angiodisplasia art

Review article: gastrointestinal angiodysplasia pathogenesis,diagnosis and managementS. S. Sami*, S. A. Al-Araji & K. Ragunath*

*Nottingham Digestive DiseasesCentre & NIHR Biomedical researchUnit, Queens Medical Centre,Nottingham, UK.University Hospital of NorthStaffordshire, Stoke-on-Trent,Staffordshire, UK.

Correspondence to:Prof. K. Ragunath, NottinghamDigestive Diseases Centre & NIHRBiomedical research Unit, Level E,West Block, Queens Medical Centre,Nottingham, NG7 2UH, UK.E-mail: [email protected]

Publication dataSubmitted 22 July 2013First decision 14 August 2013Resubmitted 16 September 2013Accepted 18 September 2013EV Pub Online 20 October 2013

This commissioned review article wassubject to full peer-review and theauthors received an honorarium fromWiley, on behalf of AP&T.

SUMMARY

BackgroundAngiodysplasia (AD) of the gastrointestinal (GI) tract is an important con-dition that can cause signicant morbidity and rarely mortality.

AimTo provide an up-to-date comprehensive summary of the literature evaluat-ing this disease entity with a particular focus on pathogenesis as well ascurrent and emerging diagnostic and therapeutic modalities. Recommenda-tions for treatment will be made on the basis of the current available evi-dence and consensus opinion of the authors.

MethodsA systematic literature search was performed. The search strategy used thekeywords angiodysplasia or arteriovenous malformation or angioectasiaor vascular ectasia or vascular lesions or vascular abnormalities or vas-cular malformations in the title or abstract.

ResultsMost AD lesions (5481.9%) are detected in the caecum and ascendingcolon. They may develop secondary to chronic low-grade intermittentobstruction of submucosal veins coupled with increased vascular endothelialgrowth factor-dependent proliferation. Endotherapy with argon plasmacoagulation resolves bleeding in 85% of patients with colonic AD. Inpatients who fail (or are not suitable for) other interventions, treatmentwith thalidomide or octreotide can lead to a clinically meaningful responsein 71.4% and 77% of patients respectively.

ConclusionsAngiodysplasia is a rare, but important, cause of both overt and occult GIbleeding especially in the older patients. Advances in endoscopic imagingand therapeutic techniques have led to improved outcomes in thesepatients. The choice of treatment should be decided on a patient-by-patientbasis. Further research is required to better understand the pathogenesisand identify potential therapeutic targets.

Aliment Pharmacol Ther 2014; 39: 1534

2013 John Wiley & Sons Ltd 15doi:10.1111/apt.12527

Alimentary Pharmacology and Therapeutics

INTRODUCTIONThere are several types of vascular malformations thatcan be found in the gastrointestinal (GI) tract. They rep-resent aberrations in the normal vascular structure of theaffected arteries, veins or capillaries. Some of those canbe benign like haemangiomas, while others are malig-nant, for example, angiosarcomas. Similarly, these vascu-lar anomalies could be hereditary, such as hereditaryhaemorrhagic telangiectasia or acquired like angiodyspla-sia (AD), gastric antral vascular ectasia (GAVE), radia-tion-induced vascular ectasia and Dieulafoys lesions.1

The rst case of AD in the literature was described in1839, but it was not until 1974, when the term AD wasrst used describing abnormal clusters of mucosal vesselsin the colon.2 Since then, there has been some debate inthe literature regarding the exact aetiology of theselesions, which resulted in a variety of synonymous termslike angioectasia, arteriovenous malformations and vas-cular ectasia.

AD can be dened as the nding of abnormal, ectatic,dilated, tortuous and usually small (

or melaena) and the rest had features of occult GI bleed-ing. Multiple lesions were found in 63% of cases andcolonic AD was detected 50% of those who had a colo-noscopy performed. This highlights the fact thatalthough AD in the upper GI tract is uncommon, itshould be considered as a cause of both occult and overtGI bleeding.

Small bowelIn patients under 50 years of age with obscure GI bleed-ing (OGIB), small bowel tumours are commonly identi-ed as the cause in 57%. However, in patients olderthan 50 years, the source is likely to be small bowelAD.17, 18

Liao et al.19 performed a systematic review of all origi-nal articles relevant to wireless capsule endoscopy(WCE) for the evaluation of patients with small bowelsigns and symptoms published between 2000 and 2008.A total of 227 studies involving 22 840 procedures wereincluded. OGIB (overt and occult) was the most com-mon indication (66.0%) and AD was the most commoncause (50.0%) of bleeding in those patients. In anotherstudy, small bowel AD lesions were the most commoncause (35%) of severe life-threatening overt OGIB.20

ColonThe colon is the most frequent site of AD in the GItract.4, 21 In western patients, lesions are predominantlylocated in the caecum and ascending colon (5481.9%),while lesions diagnosed in Japanese patients are morelikely to be in the descending colon (41.7%).21, 22 Theprevalence of colonic AD in healthy asymptomatic adultswas estimated to be 0.83% and none of these individualsdeveloped bleeding over a mean follow-up duration of3 years.4 Therefore, treatment of nonbleeding lesions isgenerally not recommended. The frequency of colonic AD

as a cause of lower GI haemorrhage varies between 3% and40%.2326 Bleeding from colonic AD can be mild, chronic,recurrent and can stop spontaneously in up to 90% ofpatients; nonetheless, it can also be life threatening.21, 27

