Angiodisplasia Art.

Alimentary Pharmacology and Therapeutics
Review article: gastrointestinal angiodysplasia pathogenesis, diagnosis and management

S. S. Sami*, S. A. Al-Araji & K. Ragunath*
*Nottingham Digestive Diseases Centre & NIHR Biomedical research Unit, Queens Medical Centre, Nottingham, UK. University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, UK.
SUMMARY Background Angiodysplasia (AD) of the gastrointestinal (GI) tract is an important condition that can cause signicant morbidity and rarely mortality. Aim To provide an up-to-date comprehensive summary of the literature evaluating this disease entity with a particular focus on pathogenesis as well as current and emerging diagnostic and therapeutic modalities. Recommendations for treatment will be made on the basis of the current available evidence and consensus opinion of the authors. Methods A systematic literature search was performed. The search strategy used the keywords angiodysplasia or arteriovenous malformation or angioectasia or vascular ectasia or vascular lesions or vascular abnormalities or vascular malformations in the title or abstract. Results Most AD lesions (5481.9%) are detected in the caecum and ascending colon. They may develop secondary to chronic low-grade intermittent obstruction of submucosal veins coupled with increased vascular endothelial growth factor-dependent proliferation. Endotherapy with argon plasma coagulation resolves bleeding in 85% of patients with colonic AD. In patients who fail (or are not suitable for) other interventions, treatment with thalidomide or octreotide can lead to a clinically meaningful response in 71.4% and 77% of patients respectively. Conclusions Angiodysplasia is a rare, but important, cause of both overt and occult GI bleeding especially in the older patients. Advances in endoscopic imaging and therapeutic techniques have led to improved outcomes in these patients. The choice of treatment should be decided on a patient-by-patient basis. Further research is required to better understand the pathogenesis and identify potential therapeutic targets. Aliment Pharmacol Ther 2014; 39: 1534
Correspondence to: Prof. K. Ragunath, Nottingham Digestive Diseases Centre & NIHR Biomedical research Unit, Level E, West Block, Queens Medical Centre, Nottingham, NG7 2UH, UK. E-mail: k.ragunath@nottingham.ac.uk
Publication data Submitted 22 July 2013 First decision 14 August 2013 Resubmitted 16 September 2013 Accepted 18 September 2013 EV Pub Online 20 October 2013
This commissioned review article was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T.
2013 John Wiley & Sons Ltd doi:10.1111/apt.12527
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S. S. Sami et al. INTRODUCTION There are several types of vascular malformations that can be found in the gastrointestinal (GI) tract. They represent aberrations in the normal vascular structure of the affected arteries, veins or capillaries. Some of those can be benign like haemangiomas, while others are malignant, for example, angiosarcomas. Similarly, these vascular anomalies could be hereditary, such as hereditary haemorrhagic telangiectasia or acquired like angiodysplasia (AD), gastric antral vascular ectasia (GAVE), radiation-induced vascular ectasia and Dieulafoys lesions.1 The rst case of AD in the literature was described in 1839, but it was not until 1974, when the term AD was rst used describing abnormal clusters of mucosal vessels in the colon.2 Since then, there has been some debate in the literature regarding the exact aetiology of these lesions, which resulted in a variety of synonymous terms like angioectasia, arteriovenous malformations and vascular ectasia. AD can be dened as the nding of abnormal, ectatic, dilated, tortuous and usually small (<10 mm) blood vessels visualised within the mucosal and submucosal layers of the gut (Figure 1). Histologically, the affected vessels are lined by endothelium only with little or no smooth muscle3 (Figure 2). These lesions are increasingly detected nowadays, possibly because of the improvements in endoscopic image resolution and the increased recognition by clinicians of AD as an important cause of GI blood loss. This review will focus on AD, which is an acquired disease that can affect any part of the GI tract and is not usually associated with any familial, cutaneous or systemic disorder. Other vascular abnormalities including GAVE are outside the remit of this review. METHODS A systematic literature search was performed independently by two reviewers (SSS, SAA) to elicit all relevant
articles. Sources searched included Cochrane Library, MEDLINE and EMBASE electronic databases for the period from January 1946 to April 2013. The search strategy used the keywords angiodysplasia or arteriovenous malformation or angioectasia or vascular ectasia or vascular lesions or vascular abnormalities or vascular malformations in the title or abstract. The search was limited to papers published in English language only. A secondary manual search through references lists of all identied primary journal articles was also undertaken. This search strategy generated an initial list of 5241 articles, which were all screened for inclusion in this narrative review. Only papers judged to be of possible relevance to the aims of the review were read in more detail and included in a nal list of references. Articles were then divided into subgroups under the headings epidemiology, pathogenesis, diagnosis, management to facilitate the review process.
EPIDEMIOLOGY AD is the most common vascular malformation of the GI tract in the general population.4 Most AD lesions are detected in patients older than 60 years of age,48 although presentation in patients with chronic renal failure (CRF) can be earlier.9 Patients with AD can be asymptomatic or may present with signs and symptoms consistent with GI bleeding.10 The severity of bleeding may range from chronic well compensated in the majority of patients, to acute life threatening in others.1113 Upper GI tract AD is reportedly the culprit in 47% of patients presenting with nonvariceal upper GI bleeding.1416 In the largest study, 676 patients underwent endoscopy for suspected UGIB over a 40-month period. AD was found in 4% of patients, of whom 77% had experienced at least one episode of overt upper GI bleeding (haematemesis
(a)
(b)
Figure 1 | (a) Angiodysplasia (AD) in small bowel diagnosed by single-balloon enteroscopy. (b) AD in the ascending colon diagnosed by colonoscopy (arrow demonstrates the feeding vessel).
16 Aliment Pharmacol Ther 2014; 39: 15-34 2013 John Wiley & Sons Ltd
Review: gastrointestinal angiodysplasia

