Overview of small bowel angioectasias: clinical presentation and treatment options.

Expert Review of Gastroenterology & Hepatology

ISSN: 1747-4124 (Print) 1747-4132 (Online) Journal homepage: http://www.tandfonline.com/loi/ierh20

Overview of small bowel angioectasias: clinical presentation and treatment options. Stefania Chetcuti Zammit, Anastasios Koulaouzidis, David S Sanders, Mark E McAlindon, Emanuele Rondonotti, Diana E Yung & Reena Sidhu To cite this article: Stefania Chetcuti Zammit, Anastasios Koulaouzidis, David S Sanders, Mark E McAlindon, Emanuele Rondonotti, Diana E Yung & Reena Sidhu (2017): Overview of small bowel angioectasias: clinical presentation and treatment options., Expert Review of Gastroenterology & Hepatology, DOI: 10.1080/17474124.2018.1390429 To link to this article: http://dx.doi.org/10.1080/17474124.2018.1390429

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Date: 10 October 2017, At: 11:54

Publisher: Taylor & Francis Journal: Expert Review of Gastroenterology & Hepatology DOI: 10.1080/17474124.2018.1390429

Review Overview of small bowel angioectasias: clinical presentation

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and treatment options.

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McAlindon1, Emanuele Rondonotti3, Diana E Yung2, Reena Sidhu1 1

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Gastroenterology Department, Royal Hallamshire Hospital, Sheffield, UK.

2

Endoscopy Unit, the Royal Infirmary of Edinburgh, Edinburgh, UK.

3

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Gastroenterology Unit, Ospedale Valduce-Como , Como, Italy.

Stefania Chetcuti Zammit

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Correspondence:

Gastroenterology Department, Royal Hallamshire Hospital, Sheffield, UK.

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Email: [email protected]

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Downloaded by [Australian Catholic University] at 11:54 10 October 2017

Stefania Chetcuti Zammit1, Anastasios Koulaouzidis2, David S Sanders1, Mark E

1

Abstract Introduction: Elderly patients with multiple co-morbidities are at an increased risk of developing small bowel angioectasias. Treating these lesions can be both challenging and costly with patients requiring extensive investigations and recurrent admissions for iron infusions and blood transfusions as well as invasive procedures. This review presents treatment options and describes in detail drugs that should be considered

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whilst taking into account their effectiveness and their safety profile. Areas covered: A PubMed search was carried out using the following keywords:

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obscure gastrointestinal bleeding to assess existing evidence. The pathophysiology and risk factors are covered in this review together with appropriate methods of

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investigation and management. Treatment options discussed are endoscopic

measures, surgical options and pharmacotherapy. The role of serum biomarkers is

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also discussed.

Expert commentary: Future work should be directed at alternative drugs with a good

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safety profile that target biomarkers. Novel pharmacotherapy directed at biomarkers could potentially provide a non-invasive treatment option for angioectasias particularly

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in the elderly where management can be challenging. Keywords: Argon plasma coagulation, Capsule endoscopy, Double balloon

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enteroscopy, Serum biomarkers, Small bowel angioectasias, Somatostatin analogues, Thalidomide

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small bowel angiodysplasias, small bowel angioectasias, small bowel bleeding and

2

1. Introduction Small bowel (SB) bleeding occurs in 5-10%1, 2, 3 of patients who present with gastrointestinal (GI) bleeding where no source is found at bidirectional endoscopy. The SB is the commonest source of bleeding when there is no clear pathology. SB bleeding can be overt presenting with melaena or altered blood4 or occult i.e. presenting as iron deficiency anaemia.5 A mortality rate of 3.5% has been reported as

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a direct consequence of bleeding from SBAs.6 The commonest lesions responsible for SB bleeding are vascular malformations or

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medications. Angioectasias are the most common cause of bleeding in patients > 40 middle-aged patients (41 – 64 years).7

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years, diagnosed with SB bleeding.2, 3 They are reportedly present in 34.82% of

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This review provides an overview of SB angioectasias (SBAs) and the diagnostic modalities currently available. It also provides a detailed evaluation of the available treatment modalities including endoscopic therapy, pharmacological treatment,

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radiological and surgical options and the possible role of biomarkers in the diagnosis of SBAs.

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A Medline search was performed to identify relevant literature from 1985 through 2017 using the following keywords: small bowel angiodysplasias, small bowel

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angioectasias, small bowel bleeding and obscure gastrointestinal bleeding to assess existing evidence.

2. Pathophysiology

Angioectasias are ectatic blood vessels with or without endothelial lining that have a propensity to bleed.8 Chronic low-grade obstruction of vessels leads to hypoxia. This

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angioectasias, with other causes being SB tumours, inflammatory lesions, and/or

in turn leads to the induction of neovascular growth factors that propagate the formation of new, abnormal blood vessels.9

According to the Yano-Yamamoto classification, angioectasias, are either type 1a (punctate erythema, less than 1mm with or without oozing) (figure 1) or or type 1b lesions (patchy erythema, more than 1mm with or without oozing).10 (figure 2, 3 and 4) Angioectasias are venous / capillary lesions that can be treated with cautery.

3

VEGF expression has been shown to be high in intestinal specimens from patients with SB and colonic angiodysplasias when compared to surrounding healthy tissue and when compared to controls.11 Different stimuli have been found to induce VEGF expression, including hypoxia, growth factors, cytokines, nitric oxide (NO), hormones, phorbol esters and oncogenes.12 This in turn leads to abnormal endothelial cell proliferation and migration and to extracellular matrix production and degradation. Thus the endothelium becomes disengaged from the surrounding mural cells and

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results in blood vessels that are prone to bleed.13

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Numerous studies have assessed clinical factors associated with angioectasias.

Patients with SBAs are often elderly14 with multiple co-morbidities.15 In a study by

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Igawa et al, patients with small bowel bleeding who underwent both CE and DBE were included. Patients with SBAs were significantly older (71.2 ± 13.9) than those

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without SBAs (63.4 ± 17.3).(p=0.01)16 Cardiovascular diseases, liver cirrhosis, respiratory diseases, thromboembolic disease, chronic renal failure, hypertension and hypercholesterolaemia and anticoagulant use are risk factors that are positively

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associated with angioectasias in some studies.15, 17, 18 Patients with renal failure are commonly affected by SBAs19 possibly due to a decreased vascular supply to the intestinal mucosa due to atherosclerotic plaques,20 uraemic platelet dysfunction21, 22

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and the increased use of anticoagulants in these patients.23 Furthermore, the majority of patients with SBAs included in the studies in tables 2, 3 and 4 consist of elderly

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patients (median age 71.5 years; range: 50.7 – 94).

