Alimentary Pharmacology and Therapeutics

Review article: the diagnosis and investigation of obscure

gastrointestinal bleeding
K. Liu* & A. J. Kaffes

*Faculty of Medicine, University of

Sydney, Sydney, NSW, Australia.

AW Morrow Gastroenterology and

Liver Centre, Royal Prince Alfred
Hospital, Camperdown, Sydney,
NSW, Australia.

Correspondence to:
K. Liu, Faculty of Medicine, University
of Sydney, 23 10 Pyrmont Bridge
Road, Camperdown, Sydney, NSW
2050, Australia.
E-mail: [email protected]

Publication data
Submitted 5 April 2011
First decision 28 April 2011
Resubmitted 29 May 2011
Accepted 1 June 2011
EV Pub Online 21 June 2011
This uncommissioned review article was
subject to full peer-review.

SUMMARY
Background
Obscure gastrointestinal bleeding (OGIB) is a commonly encountered clinical problem in gastroenterology and is associated with signicant morbidity
and mortality. The investigation and management of OGIB has changed
dramatically over the past decade with the advent of newer gastroenterological and radiological technologies.
Aim
To review the current evidence on the diagnosis and investigation of OGIB.
Methods
We searched the PubMed database (19852010) for full original articles in
English-language journals relevant to the investigation of OGIB. The search
terms we used were gastrointestinal bleeding or gastrointestinal hemorrhage or small bowel bleeding each in combination with obscure, or
capsule endoscopy, or enteroscopy or enterography or enteroclysis.
Results
Capsule endoscopy (CE) or double balloon enteroscopy (DBE) should be
rst line investigations. They are complimentary procedures with comparable high diagnostic yields. DBE is also able to provide therapeutic intervention. Newer technologies such as single balloon and spiral enteroscopy are
currently being evaluated. Radiological and nuclear medicine investigations,
such as CT enterography and CT enteroclysis, are alternative diagnostic
tools when CE or DBE are contraindicated. Repeating the gastroscopy
and or colonoscopy may be considered in selective situations. An algorithm
for investigation of obscure bleeding is proposed.
Conclusions
The development of capsule endoscopy and double balloon enteroscopy has
transformed the approach to the evaluation and management of obscure
gastrointestinal bleeding over the past decade. Older diagnostic modalities
still play a complementary, but increasingly selective role.
Aliment Pharmacol Ther 2011; 34: 416423

416

2011 Blackwell Publishing Ltd

doi:10.1111/j.1365-2036.2011.04744.x

Review: obscure gastrointestinal bleeding

INTRODUCTION
Obscure gastrointestinal bleeding (OGIB) is dened as
persistent or recurrent bleeding from the gastrointestinal
(GI) tract after negative evaluations with upper and
lower endoscopies. This represents approximately 5% of
all GI bleeds.13 Obscure GI bleeding can be further categorised into obscure overt GI bleeding in patients with
clinically evident bleeding (haematemesis, melaena and
haematochezia) or obscure occult GI bleeding which
manifests as iron deciency anaemia or positive faecal
occult blood test (FOBT). Common causes of OGIB are
listed in Table 1.
Although missed lesions from oesophagogastroduodenoscopy and colonoscopy occur frequently, evaluation of
OGIB usually focuses on visualisation of the small bowel.

Table 1 | Causes of obscure gastrointestinal bleeding

Upper GI lesions
Cameron erosions

515

Angioectasia

510

Varices

15

Dieulafoy lesion

23

Gastric antral vascular ectasia (GAVE)

12

Portal hypertensive gastropathy

12

Small bowel lesions

Angioectasia

2055

Small bowel tumours

1020

Crohns disease

210

Coeliac disease

25

Meckels diverticulum

25

NSAID enteropathy

Dieulafoy lesion

12

Ectopic varices
Portal hypertensive enteropathy

Radiation enteritis

12
12 (but 6070in
those with portal
hypertension)
<1

Lower GI lesions
Angioectasias

Neoplasms

Dieulafoy lesion

<1

Rare lesions
Haemobilia
Haemosuccus pancreaticus
Values are expressed as percentages.

