GASTROENTEROLOGY 2007;133:16971717

American Gastroenterological Association (AGA) Institute Technical

Review on Obscure Gastrointestinal Bleeding

CME quiz on page 1692.

he diagnosis and management of patients with obscure gastrointestinal (GI) bleeding was challenging
for the gastroenterologist until the development of small
bowel capsule endoscopy and double-balloon enteroscopy (DBE). Both of these techniques have revolutionized
the management of patients with obscure GI bleeding.
Detection of lesions such as small intestinal angioectasia
has become possible with the advent of capsule endoscopy, and therapy of such lesions can be accomplished
with DBE, without the need for intraoperative enteroscopy. The goal of this review is to shed light on the recent
paradigm shift to the use of endoscopy in the diagnosis
and management of patients with obscure GI bleeding.
Obscure GI bleeding, defined as bleeding from the GI
tract that persists or recurs without an obvious etiology
after esophagogastroduodenoscopy (EGD), colonoscopy,
and radiologic evaluation of the small bowel such as
small bowel follow-through or enteroclysis, could be categorized into obscure overt and obscure occult bleeding
based on the presence or absence of clinically evident
bleeding.1,2
Occult GI bleeding is detected by fecal occult blood
testing. There is no recent publication that recommends
or has studied the role of fecal occult blood testing
beyond the clinical context of colorectal cancer screening.
A fecal occult blood test should be performed only in the
appropriate context of colorectal cancer screening. If
the test result is positive and the findings of a recommended colon cancer screening workup are negative, in
the absence of iron deficiency anemia and GI symptoms, no further workup is recommended. If associated (iron deficiency) anemia is present, and if the
clinical presentation satisfies the definition of obscure
GI bleeding, then only it should be worked up as
obscure GI bleeding.
Obscure GI bleeding could be due to lesions that are
overlooked in the esophagus, stomach, and colon during
initial workup or lesions in the small intestine that are
difficult to visualize with conventional endoscopy and
radiologic imaging. Explanations for overlooking a lesion
and missing the diagnosis include lesions that have
stopped bleeding during endoscopic examination, lesions

that are obscured by blood clots that are unable to be

mobilized during endoscopy, hypovolemia and significant anemia causing lesions to look less obvious, and
intermittent and slow bleeding leading to negative findings on endoscopic and nuclear scans.
Overall, lesions in the small intestine account for approximately 5% of causes of obscure GI bleeding. Medical
imaging of the small intestine has been a very difficult
and limited undertaking. Several factors account for the
difficulty encountered in small bowel visualization. The
length of the small intestine, in addition to its free
intraperitoneal location, vigorous contractility, and overlying loops, confounds the usual diagnostic techniques.
These attributes limit the diagnostic ability of barium
studies, endoscopic intubation, and the identification of
specific sites by the special imaging techniques of nuclear
medicine scans and angiography. In patients with obscure GI bleeding, the bleeding rate may be slow or
intermittent, thereby not allowing identification by either
angiography or bleeding scan.3 The yield of a small bowel
series for diagnosing tumors of the small intestine is
quite low and barium studies, even enteroclysis, cannot
diagnose angiectasias, which are the most common
causes of small intestinal bleeding.4,5 The distal small
intestine has been relatively inaccessible to endoscopic
intubation despite the development of various enteroscopes. Because of the inability to localize a bleeding site
in the small bowel, patients with obscure GI bleeding
typically present with prolonged occult blood loss or
recurrent episodes of melena or maroon stool without a
specific diagnosis. In this group of patients, an early
diagnosis of the bleeding site has been the exception
rather than the norm until recently with the development
of capsule endoscopy and DBE.
A MEDLINE search of English-language publications
was performed from 1966 to June 2006 related to obscure
GI bleeding by using the following search terms: obscure
GI bleeding, occult GI bleeding, video capsule endoscopy,
Abbreviations used in this paper: CT, computed tomography; DBE,
double-balloon enteroscopy; EGD, esophagogastroduodenoscopy;
HHT, hereditary hemorrhagic telangiectasia; vWF, von Willebrands
factor.
2007 by the AGA Institute
0016-5085/07/$32.00
doi:10.1053/j.gastro.2007.06.007

AGA
INSTITUTE

This literature review and the recommendations therein were prepared for the AGA Institute Clinical Practice and Economics
Committee. The paper was approved by the Committee on March 12, 2007, and by the AGA Institute Governing Board on May
19, 2007.

1698

AGA INSTITUTE

GASTROENTEROLOGY Vol. 133, No. 5

Table 1. Etiology of Obscure GI Bleeding

Upper GI and lower GI bleeding
overlooked
Upper GI lesions
Camerons erosions
Fundic varices
Peptic ulcer
Angiectasia
Dieulafoys lesion
Gastric antral vascular ectasia
Lower GI lesions
Angiectasia
Neoplasms

Mid GI bleeding
Younger than 40 years of age
Tumors
Meckels diverticulum
Dieulafoys lesion
Crohns disease
Celiac disease
Older than 40 years of age
Angiectasia
NSAID enteropathy
Celiac disease
Uncommon
Hemobilia
Hemosuccus pancreaticus
Aortoenteric fistula

and enteroscopy. Reference lists from relevant manuscripts were also inspected to identify additional applicable articles missed with the above search strategy. The
following sections describe recent advances in our understanding of the etiology, diagnosis, and management of
obscure GI bleeding since the publication of American
Gastroenterological Association medical position statement entitled Evaluation and Management of Occult
and Obscure Gastrointestinal Bleeding in 2000.1 Studies
published only as abstracts were excluded. For assessment of procedural outcomes, case series were not included. To calculate yearly probabilities, the formula p
1 e(rt) was used, where p represents probability, r
represents rate, and t represents time.

Etiology

AGA
INSTITUTE

Causes of obscure GI bleeding may potentially

include any lesion from the oral cavity to the anorectum
that may bleed into the GI tract (see Table 1). To date,
there are no longitudinal or population-based studies on
the frequency and location of specific causes of obscure
GI bleeding.
Commonly overlooked lesions in the upper GI tract
include Camerons erosions in large hiatal hernias,6 fundic varices,7,8 peptic ulcer disease, angioectasias,6 Dieulafoys lesion,9 and gastric antral vascular ectasia.10,11
Lesions missed during colonoscopy include angioectasias
and neoplasms.12
The etiology of small intestinal bleeding is dependent
on the age of the patient. Patients younger than 40 years
are more likely to have small intestinal tumors (such as
lymphomas, carcinoid tumors, and adenocarcinoma, and
polyps from hereditary polyposis syndrome), Meckels
diverticulum, Dieulafoys lesion, and Crohns disease. Patients who are older than 40 years are more prone to
bleeding from vascular lesions, which comprise up to 40%
of all causes, and nonsteroidal anti-inflammatory drug
(NSAID)-induced small bowel disease. Less common eti-

ologies of bleeding, which originate in the C-loop of

duodenum, include hemobilia in patients with liver
biopsy, trauma, and hepatocellular cancer, hemosuccus pancreaticus in patients with necrotizing pancreatitis or pancreatic transplantation, and aortoenteric
fistula in patients with prior abdominal aortic aneurysm repair.
Approximately 5% of patients presenting with GI hemorrhage have no source found by upper endoscopy and
colonoscopy.13 In approximately 75% of these patients,
responsible lesions can be detected in the small
bowel.14 16 In patients presenting with obscure overt
bleeding (defined as the presence of recurrent melena or
hematochezia with normal evaluation by upper endoscopy and colonoscopy), small bowel angiectasias are detected in 30% 60% of examinations.17
Recent advances in endoscopic imaging of the small
intestine provide us an opportunity to revisit the traditional definitions of the source of GI bleeding. GI bleeding has been defined as upper or lower GI bleeding based
on the location of the bleeding either proximal or distal
to the ligament of Treitz. Reclassifying GI bleeding (and
obscure GI bleeding) into 3 categories (upper, mid, and
lower GI bleeding) instead of adhering to the traditional
classification of upper GI and lower GI bleeding may be
useful to improve our understanding of the problem.
Bleeding above the ampulla of Vater, within the reach of
an EGD, is defined as upper GI bleeding; small intestinal
bleeding from the ampulla of Vater to the terminal ileum, best investigated by capsule endoscopy and DBE, is
defined as mid GI bleeding; and colonic bleeding is defined as lower GI bleeding, which can be evaluated by
colonoscopy.18
Angiectasias are ectatic blood vessels made of thin wall
with or without endothelial lining. Small arteriovenous
communications are often present due to incompetence
of the precapillary sphincter. Although they are often
incidentally identified during endoscopic procedures,
they are increasingly recognized as a major cause of GI
bleeding, particularly in the elderly. The factors that
trigger these common incidentally detected lesions to
present with obscure and often clinically overt GI bleeding have not been clearly elucidated.
The association of abnormal von Willebrands factor
(vWF) is receiving increasing attention in the management of patients with bleeding GI angiectasias. Von Willebrands disease is a bleeding disorder that results from
a qualitative or quantitative defect in vWF. vWF is a
complex multimeric glycoprotein present in platelets,
plasma, and subendothelium. vWF is essential to platelet
adhesion and aggregation at the site of vascular injury. In
an elegant study of patients with both bleeding and
nonbleeding angiectasias of the GI tract and control
patients with colonic diverticular hemorrhage, Veyradier
et al showed that most patients with bleeding angiectasias of the GI tract lack the largest multimers of vWF

induced by a latent acquired form of von Willebrands

disease.19 Because these specific multimers are the most
effective in inducing platelet aggregation in condition of
high shear stress that is commonly present in the microcirculation of angioectatic lesions, it was concluded their
deficiency contributes to active bleeding.
Bleeding from angiectasias in patients with aortic stenosis, called Heydes syndrome, has been recently reviewed.20,21 Whether such an association actually exists
has been questioned by an earlier prospective study,22
while a more recent larger but retrospective study lent
support in its favor.23 In patients with aortic stenosis, the
aortic wall shear stress is high. At such high macrovascular shear stress, increased consumption of high-molecular-weight multimers of vWF appears to occur possibly
related to the increased activity of the shear-dependent
vWF-cleaving metalloprotease. This leads to a relative
deficiency of high-molecular-weight multimers of vWF,
leading to clinically manifest bleeding from angiodysplastic lesions in the GI tract. Support for this hypothesis
comes from the fact that after aortic valve replacement,
the severity of bleeding from these lesions decreases
along with an increase in the level of the circulating
high-molecular-weight multimers of vWF. Presumably
other factors such as tissue hypoxemia due to reduced GI
mucosal perfusion related to hemodynamically significant aortic stenosis might play a role in this situation.
Thus, this may be an urban legend; even if there is an
association, it is weak and often exaggerated.
It is possible that similar pathophysiology can occur in
the setting of other common cardiovascular disorders
such as severe peripheral vascular occlusive disease and
may help explain why elderly people often develop recurrent GI bleeding or iron deficiency anemia from bleeding
angiectasias in the GI tract.20
The issue of specific coagulation disorders in patients
with bleeding GI angiectasias was also recently studied in
a prospective cohort of 21 patients.24 Plasma levels of
vWF, D-dimer, and tissue plasminogen activator activity
were significantly different in patients with GI angiectasia compared with control patients with bleeding duodenal ulcer. The plasminogen activator inhibitor type 1 was
shown to be an independent predictor of future bleeding
in these patients on multivariate analysis.
Angiectasias are usually distinguished from telangiectasias, which, although anatomically similar, are usually
referred to in the context of systemic or hereditary
diseases. Hereditary hemorrhagic telangiectasia (HHT,
RenduOslerWeber syndrome) is one of the most wellknown hereditary entities associated with obscure GI
bleeding.25 Most patients with HHT will have a history of
epistaxis that tends to antedate development of cutaneous or visceral telangiectasias by a decade or more. In a
recent report from Denmark, the overall incidence of GI
bleeding was 33% in patients with HHT and appeared to
develop in the fourth or fifth decade of life.26 HHT is an

AGA INSTITUTE

1699

autosomal dominant disease with high penetrance, and

prevalence is estimated to range from 1:40,000 to
1:100,000. The gene for HHT has been located on chromosome 9q3, and there are 2 disease types described as
HHT1 and HHT2, caused by mutations in the endoglin
and ALK1 genes, respectively.27 HHT1 has been associated with a higher frequency of visceral manifestations,
including GI bleeding, and HHT2 is believed to be associated with a lower penetrance and milder disease manifestations.28,29
Blue rubber bleb nevus syndrome is a rare disorder
characterized by the development of cavernous hemangiomas,30 which most commonly involve the skin and the
GI tract. The most common presentations of blue rubber
bleb nevus syndrome are either the appearance of the
skin lesions alone or iron deficiency anemia. Most patients with GI bleeding are asymptomatic and generally
respond to a blood transfusion and an iron supplement
given orally. The lesions can also cause numerous extraintestinal problems such as orthopedic deformities,
central nervous system involvement, spinal cord compression, disseminated intravascular coagulation, thrombocytopenia, hemothorax, and hemopericardium. Blue
rubber bleb nevus syndrome is a rare, probably inherited disorder that frequently presents as GI blood loss
for which endoscopic therapy and surgery is often of
value.31,32

Evaluation
History and Physical Examination
The importance of a thorough history and physical examination cannot be overemphasized in the evaluation of a patient with obscure GI bleeding. The nature
of the exact presenting symptom is important in deciding
a practical, efficient, and cost-effective evaluation plan.
For example, recurrent hematemesis from an unknown
source usually signifies a bleeding lesion above the ligament of Treitz, and lower GI evaluations are generally not
warranted in such a scenario. Severity and temporal pattern of the associated anemia should have a significant
impact on subsequent management decisions. For example, in a patient with mild anemia and a very slow decrease in hematocrit who has multiple severe comorbidities, a conservative workup may be prudent, although
little information is available on the safety and efficacy of
such a strategy. Also, the degree of severity of anemia has
a bearing on planning endoscopic evaluation in terms of
potential complications related to sedation.
Although abdominal symptoms may sometimes help
in targeting focused evaluation, conclusions from few
available studies are too divergent to recommend targeted evaluation based on abdominal symptoms.1 A thorough history of consumption of prescription and overthe-counter medications is very important to exclude

AGA
INSTITUTE

November 2007

1700

AGA INSTITUTE

medication-related mucosal lesions that may precipitate

or exacerbate bleeding.
A recent review stresses the importance of skin signs
that may enable a clinician to make a diagnosis of the
etiology of obscure GI bleeding.33 In HHT, the vascular
lesions develop primarily on the lips, nasal mucosa,
tongue, palms, and palate, but they also can be found
under the nails, on the soles of the feet, and even on the
tympanic membrane. They appear as dark red, slightly
elevated lesions with an ill-defined border and one or
more legs radiating from an eccentrically placed punctum. The lesions are often more prominent after blood
transfusion and may be missed in an anemic patient.33 In
patients with blue rubber bleb nevus syndrome, classically the skin lesions present in childhood but can develop later in life. They are usually blue in color and easily
compressible with light palpation. Complete compression classically results in an empty, slowly refilling sac.33
Other rare causes of obscure GI bleeding with cutaneous stigma are celiac disease (dermatitis herpetiformis),
acquired immunodeficiency syndrome (Kaposis sarcoma), PlummerVinson syndrome, tylosis, pseudoxanthoma elasticum (brittle spoon nails), EhlersDanlos syndrome (chicken skin appearance, angioid streaks in
retina), SchoenleinHenoch purpura, neurofibromatosis,
malignant atrophic papulosis (painless papules), and inherited polyposis syndromes. Reports of severe GI bleeding in patients with KlippelTrnaunayWeber syndrome
exist34,35; these patients can be identified during physical
examination because of the presence of hemihypertrophy
involving the extremities and external genitalia.