Dysregulated vasculogenesis secondary to decreased circulating endothelial precursors24 and high levels of VEGF25,26 in patients with systemic sclerosis might play a role in the predisposition to the formation of angioectasias in the gastrointestinal

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3. Clinical Factors

tract. In a study on 50 patients by Marie et al, gastric and/or small intestinal angioectasias were reported in 38.5% of patients with systemic sclerosis.27

Von Willebrand factor (vWF) is an adhesive glycoprotein that is synthesized in endothelial cells and megakaryocytes. It helps with platelet–subendothelium adhesion and platelet aggregation.28 It carries factor VIII in plasma thus prolonging its half-life by protecting it from proteolytic degradation. It delivers factor VIII to the site of vascular injury, thus enhancing the hemostatic process.29 Patients with either

4

hereditary or acquired Von Willebrand disease (e.g. secondary to aortic stenosis) have an increased tendency for GI bleeding from angioectasias.30 The association of aortic stenosis and GI bleeding was first reported in 1958 by Heyde 31

and then subsequently by Schwartz et al.32 A retrospective case-control study

shortly after, reported the incidence of aortic stenosis in patients with SB bleeding to be 25.5%, much higher than when compared with controls (4.4%).33 Since then, there

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have been other studies confirming the association between SBAs and aortic

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High shear forces across the stenotic valve lead to increased consumption of high molecular weight multimers of vWF35 by rendering vWF susceptible to proteolytic

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cleavage,36 possibly by changing the shape and unfolding of the molecule37 and exposing the bond between residues Tyr842 and Met843 to specific protease

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activity.38 Also, high shear stress may induce binding of the high molecular weight multimers of vWF to the platelet membrane39 with subsequent aggregation.40 (Figure 5) These mechanisms predispose patients to bleeding.41 Platelet function, factor VIII

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coagulant activity and vWF antigen levels are increased post-aortic valve replacement.42 Several studies and case reports, emphasize the need to consider aortic valve replacement early as this will help treat gastrointestinal bleeding.43, 44, 45, 46, Similar to surgery, transcatheter aortic valve implantation (TAVI) leads to restoration

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47

of high molecular weight multimers of vWF,48 as well as other haemostasis

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parameters of vWF.49 This can be a useful consideration in patients who are not fit for surgery. Godino et al described a patient with Heyde’s syndrome who underwent aortic balloon valvuloplasty with resolution of bleeding for the six months following the procedure.50 They justify this approach as there is still a persistent risk of re-bleeding related to dual antiplatelet therapy for 3 to 6 months required after TAVI.51, 52, 53

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stenosis.34

Hereditary haemorrhagic telangiectasias (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Complications can include anaemia, epistaxis, pulmonary hypertension, cardiac failure or liver failure secondary to hepatic AVMs and cerebral AVMs.54 Studies on patients with HHT have revealed a

prevalence of up to 86.7% of small bowel telangiectasias on capsule endoscopy (CE).55, 56 In a study by Ingrosso et al, telangiectasias were more frequently found in elderly patients.57

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4. Diagnosis and Management 4.1.

Endoscopic modalities

Several endoscopic modalities exist to diagnose SBAs. CE allows visualization of the entire SB wirelessly.58 The detection rate for SBAs using CE is up to 50% in studies of patients with SB bleeding.59, 60 Some studies have shown the detection of SBAs with CE is significantly higher than push enteroscopy (PE),61 CT enterography (CTE)62 and double-balloon enteroscopy (DBE).63 Most studies report that angioectasias are more

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commonly located in the proximal SB.64, 65 Angioectasias are often multiple, being present in more than one location in up to 60% of patients.66 The American College of

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upper and lower GI sources have been excluded provided that a patient is stable and that there is no suspicion of obstruction.2 Table 1 summarizes the diagnostic yield of

Type of

Numbe

study

r of

Diagnostic

Diagnostic yield

an

Study

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CE, PE, DBE and CTE in patients with small bowel bleeding.

modality

patients retrospective

(59) 2013

55

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(60) 2012

retrospective

ed

Lecleire et al

122

Segarajasing

randomized

am et al (61)

prospective

CE

M

Khan et al

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Gastroenterology recommends CE as the first line procedure for SB evaluation after

79

CE

2016

bleeding had angioectasias; Blood in 75%, 35% angioectasias in the small bowel of patients presenting with obscure, overt GI bleeding respectively on emergency CE;

CE, PE

72.5% (CE) vs 48.7% (PE) yield in patients with

2015

Chu et al (62)

35% of patients with overt

obscure GI bleeding; retrospective

121

CE, DBE,

Diagnostic yield for

CTE

angioectasias: 73% CE vs 8% CTE (p=0.001), CE 39.1% vs DBE 17.4% (p=0.013) in patients with obscure GI bleeding;

6

Hadithi et al

prospective

35

CE, DBE

(63) 2006

All patients with obscure gastrointestinal bleeding underwent both CE and DBE. 54% had AVMs on CE vs 45% at DBE;

Table 1: Diagnostic yield of CE, DBE, PE and CTE in patients with small bowel bleeding;

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There is increasing evidence that demonstrate a high re-bleeding rate in patients with small bowel bleeding and a positive CE. On the other hand, a negative CE is

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associated with a low likelihood of re-bleeding in the short term. A watch and wait policy with a low threshold to repeat the CE in the case of a Hb drop (≥ 4g/dl) or a

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change in presentation from occult to overt GI bleeding, is prudent in these patients. However more studies are needed that provide evidence on the re-bleeding rate in

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patients with a negative CE beyond 24 months of follow up.67 Device assisted enteroscopy provides the ability of intervention and overcomes the limitation of CE. The depth of insertion during PE and the length of SB examined (30–