(a) (b)
Figure 2 | (a) Histological appearance of a predominantly submucosal angiodysplasia (AD) with dilated thick-walled arteries and thin-walled veins. (b) Histological appearances of caecal angiodysplasia showing dilated vessels within the mucosa adjacent to the epithelial cells. (Reproduced with permission from Gordon FH, et al.1 Copyright Elsevier).
or melaena) and the rest had features of occult GI bleeding. Multiple lesions were found in 63% of cases and colonic AD was detected 50% of those who had a colonoscopy performed. This highlights the fact that although AD in the upper GI tract is uncommon, it should be considered as a cause of both occult and overt GI bleeding.
Small bowel In patients under 50 years of age with obscure GI bleeding (OGIB), small bowel tumours are commonly identied as the cause in 57%. However, in patients older than 50 years, the source is likely to be small bowel AD.17, 18 Liao et al.19 performed a systematic review of all original articles relevant to wireless capsule endoscopy (WCE) for the evaluation of patients with small bowel signs and symptoms published between 2000 and 2008. A total of 227 studies involving 22 840 procedures were included. OGIB (overt and occult) was the most common indication (66.0%) and AD was the most common cause (50.0%) of bleeding in those patients. In another study, small bowel AD lesions were the most common cause (35%) of severe life-threatening overt OGIB.20 Colon The colon is the most frequent site of AD in the GI tract.4, 21 In western patients, lesions are predominantly located in the caecum and ascending colon (5481.9%), while lesions diagnosed in Japanese patients are more likely to be in the descending colon (41.7%).21, 22 The prevalence of colonic AD in healthy asymptomatic adults was estimated to be 0.83% and none of these individuals developed bleeding over a mean follow-up duration of 3 years.4 Therefore, treatment of nonbleeding lesions is generally not recommended. The frequency of colonic AD
Aliment Pharmacol Ther 2014; 39: 15-34 2013 John Wiley & Sons Ltd
as a cause of lower GI haemorrhage varies between 3% and 40%.2326 Bleeding from colonic AD can be mild, chronic, recurrent and can stop spontaneously in up to 90% of patients; nonetheless, it can also be life threatening.21, 27 Approximately 4060% of patients with upper or lower GI AD have more than one lesion15, 16 and 27% of patients with colonic AD had multiple lesions involving two or more segments of the large bowel.28 Moreover, while AD is usually present in the same part of the GI tract, synchronous lesions elsewhere can occur in approximately 20% of patients.29, 30 These ndings suggest that local factors may be important in the pathogenesis of nonhereditary AD. It also highlights the importance of evaluating both the upper and lower GI tract in patients with symptomatic AD.29 AD can only be condently diagnosed as the cause of blood loss if it was actively bleeding at the time of endoscopy.30
RISK FACTORS AND ASSOCIATED CONDITIONS Aortic stenosis (AS) Heyde et al.31 and then Schwartz et al.32 were the rst to report a possible association between AS and bleeding from AD in 1958. This was called Heydes Syndrome. A subsequent retrospective casecontrol study of 1443 patients found that the incidence of AS in patients with OGIB was much higher (25.5%) compared with controls (4.4).33 Several other studies have also suggested an association between AS and idiopathic or recurrent GI bleeding, which was not noted with other valvular diseases of the heart like mitral stenosis.3437 Further support for this hypothesis comes from evidence of improvement or cessation of chronic GI bleeding in the vast majority of patients with AS after aortic valve replacement (AVR). This effect was sustained for up to 12 years after surgery in the largest case series of 91 patients.3843
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The issue of whether there is an association between AS and bleeding from AD per se remains somehow controversial. Several initial case reports and case series have supported this association.28, 4449 However, most of these studies had major deciencies in their methodology.50 Other reports have failed to show an association between AD and AS.8, 51, 52 Nonetheless, they showed a higher risk of bleeding from AD in patients with aortic sclerosis rather than AS.5153 A recent study has estimated the prevalence of AS using echocardiography in 73 elderly patients with endoscopically conrmed AD. This was reported to be 32%, which was signicantly higher that the prevalence in the control group (14%).54 In the largest and most recent epidemiological study so far, investigators examined data from hospital discharge coding in an all Irish population cohort between 1997 and 2001 (3.8 million events). There was a signicant association between AS and GI bleeding secondary to presumed AD. The prevalence of patients with both conditions was very low, which, the authors thought, may explain why some smaller studies have not shown a signicant association.55 There seems to be sufcient evidence to support an association between AS and bleeding from AD, but whether the association is causal remains very much doubtful. This observation has led to the hypothesis that abnormal von Willebrand factors (vWF) could provide the explanation to the increased risk of bleeding in patients with AS or aortic sclerosis and otherwise silent AD. regardless of the site of AD and nonbleeding lesions remain visible on endoscopy post-operatively.47, 66 However, decision about performing metallic AVR should be considered with caution in view of the need for warfarin, which has been reported to contribute to ongoing bleeding after surgery.67 While another report showed that bleeding stopped after metallic AVR despite warfarin.68 There is now evidence of clear association between abnormalities in vWF HMW multimers and increased risk of bleeding from AD both from case reports and prospective studies.62, 6971 The current most accepted concept is that AS and AD are both diseases of older age and low levels of HMW multimers precipitate GI bleeding from existing AD in patients with co-existent AS. Surgery (AVR) may be an option in patients with AS and signicant GI bleeding from AD, but that has to weighed carefully against the option of bowel resection. Although there is strong association between abnormalities in vWF and AS, it is worth noting that GI bleeding from AD remains rare in these patients.56
Von Willebrand disease (vWD) Patients with certain subtypes of vWD are at an increased risk of GI bleeding from colonic AD.5662 Those patients have low levels of the high molecular weight (HMW) multimers of vWF, which is either hereditary (type 2a vWD) or acquired (AS). VWF is essential in mediating the adhesion and aggregation of platelets to the sub-endothelium of damaged blood vessels. HMW multimers are the most effective in this process.63 In the acquired form, vWF multimers are disrupted by the high shear stress as they pass through the stenotic aortic valve leading to cleavage and subsequent reduction in the HMW multimers causing acquired vWD.64 In one prospective study, abnormalities in vWF multimers and platelet function reverted back to normal after AVR in all patients post-operatively.41 These ndings were replicated in a more recent case report.65 Other studies have shown that AVR was effective in stopping bleeding
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Chronic renal failure (CRF) AD is more common in patients with CRF and the prevalence is thought to be related to the duration and severity of the kidney disease.72 AD accounts for 1932% of Lower GI bleeding episodes in patients with CRF compared with 56% of episodes in the general population.4 Likewise, gastric and small bowel AD are reportedly the most common causes of upper GI bleeding and OGIB in those patients, respectively.73, 74 The reason for this observed high prevalence of AD among subjects with CRF remains unclear and it is conceivable that it is due to the increased risk of bleeding that these lesions are more likely to be detected during endoscopic investigations, which result in overestimating the real prevalence. Patients with CRF are at an increased risk of bleeding due to several mechanisms including uraemic platelet dysfunction75, 76 and use of anti-coagulants.77 The causes of platelet dysfunction (aggregation and adhesion) are thought to be due to both intrinsic and extrinsic factors.76, 78 Intrinsic factors include reduced levels of agonists like adenosine diphosphate, serotonin, epinephrine, thrombin and collagen leading to impaired platelet function.79 It has also been noted that levels of platelet cyclic adenosine mono-phosphate which causes platelet dysfunction by mobilising calcium were high in patients with CRF. Extrinsic factors include release of toxins and increased nitric oxide, which inhibits platelet-to-platelet interaction and affects platelet to vessel wall interaction.79