Investigations

AGA
INSTITUTE

A number of investigations can be undertaken to

define the etiology of obscure GI bleeding, and the choice
depends on the clinical presentation.
Repeat EGD and colonoscopy should be undertaken if
there is a suspicion of an overlooked lesion, particularly
if the fundus has not been well visualized on the initial
EGD. Detailed examination of the C-loop of the duodenum should be considered in patients with clinical suspicion of pancreaticobiliary pathology or previous aortic
aneurysm repair.
Small bowel examination can be performed with a
number of radiologic and endoscopic modalities. Radiographic techniques include barium studies, such as small
bowel follow-through and enteroclysis; nuclear studies,
such as tagged red blood cell scans and Meckels scan;
computed tomography (CT) and magnetic resonance imaging with enteroclysis; and angiography. Endoscopic
techniques include cable endoscopy techniques such as
repetition of standard endoscopy (EGD and colonoscopy), push enteroscopy, DBE, and cableless (wireless)
capsule endoscopy. Surgical procedures include exploratory laparotomy with and without intraoperative enteroscopy.

GASTROENTEROLOGY Vol. 133, No. 5

Repeat standard endoscopy. Lesions overlooked

during prior EGD, such as Camerons lesions, Dieulafoys
lesions, vascular ectasias, peptic ulcers, and gastric antral
vascular ectasias, account for up to half of the cases.6,36 38
Repeat EGD should be considered in patients with hematemesis and in those taking NSAIDs and the fundus
should be carefully examined, with special attention to
the site of diaphragmatic hiatus for Camerons lesion,
which remains an underrecognized etiology of obscure
GI bleeding. In addition, a transparent cap (band-ligator
cap after deploying the bands) fitted to the end of the
endoscope may serve as a retractor to examine the blind
areas of the upper GI tract, such as the posterior and
inferior wall of the duodenum, antrum, high lesser curve,
and anastomotic sites, for ulcers and is helpful in uncovering hidden ulcers.39 If a capsule endoscopy is performed, instead of repeating the EGD, careful review of
the capsule endoscopic images of the stomach and colon
might be useful in the detection of lesions missed on
prior EGD, such as gastric antral vascular ectasias and
inflamed pyloric canal polyps,40 although the capsule is
unlikely to reveal sources of bleeding that are only seen
on retroflexed view of the stomach.
Although the yield of repeat colonoscopy is low (6%), it
may be useful in the diagnosis of cancers that were
overlooked during initial endoscopy, especially in elderly
patients.41,42 Use of naloxone may improve the detection
of colonic angiectasias that were not obvious at index
examination.43 Close review of the capsule endoscopic
examination of the proximal colon may identify rightsided colon cancer and cecal angiectasias.40
In patients with a history of abdominal aortic aneurysm repair, the possibility of an aortoenteric fistula
should be seriously considered, and examination of the
C-loop of the duodenum, especially the third portion of
the duodenum, should be undertaken with a pediatric
colonoscope or an enteroscope. Endoscopic findings in
these patients may include blood clots in the second part
of the duodenum, an ulcer with black spots in the descending duodenum distal of the papilla of Vater, and
submucosal hemorrhages in the stomach, or they may
even be normal. Clear documentation of a fistula may not
be possible, and the delay in diagnosis and surgery could
be life-threatening.44,45
Endoscopy with duodenal biopsies is the mainstay for
diagnosing celiac disease. Although characteristic endoscopic features may be useful, their absence does not
exclude celiac disease. Random biopsy, even of normalappearing mucosa, is necessary for the diagnosis of celiac
disease.46 Magnification endoscopy with chromoendoscopy is a promising technique for the evaluation of patients with suspected malabsorption. This technique is
especially valuable in patients with partial atrophy, where
villous abnormalities can be patchy and the duodenum
usually appears normal during standard endoscopy.47
The yield of random small bowel biopsies in patients

with occult GI bleeding and iron deficiency anemia for

celiac disease may be as high as 12%.48,49
It is recommended that gastroenterologists use a sideviewing endoscope to examine the ampulla in patients
with hemobilia and hemosuccus pancreaticus.
Small bowel series and enteroclysis. The role of
small bowel series and enteroclysis in the evaluation of
obscure GI bleeding has declined substantially with the
advent of capsule endoscopy because of its extremely low
diagnostic yield. Compared with small bowel radiography, the diagnostic yield of capsule endoscopy is higher
in the detection of small bowel lesions (67% vs 8%; P
.00001) and clinically significant findings (42% vs 6%)
with a number needed to treat of 3.50,51 Neither of these
radiographic studies can diagnose angiectasias, which are
the most common cause of small intestinal bleeding.4,5,52
In a recent retrospective review of enteroclysis in 98
patients, it was believed to change management in only
10% of patients.53 In a study of 20 patients with obscure
GI bleeding, no patient with negative findings on capsule
endoscopy had positive findings on enteroscopy and
small bowel follow-through.54 Unless the clinical findings
suggest small bowel obstruction due to malignancy,
Crohns disease, or prior use of NSAIDs, there is no role
for either small bowel series or enteroclysis in the evaluation of obscure GI bleeding.
Cross-sectional imaging. Novel cross-sectional
imaging techniques for evaluation of small bowel include
helical CT enteroclysis, helical CT angiography, and magnetic resonance enteroclysis.
Helical CT enteroclysis combines standard enteroclysis
to distend the small bowel followed by helical CT.55 CT
enteroclysis is superior to magnetic resonance enteroclysis in the detection of small bowel pathology.56 Few
recent reports suggest the utility of helical CT in identifying small and large intestinal bleeding angiectasias.57,58
CT angiography involves catheterization of the abdominal aorta followed by helical CT angiography before
and after intra-arterial injections of a contrast medium,
and the site of hemorrhage is recognized as a hyperdense
area due to the extravasation of contrast medium in the
intestinal lumen. In a prospective study of 18 patients
with bleeding colonic angiectasias, the sensitivity, specificity, and positive predictive value of helical CT angiography were 70%, 100%, and 100%, respectively, when compared with a gold standard of colonoscopy and
mesenteric angiography.59 In a report of 22 patients with
obscure GI bleeding, CT enteroclysis was found to be
inferior to capsule endoscopy in the detection of potential bleeding lesions such as angiectasias in the small
bowel.60
Nuclear scans. The role of nuclear scans and, in
particular, technetium-99mlabeled red blood cell scans
continues to be limited in patients with obscure GI bleeding. The nuclear scans may be positive in a significant
proportion of patients presenting with rapid bleeding,

AGA INSTITUTE

1701

particularly in delayed images obtained 3 4 hours after

injection of the radioactive material. The ability to localize the source of bleeding, especially in the foregut, has
been repeatedly demonstrated to be poor.61
Angiography. The data on the clinical utility
of angiography in the specific setting of obscure GI
bleeding are very limited. Arguably, angiography may
detect both acutely bleeding and nonbleeding lesions
(particularly angiectasias, which often have characteristic
angiographic features) and also offers a therapeutic option with embolization if a bleeding lesion is identified.
There have been a few recent reports of provocative
angiography.62 64 A small case series suggests that although provocative angiography can be performed safely,
the overall yield of this technique is low.62
Endoscopic imaging. Until recently, most of the
small intestine has been relatively inaccessible to endoscopic imaging and therapy without surgery. Because of
the inability to localize a bleeding site in the small bowel,
early diagnosis of the bleeding site was rarely made in
patients with obscure GI bleeding. Complete endoscopic
imaging of the small intestine has certainly evolved from
an invasive intraoperative endoscopy to a noninvasive
examination of the entire small intestine with capsule
endoscopy. Recently, the development of DBE has allowed us to offer endoscopic hemostatic therapy without
the need for laparotomy. In between these 2 periods,
Sonde enteroscopy and push enteroscopy were utilized to
diagnose and manage this problem. The following sections describe each endoscopic modality and the evidence
that supports their use in patients with obscure GI bleeding. For assessment of procedural outcomes, case series
were not included.
Intraoperative enteroscopy. Intraoperative enteroscopy, involving insertion of an endoscope through an
incision in the mid-small intestine (enterotomy), was
initially performed in the 1950s with a sterile rigid sigmoidoscope passed through an operative colotomy or
enterotomy.65 By the 1970s, fiber-optic endoscopes were
being used intraoperatively.66 In 1980, Bowden et al performed intraoperative enteroscopy by passing a fiberoptic colonoscope first orally and then anally while the
surgeon manually telescoped the bowel over the tip of the
endoscope.67 The terminal ileum can be reached in more
than 90% of patients using this technique, while minimizing the mortality and morbidity associated with enterotomy for earlier intraoperative enteroscopy procedures.68 Unlike standard endoscopy, the mucosa should
be examined carefully during intubation because trauma
induced by insertion of the endoscope and bowel manipulation can be confused with angiectasias upon withdrawal of the enteroscope.
The diagnostic yield of intraoperative enteroscopy in
patients with obscure GI bleeding has ranged between
58% and 88% (Table 2).68 76 Laparoscopy and exploratory
laparotomy with intraoperative endoscopy remain im-

AGA
INSTITUTE

November 2007

1702

AGA INSTITUTE

GASTROENTEROLOGY Vol. 133, No. 5

Table 2. Yield of Intraoperative Enteroscopy in Patients With Obscure Bleeding

Author, year (reference)

No. of patients with

bleeding

Diagnostic yield
(%)

Yearly recurrence
(%)a

Mortality
(%)

Desa et al, 199169

Ress et al, 199271
Lopez et al, 199672
Zaman et al, 199968
Douard et al, 200073
Kendrick et al, 200174
Hartmann et al, 200575
Jakobs et al, 200676

12
44
16
14
25
70
47
81

83
70
88
58
81
74
72
84

30
60
12.5
43
38
48
N/A
N/A

17
11
0
0
4
6
2
0

aCalculated

from p 1 e(rt), where r represents rate and t represents time.

AGA
INSTITUTE

portant diagnostic tools for evaluation of an obscure

cause of GI bleeding.73,77,78 In a recent case series of 25
patients with obscure GI bleeding, intraoperative enteroscopy enabled complete evaluation of the small intestine
in all and resulted in a therapeutic intervention in 16
patients; over a 19-month follow-up period, there was no
recurrence of bleeding in the majority (70%) of these
patients.73 Intraoperative enteroscopy is associated with
significant morbidity, including ileus, and high mortality
rates up to 17%. Despite intraoperative enteroscopy,
bleeding has been reported to recur in 12.5% 60% of
patients because pathology is overlooked due to limited
visibility and/or due to the evanescent nature of ectasias.
Therefore, this technique currently is reserved as a last
option or if DBE cannot be successfully performed due to
the presence of abdominal adhesions or other technical
factors.
Sonde enteroscopy. Sonde enteroscopy involves peroral placement of a long (3-m) enteroscope with a distal
balloon into the proximal small intestine that is propelled by peristaltic activity into the ileum, thereby allowing the detection of bleeding lesions located beyond
the reach of push enteroscopy.79 81 Because of prolonged
examination (7 hours), patient discomfort, need for additional endoscopy staff to perform the procedure, and
inability to perform therapy, Sonde enteroscopy is rarely
used in clinical practice.82
Push enteroscopy. Video push enteroscopy is widely
used in the diagnosis and management of obscure GI
bleeding. Originally, adult or pediatric colonoscopes were
used to examine the proximal small intestine; subsequently, dedicated push enteroscopes were developed
with working lengths of 220 250 cm.83 85 Looping of the
enteroscope in the stomach results in patient discomfort
and limits the extent of the examination to 50 150 cm of
proximal small bowel. Use of an overtube has been shown
to prevent looping and improve the depth of insertion of
a push enteroscope but without an impact on diagnostic
yield.86,87
The diagnostic yield of push enteroscopy in
patients with obscure bleeding ranges from 3% to
70%.6,14 16,37,52,84,88 102 Angioectasias are the most common
lesions, identified in 7% 60% of examinations (Table 3). In

addition to the detection of lesions in the proximal small

intestine, push enteroscopy allows diagnosis of lesions
overlooked in the stomach and duodenum during prior
EGD in 6%37% of patients. Hence, it is important to
carefully examine the stomach and duodenum, if necessary with a standard upper endoscope before the push
enteroscopy, depending on the quality of the prior examination and experience of the endoscopist.37,102 In patients with angiectasia who underwent endoscopic therapy during push enteroscopy, bleeding cessation ranged
from 27% to 85% per year; however, more than half of the
clinical trials did not report cessation rates after endoscopic therapy. Outcomes of comparative studies of capsule endoscopy and push enteroscopy provide insight on
the role of these 2 imaging modalities in the evaluation
of the small intestine (Table 4).
Capsule endoscopy. An endoscopic capsule was initially developed to obtain images from the small bowel
(Given Imaging Ltd, Yoqneam, Israel). The present small
bowel capsules, which measure 11 26 mm, contain
light-emitting diodes, a lens, a color camera chip, 2 batteries, a radiofrequency transmitter, and an antenna.103
Depending on the manufacturer, the camera can be a
complementary metal oxide semiconductor chip or a
charge-coupled device. The capsule obtains images and
transmits the data via radiofrequency to a recording
device worn about a patients waist. Once the acquisition
time is reached, the recording device is downloaded to a
computer workstation whose software provides the images to the computer screen. The capsule is disposable
and does not need to be retrieved by the patient. It is
passed naturally. In addition to the images, software is
available to provide localization of the capsule based on
signal strength to the skin sensors, and other algorithms
can aid in the identification of blood or vascular lesions.
Small bowel obstruction is a contraindication for capsule
endoscopy. In patients with swallowing disorders, the
capsule can be placed into the duodenum directly using
a capsule-loading device. Small case series have suggested
that capsule endoscopy is safe in patients with pacemakers104,105 and defibrillators,106 although patients should
be carefully monitored during the capsule examination.
The cost-effectiveness of the capsule endoscopy study in

