Higher waist circumference as a risk factor for rebleeding of small bowel angiodysplasia

Introduction

Angiodysplasia is the most prevalent cause of chronic or recurrent gastrointestinal hemorrhage in older adults (1-5). This condition is frequently observed in the colon (1,6), but small bowel angiodysplasia (SBA) is the leading cause of middle gastrointestinal bleeding (7-9).

Angiodysplasia are believed to arise from dysregulation within the angiogenic pathway, characterized by a fragile equilibrium between the initiation and maturation stages of new vessel formation (10-12). Angiodysplasia are characterized by stimuli, including hypoxia and inflammation, which are believed to alter the angiogenic cascade. This alteration results in the excessive formation of inadequately structured blood vessels that lack smooth muscle layers, rendering them susceptible to hemorrhage. Although the specific angiogenic factors involved in sporadic SBA are not yet identified, vascular endothelial growth factor (VEGF) is recognized as a significant contributor to colonic angiodysplasia (13). VEGF, part of the platelet-derived growth factor (PDGF) family, along with angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2), is crucial in the process of angiogenesis (10). A recent study by Holleran et al. (14) observed an unbalanced Ang-1/Ang-2 ratio in SBA patients with bleeding; an Ang-2 level of >2,600 pg/mL was found to be predictive of SBA and the authors suggest shared changes in Ang-1 and Ang-2 levels across a variety of gastrointestinal vascular disorders, including SBA, gastric antral vascular ectasia (GAVE) and portal hypertensive gastropathy (PHG). Recent evidence in murine models shows that Ang-2 facilitates angiogenesis in adipose tissue, promoting vascular expansion during obesity, and exacerbates adipose tissue inflammation in obesity by macrophage recruitment. Still, non-endothelial factors like integrins in immune cells or adipocytes may influence the Ang-2expression, underscoring the need for new studies to integrate all processes experimentally (15-17).

Numerous therapeutic approaches, including endoscopic hemostasis, conservative management with blood and iron infusions, and pharmacotherapy with thalidomide and somatostatin analogs, have been proposed for symptomatic SBAs (18,19). Two years after diagnosis, these patients continue to have an elevated risk of rebleeding up to 50% (19,20). Few studies (21-23) have investigated rebleeding risk factors that could reduce morbidity and mortality in these patients. This study aimed to identify the independent risk factors associated with rebleeding in symptomatic patients initially managed conservatively. We present this article in accordance with the STROBE reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-6/rc).

Methods

Patients and study design

We conducted a retrospective cross-sectional examination of 104 capsule endoscopies performed for mid-gastrointestinal bleeding between January 2012 and December 2016 at the Gastroenterology Department of the “Francisco Morato de Oliveira” State Government Employee Hospital (HSPE-FMO), Brazil. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Research Ethics Committee (CEP/IAMSPE) approved the study (approval ID 64950517.5.0000.5463), and individual consent for this retrospective analysis was waived.

Data collection

Data were collected by reviewing medical records and consulting the capsule endoscopy reports database in the gastroenterology service archives. Two specialists with expertise in endoscopic capsules compiled these reports. PillCam SB2 capsules (Given Imaging, Yokneam, Israel) were used for examinations.

This study recruited adults with bleeding angiodysplasia confirmed by capsule endoscopy. A follow-up period of over one year was utilized to evaluate the rebleeding rate. Patients undergoing invasive treatments such as endoscopic, arteriographic, surgical, or specific pharmacological therapy at the start of the follow-up were excluded, as these treatments could reduce the rebleeding rate and introduce bias.

Demographic, clinical, and follow-up information was extracted from the hospital’s medical records and capsule endoscopy database. Overt or occult gastrointestinal bleeding presentation, active bleeding during capsule endoscopy, location and distribution of angiodysplasia in the small bowel, age, sex, body mass index (BMI), hemoglobin level, comorbidities, medication use (including antiplatelet aggregators, anticoagulants, or non-steroidal anti-inflammatory drugs), and other factors as well as the presence of concomitant GAVE were among them. As a routine in our service when performing the capsule endoscopy exam, the waist circumference (WC) is measured with a tape measure before putting on the belt with a recorder that will be placed around your waist during the exam, and the value is recorded on the report form of the capsule endoscopic exam performed.

After examination, the minimum follow-up time required to evaluate the rebleeding index was 12 months. If patients were managed conservatively initially and then switched to some specific treatment during follow-up, they were not excluded from the study. The location of angiodysplasia in the small intestine was classified as proximal or distal. It was considered distal when the small intestine’s transit time exceeded 40% (ileal topography). Multiple lesions were present when the small intestine contained three or more angiodysplasia.