AD is therefore an important cause of GI bleeding in patients with CRF. Other factors, which contribute to abnormalities in haemostasis, include reduced production of erythropoietin and effect of drugs.79 This leads to congestion of the capillaries and failure of the pre-capillary sphincters, resulting in the formation of small arterio-venous collaterals (Figure 3). This theory could be supported in part by the fact that AD commonly occurs in the older population with predilection to the ascending colon and caecum. The bowel is cylinder-shaped and according to the Law of Laplace (T = p 9 r/[(2 9 t], where T = wall tension, p = pressure, r = radius, t = wall thickness), tension is highest when the radius increases and wall thickness reduces.81 This applies to the ascending colon and caecum (large diameter with thin wall) where the bowel wall tension is highest, which compresses the submucosal venules, but not arterioles. A similar mechanism takes place in the gastric antrum and pylorus where muscle contraction is most vigorous leading to the development of ectatic vessels and AD.82
PATHOGENESIS The aetiology and mechanism for the development of AD is not fully understood. The most widely quoted hypothesis in the literature is the one proposed by Boley et al.,80 in a study using resected colon specimens from patients with angiographic and clinical evidence of caecal vascular lesions. Histological evaluation revealed dilated and tortuous veins in the submucosa even without obvious mucosal lesion. It was suggested that those lesions develop with ageing due to chronic low-grade intermittent obstruction of submucosal veins as a result of increased contractility at the level of muscularis propria.
Lumen (a) (b)
Lumen (c)
Lumen Mucosa Submucosa
Muscularis propria Serosa
Angiogenesis +AS Associated conditions Cardiac output Mucosal & submucosal ischemia/hypoxia Bleeding (d) +VWD VWF multimers VEGF-dependant proliferation New vessel formation
+CRF
Intrinsic extrinsic drugs erythropoietin
Platelet adhesion & aggregation
Figure 3 | The pathophysiological mechanisms contributing to the development of angiodysplasia (AD) and subsequent bleeding. The relationship between those mechanisms and the increased risk of bleeding in patients with Aortic stenosis (AS), Von Willebrand disease (vWD) and chronic renal failure (CRF) is also detailed. Chronic lowgrade intermittent obstruction of submucosal veins as a result of increased contractility at the level of muscularis propria (a, b). This leads to congestion of the capillaries and failure of the pre-capillary sphincters (c) resulting in the formation of small arterio-venous collaterals (d).
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Some other investigators have observed that patients with AD are more likely to have underlying cardiac, vascular or pulmonary diseases and therefore suggested that mucosal ischaemia from chronic hypoxia or hypo-perfusion may contribute to the development of AD; however, these were small observational casecontrol studies with no histological correlation.8, 49 This has led to the suggestion that the increased incidence of bleeding AD in patients with AS could be due to reduced cardiac output and tissue perfusion in this subgroup.83 Angiogenesis is an essential biological process to increase vascularity in human tissues when there is hypoxia or ischaemia. This results in the formation of new vessels (neovascularisation) as a result of imbalance between pro-angiogenic and anti-angiogenic factors (Figure 3).84 In vitro studies have shown that the expression of vascular endothelial growth factor (VEGF) under hypoxia is higher compared with normoxia.85 Increased expression of angiogenic factors, namely VEGF and basic broblast growth factor, has been demonstrated in human colonic AD and is therefore likely to play a very important role in the development of these lesions as well as in modifying the risk of bleeding.84, 86 This represented a novel therapeutic target and led to subsequent development of anti-angiogenic drugs like thalidomide. More recently, the role of vWF in regulating angiogenesis has been studied. Inhibition of vWF expression in endothelial cells in vitro caused increased angiogenesis and increased VEGF-dependent proliferation and migration. There was also in vitro and in vivo increase in vascularisation in vWF-decient mice. This represents an important link between angiogenesis and haemostasis and has some therapeutic implications in management of patients with AD with and without vWD.87 The factors contributing to the development of AD and risk of bleeding are summarised in Figure 3 below.
DIAGNOSIS The extent to which investigations should be performed in patients with OGIB largely depends on the clinical scenario and severity of bleeding. The main investigations for the diagnosis of AD are: Endoscopic imaging Endoscopy is currently the main tool for diagnosis of AD; this is largely due to signicant improvements in video endoscopy equipment and image resolution. Upper GI and colonic AD are usually diagnosed by standard upper GI endoscopy and colonoscopy, respectively. Commonly used endoscopic modalities for assessment of the small bowel include WCE, push enteroscopy, deep small bowel enteroscopy [double-balloon enteroscopy (DBE), single-balloon enteroscopy (SBE) and spiral enteroscopy (SE)] or intra-operative enteroscopy. Various endoscopic appearances of AD are shown in Figures 1, 4 and 5. Sometimes, a prominent feeding vessel might be visualised at the time of endoscopy (Figure 1b).10 Furthermore, the mucosa at the lesion margins is often more pale, giving the characteristic appearance of the pale halo sign (Figure 5a). These lesions can be missed during endoscopy due to a variety of reasons, for example, operator experience, poor visibility as well as size and location of AD, in particular if they are located behind mucosal folds.17 They can also be wrongly diagnosed as a localised area of inammation or trauma.88 It is therefore recommended that repeat examinations should be considered especially in cases of high clinical suspicion or when the initial
(a)
(b)
Figure 4 | (a) Arterial phase of selective superior mesenteric angiogram showing arterial and simultaneous early venous lling (indicating rapid shunting), with dilated areas of vasculature in the caecal wall. (b) Venous phase of the same angiogram. (Reproduced with permission from Gordon FH, et al.1 Copyright Elsevier).