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160 cm) is variable.68, 69 Due to the presence of an overtube and the push and pull technique that is applied, antegrade DBE is superior to PE in length of insertion.70 The reported complication rate of DBE is 0.9 to 1.2%.71, 72 Single balloon enteroscopy

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(SBE) was introduced later in 2007.73 Evidence suggests that DBE and SBE are equivalent in diagnostic yield, therapeutic yield and complication rate.74 There is still no consensus on the best endoscopic treatment of SBAs. The ACG review on the management of SBAs states that data on endoscopic therapy is limited

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arteriovenous malformations, DBE double balloon enteroscopies;

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GI gastrointestinal, CE capsule endoscopy, PE push enterosocpy, AVMs

and its effectiveness has not been determined by comparing endoscopic therapy to sham therapy.2

APC (Argon Plasma co-angulation; non-contact thermal therapy) is the traditional method of treating SBAs at DBE.75 APC is a safe therapeutic procedure with very few side effects.76 In a study by Bizid et al, patients having angioectasias treated with APC had a rise in their haemoglobin (Hb), a decrease of transfusion requirements and 93.6% of patients were able to avoid surgery.77 Table 2 summarizes the efficacy of APC in the management of patients with SBAs.

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Study

Type of study

Number of

Mean /

patients with

median

SBAs

follow

Intrvention & Outcome

up (months) 18

SBAs were treated with

Prospective

20 patients

(76) 2005

cohort study

(mean age 72

APC. Overt bleeding

years)

resolved & Hb stabilized

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Olmos et al

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Mean Hb increased

from 8.1 g/dl to 11.5 g/dl

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(p=0.01); Probability of remaining re-bleeding

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free at 1 year was 80%;

Patients underwent

Prospective

40 patients

(78) 2009

cohort study

(mean age 64

DBE & APC; 17 (43%)

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12

Gerson et al

reported no recurrence

years)

of bleeding or need for iron/transfusion therapy,

ed ce pt May et al

Retrospective

(79) 2011

cohort study

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in 65% of patients;

50 patients

11 (28%) reported recurrent overt bleeding, and 12 (30%) reported ongoing need for iron or transfusion therapy; 55

44 patients (88%) had DBE & APC. Hb increased after DBE &APC (7.6 g/dL vs 11.0 g/dL); Blood transfusion requirements declined, from 30 patients (60%) to 8 (16%); Re-bleeding in 21 patients (42%);

8

Samaha et

Retrospective

133 patients

al (84) 2012

cohort study

(mean age 68

APC; Re-bleeding rate

years)

was 46% at 36 months;

Jackson et

Systemic

14 studies (341

al (80) 2014

review &

patients)

22.6

129 (97%) received

22

Re-bleeding rate in patients with

meta-analysis

endoscopic therapy was

69 patients

(77) 2015

observational

(mean age 68.7

study

years;

12.3

9.3 g/ dl; p = 0.0001),

Romagnuolo Systemic

Pinho et al (82) 2016

Retrospective

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30 days) occurred in 7.69% of patients in a study by Teng et al.102 SSTCE is associated with the risk of bowel infarction.103 Mucosal

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ischaemia104 has also been reported. It can occur secondary to embolization of proximal branches supplying a large area of bowel, or the embolization of multiple

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is a history of prior GI surgery or radiation treatment.105

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The most commonly used agents include absorbable gelatin sponge, particulate

agents such as polyvinyl alcohol and microcoils. Microcoils have good radiopacity that

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allows for a precise deployment permitting reduction of the arterial perfusion pressure to the bleeding site while preserving sufficient collateral flow. The coil physically occludes the vascular lumen and causes a decreased perfusion pressure, while the

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attached synthetic fibers maximize thrombogenicity. Gelfoam and particulate agents are more difficult to control than microcoils. Gelfoam is a temporary agent and often cannot easily be deployed superselectively. A disadvantage of the particulate agents

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is that small diameters may reach the intramural circulation distal to the collaterals, thereby risking bowel infarction, or may reflux into non-target arteries. The liquid embolic agents n-butyl cyanoacrylate has the advantage that it may be used

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effectively in very small calibre vessels.106 4.3.

Surgical management

Intraoperative enteroscopy (IOE) is mentioned in older studies as being crucial in diagnosing angioectasias in patients with SB bleeding.107 In most of these small

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distal arteries without sufficient collateral flow. This is especially pertinent when there

studies or case reports, exact localisation of angioectasias at IOE allowed limited segmental resection of the small intestine to be performed. It also ensured that no lesion was left undetected. In patients with SB bleeding, the agreement between CE and IOE was 70%.108 In the same study, the procedure-related mortality was 5% and

the postoperative complication rate was 21%.109 Other complications that are associated with IOE include intestinal wall hematoma, mesenteric hemorrhage, prolonged ileus, intestinal ischemia, serosal tear, ruptured mesenteric vein and perforation.110 Until a few years ago, IOE was the first line investigation in patients with SB bleeding. However, with the introduction of much safer procedures such as

12

CE and DBE, IOE is now only reserved for patients with an unknown cause of SB bleeding where surgical resection is one of the few remaining options.

5. Pharmacological therapy 5.1.

Somatostatin analogues

Somatostatin is a cyclic peptide secreted by D cells in the gastric and intestinal

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mucosa, and by enteric neurons and islet cells of the pancreas. Somatostatin is mostly inhibitory, resulting in the reduction of acid secretion, pancreatic enzyme

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lanreotide exert their effects by mainly binding to 3 types of receptors: SSTR2, SSTR3 and SSTR5.112 Several mechanisms are thought to play a role in the cessation of

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bleeding of angioectasias. These include improved platelet aggregation113, decreased duodenal and splanchnic blood flow114, increased vascular resistance111 and inhibition

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of angiogenesis.115

Octreotide is the most studied somatostatin analogue in the treatment of SBAs.