November 2007

AGA INSTITUTE

1703

Table 3. Selected Studies Using Push Enteroscopy for Obscure GI Bleeding

Author, year (reference)

No. of patients and type

of bleeding

Diagnostic
yield (%)

Examinations with
angiectasias (%)

Endoscopic
therapy (%)

Bleeding cessation
per year/patients
with angiectasias
(%)a

Foutch et al, 199084

Chong et al, 199415
Pennazio et al, 199514
Davies et al, 199516
Schmit et al, 199688
Adrain et al, 199889
Zaman et al, 19986
Shackel et al, 199890
Descamps et al, 199937
Hayat et al, 200091
Sharma et al, 200092
Landi et al, 200293
Lewis et al, 200294
Ell et al, 200295
Mylonaki et al, 200396
Saurin et al, 2003 52
Keizman et al, 200397
Romelaer et al, 200498
Adler et al, 200499
Mata et al, 2004100
Pennazio et al, 2004101
Lara et al, 2005102

20 overt, 19 occult
55 overt
21 overt
11 overt, 7 occult
37 overt, 46 occult
41 overt
75 overt, 20 occult
23 overt, 21 occult
110 overt, 123 occult
50 occult, 28 overt
21 overt, 5 occult
49 overt, 56 occult
21 overt
32 overt
50 overt
28 overt, 32 occult
36 overt, 57 occult
66 overt, 53 occult
20 occult
26 overt, 16 occult
34 overt, 17 occult
44 overt, 19 occult

15 (38)
35 (64)
9 (43)
6 (33)
49 (59)
32 (78)
39 (41)
23 (52)
125 (53)
43 (78)
9 (43)
49 (47)
6 (30)
9 (32)
16 (32)
3 (3)
51 (40)
50 (42)
5 (25)
8 (19)
15 (29)
35 (56)

31
4
38
11
40
49
46
65
63
26
4.7
37
30
22
20
7
35
66
10
9.5
N/A
30

92
N/A
12.5
100
42
N/A
61
73
N/A
100
N/A
44
100
14
N/A
N/A
100
76
100
50
N/A
100

44
N/A
N/A
N/A
38
27
60
40
N/A
70
N/A
70
N/A
N/A
N/A
N/A
85
76
60
N/A
N/A
N/A

N/A, not available.

aCalculated from p 1 e(rt), where r represents rate and t represents time.

the evaluation of patients with obscure GI bleeding may

be increased by the preview of the recordings by an
endoscopy nurse or an assistant.107109
In a pilot study by Appleyard et al in 2000, radioopaque beads were sewn into canine small bowels to
compare the diagnostic yield between push enteroscopy
and capsule endoscopy. Capsule enteroscopy identified
more beads overall (64%) compared with push enteroscopy (37%), although push enteroscopy was found to be
more sensitive for bead detection in the first meter of the
examination (94% compared with 53% for capsule).110 In
a prospective comparative study, capsule endoscopy un-

derestimated the number of small bowel polyps in persons with familial adenomatous polyposis compared
with push enteroscopy.111 Therefore, negative findings on
a capsule endoscopic examination do not exclude pathology in the small intestine. Because lesions limited to 3 4
frames may be easily missed, it is important to review the
capsule endoscopy at a slower frame rate to detect subtle
lesions.112
Published experience has shown that capsule endoscopy identifies causes of blood loss in the small bowel
twice as often as push enteroscopy. There have been 10
published studies comparing capsule endoscopy with

Table 4. Push Enteroscopy Compared With Capsule Endoscopy

Push enteroscopy
positive (%)

Capsule endoscopy
positive (%)

Lewis and Swain, 200294

Ell et al, 200295
Mylonaki et al, 200396
Saurin et al, 200352
Hartmann et al, 2003113
Adler et al, 200499
Mata et al, 2004100
Ge et al, 2004184
Pennazio et al, 2004101
Neu et al, 2005185
Totals

21 overt
32 overt
50 overt
28 overt, 32 occult
33 overt
20 occult
26 overt, 16 occult
32 overt
34 overt, 17 occult
37 overt, 19 occult
397

6 (30)
9 (28)
16 (32)
3 (3)
7 (21)
5 (25)
8 (19)
9 (25)
15 (29)
15 (38)
93 (23)

11 (55)
21 (66)
38 (76)
21 (35)
25 (76)
14 (70)
31 (74)
21 (66)
30 (59)
38 (68)
250 (63)

N/A, not available.

Findings on both push

enteroscopy and
capsule endoscopy (%)
6 (30)
6 (19)
N/A
19 (32)
31 (94)
N/A
8 (19)
9 (25)
12 (24)
N/A

Additional capsule
yield (%)
25
38
44
32
55
45
55
41
30
30
39.5

AGA
INSTITUTE

Author, year (reference)

No. of patients and

type of bleeding

1704

AGA INSTITUTE

AGA
INSTITUTE

push enteroscopy in the evaluation of patients with obscure GI bleeding.52,94 96,99,100,113,114,184,185 All 10 studies
were prospective, and 7 were blinded. Together, these
reports show a 63% (250/297) yield for capsule endoscopy
and a 23% (93/397) yield for push enteroscopy. A pooled
analysis of raw data from manufacturer-sponsored trials
showed that capsule endoscopy has a significantly increased capability to detect pathology as compared with
push enteroscopy, small bowel series, and colonoscopy
with ileal intubation.117 Capsule endoscopy identified
pathology in approximately 70% of the examinations in
the pooled data analysis of 530 capsule examinations.
This was double the yield of other methods. Approximately 90% of 1349 pathologies were not identified by
any other method other than capsule endoscopy. A metaanalysis of both published trials and abstracts also attests
to this increased yield.51 A total of 14 studies comparing
capsule endoscopy with push enteroscopy were reviewed,
with a combined yield of 63% for capsule endoscopy and
28% for push enteroscopy.
The validity of the findings made by capsule endoscopy
was confirmed by a prospective study comparing capsule
endoscopy with what has been considered the gold standard in small bowel visualization, intraoperative endoscopy, in 47 patients.75 The overall yield for capsule endoscopy was 74%, and the overall yield for both
procedures was 76.6%. Bleeding sites were identified by
both techniques in 36, by capsule only in 2, and by
intraoperative enteroscopy only in 1. The findings of
both examinations were negative in 11. The calculated
sensitivity for capsule endoscopy was 95%, specificity was
75%, and positive and negative predictive values were 95%
and 86%, respectively.
Long-term follow-up studies have allowed calculation
of sensitivity and specificity for capsule endoscopy by
obtaining a final diagnosis during the follow-up period.
Pennazio et al reported a 1-year follow-up of 100 patients
with obscure bleeding.101 Sensitivity, specificity, and positive and negative predictive values of capsule endoscopy
were 89%, 95%, 97%, and 83%, respectively, in the 56 patients
in whom a definite confirmed diagnosis was obtained. Delvaux et al reported 1-year follow-up experience in 44 patients.118 The positive predictive value of capsule endoscopy
was 94.4% in those with findings at capsule endoscopy,
and the negative predictive value was 100% in patients
with normal findings on capsule examination.
In addition to the ability of capsule endoscopy to make
more diagnoses with accuracy, its therapeutic impact has
begun to be measured. Kraus et al reported that in 33% of
cases, findings on capsule examination guided additional
diagnostic and therapeutic steps.119 Ben Soussan et al
reported that in 37% of examinations, new steps in management were undertaken, including endoscopic management in 10, surgery in 2, and medical therapy in 1.120
Mylonaki et al reported that capsule endoscopy led to an
alteration of therapy in 66% of patients with positive

GASTROENTEROLOGY Vol. 133, No. 5

findings.96 Pennazio et al reported that in 20 of 23 patients in who capsule endoscopy was performed for ongoing-overt bleeding, directed treatments led to resolution of bleeding in 87%.101 Overall, follow-up data on 91
patients during a mean follow-up period of 18 months
showed that subsequent management dictated by capsule
endoscopy led to the resolution of bleeding in 59 (65%).
There is a lack of other published data concerning outcomes following capsule endoscopy and subsequent interventions. There are no published data to date on the
rate of continued bleeding or further testing initiated. In
addition, the recurrence of angiectasias after endoscopic
therapy is currently unknown.
Investigators have looked at patient selection for capsule endoscopy to determine if this influences the yield of
the examination. Bresci et al reported a greater yield for
capsule endoscopy (91% vs 34%) if capsule endoscopy
were performed within 2 weeks of a bleeding episode.121
May et al reported that patient selection for capsule
endoscopy also affected yields.122 Patients who had been
enrolled in a study of capsule endoscopy in which inclusion criteria included a decrease in hemoglobin level less
than 10 g, anemia, or bleeding persisting for more than 6
months and the occurrence of more than 1 bleeding
episode were more likely to have a source of bleeding
identified. None of the patients who had a minimum
hemoglobin value 10 g/dL had a positive capsule
result.122
Provocation of bleeding using anticoagulation may
increase the detection of lesions during capsule endoscopy, as reported in 2 cases recently.123
Despite extensive literature concerning the effectiveness of this technology, most overlook the importance
and intensity of examining the obtained images.124 Typical examinations obtain images over 8 hours. Because
images are obtained at a rate of 2 images per second, a
total of 57,600 images are produced. The computer workstation allows images to be viewed singly or as a video
stream. Although obtained at 2 images/second, images
may be reviewed up to 40 images/second. Because an
abnormality may be present on only one image, most
physicians familiar with the system believe that lesions
could easily be missed at the faster rates. A single image
is only on the monitor for less than 2/100th of a second
when viewing at 40 images/second. A consensus conference of users in 2002 agreed that 15 frames/second is the
fastest acceptable rate of review. At this rate, 57,600
images can be seen in 64 minutes. This only takes into
account running the images as a video without stopping
to examine individual images. Lewis and Swain reported
the viewing times of 20 examinations performed using
the Given system (Given Imaging Ltd). They averaged 56
minutes to review only the small bowel images, with a
range of 34 94 minutes.94 Ell et al also reported taking
an average of 50 minutes in examining the small bowel
data of 32 patients.95 The range was from 30 to 120

minutes. Costamagna et al reported taking 2 hours to

review each study.50 It was unclear in this study if the
images reviewed included the gastric and colonic portions. In an effort to shorten the review time, software
has been developed to allow the reader to view 2 or 4
images simultaneously. Dual image reading places 2 images, one full second of image collection, on one screen,
side by side, while a quad view places 4 images or 2
seconds of imaging on each screen. This could theoretically shorten the reading time by as much as 50%. In
addition to the length of time the review takes, physicians are also concerned about reading the studies properly and not missing lesions. To aid physicians in this
regard, software has been added to the system to identify
red pixels as suspected bleeding areas.
In addition to vigilance, physicians must have experience in interpreting endoscopic images. Only one part of
capsule endoscopy is the vigilant reader, who is able to
identify an area that is different or abnormal from other
areas examined. An equally important part of the examination is the proper identification of these abnormalities. The reader must be able to make a diagnosis based
on the images. This will allow the dismissal of normal
variants and nonpathologic lesions and the identification
of specific pathologies requiring specific therapies. The
images obtained at capsule endoscopy are slightly different from traditional endoscopy because there is no air
distention of the bowel wall and the capsule is at times
located within millimeters of the mucosa. This is socalled physiologic endoscopy. The bowel is not altered
by the process of the examination. There is no sedation
used, and thus there are no hemodynamic effects. There
is no trauma caused by the capsule. There is no air
insufflation to affect the microvasculature. Thus, all findings are real and their location has not been altered by
the examination. Expertise must be obtained to allow
review of the images not only in an efficient manner but
also to provide a precise diagnosis.
There are specific problems when interpreting some
capsule images. These include single image abnormalities, proper identification of submucosal processes, and
differentiating dark blood from dark bile. Unlike traditional endoscopy, a single image abnormality cannot be
viewed from different angles but rather must be identified by a single 0.5-second image. This is dependent on
experience and confidence of the reader. Equally troubling, a submucosal lesion can be mistaken for the bulge
created by another loop of bowel overlying the loop being
inspected. There are visual cues that allow for this differentiation. The presence of bridging folds speaks to a
submucosal process. Capsule images can also clearly
show the stretching of the mucosa as well as mucosal
edema. Conversely, overlying loops can be suspected
when the indentation moves with peristalsis, indicating
its softness. Bubbles from bile could interfere with the
capsule endoscopic examination, which could be avoided

AGA INSTITUTE

1705

with the use of simethicone before the examination.125

Dark bile is another situation that can be difficult to
interpret because it can be mistaken for dark blood. This
is avoided by examining the mucosa beyond the stained
area to see if coffee ground or bloody material is seen.
Its absence indicates likely bile proximally. Endoscopically evident small intestinal mucosal injury is very
common among chronic NSAID users, which can complicate the interpretation of images in arriving at a
final diagnosis.126,127
Patients with ongoing hospitalization may be at risk of
retention of the capsule in the stomach for a prolonged
period. This could be prevented by the use of prokinetics
before capsule ingestion or endoscopic delivery of the
capsule in patients with gastric outlet obstruction.128 131
Although small intestinal capsule retention has not been
reported in normal subjects or those with diverticulosis,
capsule retention can occur in less than 1% of patients
due to localized pathology.132,133 Sources of bleeding can
be localized in all the cases with capsule retention in the
small intestine. A history of NSAID use may be associated
with an increased risk of capsule retention.133 Although
the majority of patients with capsule retention are
asymptomatic, complications such as aspiration, retention in Zenkers diverticulum, intestinal perforation, and
obstruction have been reported.134 137 Retained capsules
may be removed by endoscopy or surgery.138,139 Patients
should not undergo magnetic resonance imaging until
they have passed the capsule, which can be easily confirmed by a plain radiograph if necessary.
The International Conference on Capsule Endoscopy
produced a consensus statement on obscure GI bleeding.115 Their conclusion was as follows:
capsule endoscopy is currently the preferred test for mucosal imaging of the entire small intestine and should be part of the initial
investigation in patients with obscure bleeding. Its diagnostic yield
is high and potentially it can produce earlier diagnosis. When
integrated into a global approach to the patient, capsule endoscopy
is helpful in achieving effective decision-making concerning subsequent investigations and treatments. This in turn could mean more
timely treatment and lower overall utilization and cost. Large prospective studies are however necessary to better assess the impact of
capsule endoscopy on clinical outcomes.