(a) (b)
(c)
(d)
Figure 5 | (a) Angiodysplasia (AD) in stomach with black arrow highlighting the pale halo sign around the lesion. (b) Close-up view of lesion appearance. (c) Argon Plasma Coagulation (APC) noncontact ablation. (d) Appearances immediately post-APC ablation.
examination was suboptimal before embarking on investigations of the small bowel.17 Wireless capsule endoscopy is the preferred rst-line investigation for the small bowel in the context of OGIB as it is safe, acceptable and has signicantly higher or at least equivalent yield for lesions when compared with other, more invasive modalities like push enteroscopy, mesenteric angiography and intra-operative enteroscopy.89, 90 The British Society of Gastroenterology guidelines recommend that patients over the age of 50 years presenting with OGIB who have a negative gastroscopy and colonoscopy should undergo WCE to look for AD.17 The diagnostic yield of both WCE and DBE is similar, but complete small bowel examination was more frequently achieved with WCE (90.6%) compared with DBE (62.5%, P < 0.05).91, 92 The main limitation of WCE is the relatively poor visibility in the distal small bowel due to dark intestinal liquid contents. Moreover, no therapeutic intervention can be performed via the WCE. In patients with recurrent OGIB or severe iron deciency anaemia who had negative WCE, a repeat testing with WCE revealed the presence of AD in up to 29% of patients (75% for all ndings) and led to changes in patient management in two small studies.93, 94 WCE can be highly useful in localising the site, size and number of AD lesions to guide in decision about best insertion route for enteroscopy (oral or anal) to apply therapy.95, 96
All three techniques for deep small bowel enteroscopy (DBE, SBE and SE) are comparable in terms of diagnostic yield, therapeutic capabilities and adverse events.97 There was signicantly higher total enteroscopy rates achieved with DBE (5766%) compared with SBE (0 22%, P < 0.003) reported in two out of three randomised controlled trials comparing the two techniques, but that did not translate to a difference in diagnostic yield.98100 DBE was equivalent to SE in one of two small prospective trials,101 whereas the other study showed better mean procedure time for SE (43 min vs. 65 min; P = 0.007), but DBE was superior in terms of median maximum insertion depth (310 cm vs. 250 cm; P = 0.004).102 Performance characteristics of SBE and SE were equivalent in one retrospective study.103 Other advantages of enteroscopy include the facility for taking biopsies, ushing the mucosa to improve visibility and marking of lesions that will require surgical resection.17 The choice of enteroscopy technique will ultimately depend on the local expertise and availability of equipment. Deep enteroscopy techniques are superior to push enteroscopy in terms of insertion depth into small bowel and signicantly higher diagnostic yield of clinically important lesions.104106 Intra-operative enteroscopy facilitates complete examination of the small bowel and is performed jointly by a surgeon and an endoscopist. This procedure is associated with potentially serious
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complications,107110 and should be reserved for selected group of patients in whom less invasive tests have failed to identify or treat the source of bleeding. who are asymptomatic because the risk of future bleeding in these subgroups of patients is low and most remain asymptomatic.4, 7 Furthermore, patients found to have lesions in one part of the GI tract will often have additional AD elsewhere in the GI tract.22 On the other hand, treatment should be considered in patients with nonbleeding AD and symptoms of occult or overt OGIB where no other source of bleeding is found. The degree to which invasive treatment is pursued will depend on the size, site and number of lesions as well as the clinical severity of anaemia and blood loss. Evidence from prospective randomised controlled trials evaluating medical and nonmedical interventions to treat AD is relatively scarce. Therefore, most of the data on therapy come from large or small case series as well as case reports.
Radiographic imaging Radiographic imaging techniques can be implemented only in patients who present with signs of active overt GI bleeding to obtain a primary diagnosis or to conrm the location of suspected bleeding site seen on endoscopy. Modalities useful in patients with bleeding from AD include radionuclide scanning, computed tomography (CT) angiography, magnetic resonance (MR) angiography or standard angiography. Radionuclide scanning uses technetium (99mTc) labelled red blood cells techniques to localise bleeding that occurs at a rate of about 0.1 mL/min. It is a non-invasive and sensitive test,111 but its localisation is general and could be anywhere in the abdomen. Accuracy rates vary from 24% to 91% among different studies.112, 113 Furthermore, patients will still require a therapeutic intervention like standard angiography; hence, this technique is not widely used nowadays in the acute setting. Computed tomography and MR angiography also provide rapid non-invasive diagnosis in the context of active GI bleeding, but there are concerns regarding radiation exposure (with CT) and contrast allergy in addition to the lack of therapeutic capability. Standard angiography had a lower diagnostic yield in patients with overt OGIB when compared with immediate WCE (20.0% vs. 53.3%, P = 0.016) in a recent prospective randomised study.114 Nonetheless, standard angiography does not require bowel preparation, so there are no concerns regarding visualisation. It also allows accurate localisation and therapeutic embolisation of the bleeding point to be achieved at the same time (Figure 4). The decision to use this technique has to be carefully weighed against the potential risks of bowel ischaemia and other potential complications. Therefore, this procedure is generally reserved for patients in whom other modalities have failed to identify the source of bleeding or those with severe bleeding and hemodynamic instability. MANAGEMENT Decisions regarding management of patients with nonbleeding AD largely depend on the clinical context in which it was diagnosed. For instance, treatment is not required for lesions that are found incidentally in patients with nonbleeding-related symptoms or those
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Endoscopic therapies Argon plasma coagulation (APC). This method uses synchronised delivery of electrical current and argon gas. The argon gas is ionised and allows transmission of the high-frequency current to the target lesion or tissue without direct contact. It has become the most widely used method for treating AD (Figure 5).115 It is also used for other bleeding and nonbleeding lesions of the GI tract.115 One perceived advantage of APC is the limited depth of tissue injury. However, that has not been clearly shown from animal studies with the settings used in clinical practice.116, 117 In the upper GI tract, one study using human surgical specimens have shown that coagulation depth in stomach depends on the device power setting and duration of application, while these factors did not correlate with depth of coagulation in oesophageal specimens.118 Several studies have evaluated the safety, efcacy and long-term outcomes of APC for treatment of AD in the small bowel mainly by using balloon-assisted enteroscopy techniques. Re-bleeding rates ranged from 11% to 19% mainly resulting from the nding of new lesions, mean follow-up duration was up to 18 months in one study and there were no serious complications.119123 The performance of APC in treatment of colonic AD was recently evaluated in a prospective study of 100 patients.124 Bleeding resolved in 85% of patients after a median follow-up of 20 months requiring 118 procedures. Transfusion requirements ceased in 90% of patients and one patient required surgery. The mean Haemoglobin levels increased after treatment and re-bleeding rate was 2% and 10% at 1- and 2-year follow-up, respectively. Complications occurred in 1.7% of