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Several small studies and case reports demonstrate the usefulness of Octreotide in the management of SBAs. Doses used vary from the short acting subcutaneous formulation twice a day to the long acting intramuscular injection every 4 weeks.116, 117, In a study by Holleran et al 24 patients with SBAs were treated with 20mg of long

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118

acting Octreotide every 4 weeks. An improvement in Hb level, a reduction in

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transfusion requirement and re-bleeding episodes were recorded.119 There are only few studies on the use of Lanreotide as a long-acting somatostatin analogue in the treatment of SBAs instead of Octreotide. Bon et al, studied 15 patients with angioectasias who were given long-acting Octreotide or Lanreotide. There was a significant reduction in the need for blood transfusions, hospital admissions due to

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release and bile flow.111 Somatostatin can bind to six receptors. Octreotide and

bleeding and an improvement in mean Hb after starting somatostatin analogues.120 In another study by Riccioni et al investigating the usefulness of CE in patients who present with iron deficiency anaemia, 10 out of 46 patients (21.7%) diagnosed with angioectasias had their iron deficiency anaemia resolved after being given lanreotide (60mg).121 In 2 cases presented by Huascar et al, 2 elderly patients with SBAs on Octreotide were successfully switched to lanreotide due to persistent admissions with bleeding. Both patients were followed up for 10 months with no further bleeding episodes.122

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Lanreotide can be given by either intramuscular injection or deep subcutaneous injection. Somatuline LA (30mg vial) can be administered by intramuscular injection. Somatuline Autogel (60mg, 90mg, 120mg vials) can be given by deep subcutaneous injection.123 In fact, the main advantage of lanreotide over octreotide is that it can be given subcutaneously thus avoiding painful intramuscular administration and the risk of haematomas in patients with clotting abnormalities especially those with underlying

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cirrhosis or those on anti-coagulants. The major limitation for prolonged use of somatostatin analogues is the potential for

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hypothyroidism, gallstone formation, kidney stones, and pancreatic enzyme

deficiency. Side effects of octreotide were reported to be 30% by Holleran et al.124 In a

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study by O’Toole et al, mild episodes of abdominal pain, nausea and vomiting were more commonly reported in patients on octreotide (29%) than in those patients on

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lanreotide (14%).125

Despite the promising characteristics of this group of drugs, most studies include a

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small number of patients. There are no studies comparing the use of somatostatin analogues to endoscopic therapy or natural history cohorts. The data included is rather heterogenous with patients having different comorbidities grouped together and

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with different doses of somatostatin analogues administered. Table 3 summarizes the

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available literature on somatostatin analogues.

Study

Treatment

Mean /

Type of

Number of

study

patients with

median

SBAs/ studies

follow

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long-term side effects including diarrhoea, abdominal pain, constipation,

Outcome

Outcome

Bleeding stopped

Bleeding

in 10 patients

stopped in

up (months )

Nardone

Prospecti

17 (mean age

SC

et al

ve cohort

63)

Octreotide

(117)

study

12

100mcg/12

1999

10 patients

hours for 6 months

Junquera

Prospecti

32 vs 38

SC

et (126)

ve case-

(mean age 71)

Octreotide

12

Probability of

Probability of

remaining free of

remaining

14

controlled

50mcg/12

re-bleeding at 1 &

free of re-

study

hours for a

2 years

bleeding at 1

1–2 years

was 77% & 68%,

& 2 years

respectively

was 77% &

(octreotide) &

68%,

55% and 36%,

respectively

respectively

(octreotide)

(placebo) (log

& 55% and 36%,

No significant

respectively

differences in

(placebo)

number of

(log rank p =

bleeding episodes

0.030);

& transfusion

No

requirements

significant

between groups;

differences

Iron requirements

in number of

were lower in the

bleeding

octreotide than in

episodes &

the placebo group

transfusion

(22 vs 166 units;

requirements

P = 0.001).

between

ed

M

an

us

cr

rank p = 0.030);

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groups; Iron requirements were lower in the octreotide than in the

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ip t

2007

placebo group (22 vs 166 units; P = 0.001).

Scaglion

Prospecti

13 (mean age

IM

e et al

ve cohort

76.8)

(118)

study

2007

32

69% needed no

69% needed

Octreotide

further blood

no further

10mg /

transfusions and

blood

month for

iron

transfusions

15

12 months Prospecti

11 (median

IM

al (127)

ve cohort

age 74 years)

2009

study

15

Reduction in red

Reduction in

Octreotide

cell packets (14

red cell

20mg

(9-49) vs 4 (0-9),

packets (14

(duration

p=0.002) and in

(9-49) vs 4

unclear)

admission days

(0-9),

related to

p=0.002)

gastrointestinal

and in admission

99) vs 7(0-23),

days related

p=0,001). No side

to

effects

gastrointesti

cr

bleeding (27 (10-

nal bleeding

us et al

tive

age 61.4

(121)

cohort

years)

2010

study

an

Retrospec 46 (median

IM

ed

ce pt

12

(27 (10-99) vs 7(0-23), p=0,001). No side effects

In 10 patients IDA

In 10

Lanreotide

resolved with

patients IDA

60mg

regular

resolved with

(frequency,

intramuscular

regular

duration

Lanreotide;

intramuscula

M

Riccioni

unclear)

r Lanreotide;

Bon et al

Prospecti

15 (median

IM

(120)

ve cohort

age 76)

2012

study

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ip t

Molina et

and iron

14

Number of

Number of

Octreotide

transfusions

transfusions

20mg /

decreased: 2 (0–

decreased: 2

month for

14) vs. 10 (6–

(0–14) vs. 10

12 months

24) p = 0.001;

(6–

Lower re-bleeding

24) p < 0.00

during

1; Lower re-

somatostatin -

bleeding

analogues (20%

during

vs.

somatostatin

73%; p = 0.01);

-analogues

The mean Hb was

(20% vs.

