article review

Review article: the diagnosis and investigation of obscuregastrointestinal bleedingK. Liu* & A. J. Kaffes

*Faculty of Medicine, University ofSydney, Sydney, NSW, Australia.AW Morrow Gastroenterology andLiver Centre, Royal Prince AlfredHospital, Camperdown, Sydney,NSW, Australia.

Correspondence to:K. Liu, Faculty of Medicine, Universityof Sydney, 23 10 Pyrmont BridgeRoad, Camperdown, Sydney, NSW2050, Australia.E-mail: [email protected]

Publication dataSubmitted 5 April 2011First decision 28 April 2011Resubmitted 29 May 2011Accepted 1 June 2011EV Pub Online 21 June 2011

This uncommissioned review article wassubject to full peer-review.

SUMMARY

BackgroundObscure gastrointestinal bleeding (OGIB) is a commonly encountered clini-cal problem in gastroenterology and is associated with signicant morbidityand mortality. The investigation and management of OGIB has changeddramatically over the past decade with the advent of newer gastroenterolog-ical and radiological technologies.

AimTo review the current evidence on the diagnosis and investigation of OGIB.

MethodsWe searched the PubMed database (19852010) for full original articles inEnglish-language journals relevant to the investigation of OGIB. The searchterms we used were gastrointestinal bleeding or gastrointestinal hemor-rhage or small bowel bleeding each in combination with obscure, orcapsule endoscopy, or enteroscopy or enterography or enteroclysis.

ResultsCapsule endoscopy (CE) or double balloon enteroscopy (DBE) should berst line investigations. They are complimentary procedures with compara-ble high diagnostic yields. DBE is also able to provide therapeutic interven-tion. Newer technologies such as single balloon and spiral enteroscopy arecurrently being evaluated. Radiological and nuclear medicine investigations,such as CT enterography and CT enteroclysis, are alternative diagnostictools when CE or DBE are contraindicated. Repeating the gastroscopyand or colonoscopy may be considered in selective situations. An algorithmfor investigation of obscure bleeding is proposed.

ConclusionsThe development of capsule endoscopy and double balloon enteroscopy hastransformed the approach to the evaluation and management of obscuregastrointestinal bleeding over the past decade. Older diagnostic modalitiesstill play a complementary, but increasingly selective role.

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Alimentary Pharmacology and Therapeutics

INTRODUCTIONObscure gastrointestinal bleeding (OGIB) is dened aspersistent or recurrent bleeding from the gastrointestinal(GI) tract after negative evaluations with upper andlower endoscopies. This represents approximately 5% ofall GI bleeds.13 Obscure GI bleeding can be further cate-gorised into obscure overt GI bleeding in patients withclinically evident bleeding (haematemesis, melaena andhaematochezia) or obscure occult GI bleeding whichmanifests as iron deciency anaemia or positive faecaloccult blood test (FOBT). Common causes of OGIB arelisted in Table 1.

Although missed lesions from oesophagogastroduode-noscopy and colonoscopy occur frequently, evaluation ofOGIB usually focuses on visualisation of the small bowel.

As a result of technological advances in endoscopy, therehas been a paradigm shift in the evaluation of OGIB andsmall bowel bleeding over the past decade. Modalitiesused to investigate the small bowel previously such aspush, Sonde and intraoperative enteroscopy are now lim-ited to increasingly selective situations. Newer technolo-gies including capsule endoscopy (CE) and doubleballoon enteroscopy (DBE) both play a major role in theevaluation of OGIB today.

In this article, we review the clinical evaluation ofobscure gastrointestinal bleeding.

HISTORY AND EXAMINATIONHistory taking and examination can help predict the aeti-ology and localise the site of bleeding. It is important totake into account the age of the patient. Small boweltumours such as leiomyomas, carcinoid tumours, adeno-carcinomas and lymphomas are the most common causeof OGIB in patients

erally observed more often in patients with obscure overtbleeding compared with those with obscure occult bleed-ing,79 although this is not conrmed by all studies.10, 11

Other factors such as performing CE within 2 weeks of ableeding episode, Hb 6 monthsand >1 bleeding episode also increase the yield of theexamination.12, 13

Capsule endoscopy has consistently been shown to besuperior to push enteroscopy (PE) and small bowel radi-ography in detecting small bowel lesions.7, 8, 14, 15 Ameta-analysis of studies comparing the yield of CE toother diagnostic modalities in OGIB showed that in 14studies, the yield of CE was double that of PE (63% vs.28%).14 The same meta-analysis reported the yield of CEwas also found to be higher than small bowel radiogra-phy for clinically signicant lesions (42% vs. 6%) inpooled data from three studies.14 These ndings are sup-ported by another meta-analysis of 24 studies (530patients), which reported the yield of CE (for all indica-tions) to be 87% compared to 14.8% and 9.9% for PEand small-bowel series respectively.15