procedures.124 Another study showed similar efcacy and safety prole in patients with bleeding GI AD.125 Complications including caecal perforation have been reported.126 The utility of submucosal saline injection (with or without adrenaline) to form a uid cushion in the colon before APC therapy has been demonstrated in animal and human studies.127, 128 It is safe and proven to reduce the depth of tissue injury. This technique is now recommended and been used in clinical practice, in particular, for lesions more than 10 mm in size in the right colon where the bowel wall is thinnest (Figure 6).128, 129 There are also several cases reported in the literature of colonic gas explosion during APC leading to perforation in some cases.130 This has also been reported using other electrocautery techniques131 and is thought to be due to the accumulation of combustible gases at explosive concentrations due to poor bowel preparation. Therefore, full bowel cleansing with oral purgatives (polyethylene glycol or sodium phosphate solutions) is highly recommended prior to undertaking any electrocautery procedures in the large bowel.130 APC is therefore safe, available, easy to use and cost-effective115, 125, 129. Subsequently, contact probes were introduced into practice for treatment of AD in the late 1980s and used until now.135137 There are few devices now commercially available, for example, HeatProbe (Olympus, Japan), which is a monopolar device with an inner coil that is heated by the electrical current and allows direct heat transfer to the tissue by applying pressure. Another example is the GoldProbe (Boston Scientic), which is a bi-polar device, so it delivers heat via a current that ows between the two electrodes at the tip of the probe. This limits the maximum temperature generated as well as the depth and surface area of tissue injury.138 Thermal ablation using contact probes and APC has been used for treatment of AD with possibly similar efcacy proles.139 Complications including perforation have been reported with both techniques;139 however, the amount of published evidence supporting the efcacy and safety of APC in this clinical setting is much larger compared with contact probes. Both techniques should be used with caution in the duodenum and ascending colon. In the absence of prospective comparative trials, we recommend using APC as the rst line; otherwise, a bi-polar probe is similarly effective with choice depending on availability and local expertise.
Electrocoagulation. Lesion coagulation by hot biopsy forceps (monopolar electrocoagulation) was the rst through-the-scope technique used to treat AD in the early 1980s.49, 132 This technique is not recommended in current practice due to relatively high risk of serious complications in up to 9% of patients including perforation in approximately 3% of cases especially in the ascending colon and caecum.49, 132134 High rates of re-bleeding (53% at 3 years) have also been reported.132
(a) (b)
Photocoagulation (Laser). Photoablation of AD using Nd:YAG (neodymium:yttrium-aluminium-garnet) and Argon laser has been reported in few studies. Recent evidence using this technique focused mainly on patients with GAVE.140, 141 In the most recent study, Nd:YAG laser resulted in cessation of blood transfusion in 61% of the 59 patients after 300 sessions. No serious complications were reported.142 This is in contrast to previous
(c)
Figure 6 | The submucosal adrenaline injection technique prior to Argon Plasma Coagulation (APC). (a) Caecal angiodysplasia (AD). (b) Diluted adrenaline (1:200,000) injected beneath the lesion; vascular shrinkage and pallor of the mucosa was noted. (c) Post-ablation of AD lesion with APC 50 W. (reproduced with permission from Suzuki N, et al.128 Copyright Elsevier).
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data reporting complications in up to 10% of patients,134, 143147 with a cumulative incidence of perforation (both upper and lower GI tract) in 2.4% of patients from four studies.134, 144146 The argon laser is less well studied135, 147, 148 and although it has shown good efcacy, concerns remain regarding the risk of perforation of 2.6% in one study.147 Other limitations of these techniques are the high cost and specialist expertise required to deliver the treatment. plications. However, this technique can be challenging and time consuming depending of the site, number and ease of access to the lesions. No further studies have been performed possibly due to the availability of other therapeutic options like APC.
Endoscopic clips. This approach has shown safety and efcacy in few case reports using endoscopic clipping for bleeding colonic AD either as a monotherapy149 or in combination with thermal ablation using APC and contact probes.150152 Clipping is particularly useful in cases of isolated and relatively large lesions to obliterate the feeding vessel and reduce the risk of precipitating bleeding from subsequent electrocoagulation. It can also be useful in patients with high risk of bleeding due to drugs (anti-platelets, anti-coagulants) or coagulation defects.151, 152 Endoscopic ligation. Successful treatment of bleeding gastric AD with multiband ligation devices has been demonstrated in few case series.153156 No serious complications were reported and efcacy was equivalent to bipolar electrocoagulation in one prospective study.154 Ljubici et al.157 used a novel detachable mini-loop ligation device to treat upper GI AD in 11 patients. There was one case of severe bleeding from a post-ligation ulcer in the duodenum requiring endoscopic therapy. Endoscopic multiband ligation achieved haemostasis in 14 patients with bleeding small bowel AD.158 However, re-bleeding occurred in 43% of patients during a mean follow-up period of 18 months; therefore, long-term efcacy of this technique remains doubtful. Endoscopic resection. Two cases reported of polypoid colonic angiodysplasia treated by polypectomy using polyloop ligation device in one case with no complications.159, 160 Injection therapy. Injection sclerotherapy was reported in two studies. Marwick et al.161 used 0.51.0 mL of 1.5% sodium tetracedyl sulphate to treat 10 patients with upper GI AD directly injecting the sclerosant beneath the lesion. Another study demonstrated the feasibility and safety of ethanolamine injection to treat eight patients with 15 lesions predominantly in the right colon.162 None of the studies reported any serious com24
Transcatheter angiography and intervention (TAI) This is usually indicated in patients with active GI bleeding who either fail endoscopic therapy or in whom endoscopy is not a suitable option. TAI can also be considered as an alternative to surgery in high-risk patients or to localise the lesion prior to surgery.163 Control of bleeding can be achieved by intra-arterial infusion of vasopressin at the bleeding site to reduce perfusion and allow clot formation. However, high rates of rebleeding have been reported with this technique in addition to concerns regarding systemic complications resulting from vasoconstriction and leading to ischaemia.164, 165 It is also contraindicated in individuals with coronary artery disease, severe hypertension, peripheral vascular disease and arrhythmias. Nonetheless, this modality can be useful in inaccessible lesions.166 Superselective transcatheter embolization is the current angiographic method of choice for treatment of bleeding AD.164, 166 The most common agents used are biodegradable gelatine sponges and microcoils. Other options include liquid agents like polyvinyl alcohol and cyanoacrylate. This technique can be successful in 8090% of patients with relatively low rebleeding rates.167171 Repeat embolization can be performed if rebleeding occurs. Overall, complications can occur in approximately 59% of patients, while serious complications are reported in less than 2% with modern techniques.166, 172 These include haematomas; arterial dissection; thrombosis; pseudo-aneurysm formation; and bowel infarction.172 Surgery Advances in endoscopic and angiographic diagnostic and therapeutic capabilities have resulted in marked reduction in the need for operative intervention in patients with bleeding AD.173 Surgical resection is now reserved for patients with either acute, severe bleeding not controlled by other alternatives or for patients with recurrent chronic bleeding who are transfusion-dependent; have clearly identied source of blood loss; and failed other treatment options. Surgery is curative; however, accurate localisation of the bleeding lesion pre-operatively should be attempted to avoid recurrence of bleeding from missed lesions elsewhere in the GI tract.