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2011 Blackwell Publishing Ltd

<1
<1
27, 40, 6569

As a result of technological advances in endoscopy, there

has been a paradigm shift in the evaluation of OGIB and
small bowel bleeding over the past decade. Modalities
used to investigate the small bowel previously such as
push, Sonde and intraoperative enteroscopy are now limited to increasingly selective situations. Newer technologies including capsule endoscopy (CE) and double
balloon enteroscopy (DBE) both play a major role in the
evaluation of OGIB today.
In this article, we review the clinical evaluation of
obscure gastrointestinal bleeding.

HISTORY AND EXAMINATION

History taking and examination can help predict the aetiology and localise the site of bleeding. It is important to
take into account the age of the patient. Small bowel
tumours such as leiomyomas, carcinoid tumours, adenocarcinomas and lymphomas are the most common cause
of OGIB in patients <50 years old.4 Other common lesions
in younger patients include Meckels diverticulum Dieulafoys lesion and Crohns disease. By contrast, angiodysplasias are the most common cause of small bowel bleeding
in older patients.5 Presentations with haematemesis, melaena, bloody nasogastric lavage uid or isolated elevations
in urea are typically (but not exclusively) associated with
lesions in the upper gastrointestinal tracts, while haematochezia suggests lower GI bleeding.3 Patients should be
asked about non-steroidal anti-inammatory drug
(NSAID) use for the possibility of NSAID-induced small
bowel disease. A prior history of abdominal aortic aneurysm repair, necrotising pancreatitis or liver injury
(trauma, biopsy and hepatocellular carcinoma) should
alert the clinician to search for an aortoenteric stula, haemosuccus pancreaticus and haemobilia respectively. A
thorough physical examination can detect skin signs associated with diagnoses responsible for OGIB such as hereditary haemorrhagic telangiectasia or coeliac disease.
CAPSULE ENDOSCOPY
The development of the wireless capsule endoscopy has
revolutionised the investigation of the small intestine. It
offers a safe, minimally invasive and effective tool for the
next step in the evaluation of GI bleeding after negative
standard endoscopies. The latest systematic review of 227
articles on CE revealed OGIB was by far the most common indication comprising 66% of patients undergoing
CE.6 The diagnostic yield of CE in OGIB is 60.5% with
the most common diagnosis being angiodysplasias
accounting for 50% of lesions followed by ulcers (26.8%)
and neoplastic lesions (8.8%).6 A positive nding is gen417

K. Liu and A. J. Kaffes

erally observed more often in patients with obscure overt
bleeding compared with those with obscure occult bleeding,79 although this is not conrmed by all studies.10, 11
Other factors such as performing CE within 2 weeks of a
bleeding episode, Hb <10 g dL, bleeding for >6 months
and >1 bleeding episode also increase the yield of the
examination.12, 13
Capsule endoscopy has consistently been shown to be
superior to push enteroscopy (PE) and small bowel radiography in detecting small bowel lesions.7, 8, 14, 15 A
meta-analysis of studies comparing the yield of CE to
other diagnostic modalities in OGIB showed that in 14
studies, the yield of CE was double that of PE (63% vs.
28%).14 The same meta-analysis reported the yield of CE
was also found to be higher than small bowel radiography for clinically signicant lesions (42% vs. 6%) in
pooled data from three studies.14 These ndings are supported by another meta-analysis of 24 studies (530
patients), which reported the yield of CE (for all indications) to be 87% compared to 14.8% and 9.9% for PE
and small-bowel series respectively.15
In terms of clinical outcomes, Mylonaki et al. found that
capsule endoscopy led to an alteration in therapy in 25 38
(66%) of patients with OGIB.16 Enteroclysis, in comparison
changes 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 obscure
bleeding, previous overt obscure bleeding and occult
obscure bleeding respectively.18 The rate of rebleeding in
patients with OGIB and a negative CE is less than 6%.19
The main limitation of capsule endoscopy is its inability
to obtain biopsies or administer therapy. CE also does not
obtain satisfactory views of the oesophagus, stomach or
colon and should not replace or bypass upper or lower endoscopies.20 Diagnostic yield may be reduced in patients
with poor bowel preparation or incomplete examinations
because of delayed gastric emptying or failure of capsule to
enter duodenum within 1.5 h. The most common complication is capsule retention (or non-natural excretion),
which occurs in 1.4% of patients with OGIB.6 Risk factors
for capsule retention include NSAID use abdominal radiation injury, extensive Crohns disease and previous major
abdominal surgery. There have been no reported deaths
from CE to date.6 Patients with pacemakers or debrillators should be closely monitored during CE.