In terms of clinical outcomes, Mylonaki et al. found thatcapsule endoscopy led to an alteration in therapy in 25 38(66%) of patients with OGIB.16 Enteroclysis, in comparisonchanges the clinical management in only 10% of patients.17

Pennazio et al. showed resolution of bleeding in 86.9%,41% and 69.2% of patients with ongoing overt obscurebleeding, previous overt obscure bleeding and occultobscure bleeding respectively.18 The rate of rebleeding inpatients with OGIB and a negative CE is less than 6%.19

The main limitation of capsule endoscopy is its inabilityto obtain biopsies or administer therapy. CE also does notobtain satisfactory views of the oesophagus, stomach orcolon and should not replace or bypass upper or lower en-doscopies.20 Diagnostic yield may be reduced in patientswith poor bowel preparation or incomplete examinationsbecause of delayed gastric emptying or failure of capsule toenter duodenum within 1.5 h. The most common compli-cation is capsule retention (or non-natural excretion),which occurs in 1.4% of patients with OGIB.6 Risk factorsfor capsule retention include NSAID use abdominal radia-tion injury, extensive Crohns disease and previous majorabdominal surgery. There have been no reported deathsfrom CE to date.6 Patients with pacemakers or debrilla-tors should be closely monitored during CE.

DEVICE ASSISTED ENTEROSCOPY (BALLOONASSISTED, SPIRAL AND PUSH)Several new device assisted enteroscopes (DAE) havebeen released and studied. The rst of these was the

double balloon enteroscope (Fijinon) described in 2001and made available for clinical use in 2004. This was fol-lowed by the release of a single balloon system (Olympusoptical) and more recently spiral enteroscopy (Spirusmedical). These devices enable endoscopic inspection ofthe entire small bowel through the use of a 200 cm ente-roscope and an overtube. The single and double balloonsystems utilise inatable balloons to grip the intestine tofacilitate deep enteroscopy whereas the spiral systemconsists of a specialised overtube with a compliant spirallocated at the distal tip. The majority of clinical evidenceis with DBE but emerging literature shows similar bene-ts with the other modalities. Comparative studiesbetween all of these techniques show technical differ-ences (e.g. procedure time, depth of insertion, rates oftotal enteroscopy) but few if any show diagnostic ortherapeutic benet for one over the other.2124 The liter-ature on this is in its infancy and further evaluation willbe needed before one modality could be recommendedover the other.

Double balloon enteroscopy and CE have comparablediagnostic yields in patients with OGIB.2530 A meta-analysis of 11 studies (397 patients) demonstrated thepooled overall yield for CE and DBE was 60% and 57%respectively.31 The yields of each study for vascular mal-formations, inammatory lesions and polyps or tumourswere also found to be similar. The main advantage ofDBE is its ability to perform therapeutic interventionsand obtain biopsies, not possible on CE. Endoscopictherapies and biopsies are performed in 2757% and27% of patients undergoing DBE respectively.5, 26, 29, 32

One shortfall of DAE is its inability to achieve totalenteroscopy in all patients. Rates of achieving totalenteroscopy with DBE vary widely from 0% to 86%.Raju et al. pooled data from 12 studies on 723 patientsand found that total enteroscopy was performed inonly 29% of patients.33 Other limitations include itslimited availability, time and sedation requirementsand failure to perform adequate retrograde examina-tions because of poor colon preparation or adhesionsfrom prior surgery. Double balloon enteroscopy is asafe procedure with major complications reported infewer than 1% of patients. The most commonlyreported complications include intestinal perforation(0.4%), pancreatitis (0.3%) and ileus.34, 35 Complicationrates are higher after a therapeutic procedure and sig-nicantly more perforations occur in patients withaltered surgical anatomy. Surprisingly, increased age(>75) is not a predictor of having a complication fromDBE.5

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Push enteroscopy (PE), despite having a lower diag-nostic yield compared with CE, is still widely used indiagnosis and management of OGIB. PE can obtainbiopsies and provide therapeutic interventions for lesionswithin 50150 cm of the proximal small bowel. A pro-spective comparison between PE and DBE demonstratedthat although the diagnostic yield was superior for DBE,PE still had high diagnostic yields and therapeutic rates.Therefore very proximal lesions should be targeted withPE, especially if DBE is not available.36

INTRAOPERATIVE ENTEROSCOPYIntraoperative enteroscopy (IOE), once considered thegold standard for OGIB, has a diagnostic yield ofbetween 70% and 100% in these patients.37 In a prospec-tive study comparing CE with IOE, the diagnostic yieldof IOE in obscure overt bleeding, previous overt bleedingand obscure occult bleeding were 100%, 70.8% and 50%respectively.38 Capsule endoscopy compared favourablydetecting lesions found by IOE with good sensitivity(95%) and specicity (75%). However, a follow-up studyof these OGIB patients performed by the same groupfound recurrent bleeding in over 25% despite treatmentduring time of IOE.39