Several intra-operative localisation techniques can also be used to ensure accurate resection of the target lesion.174
Pharmacological therapies Treatment of AD using angiographic, endoscopic and surgical techniques can be associated with serious complications and is sometimes ineffective in preventing recurrence of GI bleeding. This could be due to the fact that it is usually hard to determine the exact locations of all lesions, particularly in the small bowel.120, 175 Therefore, a safe and cost-effective pharmacological agent can represent an attractive option, which can be offered to patients with signicant co-morbidities; high risk of complications from more invasive therapy; and those who do not respond to the other treatment options.
Hormonal therapy. There are ve studies in the literature evaluating the efcacy of combined hormonal therapy (oestrogen and progesterone) in management of patients with diffuse and sporadic bleeding AD (Table 1).176180 All studies were published between 1990 and 2001. The most common outcomes measured were the reduction in number of bleeding episodes and transfusion requirements. Most studies had signicant weaknesses in their methodology and only one study included a control group.176 Evidence from the three either small or retrospective and uncontrolled studies suggested a possible advantage from hormonal therapy;177, 179, 180 however, these ndings were not replicated in larger two studies with more sound methodology.176, 178
Table 1 | Primary studies evaluating the efcacy of combined hormonal therapy in adult patients with transfusiondependent gastrointestinal (GI) bleeding and endoscopically conrmed sporadic angiodysplasia (AD) of the GI tract
Study Design Sample Treatment dose size and duration Norethisterone 2 mg and ethinylestradiol 10 mcg OD for 12 years Lynestrenol 2.5 mg and mestranol 75 mcg OD for 360 months Comparator Follow-up Placebo 1 year (13)* 1 outcome % failure of Rx Results 39% (Rx) vs. 46% (placebo) (P value NS) Mean 4.4 1.2 before Rx vs. 0.7 0.5 during Rx (P < 0.05) 50% (Rx) vs. 44% (controls) (P value NS)
72 Prospective Junquera multicentre, et al.,176 2001, Spain double-blinded randomised Junquera et al.,177 1995, Spain Retrospective cohort 18
None
No. of bleeding episodes
Lewis et al.,178 1992, USA
Retrospective casecontrol
64
Van Cutsem et al.,179 1990, Belgium Barkin et al.,180 1998, USA
Prospective doubleblinded crossover Prospective cohort
10
25
None 510 mg OD (untreated norethynodrel historical either with control mestranol group) 75150 mcg (n = 24) or Premarin, 625 mcg OD(n = 6) Placebo 50 mcg ethinyloestradiol plus 1 mg norethisterone OD for 6 months 5 mg norethynodrel None and 75 mcg mestranol OD or 1 mg norethindrone and 50 mcg mestranol, BD
15.6 months % patients required (231) Rx no further group and 13.4 months Tx (123) control
% patients requiring Tx
22% (Rx) vs. 100% (placebo) (P < 0.002)
535 days (251551)
100% before % patients with recurrent Rx and 0% after Rx bleeding
Rx, treatment; OD, once daily; BD, twice daily; No., number; Tx, transfusion. * Median and range. Mean and range.
S. S. Sami et al.
There is only one good quality multicentre, randomised, double-blinded, placebo-controlled trial evaluating this intervention in a group of 72 consecutive noncirrhotic patients. Subjects presented with acute or chronic GI bleeding from AD (conrmed by endoscopy or angiography) were randomly assigned to receive either ethinylestradiol (0.01 mg) plus norethisterone (2 mg) (one tablet per day orally) or placebo (one tablet per day orally). There was no difference in outcomes and major adverse events between the two groups after a follow-up period ranging from 1 to 3 years.176 The efcacy of hormonal therapy in patients with CRF has been evaluated in two small case series with positive results.181, 182 Current evidence suggests that there is no role for hormonal therapy in patients with sporadic AD. were initially observed for 1 year and then randomised to receive oral thalidomide 100 mg daily or oral iron therapy 400 mg daily for 4 months. Response to treatment was dened as a decrease in bleeding episodes of at least 50% within the rst year of follow-up. Response rates were signicantly higher in the treatment group (71%) compared with the iron-controlled group (4%). Bleeding stopped in 46% of patients receiving thalidomide compared with none in the control group. Treatment with thalidomide also reduced the number of transfusion-dependent patients (11% vs. 48%) and hospitalisation episodes for bleeding (39% vs. 100%). These benets were sustained after a minimum of 1-year follow-up. Response rates did not change when the three patients with GAVE were excluded from the analysis. Adverse events were higher in the thalidomide group (71.4% vs. 33.3%) and included fatigue (32%); constipation (25%); dizziness (21%); and peripheral oedema (14%). Less frequent side effects included abdominal distension, thrombocytopenia, leukopenia, blurred vision, dry eyes, pruritus, rash, tinnitus, headache and herpes zoster. There are no other controlled trials evaluating this treatment in the literature (Table 2). But the current evidence demonstrates that thalidomide can be considered as a treatment option in patients who have failed or are not suitable for other therapies. However, there have
Thalidomide. Thalidomide acts by inhibiting angiogenesis through suppressing the expression of VEGF.85 Its effectiveness in the treatment of chronic bleeding from AD has been initially demonstrated in numerous case reports and case series, all published in the last decade.183191 A reduction in the number and size of AD has also been reported post-therapy.188, 192 These ndings were subsequently conrmed by a recent open-label, randomised controlled trial including 55 patients (AD n = 52 and GAVE n = 3) either refractory or unsuitable for other therapies.192 All participants
Table 2 | Primary studies evaluating the efcacy of thalidomide therapy in adult patients with transfusion-dependent GI bleeding and endoscopically conrmed sporadic AD of the GI tract (studies with sample size 3 were excluded)
Treatment dose and duration 25 mg QDS (100 mg per day) for 4 months
Study Ge et al., 2011, China