DBE. DBE, first described by Yamamoto et al in

2001, allows complete visualization of the small intestine
using a 200-cm enteroscope with an OD of 8.5 mm
equipped with a 140-cm overtube with an OD of 12 mm
(Fujinon Inc, Saitama, Japan).116 Latex balloons at the tip
of the enteroscope and the overtube are inflated and
deflated with air from a pressure-controlled pump system. By inflating the overtube balloon enough to grip the
intestinal wall (which can occur at a balloon pressure of
45 mm Hg), the endoscope can be inserted further without forming redundant loops in the small intestine. The
overtube can then be inserted while the endoscope balloon is inflated. This method allows for insertion of the

AGA
INSTITUTE

November 2007

1706

AGA INSTITUTE

GASTROENTEROLOGY Vol. 133, No. 5

Table 5. Yield of DBE in Patients With Obscure GI Bleeding

Patients with bleedinga/
DBE examinations (%)

Diagnostic
yield (%)

Diagnostic or
treatment
success (%)

Yamamoto et al, 2004142

66/178 (37)

76

61

86

N/A

May et al, 2005140

Ell et al, 2005144
Di Caro et al, 2005145
Matsumoto et al, 2005151
Mehdizadeh et al, 2006141

90/248 (36)
64/147 (44)
33/89 (37)
13/22 (59)
130/237 (55)

80
72
80
46
43

76
62
42
N/A
60

45
16
44
14
0

N/A
N/A
N/A
N/A
N/A

Hadithi et al, 2006146

Heine et al, 2006147

35/35 (100)
168/275 (61)

60
73

77
55

20
42

20
N/A

Kaffes et al, 2006148

32/40 (80)

48

75

N/A

Monkemuller et al, 2006149

29/70 (41)

67

57

30

Nakamura et al, 2006150

32/28 (100)

41

43

62.5

74
65

74
64

29
29

Author, year (reference)

Manabe et al, 2006152

Totals

31/31 (100)
723 patients, 1400
examinations

Total DBE
(%)b

Rebleed rate
(%)

91

Complications
Perforation, 1
(0.6)
None
None
None
None
Perforation, 1
(0.4)
None
Pancreatitis,
3 (1)
Perforation, 1
(2.5)
Polypectomy
bleed, 1
(1.4)
Perforation, 1
(3.6)
None
Perforation, 4
(0.3)

N/A, not available.

patients with obscure overt and/or obscure occult bleeding.
bDefined as initial DBE from one approach with tattoo at most distal insertion point followed by DBE from opposite direction with prior tattoo site
identified.
aIncludes

AGA
INSTITUTE

endoscope deep into the small intestine and is also

known as push-and-pull enteroscopy.
To estimate the mean depth of insertion during a DBE
examination, 2 methods have been proposed. In the first
method, which has been the most commonly used, the
length of endoscope advancement in each round of the
push-pull cycle is added; the distance lost if slippage
occurred is estimated and subtracted to calculate a metric
measure of the length of the small bowel examined.
Using this method, the mean (SD) distance achieved
was 240 100 cm during the antegrade approach and
140 90 cm for the retrograde approach in the study by
May et al, with mean examination times of 72.5 23
and 75 28 minutes, respectively.140 In the US multicenter trial, the estimated depths of insertion were
360 178 cm for the oral DBE examinations with a
mean examination time of 95 41 minutes and 182
165 cm for the retrograde DBE examinations with a
mean examination time of 102 38 minutes. In the
second method, information from contrast injection
during fluoroscopy and position of the tip of the DBE
scope was used to estimate the farthest reach of the
endoscope. Per-oral examinations achieved a mean distance of 360 177 cm from the pylorus in the 4
centers in the US multicenter study.141
Except for rare instances, complete small bowel enteroscopy with cecal intubation by the antegrade approach alone is not feasible. In addition, total enteroscopy, defined as initial DBE from one approach with

India ink tattooing using a sclerotherapy needle at the

furthest insertion point followed by a DBE in the opposite direction with visualization of the tattoo mark, is not
necessary. In the initial series by Yamamoto et al where
total enteroscopy was the goal,142,143 there was success in
24 of 28 patients (86%). However, in the subsequent series
from Germany,140 total enteroscopy was only achieved in
45% of examinations, primarily due to time limitations
for each endoscopic examination. In the series by May
et al, total enteroscopy was indicated in less than 50% of
the patients because the diagnostic yield was approximately 80% from the initial examination. Published studies examining outcomes associated with DBE are shown
in Table 5.140 142,144 152 Overall, total enteroscopy was
performed in 29% of the DBE examinations.
Because the majority of the lesions responsible for
obscure GI bleeding are located in the proximal small
bowel and the retrograde approach is more technically
challenging due to the floppy nature of the enteroscope,
it is preferable to start the procedure with the oral route
unless other imaging modalities suggest a lesion in the
ileum. As described previously, there is no need for anal
DBE after a successful oral procedure in the majority of
patients. Enteroscopic examination of the entire small
intestine (total enteroscopy), using a combination of antegrade and retrograde approaches, if necessary, should
be attempted on different days to minimize patient discomfort from both procedures in one setting, which tend
to be prolonged.

No specific preparation is required for the oral approach, while bowel cleansing is required for the anal
approach. Although many centers have performed the
procedure using general anesthesia, the procedure can be
safely performed under conscious sedation. DBE via the
anal approach can be challenging due to bowing of
the floppy enteroscope and difficulty in maintaining the
enteroscope proximal to the ileocecal valve for successful
ileal intubation. In addition, poor colon preparation limits advancement through the colon, and adhesions from
previous surgery or radiation may limit endoscope insertion. The failure rate of the anal approach and retrograde
ileal intubation varies from 5% to 30%.145 The learning
curve for retrograde DBE examinations appears to be
steep but has not been quantified. Successful reduction
of colonic loops starting early during the procedure and
continuing until entrance into the ileocecal valve and
keeping a relatively straight position of the endoscope
may improve the ileal intubation rate. Introduction of a
stiffer double-balloon therapeutic enteroscope did not
improve ileal intubation rates. Recently, a balloon-assisted technique has been proposed as an aid for ileal
intubation.153
DBE is safe. There are no deaths reported to date, and
the morbidity is low. Intestinal perforation occurred in 4
of 1378 procedures (0.3%): one patient with intestinal
lymphoma undergoing chemotherapy,142 another patient
with a recent laparotomy who sustained a peristomal
perforation,141 a third patient after cautery of an angiectasia,148 and a fourth patient with a duodenal perforation.150 Mild pancreatitis possibly due to duodenal hypertension from double-balloon inflation was reported in
3 patients.147,154 Prolonged ileus lasting for 4 days was
reported in a patient after DBE.155
Training in the use of DBE can be accomplished by
observation of live cases followed by hands-on training
using porcine specimens on the Erlangen Endo-Trainer.
The European experience of DBE hands-on training of 97
participants in 13 workshops using the Erlangen EndoTrainer is encouraging.156 The evaluation of the depth of
measurement method during the workshops using the
100-cm and 200-cm insertion points showed that the
estimation of the insertion depths was accurate, with a
mean deviation of 10%. Such a training program might
be useful in providing training to US gastroenterologists.
Fluoroscopy is useful during the early training period to
guide endoscope passage, confirm final endoscope tip
position, and monitor and reduce any looping of the
enteroscope that may occur during the procedure. After
the first 10 cases of DBE, both the procedural time
(109 44.6 minutes initially and 92.4 37.6 minutes
after 10 cases; P .005) and the use of fluoroscopy
decreases significantly.141 Although there is no significant
change in the anal DBE procedure time, the antegrade
examination time decreases significantly after the first 7
cases (P .003).

AGA INSTITUTE

1707

Based on the current published data on DBEs, 723

patients have undergone 1400 DBE examinations with an
average diagnostic yield of 65% and diagnostic or treatment success of 64%. Obscure bleeding was the indication for DBE in approximately 36%100% of examinations, and the overall diagnostic yield from DBE ranged
from 43% to 80%. Diagnostic or therapeutic success was
reached in 55%75% of examinations, which is comparable to other diagnostic modalities for the small bowel.
Patients with obscure bleeding as an indication for DBE
have a higher success rate. Data regarding rebleeding
rates after endoscopic or other therapy for angiectasias
are needed for DBE, as for all of the other endoscopic
modalities.
In 8 of the 12 DBE studies published to date (Table 5),
specific findings were detailed for 488 patients presenting
with obscure bleeding. In total, angioectasias were found
in 153 (31%) of examinations (range, 6%55%), ulcerations (including inflammatory bowel disease) in 66 patients (13%; range, 2%35%), malignancies in 40 patients
(8%; range, 3%26%), other etiologies (including small
bowel diverticula) in approximately 28 (6%; range, 2%
22%), and no findings in 198 patients (40%; range,
0 57%). In the study by Manabe et al, 91% of the patients
treated endoscopically or surgically for a bleeding source
did not have any further bleeding over a mean of 8.5
0.6 months (range, 4 14 months).152
Three studies to date have compared capsule endoscopy with DBE for patients with obscure GI bleeding.141,146,150 In all 3 studies, the yield for capsule endoscopy was higher than that for DBE. The reasons for the
higher yield on capsule endoscopy include complete visualization of the small bowel and potential false-positive
lesions that are not confirmed on DBE, including nonspecific red spots. The agreement between capsule endoscopy and DBE has ranged between 61% and 74%. In
the US multicenter trial, the agreement was calculated to
be 74% for angioectasias, 96% for ulcerations, 94% for
mucosal and submucosal polyps, and 96% for large tumors.141 Using the statistic, the agreement for 115
patients who underwent both capsule endoscopy and
DBE was substantial for ulcers and large masses (0.74
and 0.59, respectively) but only moderate for angioectasias (0.42) and poor for mucosal polyps (0.2), potentially
due to false readings of mucosal bulges on the capsule
endoscopy examinations. The calculated miss rates were
28% for DBE and 20% for capsule endoscopy. In another
study examining 13 patients with GI bleeding and 9
patients with polyposis, patients were examined by DBE
followed by capsule endoscopy within 1 week.151 Patients
who had a positive capsule endoscopy underwent a repeat DBE from the opposite approach. In the patients
with obscure bleeding the agreement was 92%, whereas
the yield in patients with polyposis was 67% for DBE
compared with 33% for capsule endoscopy. More com-

AGA
INSTITUTE

November 2007

1708

AGA INSTITUTE

parative studies are warranted for the 2 diagnostic modalities in patients with obscure bleeding.
In summary, DBE appears to have superior diagnostic
capability compared with push enteroscopy and equivalent yield compared with intraoperative enteroscopy
without the associated morbidity of the latter procedure.
While DBE does not allow visualization of the entire
small bowel in one examination compared with capsule
endoscopy, it has been shown to be associated with an
equivalent detection rate, has the capability to detect
lesions missed by capsule endoscopy, and offers the advantages of therapeutic treatment. With the advent of
DBE, intraoperative enteroscopy can be relegated to the
archives of diagnostic procedures along with Sonde enteroscopy, except for cases where the success of DBE is
limited by the presence of adhesions or other anatomic
factors.
A single-balloon enteroscopy is currently undergoing
evaluation and will be released into the market soon.

Cost

AGA
INSTITUTE

The current medical literature lacks sufficient information concerning the costs associated with diagnosing obscure GI bleeding. The most comprehensive review
of the economic literature for the period from 1985 to
1995 has limited information of value in understanding
the costs and was not limited to obscure bleeding.157
There are various issues that contribute to the medical
costs incurred in these patients. It may take considerable
time to diagnose a patient with obscure bleeding. The
median time to diagnose patients with obscure bleeding
has been estimated as 2 years, with a range from 1 month
to 8 years. In addition to this extended time to diagnosis,
patients undergo numerous diagnostic tests and evaluations before a bleeding source is identified. Foutch et al
reported that 39 patients undergoing push enteroscopy
for unidentified obscure bleeding had a total of 277
diagnostic tests performed before study entry.84 This was
an average of 7.3 tests per patient. In this study, 49% of
the patients continued to have an unknown bleeding
source after push enteroscopy. The difficulties in locating
the bleeding site with currently available diagnostic tools
often result in the need for repeat testing, thus increasing
the economic burden of obscure bleeding. In addition,
patients with obscure bleeding may require blood transfusions and repeated hospitalizations. Flickinger et al
reported 14 patients with obscure bleeding who had an
average of 5 hospital admissions and an average of 46
units of blood transfused before undergoing intraoperative enteroscopy.158
In an attempt to calculate the cost of obscure GI
bleeding, Goldfarb et al reported costs incurred in 21
patients with obscure bleeding.159 The mean length of
time from first recognition of bleeding to study entry was
2.7 years. One patient who had gone 12 years since first
bleed was excluded in this calculation. Because actual

GASTROENTEROLOGY Vol. 133, No. 5

cost and charge data were not available, costs from a

payer reimbursement perspective were based on average
Medicare fees. For example, for hospitalizations, the average Medicare reimbursement for DRG 174 (GI hemorrhage with complications or comorbid conditions) is
$4264. Commercial reimbursements would be significantly higher. Transfusion costs were based on a prior
economic analysis. The costs associated with diagnosing
obscure bleeding and treating the anemia were significant, averaging $33,630 per patient without a diagnosis
made in capsule study patients before entry. Furthermore, data on other utilizations contributing to direct
medical costs, such as physician visits, emergency
department visits, and prescriptions, were not collected
as part of the trial. Therefore, it appears that these figures
significantly underestimate the total cost of care and
diagnosis of patients with obscure GI bleeding.
Recently, Kamal and Gerson published a cost-effectiveness analysis examining potential strategies for the diagnosis and management of bleeding small bowel angioectasias.160 The base-case patient for the analysis was a
70-year-old patient with obscure overt bleeding from
small bowel angioectasias. The diagnostic and treatment
alternatives in the model included (1) no therapy (reference arm); (2) push enteroscopy; (3) intraoperative enteroscopy; (4) angiography; (5) initial empirical DBE via
the oral approach, followed by repeat DBE via the rectal
approach if the oral examination was normal; and (6)
small bowel capsule endoscopy followed by DBE using
the approach dictated by capsule findings. Cost estimates
were obtained from a third-party payer perspective. Primary outcome measures were number of patients with
cessation of bleeding, average cost per patient, and procedural complications. Patients in the reference arm or
with unsuccessful treatment were assumed to have ongoing transfusion requirements of 2 units/month.
The results of the model demonstrated that capsuledirected DBE and the initial DBE strategy were equally
effective, but the initial DBE arm was less expensive and
was the most cost-effective approach with an incremental
cost-effectiveness ratio of $1653 per patient successfully
treated. Assuming a cohort of 1000 patients with obscure
bleeding from small bowel angioectasias, approximately
741/1000 (74%) would have cessation of bleeding in the
DBE arm over the course of 1 year with a per-patient cost
of $1717 compared with a 40% bleeding cessation rate at
a cost of $1171 per patient for the no therapy arm.
Sensitivity analyses demonstrated that capsule-directed
DBE would be the preferred approach if there was a
probability of 85% or greater that an angioectasias would
be detected on capsule endoscopy and a probability of
62% or less that an angioectasias would be detected on
DBE. Angiography would be the preferred approach if
the probability of finding a lesion on angiography exceeded 85%, if the success rate associated with DBE was
64% or less, or if the probability of finding an angioecta-

sias on DBE was 35% or less. Intraoperative enteroscopy

was preferred if the success rate after treatment exceeded
80%. The investigators concluded that for patients with
obscure occult bleeding from small bowel angioectasias,
initial DBE is a cost-effective approach. More research
examining the ideal strategies for patients with obscure
bleeding and the effect of obscure bleeding on healthrelated quality of life is warranted.