The standard approach consists of gaining intra-abdom-inal access via a laparotomy or laparoscopy followed bycreation of an enterotomy through which an endoscope isintroduced. The passage of the enteroscope is assisted bythe surgeon to achieve total enteroscopy. Surgically or la-paroscopically assisted transoral and transanal approacheshave also been described removing the need for an enterot-omy. However, these approaches are time consuming andare less likely to achieve total enteroscopy.37

Intraoperative enteroscopy is associated with signicantmorbidity and mortality largely related to the laparoscopy,laparotomy or enterotomy. It should therefore be reservedfor situations where CE, DBE or PE have been contraindi-cated, unsuccessful or technically difcult.37

REPEAT UPPER OR LOWER ENDOSCOPYBleeding lesions within the reach of oesophagogastroduo-denoscopy are identied in 1064% of patients withOGIB on PE4043 and 2425% on DBE.44, 45 Theselesions were often overlooked or difcult to visualise oninitial endoscopy and include erosions in large hiatushernias (Cameron lesions), peptic ulcers, vascular ecta-sias, watermelon stomach and portal hypertensive gastr-opathy.4043, 46 Missed lesions on colonoscopy are lesscommon but can occur in up to 7% of patients,45 espe-cially when bowel preparation on initial evaluation was

poor or incomplete. Commonly overlooked lesions in thelower GI tract include angiodysplasia and neoplasia. Arecent Australian study demonstrated that repeat upperand lower endoscopies after initial (negative) endoscopicevaluations in 50 patients with OGIB detected a missedlesion in only 2 50 (4%) patients. This approach was lesscost effective than progressing onto capsule endoscopywithout repeating conventional endoscopies (A$148 364vs. A$123 199 for 50 patients respectively).47 Conversely,in another Australian study, patients with OGIB and alesion seen on CE still had a missed lesion within reachof standard scopes in up to 15% of patients.45 Oneshould therefore proceed straight to capsule endoscopyas the next test in evaluating patients with OGIB with aclose review of capsule images of the stomach and colonfor potential missed lesions. Repeat endoscopic examina-tions should be considered in patients with ongoingovert bleeding or poor visualisation of the fundus orcolon on initial examination. A side viewing endoscopeshould be used to examine the ampulla if haemobilia orhaemosuccus pancreaticus (wirsungorrhagia) is suspected.

SMALL BOWEL FOLLOW-THROUGH,CONVENTIONAL ENTEROCLYSIS, CTENTEROGRAPHY AND CT ENTEROCLYSISCapsule endoscopy and DBE have largely eliminated therole of radiographic studies such as small bowel seriesand conventional enteroclysis in the evaluation ofobscure GI bleeding. The diagnostic yield of small bowelseries and enteroclysis have been disappointing being 05%48, 49 and 021% respectively.17, 5052 These studiesare particularly ineffective for detecting mucosal lesionssuch as angioectasias, which are the most common causeof small bowel bleeding.3 Emerging diagnostic tools inOGIB are CT enterography and CT enteroclysis usingnewer multidetector CT systems. These offer an alterna-tive means of detecting mass lesions as well as improvedvisualisation of small bowel mucosa including vascularlesions such as angioectasias, previously poorly seenusing conventional radiographic studies.

The use of these radiological studies is generally notrst line in the evaluation of obscure GI bleeding unlessthere is suspicion of bowel obstruction secondary tomalignancy or Crohns disease preventing the safe pas-sage of a capsule endoscope.9

NUCLEAR SCANS AND ANGIOGRAPHYRadionuclide scans with technetium-99m-labelled redcells are a sensitive, non-invasive technique for detectingboth arterial and venous GI bleeding. However, its role

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in patients with obscure GI bleeding is limited topatients presenting with bleeding at a rate of >0.1 mL min.9, 53 Delayed scans, although useful for detectingintermittent bleeding, can be misleading by identifyingpooled blood at points separate from the bleeding site.In general, its ability to localise bleeding lesions, especiallyin the foregut, is reported to be poor.9

Angiography identies bleeding lesions if the rate is>0.5 mL min and is better at localising the source ofbleeding than nuclear scans.9 It also detects non-bleedinglesions such as angioectasias, tumours and inammatorylesions based on characteristic vascular patterns.9 Angi-ography provides the added advantage of therapeuticintervention with embolisation once a bleeding source isfound. It is generally reserved for situations where othermodalities have failed. Although provocative angiography(with anticoagulants, vasodilators and thrombolytics) hasbeen shown to be safe in some studies,54 it use is rarelyrecommended because of risk of uncontrolled bleedingand low diagnostic yield.