16

higher on

73%; p = 0.0

somatostatin

1); The

analogues

mean Hb

(median: 10 g/dL

was higher

(9–13) vs. 7 (5–

on

8.5); p = 0.001;

somatostatin

No side effects;

analogues

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(median: 10 g/dL (9–

cr

8.5); P < 0.0

24 (average

IM

et al

ve cohort

age 75.5)

Octreotide

(119)

study

ed ce pt

effects;

Average Hb rates

Average

increased from

haemoglobin

20mg /

9.19 g/dl to

rates

month for 3

11.35 g/dl

increased

months

(p = 0.0027,

from

minimum

95% confidence

9.19 g/dl to

interval (CI) −3.5

11.35 g/dl

to −1.1) in the

(p = 0.002

group overall and

7, 95%

70% remained

confidence

transfusion-free

interval (CI)

after a mean

−3.5 to −1.1)

treatment duration

in the group

of 8.8 months.

overall and

The rate of

70%

adverse events

remained

was higher than

transfusion-

previously

free after a

reported at 30%

mean

M

2016

01; No side

us

Prospecti

8.8

an

Holleran

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13) vs. 7 (5–

treatment duration of 8.8 months. The rate of

17

adverse events was higher than previously reported at 30% Case

et al

report

1

Female patient

(116)

with chronic renal

patient with

failure due to

chronic renal

suspected

failure due to

sarcoidosis

suspected

>200 units of

sarcoidosis

blood before

>200 units

treatment;

of blood

Transfusion

before

requirements and

treatment;

hospital

Transfusion

admissions were

requirements

reduced

and hospital

drastically;

admissions

ce pt

ed

M

an

us

cr

2016

were reduced drastically;

Ramos-

Case

2 (94 & 84

IM

Both patients

Both patients

Rosario

series

years)

Octreotide

improved when

improved

et al

20mg /

switched from

when

(121)

month to

Octroetide to

switched

2016

SC

Lanreotide;

from

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Female

ip t

Velasco

5&6

Lanreotide

Octroetide to

120mg / 6

Lanreotide;

weeks Chetcuti

Retrospec 12 (mean age

SC

Zammit

tive

Lanreotide

mean Hb: 86.8 vs

et al

cohort

given at

98.0 (131–166

(128)

study

60m,

g/L, p=0.012),

74)

42

Improvement in

Improvement in mean hb: 86.8 vs 98.0 (131–166

18

2017

90mg,

bleeding episodes

g/L,

120mg at 4

(4.18 vs 1.09,

p=0.012),

to 6 weeks

p=0.010) and

for 19

packed red cells

months

(323 vs

bleeding episodes (4.18 versus

152, p=006); Patients required less DBEs ±

1.09, p=010) and packed

ip t

red cells

APCs (19 vs

(323 vs

cr

152, p=006); Patients

us

required less DBEs ±

an

APCs (19 vs 11 p=0.048);

Table 3: Somatostatin analogues in the management of SBAs.

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SC subcutaneous, IM intramuscular, IDA iron deficiency anaemia, Hb haemoglobin, coagulation; 5.2.

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CI confidence interval, DBE double balloon enteroscopy, APC argon plasma

Hormonal therapy

ce pt

Hormonal therapy with oestrogen and progesterone have been used to treat SBAs.129, 130

Several mechanisms of hormonal therapy in reducing bleeding have been proposed including: an increase the number of circulating activated platelets131, an increase vascular sensitivity to catecholamines promoting vasoconstriction132 and promoting

Ac


11 p=0.048);

the repair of the endothelium.133 Whilst some initial studies have shown the benefits of combination hormone therapy with oestrogen and progesterone, others have failed to substanstiate this benefit. In 2 randomized double blind trials, patients with HHT and angioectasias who received oestrogen on its own or combined with progesterone or placebo experienced no significant improvement in Hb or bleeding episodes.134, 135 In a meta-analysis by Swanson et al, the combination of oestrogen and progesterone did not significantly reduce bleeding episodes.136 Hormonal use in the management of angioectasias is

19

also limited by the side effects of thrombosis137 and the increased risk of endometrial cancer.138 5.3.

Thalidomide

Thalidomide is an immunomodulatory drug with anti-inflammatory and antiangiogenic properties. It has been used successfully in the treatment of angioectasias in a number of patients,139 however very often after having failed other therapy including

ip t

endotherapy140 or in combination with other therapy such as somatostatin analogues.141 In a meta-analysis by Swanson et al, thalidomide reduced the bleeding

cr

to 300mg per day is used in several studies.140 In a randomized controlled trial by Zhi– Zheng et al, 100mg of thalidomide was more effective in reducing bleeding episodes

us

than 400mg of iron.143

an

Thalidomide is also considered a useful treatment in patients with HHT.144 One mechanism of action of thalidomide is its ability to downregulate the expression of vascular endothelial growth factor (VEGF) both at protein and mRNA levels.145

M

Thalidomide at low concentrations has also been shown to activate mural cells increasing both the rate of their proliferation and their ability to form protrusions around blood vessels, thus stabilizing them and decreasing the risk of bleeding.146 The

ed

anti-angiogenic effect of thalidomide can persist even on stopping it.147 Thus patients can have the added benefit of having a bleeding free period even after stopping

ce pt

thalidomide.

Lenalidomide is a second-generation immunomodulatory drug that is more potent than thalidomide and has anti-migratory effects on endothelial cells.148 Lenalidomide can

also inhibit regulatory T cell suppressor activity.149

Ac


episodes as compared to iron therapy but with no effect on mortality.142 A dose of 100

The use of anti-angiogenic drugs such as Thalidomide and Lenalidomide is limited by severe side effects including peripheral neuropathy in up to 50% of patients,150 teratogenicity151 and thromboembolism.152 Haematological abnormalities such as neutropenia and thrombocytopenia are also common adverse effects to thalidomide and lenalidomide.153, 154 Bevacizumab (Avastin®) is a humanized monoclonal antibody against VEGF. It has

also been used in refractory SBAs at a dose of 5 mg/kg every 2 weeks initially, with maintenance treatment of 5 mg/kg per month.155 Both patients had underlying

20

Glanzmann’s thrombasthenia and experienced a reduction in bleeding episodes and transfusion requirements after Bevacizumab was started. Similarly other studies have shown some benefit in patients with HHT.156 An incidence rate of bowel perforation of up to 5.4% has been reported with the use of Bevacizumab, mostly in patients with underlying malignancy.157 Tranexamic acid is an antifibrinolytic that increases endoglin and ALK-1 levels at the

ip t

surface of endothelial cells158 that activate proliferation and migration of endothelial cells during the angiogenic process.159 Both aminocaproic acid and tranexamic acid

cr

activation and transformation to plasmin160 thus resulting in the stabilization of clots.