All patients included in the study had regular outpatient follow-up, including routine laboratory tests. Rebleeding was identified by either a new episode of melena or hematochezia or a hemoglobin decrease of ≥2 g/dL during follow-up. In instances of rebleeding, upper digestive endoscopy and colonoscopy were conducted to identify any additional gastrointestinal lesions responsible for the bleeding.

Statistical analysis

After evaluating medical records containing the necessary data for the study, statistical tests were applied to analyze the variables. SPSS v23 (IBM, Armonk, NY, USA) was used for statistical analysis.

Initially, a descriptive analysis of the indications for capsule endoscopy was conducted concerning the diagnosis derived diagnosis and the performance of the examination in detecting significant lesions, as well as an analysis of the rate and causes of inconclusive reports. Following the selection of cases of SBAs, a descriptive statistical study was conducted to compare the patients who experienced rebleeding with the variables of interest and to determine which variables influence rebleeding. Mean, standard deviation, median, minimum, and maximum were used to describe continuous variables, whereas frequencies and percentages were used to describe categorical variables. The association between the rebleeding rate and these factors was calculated using statistical analysis. To compare continuous variables, we used the Student’s t-test and the Mann-Whitney U-test, and to compare categorical variables, we utilized the Chi-square test and Fisher’s exact test. In addition, the characteristics found to have a significant (P<0.05) correlation with rebleeding were identified using a logistic regression model. A selection method was used to determine the factors with the strongest association with rebleeding at a 5% significance level.

Results

Between January 2012 and December 2016, capsule endoscopy was performed on 239 patients. Upon review of the medical records and application of the inclusion and exclusion criteria, 109 cases were determined to be affected by SBAs. Five patients were ineligible for the study because of a shorter-than-one-year follow-up or early use of a specific treatment. Only patients with conservative treatment were selected since invasive therapy in the initial approach may decrease the rebleeding rate. Thus, 104 patients with clinically significant SBAs were chosen to analyze the rebleeding rate and potential risk factors. The mean follow-up period was 26±13.1 months, with women accounting for 71.2 percent of the sample population. The mean age was 67.4±12.8 years, and 70.2% of the sample consisted of participants aged 60 or older, a significant proportion. In 70.2% of the cases, the most common clinical presentation of the lesions was obscure hemorrhage. Twelve patients (11.5%) experienced active hemorrhage during the examination. The majority (n=87, 83.7%) exhibited multiple lesions in the small intestine, with diffuse involvement predominating (45.2%), followed by isolated lesions in the ileum in 40.4%, and concomitant gastric angiodysplasia were observed in only 6 (5.8%) patients.

Regarding baseline values of basal serum hemoglobin, 36.5% (n=38) had values less than or equal to 8 g/dL, and 26.9% reached values less than or equal to 7 g/dL, with an average value of 8.5±2.1 g/dL.

The BMI among the sample’s anthropometric data was 27.3±5.4 kg/m². Most patients, 65.5% of the sample, were categorized as overweight or obese, and 58.7% had an increased WC.

In terms of the general characteristics of the sample population (Table 1), systemic arterial hypertension is present in 73 cases (70.2%), dyslipidemia in 45 cases (43.3%), and type 2 diabetes mellitus in 44 patients (42.3%), which were the most prevalent comorbidities, in descending order. Anti-aggregator agents were taken by 34.6%, anticoagulants by 10.6%, and non-steroidal anti-inflammatory drugs by 9.6%.

The study found that 57 (54.8%) patients experienced rebleeding during a mean follow-up period of 26±13.1 (min 12; max 59) months after diagnosis. Univariate analysis comparing the two groups revealed no significant differences in rebleeding rates based on sex, BMI, serum hemoglobin levels before the examination, a form of clinical presentation of bleeding, the topography of lesions, presence of multiple lesions, comorbidities, active bleeding during the examination, or use of antiplatelet pharmacotherapy or anticoagulation (Table 2).

The group with rebleeding had a significantly greater WC than those without rebleeding (92.6 ±12.2 vs. 98.3 ±11.8 cm, P=0.02). In the univariate analysis, we used the three components with P< 0.20 to build a multiple logistic regression model that revealed that WC increased the risk of rebleeding by SBAs by 4% [odds ratio (OR) for every 1 cm increment =1.04; 95% confidence interval (CI): 1.01–1.08, P=0.02].

Discussion

Capsule endoscopy has significantly transformed the diagnosis and management of small bowel diseases, particularly in cases of mid-gastrointestinal hemorrhage (9).

Capsule endoscopy studies have identified SBAs as a significant source of obscure gastrointestinal bleeding. They are characterized by intermittent bleeding and, according to recent studies (19,24-26), an increased rebleeding rate of up to 50 percent. Identifying the high risk of rebleeding from SBAs is one of the first stages in defining the appropriate medical management of gastrointestinal bleeding, which reduces hospitalization and additional costs associated with procedures.