Approximately 4060% of patients with upper orlower GI AD have more than one lesion15, 16 and 27%of patients with colonic AD had multiple lesions involv-ing two or more segments of the large bowel.28 More-over, while AD is usually present in the same part of theGI tract, synchronous lesions elsewhere can occur inapproximately 20% of patients.29, 30 These ndings sug-gest that local factors may be important in the pathogen-esis of nonhereditary AD. It also highlights theimportance of evaluating both the upper and lower GItract in patients with symptomatic AD.29 AD can onlybe condently diagnosed as the cause of blood loss if itwas 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 rstto report a possible association between AS and bleedingfrom AD in 1958. This was called Heydes Syndrome.A subsequent retrospective casecontrol study of 1443patients found that the incidence of AS in patients withOGIB was much higher (25.5%) compared with controls(4.4).33 Several other studies have also suggested an asso-ciation between AS and idiopathic or recurrent GI bleed-ing, which was not noted with other valvular diseases ofthe heart like mitral stenosis.3437 Further support forthis hypothesis comes from evidence of improvement orcessation of chronic GI bleeding in the vast majority ofpatients with AS after aortic valve replacement (AVR).This effect was sustained for up to 12 years after surgeryin the largest case series of 91 patients.3843

(a) (b)

Figure 2 | (a) Histological appearance of a predominantly submucosal angiodysplasia (AD) with dilated thick-walledarteries and thin-walled veins. (b) Histological appearances of caecal angiodysplasia showing dilated vessels withinthe mucosa adjacent to the epithelial cells. (Reproduced with permission from Gordon FH, et al.1 Copyright Elsevier).

Aliment Pharmacol Ther 2014; 39: 15-34 17

2013 John Wiley & Sons Ltd

Review: gastrointestinal angiodysplasia

The issue of whether there is an association betweenAS and bleeding from AD per se remains somehow con-troversial. Several initial case reports and case series havesupported this association.28, 4449 However, most ofthese studies had major deciencies in their methodol-ogy.50 Other reports have failed to show an associationbetween AD and AS.8, 51, 52 Nonetheless, they showed ahigher risk of bleeding from AD in patients with aorticsclerosis rather than AS.5153 A recent study has esti-mated the prevalence of AS using echocardiography in73 elderly patients with endoscopically conrmed AD.This was reported to be 32%, which was signicantlyhigher that the prevalence in the control group (14%).54

In the largest and most recent epidemiological studyso far, investigators examined data from hospital dis-charge coding in an all Irish population cohort between1997 and 2001 (3.8 million events). There was a signi-cant association between AS and GI bleeding secondaryto presumed AD. The prevalence of patients with bothconditions was very low, which, the authors thought,may explain why some smaller studies have not shown asignicant association.55

There seems to be sufcient evidence to support anassociation between AS and bleeding from AD, butwhether the association is causal remains very muchdoubtful. This observation has led to the hypothesis thatabnormal von Willebrand factors (vWF) could providethe explanation to the increased risk of bleeding inpatients with AS or aortic sclerosis and otherwise silentAD.

Von Willebrand disease (vWD)Patients with certain subtypes of vWD are at anincreased risk of GI bleeding from colonic AD.5662

Those patients have low levels of the high molecularweight (HMW) multimers of vWF, which is eitherhereditary (type 2a vWD) or acquired (AS). VWF isessential in mediating the adhesion and aggregation ofplatelets to the sub-endothelium of damaged bloodvessels. HMW multimers are the most effective in thisprocess.63

In the acquired form, vWF multimers are disruptedby the high shear stress as they pass through the stenoticaortic valve leading to cleavage and subsequent reductionin the HMW multimers causing acquired vWD.64 In oneprospective study, abnormalities in vWF multimers andplatelet function reverted back to normal after AVR inall patients post-operatively.41 These ndings were repli-cated in a more recent case report.65 Other studies haveshown that AVR was effective in stopping bleeding

regardless of the site of AD and nonbleeding lesionsremain visible on endoscopy post-operatively.47, 66 How-ever, decision about performing metallic AVR should beconsidered with caution in view of the need for warfarin,which has been reported to contribute to ongoing bleed-ing after surgery.67 While another report showed thatbleeding stopped after metallic AVR despite warfarin.68

There is now evidence of clear association betweenabnormalities in vWF HMW multimers and increasedrisk of bleeding from AD both from case reports andprospective studies.62, 6971 The current most acceptedconcept is that AS and AD are both diseases of older ageand low levels of HMW multimers precipitate GI bleed-ing from existing AD in patients with co-existent AS.Surgery (AVR) may be an option in patients with ASand signicant GI bleeding from AD, but that has toweighed carefully against the option of bowel resection.Although there is strong association between abnormali-ties in vWF and AS, it is worth noting that GI bleedingfrom AD remains rare in these patients.56

Chronic renal failure (CRF)AD is more common in patients with CRF and the prev-alence is thought to be related to the duration and sever-ity of the kidney disease.72 AD accounts for 1932% ofLower GI bleeding episodes in patients with CRF com-pared with 56% of episodes in the general population.4

Likewise, gastric and small bowel AD are reportedly themost common causes of upper GI bleeding and OGIB inthose patients, respectively.73, 74 The reason for thisobserved high prevalence of AD among subjects withCRF remains unclear and it is conceivable that it is dueto the increased risk of bleeding that these lesions aremore likely to be detected during endoscopic investiga-tions, which result in overestimating the real prevalence.

Patients with CRF are at an increased risk of bleedingdue to several mechanisms including uraemic plateletdysfunction75, 76 and use of anti-coagulants.77 The causesof platelet dysfunction (aggregation and adhesion) arethought to be due to both intrinsic and extrinsic fac-tors.76, 78 Intrinsic factors include reduced levels of agon-ists like adenosine diphosphate, serotonin, epinephrine,thrombin and collagen leading to impaired platelet func-tion.79 It has also been noted that levels of platelet cyclicadenosine mono-phosphate which causes platelet dys-function by mobilising calcium were high in patientswith CRF. Extrinsic factors include release of toxins andincreased nitric oxide, which inhibits platelet-to-plateletinteraction and affects platelet to vessel wall interac-tion.79

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S. S. Sami et al.