Tranexamic acid is 7 to 10 times more potent than aminocaproic acid and has a half-

us

life of 80 hours as compared to 4 hours of aminocaproic acid.161 Doses of tranexamic acid of up to 4.5g/day have been used successfully to treat patients with HHT.162

an

Tranexamic acid was used to treat upper GI bleeding163 and colonic angioectasias.164 In 2 case reports, tranexamic acid was used to treat SB bleeding.165, 166 The HALT-IT with acute GI bleeding.167

M

trial will shed more light on the use of tranexamic acid in the management of patients

Tranexamic acid has been shown to increase the incidence of DVT postoperatively, in

ed

the absence of thromboprophylaxis.168 However, a systematic review on the use of antifibrinolytics in surgery did not show any increased risks of thromboembolic events.169 Another more recent study confirms the low risk of thromboembolic events

ce pt

in patients undergoing surgeries and receiving tranexamic acid preoperatively.170 Renal failure secondary to tranexamic acid was proven on biopsy to be secondary to acute renal cortical necrosis.171 Overall, tranexamic acid is well tolerated and nausea and diarrhea are the most common minor adverse events.172

Ac


bind reversibly to plasminogen, blocking the binding of plasminogen to fibrin and its

Other drugs that have been used in in the management of SBAs are danazol, desmopressin, tamoxifen. However none of these have significant evidence to support their use.

21

Type

Number of

Treatment:

Mean /

of

patients with

Thalidomide

median

study

SBAs/

follow up

studies

(months)

Shurafa

Case

et al

report

1 (60)

Thalidomide

3

Outcome

Outcome

Less transfusions;

Less transfusion

(139)

increased to

s;

2003

200mg daily Case

6 (mean age

Thalidomide

et al

series

50.7 years)

300mg daily 50 – 100mg

2004

after 6 - 9

Bleeding

within 2 weeks; Hb

stopped

normalized; No

within 2

further transfusions;

et al

series

(174)

ce pt

2006

3

M

Case

Thalidomide 100mg daily

ed

Bauditz

34

weeks; Hb normalized; No further

an

months

Bleeding stopped

us

(173)

33

cr

Bauditz

ip t

100mg daily

transfusion s; No bleeding

No

episodes; Hb

bleeding

stabilized; Repeat

episodes;

CE after 3 months'

Hb

thalidomide -

stabilized;

reductions in the

Repeat CE

number, size, and

after 3

colour, intensity of

months'

angiodysplasias;

thalidomide - reductions

Ac


Study

in the number, size, and colour, intensity of angiodyspl asias;

22

Dabak et al (175) 2008

Case

3

Thalidomide

series

8

Decreased blood

Decreased

100 – 400

transfusions in 2

blood

mg daily

patients & remained

transfusion

transfusion free

s in 2

during follow-up;

patients & remained transfusion

ip t

free during

orn et al

series

7

Thalidomide

4 patients

4 patients

discontinued

discontinue

thalidomide within 3-

d

8 weeks, due to side

thalidomide

effects; 3 who

within 3-8

200mg for 6

continued

weeks, due

months

thalidomide did not

to side

require any

effects;

50mg daily

(147)

increased

2009

by 50mg/

transfusions; loss of response when

3 who continued

treatment was

thalidomide

stopped.

did not require any

ce pt

ed

M

an

week till

12

cr

Case

us

Kamalop

transfusion s; loss of response when

Ac


follow-up;

treatment was stopped.

23

Prospe

55 (median

Thalidomide

al (143)

ctive

age 58

2011

rando

years)

39

Rates of response in

Rates of

100mg daily

the thalidomide &

response in

of

control groups:

the

mized

thalidomide

71.4% & 3.7%,

thalidomide

study

or iron for 4

(p =0.001); Average

& control

months

Hb level increased

groups:

by

71.4% & 3.7%,

ip t

Ge ZZ et

3.06 g/dL

cr

g/dL (iron-controlled group) (P = 0.001).

us

Hospitalization rates

M

an

decreased

(p =0.001); Average Hb level increased by

significantly in the

3.06 g/dL

thalidomide group vs

(thalidomid

iron-controlled group

e) vs 1.32

(p=0.001)

g/dL (ironcontrolled group) (P =

ed

0.001). Hospitalizat

ce pt

ion rates decreased significantly in the

Ac


(thalidomide) vs 1.32

thalidomide group vs ironcontrolled group (p=0.001)

Garrido

Prospe

12 (mean

Thalidomide

4

Mean Hb increased

24

Mean Hb

et al

ctive

age 77

(140)

200mg daily

years)

from 6.5g/dL to 12.1

increased

g/dL

from

2012

6.5g/dL to

Case

et al

report

1 (75 years)

Thalidomide

Patient failed to

Patient

100mg daily

respond to

failed to

(150)

endoscopic

respond to

2016

treatment &

endoscopic

Ocrtreotide & iron;

treatment &

Thalidomide was

Ocrtreotide

cr

ip t

Izquierdo

& iron;

paraesthesia &

Thalidomid

persistent Hb drop;

e was

He finally underwent

stopped

surgery;

due to paraesthesi a& persistent

M

an

us

stopped due to

Hb drop; He finally

ed ce pt Ou et al

Case

1 (58 years)

Bevacizuma

(156)

report

with HHT

2016

Ac


12.1 g/dL

surgery; Decreased GI

Decreased

b 5 mg/kg /

bleeding, transfusion

GI

2 weeks

requirement;

bleeding,

12

transfusion requiremen t;

Barré et

Case

1 (64 years)

Bevacizuma

al (155)

report

with

2016

underwent

Failed somatostain

Failed

b 5 mg/kg /

analogue

somatostai

Glanzmann's

2 weeks (6

monotherapy; No

n analogue

thrombasthe

infusions);

transfusions after 2

monothera

infusions of

py; No

bevacizumab;

transfusion

maintained Hb at

s after 2

nia

maintenanc e treatment

10

25

with

12.4 g/dL;

infusions of

bevacizuma

bevacizum

b 5 mg/kg/

ab;

month

maintained Hb at 12.4 g/dL;

ip t

Table 4: anti-angiogenic therapy in patients with SBAs; Hb haemoglobin, HHT hereditary haemorrhagic telangietctasia, CE capsule

cr

6. Potential serum biomarkers:

us

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are both family members of

vascular growth factors that play a role in embryonic and postnatal angiogenesis.