DEVICE ASSISTED ENTEROSCOPY (BALLOON

ASSISTED, SPIRAL AND PUSH)
Several new device assisted enteroscopes (DAE) have
been released and studied. The rst of these was the
418

double balloon enteroscope (Fijinon) described in 2001

and made available for clinical use in 2004. This was followed by the release of a single balloon system (Olympus
optical) and more recently spiral enteroscopy (Spirus
medical). These devices enable endoscopic inspection of
the entire small bowel through the use of a 200 cm enteroscope and an overtube. The single and double balloon
systems utilise inatable balloons to grip the intestine to
facilitate deep enteroscopy whereas the spiral system
consists of a specialised overtube with a compliant spiral
located at the distal tip. The majority of clinical evidence
is with DBE but emerging literature shows similar benets with the other modalities. Comparative studies
between all of these techniques show technical differences (e.g. procedure time, depth of insertion, rates of
total enteroscopy) but few if any show diagnostic or
therapeutic benet for one over the other.2124 The literature on this is in its infancy and further evaluation will
be needed before one modality could be recommended
over the other.
Double balloon enteroscopy and CE have comparable
diagnostic yields in patients with OGIB.2530 A metaanalysis of 11 studies (397 patients) demonstrated the
pooled overall yield for CE and DBE was 60% and 57%
respectively.31 The yields of each study for vascular malformations, inammatory lesions and polyps or tumours
were also found to be similar. The main advantage of
DBE is its ability to perform therapeutic interventions
and obtain biopsies, not possible on CE. Endoscopic
therapies and biopsies are performed in 2757% and
27% of patients undergoing DBE respectively.5, 26, 29, 32
One shortfall of DAE is its inability to achieve total
enteroscopy in all patients. Rates of achieving total
enteroscopy with DBE vary widely from 0% to 86%.
Raju et al. pooled data from 12 studies on 723 patients
and found that total enteroscopy was performed in
only 29% of patients.33 Other limitations include its
limited availability, time and sedation requirements
and failure to perform adequate retrograde examinations because of poor colon preparation or adhesions
from prior surgery. Double balloon enteroscopy is a
safe procedure with major complications reported in
fewer than 1% of patients. The most commonly
reported complications include intestinal perforation
(0.4%), pancreatitis (0.3%) and ileus.34, 35 Complication
rates are higher after a therapeutic procedure and signicantly more perforations occur in patients with
altered surgical anatomy. Surprisingly, increased age
(>75) is not a predictor of having a complication from
DBE.5
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Review: obscure gastrointestinal bleeding

Push enteroscopy (PE), despite having a lower diagnostic yield compared with CE, is still widely used in
diagnosis and management of OGIB. PE can obtain
biopsies and provide therapeutic interventions for lesions
within 50150 cm of the proximal small bowel. A prospective comparison between PE and DBE demonstrated
that although the diagnostic yield was superior for DBE,
PE still had high diagnostic yields and therapeutic rates.
Therefore very proximal lesions should be targeted with
PE, especially if DBE is not available.36