AD is therefore an important cause of GI bleeding inpatients with CRF. Other factors, which contribute toabnormalities in haemostasis, include reduced productionof erythropoietin and effect of drugs.79

PATHOGENESISThe aetiology and mechanism for the development ofAD is not fully understood. The most widely quotedhypothesis in the literature is the one proposed by Boleyet al.,80 in a study using resected colon specimens frompatients with angiographic and clinical evidence of caecalvascular lesions. Histological evaluation revealed dilatedand tortuous veins in the submucosa even without obvi-ous mucosal lesion. It was suggested that those lesionsdevelop with ageing due to chronic low-grade intermit-tent obstruction of submucosal veins as a result ofincreased contractility at the level of muscularis propria.

This leads to congestion of the capillaries and failure ofthe pre-capillary sphincters, resulting in the formation ofsmall arterio-venous collaterals (Figure 3).

This theory could be supported in part by the factthat AD commonly occurs in the older population withpredilection to the ascending colon and caecum. Thebowel is cylinder-shaped and according to the Law ofLaplace (T = p 9 r/[(2 9 t], where T = wall tension,p = pressure, r = radius, t = wall thickness), tension ishighest when the radius increases and wall thicknessreduces.81 This applies to the ascending colon and cae-cum (large diameter with thin wall) where the bowelwall tension is highest, which compresses the submucosalvenules, but not arterioles. A similar mechanism takesplace in the gastric antrum and pylorus where musclecontraction is most vigorous leading to the developmentof ectatic vessels and AD.82

Lumen

+AS

Asso

ciat

ed c

ondi

tions

+VWD

+CRF

Lumen Lumen

Mucosa

Mucosal & submucosalischemia/hypoxia

Cardiacoutput

VWFmultimers

VEGF-dependantproliferation

Platelet adhesion &aggregation

Intrinsicextrinsicdrugs

Submucosa

Muscularis propria

Serosa

erythropoietin

Angiogenesis

Bleeding New vesselformation

(a) (b) (c)

(d)

Figure 3 | The pathophysiological mechanisms contributing to the development of angiodysplasia (AD) andsubsequent bleeding. The relationship between those mechanisms and the increased risk of bleeding in patients withAortic stenosis (AS), Von Willebrand disease (vWD) and chronic renal failure (CRF) is also detailed. Chronic low-grade intermittent obstruction of submucosal veins as a result of increased contractility at the level of muscularispropria (a, b). This leads to congestion of the capillaries and failure of the pre-capillary sphincters (c) resulting in theformation of small arterio-venous collaterals (d).




Some other investigators have observed that patientswith AD are more likely to have underlying cardiac, vas-cular or pulmonary diseases and therefore suggested thatmucosal ischaemia from chronic hypoxia or hypo-perfu-sion may contribute to the development of AD; however,these were small observational casecontrol studies withno histological correlation.8, 49 This has led to the sug-gestion that the increased incidence of bleeding AD inpatients with AS could be due to reduced cardiac outputand tissue perfusion in this subgroup.83

Angiogenesis is an essential biological process toincrease vascularity in human tissues when there ishypoxia or ischaemia. This results in the formation ofnew vessels (neovascularisation) as a result of imbalancebetween pro-angiogenic and anti-angiogenic factors (Fig-ure 3).84 In vitro studies have shown that the expressionof vascular endothelial growth factor (VEGF) underhypoxia is higher compared with normoxia.85 Increasedexpression of angiogenic factors, namely VEGF and basicbroblast growth factor, has been demonstrated inhuman colonic AD and is therefore likely to play a veryimportant role in the development of these lesions aswell as in modifying the risk of bleeding.84, 86 This rep-resented a novel therapeutic target and led to subsequentdevelopment of anti-angiogenic drugs like thalidomide.

More recently, the role of vWF in regulating angio-genesis has been studied. Inhibition of vWF expressionin endothelial cells in vitro caused increased angiogenesisand increased VEGF-dependent proliferation and migra-tion. There was also in vitro and in vivo increase in vas-cularisation in vWF-decient mice. This represents animportant link between angiogenesis and haemostasisand has some therapeutic implications in managementof patients with AD with and without vWD.87

The factors contributing to the development of ADand risk of bleeding are summarised in Figure 3 below.

DIAGNOSISThe extent to which investigations should be performedin patients with OGIB largely depends on the clinicalscenario and severity of bleeding. The main investiga-tions for the diagnosis of AD are:

Endoscopic imagingEndoscopy is currently the main tool for diagnosis ofAD; this is largely due to signicant improvements invideo endoscopy equipment and image resolution. UpperGI and colonic AD are usually diagnosed by standardupper GI endoscopy and colonoscopy, respectively.Commonly used endoscopic modalities for assessment ofthe small bowel include WCE, push enteroscopy, deepsmall bowel enteroscopy [double-balloon enteroscopy(DBE), single-balloon enteroscopy (SBE) and spiral ent-eroscopy (SE)] or intra-operative enteroscopy. Variousendoscopic appearances of AD are shown in Figures 1, 4and 5. Sometimes, a prominent feeding vessel might bevisualised at the time of endoscopy (Figure 1b).10 Fur-thermore, the mucosa at the lesion margins is oftenmore pale, giving the characteristic appearance of thepale halo sign (Figure 5a).

These lesions can be missed during endoscopy due toa variety of reasons, for example, operator experience,poor visibility as well as size and location of AD, in par-ticular if they are located behind mucosal folds.17 Theycan also be wrongly diagnosed as a localised area ofinammation or trauma.88 It is therefore recommendedthat repeat examinations should be considered especiallyin cases of high clinical suspicion or when the initial

(a) (b)

Figure 4 | (a) Arterial phaseof selective superiormesenteric angiogramshowing arterial andsimultaneous early venouslling (indicating rapidshunting), with dilated areasof vasculature in the caecalwall. (b) Venous phase of thesame angiogram. (Reproducedwith permission from GordonFH, et al.1 Copyright Elsevier).



