penile erection sufficient for sexual activity. The prevalence of ED increases with age and can reach 20% to 40% for men in their 60 s.14 Evidence has shown that ED is associated with cardiovascular disease and coronary artery disease (CAD).15,16 Erectile dysfunction was considered a predictor of silent CAD in diabetic populations.17 Studies also found that ED became evident before angina symptoms18 and preceded CAD by an average of 2 to 3 years.19 Subclinical endothelial dysfunction and low-grade inflammation may be the underlying pathogenesis of ED.20
Colonic diverticulosis was closely linked to chronic inflammation and thromboembolism which were important etiological factors of ED. It is possible that CD can increase ED. So we conducted a large population-based cohort study to see if CD was associated with ED.
The National Health Insurance Research Database (NHIRD) is derived from the mandatory single-payer National Health Insurance (NHI) program initiated by the Taiwan government in 1995. By 2014, >24 million people, representing ∼99% of the population of Taiwan, were covered by the NHI program.21 In this study, we analyzed data from the Longitudinal Health Insurance Database 2000, a subset of the NHIRD that contains the data of 1,000,000 randomly sampled patients, who were traced retrospectively to 1996 and followed-up to 2011. The National Health Research Institute (NHRI) has confirmed these random samples as representative of the general population of Taiwan. The NHRI safeguards the privacy of patients and provides data to researchers after ethical approval has been obtained. This retrospective study was approved to fulfill the condition for exemption by the Institutional Review Board (IRB) of China Medical University (CMUH-104-REC2-115). The IRB also specifically waived the consent requirement.
Male patients, aged 20 years and older and newly diagnosed with CD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 562.10, 562.11, 562.12, 562.13) from 1998 to 2011, were identified as the CD cohort. The date of CD diagnosis was considered the index date. Patients with a history of ED (ICD-9-CM codes 302.72, 607.84) diagnosed before the index date, with missing information, and aged <20 years were excluded. The comparison cohort included patients without a history of CD or ED, frequency-matched with the CD cohort patients at a ratio of 1:4 for age (in 5-year bands) and year of CD diagnosis by using the same exclusion criteria. The index date for comparison subjects was randomly appointed a month and day with the same index year of the matched CD cases.
Outcome and Comorbidities
The main outcome was outpatient visits or hospitalization with a new diagnosis of ED during the follow-up. The duration of follow-up was estimated from the index date until ED occurred, withdrawal from the insurance system, or the end of 2011. Baseline comorbidities included CAD (ICD-9-CM codes 410–414), chronic obstructive pulmonary disease (COPD) (ICD-9-CM codes 491, 492, 496), chronic kidney disease (CKD) (ICD-9-CM codes 580–589), hypertension (ICD-9-CM codes 401–405), diabetes (ICD-9-CM code 250), hyperlipidemia (ICD-9-CM code 272), depression (ICD-9-CM codes 296.2–296.3, 300.4, 311), stroke (ICD-9-CM codes 430–438), asthma (ICD-9-CM code 493), and alcohol-related illness (ICD-9-CM codes 291, 303, 305, 571.0, 571.1, 571.2, 571.3, 790.3, A215, and V11.3).
The distribution of categorical demographic characteristics and comorbidities were compared between CD and comparison cohorts. Differences were examined using the chi-square test for categorical variables. The mean ages and follow-up periods were measured and examined using a Student t test. The overall and age-specific incidence density rates of ED (per 1000 person-years) were calculated. Univariate and multivariate Cox proportional hazards regression models were used for examining the effects of CD on the risk of ED, and shown as hazard ratios (HRs) with 95% confidence intervals (CIs). The multivariate models were simultaneously adjusted for age and the comorbidities of CAD, COPD, CKD, hypertension, diabetes, hyperlipidemia, depression, stroke, asthma, and alcohol-related illness. A Kaplan–Meier analysis plot was used for showing the cumulative incidence of ED, and log-rank test was used for examining the differences between the 2 cohorts. All data analyses were conducted using SAS statistical software (version 9.3 for Windows; SAS Institute Inc., Cary, NC). Two-tailed P < .05 was considered significant.