INTRAOPERATIVE ENTEROSCOPY
Intraoperative enteroscopy (IOE), once considered the
gold standard for OGIB, has a diagnostic yield of
between 70% and 100% in these patients.37 In a prospective study comparing CE with IOE, the diagnostic yield
of IOE in obscure overt bleeding, previous overt bleeding
and obscure occult bleeding were 100%, 70.8% and 50%
respectively.38 Capsule endoscopy compared favourably
detecting lesions found by IOE with good sensitivity
(95%) and specicity (75%). However, a follow-up study
of these OGIB patients performed by the same group
found recurrent bleeding in over 25% despite treatment
during time of IOE.39
The standard approach consists of gaining intra-abdominal access via a laparotomy or laparoscopy followed by
creation of an enterotomy through which an endoscope is
introduced. The passage of the enteroscope is assisted by
the surgeon to achieve total enteroscopy. Surgically or laparoscopically assisted transoral and transanal approaches
have also been described removing the need for an enterotomy. However, these approaches are time consuming and
are less likely to achieve total enteroscopy.37
Intraoperative enteroscopy is associated with signicant
morbidity and mortality largely related to the laparoscopy,
laparotomy or enterotomy. It should therefore be reserved
for situations where CE, DBE or PE have been contraindicated, unsuccessful or technically difcult.37
REPEAT UPPER OR LOWER ENDOSCOPY
Bleeding lesions within the reach of oesophagogastroduodenoscopy are identied in 1064% of patients with
OGIB on PE4043 and 2425% on DBE.44, 45 These
lesions were often overlooked or difcult to visualise on
initial endoscopy and include erosions in large hiatus
hernias (Cameron lesions), peptic ulcers, vascular ectasias, watermelon stomach and portal hypertensive gastropathy.4043, 46 Missed lesions on colonoscopy are less
common but can occur in up to 7% of patients,45 especially when bowel preparation on initial evaluation was
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poor or incomplete. Commonly overlooked lesions in the

lower GI tract include angiodysplasia and neoplasia. A
recent Australian study demonstrated that repeat upper
and lower endoscopies after initial (negative) endoscopic
evaluations in 50 patients with OGIB detected a missed
lesion in only 2 50 (4%) patients. This approach was less
cost effective than progressing onto capsule endoscopy
without repeating conventional endoscopies (A$148 364
vs. A$123 199 for 50 patients respectively).47 Conversely,
in another Australian study, patients with OGIB and a
lesion seen on CE still had a missed lesion within reach
of standard scopes in up to 15% of patients.45 One
should therefore proceed straight to capsule endoscopy
as the next test in evaluating patients with OGIB with a
close review of capsule images of the stomach and colon
for potential missed lesions. Repeat endoscopic examinations should be considered in patients with ongoing
overt bleeding or poor visualisation of the fundus or
colon on initial examination. A side viewing endoscope
should be used to examine the ampulla if haemobilia or
haemosuccus pancreaticus (wirsungorrhagia) is suspected.

SMALL BOWEL FOLLOW-THROUGH,

CONVENTIONAL ENTEROCLYSIS, CT
ENTEROGRAPHY AND CT ENTEROCLYSIS
Capsule endoscopy and DBE have largely eliminated the
role of radiographic studies such as small bowel series
and conventional enteroclysis in the evaluation of
obscure GI bleeding. The diagnostic yield of small bowel
series and enteroclysis have been disappointing being 0
5%48, 49 and 021% respectively.17, 5052 These studies
are particularly ineffective for detecting mucosal lesions
such as angioectasias, which are the most common cause
of small bowel bleeding.3 Emerging diagnostic tools in
OGIB are CT enterography and CT enteroclysis using
newer multidetector CT systems. These offer an alternative means of detecting mass lesions as well as improved
visualisation of small bowel mucosa including vascular
lesions such as angioectasias, previously poorly seen
using conventional radiographic studies.
The use of these radiological studies is generally not
rst line in the evaluation of obscure GI bleeding unless
there is suspicion of bowel obstruction secondary to
malignancy or Crohns disease preventing the safe passage of a capsule endoscope.9
NUCLEAR SCANS AND ANGIOGRAPHY
Radionuclide scans with technetium-99m-labelled red
cells are a sensitive, non-invasive technique for detecting
both arterial and venous GI bleeding. However, its role
419

K. Liu and A. J. Kaffes

in patients with obscure GI bleeding is limited to
patients presenting with bleeding at a rate of >0.1 mL
min.9, 53 Delayed scans, although useful for detecting
intermittent bleeding, can be misleading by identifying
pooled blood at points separate from the bleeding site.
In general, its ability to localise bleeding lesions, especially
in 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 of
bleeding than nuclear scans.9 It also detects non-bleeding
lesions such as angioectasias, tumours and inammatory
lesions based on characteristic vascular patterns.9 Angiography provides the added advantage of therapeutic
intervention with embolisation once a bleeding source is
found. It is generally reserved for situations where other
modalities have failed. Although provocative angiography
(with anticoagulants, vasodilators and thrombolytics) has
been shown to be safe in some studies,54 it use is rarely
recommended because of risk of uncontrolled bleeding
and low diagnostic yield.