S. S. Sami et al.

examination was suboptimal before embarking on inves-tigations of the small bowel.17

Wireless capsule endoscopy is the preferred rst-lineinvestigation for the small bowel in the context of OGIBas it is safe, acceptable and has signicantly higher or atleast equivalent yield for lesions when compared withother, more invasive modalities like push enteroscopy,mesenteric angiography and intra-operative enteros-copy.89, 90 The British Society of Gastroenterology guide-lines recommend that patients over the age of 50 yearspresenting with OGIB who have a negative gastroscopyand 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 fre-quently achieved with WCE (90.6%) compared withDBE (62.5%, P < 0.05).91, 92 The main limitation ofWCE is the relatively poor visibility in the distal smallbowel due to dark intestinal liquid contents. Moreover,no therapeutic intervention can be performed via theWCE. In patients with recurrent OGIB or severe irondeciency anaemia who had negative WCE, a repeattesting with WCE revealed the presence of AD in up to29% of patients (75% for all ndings) and led to changesin patient management in two small studies.93, 94 WCEcan be highly useful in localising the site, size and num-ber of AD lesions to guide in decision about best inser-tion route for enteroscopy (oral or anal) to applytherapy.95, 96

All three techniques for deep small bowel enteroscopy(DBE, SBE and SE) are comparable in terms of diagnos-tic yield, therapeutic capabilities and adverse events.97

There was signicantly higher total enteroscopy ratesachieved with DBE (5766%) compared with SBE (022%, P < 0.003) reported in two out of three randomisedcontrolled trials comparing the two techniques, but thatdid not translate to a difference in diagnostic yield.98100

DBE was equivalent to SE in one of two small prospec-tive trials,101 whereas the other study showed bettermean procedure time for SE (43 min vs. 65 min;P = 0.007), but DBE was superior in terms of medianmaximum insertion depth (310 cm vs. 250 cm;P = 0.004).102 Performance characteristics of SBE and SEwere equivalent in one retrospective study.103 Otheradvantages of enteroscopy include the facility for takingbiopsies, ushing the mucosa to improve visibility andmarking of lesions that will require surgical resection.17

The choice of enteroscopy technique will ultimatelydepend on the local expertise and availability of equip-ment.

Deep enteroscopy techniques are superior to push ent-eroscopy in terms of insertion depth into small boweland signicantly higher diagnostic yield of clinicallyimportant lesions.104106 Intra-operative enteroscopyfacilitates complete examination of the small bowel andis performed jointly by a surgeon and an endoscopist.This procedure is associated with potentially serious

(a) (b)

(c) (d)Figure 5 | (a) Angiodysplasia(AD) in stomach with blackarrow highlighting the palehalo sign around the lesion.(b) Close-up view of lesionappearance. (c) Argon PlasmaCoagulation (APC) noncontactablation. (d) Appearancesimmediately post-APCablation.




complications,107110 and should be reserved for selectedgroup of patients in whom less invasive tests have failedto identify or treat the source of bleeding.

Radiographic imagingRadiographic imaging techniques can be implementedonly in patients who present with signs of active overtGI bleeding to obtain a primary diagnosis or to conrmthe location of suspected bleeding site seen on endos-copy. Modalities useful in patients with bleeding fromAD include radionuclide scanning, computed tomogra-phy (CT) angiography, magnetic resonance (MR) angi-ography or standard angiography.

Radionuclide scanning uses technetium (99mTc)labelled red blood cells techniques to localise bleedingthat occurs at a rate of about 0.1 mL/min. It is anon-invasive and sensitive test,111 but its localisation isgeneral and could be anywhere in the abdomen. Accu-racy rates vary from 24% to 91% among different stud-ies.112, 113 Furthermore, patients will still require atherapeutic intervention like standard angiography;hence, this technique is not widely used nowadays in theacute setting.

Computed tomography and MR angiography also pro-vide rapid non-invasive diagnosis in the context of activeGI bleeding, but there are concerns regarding radiationexposure (with CT) and contrast allergy in addition tothe lack of therapeutic capability.

Standard angiography had a lower diagnostic yield inpatients with overt OGIB when compared with immedi-ate WCE (20.0% vs. 53.3%, P = 0.016) in a recent pro-spective randomised study.114 Nonetheless, standardangiography does not require bowel preparation, so thereare no concerns regarding visualisation. It also allowsaccurate localisation and therapeutic embolisation of thebleeding point to be achieved at the same time (Fig-ure 4). The decision to use this technique has to be care-fully weighed against the potential risks of bowelischaemia and other potential complications. Therefore,this procedure is generally reserved for patients in whomother modalities have failed to identify the source ofbleeding or those with severe bleeding and hemodynamicinstability.

MANAGEMENTDecisions regarding management of patients with nonb-leeding AD largely depend on the clinical context inwhich it was diagnosed. For instance, treatment is notrequired for lesions that are found incidentally inpatients with nonbleeding-related symptoms or those

who are asymptomatic because the risk of future bleed-ing in these subgroups of patients is low and mostremain asymptomatic.4, 7 Furthermore, patients found tohave lesions in one part of the GI tract will often haveadditional AD elsewhere in the GI tract.22 On the otherhand, treatment should be considered in patients withnonbleeding AD and symptoms of occult or overt OGIBwhere no other source of bleeding is found. The degreeto which invasive treatment is pursued will depend onthe size, site and number of lesions as well as the clini-cal severity of anaemia and blood loss. Evidence fromprospective randomised controlled trials evaluating med-ical and nonmedical interventions to treat AD is rela-tively scarce. Therefore, most of the data on therapycome from large or small case series as well as casereports.