Eligible study participants comprised 2879 patients in the CD cohort and 11,504 persons in the comparison cohort, with a similar age distribution (Table 1). The mean age in the CD and comparison cohorts were 55.2 (SD = 17.7) years and 54.6 (SD = 17.8) years, respectively. At baseline, the comorbidities of CAD, COPD, CKD, hypertension, diabetes, hyperlipidemia, depression, stroke, asthma, and alcohol-related illness were more prevalent in the CD cohort than in the comparison cohort. The average follow-up duration was 4.76 years for patients with CD and 4.97 years for the comparison cohort. Kaplan–Meier analysis showed that the cumulative incidence of ED after 14 years of follow-up was higher in the CD cohort than in the comparison cohort (log-rank test, P = 0.004, Figure 1). The overall incidence of ED was 1.70-fold higher in the CD cohort than in the comparison cohort (2.92 and 1.71 per 1000 person-years, respectively, Table 2). After we adjusted for age and the comorbidities of CAD, COPD, CKD, hypertension, diabetes, hyperlipidemia, depression, stroke, asthma, and alcohol-related illness, patients with CD were associated with an increased risk of ED compared with those without CD (aHR = 1.56, 95% CI = 1.07–2.28). The age-specific incidence and relative risk of ED were highest for men aged ≥60 years in the CD cohort (3.46 per 1000 person-years, aHR = 1.97, 95% CI = 1.09–3.56). We analyzed the association between CD and the risk of ED stratified by comorbidity and found an ∼1.50-fold ED risk was observed in patients without comorbidities (adjusted HR = 1.50, 95% CI: 1.22–3.13).
The results of multivariate Cox proportional hazard regression models for the risk of related variables contributing to ED are shown in Table 3. The risk of developing ED increased 3.16-fold (95% CI = 1.84–5.45) with the comorbidity of depression and 1.71-fold (95% CI = 1.06–2.76) with the comorbidity of asthma. Furthermore, CD patients with depression were at a higher risk of ED than comparison patients without depression (aHR = 4.71, 95% CI = 2.13–10.4, Table 4). Relative to the patients without CD and asthma, the CD patients with asthma were at a higher risk of ED (aHR = 2.22, 95% CI = 1.02–4.84).
To best of our knowledge, this is the first study to investigate the association between CD and ED by using a nationwide population database. Patients with CD had an increased risk of developing ED after adjusting major comorbidities. The patients with CD had 1.56-fold higher incidence of ED than non-CD patients. We also found that depression and asthma were associated with ED. The CD patients with depression had the highest incidence of ED.
Alcohol consumption and smoking habit are important risk factors for ED.22 Similarly, alcohol consumption and smoking are also risk factors for CD.23,24 Could the increase in ED on the CD group observed be due to an increased alcohol consumption and smoking in the CD group? To minimize the influence from smoking and alcohol, we used an alternative way and adjusted for smoking-related diseases (including COPD, CAD, stroke, asthma) and alcohol-related illness in our analysis. After we adjusted for age and comorbidities, the CD patients still exhibited a significantly increase risk of ED than did the comparison cohort. We speculated that the increase of ED incidence in our CD patients cannot be fully explained by sharing similar risk factors.