192
Design
Sample size
Comparator
Follow-up
1 outcome
Results
55 Prospective randomised open-label
Garrido Prospective et al.,191 cohort 2012, Spain Kamal-aporn Pilot case series et al.,190 2009, Canada
71.4% (Rx) 39 months % of patients 100 mg iron and 3.7% (852)* with 50% (ferrous (iron-control) decrease in succinate) (P < 0.001 bleeding tablets QDS episodes in for 4 months 1st year of follow-up 12 200 mg per None 4 months Mean 6.5 before Rx day for 4 haemoglobin vs. 12.1 at months level (g/dL) end of Rx None 12 months Tx requirement All 3/3 required 7 (4 discontinued 50 mg/day no Tx in 1st increased by Rx due to 6 months, but 50 mg every intolerance then all 3/3 week up to and 3 remained lost response 200 mg/day in study after for 6 months
Rx, treatment; QDS, four times a day; Tx, transfusion. * Median and range.

been reports of peripheral neuropathy, liver toxicity and acute liver failure with higher doses of this drug. Moreover, it has also been associated with birth defects. Therefore, the maximum recommended dose is 100 mg per day. It should be reserved for patients who are transfusion-dependent and not used in women of child-bearing age unless they use a reliable contraception method during treatment. Lenalidomide is a newer angiogenic inhibitor, which is thought to be less toxic and better tolerated. However, its role in treatment of AD remains to be evaluated in prospective controlled trials.193 tance; decreased splanchnic blood ow; and enhanced platelet aggregation.194 Endoscopic resolution of AD lesions after octreotide therapy has been reported, although the effect was not quantied.195 Its role in the management of AD has not been evaluated in prospective randomised controlled trials. Nevertheless, multiple case reports and case series have demonstrated a signicant benet.67, 186, 196202 The largest piece of evidence supporting the use of octreotide comes from a meta-analysis reported by Brown et al203 in 2010 including three studies with a total sample size of 62 patients.195, 204, 205 All studies had a prospective cohort design and only one of them included a control group, which was externally matched.205 The authors calculated a pooled response rate of 0.76 (95% CI 0.640.85) to octreotide. They concluded that this compares favourably to data from natural history studies reporting
Octreotide. The effect of the somatostatin analogue octreotide on bleeding from AD is thought to be due to several mechanisms including inhibition of angiogenesis by downregulation of VEGF; increase in vascular resis-
Table 3 | Primary studies evaluating the efcacy of Octreotide therapy in adult patients with transfusion-dependent GI bleeding and endoscopically conrmed sporadic AD of the GI tract (studies with sample size 3 were excluded)
Study Bon et al.,206 2012, France Design Prospective cohort Sample size 15 Treatment dose and duration Comparator Octreotide LAR 20 mg/month IM for 12 months (636)* Octreotide LAR 20 mg/month IM Octreotide LAR 10 mg/ month IM for 1 year None Follow-up 14 months (1036)* 1 outcome No. of blood transfusions (median and range) Results 2(014) during Rx vs. 10(624) before Rx (P < 0.001) 4(04) during Rx vs. 14(949) before Rx (P = 0.002) 69% required no further Tx or iron supplements after Rx 23% Rx vs. 48% placebo (odds ratio = 3.1, P = 0.043)
Molina et al.,199 2009, Spain
Prospective cohort
11
None
15 months (548)*
Scaglione et al.,204 2007, Italy
Prospective cohort
13
None
No. of units blood Tx (median and range) 33 months Tx (1260) requirement
Junquera et al.,205 2007, Spain
Octreotide 70 (32 Prospective 50 mcg Rx and Rx cohort BD SC for 38 compared placebo) 12 year with external control group
Nardone et al.,195 Prospective 1999, Italy cohort
17
Octreotide 100 mcg TDS SC for 6 months
13 months 38 patients (1236) who had received placebo in a concurrent randomised trial None 12 months
% failure of Rx
a- 5.7 before a- Mean Haemoglobin Rx vs. 11.1 after Rx (P < 0.0005) level (g/dL) b- 8.8 before and b- Units Rx vs. 1.5 after blood Tx Rx (P < 0.0005) per year
LAR, long-acting release; IM, intramuscular injection; SC, subcutaneous injection; BD, twice daily; Rx, treatment; Tx, transfusion; No., number. * Median and range. Mean and range.
S. S. Sami et al.
re-bleeding rates of 4454% in patients with AD with no treatment. The weighted mean difference in transfusion requirement before and after therapy was 2.2 (95% CI 3.9 to 0.5). It is difcult to ascertain whether this represents the true effect of octreotide as this meta-analysis had some inherent weaknesses. The included studies all had a small sample size with the lack of an appropriate control group. There was a signicant heterogeneity in the studied population. The prevalence of liver cirrhosis, CRF, valvular heart disease and coagulopathy was highly variable. There were also variations in the dose and type of drug used with one study using octreotide long-acting release (LAR) 10 mg/month intra-muscularly (IM) for 1 year,204 while the other two studies used octreotide normal release subcutaneously at a dose of 50 mcg twice a day for 12 years205 or 100 mcg three times a day for 6 months.195 A very recent study by Bon et al,206 evaluated octreotide LAR in 15 patients with chronic recurrent bleeding.