Endoscopic therapiesArgon plasma coagulation (APC). This method usessynchronised delivery of electrical current and argon gas.The argon gas is ionised and allows transmission of thehigh-frequency current to the target lesion or tissuewithout direct contact. It has become the most widelyused method for treating AD (Figure 5).115 It is alsoused for other bleeding and nonbleeding lesions of theGI tract.115 One perceived advantage of APC is the lim-ited depth of tissue injury. However, that has not beenclearly shown from animal studies with the settings usedin clinical practice.116, 117

In the upper GI tract, one study using human surgicalspecimens have shown that coagulation depth in stom-ach depends on the device power setting and duration ofapplication, while these factors did not correlate withdepth of coagulation in oesophageal specimens.118

Several studies have evaluated the safety, efcacy andlong-term outcomes of APC for treatment of AD in thesmall bowel mainly by using balloon-assisted enteroscopytechniques. Re-bleeding rates ranged from 11% to 19%mainly resulting from the nding of new lesions, meanfollow-up duration was up to 18 months in one studyand there were no serious complications.119123

The performance of APC in treatment of colonic ADwas recently evaluated in a prospective study of 100patients.124 Bleeding resolved in 85% of patients after amedian follow-up of 20 months requiring 118 proce-dures. Transfusion requirements ceased in 90% ofpatients and one patient required surgery. The meanHaemoglobin levels increased after treatment andre-bleeding rate was 2% and 10% at 1- and 2-year fol-low-up, respectively. Complications occurred in 1.7% of



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procedures.124 Another study showed similar efcacyand safety prole in patients with bleeding GI AD.125

Complications including caecal perforation have beenreported.126 The utility of submucosal saline injection(with or without adrenaline) to form a uid cushion inthe colon before APC therapy has been demonstrated inanimal and human studies.127, 128 It is safe and provento reduce the depth of tissue injury. This technique isnow recommended and been used in clinical practice, inparticular, for lesions more than 10 mm in size in theright colon where the bowel wall is thinnest (Fig-ure 6).128, 129

There are also several cases reported in the literatureof colonic gas explosion during APC leading to perfora-tion in some cases.130 This has also been reported usingother electrocautery techniques131 and is thought to bedue to the accumulation of combustible gases at explosiveconcentrations due to poor bowel preparation. Therefore,full bowel cleansing with oral purgatives (polyethyleneglycol or sodium phosphate solutions) is highly recom-mended prior to undertaking any electrocautery proce-dures in the large bowel.130 APC is therefore safe,available, easy to use and cost-effective115, 125, 129.

Electrocoagulation. Lesion coagulation by hot biopsyforceps (monopolar electrocoagulation) was the rstthrough-the-scope technique used to treat AD in theearly 1980s.49, 132 This technique is not recommended incurrent practice due to relatively high risk of seriouscomplications in up to 9% of patients including perfora-tion in approximately 3% of cases especially in theascending colon and caecum.49, 132134 High rates ofre-bleeding (53% at 3 years) have also been reported.132

Subsequently, contact probes were introduced intopractice for treatment of AD in the late 1980s and useduntil now.135137 There are few devices now commer-cially available, for example, HeatProbe (Olympus,Japan), which is a monopolar device with an inner coilthat is heated by the electrical current and allows directheat transfer to the tissue by applying pressure. Anotherexample is the GoldProbe (Boston Scientic), which is abi-polar device, so it delivers heat via a current thatows between the two electrodes at the tip of the probe.This limits the maximum temperature generated as wellas the depth and surface area of tissue injury.138

Thermal ablation using contact probes and APC hasbeen used for treatment of AD with possibly similar ef-cacy proles.139 Complications including perforationhave been reported with both techniques;139 however,the amount of published evidence supporting the efcacyand safety of APC in this clinical setting is much largercompared with contact probes. Both techniques shouldbe used with caution in the duodenum and ascendingcolon. In the absence of prospective comparative trials,we recommend using APC as the rst line; otherwise, abi-polar probe is similarly effective with choice depend-ing on availability and local expertise.

Photocoagulation (Laser). Photoablation of AD usingNd:YAG (neodymium:yttrium-aluminium-garnet) andArgon laser has been reported in few studies. Recent evi-dence using this technique focused mainly on patientswith GAVE.140, 141 In the most recent study, Nd:YAGlaser resulted in cessation of blood transfusion in 61% ofthe 59 patients after 300 sessions. No serious complica-tions were reported.142 This is in contrast to previous

(a) (b) (c)

Figure 6 | The submucosal adrenaline injection technique prior to Argon Plasma Coagulation (APC). (a) Caecalangiodysplasia (AD). (b) Diluted adrenaline (1:200,000) injected beneath the lesion; vascular shrinkage and pallor ofthe mucosa was noted. (c) Post-ablation of AD lesion with APC 50 W. (reproduced with permission from Suzuki N,et al.128 Copyright Elsevier).




data reporting complications in up to 10% ofpatients,134, 143147 with a cumulative incidence of perfo-ration (both upper and lower GI tract) in 2.4% ofpatients from four studies.134, 144146 The argon laser isless well studied135, 147, 148 and although it has showngood efcacy, concerns remain regarding the risk of per-foration of 2.6% in one study.147 Other limitations ofthese techniques are the high cost and specialist expertiserequired to deliver the treatment.

Endoscopic clips. This approach has shown safety andefcacy in few case reports using endoscopic clipping forbleeding colonic AD either as a monotherapy149 or incombination with thermal ablation using APC andcontact probes.150152 Clipping is particularly useful incases of isolated and relatively large lesions to obliteratethe feeding vessel and reduce the risk of precipitatingbleeding from subsequent electrocoagulation. It can alsobe useful in patients with high risk of bleeding due todrugs (anti-platelets, anti-coagulants) or coagulationdefects.151, 152

Endoscopic ligation. Successful treatment of bleedinggastric AD with multiband ligation devices has beendemonstrated in few case series.153156 No serious com-plications were reported and efcacy was equivalent tobipolar electrocoagulation in one prospective study.154

Ljubici et al.157 used a novel detachable mini-loop liga-tion device to treat upper GI AD in 11 patients. Therewas one case of severe bleeding from a post-ligationulcer in the duodenum requiring endoscopic therapy.