Management
The American Gastroenterological Association
medical position statement concerning the evaluation
and management of obscure GI bleeding was published
in January 2000, before the initial studies utilizing capsule endoscopy and DBE.1 The position statement proposes progressive testing with bleeding scans and angiography for those patients with active bleeding, as well as
repeat endoscopy, enteroscopy, enteroclysis, or small
bowel series for those not actively bleeding. With continued blood loss, intraoperative enteroscopy is suggested.
This guideline is similar to the management of the 21
patients reported by Goldfarb et al.159 The costs of this
type of management were at least $33,630 per patient
without a diagnosis made. This paradigm of progressive
testing has become obsolete with the availability of capsule endoscopy and DBE during the past 5 years.
The extent of the evaluation of the patient with obscure bleeding is dependent on 2 major factors: the extent
of the bleeding and the age of the patient. Patients with
occult blood in their stool but no associated anemia most
likely do not require evaluation beyond colonoscopy unless upper tract symptoms are present. Certainly advanced testing beyond colonoscopy and upper endoscopy
is not warranted in this group. Patients with an ongoing
transfusion requirement need a full evaluation. The most
common cause of obscure bleeding in this group is angiectasias, accounting for up to 80% of causes. These
patients are typically older than 60 years. Small bowel
tumors are the most common cause of obscure bleeding
in patients younger than 50 years. Young patients should
be handled differently than older patients. Management
decisions in the older group are often quite difficult
because the natural history of angiectasias is still not
known. It is estimated that less than 10% of all patients
with angiectasias will eventually bleed. Once lesions have
bled, their tendency to rebleed is also not known. Although physicians are anxious to treat these lesions, it
may be that as many as 50% will not rebleed.
In the patient presenting with obscure GI bleeding
with either positive fecal occult blood testing and associated anemia or overt bleeding with melena or maroon
blood per rectum, colonoscopy and upper endoscopy
should be performed. Barium studies can be considered
but should not replace endoscopic examinations. In the
face of continued bleeding and initially negative findings
on colonoscopy and upper endoscopy, repeated endo-

AGA INSTITUTE

1709

scopic examinations can be worthwhile. Repeated barium

studies are not indicated. Once all the standard examinations are negative, the small bowel may be assumed to
be the source of blood loss.
Worldwide experience suggests that capsule endoscopy
is the preferred method of small bowel evaluation due to
the length of the small bowel examined, the quality of the
examination, and the noninvasive nature of the test.
Capsule endoscopy should be the third test in the evaluation of patients with GI bleeding, once findings on
upper endoscopy and colonoscopy are negative. In the
patient with active bleeding, capsule endoscopy can confirm the small bowel as the site of bleeding, providing a
location. Even if the study findings are negative for the
small bowel in the actively bleeding patient, the study
may indicate that the bleeding is actually colonic or even
gastric in origin. In the patient with active bleeding
within the small intestine, the capsule will guide further
evaluation and therapy. A patient with a small bowel
tumor detected by capsule endoscopy will proceed directly to laparoscopic surgery. If the site of bleeding is
identified in the proximal small bowel and there is no
mass, push enteroscopy will be used to reidentify the site
and cauterize the lesion. In cases where a distal small
bowel site is identified, surgical intervention coupled
with intraoperative enteroscopy or DBE will be necessary.
Because the entire small bowel has been examined with
the capsule examination, both examinations can be targeted and for surgery a laparoscopic-assisted approach
coupled with intraoperative enteroscopy would only examine the suspected area. In patients with isolated iron
deficiency or a more occult or intermittent type of bleeding, capsule endoscopy should be used similarly to identify an intestinal bleeding lesion and thereby direct subsequent testing or treatment. The early diagnosis of
tumors of the small bowel will be obtained, and those
with negative examinations will be reassured. Given the
possibility of overlooked lesions on capsule endoscopy, it
is critical to follow up the patients carefully and, if
necessary, either a repeat examination with a capsule
endoscope or enteroscopy should be considered. Although outcomes studies are needed, it would appear
that the early use of capsule endoscopy would not only
allow more rapid diagnosis and thus improved patient
care but could also lessen the costs associated with obscure bleeding. Repeated colonoscopy and upper endoscopy would be avoided and, with a diagnosis, repeat
hospitalizations and transfusions could be averted.
The major difficulty that will remain in the future is
the patient with diffuse vascular lesions of the bowel or
the patient with a distal lesion who cannot tolerate or
will not permit surgical intervention. Fortunately, such
patients are quite uncommon. Berner et al reported the
results of enteroscopy in 450 patients with obscure bleeding.81 Only 4 patients had vascular lesions in the stomach, duodenum, jejunum, and ileum. Diffuse illness of

AGA
INSTITUTE

November 2007

1710

AGA INSTITUTE

GASTROENTEROLOGY Vol. 133, No. 5

OBSCURE GASTROINTESTINAL
BLEEDING
Occult

Overt

Second-look
Endoscopy
massive bleeding

Negative

Capsule Endoscopy
Negative
Further work-up needed?

SPECIFIC MANAGEMENT

Yes

No
Observation
Medical treatment

Recurrence

Repeat routine endoscopy/CE

Meckels scan
Laparoscopy / IOE

Yes

Angiography

Positive

Negative

Medical treatment
PE or DBE + cauterization
Angiography + embolization
Laparoscopy / IOE

Positive

No
No further
work-up

Follow-up

SPECIFIC
MANAGEMENT

Figure 1. Proposed algorithm for the diagnosis and management of

obscure GI bleeding. PE, push enteroscopy; IOE, intra-operative enteroscopy; CE, capsule endoscopy. Adapted from Pennazio et al.115
(Color version of this figure available online at www.gastrojournal.org)

AGA
INSTITUTE

the bowel may suggest the presence of a systemic illness

such as HHT or cirrhosis. Medical therapy of vascular
lesions is contrary to general present practice. Endoscopic or surgical therapy is considered best at present
due to its ease, relatively good long-term results, and the
lack of a clearly effective, well-tolerated medical therapy
(Figure 1).
The natural history of vascular lesions in the small
bowel has not been well characterized. On close review of
the placebo-controlled trials of hormonal therapy in the
management of angiectasias of the GI tract, the spontaneous bleeding cessation rate in these patients varies
from 40% to 50% per year.161,162 For example, in a 1992
study by Lewis et al, 44% of 34 untreated patients with
small bowel angiectasias did not receive any transfusions
over a mean follow-up period of 13.4 months (calculated
spontaneous cessation rate of 38% per year).162 Recurrent
bleeding occurs in about one third of patients who undergo investigation by push enteroscopy for GI bleeding
of obscure origin, with a trend toward more frequent
rebleeding in patients with angioectasias. Frequent previous bleeding episodes and transfusion requirements are
predictive of recurrent bleeding.93 Findings on capsule
endoscopy may assist in the follow-up evaluation of patients with obscure GI bleeding. In a recent study of 49
consecutive patients with obscure GI bleeding followed
up for 19 months (range, 1231 months), 48% of patients
with positive findings on capsule endoscopy experienced
rebleeding on long-term follow-up, compared with 5.6%
of patients with negative findings on capsule endoscopy.
Further invasive investigations can be deferred in patients with obscure GI bleeding and negative findings on
capsule endoscopy.163

Medical Management
The initial medical management of patients with
overt brisk GI hemorrhage of an obscure source is similar

to that of acute GI hemorrhage. Resuscitation takes priority over diagnostic workup, and many of these patients
require inpatient management, including blood transfusion. Decisions regarding blood transfusion should be
based on the patients clinical status, assessment of volume depletion, rate of bleeding, age, and other comorbid
conditions. If the patient is on anticoagulation or platelet
inhibitors, then consideration should be given on an
individualized basis for withholding these drugs or even
reversing their adverse effect on hemostasis.
Most patients with slow or intermittent obscure or
occult GI bleeding will have coexistent iron deficiency
anemia, which requires active management.164 The aim of
the treatment should be to restore hemoglobin levels and
mean corpuscular volume to normal and also replenish
body stores. Laboratory measurements of body iron
stores such as serum ferritin are helpful to assess the
effectiveness of iron supplementation. This is achieved
most easily with oral iron supplementation. Numerous
oral iron preparations are available, although ferrous
sulfate and ferrous gluconate are preferred forms of oral
iron because of low cost and high bioavailability. A liquid
preparation often is tolerated better. Ascorbic acid enhances iron absorption. Parenteral iron should only be
used when there is intolerance to at least 2 oral iron
preparations or noncompliance or when there is an element of iron malabsorption.165 Iron dextran was the only
formulation approved for use in the United States until
recently, when iron gluconate and iron sucrose were approved. The total required dose of iron can be administered as a single infusion using iron dextran; however,
serious allergic reaction, including anaphylaxis, can occur
in up to 10% of patients. With the other 2 iron salts for
parenteral administration, anaphylaxis is less of a concern, but it usually takes multiple administrations to
supplement the total dose.
Some patients with obscure GI bleeding are managed
clinically with intermittent blood transfusions along
with other nonspecific supportive measures such as
avoidance of aspirin and anticoagulants as well as oral
iron supplementation. These patients often do not have
a definite diagnosis despite extensive workup, have diffuse GI angiectasias often in inaccessible locations, have
failed endoscopic or surgical or other specific therapies,
or are elderly with many comorbid conditions in whom
the risk of further diagnostic evaluation is considered to
be greater than the risk of nonspecific management.
Although older reports suggest that nonspecific measures are often sufficient to maintain status quo,166,167
there is very little recent published information on the
natural history and long-term prognosis of these patients.

Pharmacologic Therapy
Pharmacotherapy should be considered whenever endoscopic therapy, surgical intervention, or an-

November 2007

1711

mucosa; the exact mechanism is not known but may be

related to the complex effect of erythropoietin on the
platelet-subendothelial interactions and also on protein
C, protein S, and anti-thrombin III levels.176
Potential therapeutic strategies focusing on replenishing and maintaining the level of the reduced high-molecular-weight multimer of the vWD factor may offer a
therapeutic potential for management of patients with
bleeding angiectasias and remain to be explored. Replacement therapies that have been traditionally used for
treatment of patients with von Willebrands disease (factor VIII/vWF concentrates) are, however, relatively deficient in the high-molecular-weight multimers of vWF;
and this may explain their lack of apparent benefit in
treating patients with bleeding angiectasias.20,177

Endoscopic Intervention for Angioectasias

Endoscopic therapy through a push enteroscope
has been shown to improve the outcome in patients with
angioectasias. In a retrospective comparative study of 83
patients with GI bleeding from small bowel angiectasias,
cautery of the angiectasias decreased bleeding and the
need for transfusions compared with controls (0.32
0.91 vs 2.40 3 units/month; P .001) during a follow-up of 26 months. On average, the treated patients
underwent 1.9 sessions of cauterization.178 Another
smaller study of 20 patients confirmed these observations; there was a reduced need for transfusions from
13 6 units of packed red cells per year to 6 3 units
after cautery (P .02), and 31% of patients no longer
required transfusions.179 In a study of 11 patients with
transfusion-dependent bleeding from angiectasias, a single session of cautery of 2 lesions resulted in significant
improvement of the hemoglobin level from 8.5 to 13.5
g/dL (P .01) during 6 months after therapy. Current
evidence supports improved patient outcomes after endoscopic treatment via push enteroscopy, up to an additional 20% 40% benefit over the spontaneous cessation
of bleeding.180

Angiographic Therapy
Angiographic therapy is usually reserved for
acutely bleeding lesions detected during diagnostic angiography. The minimal bleeding rate for angiographic
detection is approximately 0.5 mL/min. Angiography,
however, becomes optimally sensitive when the bleeding
rate is at least 1.0 mL/min, which is equivalent to 3 units
of blood loss per day. Selective intra-arterial vasopressin
therapy had been considered to be the standard therapy,
but superselective embolotherapy with microcoils alone
or with gelatin sponge pledglets or polyvinyl alcohol
embolospheres is becoming increasingly popular.181 The
major advantages of successful embolotherapy are immediate bleeding cessation, which permits angiography
catheter removal and avoids the risk of prolonged cath-

AGA
INSTITUTE

giographic therapy is not practical or ineffective, such as

patients in whom the source and the etiology of bleeding
is unknown or the pathology is too diffuse to be amenable to ablative therapies.
The role of hormonal therapy continues to be most
debated.168 170 Extrapolating clinical observation of beneficial effects of hormonal therapy in patients with HHT
and nasal bleeding, hormonal therapy (eg, ethinyl estradiol and norethisterone) has been used for GI angiectasias. In a recent randomized placebo-controlled trial, 72
consecutive patients with acute and chronic bleeding
due to gastroduodenal, colonic, and diffuse angiectasias
were treated with ethinyl estradiol and norethisterone.
Patients with HHT and those with cirrhosis were excluded. The primary end point was failure to prevent
recurrent bleeding, either an acute episode or recurrent
iron deficiency anemia despite persistent iron therapy.
The results were uniformly negative for a beneficial effect
of hormonal therapy, irrespective of disease site. Treatment failed in 39% of the treated patients and 46% of the
placebo group, with similar rebleeding rates and transfusion requirements during a follow-up of up to 2 years.
The actuarial chance of remaining free from bleeding
after 2 years was 55% (95% confidence interval, 36%74%)
for the treatment group and 36% (14%58%) for the
placebo group (log-rank test; P .649). Rebleeding was
more likely to occur among patients with a previous
history of multiple bleeds and in patients with chronic
renal failure. However, the findings of the study do not
apply to patients with HHT and those with chronic liver
diseases, which was a frequent association, and the study
was underpowered to identify a beneficial effect in patients with chronic renal failure. Also, the study patients
had somewhat milder disease and did not receive concomitant or prior endoscopic therapy. Therefore, these
disappointing results may not be applicable to all patients, in particular those with severe disease and who
have failed endoscopic interventions. On the other hand,
opponents of hormonal therapy commonly cite the increasing evidence of side effects, particularly cardiovascular, in patients on chronic hormonal therapy. It appears
that appropriately powered controlled trials of hormonal
therapy that include patients with severe disease and who
have not responded to endoscopic therapy alone will be
needed with long-term follow-up to answer these persistent issues.
Somatostatin and its analogue octreotide have been
anecdotally reported to be beneficial in patients with
obscure GI bleeding from angiectasias and blue rubber
bleb nevus syndrome, possibly due to their inhibitory
effect on angiogenesis and splanchnic blood flow.171173
Recent case reports of a beneficial effect of thalidomide
and its antiangiogenic effects in patients with obscure GI
bleeding due to angiectasias and HHT have been
reported.174,175 In a recent case report, erythropoietin was
believed to stop chronic diffuse hemorrhage from GI

AGA INSTITUTE

1712

AGA INSTITUTE

eter placement and systemic complications of vasopression.182,183

In summary, both capsule endoscopy and DBE have
revolutionized our approach to the diagnosis and management of patients with obscure GI bleeding. Training
in the use of these novel technologies and further research on the optimum utilization of these technologies
will improve the quality of care of patients with obscure
GI bleeding.