Angiodysplasia
The majority of them had failed APC therapy. There was a signicant reduction in bleeding episodes and transfusion requirements with higher mean Hb concentrations after treatment with IM injections at a dose of 20 mg per month for 6 months. It appears that octreotide is likely to be benecial and can be used to treat patients with recurrent chronic bleeding from AD (Table 3). It is well tolerated with no serious adverse events. The IM mode of administration once per month could be more convenient for some patients and may encourage compliance. A practical treatment guide is proposed (Figure 7) to aid physicians in the management of patients diagnosed with AD.
CONCLUSION AD is the most common vascular malformation of the GI tract. It is most commonly detected in older patients
Incidental/Asymptomatic
Overt OGIB Occult OGIB
No treatment Signs of shock or failed endotherapy
Inaccessible/Diffuse
Accessible
Assess for AS +/ AVR
APC/Bipolar*
No signs of shock
Recurrence and/or Transfusion-dependant
Thalidomide or Octreotide**
Interventional radiology
Unsuccessful Consider repeat endoscopy +/ endotherapy Consider Surgery***
*Caution in the right colon and lesions >10 mm (consider submucosal saline+/adrenaline injection). Recommend manufacturers settings. Caution if poor bowel preparation. Consider use of clips for large feeding vessels. **Only consider in patients who are transfusion-dependant and deemed not responsive or not suitable for other therapeutic interventions. Consider contraindications and side effects of thalidomide. Thalidomide dose 100 mg per day for 4 months. Octreotide 10-20 mg per month IM or 100-300 mcg per day SC for 6-12 months. ***In patients with a clearly identified source of blood loss.
Figure 7 | Proposed practical treatment guide based on the clinical presentation and angiodysplasia (AD) lesion characteristics (blue boxes) to guide different interventions (red boxes).
28

and located more often in the caecum and ascending colon. Majority of patients have more than one lesion in one or more parts of the GI tract. Clinical presentation can range from being asymptomatic and nonbleeding to overt life-threatening haemorrhage. The association between the increased risk of bleeding from AD and AS; vWD and CRF is now more established. Moreover, recent evidence has highlighted the complex mechanisms that underpin this association. Endoscopy is currently the modality of choice to diagnose and treat these lesions. APC is the most cost-effective endoscopic therapy, while pharmacological treatments like thalidomide and octreotide can serve as a second line of therapy in a selected group of patients after careful consideration of the benet/risk ratio. Transcatheter angiography with or without intervention is effective in management of patients with severe bleeding.
AUTHORSHIP Guarantor of the article: Sarmed S. Sami. Author contributions: Sami SS contributed to the design, literature search, data collection; performed data analysis and written the manuscript. Al-Araji SA contributed to the design, literature search and data collection. Ragunath K contributed to the design of the study and critical review of the manuscript. All authors approved the nal version of the manuscript. ACKNOWLEDGEMENT Declaration of personal and funding interests: None.
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Alimentary Pharmacology and Therapeutics

Review article: gastrointestinal angiodysplasia pathogenesis, diagnosis and management

2013 John Wiley & Sons Ltd doi:10.1111/apt.12527

Review: gastrointestinal angiodysplasia

Review: gastrointestinal angiodysplasia

Lumen (a) (b)

Lumen Mucosa Submucosa

Muscularis propria Serosa

Intrinsic extrinsic drugs erythropoietin

Platelet adhesion & aggregation

Review: gastrointestinal angiodysplasia

Review: gastrointestinal angiodysplasia

Review: gastrointestinal angiodysplasia

No. of bleeding episodes

Lewis et al.,178 1992, USA

Van Cutsem et al.,179 1990, Belgium Barkin et al.,180 1998, USA

Prospective doubleblinded crossover Prospective cohort

22% (Rx) vs. 100% (placebo) (P < 0.002)

535 days (251551)

100% before % patients with recurrent Rx and 0% after Rx bleeding

Study Ge et al., 2011, China

55 Prospective randomised open-label

Review: gastrointestinal angiodysplasia

Molina et al.,199 2009, Spain

Scaglione et al.,204 2007, Italy

No. of units blood Tx (median and range) 33 months Tx (1260) requirement

Junquera et al.,205 2007, Spain

Nardone et al.,195 Prospective 1999, Italy cohort

Octreotide 100 mcg TDS SC for 6 months

Overt OGIB Occult OGIB

No treatment Signs of shock or failed endotherapy

Assess for AS +/ AVR

Recurrence and/or Transfusion-dependant

Unsuccessful Consider repeat endoscopy +/ endotherapy Consider Surgery***

Review: gastrointestinal angiodysplasia

Review: gastrointestinal angiodysplasia

Review: gastrointestinal angiodysplasia

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