Endoscopic multiband ligation achieved haemostasisin 14 patients with bleeding small bowel AD.158

However, re-bleeding occurred in 43% of patients duringa mean follow-up period of 18 months; therefore,long-term efcacy of this technique remains doubtful.

Endoscopic resection. Two cases reported of polypoidcolonic angiodysplasia treated by polypectomy usingpolyloop ligation device in one case with no complica-tions.159, 160

Injection therapy. Injection sclerotherapy was reportedin two studies. Marwick et al.161 used 0.51.0 mL of1.5% sodium tetracedyl sulphate to treat 10 patients withupper GI AD directly injecting the sclerosant beneaththe lesion. Another study demonstrated the feasibilityand safety of ethanolamine injection to treat eightpatients with 15 lesions predominantly in the rightcolon.162 None of the studies reported any serious com-

plications. However, this technique can be challengingand time consuming depending of the site, number andease of access to the lesions. No further studies havebeen performed possibly due to the availability of othertherapeutic options like APC.

Transcatheter angiography and intervention (TAI)This is usually indicated in patients with active GI bleed-ing who either fail endoscopic therapy or in whomendoscopy is not a suitable option. TAI can also be con-sidered as an alternative to surgery in high-risk patientsor to localise the lesion prior to surgery.163

Control of bleeding can be achieved by intra-arterialinfusion of vasopressin at the bleeding site to reduce per-fusion and allow clot formation. However, high rates ofrebleeding have been reported with this technique inaddition to concerns regarding systemic complicationsresulting from vasoconstriction and leading to ischae-mia.164, 165 It is also contraindicated in individuals withcoronary artery disease, severe hypertension, peripheralvascular disease and arrhythmias. Nonetheless, thismodality can be useful in inaccessible lesions.166

Superselective transcatheter embolization is the cur-rent angiographic method of choice for treatment ofbleeding AD.164, 166 The most common agents used arebiodegradable gelatine sponges and microcoils. Otheroptions include liquid agents like polyvinyl alcoholand cyanoacrylate. This technique can be successful in8090% of patients with relatively low rebleedingrates.167171 Repeat embolization can be performed ifrebleeding occurs. Overall, complications can occur inapproximately 59% of patients, while serious complica-tions are reported in less than 2% with modern tech-niques.166, 172 These include haematomas; arterialdissection; thrombosis; pseudo-aneurysm formation; andbowel infarction.172

SurgeryAdvances in endoscopic and angiographic diagnostic andtherapeutic capabilities have resulted in marked reduc-tion in the need for operative intervention in patientswith bleeding AD.173 Surgical resection is now reservedfor patients with either acute, severe bleeding not con-trolled by other alternatives or for patients with recur-rent chronic bleeding who are transfusion-dependent;have clearly identied source of blood loss; and failedother treatment options. Surgery is curative; however,accurate localisation of the bleeding lesion pre-opera-tively should be attempted to avoid recurrence of bleed-ing from missed lesions elsewhere in the GI tract.



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Several intra-operative localisation techniques can also beused to ensure accurate resection of the target lesion.174

Pharmacological therapiesTreatment of AD using angiographic, endoscopic andsurgical techniques can be associated with serious com-plications and is sometimes ineffective in preventingrecurrence of GI bleeding. This could be due to the factthat it is usually hard to determine the exact locations ofall lesions, particularly in the small bowel.120, 175 There-fore, a safe and cost-effective pharmacological agent canrepresent an attractive option, which can be offered topatients with signicant co-morbidities; high risk ofcomplications from more invasive therapy; and thosewho do not respond to the other treatment options.

Hormonal therapy. There are ve studies in the litera-ture evaluating the efcacy of combined hormonal ther-apy (oestrogen and progesterone) in management ofpatients with diffuse and sporadic bleeding AD(Table 1).176180 All studies were published between1990 and 2001. The most common outcomes measuredwere the reduction in number of bleeding episodes andtransfusion requirements. Most studies had signicantweaknesses in their methodology and only one studyincluded a control group.176 Evidence from the threeeither small or retrospective and uncontrolled studiessuggested a possible advantage from hormonaltherapy;177, 179, 180 however, these ndings were notreplicated in larger two studies with more soundmethodology.176, 178

Table 1 | Primary studies evaluating the efcacy of combined hormonal therapy in adult patients with transfusion-dependent gastrointestinal (GI) bleeding and endoscopically conrmed sporadic angiodysplasia (AD) of the GI tract

Study DesignSamplesize

Treatment doseand duration Comparator Follow-up 1 outcome Results

Junqueraet al.,176

2001, Spain

Prospectivemulticentre,double-blindedrandomised

72 Norethisterone2 mg andethinylestradiol10 mcg OD for12 years

Placebo 1 year (13)* % failureof Rx

39% (Rx) vs.46% (placebo)(P value NS)

Junqueraet al.,177

1995, Spain

Retrospectivecohort

18 Lynestrenol 2.5 mgand mestranol75 mcg OD for360 months

None _ No. ofbleedingepisodes

Mean 4.4 1.2before Rx vs.0.7 0.5during Rx(P < 0.05)

Lewiset al.,178

1992, USA

Retrospectivecasecontrol

64 510 mg ODnorethynodreleither withmestranol75150 mcg(n = 24)or Premarin,625 mcgOD(n = 6)

None(untreatedhistoricalcontrolgroup)

15.6 months(231) Rxgroup and13.4 months(123)control

% patientsrequiredno furtherTx

50% (Rx) vs.44% (controls)(P value NS)

Van Cutsemet al.,179

1990,Belgium

Prospectivedouble-blindedcrossover

10 50 mcgethinyloestradiolplus 1 mgnorethisteroneOD for 6 months

Placebo _ % patientsrequiring Tx

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

Barkinet al.,180

1998, USA

Prospectivecohort

25 5 mg norethynodreland 75 mcgmestranol OD or1 mg norethindroneand 50 mcgmestranol, BD

None 535 days(251551)

% patientswith recurrentbleeding

100% beforeRx and 0%after Rx

Rx, treatment; OD, once daily; BD, twice daily; No., number; Tx, transfusion.

* Median and range.

Mean and range.




There is only one good quality multicentre, rando-mised, double-blinded, placebo-controlled trial evaluatingthis intervention in a group of 72 consecutive noncirrh-otic patients. Subjects presented with acute or chronic GIbleeding from AD (conrmed by endoscopy or angiogra-phy) were randomly assigned to receive either ethinylest-radiol (0.01 mg) plus norethisterone (2 mg) (one tabletper day orally) or placebo (one tablet per day orally).There was no difference in outcomes and major adverseevents between the two groups after a follow-up periodranging from 1 to 3 years.176 The efcacy of hormonaltherapy in patients with CRF has been evaluated in twosmall case series with positive results.181, 182

Current evidence suggests that there is no role forhormonal therapy in patients with sporadic AD.

Thalidomide. Thalidomide acts by inhibiting angiogene-sis through suppressing the expression of VEGF.85 Itseffectiveness in the treatment of chronic bleeding fromAD has been initially demonstrated in numerous casereports and case series, all published in the lastdecade.183191 A reduction in the number and size of ADhas also been reported post-therapy.188, 192

These ndings were subsequently conrmed by arecent open-label, randomised controlled trial including55 patients (AD n = 52 and GAVE n = 3) either refrac-tory or unsuitable for other therapies.192 All participants

were initially observed for 1 year and then randomisedto receive oral thalidomide 100 mg daily or oral irontherapy 400 mg daily for 4 months. Response to treat-ment was dened as a decrease in bleeding episodes ofat least 50% within the rst year of follow-up. Responserates were signicantly higher in the treatment group(71%) compared with the iron-controlled group (4%).Bleeding stopped in 46% of patients receiving thalido-mide compared with none in the control group. Treat-ment with thalidomide also reduced the number oftransfusion-dependent patients (11% vs. 48%) and hospi-talisation episodes for bleeding (39% vs. 100%). Thesebenets were sustained after a minimum of 1-year fol-low-up. Response rates did not change when the threepatients with GAVE were excluded from the analysis.Adverse events were higher in the thalidomide group(71.4% vs. 33.3%) and included fatigue (32%); constipa-tion (25%); dizziness (21%); and peripheral oedema(14%). Less frequent side effects included abdominal dis-tension, thrombocytopenia, leukopenia, blurred vision,dry eyes, pruritus, rash, tinnitus, headache and herpeszoster.

There are no other controlled trials evaluating thistreatment in the literature (Table 2). But the current evi-dence demonstrates that thalidomide can be consideredas a treatment option in patients who have failed or arenot suitable for other therapies. However, there have

Table 2 | Primary studies evaluating the efcacy of thalidomide therapy in adult patients with transfusion-dependentGI bleeding and endoscopically conrmed sporadic AD of the GI tract (studies with sample size 3 were excluded)

Study Design Sample size

Treatmentdose andduration Comparator Follow-up 1 outcome Results

Ge et al.,192

2011, ChinaProspectiverandomisedopen-label

55 25 mg QDS(100 mg perday) for4 months

100 mg iron(ferroussuccinate)tablets QDSfor 4 months

39 months(852)*

% of patientswith 50%decrease inbleedingepisodes in1st year offollow-up

71.4% (Rx)and 3.7%(iron-control)(P < 0.001

Garridoet al.,191

2012, Spain

Prospectivecohort

12 200 mg perday for 4months

None 4 months Meanhaemoglobinlevel (g/dL)

6.5 before Rxvs. 12.1 atend of Rx

Kamal-apornet al.,190

2009,Canada

Pilot caseseries

7 (4 discontinuedRx due tointoleranceand 3 remainedin study

50 mg/dayincreased by50 mg everyweek up to200 mg/dayfor 6 months

None 12 months Tx requirement All 3/3 requiredno Tx in 1st6 months, butthen all 3/3lost responseafter

Rx, treatment; QDS, four times a day; Tx, transfusion.

* Median and range.



S. S. Sami et al.

been reports of peripheral neuropathy, liver toxicity andacute liver failure with higher doses of this drug. More-over, it has also been associated with birth defects.Therefore, the maximum recommended dose is 100 mgper day. It should be reserved for patients who are trans-fusion-dependent and not used in women of child-bear-ing age unless they use a reliable contraception methodduring treatment.

Lenalidomide is a newer angiogenic inhibitor, which isthought to be less toxic and better tolerated. However,its role in treatment of AD remains to be evaluated inprospective controlled trials.193

Octreotide. The effect of the somatostatin analogueoctreotide on bleeding from AD is thought to be due toseveral mechanisms including inhibition of angiogenesisby downregulation of VEGF; increase in vascular resis-

tance; decreased splanchnic blood ow; and enhancedplatelet aggregation.194 Endoscopic resolution of ADlesions after octreotide therapy has been reported,although the effect was not quantied.195 Its role in themanagement of AD has not been evaluated in prospec-tive randomised controlled trials. Nevertheless, multiplecase reports and case series have demonstrated a signi-cant benet.67, 186, 196202

The largest piece of evidence supporting the use ofoctreotide comes from a meta-analysis reported by Brownet al203 in 2010 including three studies with a total samplesize of 62 patients.195, 204, 205 All studies had a prospectivecohort design and only one of them included a controlgroup, which was externally matched.205 The authors cal-culated a pooled response rate of 0.76 (95% CI 0.640.85)to octreotide. They concluded that this compares favour-ably to data from natural history studies reporting