GOTTUMUKKALA S. RAJU
Department of Medicine
University of Texas Medical Branch, Galveston
Galveston, Texas
LAUREN GERSON
Department of Medicine
Stanford University
Stanford, California
ANANYA DAS
Department of Medicine
Mayo Clinic, Scottsdale
Scottsdale, Arizona
BLAIR LEWIS
Department of Medicine
Mount Sinai School of Medicine
New York, New York
References

AGA
INSTITUTE

1. American Gastroenterological Association medical position

statement: evaluation and management of occult and obscure gastrointestinal bleeding. Gastroenterology 2000;118:
197201.
2. Gralnek IM. Obscure-overt gastrointestinal bleeding. Gastroenterology 2005;128:1424 1430.
3. Rantis PC Jr, Harford FJ, Wagner RH, Henkin RE. Technetiumlabelled red blood cell scintigraphy: is it useful in acute lower
gastrointestinal bleeding? Int J Colorectal Dis 1995;10:210
215.
4. Ott DJ, Chen YM, Gelfand DW, Van Swearingen F, Munitz HA.
Detailed per-oral small bowel examination vs. enteroclysis. Part
I: expenditures and radiation exposure. Radiology 1985;155:
29 31.
5. Ott DJ, Chen YM, Gelfand DW, Van Swearingen F, Munitz HA.
Detailed per-oral small bowel examination vs. enteroclysis. Part
II: radiographic accuracy. Radiology 1985;155:3134.
6. Zaman A, Katon RM. Push enteroscopy for obscure gastrointestinal bleeding yields a high incidence of proximal lesions within
reach of a standard endoscope. Gastrointest Endosc 1998;47:
372376.
7. Mullan FJ, McKelvey ST. Pancreatic carcinoma presenting as
bleeding from segmental gastric varices: pitfalls in diagnosis.
Postgrad Med J 1990;66:401 403.
8. Kovacs TO, Jensen DM. Recent advances in the endoscopic
diagnosis and therapy of upper gastrointestinal, small intestinal, and colonic bleeding. Med Clin North Am 2002;86:
1319 1356.
9. Lee YT, Walmsley RS, Leong RW, Sung JJ. Dieulafoys lesion.
Gastrointest Endosc 2003;58:236 243.

GASTROENTEROLOGY Vol. 133, No. 5

10. Burak KW, Lee SS, Beck PL. Portal hypertensive gastropathy
and gastric antral vascular ectasia (GAVE) syndrome. Gut 2001;
49:866 872.
11. Raju GS, Morris K, Boening S, Carpenter D, Gomez G. Capillary
refilling sign demonstrated by capsule endoscopy. Gastrointest
Endosc 2003;58:936 937.
12. Leighton JA, Goldstein J, Hirota W, Jacobson BC, Johanson JF,
Mallery JS, Peterson K, Waring JP, Fanelli RD, Wheeler-Harbaugh J, Baron TH, Faigel DO. Obscure gastrointestinal bleeding. Gastrointest Endosc 2003;58:650 655.
13. Szold A, Katz LB, Lewis BS. Surgical approach to occult gastrointestinal bleeding. Am J Surg 1992;163:90 92; discussion
9293.
14. Pennazio M, Arrigoni A, Risio M, Spandre M, Rossini FP. Clinical
evaluation of push-type enteroscopy. Endoscopy 1995;27:164
170.
15. Chong J, Tagle M, Barkin JS, Reiner DK. Small bowel push-type
fiberoptic enteroscopy for patients with occult gastrointestinal
bleeding or suspected small bowel pathology. Am J Gastroenterol 1994;89:21432146.
16. Davies GR, Benson MJ, Gertner DJ, Van Someren RM, Rampton
DS, Swain CP. Diagnostic and therapeutic push type enteroscopy in clinical use. Gut 1995;37:346 352.
17. Thompson JN, Hemingway AP, McPherson GA, Rees HC, Allison
DJ, Spencer J. Obscure gastrointestinal haemorrhage of smallbowel origin. Br Med J (Clin Res Ed) 1984;288:16631665.
18. Ell C, May A. Mid-gastrointestinal bleeding: capsule endoscopy
and push-and-pull enteroscopy give rise to a new medical term.
Endoscopy 2006;38:7375.
19. Veyradier A, Balian A, Wolf M, Giraud V, Montembault S, Obert
B, Dagher I, Chaput JC, Meyer D, Naveau S. Abnormal von
Willebrand factor in bleeding angiodysplasias of the digestive
tract. Gastroenterology 2001;120:346 353.
20. Warkentin TE, Moore JC, Anand SS, Lonn EM, Morgan DG.
Gastrointestinal bleeding, angiodysplasia, cardiovascular disease, and acquired von Willebrand syndrome. Transfus Med Rev
2003;17:272286.
21. Williams RC Jr. Aortic stenosis, von Willebrand factor, and
bleeding. N Engl J Med 2003;349:17731774; author reply
17731774.
22. Bhutani MS, Gupta SC, Markert RJ, Barde CJ, Donese R, Gopalswamy N. A prospective controlled evaluation of endoscopic
detection of angiodysplasia and its association with aortic valve
disease. Gastrointest Endosc 1995;42:398 402.
23. Pate GE, Mulligan A. An epidemiological study of Heydes syndrome: an association between aortic stenosis and gastrointestinal bleeding. J Heart Valve Dis 2004;13:713716.
24. Junquera F, Saperas E, Angles A, Abadia C, Monasterio J,
Malagelada JR. Increased plasma fibrinolytic activity in bleeding
gastrointestinal angiodysplasia. Eur J Gastroenterol Hepatol
2005;17:199 205.
25. Longacre AV, Gross CP, Gallitelli M, Henderson KJ, White RI Jr,
Proctor DD. Diagnosis and management of gastrointestinal
bleeding in patients with hereditary hemorrhagic telangiectasia.
Am J Gastroenterol 2003;98:59 65.
26. Kjeldsen AD, Kjeldsen J. Gastrointestinal bleeding in patients
with hereditary hemorrhagic telangiectasia. Am J Gastroenterol
2000;95:415 418.
27. Begbie ME, Wallace GM, Shovlin CL. Hereditary haemorrhagic
telangiectasia (Osler-Weber-Rendu syndrome): a view from the
21st century. Postgrad Med J 2003;79:18 24.
28. Abdalla SA, Geisthoff UW, Bonneau D, Plauchu H, McDonald J,
Kennedy S, Faughnan ME, Letarte M. Visceral manifestations in
hereditary haemorrhagic telangiectasia type 2. J Med Genet
2003;40:494 502.
29. Kjeldsen AD, Moller TR, Brusgaard K, Vase P, Andersen PE.
Clinical symptoms according to genotype amongst patients with

30.
31.
32.

33.
34.

35.

36.

37.

38.

39.
40.

41.

42.

43.

44.

45.

46.
47.

48.

49.

50.

hereditary haemorrhagic telangiectasia. J Intern Med 2005;

258:349 355.
Echenique-Elizondo M. Chronic digestive bleeding in blue rubber-bleb nevus (Bean syndrome). J Am Coll Surg 2003;196:816.
Beck PL, Aspinall AI, Kilvert VM, Dort J. Blue rubber bleb nevus
syndrome. Gastrointest Endosc 2002;56:598 600.
Fishman SJ, Smithers CJ, Folkman J, Lund DP, Burrows PE,
Mulliken JB, Fox VL. Blue rubber bleb nevus syndrome: surgical
eradication of gastrointestinal bleeding. Ann Surg 2005;241:
523528.
Braverman IM. Skin signs of gastrointestinal disease. Gastroenterology 2003;124:15951614.
Sato T, Ohta K, Ohyama S, Suenaga M, Ueno M, Oya M,
Yamamoto J, Yamaguchi T, Muto T, Kato Y. Klippel-TrenaunayWeber syndrome and duodenal hemorrhage. Gastrointest Endosc 2003;58:756 757.
Wilson CL, Song LM, Chua H, Ferrara M, Devine RM, Dozois RR,
Nehra V. Bleeding from cavernous angiomatosis of the rectum
in Klippel-Trenaunay syndrome: report of three cases and literature review. Am J Gastroenterol 2001;96:27832788.
Chak A, Cooper GS, Canto MI, Pollack BJ, Sivak MV Jr. Enteroscopy for the initial evaluation of iron deficiency. Gastrointest
Endosc 1998;47:144 148.
Descamps C, Schmit A, Van Gossum A. Missed upper gastrointestinal tract lesions may explain occult bleeding. Endoscopy 1999;31:452 455.
Lin S, Branch MS, Shetzline M. The importance of indication in
the diagnostic value of push enteroscopy. Endoscopy 2003;35:
315321.
Yap CK, Ng HS. Cap-fitted gastroscopy improves visualization
and targeting of lesions. Gastrointest Endosc 2001;53:9395.
Kitiyakara T, Selby W. Non-small-bowel lesions detected by capsule endoscopy in patients with obscure GI bleeding. Gastrointest Endosc 2005;62:234 238.
Spiller RC, Parkins RA. Recurrent gastrointestinal bleeding of
obscure origin: report of 17 cases and a guide to logical management. Br J Surg 1983;70:489 493.
Leaper M, Johnston MJ, Barclay M, Dobbs BR, Frizelle FA.
Reasons for failure to diagnose colorectal carcinoma at colonoscopy. Endoscopy 2004;36:499 503.
Brandt LJ, Spinnell MK. Ability of naloxone to enhance the
colonoscopic appearance of normal colon vasculature and colon
vascular ectasias. Gastrointest Endosc 1999;49:79 83.
Katsinelos P, Paroutoglou G, Papaziogas B, Beltsis A, Mimidis
K, Pilpilidis I, Tsolkas P, Soufleris K, Vradelis S, Koutelidakis I.
Secondary aortoduodenal fistula with a fatal outcome: report of
six cases. Surg Today 2005;35:677 681.
Wood A, Bendjelid SM, Bendjelid K. Primary aortoenteric fistula:
should enhanced computed tomography be considered in the
diagnostic work-up? Anesth Analg 2005;101:11571159.
Lee SK, Green PH. Endoscopy in celiac disease. Curr Opin
Gastroenterol 2005;21:589 594.
Siegel LM, Stevens PD, Lightdale CJ, Green PH, Goodman S,
Garcia-Carrasquillo RJ, Rotterdam H. Combined magnification
endoscopy with chromoendoscopy in the evaluation of patients
with suspected malabsorption. Gastrointest Endosc 1997;46:
226 230.
Ackerman Z, Eliakim R, Stalnikowicz R, Rachmilewitz D. Role of
small bowel biopsy in the endoscopic evaluation of adults with
iron deficiency anemia. Am J Gastroenterol 1996;91:2099
2102.
Carroccio A, Iannitto E, Cavataio F, Montalto G, Tumminello M,
Campagna P, Lipari MG, Notarbartolo A, Iacono G. Sideropenic
anemia and celiac disease: one study, two points of view. Dig
Dis Sci 1998;43:673 678.
Costamagna G, Shah SK, Riccioni ME, Foschia F, Mutignani M,
Perri V, Vecchioli A, Brizi MG, Picciocchi A, Marano P. A prospec-

AGA INSTITUTE

51.

52.

53.

54.

55.
56.

57.

58.

59.

60.

61.

62.

63.

64.

65.
66.

67.

68.

1713

tive trial comparing small bowel radiographs and video

capsule endoscopy for suspected small bowel disease. Gastroenterology 2002;123:999 1005.
Triester SL, Leighton JA, Leontiadis GI, Fleischer DE, Hara AK,
Heigh RI, Shiff AD, Sharma VK. A meta-analysis of the yield of
capsule endoscopy compared to other diagnostic modalities in
patients with obscure gastrointestinal bleeding. Am J Gastroenterol 2005;100:24072418.
Saurin JC, Delvaux M, Gaudin JL, Fassler I, Villarejo J, Vahedi K,
Bitoun A, Canard JM, Souquet JC, Ponchon T, Florent C, Gay G.
Diagnostic value of endoscopic capsule in patients with
obscure digestive bleeding: blinded comparison with video
push-enteroscopy. Endoscopy 2003;35:576 584.
Malik A, Lukaszewski K, Caroline D, Parkman H, DeSipio J,
Banson F, Bazir K, Reddy L, Srinivasan R, Fisher R, Miller L.
A retrospective review of enteroclysis in patients with obscure
gastrointestinal bleeding and chronic abdominal pain of undetermined etiology. Dig Dis Sci 2005;50:649 655.
Leighton JA, Sharma VK, Hentz JG, Musil D, Malikowski MJ,
McWane TL, Fleischer DE. Capsule endoscopy versus push
enteroscopy for evaluation of obscure gastrointestinal bleeding
with 1-year outcomes. Dig Dis Sci 2006;51:891 899.
Rajesh A, Maglinte DD. Multislice CT enteroclysis: technique
and clinical applications. Clin Radiol 2006;61:3139.
Schmidt S, Lepori D, Meuwly JY, Duvoisin B, Meuli R, Michetti P,
Felley C, Schnyder P, van Melle G, Denys A. Prospective comparison of MR enteroclysis with multidetector spiral-CT enteroclysis: interobserver agreement and sensitivity by means of
sign-by-sign correlation. Eur Radiol 2003;13:13031311.
Grassi R, di Mizio R, Romano S, Cappabianca S, del Vecchio W,
Severini S. Multiple jejunal angiodysplasia detected by enemahelical CT. Clin Imaging 2000;24:61 63.
Miller FH, Hwang CM. An initial experience: using helical CT
imaging to detect obscure gastrointestinal bleeding. Clin Imaging 2004;28:245251.
Junquera F, Quiroga S, Saperas E, Perez-Lafuente M, Videla S,
Alvarez-Castells A, Miro JR, Malagelada JR. Accuracy of helical
computed tomographic angiography for the diagnosis of colonic
angiodysplasia. Gastroenterology 2000;119:293299.
Voderholzer WA, Ortner M, Rogalla P, Beinholzl J, Lochs H.
Diagnostic yield of wireless capsule enteroscopy in comparison
with computed tomography enteroclysis. Endoscopy 2003;35:
1009 1014.
Howarth DM, Tang K, Lees W. The clinical utility of nuclear
medicine imaging for the detection of occult gastrointestinal
haemorrhage. Nucl Med Commun 2002;23:591594.
Bloomfeld RS, Smith TP, Schneider AM, Rockey DC. Provocative
angiography in patients with gastrointestinal hemorrhage of
obscure origin. Am J Gastroenterol 2000;95:28072812.
Berkelhammer C, Radvany A, Lin A, Hopkins W, Principe J.
Heparin provocation for endoscopic localization of recurrent
obscure GI hemorrhage. Gastrointest Endosc 2000;52:555
556.
Shetzline MA, Suhocki P, Dash R, Rockey DC. Provocative angiography in obscure gastrointestinal bleeding. South Med J
2000;93:12051208.
Strodel WE, Eckhauser FE, Knol JA, Nostrant TT, Dent TL. Intraoperative fiberoptic endoscopy. Am Surg 1984;50:340 344.
Greenberg GR, Phillips MJ, Tovee EB, Jeejeebhoy KN. Fiberoptic
endoscopy during laparotomy in the diagnosis of small intestinal bleeding. Gastroenterology 1976;71:133135.
Bowden TA Jr, Hooks VH 3rd, Teeslink CR Parrish RA Jr, Mansberger AR Jr. Occult gastrointestinal bleeding: locating the
cause. Am Surg 1980;46:80 87.
Zaman A, Sheppard B, Katon RM. Total peroral intraoperative
enteroscopy for obscure GI bleeding using a dedicated push

AGA
INSTITUTE

November 2007

1714

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.
AGA
INSTITUTE

83.
84.