an

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are antagonistic ligands that bind to the extracellular domain of the Tie2 receptor, which is almost exclusively expressed by endothelial cells.176 Ang-1 is critical for vessel maturation. Binding of Ang-1 to Tie2

M

promotes vessel integrity, inhibits vascular leakage and suppresses inflammatory gene expression.177 Ang-2 works as an antagonist of Ang-1 and promotes vessel regression in the absence of VEGF when it binds to Tie2 receptor. Thus, Ang-2

ed

synergizes with VEGF to increase proliferation and migration of endothelial cells.178 Ang-2 regulates blood vessel remodelling through different effects on Tie-2 signalling. It can either support stable enlargement of normal non leaky vessels or promotes

ce pt

vascular remodelling and leakage.179 This mechanism involves TNF-α and expression of endothelial cell adhesion molecules.180 TNF-α induces matrix metalloproteinases that degrade extracellular matrix around blood vessels and damage endothelial cells, which could result in destabilization and potential weakening of the vessel wall, passive dilation, and rupture.181 Holleran at al have shown that a higher level of Ang-2

Ac


endoscopy, GI gastrointestinal;

exists in patients with SBAs when compared to controls. They also showed lower levels of Ang-1 and TNF-α in patients with SBAs. Gene expression levels of Ang-1, Ang-2, and their receptor Tie2 were all significantly higher in biopsies from areas of angiodysplasias compared with normal SB and controls.182 Ang-2, could potentially be used as a serum biomarker and future therapeutic target to improve outcome in affected patients. However the evidence on the potential use of serum biomarkers is scarce and there is only 1 study that has shown a difference in angiogenic factors in patients with SBAs and controls.

26

Figure 6 provides a useful algorithm that can be considered when managing patients with SBAs. Radiological intervention should always be considered in cases where patients are haemodynamically unstable. A conservative approach may be adopted in elderly patients with multiple co-morbidities in whom a DBE may pose significant risk and not be a suitable option. Patients who respond well to treatment with DBE and APC can be monitored regularly with serial haemoglobin measurements. If clinically indicated repeat DBE & APC may be performed as guided by repeat CE showing

ip t

persisting or recurrent SBA. Pharmacological therapy can be considered as salvage therapy if in patients who fail to respond to APC as monotherapy or earlier in the

cr

risks associated with pharmacotherapy. Long acting somatostatin analogues are

preferred to anti-angiogenic drugs due to their better side-effect profile. If patients fail

us

to respond to endoscopic treatment and pharmacological therapy, IOE and surgery

an

can be considered as a last resort. 7. Conclusions

CE should be the first line investigation for SBAs. Although DBE and APC remain a

M

mainstay in treatment, there remains little evidence of benefit from this approach and the high re-bleeding rate highlights the need to consider other additional modalities of treatment. Several reasons can explain the high re-bleeding rate including the

ed

multiplicity of SBAs, underlying co-morbidities, which predispose patients to SBAs and inadequate stratification of patients in studies. Patients are not stratified according to

ce pt

size, location and number of lesions. Despite its invasive nature, APC still remains the first line approach to active treatment. Pharmacological therapies such as somatostatin analogues and / or thalidomide offer a non-invasive salvage approach with a reasonable safety profile. At present time, we can hypothesize that we might improve long-term outcomes by systematically combining available therapies i.e. endoscopy for treatment of reacheable SBAs and somatostatin analogues /

Ac


management plan in patients in whom the risks of DBE are greater higher than the

thalidomide to reduce the risk of bleeding from unreacheable SBAs and decreasing the rate of formation of new SBAs. This strategy has not been systematically tested as so far, drugs are often used as “salvage” therapy in case of unsuccessful endoscopic or radiological treatment. In the future, serum biomarkers such as Ang-2 might have a role in identifying patients who should be referred for CE for likely SBAs and could represent novel therapeutic targets in the development of new antiangiogenic drugs for the management of SBAs.

27

8. Expert commentary Small bowel angioectasia (SBas) are one of the commonest causes of small bowel (SB) bleeding. They commonly occur in the elderly who have multiple co-morbidities. The concomitant medications particularly anti-platelet therapy and anticoagulation further predispose to bleeding. Therapeutic endoscopy in this cohort can be challenging. Anti-angiogenic drugs are associated with peripheral neuropathy and thromboembolism. The use of hormonal therapy is also limited by side effects such

ip t

as thromboembolism and endometrial cancer.

cr

compared to standard radiological tests. SBAs have traditionally been managed

conservatively or by endotherapy. Literature is available mostly on Argon Plasma

us

Coagulation (APC) applied at double balloon enteroscopy (DBE). There is very limited data on other modalities of treatment such as haemostatic clips and

an

sclerotherapy or the combination of more than one method at endotherapy. Initial studies reported DBE and APC as reducing transfusion requirement and improving mean haemoglobin measurements.79 However more recently, few studies have

M

reported a re-bleeding rate of 45% in patients with SBAs treated with APC, not dissimilar to those not receiving endotherapy.80 This is due to SBAs reoccurring, reach at DBE.

ed

driven by the persistent underlying co-morbidities and angioectasias that were beyond

ce pt

Treating patients with SBAs with blood transfusions, iron infusions and repeated endoscopic procedures is costly. This is in addition to the emergency hospital stays that are very often precipitated by gastrointestinal bleeding and acute decline in haemoglobin.