Table 3 | Primary studies evaluating the efcacy of Octreotide therapy in adult patients with transfusion-dependentGI bleeding and endoscopically conrmed sporadic AD of the GI tract (studies with sample size 3 were excluded)

Study DesignSamplesize

Treatment doseand duration Comparator Follow-up 1 outcome Results

Bon et al.,206

2012, FranceProspectivecohort

15 Octreotide LAR20 mg/monthIM for12 months(636)*

None 14 months(1036)*

No. of bloodtransfusions(medianand range)

2(014) duringRx vs. 10(624)before Rx(P < 0.001)

Molina et al.,199

2009, SpainProspectivecohort

11 Octreotide LAR20 mg/monthIM

None 15 months(548)*

No. of unitsblood Tx(medianand range)

4(04) duringRx vs. 14(949)before Rx(P = 0.002)

Scaglioneet al.,204

2007, Italy

Prospectivecohort

13 OctreotideLAR 10 mg/month IMfor 1 year

None 33 months(1260)

Txrequirement

69% requiredno further Txor ironsupplementsafter Rx

Junqueraet al.,205

2007, Spain

ProspectiveRx cohortcomparedwith externalcontrol group

70 (32Rx and38placebo)

Octreotide50 mcgBD SC for12 year

38 patientswhohad receivedplacebo in aconcurrentrandomisedtrial

13 months(1236)

% failureof Rx

23% Rx vs.48% placebo(oddsratio = 3.1,P = 0.043)

Nardone et al.,195

1999, ItalyProspectivecohort

17 Octreotide100 mcgTDS SC for6 months

None 12 months a- MeanHaemoglobinlevel (g/dL)and b- Unitsblood Txper year

a- 5.7 beforeRx vs. 11.1 afterRx (P < 0.0005)b- 8.8 beforeRx vs. 1.5 afterRx (P < 0.0005)

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.




re-bleeding rates of 4454% in patients with AD with notreatment. The weighted mean difference in transfusionrequirement before and after therapy was 2.2 (95% CI3.9 to 0.5). It is difcult to ascertain whether this repre-sents the true effect of octreotide as this meta-analysis hadsome inherent weaknesses. The included studies all had asmall sample size with the lack of an appropriate controlgroup. There was a signicant heterogeneity in the studiedpopulation. The prevalence of liver cirrhosis, CRF, valvularheart disease and coagulopathy was highly variable. Therewere also variations in the dose and type of drug used withone study using octreotide long-acting release (LAR)10 mg/month intra-muscularly (IM) for 1 year,204 whilethe other two studies used octreotide normal release subcu-taneously 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 octreo-tide LAR in 15 patients with chronic recurrent bleeding.

The majority of them had failed APC therapy. Therewas a signicant reduction in bleeding episodes andtransfusion requirements with higher mean Hb concen-trations after treatment with IM injections at a dose of20 mg per month for 6 months.

It appears that octreotide is likely to be benecial andcan be used to treat patients with recurrent chronicbleeding from AD (Table 3). It is well tolerated with noserious adverse events. The IM mode of administrationonce per month could be more convenient for somepatients and may encourage compliance.

A practical treatment guide is proposed (Figure 7) toaid physicians in the management of patients diagnosedwith AD.

CONCLUSIONAD is the most common vascular malformation of theGI tract. It is most commonly detected in older patients

Angiodysplasia

Incidental/Asymptomatic

Signs of shock orfailed endotherapyAccessible

Thalidomide orOctreotide**

Recurrence and/orTransfusion-dependant

Consider Surgery***

Consider repeat endoscopy+/ endotherapy

Unsuccessful

*Caution in the right colon and lesions >10 mm (consider submucosalsaline+/adrenaline injection). Recommend manufacturers settings.Caution if poor bowel preparation. Consider use of clips for large feedingvessels.

Interventionalradiology

No signsof shock

APC/Bipolar*Assess forAS +/ AVR

Inaccessible/Diffuse

Occult OGIBNo treatment

Overt OGIB

**Only consider in patients who are transfusion-dependant and deemednot responsive or not suitable for other therapeutic interventions.Consider contraindications and side effects of thalidomide. Thalidomidedose 100 mg per day for 4 months. Octreotide 10-20 mg per month IM or100-300 mcg per day SC for 6-12 months.***In patients with a clearly identified source of blood loss.

Figure 7 | Proposed practicaltreatment guide based on theclinical presentation andangiodysplasia (AD) lesioncharacteristics (blue boxes) toguide different interventions(red boxes).



S. S. Sami et al.

and located more often in the caecum and ascendingcolon. Majority of patients have more than one lesion inone or more parts of the GI tract. Clinical presentationcan range from being asymptomatic and nonbleeding toovert life-threatening haemorrhage.

The association between the increased risk of bleedingfrom AD and AS; vWD and CRF is now more estab-lished. Moreover, recent evidence has highlighted thecomplex mechanisms that underpin this association.Endoscopy is currently the modality of choice to diag-nose and treat these lesions. APC is the most cost-effec-tive endoscopic therapy, while pharmacologicaltreatments like thalidomide and octreotide can serve as asecond line of therapy in a selected group of patientsafter careful consideration of the benet/risk ratio.Transcatheter angiography with or without intervention

is effective in management of patients with severe bleed-ing.

AUTHORSHIPGuarantor of the article: Sarmed S. Sami.Author contributions: Sami SS contributed to the design,literature search, data collection; performed data analysisand written the manuscript. Al-Araji SA contributed tothe design, literature search and data collection. Ragun-ath K contributed to the design of the study and criticalreview of the manuscript. All authors approved the nalversion of the manuscript.

ACKNOWLEDGEMENTDeclaration of personal and funding interests: None.

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