85.
86.
87.

AGA INSTITUTE

enteroscope: diagnostic yield and patient outcome. Gastrointest Endosc 1999;50:506 510.
Desa LA, Ohri SK, Hutton KA, Lee H, Spencer J. Role of intraoperative enteroscopy in obscure gastrointestinal bleeding of
small bowel origin. Br J Surg 1991;78:192195.
Lewis BS, Wenger JS, Waye JD. Small bowel enteroscopy and
intraoperative enteroscopy for obscure gastrointestinal bleeding. Am J Gastroenterol 1991;86:171174.
Ress AM, Benacci JC, Sarr MG. Efficacy of intraoperative enteroscopy in diagnosis and prevention of recurrent, occult gastrointestinal bleeding. Am J Surg 1992;163:94 98; discussion
98 99.
Lopez MJ, Cooley JS, Petros JG, Sullivan JG, Cave DR. Complete
intraoperative small-bowel endoscopy in the evaluation of occult
gastrointestinal bleeding using the sonde enteroscope. Arch
Surg 1996;131:272277.
Douard R, Wind P, Panis Y, Marteau P, Bouhnik Y, Cellier C,
Cugnenc P, Valleur P. Intraoperative enteroscopy for diagnosis
and management of unexplained gastrointestinal bleeding. Am J
Surg 2000;180:181184.
Kendrick ML, Buttar NS, Anderson MA, Lutzke LS, Peia D, Wang
KK, Sarr MG. Contribution of intraoperative enteroscopy in the
management of obscure gastrointestinal bleeding. J Gastrointest Surg 2001;5:162167.
Hartmann D, Schmidt H, Bolz G, Schilling D, Kinzel F, Eickhoff A,
Huschner W, Moller K, Jakobs R, Reitzig P, Weickert U, Gellert K,
Schultz H, Guenther K, Hollerbuhl H, Schoenleben K, Schulz HJ,
Riemann JF. A prospective two-center study comparing wireless
capsule endoscopy with intraoperative enteroscopy in patients
with obscure GI bleeding. Gastrointest Endosc 2005;61:826
832.
Jakobs R, Hartmann D, Benz C, Schilling D, Weickert U, Eickhoff
A, Schoenleben K, Riemann JF. Diagnosis of obscure gastrointestinal bleeding by intra-operative enteroscopy in 81 consecutive patients. World J Gastroenterol 2006;12:313316.
Lee KH, Yeung CK, Tam YH, Ng WT, Yip KF. Laparascopy for
definitive diagnosis and treatment of gastrointestinal bleeding
of obscure origin in children. J Pediatr Surg 2000;35:1291
1293.
Kim J, Kim YS, Chun HJ, Hyun JH, Cho MY, Suh SO. Laparoscopy-assisted exploration of obscure gastrointestinal bleeding
after capsule endoscopy: the Korean experience. J Laparoendosc Adv Surg Tech A 2005;15:365373.
Tada M, Misaki F, Kawai K. Pediatric enteroscopy with a sondetype small intestinal fiberscope (SSIF-type VI). Gastrointest Endosc 1983;29:44 47.
Tada M, Shimizu S, Kawai K. A new transnasal sonde type
fiberscope (SSIF type VII) as a pan-enteroscope. Endoscopy
1986;18:121124.
Berner JS, Mauer K, Lewis BS. Push and sonde enteroscopy for
the diagnosis of obscure gastrointestinal bleeding. Am J Gastroenterol 1994;89:2139 2142.
Gostout CJ. Sonde enteroscopy. Technique, depth of insertion,
and yield of lesions. Gastrointest Endosc Clin North Am 1996;
6:777792.
Ogoshi K, Hara Y, Ashizawa S. New technic for small intestinal
fiberoscopy. Gastrointest Endosc 1973;20:64 65.
Foutch PG, Sawyer R, Sanowski RA. Push-enteroscopy for diagnosis of patients with gastrointestinal bleeding of obscure origin. Gastrointest Endosc 1990;36:337341.
Lewis BS. The history of enteroscopy. Gastrointest Endosc Clin
North Am 1999;9:111.
Benz C, Jakobs R, Riemann JF. Do we need the overtube for
push-enteroscopy? Endoscopy 2001;33:658 661.
Taylor AC, Chen RY, Desmond PV. Use of an overtube for
enteroscopy does it increase depth of insertion? A prospec-

GASTROENTEROLOGY Vol. 133, No. 5

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.
104.

105.

tive study of enteroscopy with and without an overtube. Endoscopy 2001;33:227230.

Schmit A, Gay F, Adler M, Cremer M, Van Gossum A. Diagnostic
efficacy of push-enteroscopy and long-term follow-up of patients
with small bowel angiodysplasias. Dig Dis Sci 1996;41:2348
2352.
Adrain AL, Dabezies MA, Krevsky B. Enteroscopy improves the
clinical outcome in patients with obscure gastrointestinal bleeding. J Laparoendosc Adv Surg Tech A 1998;8:279 284.
Shackel NA, Bowen DG, Selby WS. Video push enteroscopy in
the investigation of small bowel disease: defining clinical indications and outcomes. Aust N Z J Med 1998;28:198 203.
Hayat M, Axon AT, OMahony S. Diagnostic yield and effect on
clinical outcomes of push enteroscopy in suspected smallbowel bleeding. Endoscopy 2000;32:369 372.
Sharma BC, Bhasin DK, Makharia G, Chhabra M, Vaiphei K,
Bhatti HS, Singh K. Diagnostic value of push-type enteroscopy:
a report from India. Am J Gastroenterol 2000;95:137140.
Landi B, Cellier C, Gaudric M, Demont H, Guimbaud R, Cuillerier
E, Couturier D, Barbier JP, Marteau P. Long-term outcome of
patients with gastrointestinal bleeding of obscure origin explored by push enteroscopy. Endoscopy 2002;34:355359.
Lewis BS, Swain P. Capsule endoscopy in the evaluation of
patients with suspected small intestinal bleeding: results of a
pilot study. Gastrointest Endosc 2002;56:349 353.
Ell C, Remke S, May A, Helou L, Henrich R, Mayer G. The first
prospective controlled trial comparing wireless capsule endoscopy with push enteroscopy in chronic gastrointestinal bleeding.
Endoscopy 2002;34:685 689.
Mylonaki M, Fritscher-Ravens A, Swain P. Wireless capsule
endoscopy: a comparison with push enteroscopy in patients
with gastroscopy and colonoscopy negative gastrointestinal
bleeding. Gut 2003;52:11221126.
Keizman D, Brill S, Umansky M, Rattan Y, Hallak A, Halpern Z,
Konikoff FM. Diagnostic yield of routine push enteroscopy with a
graded-stiffness enteroscope without overtube. Gastrointest Endosc 2003;57:877 881.
Romelaer C, Le Rhun M, Beaugerie L, Gournay J, Masliah C,
Coron E, Galmiche JP, Bruley Des Varannes S. Push enteroscopy for gastrointestinal bleeding: diagnostic yield and longterm follow-up. Gastroenterol Clin Biol 2004;28:10611066.
Adler DG, Knipschield M, Gostout C. A prospective comparison
of capsule endoscopy and push enteroscopy in patients with GI
bleeding of obscure origin. Gastrointest Endosc 2004;59:492
498.
Mata A, Bordas JM, Feu F, Gines A, Pellise M, FernandezEsparrach G, Balaguer F, Pique JM, Llach J. Wireless capsule
endoscopy in patients with obscure gastrointestinal bleeding:
a comparative study with push enteroscopy. Aliment Pharmacol
Ther 2004;20:189 194.
Pennazio M, Santucci R, Rondonotti E, Abbiati C, Beccari G,
Rossini FP, De Franchis R. Outcome of patients with obscure
gastrointestinal bleeding after capsule endoscopy: report of 100
consecutive cases. Gastroenterology 2004;126:643 653.
Lara LF, Bloomfeld RS, Pineau BC. The rate of lesions found
within reach of esophagogastroduodenoscopy during push enteroscopy depends on the type of obscure gastrointestinal
bleeding. Endoscopy 2005;37:745750.
Meron GD. The development of the swallowable video capsule
(M2A). Gastrointest Endosc 2000;52:817 819.
Payeras G, Piqueras J, Moreno VJ, Cabrera A, Menendez D,
Jimenez R. Effects of capsule endoscopy on cardiac pacemakers. Endoscopy 2005;37:11811185.
Leighton JA, Sharma VK, Srivathsan K, Heigh RI, McWane TL,
Post JK, Robinson SR, Bazzell JL, Fleischer DE. Safety of capsule endoscopy in patients with pacemakers. Gastrointest Endosc 2004;59:567569.

106. Leighton JA, Srivathsan K, Carey EJ, Sharma VK, Heigh RI, Post
JK, Erickson PJ, Robinson SR, Bazzell JL, Fleischer DE. Safety of
wireless capsule endoscopy in patients with implantable
cardiac defibrillators. Am J Gastroenterol 2005;100:1728
1731.
107. Bossa F, Cocomazzi G, Valvano MR, Andriulli A, Annese V.
Detection of abnormal lesions recorded by capsule endoscopy.
A prospective study comparing endoscopists and nurses accuracy. Dig Liver Dis 2006;38:599 602.
108. Caunedo Alvarez A, Garcia-Montes JM, Herrerias JM. Capsule
endoscopy reviewed by a nurse: is it here to stay? Dig Liver Dis
2006;38:603 604.
109. Chen GC, Enayati P, Tran T, Lee-Henderson M, Quan C, Dulai G,
Arnott I, Sul J, Jutabha R. Sensitivity and inter-observer variability for capsule endoscopy image analysis in a cohort of novice
readers. World J Gastroenterol 2006;12:1249 1254.
110. Appleyard M, Fireman Z, Glukhovsky A, Jacob H, Shreiver R,
Kadirkamanathan S, Lavy A, Lewkowicz S, Scapa E, Shofti R,
Swain P, Zaretsky A. A randomized trial comparing wireless
capsule endoscopy with push enteroscopy for the detection of
small-bowel lesions. Gastroenterology 2000;119:14311438.
111. Wong RF, Tuteja AK, Haslem DS, Pappas L, Szabo A, Ogara MM,
DiSario JA. Video capsule endoscopy compared with standard
endoscopy for the evaluation of small-bowel polyps in persons
with familial adenomatous polyposis (with video). Gastrointest
Endosc 2006;64:530 537.
112. Kong H, Kim YS, Hyun JJ, Cho YJ, Keum B, Jeen YT, Lee HS,
Chun HJ, Um SH, Lee SW, Choi JH, Kim CD, Ryu HS, Hyun JH.
Limited ability of capsule endoscopy to detect normally positioned duodenal papilla. Gastrointest Endosc 2006;64:538
541.
113. Hartmann D, Schilling D, Bolz G, Hahne M, Jakobs R, Siegel E,
Weickert U, Adamek HE, Riemann JF. Capsule endoscopy versus push enteroscopy in patients with occult gastrointestinal
bleeding. Z Gastroenterol 2003;41:377382.
114. Van Gossum A, Hittelet A, Schmit A, Francois E, Deviere J. A
prospective comparative study of push and wireless-capsule
enteroscopy in patients with obscure digestive bleeding. Acta
Gastroenterol Belg 2003;66:199 205.
115. Pennazio M, Eisen G, Goldfarb N. ICCE consensus for obscure
gastrointestinal bleeding. Endoscopy 2005;37:1046 1050.
116. Yamamoto H, Sekine Y, Sato Y, Higashizawa T, Miyata T, Iino S,
Ido K, Sugano K. Total enteroscopy with a nonsurgical steerable double-balloon method. Gastrointest Endosc 2001;53:
216 220.
117. Lewis BS, Eisen GM, Friedman S. A pooled analysis to evaluate
results of capsule endoscopy trials. Endoscopy 2005;37:960
965.
118. Delvaux M, Fassler I, Gay G. Clinical usefulness of the endoscopic video capsule as the initial intestinal investigation in
patients with obscure digestive bleeding: validation of a diagnostic strategy based on the patient outcome after 12 months.
Endoscopy 2004;36:10671073.
119. Kraus K, Hollerbach S, Pox C, Willert J, Schulmann K, Schmiegel
W. [Diagnostic utility of capsule endoscopy in occult gastrointestinal bleeding]. Dtsch Med Wochenschr 2004;129:1369
1374.
120. Ben Soussan E, Antonietti M, Herve S, Savoye G, Ramirez S,
Lecleire S, Ducrotte P, Lerebours E. Diagnostic yield and
therapeutic implications of capsule endoscopy in obscure
gastrointestinal bleeding. Gastroenterol Clin Biol 2004;28:
1068 1073.
121. Bresci G, Parisi G, Bertoni M, Tumino E, Capria A. The role of
video capsule endoscopy for evaluating obscure gastrointestinal bleeding: usefulness of early use. J Gastroenterol 2005;40:
256 259.