Somatostatin analogues are an attractive pharmacological option. The mechanisms of

Ac


Capsule endoscopy (CE) has a superior diagnostic ability to detect angiectasias

action include improved platelet aggregation112, decreased duodenal and splanchnic blood flow113, increased vascular resistance110 and inhibition of angiogenesis.114

Currently somatostatin analogues are reserved for patients who have not responded well to other modalities of treatment or in whom other treatment including therapeutic endoscopy is contraindicated. The evidence however has been derived from case reports and small numbers of patients.115, 119 Observational studies where somatostatin analogues are introduced at an early stage in the management of SBAs are lacking. Randomised controlled trials where patients are assigned to DBE and

28

APC or endotherapy and somatostatin analogues are required. Such studies will establish the additional benefit of pharmacotherapy to endotherapy as prophylactic, non-invasive management of these patients. Such research will also provide more information on the side effect profile of somatostatin analogues in patients with SBAs. So far, adverse event data has mostly been derived from the use of this class of drugs in the treatment of neuroendocrine tumours and patients with agromegaly. Pooled data will also help determine the ideal length of time for which somatostatin analogues

ip t

should be administered.

cr

SBAs. There is only 1 study on Ang2 in SBAs by Holleran et al.181 Further research is needed to establish the role of Ang2 as a serum biomarker in the investigation of

us

patients with SB bleeding in addition to CE. It can also be a useful target in the

development of new drugs to treat SBAs with a better safety profile than the existing

an

classes of drugs. The same group of authors have also reported that patients with SBAs had a higher gene expression of (Angiopoietin-1) Ang-1, Ang-2 and receptor Tie 2.181 Targeting these genes in future drugs can improve the efficacy of

9. Five-year view

M

pharmacotherapy and limit the side effects.

ed

The investigation and management of patients with SBAs has been revolutionised with the invention of CE and device assisted enteroscopy. Up to a few decades ago,

ce pt

patients underwent repeated tests without a clear diagnosis and more patients underwent invasive procedures such as intra-operative enteroscopy (IOE). Radiological interventions and IOEs are now reserved for patients who have failed endoscopic and pharmacological management. At present, CE is considered the gold

standard diagnostic investigation for patients with SBAs and device assisted enteroscopy a therapeutic option to treat SBAs. Given the persistently high re-

Ac


The biomarker, Angiopoietin-2 (Ang-2) has been found to be raised in patients with

bleeding rate and the invasive nature of the procedure, the long-term role of DBE and APC comes into question. At present, somatostatin analogues can be recommended for combined treatment with endotherapy as they have the safest adverse event profile amongst classes of drugs that can be used in the management of SBAs. However randomised studies testing their efficacy in combination with endotherapy are required. Newer anti-angiogenic drugs will eventually provide a more targeted and effective management to patients with SBAs. 10. Key issues

29

•

Small bowel angioectasias (SBAs) affect the elderly who have multiple underlying co-morbidities. This makes them challenging for lengthy invasive procedures such as double balloon enterosocpy (DBE) and argon plasma coagulation (APC) as this has a higher sedation requirement or the need for general anaesthesia.

•

Capsule endoscopies (CEs) provide the ideal non-invasive modalities for investigation of SBAs. APC is the only endoscopic modality on which most of the literature is based

ip t

•

on. Despite its widespread use, there is still a persistent rate of re-bleeding

cr

management of SBAs include hamostatic clips and injection with sclerotherapy.

Invasive measures such as IOE and superselective transcatheter embolization

us

•

(SSTCE) are reserved for patients who have failed endoscopic and •

an

pharmacological management.

The use of pharmacological therapy such as anti-angiogenic drugs and hormonal therapy is limited by adverse events such as endometrial

•

M

malignancy, neurological complications and thromboembolic events. Somatostatin analogues are so far the safest class of drugs that can be proposed for the treatment of patients with SBAs. However they are still being

ed

introduced as salvage therapy where patients have failed other modalities of treatment. Introducing them earlier on and in combination with endotherapy

ce pt

might in the long term be more safe and cost effective. •

Although we know of the existence of angiogenic factors such as Ang-2, not

much literature is available. These might be ideal serum bio-markers in the complex investigation of patients with SBAs. They might also be ideal targets for future anti-angiogenic drugs with better side effect profiles than the existing ones.

Ac


associated with its use. Other endoscopic modalities that can be applied in the

Funding

This paper was not funded. Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies,

30

honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Figures Figure 1: Endoscopic classification of small-intestinal vascular lesions (Yano

cr us an M ed ce pt Ac


ip t

Yamamoto classification).10

31

ed

ce pt

Ac

ip t

cr

us

an

M


Figure 2: Small angioectasia (Type Ia lesion)

32

ed

ce pt

Ac

ip t

cr

us

an

M


Figure 3: Larger angioectasia (Type Ib lesion)

33

ed

ce pt

Ac

ip t

cr

us

an

M


Figure 4: Angioectasia with adjacent blood

34

ed

ce pt

Ac

ip t

cr

us

an

M


Figure 5 The mechanism of Heyde syndrome

35

Figure 6: Management algorithm of bleeding small bowel angioectasias

Anaemia / Overt bleeding; Negative bidirectional endoscopy; Hemodynamically unstable

Negative

SBAs on capsule endoscopy

Improve underlying conditions eg: aortic valve replacement / TAVI;

SSTCE

Failure

Haemodynamically stable

ip t

Watch & Wait policy; Monitor Hb; Repeat CE if Hb drops or signs of bleeding;

cr

Surgery

Unresponsive

Conservative approach: Consider stopping anticoagulation; Oral iron ± intravenous iron ± blood transfusions

us

DBE & APC

ce pt

ed

M

an

Unresponsive

Ac


Elderly; Multiple comorbidities endoscopy

Pharmacological therapy: Somatostatin analogues ± Anti-angiogenic drugs

Responsive

Every 3 months

Monitor Hb; Consider repeating CE if Hb falls

SSTCE

Failure

IOE & surgery

Figure 6: Management algorithm of bleeding small bowel angioectasias; Hb haemoglobin, SBA small bowel angioectasia, SSTCE super selective transcatheter embolization, IOE intraoperative enteroscopy, TAVI transcatheter aortic valve implantation, CE capsule endoscopy, DBE double balloon enteroscopy, APC argon plasma coagulation;

36

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Irritable bowel syndrome: current and emerging treatment options.

New and Emerging Treatment Options for Irritable Bowel Syndrome.

Unusual presentation of non-Hodgkin's lymphoma of the small bowel.

Delayed presentation of small bowel injury during suprapubic catheterisation.

Abdominal cocoon: an unusual presentation of small bowel obstruction.

Orthotopic neobladder perforation: an unusual presentation of small bowel obstruction.

Clinical Review of Small-Bowel Endoscopic Imaging.

Adult bowel intussusception: presentation, location, etiology, diagnosis and treatment.

Sporotrichosis: an overview and therapeutic options.

Future treatment options for atopic dermatitis - small molecules and beyond.

Treatment of renal sarcoidosis: is there a guideline? Overview of the different treatment options.

[Three options for case presentation].

Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline.