Gastrointestinal angiodysplasia (GIAD) is the most common vascular abnormality in the gastrointestinal (GI) tract, defined as pathologically dilated communications between veins and capillaries.1 Histologically, it consists of an accumulation of thin-walled veins, venules, and capillaries along the endothelium in the mucosa and submucosa. Those vessels lack a smooth muscle layer, leaving them easily prone to bleeding.1

Endoscopically, GIAD lesions are flat or slightly raised, bright red in color, and well circumscribed or fernlike stellar lesions measuring 2 to 10 mm in diameter.1 They can occur at multiple sites within the GI tract, including the colon and the stomach, where they can be easily diagnosed. It is the small bowel angiodysplasia lesions that remain a diagnostic and therapeutic challenge, in spite of the technologic advances in the field of small bowel exploration made over the past 2 decades. The distribution of GIAD lesions in the GI tract is not well known, as most studies do not include small bowel endoscopic assessment.2 GIAD lesions account for up to 5% of all causes of GI bleeding. In patients with obscure GI bleeding, which is defined by bleeding from a source that cannot be identified through upper or lower endoscopy, small bowel angiodysplasia is found in approximately 40% of examinations.3 In addition to increasing age, morbidities, such as aortic stenosis, renal failure, cirrhosis, von Willebrand disease, liver cirrhosis, and pulmonary disease, have been reported to be predisposing factors for GIAD.4 Little is currently known about the risk factors for GIAD lesion bleeding. However, the identification of those factors can aid in predicting and preventing both the occurrence and recurrence of GIAD-related bleeding. In fact, patients with a high-risk profile would benefit from preemptive endoscopic treatment, close monitoring, and possibly from early prescription of prophylactic medical therapy. Therefore, the aim of our study was to describe the clinical features of patients with GIAD lesions in a Tunisian population and to determine the risk factors promoting GIAD lesion bleeding.

In the present study, we evaluated the clinical features of GIAD in a Tunisian population and identified the following features as independent risk factors promoting GIAD bleeding: increased age, CKD, coronary artery disease, diabetes mellitus, and having ≥ 10 lesions. The natural history of GIAD is not fully understood. Nevertheless, the fact that all lesions have the potential to bleed and that incidental lesions are less likely to bleed is universally accepted.2 As for symptomatic GIAD lesions, clinical presentation varies from occult bleeding to visible bleeding (melena, hematemesis, hematochezia with or without hemodynamic instability). In our study, approximately half our patients (52.6%) had incidental GIAD lesions. In the other cases, melena was the most common symptom, followed by hypochromic anemia, hematemesis, and hematochezia. Those results corroborate the known epidemiology of GIAD lesions.4–6

In our study, the majority of the GIAD lesions were found in the colon (69.2%), followed by the small bowel (32.5%) and the stomach (19.3%). Such distribution was thought to be the most frequent, before the era of small bowel enteroscopy and video capsule endoscopy. In fact, it was once believed that GIAD lesions were mainly located in the cecum and the right colon, and to a lesser degree, in the stomach and the small bowel. However, recent studies have shown the opposite order to be true. In their study on patients with GIAD that underwent endoscopic examination of the entire GI tract, Neu et al. found that the small bowel was the most commonly involved location.7 The same distribution pattern was described by DeBedet et al. and Bollinger et al.8,9 Notably, even the distribution of angiodysplasia in the colon is controversial. The right colon is reported to be the most common colonic location in Western studies, whereas Japanese and Taiwanese studies have reported that colonic angiodysplasia is predominantly located in the left colon.5 In our study, the most frequent colonic segmental location was the cecum (56%), followed by the right colon (25.3%), the left colon (8%), the transverse colon (5.3%), and finally the rectum (1.3%).

Currently, no treatment guidelines are available for GIAD lesions, which explains the high variability in its management. This problem was highlighted by a 2015 Dutch study that applied a national web-based survey, to assess the treatment approach to GIAD by gastroenterologists.10 In current practice, clinicians tend to defer treatment of symptomatic GIAD, when no stigmata of hemorrhage are found, and most authors agree upon not treating incidental lesions. Thus, the identification of risk factors for GIAD bleeding is of paramount importance, to better understand the mechanisms and factors that cause a GIAD lesion to bleed, and consequently aid endoscopists in identifying high-risk groups, in which bleeding can be anticipated, predicted, and considered, even in the absence of stigmata of hemorrhage.

Only 2 years ago, in what is still a new area of research, the difference in risk factors between incidental and symptomatic angiodysplasia was highlighted in a case-control study, using a random sample from the general population as a control group.11 The results of that study led the authors to conclude that incidental and symptomatic GIAD lesions might be different disease states. The currently available studies on risk factors for GIAD bleeding are summarized in Table 5. However, those studies are very heterogeneous, as some of them include only one location, and different control groups are used. Unfortunately, studies whose control groups are not made up of patients with incidental GIAD lesions do not allow us to distinguish specific factors that could be used to adequately differentiate incidental from symptomatic GIAD lesions during endoscopy.

In our study, age above 75 years was identified as an independent risk factor for GIAD bleeding. Increased age is one of the most commonly identified risk factors for bleeding,5,11,12 albeit the reason for this is still unknown. In 2020, Neu et al. speculated that age might merely be a confounding factor, regarding the number of lesions and other comorbidities,7 but they have established an exponential dependency of increasing age on an increasing number of GIAD lesions. Therefore, we made sure to look for an association between the presence of multiple lesions and increased age (p = 0.92) and to adjust for age in the multivariate analysis. Another commonly accepted risk factor is the total number of lesions. In our study, ≥ 10 lesions was identified as an independent risk factor for GIAD bleeding. Those results are in accordance with the current literature. In fact, Nishimura et al. and Diggs et al. identified multiple lesions as a risk factor for active bleeding in the colon.13,14 In addition, Neu et al. identified the total number of lesions in the entire GI tract as an independent factor for GIAD bleeding.7 Based on those findings, several authors suggest exploring the entire GI tract, when an angiodysplasia lesion is diagnosed, even if it was incidentally found.

In our study, we found no association between any of the GI locations and the occurrence of GIAD-related bleeding. In fact, it is accepted that all GIAD lesions can bleed at some point, regardless of their location. However, whether certain locations themselves are associated with a higher risk of bleeding is still unknown. A study analyzing the risk factors of angiodysplasia presenting as upper GI bleeding found that non-antral locations (gastric body/fundus) were associated with GI bleeding.15 Those findings are in contrast with a classic theory suggesting that the antrum is more predisposed to venous obstruction and vascular ectasia than other segments of the stomach due to the vigor of the muscular contraction in the antrum. It is not yet known if the same theory could be proposed for gastric angiodysplasia, and even if it could, it would only explain a greater number of lesions in the antrum, and not the predisposition to bleeding.16

Regarding the distribution in the colon, Nishimura et al. found that actively bleeding angiodysplasia lesions were located mainly in the right colon,14 but with no statistical significance in the multivariate analysis. The right-sided location was also identified by Diggs et al. as an independent predictive factor of endoscopic therapy requirement.13 In contrast, those associations were not found in more recent studies.5,7 We believe that no conclusions can be drawn from the current literature concerning the possible role of GIAD size and location in the occurrence of bleeding. In our study, CKD, coronary artery disease, and diabetes mellitus were identified as independent risk factors for GIAD bleeding. Those results concur with the published literature.

Several studies have shown that CKD patients, whether undergoing hemodialysis or not, are prone to GI bleeding, regardless of the underlying cause. This can be explained by the accumulation of uremic toxins, which impairs platelet aggregation and adhesion.17 In contrast to our findings, in which hemodialysis was not identified as a risk factor for GIAD bleeding in the multivariate analysis, the risk of bleeding in patients with CKD appears to be even higher in patients undergoing hemodialysis. A recent Taiwanese nation-wide population-based cohort study investigating the impact of CKD on the incidence of lower GI bleeding found a higher incidence of angiodysplasia-related bleeding in CKD patients undergoing dialysis, when compared with dialysis-free patients and control subjects.17

Coronary artery disease was associated with GIAD-related bleeding in several studies.13,14,18 The underlying mechanism is not yet known. A possible explanation could be the wide use of antiplatelets in that population. In a prospective case-control study, Neu et al. demonstrated that the alterations in primary hemostasis that are typically observed in patients on salicylic acid are associated with an increased risk of GIAD-related bleeding.7 Indeed, antiplatelets can increase the risk of GIAD bleeding by irreversibly inhibiting platelets. This can possibly occur in the upper GI tract, by reducing prostaglandin synthesis, which can then expose the gastric mucosa to a higher level of acidity. On the other hand, in a retrospective cohort study by Cochrane et al. that primarily aimed to compare the rate of GIAD bleeding in patients with a continuous-flow left ventricular assist device (LVAD) with other causes of bleeding, those authors found that patients on proton pump inhibitors were 14-times more likely to have GI bleeding, regardless of the underlying bleeding cause.12 Those findings obviously contradict the antiplatelet and acidity theory. However, patients with LVAD form a very specific group, in which ischemic mechanisms are more amplified and probably account for the occurrence of GIAD hemorrhage. Thus, we consider that further evaluation of the role of antiplatelets on a larger and less specific population is still needed.

In the present study, we identified increased age, a higher number of lesions, and the comorbidities of CKD, diabetes mellitus, and coronary artery disease as independent predictors of GIAD bleeding. Based on those results and our review of the current literature, we strongly believe that patients with incidental GIAD lesions and multiple risk factors for GIAD bleeding should be treated and will benefit from further screening for other lesions throughout the GI tract. However, further studies analyzing the different risk profiles and the efficacy of different treatments are still needed.

No financial support was received in relation to this article.

The authors declare that there is no conflict of interest.

Dr. Nasr and Dr. Khsiba: conception and design.

Dr. Mahmoudi and Dr. Hamzaoui: analysis and interpretation of the data.

Dr. Ben Mohamed and Dr. Yaakoubi: drafting of the article.

Dr. Medhioub: critical revision of the article for important intellectual content.

Dr. Azouz: final approval of the article.