AGA INSTITUTE

1715

122. May A, Wardak A, Nachbar L, Remke S, Ell C. Influence of

patient selection on the outcome of capsule endoscopy in
patients with chronic gastrointestinal bleeding. J Clin Gastroenterol 2005;39:684 688.
123. Rieder F, Schneidewind A, Bolder U, Zorger N, Scholmerich J,
Schaffler A, Golder S, Kullmann F, Herfarth H. Use of anticoagulation during wireless capsule endoscopy for the investigation
of recurrent obscure gastrointestinal bleeding. Endoscopy
2006;38:526 528.
124. Lewis BS. How to read wireless capsule endoscopic images:
tips of the trade. Gastrointest Endosc Clin North Am 2004;14:
1116.
125. Albert J, Gobel CM, Lesske J, Lotterer E, Nietsch H, Fleig WE.
Simethicone for small bowel preparation for capsule endoscopy: a systematic, single-blinded, controlled study. Gastrointest Endosc 2004;59:487 491.
126. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG.
Video capsule endoscopy to prospectively assess small bowel
injury with celecoxib, naproxen plus omeprazole, and placebo.
Clin Gastroenterol Hepatol 2005;3:133141.
127. Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible
small-intestinal mucosal injury in chronic NSAID users. Clin
Gastroenterol Hepatol 2005;3:5559.
128. Ben-Soussan E, Savoye G, Antonietti M, Ramirez S, Lerebours
E, Ducrotte P. Factors that affect gastric passage of video
capsule. Gastrointest Endosc 2005;62:785790.
129. Hollerbach S, Kraus K, Willert J, Schulmann K, Schmiegel W.
Endoscopically assisted video capsule endoscopy of the small
bowel in patients with functional gastric outlet obstruction.
Endoscopy 2003;35:226 229.
130. Schwarzberg MN. Pro-kinetic medications as aids in imaging the
small bowel by video-capsule. Med Hypotheses 2005;64:602
607.
131. Seitz U, Bohnacker S, Soehendra N. A simple method to determine the location of the capsule and thus whether prokinetic
drugs are needed during video capsule endoscopy. Endoscopy
2002;34:1027.
132. Barkin JS, Friedman S. Wireless capsule endoscopy requiring
surgical intervention: the worlds experience. Am J Gastroenterol 2002;97:S298.
133. Sears DM, Avots-Avotins A, Culp K, Gavin MW. Frequency and
clinical outcome of capsule retention during capsule endoscopy
for GI bleeding of obscure origin. Gastrointest Endosc 2004;
60:822 827.
134. Tabib S, Fuller C, Daniels J, Lo SK. Asymptomatic aspiration of
a capsule endoscope. Gastrointest Endosc 2004;60:845 848.
135. Ford RM, Affronti J, Cohen R, Baumgarten DA, Cai Q. Zenkers
diverticulum: a contraindication for wireless capsule endoscopy? J Clin Gastroenterol 2005;39:257.
136. Fry LC, De Petris G, Swain JM, Fleischer DE. Impaction and
fracture of a video capsule in the small bowel requiring laparotomy for removal of the capsule fragments. Endoscopy 2005;
37:674 676.
137. Gonzalez Carro P, Picazo Yuste J, Fernandez Diez S, Perez
Roldan F, Roncero Garcia-Escribano O. Intestinal perforation
due to retained wireless capsule endoscope. Endoscopy 2005;
37:684.
138. May A, Nachbar L, Ell C. Extraction of entrapped capsules from
the small bowel by means of push-and-pull enteroscopy with the
double-balloon technique. Endoscopy 2005;37:591593.
139. Lee BI, Choi H, Choi KY, Ji JS, Kim BW, Cho SH, Park JM, Lee
IS, Choi MG, Chung IS. Retrieval of a retained capsule endoscope by double-balloon enteroscopy. Gastrointest Endosc
2005;62:463 465.
140. May A, Nachbar L, Ell C. Double-balloon enteroscopy (push-andpull enteroscopy) of the small bowel: feasibility and diagnostic

AGA
INSTITUTE

November 2007

1716

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

AGA
INSTITUTE

153.

154.

155.

156.

AGA INSTITUTE

and therapeutic yield in patients with suspected small bowel

disease. Gastrointest Endosc 2005;62:6270.
Mehdizadeh S, Ross A, Gerson L, Leighton J, Chen A, Schembre
D, Chen G, Semrad C, Kamal A, Harrison E, Binmoeller K,
Waxman I, Kozarek R, Lo S. What is the learning curve associated with double balloon enteroscopy? Technical details and
early experience in 6 U.S. tertiary care centers. Gastrointest
Endosc 2006;64:740 750.
Yamamoto H, Kita H, Sunada K, Hayashi Y, Sato H, Yano T,
Iwamoto M, Sekine Y, Miyata T, Kuno A, Ajibe H, Ido K, Sugano
K. Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small-intestinal diseases. Clin Gastroenterol Hepatol 2004;2:1010 1016.
May A, Nachbar L, Wardak A, Yamamoto H, Ell C. Doubleballoon enteroscopy: preliminary experience in patients with
obscure gastrointestinal bleeding or chronic abdominal pain.
Endoscopy 2003;35:985991.
Ell C, May A, Nachbar L, Cellier C, Landi B, di Caro S, Gasbarrini
A. Push-and-pull enteroscopy in the small bowel using the double-balloon technique: results of a prospective European multicenter study. Endoscopy 2005;37:613 616.
Di Caro S, May A, Heine DG, Fini L, Landi B, Petruzziello L,
Cellier C, Mulder CJ, Costamagna G, Ell C, Gasbarrini A. The
European experience with double-balloon enteroscopy: indications, methodology, safety, and clinical impact. Gastrointest
Endosc 2005;62:545550.
Hadithi M, Heine GD, Jacobs MA, van Bodegraven AA, Mulder
CJ. A prospective study comparing video capsule endoscopy
with double-balloon enteroscopy in patients with obscure gastrointestinal bleeding. Am J Gastroenterol 2006;101:5257.
Heine GD, Hadithi M, Groenen MJ, Kuipers EJ, Jacobs MA,
Mulder CJ. Double-balloon enteroscopy: indications, diagnostic
yield, and complications in a series of 275 patients with suspected small-bowel disease. Endoscopy 2006;38:42 48.
Kaffes AJ, Koo JH, Meredith C. Double-balloon enteroscopy in
the diagnosis and the management of small-bowel diseases: an
initial experience in 40 patients. Gastrointest Endosc 2006;63:
81 86.
Monkemuller K, Weigt J, Treiber G, Kolfenbach S, Kahl S,
Rocken C, Ebert M, Fry LC, Malfertheiner P. Diagnostic and
therapeutic impact of double-balloon enteroscopy. Endoscopy
2006;38:6772.
Nakamura M, Niwa Y, Ohmiya N, Miyahara R, Ohashi A, Itoh A,
Hirooka Y, Goto H. Preliminary comparison of capsule endoscopy and double-balloon enteroscopy in patients with suspected small-bowel bleeding. Endoscopy 2006;38:59 66.
Matsumoto T, Esaki M, Moriyama T, Nakamura S, Iida M.
Comparison of capsule endoscopy and enteroscopy with the
double-balloon method in patients with obscure bleeding and
polyposis. Endoscopy 2005;37:827 832.
Manabe N, Tanaka S, Fukumoto A, Nakao M, Kamino D,
Chayama K. Double-balloon enteroscopy in patients with GI
bleeding of obscure origin. Gastrointest Endosc 2006;64:135
140.
Ross AS, Waxman I, Semrad C, Dye C. Balloon-assisted intubation of the ileocecal valve to facilitate retrograde double-balloon
enteroscopy. Gastrointest Endosc 2005;62:987988.
Groenen MJ, Moreels TG, Orlent H, Haringsma J, Kuipers EJ.
Acute pancreatitis after double-balloon enteroscopy: an old
pathogenetic theory revisited as a result of using a new endoscopic tool. Endoscopy 2006;38:82 85.
Attar A, Maissiat E, Sebbagh V, Cellier C, Wind P, Benamouzig
R. First case of paralytic intestinal ileus after double balloon
enteroscopy. Gut 2005;54:18231824.
May A, Nachbar L, Schneider M, Neumann M, Ell C. Push-andpull enteroscopy using the double-balloon technique: method of
assessing depth of insertion and training of the enteroscopy

GASTROENTEROLOGY Vol. 133, No. 5

157.

158.

159.

160.

161.

162.

163.

164.

165.
166.

167.

168.
169.
170.

171.

172.

173.

174.

175.

technique using the Erlangen Endo-Trainer. Endoscopy 2005;

37:66 70.
Sahai AV, Pineault R. An assessment of the use of costs and
quality of life as outcomes in endoscopic research. Gastrointest
Endosc 1997;46:113118.
Flickinger EG, Stanforth AC, Sinar DR, MacDonald KG, Lannin
DR, Gibson JH. Intraoperative video panendoscopy for diagnosing sites of chronic intestinal bleeding. Am J Surg 1989;157:
137144.
Goldfarb N, Phillips A, Conn M, Lewis B, Nash D. Economic and
health outcomes of capsule endoscopy. Dis Manage 2002;5:
123135.
Kamal A, Gerson LB. Cost-benefit analysis of double balloon
enteroscopy compared to other diagnostic modalities for obscure gastrointestinal hemorrhage. Gastrointest Endosc 2006;
63:AB90.
Junquera F, Feu F, Papo M, Videla S, Armengol JR, Bordas JM,
Saperas E, Pique JM, Malagelada JR. A multicenter, randomized, clinical trial of hormonal therapy in the prevention of
rebleeding from gastrointestinal angiodysplasia. Gastroenterology 2001;121:10731079.
Lewis BS, Salomon P, Rivera-MacMurray S, Kornbluth AA,
Wenger J, Waye JD. Does hormonal therapy have any benefit for
bleeding angiodysplasia? J Clin Gastroenterol 1992;15:99
103.
Lai LH, Wong GL, Chow DK, Lau JY, Sung JJ, Leung WK. Longterm follow-up of patients with obscure gastrointestinal bleeding after negative capsule endoscopy. Am J Gastroenterol
2006;101:1224 1228.
Goddard AF, McIntyre AS, Scott BB. Guidelines for the management of iron deficiency anaemia. British Society of Gastroenterology. Gut 2000;46(Suppl 3 4):IV1IV5.
Cook JD. Diagnosis and management of iron-deficiency anaemia. Best Pract Res Clin Haematol 2005;18:319 332.
Hutcheon DF, Kabelin J, Bulkley GB, Smith GW. Effect of therapy
on bleeding rates in gastrointestinal angiodysplasia. Am Surg
1987;53:6 9.
Richter JM, Christensen MR, Colditz GA, Nishioka NS. Angiodysplasia. Natural history and efficacy of therapeutic interventions.
Dig Dis Sci 1989;34:15421546.
Grant EC. Avoid hormones in gastrointestinal angiodysplasia.
Lancet 2002;360:1254.
Hodgson H. Hormonal therapy for gastrointestinal angiodysplasia. Lancet 2002;359:1630 1631.
Madanick RD, Barkin JS. Hormonal therapy in angiodysplasia:
should we completely abandon its use? Gastroenterology
2002;123:2156; author reply 2156 2157.
Blich M, Fruchter O, Edelstein S, Edoute Y. Somatostatin therapy ameliorates chronic and refractory gastrointestinal bleeding
caused by diffuse angiodysplasia in a patient on anticoagulation therapy. Scand J Gastroenterol 2003;38:801 803.
Bowers M, McNulty O, Mayne E. Octreotide in the treatment of
gastrointestinal bleeding caused by angiodysplasia in two patients with von Willebrands disease. Br J Haematol 2000;108:
524 527.
Gonzalez D, Elizondo BJ, Haslag S, Buchanan G, Burdick JS,
Guzzetta PC, Hicks BA, Andersen JM. Chronic subcutaneous
octreotide decreases gastrointestinal blood loss in blue rubberbleb nevus syndrome. J Pediatr Gastroenterol Nutr 2001;33:
183188.
Perez-Encinas M, Rabunal Martinez MJ, Bello Lopez JL. Is thalidomide effective for the treatment of gastrointestinal bleeding
in hereditary hemorrhagic telangiectasia? Haematologica
2002;87:ELT34.
Shurafa M, Kamboj G. Thalidomide for the treatment of bleeding
angiodysplasias. Am J Gastroenterol 2003;98:221222.

176. Zaharia-Czeizler V. Erythropoietin stops chronic diffuse transfusion-dependent gastrointestinal bleeding. Ann Intern Med
2001;135:933.
177. Morris ES, Hampton KK, Nesbitt IM, Preston FE, Thomas EG,
Makris M. The management of von Willebrands disease-associated gastrointestinal angiodysplasia. Blood Coagul Fibrinolysis 2001;12:143148.
178. Askin MP, Lewis BS. Push enteroscopic cauterization: long-term
follow-up of 83 patients with bleeding small intestinal angiodysplasia. Gastrointest Endosc 1996;43:580 583.
179. Vakil N, Huilgol V, Khan I. Effect of push enteroscopy on transfusion
requirements and quality of life in patients with unexplained gastrointestinal bleeding. Am J Gastroenterol 1997;92:425428.
180. Morris AJ, Mokhashi M, Straiton M, Murray L, Mackenzie JF.
Push enteroscopy and heater probe therapy for small bowel
bleeding. Gastrointest Endosc 1996;44:394 397.
181. dOthee BJ, Surapaneni P, Rabkin D, Nasser I, Clouse M. Microcoil embolization for acute lower gastrointestinal bleeding.
Cardiovasc Intervent Radiol 2006;29:49 58.
182. Lefkovitz Z, Cappell MS, Kaplan M, Mitty H, Gerard P. Radiology
in the diagnosis and therapy of gastrointestinal bleeding. Gastroenterol Clin North Am 2000;29:489 512.

AGA INSTITUTE

1717

183. Kramer SC, Gorich J, Rilinger N, Siech M, Aschoff AJ, Vogel J,

Brambs HJ. Embolization for gastrointestinal hemorrhages. Eur
Radiol 2000;10:802 805.
184. Ge ZZ, Hu YB, Xiao SD. Capsule endoscopy and push enteroscopy in the diagnosis of obscure gastrointestinal bleeding. Chin
Med J (Engl) 2004;117:10451049.
185. Neu B, Ell C, May A, Schmid E, Riemann JF, Hagenmuller F,
Keuchel M, Soehendra N, Seitz U, Meining A, Rosch T.
Capsule endoscopy versus standard tests in influencing management of obscure digestive bleeding: results from a German multicenter trial. Am J Gastroenterol 2005;100:1736
1742.

Address requests for reprints to: Chair, Clinical Practice and Economics Committee, AGA Institute National Ofce, c/o Membership
Department, 4930 Del Ray Avenue, Bethesda, Maryland 20814. Fax:
(301) 654-5920.
The Clinical Practice and Economics Committee acknowledges the following individuals whose critiques of this review
paper provided valuable guidance to the authors: Don C. Rockey,
MD, John A. Schaffner, MD, Joseph Sellin, MD, and Virender K.
Sharma, MD.

AGA
INSTITUTE

November 2007