The exact pathophysiology of CD leading to ED is not clear. Chronic inflammation, an important mechanism of CD, may be possible reason for increasing subsequent ED. It is widely accepted that chronic intestinal inflammation may cause a low-grade inflammation status in CD patients.6–8 Lymphocytic inflammation of colon was noted in CD patients without overt colitis.25 Also, colon mucosa around the diverticula from patients who underwent surgery for symptomatic uncomplicated diverticular disease (SUDD) often demonstrated chronic inflammation.26 Some indirect evidence supports a potential association between intestinal microbiota and CD, therefore leading to chronic inflammation. For example, Rifaximin, a nonsystemic antibiotic, may reduce the attacks of recurrent diverticulitis and treat gastrointestinal symptoms in patients with SUDD.9,10 A low-fiber diet may change gut microbiota and is a possible risk factor for CD.11 Bacteria overgrowth was also observed in patients with uncomplicated acute diverticulitis.27 Chronic inflammation was known as a pathologic factor of cardiovascular disease, venous thromboembolism, and arterial atherosclerosis.12 This was demonstrated by the fact that both inflammatory bowel disease and CD were associated with vascular disease and thromboembolic events.13,28,29 ED was closely linked to chronic inflammation and vascular disease.15,20 Increased inflammatory and endothelial-prothrombotic activation were significantly increased in patients with ED.30 Atherosclerosis of penis arteries was proposed as the vascular etiology of ED.31 These sharing pathophysiological factors between ED and CD may support our study findings. In our study, we also found that asthma was an independent risk of ED (aHR: 1.71, 95% CI: 1.06–2.76). We think this finding can also be explained by the fact that asthma is also associated with systemic inflammation.32–34 Asthma was also found to increase ED risk in another population-based study.35 The author also proposed that systemic inflammation may subsequently contribute to endothelial dysfunction, which is central to the pathogenesis of ED.
Our study result suggested that both depression and CD are independent risk factors for ED. Depressive symptoms are established as a definite risk factor for ED.36 Could the coexisted depression in CD patients is the true causal factor to subsequent ED? Indeed, CD patients reported lower health-related quality of life and higher emotional stress than controls. And CD patients also had higher incidence of anxiety and stress than no-CD patients.37–39 However, depression significantly affects CD patients not only in psychological dimension. For example, increased depression and anxiety are known to associate with recurrent pain in CD patients, independent of previous colonic inflammation (like history of acute diverticulitis).39 Thus, CD patients may have more gastrointestinal symptoms if they had depressed mood. On the other hand, the severity of gastrointestinal symptoms in other function gastrointestinal diseases like irritable bowel syndrome (IBS) and functional dyspepsia has been demonstrated to be positively associated with sexual dysfunction, independent of psychological symptom severity.40 Irritable bowel syndrome and CD are closely related.41 Diverticulitis appears to predispose patients to long-term gastrointestinal and emotional symptoms after resolution of inflammation, which is called postdiverticulitis IBS.42 But it is also possible that ongoing gastrointestinal symptoms after a diverticulitis attack result from recurrent low-grade diverticulitis. Part of CD patients may suffer from chronic pain and depression that persist out of their acute attack. From aforementioned study findings, depression and bowel symptoms are both independent risk factors for ED. This was also compatible with our study finding, which suggested that depression and CD had a synergic effect to increase ED risk (aHR = 4.71, 95% CI = 2.13–10.4, Table 4). It may be warranted that we may need to care both depression and bowel symptoms of CD patients, which may cause subsequent ED.
This study had several limitations. First, the NHIRD does not contain detailed personal information, such as smoking habit, alcohol consumption, BMI, physical activity level, and body habitus. Consequently, we could not adjust for these factors, which may have influenced our results. But we had tried to eliminate the effect of smoking and alcohol by adjusting related disorders. Second, ICD-9-CM codes, instead of detailed medical history, image diagnosis, and patient self-reported questionnaire data, were used for assigning patients with CD and ED. Third, the incidence of CD locations is different from east countries to west countries. Colonic diverticulosis was dominantly on the right side in patients in Japan, in contrast to those in Europe and the United States.43 We did not have information about the location of diverticulum from the NHIRD database. So we are not sure the same result can reproduced in west countries. Finally, this was a retrospective cohort study, consequently making bias and confounders inevitable. But the large sample size of our study affords considerable statistical power for detecting real, even subtle, differences between the 2 cohorts. Additional well-designed population-based studies may confirm our findings.
In this large retrospective cohort study, we demonstrated that CD patients may have a higher risk of developing ED than non-CD patients did. The CD patients with depression had even higher risk of developing ED. Our findings support the evolving paradigm of diverticular disease as a chronic illness, which impacts on qualities of life and sexual health of our patients. It is very important that physicians should not to see CD as a merely recurrent acute illness. They should start to be awareness of potential concurrent physical and psychological stress of these patients and take action to manage them. Additional studies are also required for confirming the association between CD and ED. If the association were proved, it is also important to know whether treatment for diverticulosis can slow the development or progression of ED.
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