APPROACH TO OGIB
In the evaluation and treatment of OGIB, capsule endoscopy and double balloon enteroscopy are considered

complementary procedures.25, 27, 5557 The inability of

capsule endoscopy to obtain biopsies or administer therapy is made possible with DBE. Conversely, the low rates
of achieving total enteroscopy in patients undergoing
DBE is remedied by CE which has complete examination
rates of 83.6% in the setting of OGIB.6 Furthermore,
Bar-Meir et al. reported that 2035% of patients with
severe IDA (Hb < 10 g dL) and negative initial CE had
abnormalities detected on a second CE.56 These lesions
can be detected (and treated) by a DBE, which can discover an additional 30% of patients with OGIB when initial CE was negative.26 A suggested algorithm for
evaluation of OGIB is shown in Figure 1.
Unless contraindicated, CE is usually the initial diagnostic test in haemodynamically stable patients with suspected 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 or
endoscopic intervention or in patients whom suspicion of
small bowel bleeding is high despite a negative initial
CE.25, 27, 31, 55, 5759 This approach leads to a resolution of
bleeding and normal Hb in greater than 75% of patients
and also a reduction in transfusion and iron requirements.60 However, from a cost minimisation perspective,

Obscure gastrointestinal bleeding

Massive overt
bleeding

*
DAE
Angiography
Surgical consult

Capsule endoscopy

+ve

Second look
endoscopy

Oral DAE

+ve

ve

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

No

Yes

Observe + medical
treatment
Recurrence?

- Consider repeat routine scopes

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

Yes

No
ve
Follow up
+ve

Figure 1 | Proposed approach to diagnosis and management of obscure gastrointestinal bleeding. DAE, device assisted
enteroscopy; 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 not
readily available or is too expensive for routine use. This pathway has also been shown in clinical studies to be more
effective in high volume centres.62
420

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Review: obscure gastrointestinal bleeding

initial DBE is the least expensive strategy when the need
for therapeutic intervention or denitive diagnosis is
highly probable (>2530%).61, 62 If only visual identication is required, initial CE may be preferred.61 A recent
study by Albert et al. suggested that an initial DBE strategy
is more cost effective in high volume centres (>80100
investigations per annum) where a substantial number of
patients present with small bowel bleeding.62
As the majority of lesions responsible for IDA are
located in the proximal small bowel, it is reasonable to
start with an anterograde DBE, unless other investigations show a lesion beyond the proximal two-thirds to
three-quarters of the small bowel.60, 63 However, Hakamura et al. point out that there is currently no consensus
for choosing the DBE route.64
Currently no clear guidelines exist for further investigation of patients with a negative initial CE. It is reasonable to observe clinically stable patients and treat
medically with iron therapy, if necessary. However,
patients with evidence of ongoing or recurrent OGIB
(e.g. overt bleeding, iron deciency anaemia or positive
FOBT) should have further work-up. The options
include repeating routine endoscopies, repeating the CE,
performing radiographic or nuclear medicine scans, angiography, DBE, PE or even intraoperative enteroscopy.
Which option to pursue should be decided on a case-bycase basis determined by the clinical scenario, diagnostic

yield, risks involved, availability and patient preference.

Repeat oesophagogastroduodenoscopy and or colonoscopy should be considered in patients with ongoing overt
bleeding or if there is a suspicion of a missed lesion on
the initial examination because of suboptimal visibility or
bowel preparation.
Patients with acutely bleeding lesions should undergo
a therapeutic endoscopic procedure (e.g. PE or DBE) or
angiography + ) embolisation depending on local availability and expertise. These should be performed only
after appropriate resuscitation has been implemented.

CONCLUSION
Obscure gastrointestinal bleed is a common problem facing gastroenterologists. Various radiological, endoscopic
and surgical options are available to evaluate the cause of
OGIB, each with their own advantages and shortfalls.
The development of CE and DBE has transformed the
approach to the evaluation and management of OGIB
over the past decade. Older diagnostic modalities still
play a complementary, albeit increasingly selective role.
With growing experience in these new technologies, an
ever-reducing minority of patients presenting with OGIB
will be left without a diagnosis.
ACKNOWLEDGEMENT
Declaration of personal and funding interests: None.

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