APPROACH TO OGIBIn the evaluation and treatment of OGIB, capsule endos-copy and double balloon enteroscopy are considered

complementary procedures.25, 27, 5557 The inability ofcapsule endoscopy to obtain biopsies or administer ther-apy is made possible with DBE. Conversely, the low ratesof achieving total enteroscopy in patients undergoingDBE is remedied by CE which has complete examinationrates of 83.6% in the setting of OGIB.6 Furthermore,Bar-Meir et al. reported that 2035% of patients withsevere IDA (Hb < 10 g dL) and negative initial CE hadabnormalities detected on a second CE.56 These lesionscan be detected (and treated) by a DBE, which can dis-cover an additional 30% of patients with OGIB when ini-tial CE was negative.26 A suggested algorithm forevaluation of OGIB is shown in Figure 1.

Unless contraindicated, CE is usually the initial diag-nostic test in haemodynamically stable patients with sus-pected OGIB because of its minimally invasive nature,tolerance and ability to visualise the entire small bowel.DBE is indicated if CE detects a lesion requiring biopsy orendoscopic intervention or in patients whom suspicion ofsmall bowel bleeding is high despite a negative initialCE.25, 27, 31, 55, 5759 This approach leads to a resolution ofbleeding and normal Hb in greater than 75% of patientsand also a reduction in transfusion and iron require-ments.60 However, from a cost minimisation perspective,

Massive overtbleeding

Obscure gastrointestinal bleeding

DAEAngiography

Surgical consult

Capsule endoscopy Oral DAE Second lookendoscopy

Definitivemanagement

Ongoing bleeding?No Yes

Observe + medicaltreatment

Recurrence? Yes

No

Follow up+ve

ve

Definitive Management- Conservative treatment- Medical treatment- Embolisation- Endoscopic therapy (routine/PE/DAE)- Surgery

- Consider repeat routine scopes- Consider repeat CE- Consider PE/DAE- Consider Meckels scan- Consider haematology referral

+ve+ve ve

*

Figure 1 | Proposed approach to diagnosis and management of obscure gastrointestinal bleeding. DAE, device assistedenteroscopy; PE, push enteroscopy; CE, capsule endoscopy; routine endoscopy oesophagogastroduodenoscopy and/or colonoscopy. * This direction compared with capsule endoscopy is preferred in many countries where CE is notreadily available or is too expensive for routine use. This pathway has also been shown in clinical studies to be moreeffective in high volume centres.62




initial DBE is the least expensive strategy when the needfor therapeutic intervention or denitive diagnosis ishighly probable (>2530%).61, 62 If only visual identica-tion is required, initial CE may be preferred.61 A recentstudy by Albert et al. suggested that an initial DBE strategyis more cost effective in high volume centres (>80100investigations per annum) where a substantial number ofpatients present with small bowel bleeding.62

As the majority of lesions responsible for IDA arelocated in the proximal small bowel, it is reasonable tostart with an anterograde DBE, unless other investiga-tions show a lesion beyond the proximal two-thirds tothree-quarters of the small bowel.60, 63 However, Hakam-ura et al. point out that there is currently no consensusfor choosing the DBE route.64

Currently no clear guidelines exist for further investi-gation of patients with a negative initial CE. It is reason-able to observe clinically stable patients and treatmedically with iron therapy, if necessary. However,patients with evidence of ongoing or recurrent OGIB(e.g. overt bleeding, iron deciency anaemia or positiveFOBT) should have further work-up. The optionsinclude repeating routine endoscopies, repeating the CE,performing radiographic or nuclear medicine scans, angi-ography, DBE, PE or even intraoperative enteroscopy.Which option to pursue should be decided on a case-by-case basis determined by the clinical scenario, diagnostic

yield, risks involved, availability and patient preference.Repeat oesophagogastroduodenoscopy and or colonos-copy should be considered in patients with ongoing overtbleeding or if there is a suspicion of a missed lesion onthe initial examination because of suboptimal visibility orbowel preparation.

Patients with acutely bleeding lesions should undergoa therapeutic endoscopic procedure (e.g. PE or DBE) orangiography + ) embolisation depending on local avail-ability and expertise. These should be performed onlyafter appropriate resuscitation has been implemented.

CONCLUSIONObscure gastrointestinal bleed is a common problem fac-ing gastroenterologists. Various radiological, endoscopicand surgical options are available to evaluate the cause ofOGIB, each with their own advantages and shortfalls.The development of CE and DBE has transformed theapproach to the evaluation and management of OGIBover the past decade. Older diagnostic modalities stillplay a complementary, albeit increasingly selective role.With growing experience in these new technologies, anever-reducing minority of patients presenting with OGIBwill be left without a diagnosis.

ACKNOWLEDGEMENTDeclaration of personal and funding interests: None.

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