Regarding the 104 cases of SBA with clinical repercussions confirmed by capsule endoscopy in our investigation, the most affected age group was patients aged 60 years, with a significant decrease in cases over 80 years (70.2% vs. 15.4%, respectively). Kaufman et al. (2017) reported that most angiodysplasia cases occurred between the ages of 65 and 80, with a decline after this age, most likely due to the comorbidities and increased mortality associated with aging (5). A recent review by Oka et al. (2023) showed that angiodysplasias are the most common cause of small bowel bleeding in the elderly, and advancing age has been related to a higher risk of complications (26).

Rebleeding in patients with positive capsule endoscopy results varies between 5.9% and 61.1%, and there are conflicting results regarding associated factors from different studies (27). Similar to the rates reported by Holleran et al. (28), the rebleeding rate of SBAs in our study was 54.8%, which can be partially explained by the higher prevalence of distal lesions in the small intestine and the predominance of multiple lesions along the small bowel, since both findings have been associated with a higher risk of rebleeding (21,29,30).

In the univariate analysis of variables between the two groups, we found that the group with rebleeding had substantially greater WC values than those without rebleeding (92.6±12.2 vs. 98.3±11.8 cm, P=0.02). This study suggests a potential link between increased visceral fat and the risk of rebleeding from SBAs, which was corroborated by a 2015 study by Yamada et al. that evaluated 198 cases of obscure intestinal hemorrhage using capsule endoscopy or computed tomography (CT) scans and measured visceral and subcutaneous fat using CT scans (31). As reported by the authors, the prevalence of SBAs is positively correlated with visceral fat accumulation.

Previous studies identified decreased serum levels of Ang-1, elevated serum levels of Ang-2, and a resultant decreased ratio of Ang-1/Ang-2 in patients with SBA compared with controls (10,12). Moreover, in a murine model of nonalcoholic fatty liver disease (NAFLD), Lefere et al. described that Ang-2 inhibition directly counteracts pathological angiogenesis, resulting in partial normalization of the microvascular network as visualized by scanning electron microscopy (32). Recent studies have shown that distinct gastrointestinal vascular disorders like SBA, PHG and GAVE share a common alteration in serum levels of Ang-1 and Ang-2, which interferes with vessel remodeling and maturation, resulting in the abnormal friable, permeable vasculature with a propensity for bleeding, regardless of VEGF levels (10,12,14). Among these gastrointestinal vascular disorders, some authors presumed that GAVE could be caused by metabolic syndrome via microvascular injury with neovascular proliferation (33-36). Metabolic syndrome, especially insulin resistance, can predispose to vascular disorders, creating a hypoxic environment and causing upregulation of vascular proliferation factors that lead to microvascular injury. A similar mechanism may underlie the ecstatic vessels mentioned in SBA (Figure 1).

Figure 1 Possible mechanisms involved in the pathogenesis of SBA relating to metabolic syndrome and/or visceral fat. Figure generated by Gemini 2.0 Flash. Ang-1, angiopoietin-1; Ang-2, angiopoietin-2; GAVE, gastric antral vascular ectasia; GI, gastrointestinal; SBA, small bowel angiodysplasia; VEGF, vascular endothelial growth factor.

There were several limitations to this study. First, it was a retrospective analysis of a single center. Hence, selection bias for the catchment population, considering the fact that several specifically identified risk factors (e.g., age, number of lesions, and anticoagulant therapy) are not significant in the analysis of this study and the prevalence of aortic stenosis and cirrhosis is remarkably reduced in our patient sample, which are potential confounders limiting the generalizability of the results. Second, the study did not explore the effectiveness of interventions to decrease visceral fat, such as changes in lifestyle or pharmacological treatment for obesity, in preventing rebleeding. The limited sample size of patients in our study diminishes its statistical power due to increased data variability. Therefore, a more extensive prospective study is needed to confirm the contribution of WC as a risk factor for the rebleeding of SBA. The identified risk factor is easy to assess and appears to outperform crude BMI calculation, as existing BMI-based definitions of obesity can underestimate or overstate adiposity.

Conclusions

After analyzing the study’s findings, it can be inferred that individuals with SBA have a higher chance of rebleeding if they have a larger WC. Therefore, further studies into the actual impact of visceral fat on bleeding rates in SBA patients are necessary, and the implications of managing metabolic syndrome as a treatment option for SBA should be assessed in subsequent studies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-6/rc

Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-6/dss

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-6/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-6/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The Research Ethics Committee (CEP/IAMSPE) approved the study (approval ID64950517.5.0000.5463), and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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